NZ526699A - 8-amino derivatives and their use in treating migraine - Google Patents

8-amino derivatives and their use in treating migraine

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Publication number
NZ526699A
NZ526699A NZ526699A NZ52669902A NZ526699A NZ 526699 A NZ526699 A NZ 526699A NZ 526699 A NZ526699 A NZ 526699A NZ 52669902 A NZ52669902 A NZ 52669902A NZ 526699 A NZ526699 A NZ 526699A
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New Zealand
Prior art keywords
optionally substituted
piperazin
methyl
oxo
compound
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NZ526699A
Inventor
Marc Chapdelaine
Timothy Davenport
Markus Haeberlein
Carey Horchler
John Mccauley
Edward Pierson
Daniel Ohn
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Astrazeneca Ab
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Priority claimed from SE0103646A external-priority patent/SE0103646D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of NZ526699A publication Critical patent/NZ526699A/en

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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Provided herein are compounds represented by the Formula (I) that are useful for the treatment of migraine. The compound having the formula (I): has RI at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, thiomethoxy, -NHA, -NA2,-NHC(=O)A, aminocarbonyl, -C(=O)NHA, -C(=O)NA2, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl; R2 is represented by (i), (ii), (iii), or (iv) wherein, R3 is independently at each position represented by-H, optionally substituted Cl-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6cycloalkyl or AOH; n is 2, 3 or 4; P is a heterocyclic ring; R6 is -H or methyl; Y is -C(=O)NH-, -C(=O)NA-, -C(=O)N(A)-, -NHC(=O)-, -C(=S)NH-, -CH2NH-, -C(=O)-, -C(=O)CH2-, -CH2C(=O)-, -C=(O)- piperazine-, -NAC(=O)-, -C(=S)N(A)-, CH2NA, NACH2 or a 5-membered heterocyclic. R7 is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R8, R9 and Rl0; wherein R7 is connected to Y either by a single bond or by a ring fusion; R8 is-CH2-, -C(=O)-, -SO2-, -SO2NH-, -C(=O)NH-, -O-, -S-, -S (=O)-, a single bond as tether from R7 to R9, or a five membered heterocyclic connected to R7 by either a single bond or by ring fusion; R9 is optionally substituted heterocycle, optionally substituted aryl, optionally substituted piperazinyl-R11, optionally substituted morpholinyl-R11 or optionally substituted thiomorpholinyl or-C(=O)A; R10 is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen,-C(=O)NH2-, methylthio, -NHA, -NA2, -NHC(=O)A, C(=O)NHA, C(=O)NA2, or OA; R11 is -H, alkyl, AOH, -SO2A, -SO2NH2, -SO2NHA, -SO2NA2, -SO2NHAR9, -C(=O)R9, -alkylR9, C(=O)A, C(=O)NH2, C(=O)NHA, C (=O) NA2 or -C(=O)OA; or a pharmaceutically acceptable salt of the compound. Also provided are processes for the preparation of compounds of Formula (I) and its intermediates.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 526699 <br><br> 526699 <br><br> WO 02/055014 <br><br> pct/se02/00070 <br><br> -1 - <br><br> THERAPEUTIC CHROMAN COMPOUNDS <br><br> m <br><br> Field of the Invention <br><br> This invention relates to novel 8-amino derivatives, methods for their preparation, 5 pharmaceutical compositions containing them and their use in therapy. <br><br> Background of the Invention <br><br> Serotonin (5-HT) has been implicated in many psychiatric disorders including but not limited to depression, generalized anxiety, eating disorders, dementia, panic disorder, and sleep disorders. Furthermore serotonin has been implicated in gastrointestinal disorders, 10 cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. Serotonin receptors have been subdivided into at least 14 subtypes, see Barnes and Sharp, Neuropharmacology, 1999, 38,1083-1152, incorporated herein by reference. These various subtypes are responsible for serotonin's action in many pathophysicogical conditions. The 5-HT] family of receptors has high affinity for serotonin and consists of five 15 related receptors. This family includes the 5-HTib and 5-HTid receptor subtypes. <br><br> Compounds that interact with the 5-HTi family are known to have therapeutic potential in the above mentioned disorders and diseases. In particular, compounds that are 5HTib and 5HTjd antagonist have been known to be antidepressant and anxiolytic agents. Compounds that are 5HT ib and 5HT id agonists have been used in the treatment of migraine. <br><br> 20 Summary of the Invention <br><br> Provided herein is a compound having the formula (I): <br><br> wherein <br><br> 1 &lt;4"^' <br><br> R is, at each position, independently represented by hydrogen, optionally Substituted alkyl, 25 optionally substituted cycloalkyl,, thiomethoxy, -NHA, -NA2, -NHC(=0)A, aminocarbonyl, -C(-0)NHA, -C(=0)NA2, halogen, hydroxy, -OA, cyano or aryl; <br><br> A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl; <br><br> WO 02/055014 <br><br> -2- <br><br> PCT/SE02/00070 <br><br> R2 is represented by (i), (ii), (iii), or (iv) below: <br><br> ,N. <br><br> (CH2)„ <br><br> / <br><br> V <br><br> (ii) <br><br> R3 (iii) <br><br> (iv) <br><br> R3 is independently at each position represented by -H, optionally substituted Cj^alkyl, optionally substituted C2^alkenyl, optionally substituted C2-6alkynyl, optionally substituted 5 C3.6cycloalkyl or AOH; <br><br> n is 2, 3 or 4; <br><br> P is a heterocyclic ring; <br><br> • R6 is -H or methyl; <br><br> Y is -C(=0)NH-, -C(=0)NA-, -C(=0)N(A)-, -NHC(=0)-, -C(=S)NH-, -CH2NH-,. -C(=0&gt;, 10 -C(=0)CH2-, -CH2C(=0)-, -C(-0)-piperazine-, , -NAC(=0)-, -C(=S)N(A)-, CH2NA, NACH2 or a 5-membered heterocyclic. <br><br> R7 is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R8-R9 and R10; wherein R7 is connected to Y either by a single bond or by a ring fusion; <br><br> 15 R8 is -CH2-, -C(=0)-, -S02-, - SO2NH-, -C(=0)NH-, -0-, -S-, -S(=0)-, a single bond as tether from R7 to R9, or a five membered heterocyclic connected to R7 by either a single bond or by ring fusion; <br><br> R9 is optionally substituted heterocycle, optionally substituted aryl,- optionally substituted piperazinyl-Rl 1, optionally substituted morpholinyl-Rl 1 or optionally substituted 20 thiomorpholinyl- or -C(=0)A; <br><br> R10 is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH2-&gt; methylthio, -NHA, -NA2, -NHC(=0)A, C(=0)NHA, C(=0)NA2, or OA; <br><br> R11 is -H, alkyl, AOH, -S02A, -S02NH2, -SO2NHA, -S02NA2, -S02NHAR9, -C(=0)R9, 25 -alkylR9, C(=0)A, C(=0)NH2, C(=0)NHA, C(=0)NA2 or -C(=0)0A; or a pharmaceutically acceptable salt of said compound. <br><br> The term "hydrocarbyl" refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms. <br><br> WO 02/055014 <br><br> -3- <br><br> PCT/SE02/00070 <br><br> The term "alkyl" used alone or as a suffix or prefix, refers to straight or branched chain hydrocarbyl radicals comprising 1 to about 12 carbon atoms. <br><br> The term "alkenyl" refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms. <br><br> 5 The term "alkynyl" refers to straight or branched chain hydrocarbyl radicals having at " <br><br> least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms. <br><br> The term "cycloalkyl" refers to ring-containing hydrocarbyl radicals comprising at least 3 up to about 12 carbon atoms. <br><br> The term "cycloalkenyl" refers to ring-containing hydrocarbyl radicals having at least 10 one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms. <br><br> The term "cycloalkynyl" refers to ring-containing hydrocarbyl radicals having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms. <br><br> The term "aromatic" refers to hydrocarbyl radicals having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) 15 and comprising 6 up to about 14 carbon atoms. <br><br> The term "aryl" refers to aromatic radicals including both monocyclic aromatic radicals comprising 6 carbon atoms and polycyclic aromatic radicals comprising up to about 14 carbon atoms. <br><br> The term "alkylene" refers to divalent alkyl moieties, wherein said moiety serves to 20 link two structures together. <br><br> The term "heterocycle" or "heterocyclic" or "heterocyclic moiety" refers to ring-containing monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising at least 3 and up to about 20 atoms in the rings preferably 5 and 6 membered rings. Heterocyclic moieties may be 25 saturated or unsaturated, containing one or more double bonds, and heterocyclic moieties may contain more than one ring. <br><br> The term "heteroaryl" refers to heterocyclic monovalent and divalent radicals having aromatic character. <br><br> Heterocyclic moieties include for example monocyclic moieties such as: aziridine, 30 oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomoipholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3- <br><br> WO 02/055014 <br><br> -4- <br><br> PCT/SE02/00070 <br><br> dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-li7-azepine homopiperazine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethylene oxide. In addition heterocyclic moieties include heteroaryl rings such as: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pytrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 5 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl. Additionally, heterocyclic moieties encompass polycyclic moieties such as: indole, indoline, quinoline; tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, 1,2-benzisoxazole, 10 benzothiophene, benzoxazble, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. <br><br> In addition to the polycyclic heterocycles described above, heterocyclic moieties . include polycyclic heterocyclic moieties wherein the ring fusion between two or more rings comprises more than one bond common to both rings and more than two atoms common to 15 both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane. <br><br> The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine radicals. <br><br> The term "alkoxy" refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbyl radical. Alkoxy moieties include methoxy, ethoxy, propoxy, 20 isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.. <br><br> The term amine or amino refers to radicals of the general formula -NRR', wherein R and R' are independently selected froin hydrogen or a hydrocarby radical. <br><br> Detailed Description of the Invention <br><br> In a further aspect of the invention, A, R1 and R3, each independently, as an alkyl, 25 alkenyl, alkynyl and as a cycloalkyl, may optionally be substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carboxamido, amidino, carbamoyl, mercapto, sulfamoyl, Cm alkyl, C2A alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C3.6 cycloalkenyl, Cm alkoxy, Cm alkanoyl, Cm alkanoyloxy, N-(Cm alkyl), N(Cm alkyl)2, Cm alkanoylamino, (Cm alkanoyl)2amino,'N-(CM alkyl)carbamoyl, N,N-(Cm alkyl)2carbamoyl, (Cm)S, (Cm 30 alkyl)S(O), (CMalkyl)S(0)2, (Cm) alkoxycarbonyl, N-(Cm alkyl)sulfamoyl, N,N-Cm alkyl)sulfamoyl, Cm alkylsolfonylamino, and heterocyclic. <br><br> Examples of optional substituents for aryl and heterocyclic groups, when not otherwise defined, are halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, <br><br> WO 02/055014 <br><br> -5- <br><br> PCT/SE02/00070 <br><br> cafboxamido, amidino, carbamoyl, mercapto, sulfamoyl, Cm alkyl, C2-4 alkenyl, C2-4 alkynyl, C3.6 cycloalkyl, C3.6 cycloalkenyl, Cm alkoxy, Cm alkanoyl, Cm alkanoyloxy, N-(Cm alkyl), N(Cm alkyl)2, Cm alkanoylamino, (Cm alkanoyl)2amino, N-(Cm alkyl)carbamoyl, N,N-(Cm alkyl)2carbamoyl, (Cm)S, (Cm alkyI)S(0), (CMalkyl)S(0)2, (Cm) alkoxycarbonyl, N-(Cm 5 alkyl)sulfamoyl, N,N-Cm alkyl)sulfamoyl, Cm alkylsolfonylamino, and heterocyclic. <br><br> A, Rl and R3 each independently as an alkyl, alkenyl or alkynyl may be straight or branched, preferably having 1-6 carbon atoms. A, RJ and R3 preferably have 3-6 atoms when each are independently a cyclic alkyl. Other preferable values for A, R1 and R3 when each . are an alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 10 cyclopentyl, neopentyl and cyclohexyl. Preferable values for R1 when R1 is a halogen are fluorine, chlorine, and bromine. Other preferable values for R1 when R1 is at position 6 on the ' bicyclic ring are methyl, ethyl, ethoxy and methoxy. Preferable values for R1 when R1 is at position 5 on the bicyclic ring are -H, methyl, ethyl and methoxy. When R1 is at position 5-on the bicyclic ring, R1 is more preferably -H. When R1 is at position 7- on the bicyclic ring, 15 R1 is preferably-H. <br><br> R2 is preferably represented by Formula i. Preferably R2 is represented by formula i, wherein n equals 2. Most preferably R2 is represented by N-methyl piperazinyl. <br><br> R3 is preferably represented by hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and ferf-butyl. R3 is most preferably represented by methyl. <br><br> 20 R4 is preferably represented by hydrogen, methyl, ethyl, n-propyl, isopropyl and trimethylsilanyl-ethoxymethoxy. R4 is most preferably represented by methyl. <br><br> R6 is preferably represented by H. <br><br> Y represents a linking group. Y is preferably -C(=0)N(CH3)-, when Y is -C(=0)N(A)-. Y may also be -C(=0)-piperazine. When Y represents a five-membered 25 heterocyclic ring, Y may be represented by, for example, pyrrole, thiophene, furan, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, 1,2,3-thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4-thiadiazole or 1,3,4-oxadiazole. <br><br> More preferably, Y is -C(=0)NH-., • <br><br> 30 Examples of R7 that represent monocyclic or bicyclic aromatic ring or a heterocycle include, but are not limited to, phenyl; 1- and 2-naphthyl; 2-, 3- and 4-pyridyl; 2- and 3-thienyl; 2- and 3-furyl; 1-, 2- and 3-pyrrolyl; imidazolyl; thiazolyl; oxazolyl;pyrazolyl; isothiazolyl; isoxazolyl; 1,2,3-triazolyl; 1,2,3-thiadiazolyl; 1,2,3-oxadiazolyl; 1,2,4-triazolyl; <br><br> WO 02/055014 <br><br> -6- <br><br> PCT/SE02/00070 <br><br> 1,2,4-thiadiazolyl; 1,2,4-oxadiazolyl; 1,3,4-triazolyl; 1,3,4-thiadiazolyl; 1,3,4 oxadiazolyl; quinolyl; isoquinolyl; indolyl; benzothienyl; benzofuryl; benzimidazolyl; benzthiazolyl; benzoxazolyl; or triazinyl. <br><br> R7 may also be represented by the Formula (v): <br><br> -R8—R9 (v) <br><br> 5 R10 <br><br> R7 may further be represented by the Formula (vi): <br><br> -R8—R9 (vi) <br><br> When the values for R7 are as set forth above, R8 may be a single bond as tether, -C(=0)-, -CH2-, -C(=0)-, -S02-, -S(=0)-, -S-, -0-, -C(=0)NH-, -S02NH-, or a five membered 10 heterocycle connected to R7 by single bond or by a ring fusion; and R9 may represent an aryl, heterocyclic or heteroaryl each independently optionally substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Cm alkyl, C2-4aIkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C3.6 cycloalkenyl, Cm alkoxy, Cm alkanoyl, Cm alkanoyloxy, N-(Cm alkyl), N(Cm alkyl)2, Cm alkanoylamino, (Cm alkanoyl)2amino, N-(Ci-15 4alkyl)carbamoyl, N,N-(CM)2carbamoyl, Cm)S, CmS(0), (CMalkyl)S(=0)2, (Cm) <br><br> alkoxycarbonyl, N-(Cm alkyl)sulfamoyl, N,N-"Cm alkyl)sulfamoyl, Cm alkylsolfonylamino, or heterocyclic. Preferably R9 is an optionally substituted heterocyclic moiety. <br><br> More preferably R9 represents piperazine, thiomorpholine or moxpholine each independently optionally substituted on carbon with at least one substituent selected from A. <br><br> o ' • <br><br> 20 R may be a five membered heterocycle, incorporating at least one heteroatom selected from N, O, or S and it may be connected to R7 by a ring fusion, preferably when R7 is phenyl. <br><br> When R8 is a single bond as tether, R9 is preferably methoxy, cyano, a five-membered heterocycle optionally substituted with at least one substituent represented by A or R11 for example compounds represented by the Formulas (vii), (viii) and (ix): <br><br> N N—R11 (vii) <br><br> WO 02/055014 <br><br> -7- <br><br> PCT/SE02/00070 <br><br> N O—R11 (viii) <br><br> v_y l/ \—R11 (vii) <br><br> \__/ <br><br> 5 <br><br> When R8 is represented by a 5-membered heterocyclic comprising N and further when it is connected to R7 by a ring fusion, R9 is preferably -C(=0)A attached at the nitrogen atom. R9 is most preferably-C(=0)CH2CH3. <br><br> When R7 is phenyl or a 6-membered heterocyclic ring, R9, is attached via the R8 tether 10 at the 2-, 3- or 4-position of the phenyl or a 6-membered heterocyclic ring. Preferably, R9 is attached via the R8 tether at the 3- or 4-position of the phenyl or a 6-membered heterocyclic ring. More preferably, R9 is attached via the R8 tether at the 4 position of the phenyl or a 6-membered heterocyclic ring. <br><br> R10 may be represented by alkyl or cycloalkyl each independently optionally 15 substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, Cm alkyl, C2-4alkenyl, C2-4 alkynyl, C3.6 cycloalkyl, C3.6 cycloalkenyl, Cm alkoxy, Cm alkanoyl, Cm alkanoyloxy, N-(Cm alkyl), N(C,m alkyl)2, Cm alkanoylamino, (Cm alkanoyl)2amino, N-(CMalkyl)carbamoyl, N,N-(CM)2carbamoyl, Cm)S, CmS(0), (CMalkyl)S(0)2, (Cm) alkoxycarbonyl, N-(Cm aIkyl)sulfamoyl, N,N-Cm . 20 alkyl)sulfamoyl, Cm alkylsulfonylamino, or heterocyclic. R10 is preferably a halogen, preferably chlorine or fluorine, cyano, or -OCH3. When R10 is a halogen it is preferably chlorine or fluorine. When R7 is a phenyl or 6-membered heteroaromatic ring, Ri0 is attached at the 2-, 3- or 4-position of the phenyl or a 6-membered heterocyclic ring. Preferably, R10 is attached at the 2- or 3-pdsition of the phenyl or a 6-membered heterocyclic 25 ring when R9 is attached via the R8 tether at the 4-position of the phenyl or a 6-membered heterocyclic ring. More preferably, R10 is attached at the 3-position of the phenyl or a 6-membered heterocyclic ring when R9 is attached via the R8 tether ai the 4-position of the phenyl or a 6-membered heterocyclic ring. <br><br> WO 02/055014 <br><br> -8- <br><br> PCT/SE02/00070 <br><br> When R8 is represented by a single bond as tether, R9 is preferably represented by an optionally substituted heterocyclic, optionally substituted on carbon with at least one substituent selected from A and further substituted on a heteroatom opposite to the heteroatom attached to the tether, with a substituent represented by Ru (see e.g., Formulas (vii), (viii) and (ix)). The preferred heterocyclic compounds for R8 are piperazine, morpholine, or thiomoipholine <br><br> When R11 represents SO2A it is preferably represented by an alkylsufonyl, more preferably-S02CH3, -SO2CH2CH3. S02-n-C3H7, S02-i-C3H7, S02-n-C4H,o, -SCh-i-C^o, or -S02-t-C4Hiq. When R11 represent C(=0)A, it is preferably represented by an alkylcarbonyl more preferably-C(=0)CH3, -C(=0)CH2CH3, C(=0)-n-C4Hio, -C(=0)-i-C4Hio, -C(=0)-t-C4H10, or -C(=0)C3H7.- When R11 is represented by C(=0)NHA or C(=0)NA2 it is preferably an alkyl or dialkyl carbamoyl more preferably C(=0)NCH2CH3, C(=0)NH-cycloC6H|2, or C(=0)NH-cycloCsHio,. When Rn is represented by C(=0)R9 it is preferably -C(=0)-pyrrolidine, or -C(=0)-moiphoIine. When R11 is represented by SO2NA2 it is preferably S02N(CH3)2,. When Ru is represented by AOH, it is preferably represented by, CH2CH2OH or-C(=0)CH2CH20H. R11 may also be represented by-C(=O)OC4Hi0. <br><br> In preferred embodiments, when Y is represented by -C(=0)NH: <br><br> (a) R1 is halogen or methoxy, most preferably fluorine, at the 6th position of the bicyclic ring, and is preferably hydrogen, methyl, ethyl or methoxy at the 5th position of the bicyclic ring, and is hydrogen at the 7th position on the bicyclic ring; <br><br> (b) R2 is methyl piperazine; <br><br> (c) R6 is hydrogen; <br><br> (d) R7 is phenyl substituted with R8-R9 <br><br> (e) R8 is a single bond as tether; <br><br> (f) R9 is a heterocyclic moiety, preferably morpholine or piperazine attached to R8 by • nitrogen and optionally substituted on the other nitrogen (for piperazine) with R11 <br><br> or optionally substituted on the oxygen with R11 when R9 is morpholine; <br><br> (g) R11 is AOH or -S02A wherein A is represented by methyl or ethyl. <br><br> The compounds provided herein are useful in the form as a free base, but may also be provided in the form of a pharmaceutically acceptable salt, and/or in the form of a pharmaceutically acceptable hydrate; For example pharmaceutically acceptable salts of compounds of Formula I, include those derived from mineral acids such as for example: <br><br> WO 02/055014 <br><br> -9- <br><br> PCT/SE02/00070 <br><br> hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid. Pharmaceutically acceptable salts may also be developed with organic acids including aliphatic mono and dicarboxylates and aromatic acids. Other phaimaceutically-acceptable salts of compounds of the present invention include for 5 example hydrochloride, sulfate, pyrosulfate, bisulfate, bisulfite, nitrate, and phosphate. <br><br> Processes for the manufacture of the compounds of Formula I are provided as further features of the invention. Many of the Compounds described herein can be made by processes known in the chemical arts for the production of structurally analogous compounds. Accordingly, the compounds of this invention may be prepared by employing procedures 10 known in the literature starting from known compounds or readily prepared intermediates. For example, the core bicyclic, heterocyclic structure may be made by first preparing a chromone, quinolone or quinoline. For compounds of the present invention that have Y as an amide linker, the compounds are preferably made by the general procedure for amide coupling, that is by coupling an anime with an acid hydrochloride. The amines used in the current invention 15 if not commercially available may be made by known techniques. For example as a first step in the process of making compound of Formula I, a nitro compound may be reduced to an amine. The nitro compound may be a nitrophenyl compound. The resulting amines may be . reacted with an acid hydrochloride <br><br> Provided herein is a process for preparation of a precursor compound or use in 20 practicing aspects of the present invention by reacting a compound of Formula (Via): <br><br> *XH Halogen <br><br> Via <br><br> 25 <br><br> (R1, R2, R3, and R7 are as defined for Formula I unless otherwise specified and X is represented by O), with for example a compound represented by:: <br><br> R'O C CO pi <br><br> 2 2 , wherein R' is represented by alkyl, preferably lower alkyl (e.g., <br><br> Ci-C6) most preferably methyl or ethyl, to form a precursor compound of Formula (VIb): <br><br> WO 02/055014 <br><br> -10- <br><br> PCT/SE02/00070 <br><br> C02R' <br><br> :02R' <br><br> Halogen <br><br> Vlb <br><br> 5 <br><br> Rl is preferably fluorine, chlorine, methyl, methoxy, ethoxy or hydrogen. The Halogen is preferably Chlorine or Bromine. The reaction may be carried out in the presence of a catalyst such as tetrabultyammonium fluoride in THF. The reaction may be stirred for example at 10 room temperature and refluxed with heat. <br><br> Further provided herein is a process for the preparation of a precursor compound comprising hydrolyzing the esters of compound (VIb) to form intermediate (Vic): <br><br> 20 This reaction may be carried our for example by reacting a compound of Formula (VIb) with a base such as sodium hydroxide (aqueous). Also provided here is a process for the preparation of an intermediate by the cyclization of compound (Vic) to form intermediate <br><br> 15 <br><br> CO2H <br><br> Halogen <br><br> Vic <br><br> (VId) <br><br> WO 02/055014 <br><br> -11- <br><br> PCT/SE02/00070 <br><br> Halogen O Vld <br><br> Intermediate compound (Vld) may be formed by refiuxing a compound of Formula (Vic) with a strong acid (e.g., H2SO) and further refluxed with heat and an alkyl alcohol for 5 example R' 'OH wherein R'' is C1-C4 alkyl, preferably ethyl. <br><br> In an additional aspect of the invention, a process is provided for the preparation of an intermediate by reacting a compound of Formula (Vld) with an amine of R2 in the presence of a catalyst and a base to form intermediate Formula (Vie): <br><br> Vie <br><br> In a further embodiment of the invention, a compound of Formula (Vld) is reacted with a 15 catalyst selected from the group consisting of nickel and palladium. Preferably the palladium is provided in the presence of a phosphine ligand for example 2,2'-bis(diphenylphosphino)-l,r-binapthyl, The palladium may be provided as tris(dibenzylideneacetone) dipalladium. The base is preferably selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate and triethylamine and mixtures thereof. <br><br> 20. Further provided herein is an acid hydrochloride of a compound of Formula (Vie) <br><br> which is intermediate Formula (Vlf): <br><br> WO 02/055014 <br><br> -12- <br><br> PCT/SE02/00070 <br><br> . Vlf <br><br> The intermediate Formula (Vlf ) may be formed for example by heating a compound of Formula (Vie) in the presence of an acid and water (e.g., HCL/H20). . <br><br> In another aspect of the invention provided is intermediate Formula (VIg): <br><br> HCI <br><br> VIg <br><br> WO 02/055014 <br><br> -13- <br><br> PCT/SE02/00070 <br><br> Thus, in another aspect of the invention, a leaving group is added to the carboxylate of a compound of Formula (Vlf). L is a leaving group. This intermediate is useful in that the acid is activated to provide an electrophile. L is preferably represented by chlorine in intermediate Formula (VIg) which is prepared by reacting a compound of Formula (Vlf ) with 5 thionyl chloride (SOCI2). <br><br> Provided herein is a compound of Formula (Vlh): • <br><br> O <br><br> 10 VJh <br><br> Methods for reacting amines with acid chlorides may be used to prepare compounds of • 15 formula I such as a compound of Formula (Vlh) For example, a method for the preparation of (Vlh) may include reacting a compound of Formula (VTg) with H2N-R7 in the presence of DIPEA. <br><br> Alternatively, compounds of Formula (Vlh) may also be prepared by reacting a compound of Formula (Vlf) with H2N-R7 in the presence for example 1-20 hydroxybenzotriazole (HOBT), 0-( 1 H-Benzotriazol-1 -yl)-N,N,N 'N' -pentamethylene-uronium tetrafluorborate (TBTU), and (dimethylammo)pyridine, preferably in that order. <br><br> Compounds of Formulas (Vie), (Vlf), and (VIg), and (Vlh) may also comprise a pharmaceutically acceptable salt of said compounds. <br><br> The compounds and processes above may also be used to prepare the chroman 25 derivatives of Formula (I) via the saturation of the double bond (4H-chromene) in the bicyclic <br><br> WO 02/055014 <br><br> -14- <br><br> PCT/SE02/00070 <br><br> compound. Depending on the reduction conditions, the 4-oxo derivative may or may not be obtained. <br><br> Provided herein is a process for preparation of a precursor compound or use in practicing aspects of the present invention by reacting a compound of Formula (Via): <br><br> 5 <br><br> ^XH Halogen <br><br> Via <br><br> 10 (R1, R2, R3, and R7 are as defined for Formula I unless otherwise specified and X is represented by O), with for example a compound represented by:: <br><br> R'0,C =—CO,R* <br><br> * , wherein R' is presented by alkyl, preferably lower alkyl (e.g.. <br><br> Ci-Cg) most preferably methyl or ethyl, to form a precursor compound of Formula (VIb): <br><br> 15 <br><br> X02R' <br><br> R^N <br><br> X -^co2R' <br><br> Halogen <br><br> VIb <br><br> 20 R1 is preferably fluorine, chlorine, methyl, methoxy, ethoxy or hydrogen. The Halogen is preferably Chlorine or Bromine. The reaction may be carried out in the presence of a catalyst such as tetrabultyammonium fluoride in THF. The reaction may be stirred for example at • room temperature and refluxed with heat <br><br> Further provided herein is a process for the preparation of a precursor compound 25 comprising hydrolyzing the esters of compound (VIb) to form intermediate (Vic): <br><br> WO 02/055014 <br><br> -15- <br><br> PCT/SE02/00070 <br><br> /C02H <br><br> ^co2H Vic <br><br> This reaction may be carried our for example by reacting a compound of Formula (VIb) with a base such as sodium hydroxide (aqueous). Also provided here is a process for the 10 preparation of an intermediate by the cyclization of compound (Vic) to form intermediate (Vld) <br><br> o <br><br> Vld <br><br> Intermediate compound (Vld) may be formed by refluxing a compound of Formula 15 (Vic) with a strong acid (e.g., H2SO) and jfurther refluxed with heat and an alkyl alcohol for example R"OH wherein R" is C1-C4 alkyl, preferably ethyl. <br><br> *-0 <br><br> 'X Halogen <br><br> 20 <br><br> In an additional aspect of the invention, a process is provided for the preparation of an intermediate by reacting a compound of Formula (Vld) with an amine of R2 in the presence of a catalyst and a base to form intermediate Formula (Vie): <br><br> WO 02/055014 <br><br> -16- <br><br> PCT/SE02/00070 <br><br> o <br><br> R <br><br> ,2 <br><br> OR' <br><br> R <br><br> 0 <br><br> Vie <br><br> In a further embodiment of the invention, a compound of Formula (Vld) is reacted with a 5 catalyst selected from the group consisting of nickel and palladium. Preferably the palladium is provided in the presence of a phosphine ligand for example 2,2'-bis(diphenylphosphino)-1,1 '-binapthyl. The palladium may be provided as tris(dibenzylideneacetone) dipalladium. The base is preferably selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate and triethylamine and mixtures thereof. <br><br> 10 Further provided herein is an acid hydrochloride of a compound of Formula (Vie) . <br><br> which is intermediate Formula (Vlf): <br><br> 15 <br><br> O <br><br> OH <br><br> HCI <br><br> Vlf <br><br> WO 02/055014 <br><br> -17- <br><br> PCT/SE02/00070 <br><br> The intermediate Formula (Vlf) may be formed for example by heating a compound of Formula (Vie) in the presence of an acid and water (e.g., HCL/H2O). <br><br> In another aspect of the invention provided is intermediate Formula (VIg): <br><br> 5 <br><br> O <br><br> HCI <br><br> VIg <br><br> 10 <br><br> Thus, in another aspect of the invention, a leaving group is added to the carboxylate of a compound of Formula (Vlf). L is a leaving group. This intermediate is useful in that the acid is activated to provide an electrophile. L is preferably represented by chlorine in 15 intermediate Formula (VIg) which is prepared by reacting a compound of Formula (Vlf) with thionyl chloride (SOCI2). <br><br> Provided herein is a compound of Formula (Vlh): <br><br> 20 <br><br> WO 02/055014 <br><br> -18- <br><br> PCT/SE02/00070 <br><br> O <br><br> Vlh <br><br> Methods for reacting amines with acid chlorides may be used to prepare compounds of formula I such as a compound of Formula (Vlh) For example, a method for the preparation of (Vlh) may include reacting a compound of Formula (VIg) with H2N-R7 in the presence of DIPEA. <br><br> Alternatively, compounds of Formula (Vlh) may also be prepared by reacting a compound of Formula (Vlf) with H2N-R7 in the presence for example 1-hydroxybenzotriazole (HOBT), 0-(lHrBenzotriazol-l-yl)-N,N,N'N'-pentamethylene-uronium tetrafluorborate (TBTU), and (dimethylamino)pyridine, preferably in that order. <br><br> Compounds of Formulas (Vie), (Vlf), and (VIg), and (Vlh) may also comprise a pharmaceutically acceptable salt of said compounds. <br><br> The compounds and processes above may also be used to prepare the chroman derivatives of Formula (I) via the saturation of the double bond (4H-chromene) in the bicyclic compound. Depending on the reduction conditions, the 4-oxo derivative may or may not be obtained. <br><br> A method for preparing the-acid hydrochlorides useful in synthesis of a chromone is set-forth in Scheme 1 below: A method for preparing the acid hydrochlorides useful in synthesis of a chromone is set forth in Scheme 1 below: <br><br> WO 02/055014 <br><br> -19- <br><br> PCT/SE02/00070 <br><br> R1 <br><br> OH <br><br> Br <br><br> C02R' <br><br> Halogen <br><br> Halogen = CI, Br )q <br><br> R' = CH3I C2H5 <br><br> (R1)q = -OCH3i F, CH3. CI, OEt, H. <br><br> Via <br><br> S1(L <br><br> XT <br><br> Hal09®" O Vld H <br><br> OEt <br><br> 1. H2S04 <br><br> 2. EtOH, reflux <br><br> C" \CH2)n ^ Or precursor amines for (ii) or (iii)1 <br><br> \ &gt; - V • a ') <br><br> '—N' x structural variations of R ' <br><br> R3 <br><br> Pd catalyst phosphine ligand cesium carbonate O <br><br> O <br><br> HCI/H20 <br><br> r <br><br> 1 n <br><br> /Nv <br><br> \ (ph2)n &gt;—n nr3 <br><br> Vie <br><br> OH <br><br> yK O <br><br> ( (CH2)n <br><br> ^—N HCI <br><br> R3 <br><br> Vlf <br><br> Scheme 1: Preparation of chr9mone-2-carboxylic acids as intermediates in the synthesis of compounds of the present invention. <br><br> Alternatively, the chromone-2-carboxylic acid may be converted to the acid chloride 5 and reacted immediately with an appropriate amine, as depicted in Scheme 2, below: <br><br> WO 02/055014 <br><br> -20- <br><br> PCT/SE02/00070 <br><br> socio <br><br> OH - <br><br> /Ns, O <br><br> ( (CH2)n \ N HCI <br><br> \3 <br><br> VIg <br><br> TBTU,HOBT DMF, DIPEA <br><br> \cH2)n <br><br> V—N HCI <br><br> ■R8R9 <br><br> RBR9 <br><br> Scheme 2. Amide synthesis via acid chloride intermediate. <br><br> Additional functional group manipulations include, but are not limited to, O-dealkylation and N-dealkylation (Scheme 3). <br><br> WO 02/055014 <br><br> -21- <br><br> PCT/SE02/00070 <br><br> Scheme 3: Functional group manipulation with compounds of the present invention includes, but is not limited to, N- and O- dealkylation <br><br> Quinoline and quinolone compounds of the present invention are prepared and derivatized via synthetic routes similar to those employed for synthesis of the chrornone-2- <br><br> carboxamides described above and in Schemes 1-3. These synthetic routes to quinoline and <br><br> WO 02/055014 <br><br> t <br><br> -22- <br><br> PCT/SE02/00070 <br><br> quinolone compounds of the present invention are depicted in Scheme 4, infra. MeO^O <br><br> (T^i + <br><br> R <br><br> NH. <br><br> methanol reflux <br><br> Br <br><br> MeO^O <br><br> R1 = OCHa or F <br><br> 0^0^Si(CH3&gt;3 <br><br> NaH <br><br> OMe 2-(trimethylsilyl)ethoxy-methyl chloride <br><br> 0-o^Si&lt;CH3)a , O R " <br><br> OMe <br><br> '0M6 LiOH p2 " « THF/MeOH/HjO 42 H O <br><br> amine <br><br> NHAr <br><br> OMe <br><br> OMe <br><br> LiOH <br><br> OMe <br><br> OMe amine, Pd <br><br> 0 THF/Me0H/H20 £2 £ <br><br> NaH CH3I <br><br> amine TBTU HOBt <br><br> OMe <br><br> Br O <br><br> LiOH Q THF/MeOH/HjO <br><br> CI oxalyl chloride —OH <br><br> Br O <br><br> amine, Pd <br><br> NHAr <br><br> NHAr <br><br> NHAr amine, Pd <br><br> ^\^Si(CH3)3 <br><br> NaH <br><br> amine TBTU 0 HOBt <br><br> NHAr <br><br> 2-(trimethylsilyl)ethoxy- I pj O methyl chloride <br><br> WO 02/055014 <br><br> -23- <br><br> PCT/SE02/00070 <br><br> It will be appreciated by those skilled in the art that certain compounds of the present invention contain for example asymmetrically substituted carbon and/or sulfur atoms, and accordingly may exist in and be isolated in, optically-active and racemic forms. It will be 5 appreciated by those skilled in the art that certain compounds of the present invention contain for example asymmetrically substituted carbon and/or sulfur atoms, and accordingly may exist in and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism, thus it is to be understood that the present invention encompasses racemic, optically-active, polymorphic or stereoisomers forms, or mixtures thereof, which forms 10 possess properties useful in the treatment of the disorders set forth below. Preparation of optically active forms is well known in the art how (for example by resolution of racemic forms by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the treatment of the disorder described above. <br><br> 15 Compounds of Formula I have been found to be 5-HT]B and 5HTid agonists. The compounds of Formula I, and their pharmaceutically acceptable salts, may also be used in a method for the treatment of migraine.' The treatment of this disorder comprises administering to a warm-blooded animal, preferably a mammal, more preferably a human, in need of such treatment, an effective amount of a compound of Formula I or a pharmaceutically acceptable 20 salt of said compound. . <br><br> Further provided is the use of a compound of Formula I in the preparation of a medicament for the treatment of a disorder such as migraine in a warm-blooded animal, preferably a mammal, more preferably a human, suffering from such disorder. <br><br> The invention further provides a pharmaceutical composition suitable for the treatment 25 of the above describe disorders comprising administering to a warm-blooded animal having such disorder an effective amount of a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt. <br><br> The invention also provides a pharmaceutical composition comprising a compound of Formula I, as defined herein, or a pharmaceutically acceptable salt, in combination with a 30 pharmaceutically acceptable carrier. Preferred compounds of Formula I, for use in the compositions of the invention are as described above. <br><br> All compounds described herein demonstrate binding affinities (observed Ki values), in an assay described below, of less than about IOjaM. Further, compounds of the present <br><br> WO 02/055014 <br><br> -24- <br><br> PCT/SE02/00070 <br><br> invention not only demonstrate 5HTib antagonist activity by reversing 5HTib agonist-induced hypothermia in the guinea pig, these compounds are considered to be orally active, and hence, they are the preferred compounds. Examples 1, 10,11,31,32,34,44,55,56,57,71 and 72, infra, demontrate 5HTib antagonist activity in a dosage range of 0.006-5.5 mg/kg. In 5 addition, compounds described herein demonstrate activity in the learned helplessness assay for antidepressant/antianxiety activity. Examples 31,44,71 and 72, infra, demonstrate activity in the learned helplessness assay. In addition, compounds were tested for maximal intrinsic activity (IA), and were found to have measured IA's of negative 50% to positive 150% in the GTPyS assay described below, thus demonstrating a range of response from 10 agonism (low percentages) to antagonism (high percentages). <br><br> The compounds described herein may be provided or delivered in a form suitable for oral use, for example in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension. The compounds may be also be provided for topical administration, for example, as a cream, ointment, gel, spray, or aqueous solutions, oily 15 solutions, emulsions or suspensions. The compounds described herein may also be provided in a form suitable for nasal administration for example, as a nasal spray, nasal drops, or dry powder. The compositions may also be administered to the vagina or rectum in the form of a suppository. The compounds described herein may also be administered parentally, for example by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion. 20 The compounds may be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally or sublingually. <br><br> The compounds of the invention may accordingly be obtained by conventional, procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, 25 sweetening, flavoring and/or preservative agents. <br><br> The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending uppn the host treated and the particular route of administration. The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I, will naturally vary according to the nature and . 30 severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. Various assays and in vivo tests are known for determining the utility of the compounds in the disorders noted above and specifically as agonists and antagonists of 5HTib and 5HTid <br><br> WO 02/055014 <br><br> -25- <br><br> PCT/SE02/00070 <br><br> V <br><br> The utility of the compounds for example to treat depression maybe shown via a learned helplessness test in guinea pigs, which is used extensively as correlative to antidepressant activity in humans. The learned helplessness test may be carried out as follows: Seventy male Hartley guinea pigs, each weighing about 350-425 gm are fed ad lib, and are 5 housed under a 12-hour light/dark cycle. The procedure consists of two phases: The induction phase and the avoidance training phase. In the induction phase, subjects are placed into standard shuttle cages (20 LX16WX21 centimeters H ) which are fitted with a grid floor. Electrical stimulation (1.25 mA, 10 sec duration) is delivered to the floor of the cage every 90-sec during 1 hour daily sessions. Subjects have no opportunity to escape or to avoid 10 shocks. Induction is conducted for 2 consecutive days. <br><br> In avoidance training, testing is also conducted in the shuttle cages, except that the subjects are not returned to the same chamber in which induction had occurred. Additionally, all cages are fitted with a partition-with an arch in the center of the cage, through which animals can pass between the left and right halves of the cage. The procedure employed is a 15 standard shuttle avoidance procedure in which a compound, conditioned stimulus (a 10-sec presentation of a tone and turning on of a lamp on the side of the cage that the guinea pig was occupying) serves to indicate presentation of electrical current to the floor of the cage. Shock is presented for a 5 sec period, 5 sec after initiation of the conditioned stimulus. Entry into the opposite side of the shuttle cage via the arched partition prior to shock onset results in the 20 end of the trial (avoidance response). If shock is delivered, entry into the opposite side of the cage results in termination of the shock and CS (escape). Reversal of learned helplessness in the induction subjects correlates to antidepressant activity of the test compound. <br><br> ' Avoidance training, 45-min in duration, is conducted on 2 consecutive days, beginning 48 br after the final induction session. Seventy subjects are assigned to 1 of 6 groups of 11-12 25 animals. The groups'are as follows: <br><br> 1) No induction group. The subjects are placed into the shuttle cages but are not given inescapable shock, the animals are subsequently trained in the avoidance procedure and the vehicle is administered; <br><br> 2) Induction vehicle control group; <br><br> 30 3) Imipramine 17.8 mg/kg; <br><br> 4) 0.3 mg/kg compounds; <br><br> 5) 1 mg/kg compounds; and <br><br> 6) 5 mg/kg compounds. <br><br> WO 02/055014 <br><br> -26- <br><br> PCT/SE02/00070 <br><br> Groups 2-6 are given induction and avoidance training sessions. Injections are administered immediately following induction sessions and 1 hour prior to avoidance training sessions. A second injection is administered 7-8 hours following the first injection, for a total of 9 injections administered over 5 days. No injections are administered following the final 5 avoidance training session. <br><br> Compounds of the present invention may be administered in a volume of lmL/kg bwt. Imipramine is dissolved in DI water. The compounds are dissolved in DI water, to which was added a few drops of lactic acid (pH 5.5). The vehicle control is DI water prepared with lactic acid to the same pH as the-treated groups. . <br><br> 10 The primary dependent variable is escape failure during avoidance training. 2-way analysis of variance (ANOVA) is used to assess overall treatment effect, with Dunn's post hoc analysis used to compare the vehicle-treated group with the drug-treated groups. The no-induction group is used to gauge whether learned helplessness is established, by comparison to the vehicle treated group. <br><br> 15 Other assays that may be used to measure for example affinity of compounds of the present invention for 5HTib and 5HTid receptors are described in J. Med. Chem 41:1218-1235,1228 (1998) and J. Med. Chem 42:4981-5001, (1999) and incorporated by reference herein. These assays may be used with some modifications: Frozen membrane preparations of a stably transfected Chinese hamster ovary (CHO) cell line expressing 5-HTib receptors and 20 5-HT id receptors are thawed rapidly, briefly vortexed, and diluted in assay buffer (AB) <br><br> containing 50 mM Tris-HCl, 4 mM MgCl2,4mM CaCl2,1 mM EDTA, and adjusted to pH 7.4 with NaOH. Final protein concentrations are - 0.185 mg/ml for 5-HTib, and 0.4 mg/ml for 5-HTjd membranes. Test compounds are evaluated in competition assays using [3H]-GR125743 (Amersham). The ligand concentration in both assays was 0.27nM. Kd for [3HJ-GR125743 ■ 25 may vary feom 0.15 nM to 0.25 nM. The 5-HTiB and 5-HTid assays are performed . <br><br> simultaneously on one 96-well assay plate, one drug/compound per plate. Ten serial dilutions (1 uM to 4 pM, final concentration) of compound are prepared in DMSO from 10 mM stock solutions. Incubation mixtures are prepared in quadruplicate in 96-deep well assay plates (Matrix 1 ml). Final assay volumes per well are 10 |xl compound/nonspecific; 100 |il 30 membranes; 100 pi [3H]-GR125743; and 790 (Jl AB. Specific binding is defined by using 10 uM Methiothepine. The assay plates are shaken for 5 min., and then incubated for an additional 55 min. Then the assay plates are filtered through Beckman GF/B filters (soaked &gt; 2 hrs. in PEI) using a Packard Filtermate 196. Filters are washed 2x with 1 ml ice-cold wash . <br><br> WO 02/055014 <br><br> -27- <br><br> PCT/SE02/00070 <br><br> buffer (5 mM Tris-HCl - pH7.4 with NaOH). After the filters are dried, 35 pi of Microscint20 is added to each well. The plates are then counted on a Packard TopCount to determine CPM's per well. Ki values are determined for each test compound utilizing the graphic and analytical software package, GraphPad Prism. Compounds are then ranked in order of 5 potency, and selectivity for 5-HTib over 5-HTid receptors. <br><br> A method that may be used to determine a compound's affinity for 5-HTjb and 5HTid receptors is a guinea pig cortical test. This assay is described in detail by Roberts, et al, Br. J. Pharmacol., 1996,117,384-388, which is incorporated by reference herein. The test is carried out as follows: Guinea pigs are decapitated and the cortici is dissected out, weighed 10 and homogenized in 50 mM Tris-HCl, pH 7.7 with an Ultra-Turrax followed by centrifugation for 10 min at 48000 x g and 5°C. The pellet is resuspended and recentrifuged. <br><br> • ✓ .? <br><br> The final pellet is suspended in 0.32 M sucrose buffer to a concentration of 0.5g original wet weight per mL and stored frozen at -70°C. The radioligand binding assay is carried out as follows: [3H]GR125743 saturation studies are tested in duplicate with 3-4 mg w.w. per tube 15 in 5 mL buffer (50 mM Tris, 4 mM CaC12,4 mM MgC12 and 1 mM EDTA at pH 7.7), and a concentration range of 0.012 - 2 nM (10-12 concentrations) for the radioligand. Non-specific binding is determined in the presence of 10 mM methiothepin. In competition experiments 4-8 mg w.w. per tube and a radioligand concentration of 0.2 nM are used with 10-12 concentrations of the competing drug. The assays are run for 2-4 hours at 30°C and terminated 20 by rapid filtration through Whatman GF/B filters (pretreated with 0.1% polyethyleneimine) using a Brandel cell harvester. Bovine serum albumin (0.1%) is added to the washing buffer to reduce non-specific binding. Data from the experiments may be analyzed using the iterative non-linear curve-fitting program LIGAND. The Kd values obtained from the saturation studies are used in the calculation of the Ki values by the LIGAND program. The 25 Kd value &lt;ff [3H]GR125743 may result in a measurement of 46 ± 4 pM and the Bmax in afF measurement of 4.9 ± 0.2 pmol/g w.w. <br><br> A GTP7S binding assay may used to determine whether a compound is a 5HTib or 5HTid agonist or antagonist. One assay available measures agonist stimulated GTP binding for example as set forth by Lazareno, S. (1999) Methods in Molecular Biology 106:231-245. 30 Membrane preparations of a stably transfected CHO cell line expressing human 5-HTib receptors are purchased for example from Unisyn, Hopkinton, MA. Frozen membranes are thawed, briefly sonicated, and diluted to 167fig/ml protein in assay buffer containing 20 mM HEPES, 100 mM NaCl, ImM MgCL2 and l^iM GDP, pH adjusted to 7.4 with NaOH. <br><br> WO 02/055014 <br><br> -28- <br><br> PCT/SE02/00070 <br><br> Diluted membranes are briefly homogenized with a Polytron and allowed to equilibrate at room temperature for at least 15 minutes before use. Serial dilutions (10 pM to 1 pM, final concentration) of test compounds are prepared in buffer with and without 100 nM 5-HT (final concentration) from 10 mM DMSO stock solutions. Incubation mixtures are prepared in 5 quadruplicate in 96-well, deep-well plates and consisted of 180 p.L of membranes (30 jig protein) and 40 jiL of compound with or without 5-HT. After an incubation period of 15 minutes at room temperature, 20 |xL of [35S]GTPtS (NEN; 100 pM final concentration) is added to begin the assay. Mixtures are shaken for 2 minutes and incubated at room temperature for an additional 28 minutes. The reaction is stopped by rapid filtration through 10 Beckman GF/B glass fiber filters using a 96-well Packard cell harvester. Filters axe washed four times with 1 mL ice-cold water. The filter plates are nominally dried and 30 pL of scintillation cocktail (MicroScint 40, Packard) is added to each well. CPMs for each well is determined using a TopCount Scintillation Counter (Packard). Maximum stimulation of [35SJGTPyS binding is defined in the presence of lOOnM 5-HT. Basal [35S]GTPyS binding is 15 defined in buffer alone. IC50 values are defined as the concentration of compound at which 50% of the lOOnM 5-HT response [was] obtained. Maximal intrinsic activity (IA) of a compound is defined as the percent maximal 5-HT-induced stimulation by 10 jxM compound in the absence of 5-HT. As an inter-assay standard, a concentration response curve of 5-HT (1 jiM to lpM final) in the absence of compounds was included in each assay and an EC50 20 was determined. <br><br> Preferred compounds of the present invention include, but are not limited to, the following compositions listed in Table 1 on the following pages. <br><br> WO 02/055014 <br><br> PCT/SE02/00070 <br><br> -29- <br><br> Tablel: Compounds. <br><br> /Example <br><br> ; ;&gt;&amp;&gt;r .?•.&amp; <br><br> .life®, ■ i '"■ J-1f-viiiSf^Ki?|i'':i\1i''*-) <br><br> i <br><br> QUyYv <br><br> 9 olAo <br><br> 8-(4-methyl-1 -piperazinyl)-iV-[4-(4-moipholinyl)phenyl] -4-oxo-4#-cbromene-2-carboxamide <br><br> 2 <br><br> ccV-O^5 <br><br> Y^0^Yn^ /° <br><br> O °' <br><br> T ' <br><br> 2-{ l-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]-methanoyl} - 8-(4-methyl-piperazin-1 -yl)-chromen-4-one <br><br> 3 <br><br> X jQD <br><br> pcXcrV o ° <br><br> T <br><br> 2-{ l-[4-(l-Acetyl-2,3-dihydro-lH-indol-6-yl)-piperazin-1 -yl]-methanoyl}-8-(4-methyl-piperazin-1 -yl)-chiomen-4-one <br><br> 4 <br><br> x -jd:C! <br><br> iTYii ft 0 • ; <br><br> r <br><br> 2-Chloro-5-(4-{ l-[8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-piperazin-1 -yl)-benzonitrile <br><br> 5 <br><br> X j£T°" <br><br> Wr <br><br> 0 0 <br><br> T <br><br> 2-{ l-[4-(4-Methoxy-phenyl)-piperazin-l-yl]-methanoyl}-8-(4-methyl-piperazin-1 -yl)-chromen-4-one <br><br> 6 <br><br> ?M'TVhO <br><br> r' <br><br> 8-(4-Methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid (5-furan-2-yl-lH-pyrazol-3-yl)-amide <br><br> WO 02/055014 PCT/SE02/00070 <br><br> -30- <br><br> " - ., * <br><br> 7 <br><br> q5yy^ <br><br> 9 ° <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-imidazol-1 -yi-phenyl)-amide <br><br> 8 <br><br> .0° 0 \ <br><br> 1 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-[ 1,2,3]thiadiazol-5-yl-phenyl)-amide <br><br> 9 <br><br> /N. 0 N' <br><br> . 1 <br><br> 8 -(4-Methyl-piperaziii-1 -yl)-4-oxo-4H-cbromene-2-carboxylic acid 4-[l,2,3]thiadiazol-5-yl-benzylamide <br><br> 10 <br><br> o <br><br> TAvi <br><br> A 0 O T V <br><br> 1 0 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl] -amide <br><br> 11 <br><br> ^TtX^i" <br><br> V ^Nx <br><br> 1 0 0 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)-phenyl]-amide <br><br> 12 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (2-methoxy-4-moipholin-4-yl-phenyl)-amide <br><br> WO 02/055014 PCT/SE02/00070 <br><br> -31- <br><br> i.Rumple :5 <br><br> '^vKriii^ '• .,m <br><br> -'^.i«^'':::y.s-v'!v" 'M'i , <br><br> 13 <br><br> 'P^VnYY01 <br><br> 9 0 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide <br><br> 14 <br><br> &lt;&amp;•*&gt; <br><br> 9 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide <br><br> 15 <br><br> 9VYbYY^ <br><br> 9 X^O <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (2,5-diethoxy-4-moipholin-4-yl-phenyl)-amide <br><br> 16 <br><br> 0 <br><br> W(\ <br><br> 9 ° ^ <br><br> 8 -(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-cyanomethyl-phenyl)-amide <br><br> 17 <br><br> JL o 1!^-/ <br><br> 1 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (1 H-indol-5-yl)-axnide <br><br> 18 <br><br> 0 <br><br> QCVn O <br><br> k J o <br><br> N <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-caxboxylic acid [4-(1 -morpholin-4-yl-methanoyl)-phenyl]-amide <br><br> WO 02/055014 <br><br> -32- <br><br> PCT/SE02/00070 <br><br> sssi <br><br> . 19 <br><br> V*i. <br><br> f'S 0 ^y- <br><br> Y V <br><br> 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(2,6-dimethyI-moipholin-4-yl)-phenyl]-amide <br><br> 20 . <br><br> O <br><br> ^Xx0xr i <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-. 4H-chromene-2-carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide <br><br> 21 <br><br> ITY\ rP-O , <br><br> 9' ° <br><br> 8-(4-Methyl-piperaziri-1 -yl)-2-(6- <br><br> morpholin-4-yl-benzooxazol-2-yl)- <br><br> chromen-4-one <br><br> 22 <br><br> pVA- <br><br> 9 uo <br><br> 8-(4-Methyl-piperazixi-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (2-hydroxy-4-moipholin-4-yl-phenyl)-amide <br><br> 23 <br><br> N^n-A^Nv^s <br><br> 0 N—^ ^ <br><br> f "°A <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (5-ethoxy-benzothiazol-2-yl)-amide <br><br> 24 <br><br> 9 ^o. <br><br> 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-biomo-phenyl)-amide <br><br> WO 02/055014 <br><br> -33- <br><br> PCT/SE02/00070 <br><br> . Example i <br><br> '•"lit*# V <br><br> 9r*$! Tt. &lt; <br><br> 25 <br><br> 0 <br><br> if N Y\ <br><br> 9 ° <br><br> 8-(4-Methylpiperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid methyl-(4-morpholin-4-yl-phenyl)amide <br><br> 26 <br><br> rn o* <br><br> r° iVr <br><br> &gt;n. 0 KJ <br><br> 8-(4-Methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-morpholin-4-yI-phenyl)-amide <br><br> 27 <br><br> 0 <br><br> (^X^n^^cn ' 9. 0 I^0 • <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide <br><br> 28 <br><br> 0 <br><br> WYY <br><br> 0 <br><br> 1 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide <br><br> 29 <br><br> 9^°Vy\ <br><br> 0 • UOrY <br><br> 1 0 1 <br><br> 4-[4-({ 1 -[8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl] -methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert- . butyl ester <br><br> 30 <br><br> CX\ H <br><br> 7**1 Y^l <br><br> ■ rN^ 0 ^0 <br><br> Y k/nh <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide <br><br> WO 02/055014 <br><br> -34- <br><br> PCT/SE02/00070 <br><br> -fiV j, 'Structure <br><br> 'piSt'YS &lt;S" f % , , •»' <br><br> &gt; ■ ft@!» ;-■■&amp;&amp;- ■ <br><br> 31 <br><br> 0 <br><br> 9 oUo <br><br> 6-Methoxy-8-(4-methyl-piperazin-l.-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 32 <br><br> 0 <br><br> ^°XXJL N <br><br> 0. ^v, <br><br> V ^x <br><br> 1 0 0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)-phenyl]-amide <br><br> 33 <br><br> Xp^XrNYVcl <br><br> 9 0 <br><br> 6-Methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yi-phenyl)-amide <br><br> 34 <br><br> 9 0 uo <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-moiphoIin-4-yl-phenyl)-amide <br><br> 35 . <br><br> 9 0 <br><br> 6-Methoxy-8-(4-meth.yl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide <br><br> 36 <br><br> o <br><br> /Oy^Ai <br><br> V^Vri <br><br> 9 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-thiomorpholin-4-yl-phenyl)-amide <br><br> WO 02/055014 <br><br> -35- <br><br> PCT/SE02/00070 <br><br> * Example * <br><br> : ... *y' *"-i •'' ."•■ , /^'"v^vs-v ■ }v -v'^k* ■ <br><br> *■?^"' <br><br> 37 <br><br> 0 - <br><br> VA-Vi <br><br> V V <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(2,6-dimethyl-morpholin-4-yl)-phenyl]-amide <br><br> 38 <br><br> 'OwY^ <br><br> . jl 0 kJ&gt; <br><br> T <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-morpholin-4-yl-phenyl)-amide <br><br> 39 <br><br> o o ka <br><br> Y oh <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(2~hydroxy-ethyl)-piperazin-1 -yl]-phenyl} -amide <br><br> 40 <br><br> Y <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide <br><br> 41 <br><br> A ° TY^ <br><br> y cn k/0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-amide <br><br> 42 <br><br> Wf"^ <br><br> ^ ° <br><br> • V k/NYQV <br><br> ' o ' <br><br> 4-[4-({ l-[6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl] -piperazine-1-carboxylic acid tert-butyl ester <br><br> WO 02/055014 <br><br> -36- <br><br> PCT/SE02/00070 <br><br> ^Example*' <br><br> 43 <br><br> 9 0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide <br><br> 44 <br><br> ^°yys n st 0 if y^i ft 0 <br><br> v ^r- <br><br> 6-Mefthoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)-phenyl]-amide <br><br> 45 <br><br> /yVk <br><br> A" ° "c-vi v ^ <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethane sulfonyl-piperazin-1 -yl)-phenyl]-amide <br><br> 46 <br><br> 0 <br><br> /°YY\ <br><br> y^o-^yny^l <br><br> C) ° / <br><br> v <br><br> 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-dimethyl sulfamoyl-piperazin-1 -yl)-phenyl]-amide <br><br> 47 <br><br> 9 °^v <br><br> 4-[4-( {1 -[6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo4H-chromen-2-yl] -methanoyl}-amino)-phenyl] -piperazine-1-carboxylic acid dimethylamide ' <br><br> 48 <br><br> • N <br><br> if^[pl <br><br> /N 0 kAp <br><br> Y yrv- <br><br> 0 <br><br> 4-[4-({ l-[6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-anrino)-plienyl]-piperazine-1-carboxylic acid ethylamide <br><br> WO 02/055014 <br><br> -37- <br><br> PCT/SE02/00070 <br><br> W0 <br><br> 49 <br><br> 9 Ao <br><br> 0 <br><br> 4-[4-({ 1 -[6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl} -amino)-phenyl]-piperazine-1-carboxylic acid cyclohexylamide <br><br> 50 <br><br> 9 ^Vo <br><br> 0 <br><br> 4-[4-({ l-[6-Methoxy-8-'(4-methyl-piperazin- l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine- 1-carboxylic acid cyclopentylamide <br><br> 51 <br><br> 0 <br><br> pCVn f^s 0 <br><br> y uvo <br><br> 0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(l-pyrrolidin-1 -yl-methanoyl)-piperazin-1 -yl]-phenyl}-amide <br><br> 52 <br><br> 9 ,uoxv <br><br> '/ &lt;S <br><br> .1 0 0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(propane-2-sulfoxiyl)-piperazin-1 -yl]-phenyl} -amide <br><br> 53 <br><br> o <br><br> ^Oy-Y^, <br><br> 9 'ucv <br><br> ' .0 <br><br> 6-Methoxy-8-(4-methy3-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(2-methyl-propanoyl)-piperazm-1 -yl]-phenyl }-amide <br><br> 54 <br><br> ^Ns. o k J o <br><br> T <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(l-moipholin-4-yl-methanoyl)-piperazin-1 -yl]-phenyl)-amide <br><br> WO 02/055014 <br><br> -38- <br><br> PCT/SE02/00070 <br><br> .'JlSiilpK- <br><br> JJi, £,'■■ ■ i'd <br><br> Hviy'iOfXiSrtf&amp;t "r i!»,.''.!i|^,JI::,.; ,. ' ,&gt;•'* W.' "v, <br><br> 55 <br><br> ^?ArNY^ <br><br> 9- ° <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> 56 <br><br> n ^-n&gt;r- <br><br> 1 ■ . 0' v o <br><br> 6-Fluoro-8 -(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)-phenyl]-amide <br><br> 57 <br><br> o ft ° . T V <br><br> 1 0 <br><br> 6-Fhioro-8-(4-methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-acetyl-piperazin-l-yl)-phenyl]-amide <br><br> 58 <br><br> ^P^^'VY* <br><br> '9 ,uo <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-moipholin-4-yl-phenyl)-amide <br><br> 59 <br><br> • y <br><br> 6-Fluoro-8 -(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide <br><br> 60 <br><br> 9 0 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-aniide <br><br> WO 02/055014 <br><br> -39- <br><br> PCT/SE02/00070 <br><br> Example 5 <br><br> mmsmmmm <br><br> 61 <br><br> k J o <br><br> ■ r <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(l-morpliolin-4-yl-methanoyi)-phenyl]-amide <br><br> 62 <br><br> H3Cn^X <br><br> WyYi <br><br> • 9 <br><br> 6-Methyl-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-moipholin-4-yI-phenyl)-amide <br><br> 63 <br><br> n^XpC^Y <br><br> k y o <br><br> I <br><br> 6-Methyl-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-axnide <br><br> 64 <br><br> 0 <br><br> H3CY^Jk <br><br> VkVtY <br><br> ■' 9 ° o <br><br> 6-Methyl-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide <br><br> 65 <br><br> y ^°. <br><br> 6-Chloro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 66 <br><br> f"3' f <br><br> T^nrVl <br><br> 9 uo <br><br> 5-Methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> WO 02/055014 <br><br> -40- <br><br> PCT/SE02/00070 <br><br> 'i fsvw#m* &amp; ? '» ' MS* &amp;fcK &amp; <br><br> y, t p, i. ... i, Vt j. ' . f r jjpi^ . • , , * w. »|,i •£{.• • ' <br><br> 67 <br><br> -O 0 <br><br> lTNY^jl <br><br> 9 ° <br><br> 5 -Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morphoIin-4-yl-phenyl)-amide <br><br> 68 <br><br> ft 0 ^ <br><br> Sr k^N^^OH <br><br> ' 0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-1 -yl]-phenyl}-amide <br><br> 69 <br><br> V^ynY1 <br><br> J^S 0 <br><br> N <br><br> ' 0 ' <br><br> 4-[4-({ l-[6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl} -amino)-phenyl]-piperazine- 1-carboxylic acid tert-butyl ester <br><br> 70 <br><br> X^Aftpi p o <br><br> Y k^NH <br><br> 4-[4-({ l-[6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide <br><br> 71 <br><br> ' VA-nY\ <br><br> f'S ° N . k^N&gt;^ <br><br> 1 ii \\ <br><br> 1 0 0 <br><br> 6-Fluoro-8-(4-methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethane sulfonyl-piperazin-1 -yl)-phenyl]-amide <br><br> 72 . <br><br> Vl ft ^ftft y k/Ny^ <br><br> ' o <br><br> 6-Fluoro-8 -(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)-phenyl]-amide <br><br> WO 02/055014 <br><br> -41- <br><br> PCT/SE02/00070 <br><br> ; ^ -i.J ,'•.» ,• • ••'";t.-V.' • •• ■ •? ,•■ - '• • .• aK"V v..- <br><br> 73 <br><br> VVh- <br><br> ft 0 <br><br> kN^ k/NY^0H <br><br> ' o <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]-phenyl}-axnide <br><br> 74 <br><br> 9 o <br><br> N-[8-(4-Methyl-piperazin-1 -yl)-4- <br><br> oxo-4H-chromen-2-yl]-4- <br><br> morpholin-4-yl-benzaxmde <br><br> 75 <br><br> 0 o <br><br> ^ racemic <br><br> 8-(4-Methyl-piperazin-l -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 76 <br><br> VC\-Y*i <br><br> (+)-8-(4-Methyl-piperazin-1 -yl)-chroman-2rcarboxylic acid (4-mojpholin-4-yl-phenyl)-amide <br><br> 77 <br><br> VOY"YI <br><br> 9 ■uo <br><br> (-)-8-(4-Methyl-piperazin-1 -yl)-chroman-2-carboxyIic acid (4-morphoIin-4-yl-phenyl)-amide <br><br> 78 <br><br> QQyy^i <br><br> 9 • ^ <br><br> racemic-8-(4-methyl-piperazin-l -yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> WO 02/055014 <br><br> -42- <br><br> PCT/SE02/00070 <br><br> stss 'aw» <br><br> 79 <br><br> Wf"Y^ <br><br> 9 o <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-cbroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (faster running isomer) <br><br> 80 <br><br> 9 0 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-chroman-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide (slower running isomer). <br><br> 81 <br><br> o <br><br> ■WYVI <br><br> ft 0 <br><br> y k/N^0. <br><br> 4-[4-( {1 -[6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid ethylamide <br><br> 82 <br><br> p <br><br> T^°'T NY^l <br><br> 0 O ■ '\ <br><br> 6-Methoxy-8-(4-methyl-[ 1,4]diazepan-1 -yl)-4-oxo-4£f-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 83 <br><br> 0 <br><br> i ° i' <br><br> - 9 <br><br> 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4i/-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-axnide <br><br> 84 <br><br> ft 0 <br><br> ' 0 <br><br> 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4#-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide <br><br> WO 02/055014 <br><br> -43- <br><br> PCT/SE02/00070 <br><br> 85 <br><br> /0YYV N <br><br> Sr 0 if Y\ <br><br> N 0 kAN^ <br><br> N <br><br> 6-Methoxy-4-oxo-8-piperazixi-1 -yl-4i/"-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 86 <br><br> O <br><br> ^QOyVi <br><br> . 9 ° uo <br><br> 6-Hydroxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4i/-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 87 <br><br> /°v^X <br><br> • TX1 ? <br><br> tYYY^I <br><br> 0"0 o <br><br> / <br><br> 6-Methoxy-8-(4-methyl-[1,4] diazepan-1 -yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 88 <br><br> 0 <br><br> ■ "°YYi v <br><br> WVn <br><br> 0"1 uri <br><br> SjT k/O <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 89 <br><br> TX1 ■? <br><br> r%H 0 <br><br> . Y k/N^o <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-1,4-dihydro-quinoline- . 2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)-phenyl] -amide <br><br> 90 <br><br> o <br><br> 9 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> WO 02/055014 <br><br> -44- <br><br> PCT/SE02/00070 <br><br> 91 <br><br> VkVn ft 0 • Y <br><br> 1 '0 <br><br> 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l ,4-dihy(ko-quinolme-2-carboxylic acid [4-(4-propionyl-piperazin-l -yl)-phenyl]-amide <br><br> 92 <br><br> ^(XkQ <br><br> 1 <br><br> 8-[(2-Dimethylamino-ethyl)-methyl-aminoJ-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> 93 <br><br> 0 <br><br> TX 1 &gt;, <br><br> -V^ou y/ <br><br> 8-[(3-Dimethylamino-propyl)-methyl-amino]-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 94 <br><br> TX i • <br><br> jV ,uo <br><br> -1 <br><br> 8-((3R)-(+)-3-Dimethylamino-. pyrrolidin -l-yl)-6-methoxy-4-oxo-1,4-dihydro-quinoIine-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> 95 <br><br> o <br><br> "Wn jf) ,xxO <br><br> 8-((3 S)-(-)-3-Dimethylamino-pyrrolidin -1 -yl)-6-methoxy-4-oxo-.1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> 96 <br><br> o <br><br> /°V^A <br><br> ■TX i ^ <br><br> TTVY^i <br><br> ^0 <br><br> 6-Methoxy-8-[methyl-( 1 -methyl-pyrrolidin-3-yl)-amino]-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> WO 02/055014 <br><br> -45- <br><br> PCT/SE02/00070 <br><br> .Example* <br><br> 97 <br><br> 0 <br><br> TX i • <br><br> YVyVi rNtV <br><br> 8-[Ethyl-(l -ethyl-pyrrolidin-3-yl)-amino]-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> 98 <br><br> Y- <br><br> X <br><br> xysxv <br><br> SjT <br><br> 4-dimethylamino-6-methoxy-8-(4-methyl-piperazin-1 -yl)-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide <br><br> 99 <br><br> V- <br><br> TYi ? <br><br> T"n rNY^i <br><br> O 0 ■ <br><br> Y k/0 <br><br> 6-methoxy-4-methylamino-8-(4-methyl-piperazin-1 -yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 100 <br><br> o-" <br><br> 9 0 <br><br> 6-fluoro-4-methoxy-8-(4-methyl-piperazin-1 -yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> 101 <br><br> 0 <br><br> 'X??Xyx <br><br> .0 <br><br> 0 <br><br> 6-Fluoro-4-oxo-8-piperazin-1 -yl-4i/-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> Also provided herein are the pharmaceutically acceptable salts of the compounds set forth in Table 1. <br><br> WO 02/055014 <br><br> -46- <br><br> PCT/SE02/00070 <br><br> The following reference examples illustrate the making of intermediates in the synthesis of the compounds of the present invention, and are not intend to limit the invention in any manner. <br><br> 5 Reference Example 1 <br><br> Preparation of Reference Example 1: 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene- <br><br> 2-carboxylic acid hydrochloride. <br><br> Reference Example la: (E,Z)-2r(2-Bromo-phenoxy)-but-2-enedioic acid diethyl ester. <br><br> Diethyl acetylenedicarboxylate (20 ml, 0.162 mol) was added to 2-bromophenol (28 g, 10 0.162 mol), in anhydrous 2-propanol (60 ml) followed by the addition of a catalytic amount of tetrabutylammonium fluoride (0.5 ml, 1.0 M in THF). The solution was stirred at room temperature four hours and was then heated to reflux for one hour. The mixture was cooled to room temperature, then concentrated under vacuum to an oil (51 g = 91 %). <br><br> Reference Example lb: (E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic acid. 15 (E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic acid diethyl ester (51 g, 148 mmol) as prepared in Reference Example la was suspended in ethanol (95 ml) and a solution of sodium <br><br> &lt; <br><br> hydroxide (12.9 g, 0.323 mol) in water (95 ml) was added. The solution was refluxed for 1 h to give a clear orange solution. The mixture was cooled to room temperature and acidified with 6 M HCI (50 ml). The mixture was then concentrated under vacuum and the residue 20 azeotroped (4x)-with ethanol. The solid was filtered, washed with water and dried to give (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid as a light orange solid (24.3 g, 88 % yield). This crude product was used without further purification. <br><br> Reference Example lc: Ethyl-8-Bromo-4-oxo-4H-chromene-2-carboxylate. <br><br> Sulfuric acid (95mL) was added to crude (E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic 25 acid as prepared in Reference Example lb. After heating the mixture with a heat gun for 45 min an orange milky solution was obtained. This solution was slowly added to refluxing absolute ethanol (500 mL). After the addition, the reaction was refluxed for 30 min.then allowed to cool. Crystals started to form after 20 min and the reaction was put in the refrigerator overnight. The solid was filtered, washed with cold ethanol/ water 9:1 and dried 30 to give ethyl 8-bromo-4-oxo-4H-chromene-2-carboxylate as an off-white solid (11.7 g, 24 % yield, mp 124-126 °C). <br><br> WO 02/055014 <br><br> -47- <br><br> PCT/SE02/00070 <br><br> Reference Example Id: Ethyl-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromenec-2-carboxylic acid. <br><br> Ethyl -8-bromo-4-oxo-4H-chromene-2-carboxylate as prepared in Reference Example lc (Davies, Stephen et al., J. Chem. Soc. Perkin Trans I p 2597,1987) (3.0 g, 10.1 mmol) was 5 azeotroped with anhydrous toluene then the white solid was dissolved in 100 mL anhydrous toluene and transferred to the reaction vessel. The. mixture was subjected to vacuum / argon (x2) and the following were added in order (positive argon pressure): N-methylpiperazine (1.3 ml, 11.1 mmol), 2,2'-bis (diphenylphosphino)-l,r-binaphthyl (0.75 g, 1.2 mmol,), tris(dibenzylideneacetone) dipalladium (0) (0.48 g, 0.5 mmol) then cesium carbonate (4.6 g, 10 14.1 mmol).The mixture was again subjected to vacuum / argon and was heated at 80 °C overnight. <br><br> The cooled reaction mixture was filtered through diatomaceous earth and the toluene solution was applied directly to a 600 ml filter funnel (silica 230 - 400 mesh ASTM packed in ethyl acetate) and then washed with ethyl acetate (21). The product was eluted with 5-8 % 15 methanol / chloroform and the desired was collected to give 2.5 g of a slightly impure orange yellow solid (mp 120-123 °C). The impure product was chromatographed on a Waters Delta Prep 4000 using 1 PrepPak cartridge (Porasil 37-55(am 125A) eluting with 3-5 % methanol / chloroform. The product was collected and dried to give ethyl 8-(4-methyl-l-piperazinyl)-4-oxo-4#-chromene-2-carboxylate as a yellow solid (2.25 g, 70 % yield mp 124-125 °C). 20 GC/MS (EI, M+) m/z 316. <br><br> Reference Example le: 8-(4-methyl-1 -piperazinyi)-4-oxo-4i/-chromene-2-carboxylic acid hydrochloride. <br><br> Ethyl 8-(4-methyl-1 -piperazinyl)-4-oxo-4#-chromene-2-carboxylate as prepared in Reference Example Id (1.01 g. 3.19 mmol) was suspended in 6 M HCI (60 ml) and to reflux 25 for 1.5 h (after 20 min a clear solution was obtained). <br><br> The reaction was allowed to cool. The solution was concentrated in vacuo and anhydrous toluene was added (x3) and the solution was again concentrated in vacuo to give 8-(4-methyl-l-piperazinyl)-4-oxo-4i/-chromene-2-carboxylic acid hydrochloride as a yellow powder (1.02 g, quantitative yield). LC/MS (M+l) m /z 289. <br><br> WO 02/055014 <br><br> -48- <br><br> PCT/SE02/00070 <br><br> Reference Example 2 <br><br> ch <br><br> O <br><br> O <br><br> o. <br><br> OH <br><br> N <br><br> Preparation of 6-Methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxyiic <br><br> 5 Reference Example 2a: Diethyl (2Z)-2-(2-brpmo-4-methoxyphenoxy)-2-butenedioate. <br><br> Ethyl acetylenedicarboxylate (17.8 ml, 0.145 mol) was added to 2-bromo-4-methoxyphenol (Synlettpl241,1997) (27.3 g, 0.134 mol), in anhydrous 2-propanol (55 ml) followed by the addition of a catalytic amount of tetrabutylammonium fluoride (0.4 ml, 1.0 M in THF). The solution was stirred at room temperature overnight and was then heated to 10 reflux for 30 min. Upon cooling a precipitate formed. The solution was cooled and filtered to give diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate as a yellow solid (29.9 g, 62 % yield). Note: the solid contains 10 % of diethyl (2E)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate. GC/MS (EI, M+) m/z 344 and 346. <br><br> Reference Example 2b: (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid. 15 Diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate (29.9 g, 86.6 mmol) as prepared in Reference Example 2a was suspended in ethanol (55 ml) and a solution of sodium hydroxide (7.0 g, 0.175 mol) in water (55 ml) was added. The solution was refluxed for 1 h to give a clear orange solution. Most of the ethanol was removed in vacuo then 6 M HCI (50 ml) was added. The solid was filtered, washed with water and dried to give (2Z)-2-(2-bromo-20 4-me£hoxyphenoxy)-2-butenedidlc acid as a light orange solid (24.3 g, 88 % yield). <br><br> Reference Example 2c: Ethyl-6-methoxy-8-bromo-4-oxo-4H-chromene-2-carboxylate. <br><br> Sulfuric acid (50ml) was added to (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid (24.3g, 86.6 mmol; as prepared in Reference Example 2b above). After heating the mixture with a heat gun for 5-10 min a clear deep brown solution was obtained. This solution was 25 slowly added to refluxing absolute ethanol (250 ml). After the addition the reaction was refluxed for 30 min then allowed to cool. Crystals started to form after 20 min and the reaction was put in the refrigerator overnight. The solid was filtered, washed with cold ethanol/ water acid hydrochloride. <br><br> WO 02/055014 <br><br> -49- <br><br> PCT/SE02/00070 <br><br> 9:1 and dried to give ethyl 8-bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylate as an off-white solid (12.3 g, 50 % yield, mp 159-161 °C). <br><br> Reference Example 2d: Ethyl-6-methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylate. <br><br> 5 Ethyl 8-bromo-4-oxo-4H-cbromene-2-carboxylate (9.2 g, 28.1 mmol), as prepared in <br><br> Example 2c above, was azeotroped with anhydrous toluene then the white solid was dissolved in 300 ml anhydrous toluene in a 500 mL single-neck round bottom flask.. The mixture was degassed by alternating argon sparge and vacuum (3x), and the following were added in order: N-methylpiperazine (4.0 ml, 35.1 mmol), 2,2'-bis (diphenylphosphino)-l,l'-binaphthyl 10 (1.05 g, 1.69 mmol,), tris(dibenzylideneacetone) dipalladium (0) (0.50 g, 0.56 mmol) then cesium carbonate (12.8 g, 39.3 mmol).The mixture was again degassed via alternating argon sparge and vacuum and was heated at 80 °C for 17 h. Additional tris(dibenzylideneacetone) dipalladium (0) (0.10 g, 0.11 mmol) and 2,2'-bis (diphenylphosphino)-l,r-binaphthyl (0.20 g, 0.32 mmol,) was added and the reaction was stirred at 80 °C for another 55 h at which time 15 the conversion was essentially complete. <br><br> The cooled reaction mixture was diluted with tetrahydrofuran (250 mL), filtered and. concentrated under vacuum. The residue was purified by chromatography on a silica column eluted with 2-5 % methanol / chloroform and the desired fractions were collected and concentrated under vacuum and the residue triturated with methylene chloride to. give 7.4 g 20 (76%) of a yellow powder. <br><br> Reference Example 2e: 6-Methoxy-8-(4-Methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid. <br><br> Ethyl-6-methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene -2-carboxylate (1.0 g. 2.89 mmol), as prepared in Reference Example 2d above, was suspended in 6 M HCI (60 ml) 25 and methanol (10 mL) and wanned to reflux for 3.0 h. The reaction was allowed to cool. The solution was concentrated in vacuo and anhydrous toluene was added (x3) and the solution was again concentrated in vacuo. The residue was dried under vacuum (17 h) to yield 6-methoxy-8-(4-methyl-l-piperazinyl)-4-oxo-4tf-chromene-2-carboxylic acid hydrochloride as a yellow powder (1.0 g, quantitative yield). <br><br> 30 Reference Example 3 <br><br> WO 02/055014 <br><br> -50- <br><br> PCT/SE02/00070 <br><br> 6-FIuoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride. <br><br> Reference Example 3a: Diethyl (EZ)-2-(2-bromo-4-fluorophenoxy)-2-butenedioate. 5 This compoimd was synthesized from 2-bromo-4-fluorophenol and diethylacetylenedicarboxylate, using the same synthetic procedures and the same stoichiometry as demonstrated in Reference Example la above. <br><br> Reference Example 3b: (EZ)-2-(2-Bromo-4-fluorophenoxy)-2-butenedioic acid. <br><br> This compound was synthesized from diethyl (EZ)-2-(2-bromo-4-fluorophenoxy)-2-10 butenedioate, as prepared in Reference Example 3a above, using the same synthetic procedures and the same stoichiometry as demonstrated in Reference Example lb above. Reference Example 3c: Ethyl-6-fluoro-8-bromo-4-oxo-4H-chromene-2-carboxylate. <br><br> This compoimd was synthesized from (EZ)-2-(2-bromo-4-fluorophenoxy)-2-butenedioic acid, as prepared in Reference Example 3b above, using the same synthetic 15 procedures and the same stoichiometry as demonstrated in Reference Example lc above. Reference Example 3d: Ethyl-6-fluoro-:8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from ethyl-6-fluoro-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 3c above, using the same synthetic 20 procedures and the same stoichiometry as demonstrated in Reference Example Id above. Reference Example 3e: 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride. <br><br> This compound was synthesized starting from ethyl-6-methoxy-8-(4-MethyI-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylate, as prepared in Example 3d, using the 25 same synthetic procedures and the same stoichiometry as demonstrated in Reference Example le above. <br><br> WO 02/055014 <br><br> -51- <br><br> PCT/SE02/00070 <br><br> Reference Example 4 <br><br> OH <br><br> Preparation 6-Methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride. <br><br> 5 Reference Example 4a: Diethyl (E,Z)-2-(2-bromo-4-methylphenoxy)-2-butenedioate. 2-Brorao-4-methyl phenol (10 mL, 83mmol) was dissolved in diethyl ether (90 mL). To this was added dropwise triethyl amine (13.7 mL, 98mmol) followed by dimethyl acetylene dicarboxylate (11.2 mL, 91mmol). The resulting mixture was stirred overnight at room temperature. The reaction was worked up by adding diethyl ether (200 mL) and 10 tetrahydrofuran (50 mL) and washing the resulting mixture with IN HCI (200 mL), water (200 mL) and brine (100 mL). The organic phase was then dried (Na2SC&gt;4), filtered and concentrated to a red-brown oil which was used without further purification. <br><br> Reference 4b: (2E,Z)-2-(2-Bromo-4-fluorophenoxy)-2-butenedioic acid. <br><br> This compound was synthesized from diethyl (E,Z)-2-(2-bromo-4-methylphenoxy)-2-15 butenedioate,. as prepared in Reference Example 4a above, using the same synthetic procedures and the same stoichiometry as demonstrated in Example lb above. <br><br> Reference Example 4c: Ethyl-6-methyl-8-bromo-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from (2Z)-2-(2-bromo-4-methylphenoxy)-2-biSenedioic acid, as prepared in Reference Example 4b above, and using the same synthetic 20 procedures and the same stoichiometry as demonstrated in Reference Example lc above. Reference Example 4d: Ethyl-6-methyl-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from ethyl-6-methyl-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 4c above, using the same synthetic procedures 25 and the same stoichiometry as demonstrated in Reference Example Id above. <br><br> WO 02/055014 <br><br> -52- <br><br> PCT/SE02/00070 <br><br> Reference Example 4e: 6-Methyl-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-cbromene-2-carboxylic acid hydrochloride. <br><br> This compound was synthesized starting with ethyl-6-methyl-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 4d, using the same synthetic procedures and the same stoichiometry as demonstrated in Reference Example le above. <br><br> Reference Example 5 <br><br> acid hydrochloride. <br><br> Reference Example 5a: Diethyl (E,Z)-2-(2-bromo-4-chlorophenoxy)-2-butenedioate. <br><br> This compound was prepared from 2-bromo-4-chloro phenol and dimethyl acetylenedicarboxylate by the same synthetic procedures and in the same stoichiometry as the preparation described in Reference Example 4a. <br><br> Reference Example 5b: (2E,Z)-2-(2-Bromo-4-chlorophenoxy)-2-butenedioic acid.. <br><br> This compound was synthesized from diethyl (E,Z)-2-(2-bromo-4-chlorophenoxy)-2-butenedioate, as prepared in Reference Example 5a above, as using the same synthetic procedures and the same stoichiometry as demonstrated in Reference Example lb above. Reference Example 5c: Ethyl-6-chloro-8-bromo-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from (2E',Z)-27(2-bromo-4-chlorophenoxy)-2-butenedioic acid, as prepared in Reference Example 5b above, using the same synthetic procedures and the same stoichiometry as . demonstrated in Example 1c above. <br><br> Reference Example 5d: Ethyl-6-chloro-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylate. <br><br> WO 02/055014 <br><br> -53- <br><br> PCT/SE02/00070 <br><br> This compound was synthesized from ethyl-6-ch!oro-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 5c above, using the same synthetic procedures and the same stoichiometry as demonstrated in Example Id above. <br><br> Reference Example 5e: 6-Chloro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-5 carboxylic acid hydrochloride. <br><br> This compound was synthesized starting with ethyl-6-chloro-8-(4-methyI-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylate, prepared in Reference Example 5d above, using fee same synthetic procedures and the same stoichiometry as demonstrated in Reference Example le above. <br><br> 10 Reference Example 6 <br><br> Preparation of 5-Methyl-8-(4-methyI-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride <br><br> Reference Example 6a: Diethyl (E,Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioate. 15 This compound was prepared from 2-chloro-5-methylphenol and dimethyl acetylenedicarboxylate by the same synthetic procedures and in the same stoichiometry as the. preparation described in Reference Example la. <br><br> Reference Example 6b: (2E,Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioic acid. <br><br> This compound was synthesized from diethyl (E,Z)-2-(2-chloro-5-methylphenoxy)-2-20 butenedioate, as prepared in Reference Example 6a above, using the same synthetic procedures and the same stoichiometry as demonstrated in Reference Example lb above. Reference Example 6c: Ethyl-5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from (2Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioic acid, as prepared in Reference example 6b, using the same synthetic procedures 25 and the same stoichiometry as demonstrated in Reference Example lc above. <br><br> WO 02/055014 <br><br> -54- <br><br> PCT/SE02/00070 <br><br> Reference Example 6d: Ethyl-5-methyl-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-caiboxylate. <br><br> Ethyl 5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylate (1.0 g, 3.6 mmol) as prepared in Reference Example 6c above, was azeotroped with anhydrous toluene then the 5 white solid was dissolved in 100 ml anhydrous toluene in a 250 mL single-neck round bottom flask.. The mixture was degassed by alternating argon sparge and vacuum (3x), and the following were added'in order: N-methylpiperazine (0.6 ml, 5.37 mmol), (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (JACS 1998,120, p9722) (40 mg, 0.1 mmol,), tris(dibenzylideneacetone) dipalladium (0) (66 mg, 0.072 mmol) then cesium 10 carbonate (1.6 g, 5.37 mmol).The mixture was again degassed via alternating argon sparge and vacuum and was heated at 80 °C for 17 h. Additional tris(dibenzylideneacetone) dipalladium (0) (66 mg, 0.072 mmol) and (2'-dicyclopentylphosphanyl-biphenyl-2-yl)-dimelhyl-amiiie (40 g, 0.1 mmol,) were added and the reaction was stirred at 80 °C for another four days at which time the conversion was still only about 50% complete by HPLC. 15 Tetrahydrofuran (100 mL) was added, and the combined mixture was filtered, concentrated under vacuum and purified by chromatography on silica eluted with 2.5% methanol in chloroform. The desired fractions were concentrated under vacuum to yield a yellow powder . (250 mg = 21%)! <br><br> Reference Example 6e: 5-Methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-20 carboxylic acid hydrochloride. <br><br> This compound was synthesized starting with ethyl-5-methyl-8 -(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 6d, and using the same synthetic procedures and the same stoichiometry as demonstrated in Example le above. Reference Example 7 <br><br> h3c o o <br><br> AA <br><br> ,N <br><br> o oh hci n' <br><br> WO 02/055014 <br><br> -55- <br><br> PCT/SE02/00070 <br><br> Preparation of 5-Methoxy-8-(4-methyI-piperazin-l-yI)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride. <br><br> Reference Example 7a: (E,Z)-2-(2-Bromo-5-methoxyphenoxy)-2-butenedioate. <br><br> This compound was prepared from 2-bromo-5-methoxyphenol and dimethyl 5 acetylenedicarboxylate by the same synthetic procedures and in the same stoichiometry as the preparation described in Reference Example 1 a. <br><br> Reference Example 7b: (E,Z)-2-(2-Bromo-5-methoxyphenoxy)-2~butenedioic acid. <br><br> This compound was synthesized from diethyl (E,Z)-2-(2-bromo-5-methoxyphenoxy)-2-butenedioate, as prepared in Reference Example 7a, using the same synthetic procedures 10 and the same stoichiometry as demonstrated in Reference Example lb above. <br><br> Reference Example 7c: Ethyl-5-methoxy-8-bromo-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from (E,Z)-2-(2-bromo-5-methoxyphenoxy)-2-butenedioic acid, as prepared in Reference Example 7b above, using the same synthetic procedures and the same stoichiometry as demonstrated in Reference Example lc above. <br><br> 15 Reference Example 7d: EthyI-5-methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylate. <br><br> This compound was synthesized from ethyl-5-methoxy-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 7c above, using the same synthetic . procedures and the same stoichiometry as demonstrated in Reference Example Id above. 20 Reference Example 7e: 5-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride. <br><br> This compound was prepared from ethyl-5-methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylate, as prepared in Reference Example 7d above, using the same method as the preparation in 1 e. <br><br> 25 Reference Example 8 ^ <br><br> °y-ch3 <br><br> 0&gt;v&gt; : <br><br> Preparation of l-(6-Piperazin-l-yI-2,3-dihydro-indol-l-yl)-ethanone Reference Example 8a: l-[5-(4-Benzyl-piperazin-l-yl)-2,3-dihydro-indol-l-yl]-ethanone. l-acetyl-5-bromoindoline (3.0 g, 12.5mmol) was dissolved in toluene (60 mL). To 30 this was added, sodium t-butoxide (1.68 g, 17.5mmol), N-benzylpiperazine (2.4 mL, <br><br> WO 02/055014 <br><br> -56- <br><br> PCT/SE02/00070 <br><br> 13.8mmol), S-BINAP (0.93 g, I.5mmol) and Pd2(dba)3 (0.46 g, 0.5mmol). The mixture was degassed via three cycles of vacuum and nitrogen sparge and then stirred at 95°C until GC analysis confirmed that the reaction was complete (1 h). The mixture was diluted with ethyl acetate (150 mL), washed with water and extracted with 2N HCI (2 x 100 mL). The 5 combined aqueous extract was basified with concentrated ammonium hydroxide and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was dried (MgSO,*) and concentrated to yield a solid (2.7 g) which was purified by chromatography to yield a white -solid (1.81 g, 43%). Mp= 150.5-152.8°C. <br><br> Reference Example 8b: 1 -(6-Piperazin-1 -yl-2,3-dihydro-indol-1 -yl)-ethanone. <br><br> 10 l-[5-(4-Benzyl-piperazin-l-yl)-2,3-dihydro-indol-l-yl]-ethanone (0.37 g, l.lmmol), as prepared in Reference Example 8a above, was dissolved in methanol (5 mL). Pd/C (90 mg, 10%) and ammonium formate (0.9 g, 14mmol) was added and the resulting mixture was heated to 65°C for two hours. The mixture was filtered and the filter cake washed with hot methanol. The combined filtrate was concentrated to yield the desired product (0.26 g, 90%). <br><br> 15 Reference Example 9 <br><br> NC <br><br> ci—tK&gt; <br><br> Preparation of 2-chloro-5-piperazin-l-yl benzonitrile. <br><br> Reference Example 9a: 3-Cyano-4-chloroaniline. <br><br> 2-Chloro-5-nitrobenzonitrile (25 g, 137mmol) was dissolved in ethanol (275 mL). <br><br> 20 Stannous chloride dihydrate (154.5 g, .685 M) was added and the mixture stirred at 70°C for <br><br> 30 min. The mixture was then cooled to room temperature and poured into crushed ice. The mixture was made basic with solid sodium hydroxide. This mixture was extracted with ethyl acetate (3 x 100 mL). The extracts were combined, washed with brine, dried (MgSCU), concentrated and the residue dried under vacuum and recrystallized from ethanol to. yield light <br><br> 25 brown needles (10.6 g, 51%). <br><br> Reference Example 9b: 2-chloro-5-piperazin-l-yl benzonitrile. <br><br> 3-Cyano-4-chloroaniline (10.1 g, 66mmol), as prepared in Reference Example 9a, was dissolved in n-butanol (300 mL) bis-(2-chloroethyl)amine hydrochloride (23.2 g, 130mmol) and potassium iodide (50 mg, catalytic) were added. The mixture was heated at reflux for <br><br> 30 three days, then cooled in a refrigerator overnight. A solid precipitate was collected by filtration, washed with cold n-butanol and dried. The crude product was distributed between <br><br> WO 02/055014 <br><br> -57- <br><br> PCT/SE02/00070 <br><br> methylene chloride and 2N ammonium hydroxide. The organic layer was separated, dried (Na2SC&gt;4) and concentrated to yield a light yellow solid (9.1 g, 59%) which gave a single peak by GC and TLC analysis. <br><br> Reference Example 10 <br><br> Preparation of 4-[l,2,3]thiadiazol-5-yl-phenylamine. <br><br> SnCl2 ' H2O (3.21 g, 5 eq) was added to a slurry of (5-(4-Nitrophenyl)-1,2,3- <br><br> thiadiazole (Lancaster Synthesis) (0.59 g, 2.8 mmol) in absolute EtOH (50 mL) and the reaction heated to 70° C for 2 h. The reaction was allowed to cool to room temperature and 10 pour into saturated NaHCC&gt;3 and ice. The product was extracted with EtOAc (2X) the solution dried (MgSC&gt;4) and evaporated to dryness in vacuo to yield 0.47 g of a light yellow solid mp 126-128° C. <br><br> Reference Example 11 <br><br> h2n—f~yv x==/ v-/ CH3 <br><br> 15 Preparation of l-[4-(4-Amino-phenyl)-piperazin-l-yI]-ethanone. <br><br> Reference Example 11a: 4-(4-Nitrophenyl)-l-acetylpiperazine. <br><br> l-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2,0 ml, 14.5 mmol) was added and the reaction was cooled to 0°C. Acetic anhydride (1.25 ml, 13.3 mmol) was added dropwise and the reaction was stirred at 0 20 °C for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (x3) with dichloromethane, dr^d (MgSC&gt;4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-l-acetylpiperazine as a yellow solid (3.01 g,).GC/MS (EI, M+) m/z = 249. Reference Example lib: l-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethanone. 4-(4-Nitrophenyl)-1 -acetylpiperazine (3.0 g, 12.0 mmol), as prepared in Reference Example 25 11a above, was mixed in methanol (100 ml) and 2 M ammonia in methanol (50 ml) and 10 % palladium on carbon (300 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1.5 h. <br><br> The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo.. The crude solid was recrystallized from ethyl acetate to give 4-(4- <br><br> WO 02/055014 <br><br> -58- <br><br> PCT/SE02/00070 <br><br> acetyl-l-piperazinyl)benzenamine as a light purple solid (1.86 g, 70 % yield, mp 149.5-150.5 °C). GC/MS (EI, M+) m/z = 219 Reference Example 12 <br><br> X=z/ V-^ CH3 <br><br> 5 . Preparation of 4-(4-methanesulfonyI-piperazin-l-yl)-phenylamine <br><br> Reference 12a: 4-(4-Nitrophenyl)-l-methylsulfonylpiperazine. <br><br> 1 -(4-Nitrophenyl)piperazine (2.79 g, 13.5 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.25 ml, 16.2 mmol) was added and the reaction was cooled to 0 °C. Methanesulfonyl chloride (1.15 ml, 14,9 mmol) was added dropwise and the reaction was 10 stirred at 0 °C for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (x3) with dichloromethane, dried (MgS04), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-l-methylsulfonylpiperazine as a yellow solid (3.83 g, quantitative yield). GC/MS (EI, M+) m/z = 285. <br><br> Reference Example 12b: 4-(4-methanesulfonyl-piperazin-1 -yl)-phenylamine. 15 4-(4-Nitrophenyl)-l-methylsulfonylpiperazine (3.83 g, 13.4 mmol), as prepared in <br><br> Reference Example 12a above, was mixed in methanol (100 ml) and 2 M ammonia in methanol (50 ml) and 10 % palladium on carbon (400 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 3 h. <br><br> The reaction was allowed to cool, the catalyst was filtered, washed with methanol then 20 washed with chloroform. The chloroform portion contained a minor amount of the desired but looked purer. The chloroform portion was concentrated in vacuo and was recrystallized ethyl acetate to give 4-[4-(methylsulfonyl)-l-piperazinyl]benzenamine as a shiny brown solid (0.94 g, 27 % yield, mp 192-193 °C). GC/MS (EI, M+) m/z = 255. <br><br> Reference Example 13 <br><br> h2n <br><br> 25 <br><br> Preparation of 4-ThiomorphoIin-4-yi-phenyIamine: <br><br> Reference Example 13a: 4-(4-Nitro-phenyl)-thiomorpholine. <br><br> 4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). Thiomoipholine (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100 °C. At 17 h, the 30 mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 <br><br> WO 02/055014 <br><br> -59- <br><br> PCT/SE02/00070 <br><br> mL). The organic layer was separated, dried (Na2S04), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid. <br><br> Reference Example 13b: 4-Thiomorpholin-4-yl-phenylamine. <br><br> 4-(4-Nitro-phenyl)-thiomorpholine(3.0g, 13.4 mmol), as prepared in Reference 5 Example 13a above, was dissolved in ethanol (250 mL) and 10% palladium on carbon (250 mg) was added. This mixture was shaken on a Parr hydrogenator for 3 h. The reaction mixture was then filtered through diatomaceous earth and concentrated under vacuum. The residue was triturated with'hexane to yield an gray solid (2.1 gj). <br><br> Reference Example 14 <br><br> 10 <br><br> Preparation of l-(4-Amino-phenyI)-l-morpholin-4-yl-methanone. <br><br> Reference Example 14a; l-Morpholin-4-yl-l-(4-nitro-phenyl)-methanone: <br><br> 4-Nitrobenzoyl chloride (5 g, 27 mmol) in tetrahydrofuran (10 mL) was added slowly to a solution of morpholine (5g, 88 mmol) and triethylamine (2.7 g, 27 mmol) in 15 tetrahydrofuran (50 mL), and stirred at room temperature for four hours. Ethyl acetate (200 mL) was added to the mixture and the combined mixture was washed with water (25 mL), IN HCI (25 mL), water (25 mL), saturated sodium bicarbonate (25 mL), water (25 mL) and brine (25 mL). The mixture was dried (Na2S04), filtered and concentrated under vacuum and the residue used without further purification. <br><br> 20 Reference Example 14b: 1-(4-Amino-phenyl)-l-moipholin-4-yl-methanone. <br><br> This compound was prepared from 1 -morpholin-4-yl-1 -(4-nitro-phenyl)-methanone as prepared in Reference Example 13b. <br><br> Reference Example 15 <br><br> 25 Preparation of 5-Amino-2-morpholin-4-yl-benzonitrile <br><br> Reference Example 15a: 2-Morpholin-4-yl-5-nitro-benzonitrile. <br><br> 3-Cyano-4-fluoronitrobenzene (3.3 g, 19.9 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (3.5 mL, 20 mmol) <br><br> WO 02/055014 <br><br> -60- <br><br> PCT/SE02/00070 <br><br> were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL)-, dried (TSfeSC^), filtered and concentrated under vacuum. The residue was used without further purification. <br><br> 5 Reference Example 15b: 5-Amino-2-morpholin-4-yl-benzonitrile <br><br> This compound was prepared from 2-Moipholin-4-yl-5-nitro-benzonitrile (as prepared <br><br> Reference Example 16a: 4-(2-Fluoro-4-nitro-phenyl)-moipholine. <br><br> 3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 15 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (NaaSCU), filtered and concentrated under vacuum. The residue was used without further purification. <br><br> Reference Example 16b: 3-Fluoro-4-morpholin-4-yl-phenylamine. <br><br> ■ This compoimd was prepared from 4-(2-Fluoro-4-nitro-phenyl)-morpholine, (as prepared in 20 Reference Example 16a above) as prepared in Reference Example 13b. <br><br> Reference Example 17 <br><br> Reference Example 17a: 4-(4-Nitro-phenyl)-piperazine-l-carboxylic acid tenf-butyl ester. <br><br> 25 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in etihyl acetate (25 mL). Piperazine-1-carboxylic acid ferf-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65 °C for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water in Reference Example 15a above), as prepared in Reference Example 13b. Reference Example 16 <br><br> F <br><br> 10 <br><br> Preparation of 3-Fluoro-4-morpholin-4-yl-phenylamine <br><br> WO 02/055014 <br><br> -61- <br><br> PCT/SE02/00070 <br><br> (25 mL) Mid brine (25 mL), dried (Na2S04), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77%). <br><br> Reference Example 17b: 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. 4-(4-Amino-phenyl)-piperazine-l-carboxylic acid ferf-butyl ester was prepared from 5 4-(4-Nitro-phenyl)-piperazine-l-carboxylic acid terf-butyl ester, (as prepared in Reference Example 17a) as prepared in Reference Example 13b. <br><br> Reference Example 18 <br><br> Preparation of 3-Morpholin-4-yl-phenylamine 10 Reference Example 18a: 4-(3-Nitro-phenyl)-morpholine. <br><br> 3-Fluoronitrobenzene (10 g, 71 mmol) was dissolved in acetonitrile (100 mL). Morpholine (30 mL, 350 mmol) was added and the mixture was reacted 18 h at 150 °C/80psi in a pressure reactor. The reaction was cooled to room temperature, concentrated under vacuum and 5 g of the total mixture was purified by column chromatography on silica eluted 15 withCHaCla. The product (3.6 g) was isolated as a bright yellow oil. <br><br> Reference Example 18b: 3-Morpholin-4-yl-phenylamine <br><br> 3-Moipholin-4-yl-phenylamine was prepared from 4-(3-Nitro-phenyl)-morpholine, (as prepared in Reference Example 18a), as prepared in Reference Example 13b. <br><br> Reference Example 19 <br><br> Reference Example 19a: 2[4-(4-nitrophenyl)piperazine-l-yl]-ethanol. <br><br> 2[4-(4-nitrophenyl)piperazine-1 -yl]-ethanol is prepared from commercially available 4-fluoronitrobenzene (Aldrich) and commercially available N-(2-hydroxyethyl)piperazine 25 (Aldrich) via the same procedure as described in Reference Example 13a above. <br><br> Reference Example 19b: 2-[4-(4-amino-phenyl)-piperazin-l -yl]-ethanol. <br><br> 2-[4-(4-amino-phenyl)-piperazin-l-yl]-ethanol is prepared by catalytic hydrogenation of 2[4-(4-nitrophenyl)piperazine-l-yl]-ethanol (prepared as in Reference Example 19a) as described in Reference Example 13b <br><br> 20 <br><br> Preparation of 24 4-(4-amino-phenyI)-piperazin-l-yI]-ethanol. <br><br> WO 02/055014 <br><br> -62- <br><br> PCT/SE02/00070 <br><br> n.A <br><br> Reference Example 20 <br><br> H2N—y—O <br><br> Preparation of 4-MorphoIin-4-vl-phenylamine. <br><br> 4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster Synthesis) was 5 suspended in methanol (130 ml) and 2 M ammonia in methanol (70 mL) and 5 % palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. The crude solid was recrystallized from ethyl acetate / hexane to give 4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70 % yield, mp 132-133 °C). <br><br> 10 GC/MS (EI, M+) m/z = 178. <br><br> Reference Example 21 <br><br> HO <br><br> Preparation of 4-Amino-3-hydroxyphenylmorpholine <br><br> 4-Nitro-3- hydroxyphenylmoipholine (Maybridge Chemical) (3.34 g, 14.9mmol) was 15 dissolved in 59 ml of ethanol at 30°C. The mixture was stirred at 25°C and treated with tin (II) chloride dihydrate (16.8 grams, 74.5mmol) with stirring. The yellow suspension was heated to reflux over a 30 minute period. TLC showed reaction progress over several hours. The mixture was refluxed for 18 hours, cooled to room temperature, and concentrated to remove most of the ethanol to give a yellow slurry. The mixture was treated with saturated 20 aqueous sodium bicarbonate until it was basic. The mixture was extracted with ethyl acetate, ~r filtered, and the organic layer was separated. The aqueous layer was extracted twice more with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered, and concentrated to give 1.02 grams of a puiple solid. Proton NMR and CI mass spectral analyses were consistent for the desired product (m/z =195 base peak by positive ion CI and m/z =193 25 base peak by negative ion CI). <br><br> WO 02/055014 <br><br> -63- <br><br> PCT/SE02/00070 <br><br> Reference Example 22 <br><br> O <br><br> O <br><br> T 0 I <br><br> O ' <br><br> o <br><br> % <br><br> Preparation of 6-Methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4JHr-chromene-2- <br><br> carboxylic acid <br><br> 5 . Reference Example 22a: 6-Methoxy-8-(4-methyl- [l,4]diazepan-1 -yl)-4-oxo-4ff-chromene-2-carboxylic acid ethyl ester. <br><br> Into a 250 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 1.5 g (4.59 mmol, 1.0 equiv.) of 8-Bromo-6-methoxy-4-oxo-4#-chromene-2-carboxylic acid ethyl ester (Reference Example 2c), 84 mg (0.092 mmol, 10 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 342 mg (0.55 mmol, 0.12 equiv.) of racemic 2,2'-bis(diphenylphosphino)-l,r-binapthyl and 2 g of 4 A molecular sieves. To this suspension is added 150 mL of dry toluene. To the stirred suspension is then added 628 mg, 684 jjL, (5.50 mmol, 1.2 equiv.) of 1-methylhomopiperazine, followed by 2.05 g (6.3 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80 °C for 3 days. At the end of • 15 this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 20% methanol in methylene chloride as eluent, yielded 1.0 g, (60%) of the desired product. <br><br> 20 Mass Spec.: calc. for [C19H24N2O5+H3' Theor. m/z = 361; Obs. = 361 <br><br> Reference Example 22b: 6-Methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4if-chromene-2-carboxylic acid. <br><br> Into a 125 mL erlenmeyer equipped with a magnetic stirrer is placed 319 mg (0.89 mmol, 1.0 equiv.) of 6-Methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4if-chromene-2-25 carboxylic acid ethyl ester. This material is dissolved in 30 mL of THF, then 30 mL of methanol are added. To this stirring solution is added 30 mL of a water containing 41 mg (0.97 mmol, 1.1 equiv.) of lithium hydroxide. This mixture is stirred at room temperature for <br><br> WO 02/055014 <br><br> -64- <br><br> PCT/SE02/00070 <br><br> 2 hr. Completion of the reaction is monitored by LC/MS, then 10 mL of 2N HCI is added. This mixture is then concentrated, dried and triturated with ether to give the product as the hydrochloride salt in quantitative yield. <br><br> Mass Spec.: calc. for [CnH2oN205+H]+ Theor. m/z = 333; Obs. = 333 5 Reference Example 23 <br><br> Preparation of 6-Ethoxy-8-(4-methyl-piperazin-l-yl)-4-oxo~4/2r-chroinene-2-carboiiyl chloride <br><br> Reference Example 23a: 8-Bromo-6-hydroxy-4-oxo-4i/-chromene-2-carboxylic acid ethyl 10 ester: <br><br> The hydroxy compound, 8-Bromo-6-hydroxy-4-oxo-4#-chromene-2-carboxylic acid ethyl ester, is formed as a side product during the synthesis of 8-Bromo-6-methoxy-4-oxo-4ff-chromene-2-carboxylic acid ethyl ester. It can be separated from the crude methoxy compound by flash chromatography using a step gradient of 20% ethyl acetate in methylene 15 chloride to the same solvent containing 2% methanol. The hydroxy compound, which elutes last, is concentrated to give the pure compound. Mass Spec.: calc. for [Ci2HgBr05+H]+ <br><br> Theor. m/z = 313,315; Obs. = 313, 315 <br><br> Reference Example 23b: 8-Bromo-6-ethoxy-4-pxo-4i/-chromene-2-carboxylic acid ethyl ester: <br><br> 20 Into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is added 700 mg (2.24 mg, 1.0 equiv.) of 8-Brdmo-6-hydroxy-4-oxo-4ff-chromene-2-carboxylic acid ethyl ester (Reference Example 23 a). This material is dissolved in 50 mL of toluene, then 689 mg, 586 fiL (4.47 mmol, 2.0 equiv.) of diethyl sulfate and 309 mg (2.24 mmol, 1.0 equiv.) of K2CO3 were added. The reaction was then heated to 25 reflux for 24 hr. At the end of this time, monitoring by LC/MS reveals that the reaction is &gt;than 95% complete. The reaction is then cooled, 100 mL of ethyl acetate is added and the organic layer is washed with 0.5N HCI solution, dried over Na2S04, filtered and concentrated. The residues were subjected to flash chromatography, using 40% ethyl acetate in hexane as . <br><br> WO 02/055014 <br><br> -65- <br><br> PCT/SE02/00070 <br><br> eluent. The purified fractions were concentrated to yield 500 mg (65%) of a colorless solid. <br><br> Mass Spec.: calc. for [Ci4Hi3BrOs+H]+ Theor. m/z = 341,343; Obs. = 341,343 Reference Example 23c: 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4ff-chromene-2-carboxylic acid ethyl ester: <br><br> 5 Into a 1 OOmL, 3 neck round bottom flask equipped with a reflux condenser, magnetic <br><br> ■ stirrer and nitrogen inlet is added 350 mg (1.03 mmol, 1.0 equiv.) of 8-Bromo-6-ethoxy-4-oxo-4i?-chromene-2-carboxylic acid ethyl ester (Reference Example 23b), 18.9 mg (0.02 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 77 mg (0.123 mmol, 0.12 equiv.) of racemic 2,2'-bis(diphenylphosphino)-l,r-binapthyl and lg of 4 A molecular sieves and 60 10 mL of dry toluene. To the stirred suspension is then added 113 mg, 1255 |iL, (1.13 mmol, 1.1 equiv.) of 1 -methylpiperazine, followed by 470 mg (1.44 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80 °C for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous 15 earth, with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 40% methanol in methylene chloride as eluent, <br><br> yielded 350 mg (75%) of the desired product as a yellow solid. Mass Spec.: calc. for [Ci9H24N205+Hf Theor. m/z = 361; Obs. = 361 <br><br> Reference Example 23d: 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4i/-chromene-2-20 carboxylic acid: <br><br> Into a 125 mL Erlenmeyer equipped with a magnetic stirrer is placed 500 mg (1.39 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4i7-chromene-2-carboxylic -acid ethyl ester (Reference Example 23c). This material is dissolved in 30 mL of THF, then 30 mL of methanol are added. To this stirring solution is added 30 mL of a water containing 25 64.2 mg (J[ .53 mmol, 1.1 equiv.) of lithium hydroxide. This mixture is stirred at room . temperature for 2 hr. Completion of the reaction is monitored by LC/MS, then 10 mL of 2N HCI is added. This mixture is then concentrated, dried and triturated with ether to give the product as the hydrochloride salt in quantitative yield. <br><br> • Mass Spec.: calc. for [CnHzoNaQs+H]"1" Theor. m/z = 333; Obs. = 333 30 Reference Example 23e: 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4#-chromene-2-carbonyl chloride: <br><br> Into a 100 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin- <br><br> WO 02/055014 <br><br> -66- <br><br> PCT/SE02/00070 <br><br> l-yl)-4-oxo-4J¥-chromene-2-carboxylic acid hydrochloride salt (Reference Example 23d) and 20 mL of methylene chloride. To the stirring suspension is then added 129.5 mg, 164 L(1.02 mmol, 1.5 equiv.) of oxaiyl chloride followed by addition of one drop of DMF from a 50 microliter syringe to act as catalyst. The mixture is stirred.for 2 hours, then concentrated 5 to dryness on a rotary evaporator under a nitrogen atmosphere, followed by drying under high ' vacuum. The completeness of the reaction was ascertained by analysis of an aliquot, which was quenched with a THF solution of methylamine, by LC/MS. The crude material was used as obtained in the subsequent amidation reaction. <br><br> Reference Example 24 <br><br> Preparation of 8-Bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2- <br><br> carboxylic acid methyl ester. <br><br> Reference Example 24a: 2-(2-Bromo-4-methoxy-phenylamino)-but-2-enedioic acid dimethyl ester. <br><br> 15 A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol) in 125 mL anhydrous methanol was treated with dimethyl acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was heated at reflux under nitrogen for 8 hours. The reaction mixture was cooled, concentrated, and redissolved in hot methanol. Yellow crystals were obtained by filtration (6.93 g, 68%). A second crop of crystals was obtained from ethanol (0.942 g, 9%). The 20 filtrates were combined and purified by flash chromatography on silica gel using 4:1 <br><br> hexanesiethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%. 'H HMR (300 MHz, DMSO, d«) 8 9.60 (s, 1 H, NH), 7.26 (d, 1 H, Jm= 2.7 Hz, Artts), 6.93 (dd, 1 H, J0= 8.7, Jm= 2.7 Hz, ArHs), 6.87 (d, 1 H, J0= 8.7 Hz, ArHg), 5.34 (s, 1 H, C=CH), 3.76 (s, 3 H, OCHs), 3.68 (s, 3 H, CHCO2CH3), 3.66 (s, 3 H, CNCO2CH3); Mass Spec.: calc. for 25 [Ci3Hi4BrN05+Hf Theor. m/z = 344,346; Obs. 344,346. <br><br> Reference Example 24a: 8-Bromo-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid methyl ester. <br><br> Dow-Therm (175 mL) was heated to 244 °C and the 2-(2-bromo-4-methoxy-phenylamino)-but-2-enedioic acid dimethyl ester (9.50 g, 27.6 mmol) was added as a solid in <br><br> WO 02/055014 <br><br> -67- <br><br> PCT/SE02/00070 <br><br> portions over 7 minutes while maintaining a temperature of 230-240 °C. The brown reaction mixture was heated at 240-245 °C for 45 minutes and then cooled to room temperature. A yellow precipitate formed upon cooling. Approximately 100 mL of hexanes were added to the mixture and the solids were isolated by filtration, washed with additional hexanes, and 5 dried under high vacuum to afford the product as a yellow solid (6.73 g, 78%). ]H NMR (300 MHz, DMSO, d«) 8 12.01 (s, 1 H, NIT), 7.86 (d, 1 H, 2.7 Hz, ArHj), 7.52 (s, 1 H, C=CH), 7.48 (d, 1 H, Jm~ 2.7 Hz, ArH7), 3.93 (s, 6 H, OCH3 and CO2CH3); Mass Spec.: calc. for [C]2Hi0BrNO4+H]+ Theor. m/z = 312,314; Obs. 312,314. <br><br> Reference Example 24c: 8-Bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-10 quinoline-2-carboxylic acid methyl ester. <br><br> A brown solution of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (6.73 g, 21.6 mmol) in 100 mL N-methyl pyrolidinone was treated with sodium hydride (60% dispersion in oil, 1.028 g, 25.7 mmol). Gas evolution and warming were observed. The reaction was stirred for 10 minutes at room temperature under 15 nitrogen. Addition of 2-(trimethylsilyl)ethoxymethyl chloride (5.00 mL, 28.3 mmol) resulted in a slightly cloudy, light brown solution. After 2.5 hours at room temperature, the reaction mixture was poured into 800 mL water and stirred for 15 minutes. The resulting cream colored precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the product as a cream colored solid (9.70 g, quantitative yield). !H NMR . 20 (300 MHz, DMSO, d«) 8 7.976 (d, 1 H, Jm= 2.7 Hz, ArH7), 7.79 (s, 1 H, C=CH), 7.53 (d, 1 H, Jm= 2.7 Hz, ArHs), 5.70 (s, 2 H, OCHjO), 3.99 (s, 6 H, OCH3 and CO2CH3), 3.88 (t, 2 H, J= 8.0 Hz, OCH2CH2Si), 0.97 (t, 2 H, J= 8.0 Hz, OCH2CH2Si),), -0.04 (s, 9 H, Si(CJh) 3; Mass Spec.: calc. for [Cig^+BrNOsSi+H]* Theor. m/z = 442,444; Obs. 442,444. <br><br> Reference Example 25 <br><br> Preparation of 6-Methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-l,4-dihydro-quinolme- <br><br> 2-carboxylic acid. <br><br> WO 02/055014 <br><br> -68- <br><br> PCT/SE02/00070 <br><br> Reference Example 25a: 6-Methoxy-8-(4-methyl-[ 1,4]diazepan-1 -yl)-4-(2-trimethylsilanyl-. ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester. <br><br> To a clear, light brown solution of 2-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.01 g, 2.28 mmol), N-5 methylhomopiperazine (0.32 mL, 2.57 mmol), and 4 A sieves in 30 mL anhydrous toluene was added Pd2 (dba) 2 (43.8 mg, 0.048 mmol) and BINAP (169.8 mg, 0.27 mmol). The resulting wine colored solution was treated with cesium carbonate (1.124 g, 3.45 mmol). The reaction mixture was heated at reflux under nitrogen for 21 hours. The pea green reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified 10 by flash chromatography on silica gel using a gradient of 95:5 to 40:60 methylene chloride: methanol to afford the desired product as a yellow foam (1.004 g, 92%). 'H NMR (300 MHz, DMSO, dg) 8 7.67 (s, 1 H, ArHs), 6.94 (d, 1 H, Jm= 2.4 Hz, ArHs), 6.66 (d, 1 H, Jm= 2.4 Hz, ArH7), 5.60 (s, 2 H, OCHjO), 3.94 (s, 3 H, CO2CH3), 3.88 (s, 3 H, OCH3), 3.82 (t, 2 H, J= 8.0 Hz, OCHjCHzSi), 3.75 (bs, 4 H, ArNCH2CH2CH2NCH3 &amp; ArNCH2CH2N-CH3), 3.45 (bs, 2 15 H, ArNCH2CH2NCH3), 3.31 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.83 (s, 3 H, NCH3), 2.28 (bs, 2 H ArNCH2CH2 CH2NCH3), 0.92 (t, 2 H, J= 8.0 Hz, OC^C&amp;Si), -0.04 (s, 9 H, Si(C H3) 3; Mass Spec.: calc. for [C^^NsOsSi+H]* Theor. m/z = 476; Obs. 476. <br><br> Reference Example 25b: 6-Methoxy-8-(4-methyl-[ 1,4] diazepan-1 -yl)-4-oxo-1,4-dihydro- . quinoline-2-carboxylic acid. <br><br> 20 To a light brown solution of 6-methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-(2- <br><br> trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.00 g, 2.10 mmol) in 18 mL 3:1:1 tetrahydrofiiran:methanol:water was added lithium hydroxide monohydrate (0.267 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 5 hours, acidified to pH 4 with 1N HCI, and stirred an additional 20 minutes. The reaction 25 mixture was concentrated and dried under high vacuum to afford an orange foam. *H NMR (300 MHz, DMSO, d6) 8 11.06 (s, 1 H, NH), 7.53 (s, 1 H, C=CH), 7.00 (d, 1 H, Jm= 2.4 Hz, ArHs), 6.70 (d, 1 H, Jm= 2.4 Hz, ArH7), 4.05-3.99 (m, 2 H, ArNCH2CH2CH2NCH3), 3.87 (s, 3 H, OCH3), 3.68-3.60 (m, 2 H, ArNCfijC^NCHj), 3.54-3.47 (m, 2 H, AJNCH2CH2NCH3), 3.41-3.26 (m, 2 H, ArNOfcCHzCajNCHs), 2.82 (ds3H,J= 4.8 Hz, NCH3), 2.46-2.41 (m, 1 30 H ArNCH2CH2CH2NCH3), 2.30-2.25 (m,. 1 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [Ci7H2iN304+H]+ Theor. m/z = 332; Obs. 332. <br><br> WO 02/055014 <br><br> -69- <br><br> PCT/SE02/00070 <br><br> Reference Example 26 <br><br> Preparation of 6-FIuoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2- <br><br> carboxylic acid. <br><br> This compound was prepared via the same procedure described for preparation of Reference Example 25. <br><br> Reference Example 27 <br><br> ethoxymethoxy)-quinoline-2-carboxylic acid (4-morphoIin-4-yl-phenyl)-amide. Reference Example 27a: 8-Bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid. <br><br> . To a light brown solution of 8-bromo-6-methoxy-4~(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) (4.98 g, 11.3 mmol) in 75 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium hydroxide monohydrate (1.367 g, 32.6 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was concentrated and then poured into water. The solution was acidified to pH 2 with 1 N HCI and the resulting solids were isolated by filtration. The solids <br><br> WO 02/055014 <br><br> -70- <br><br> PCT/SE02/00070 <br><br> were then suspended in methanol and filtered to afford the desired product (2.6732 g, 80%). An additional 0.5768 g (17%) of product was obtained from the methanol filtrates. !H NMR (300 MHz, DMSO, dg, TFA Shake) 8 7.86 (d, 1 H, Jm= 2.7 Hz, ArHs), 7.55 (d, 1 H, Jm= 2.7 Hz, ArH7), 7.32 (s, 1 H, C=CH), 3.94 (s, 3 H, OCH3); Mass Spec.: calc. for 5 [Ci ,H8BrN04+H]+ Theor. m/z = 298,300; Obs. = 298,300. <br><br> Reference Example 27b: 8-Bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide. <br><br> To a yellow suspension of 8-bromo-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27a) (3.446g, 11.56 mmol), TBTU (9.039 g, 28.15 10 mmol), and HOBt (3.757 g, 27.8 mmol) in 100 mL dimethylformamide was added 4-morpholinoaniline ( 2.733 g, 15.3 mmol) and diisopropylethyl amine (8.2 mL, 50.2 mmol). The resulting marroon solution was stirred at room temperature under nitrogen for 16 hours during which time the reaction became greenish brown and formed a large amount of precipitate. The reaction mixture was filtered and the solids washed with dimethylformamide, 15 water, and methanol. Drying under high vacuum afforded the desired product as a yellow solid (3.09 g, 58%). ]H NMR (300 MHz, DMSO, d*) 8 12.13 (s, 1 H, NH), 10.18 (s, 1 H, ' C(O)NH), 7.90 (d, 1 H, Jm~ 2.7Hz, ArHs), 7.68 (d, 2 H, J0= 9.0 Hz, ArHr&amp;H6.), 7.63 (s, 1 H, C=CH), 7.51 (d, 1 H, Jm= 2.7 Hz, ArH7), 7.00 (d, 2 H, J0=9.0 Hz, ArHs'&amp;HsO, 3.94 (s, 3 . H, OCH3), 3.75 (t, 4 H, 7= 4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J= 4.8 Hz, OC.H2CH2N); Mass 20 Spec.: calc. for [C2iH2oBrN304+H]+ Theor. m/z = 458,460; Obs. = 458,460. <br><br> Reference Example 27c: 8-Bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide. <br><br> A yellow suspension of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide (Reference Example 27b) (3.092 g, 6.75 25 mmol) in 40 mL N-methylpyrolidinone was treated with sodium hydride (60% dispersion in oil, 0.410 g, 10.24 mmol). Gas evolution and warming were observed and the suspension became light brown and almost clear. The reaction was stirred for 10 minutes at room temperature under nitrogen. Addition of the 2-(trimethylsilyl)ethoxymethyl chloride (1.6 mL, 9.1 mmol) resulted in a slightly cloudy, lighter brown solution. After 4.5 hours at room 30 temperature, the reaction mixture was poured into 300 mL water, stirred for 15 minutes and then stored at 0 °C overnight. The solids were isolated by filtration, suspended in methanol, filtered again, and dried under high vacuum to afford the product as a yellow solid (3.190 g, 80%). 'H NMR (300 MHz, DMSO, dg) 8 10.18 (s, 1 H, C(O)NH), 7.95 (d, 1 H, Jm= 2.4 Hz, . <br><br> WO 02/055014 <br><br> -71- <br><br> PCT/SE02/00070 <br><br> AtHt), 7.83 (s, 1 H, ArHs), 7.69 (d, 2 H, J0= 9.0 Hz, ArHz'&amp;HeO, 7.51 (4 1 H, Jm= 2.7 Hz, ArHs), 7.00 (d, 2 H, Jo=9.0 Hz, ArH3-&amp;iis-)» 5.69 (s, 2 H, 0CH20), 3.95 (s, 3 H, OCH3), 3.85 (t, 2 H, J= 8.0 Hz, OCH2CH2Si), 3.75 (t, 4H,J= 4.7 Hz, OCHjCT^N), 3.10 (t, 4 H, J= 4.7 Hz, OCH2CH2N), 0.94 (t, 2 H, J= 8.0 Hz, OCH2CH2Si), -0.04 (s, 9 H, Si(C Hb) 3; Mass Spec.: 5 calc. for [C27H34BrN305Si+H]+ Theor. m/z = 588, 590; Obs. = 588, 590. <br><br> Reference Example 27d: 6-Methoxy-8-(4-methyl:[l,4]diazepan-l-yl)-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide. <br><br> To a yellow-green suspension of 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (Reference Example 27c) (4-morpholin-4-yl-10 phenyl)-amide (1.155 g, 1.96 mmol), N-methyl homopiperazine (0.39 mL, 3.14 mmol), and 4 A sieves in 30 mL anhydrous toluene was added Pd2 (dba) 2 (90.0 mg, 0.098 mmol) and BINAP (0.358 g, 0.58 mmol). The resulting reddish brown mixture became lighter in color upon treatment with cesium carbonate (2.544 g, 7.81 mmol). The reaction mixture was heated at reflux under nitrogen for 17 hours. The clear brown solution was cooled to room 15 temperature, concentrated, and then purified by flash chromatography on silica gel using a slow gradient of 95:5 to 50:50 methylene chloride methanol to afford the desired product' (0.989 g, 81%). *H NMR (300 MHz, DMSO, dg) 8 9.88 (s, 1 H, NH), 7.73 (s, 1 H, ArHj), 7.68 (d, 2H, J0= 8.9Hz, ArHa'&amp;JJeO, 7.00 (d, 2H, J0= 8.9Hz, ArEb.&amp;Hs-), 6.94(d, 1 H, Jm= 2.7 Hz, ArHs), 6.66 (d, 1 H, Jm= 2.7 Hz, ArH7), 5.62 (s, 2 H, 0CH20), 3.87 (s, 3 H, 20 OCH3), 3.80(t, 2 H, J= 8.0 Hz, OCEkCTfeSi), 3,73 (t, 4 H, J= 4.7 Hz, OQfcCHzN), 3.63 (t, 2 H, J= 5.9 Hz, ArNCH2CH2CH2NCH3), 3.33 (bs, 2 H, ArNCHaCHaNCHs), 3.09 (t, 4 H, /= 4.7 Hz, OCH2CH2N), 2.97 (bs, 2 H, ArNCH2CH2NCH3), 2.69 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.35 (s, 3 H, NCH3), 2.09 (bs, 2 H ArNCH2CH2CH2NCH3), 0.94 (t, 2 H, J= 8.0 Hz, OCH2CH2Si), -0.03 (s, 9 H, Si(C H3) 3; Mass Spec.: calc. for 25 [C33H47N505Si+H]+ Theor. m/z = 422; Obs. = 622. <br><br> Reference Example 28 <br><br> WO 02/055014 <br><br> -72- <br><br> PCT/SE02/00070 <br><br> Preparation of 8-Bromo-4-dimethylamino-6-methoxy-quinoIine-2-carboxyIic acid (4- <br><br> morpholin-4-yI-phenyI)-amide. <br><br> Reference Example 28a: 8-Bromo-4-chloro-6-methoxy-quinoline-2-carboxyiic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> 5 A suspension of 8-bromo-6-methoxy-4-oxo-1 )4-dihydro-quinoline-2-carboxylic acid <br><br> (Reference Example 27b) (1.75 mmol) in 20 mL methylene chloride was treated with oxalyl chloride (1.5 mL, 17.2 mmol) and catalytic dimethylformamide (3 drops). The reaction mixture bubbled vigorously and became clearer. The reaction was heated at reflux for 2 hours, cooled to ropm temperature, and concentrated to a pale yellow solid (kept under 10 nitrogen). <br><br> To a yellow solution of the acid chloride in 20 mL methylene chloride was added 4-morpholinoaniline (0.347 g, 1.94 mmol) and diisopropylethyl amine (1.0 mL, 6.1 mmol). The solution became orange and gas evolution was observed. Within 30 minutes, solids began to precipitate from the solution. The reaction was stirred at room temperature for 1 hour. The 15 solids were isolated by filtration and dried under high vacuum to afford the desired product (0.406 g, 49%). 'HNMR (300 MHz, DMSO, ds) 8 10.15 (s, 1 H, C(O)NH), 8.33 (s, 1 H, ArHj), 8.10 (d, 1 H, Jm= 2.7 Hz, ArHy), 7.70 (d, 2 H, «/„= 9.0 Hz, ArHr&amp; Hr), 7.56 (d,-1 H, Jm= 2.7 Hz, ArHs), 7.01 (d, 2 H, J0=9.0 Hz, ArH3-&amp;HsO.AOe (s, 3 H, OCH3), 3.75 (t, 4 H, /= 4.8 Hz, OCH2CH2N), 3.11 (t, 4 H, J— 4.8 Hz, OCH2CH2N); Mass Spec.: calc. for 20 . [C2IHi9BrClN303+H]+ Theor. m/z = 476,478; Obs. = 476,478. <br><br> Reference Example 28b: 8-Bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide. <br><br> A solution of 8-bromo-4-chloro-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 28a) (0.1512 g, 0.317 mmol) in 100 mL 2.0 M 25 ^dimethyl amine in tetrahydrofuran was heated at 100 °C in a Parr bomb. The initial pressure was 75-80 psi and then remained at approximately 60 psi. After 18 hours, the reaction was cooled to room temperature, concentrated and dried to afford the crude product as a brown solid. Purification on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol afforded the clean product (0.142 g, 92%). !H NMR (300 MHz, DMSO, d6) 8 10.20 (a, 1 H, 30 C(O)NH),7.90(d, 1 H,Jm= 2.7Hz,ArHs);7.69(d,2H,J0= 9.0Hz,ArHr&amp;HeO,7.60(s, 1 H, ArHs), 7.41 (d, 1 H, Jm= 2.7 Hz, ArH7), 7.01 (d, 2 H, Jo=9.0 Hz, ArHb'&amp;iisO, 3.96 (s, 3 H, OCH3), 3.75 (t, 4 H, J= 4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J= 4.8 Hz, OCH2CH2N), 3.08 <br><br> WO 02/055014 <br><br> -73- <br><br> PCT/SE02/00070 <br><br> (s, 6 H, N(CH3) 2); Mass Spec.: calc. for [C2iHi9BrCIN303+H]+ Theor. m/z = 485,487; Obs. = 485,487 <br><br> Reference Example 29 <br><br> 5 Preparation of 6-Fluoro-4-methoxy-8-(4-methy!-piperazin-l-yl)-quinoline-2-carboxylic acid <br><br> Reference Example 29a: 8-Bromo-6-flu6ro-4-methoxy-quinoline-2-carboxyIic acid methyl ester <br><br> Into a 150 mL 3 neck round bottom flask equipped with a reflux condenser, magnetic 10 stirrer and nitrogen Met is placed 2.0 g (6.76 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid methyl ester. This material is then dissolved in 50 mL of NMP. Then 300 mg (7.44 mmol, 1.1 equiv.) of a 60% dispersion of sodium hydride in oil is cautiously added portion-wise to the solution at room temperature. A yellow color then develops, indicating that formation of the anion has occurred, with hydrogen evolution. 15 Stirring of the anion solution is continued for one hour, then 1.14 g, 500 (xL (8.04 mmol, 1.2 equiv.) of iodomethane is added via syringe. The mixture is allowed to react for two hours additional, then is cautiously quenched with 20 mL of water. The solids, which precipitate upon dilution in 1L of water, are collected by filtration, then washed with water to give the pure O methylated material as 2.1 g (98%) of a colorless solid. <br><br> 20 Mass Spec.: calc. for [C]2H9BrFN03+H]+ Theor. m/z = 314,316; Obs. = 314, 316 <br><br> Alternatively, into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen Met and magnetic stirrer is placed 350 mg (1.17 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid methyl ester and 242 mg (1.75 mmol, 1.5 equiv.) of K2CO3. This material is suspended in 20 mL of DMSO then 25 heated to 70 °C for 1 hr. The anion formation of the anion is apparent when the mixture becomes cloudy. The mixture is allowed to cool to 35 °C then 331 mg, 145 |iL (2.33 mmol, 2,0 equiv.) of methyl iodide are added and stirring is continued for 2 hr. At the end of this <br><br> WO 02/055014 <br><br> -74- <br><br> PCT/SE02/00070 <br><br> time it is determined if the reaction is complete by LC/MS. Upon completion the mixture is poured into 200 mL of water and the solids which form are collected by filtration and washed with water to give 340 mg (93%) of the O-methylated product after drying. <br><br> Reference Example 29b: 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1 -yl)-quinoline-2-5 carboxylic acid methyl ester <br><br> Into a 250mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 2.1 g (6.68 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-methoxy-quinoline-2-carboxylic acid methyl ester (Reference Example 29a) (122 mg, 0.134 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 499.mg (0.802 mmol, 0.12 10 equiv.) of racemic 2,2'-bis(diphenylphosphino)-l,r-binapthyl and lg of 4 A molecular sieves and 80 mL of dry toluene. To the stirred suspension is then added 736 mg, 815 |xL, (7.35 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 3.05 g (9.35 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80 °C for 36 hr. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was 15 determined to be complete it was cooled to room temperature then filtered through a plug of celite, with toluene washing to remove solid by products. Purification by flash chromatography using a gradient of 5 to 20% methanol in methylene chloride as eluent yielded 2.0 g, (90%) of the desired product. Mass Spec.: calc. for [Ci7H2oFN303+H]+ theor. m/z = 334; Obs. = 334 <br><br> 20 Reference Example 29c: 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1 -yl)-quinoline-2-carboxylic acid <br><br> Into a 125 mL erlenmeyer flask containing 30 mL of THF and 30 mL of methanol is placed 2.1 g (6.3 mmol) of 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1 -yl)-quinoline-2-carboxylic acid methyl ester (Reference Example 29b). To this solution is added with stirring 25 30 mL of water in which is dissolved 291 mg (6.9 mmol, 1.1 equiv.) of lithium hydroxide monohydrate. This solution is allowed to react for 1 hr then is quenched with 10 mL of 2N HCI solution. The solution is then filtered and the solids washed with 10 mL of 0.5 N HCI solution. The combined filtrates are then concentrated to give 2.15 g, (95%) of the solid ■ yellow product as the hydrochloride salt. Mass Spec.: calc. for [Ci6HisFN303+H]+ Theor. m/z 30 = 320; Obs. = 320 <br><br> WO 02/055014 <br><br> -75- <br><br> PCT/SE02/00070 <br><br> Example 1 <br><br> 5 carboxamide. <br><br> 8-(4-methyl-1 -piperazinyl)-4-oxo-4//-chromene-2-carboxylic acid hydrochloride (Reference Example 1) (400 mg, 1.23 mmol) was suspended in anhydrous N,N-dimethylformamide (20 ml) and triethylamine (0.69 ml, 4.92 mmol) was added to give a clear solution. The following were added in order: 1-hydroxybenzotriazole (HOBt (205 mg, mol)), 10 0-( 1 H-Benzotriazol-1 -yl)-N,N,N',N'-pentamethylene-uronium tetrafluoroborate (TBTU (435 mg, 3.1 mmol)) then 4-(dimethylamino)pyridine (25 mg). After stirring for 5 min at room temperature, 4-(4-morpholinyl)aniline (Reference Example 21) (220 mg, mmol). The reaction stirred overnight at room temperature. The solution was concentrated in vacuo, the remains were partitioned between chloroform / saturated sodium bicarbonate, extracted (x3) 15 with chloroform, dried (MgS04) and concentrated in vacuo to give the crude product <br><br> Chromatography on silica (230 - 400 mesh ASTM) and eluting ethyl acetate followed by 2.5-5% methanol / chloroform gave 190 nig (% yield) of 8-(4-methyl-1 -piperazinyl)-JV-[4-(4-morpholinyl)phenyl]-4-oxo-4fiT-benzochromene-2-carboxamide as a yellow solid (mp 217-218° decomposition and melt 244-247C). LC/MS .(M+l) m/z = 449. <br><br> WO 02/055014 <br><br> -76- <br><br> PCT/SE02/00070 <br><br> Example 2 <br><br> T"° iN <br><br> o <br><br> N <br><br> N <br><br> 2- {1 -[4-(2-Methoxy-phenyl)-piperazih-1 -yl]-methanoyl}-8-(4-methyI-piperazin-1 -yl)-chromen-4-one. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available l-(2-Methoxy-phenyl)-piperazine (Aldrich) via the same procedure used in example 1, yielding a yellow solid. MS (M+H) m/z = 463. <br><br> Example 3 <br><br> 0 <br><br> N <br><br> 0 <br><br> 10 <br><br> 2-{l-[4-(l-Acetyl-2,3-dihydro-lH-indol-6-yl)-piperazin-l-yl]-methanoyl}-8-(4-methyi-piperazin-1 -yl)-chromen-4-one. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and l-(6-Piperazm-l-yl-2,3-dihydro-15 indol-1 -yl)-ethanone (Reference Example 8) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 516. <br><br> WO 02/055014 <br><br> -77- <br><br> PCT/SE02/00070 <br><br> Example 4 <br><br> CI <br><br> CN <br><br> N <br><br> 2-Chloro-5-(4-{l-[8-(4-methyl-piperazin-l-yI)-4-oxo-4H-chromen-2-yl]-methanoyl}-piperazin-1 -yl)-benzonitrile. <br><br> 2-carboxylic acid hydrochloride (Reference Example 1) and 2-chloro-5-piperazin-l-yl benzonitrile (Reference Example 9) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 493. <br><br> Example 5 <br><br> 2-{ 1 -[4-(4-Methoxy-phenyl)-piperazin- l-yl]-methanoyl}-8-(4-methyl-piperazin-1 -yl)-chromen-4-one. ' r- <br><br> This compoimd was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available (Aldrich) l-(4-Methoxy-phenyl)-piperazine as prepared in example 1, yielding a yellow solid. MS (M+H) m/z = 463. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene- <br><br> N <br><br> O <br><br> WO 02/055014 <br><br> -78- <br><br> PCT/SE02/00070 <br><br> Example 6 <br><br> 3-yl)-amide. . <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 5-furan-2-yl-lH-pyrazol-3-ylamine (Maybridge) as prepared in example 1, yielding a yellow solid. MS (M+H) m/z =420. <br><br> Example 7 <br><br> amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 4-imidazoi-l-yl-phenylamine (Aldrich) as prepared in Example 1, yielding a yellow solid. MS (M+H)m/z = 430. <br><br> WO 02/055014 <br><br> -79- <br><br> PCT/SE02/00070 <br><br> Example 8 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chrtimene-2-carboxylic acid (4-[ 1,2,3]thiadiazol-5-yl-phenyl)-amide. <br><br> 5 This compound was. prepared from 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene- <br><br> 2-carboxylic acid hydrochloride (Reference Example 1) and 4-[l,2,3]thiadiazol-5-yl-phenylamine (Reference Example 10) as prepared in Example 1, yielding a yellow solid. MS (M+H)m/z = 448. <br><br> Example 9 <br><br> benzylamide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 15 (Maybridge) 4-[l ,2,3]thiadiazol- 5-yl-benzylamine as prepared in Example 1, yielding ? yellow solid. MS (M+H) m/z = 462. <br><br> WO 02/055014 <br><br> -80- <br><br> PCT/SE02/00070 <br><br> Example 10 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl]-axnide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and l-[4-(4-amino-phenyl)-piperazin-l-yl]-ethanone (Reference Example 11) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 499. <br><br> Example 11 <br><br> 10 <br><br> N <br><br> o o <br><br> 8-(4-Metiiyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide. <br><br> This compound was prepared from 8-(4-M|thyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 4-(4-me1hanesulfonyl-piperazin-15 l-yl)-phenylamine (Reference Example 12) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 526. <br><br> WO 02/055014 <br><br> -81- <br><br> PCT/SE02/00070 <br><br> Example 12 <br><br> O <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (2-methoxy-4-moipholin-4-yl-phenyl)-'amide. <br><br> (Reference Example 1) (0.10 g, 0.35mmol), HOBt (0.10 g, 0.7mmol), TBTU (0.225 g, . 0.7mmol),.4-(dimethylamino) pyridine (0.01 g, catalytic amount), triethylamine (0.15 mL, 1,04mmol), and commercially available 2-methoxy-4-moipholin-4-yl-phenylamine (SALOR) (0.08 g, 0.38mmol) were dissolved in dimethylformamide (2.5 mL) and stirred at room 10 temperature overnight. Ethyl acetate (150 mL) was added and the resulting mixture was washed with water (3x50 mL), dried (N^SO,*), filtered, concentrated under vacuum and triturated with ether to yield a yellow solid (85 mg, 54%). LCMS: m/z = 480.3 Example 13 <br><br> 15 8-(4-Methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 3-chloro-4-morpholin-4-yl-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow 20 solid. (110 mg = 73%), LCMS - m/z = 483.5 <br><br> 5 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride <br><br> O <br><br> WO 02/055014 <br><br> -82- <br><br> PCT/SE02/00070 <br><br> Example 14 <br><br> phenyl)-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 4-thiomorpholin-4-yl-phenylamine (Reference Example 13) as prepared in Example 12, yielding a yellow solid. (55 mg = 38%), LCMS - m/z = 465.5 Example 15 <br><br> 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (2,5-diethoxy-4-morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 2,5-diethoxy-4-morpholin-4-yl-phenylamine (Aldrich) as prepared in Example 12, yielding a yellow solid. (80 mg = 50%), LCMS - m/z = 537.6 <br><br> WO 02/055014 <br><br> -83- <br><br> PCT/SE02/00070 <br><br> Example 16 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-cyanomethyl-phenyl)-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-ox6-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available (4-amino-phenyl)-acetonitrile (Aldrich) as prepared in Example 12, yielding a yellow solid. (65 mg = 54%),LCMS-m/z = 403.5 Example 17 <br><br> O <br><br> 10 <br><br> 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (lH-indol-5-yl)-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-1 -yI)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 1H-indol-5-ylamine (Aldrich) as prepared in Example 12, yielding a yellow solid. (35 mg = 15 29%), LCMS - m/z 4401.6 Example 18 <br><br> 0 <br><br> rap <br><br> WO 02/055014 <br><br> PCT/SE02/00070 <br><br> -84- <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-'2-carboxylic acid [4-( 1 -moipholin-4-yl-methanoyl)-phenyl]-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and l-(4-amino-phenyl)-l-5 morpholin-4-yl-methanone (Reference Example 14) as prepared in Example 12, yielding a yellow solid. (21 mg = 15%), LCMS - m/z = 477.6 Example 19 <br><br> 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(2,6-dimethyl-10 moipholin-4-yl)-phenyI]-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 4-(2,6-dimethyl-moipholin-4-yl)-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow solid. (60 mg = 42%), LCMS - m/z = 477.6 15 Example 20 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-fluoro-phenoxy)-phenyl]-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 4-(4- <br><br> O <br><br> O <br><br> WO 02/055014 <br><br> -85- <br><br> PCT/SE02/00070 <br><br> fluoro-phenoxy)-phenylatniae (Maybridge) as prepared in Example 12, yielding a yellow solid. (110 mg = 77%), LCMS - m/z = 475.6 Example 21 <br><br> 5 8-(4-Methyl-piperazin-l-yl)-2-(6-morpholin-4~yl-benzooxazoI-2-yl)-chromen-4-one. <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) (0.532 g, 1.85mmol) was placed in a 25 mL 3-neck flask under nitrogen and treated with PPA (6 g). The mixture was then treated with the prepared intermediate 4-amino-3-hydroxyphenylmorpholine (0.43 g of ~85% pure, ~2mmol). The 10 mixture was stirred and heated in an oil bath to 205°C for 3 hours to give a dark liquid. The mixture was cooled to room temperature and treated with 10 mL of water to give a dark solution. The solution was slowly neutralized with IN aqueous sodium hydroxide to pH~7 as a solid formed. The solid was collected, washed several times with water, air dried, and vacuum dried at room temperature to give 0.65 g of a black solid. TLC (10%MeOH in CHCI3 15 on SiC&gt;2) showed 2 major components at Rr0.5 and several lower Rf minor components. The solid was triturated with saturated aqueous sodium bicarbonate at room temperature. It was filtered off, washed several times with water, and air dried to give 0.65 g of a dark gray solid. TLC showed the same components seen previously. Mass spectral analysis showed m/e = 447 by positive ion CI and m/e = 446 by negative ion CI. The solid was dissolved in 2% methanol 20 in chloroform and it was chromatographed on a Megabond Elute silica gel column (10 g of SiCh) using 2% methanol in chloroform. The slightly faster Rf yellow component was concentrated to give 0.0188 g of a yellow solid. CI mass spectral analysis showed m/e = 447 as the base peak by positive ion CI. The solid was recrystallized in methanol to give 0.0178 g of a yellow solid with a melting point of 158.1-158.8°C. Proton NMR (CDCI3) and CI mass 25 spectral analyses were consistent for the desired product (m/z = 447 base peak by positive ion CI and m/z - 446 base peak by negative ion CI). <br><br> O <br><br> WO 02/055014 <br><br> -86- <br><br> PCT/SE02/00070 <br><br> Example 22 <br><br> ,l\k O . <br><br> N <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (2-hydroxy-4-morpholin-4-yl-phenyl)-amide. <br><br> 5 8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride <br><br> (Reference Example 1) (0.3768 g, 1.16 mmol) was placed in a 100 mL 3-neck flask under nitrogen and it was dissolved in 20 mL of DMF. The solution was treated with triethylamine (0,49mL, 3.5mmol) followed by HOBT hydrate (0.36g, 2.3mmol) followed by TBTU (0.74 g, 2.3mmol) and then followed by DMAP (0.020 g). The mixture was stirred for 10 minutes and 10 then it was treated with 4-amino-3-hydroxyphenylmoipholine (Reference example 21) (0.228 g, 1.17 mmol).' The mixture was stirred for 15 minutes and then it was treated with triethylamine (0.17 mL, 1.2 mmol). The mixture was stirred at room temperature for 42 hours and then it was added to a solution of 50 mL of saturated aqueous sodium bicarbonate and 50 mL of water. The mixture was extracted 4 times with ethyl acetate, dried over 15 magnesium sulfate, filtered, and concentrated to give 0.834 gram of a purple oil. The oil was dissolved in 2 percent methanol in chloroform and it was placed on a silica gel column (5.5 cm diameter by 10.5 cm long) and eluted with 2 percent methanol in chloroform followed by 5 percent methanol in chloroform. The yellow fraction was concentrated to give 0.2031 gram of an orange-yellow solid. The solid was dissolved in methanol, filtered through a medium 20 sintered glass funnel, and concentrated to a few ml volume as a solid formed. The solid was filtered off, washed with methanol, and air dried to give 0.1613 gram of a tan solid with MP of248.4 - 249.6°C. Proton COSY NMR and CI mass spectral analyses were consistent for the desired product (m/z = 465 by positive ion CI and m/z = 463 by negative ion CI). <br><br> WO 02/055014 <br><br> -87- <br><br> PCT/SE02/00070 <br><br> Example 23 <br><br> Q ^ <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (5-ethoxy-benzothiazol-2-yl)-amide. <br><br> 5 . This compound was prepared from 8-(4-Methyl-piperazin-l-yl)'-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 5-ethoxy-benzotMazol-2-yIamine (SALOR) as prepared in Example 12, yielding a yellow solid, (55 mg = 39%), LCMS - m/z = 465.3 Example 24 <br><br> T <br><br> 10 1 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-bromo-phenyl)~amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and commercially available 4-bromo-phenylamine (Aldrich) as prepared in Example 12, yielding a yellow solid. (1.0 g = 75%), 15 LCMS -m/z = 442.4 <br><br> WO 02/055014 <br><br> -88- <br><br> PCT/SE02/00070 <br><br> Example 25 <br><br> O <br><br> 8-(4-Methylpiperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid methyl-(4-moipholin-4-yL phenyl)amide. <br><br> yl-phenyl)-amide (Example 1) (0.1046 g, 0.2332 mmol) was placed in a 10 mL single neck round flask under nitrogen. The solid was dissolved in 2.8 mL of anhydrous DMF. The yellow solution was stirred at room temperature and treated with one portion of sodium hydride (0.011 g of 95%, 0.44 mmol). The mixture evolved gas and became a red solution. It 10 was stirred under nitrogen for 20 minutes and then it was treated with iodomethane (0.015 mL, 0.033 g, 0.233 mmol). The mixture was sealed and stirred at room temperature for 18 hours. <br><br> The reaction mixture was concentrated to remove most of the DMF (35 C bath @ 0.5 mm) to give a dark semisolid. It was treated with a few drops of water followed by 10 mL of 15 ethyl acetate. The mixture was dried over magnesium sulfate, filtered, and concentrated to give 0.0564 gram of a yellow glass. The glass was triturated with diethyl ether, filtered off, and dried under high vacuum to give 0.0302 g of a tan solid with MP of245.0 - 246.8 C. Proton NMR and CI mass spectral analyses were consistent for the desired product (m/z = 463 by positive ion CI). <br><br> 20 Example 26 <br><br> 5 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4- <br><br> O <br><br> WO 02/055014 <br><br> -89- <br><br> PCT/SE02/00070 <br><br> 8-(4-Methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid (3 -morpholin-4-yl-phenyl)-amide.. <br><br> This compound was prepared from 8-(4-Methyl-piperazin-l-yi)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 3-morpholin-4-yl-phenylamine 5 (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (120 mg = 86%), LCMS-m/z = 449.5 Example 27 <br><br> 10 yl-phenyl)-amide. <br><br> This compound was prepared from'8-.(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-• 2-carboxylic acid hydrochloride (Reference Example 1) and 5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as prepared in Example 12, yielding a yellow solid. (120 mg = 82%), LCMS - m/z = 474.5 15 Example 28 <br><br> yl-phenyl)-amide. <br><br> This compound was prepared from 8-(4-Methyl-piperazm-l-yl)-4-oxo-4H-chromene-20 2-carboxylic acid hydrochloride (Reference Example 1) and 3-fluoro-4-morpholin-4-yl-phenylamine (Reference Example 16) as prepared in example 12, yielding a yellow solid. (120 mg = 83%), LCMS - m/z = 467.6 <br><br> WO 02/055014 <br><br> -90- <br><br> PCT/SE02/00070 <br><br> Example 29 <br><br> 4-[4-({l-[8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-bvAyl ester. <br><br> 5 This compound was prepared from 8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene- <br><br> 2-carboxylic acid hydrochloride (Reference Example 1) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Reference Example 17) as prepared in example 12, yielding a yellow solid. (260 mg = 53%), LCMS - m/z = 548.6 <br><br> Example 30 <br><br> phenyl)-amide. <br><br> 4-[4-({l-[8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid terf-butyl ester (Example 29) (160 mg, 0.3 mmol) was 15 dissolved ethyl acetate (20 mL) and cooled to 0°C. HCI gas was bubbled in slowly for 2 minutes. A solid began to precipitate. Methanol (3-4 mL) was added to dissolve this solid and HCI gas was bubbled in for another 2 minutes. The mixture was concentrated under reduced pressure and triturated with ether and dried under vacuum to yield a tan solid (100 mg, 76%). LCMS/m/z = 448.6 <br><br> WO 02/055014 <br><br> -91- <br><br> PCT/SE02/00070 <br><br> Example 31 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide: <br><br> 5 ■ 6-Methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-caxboxylic acid hydrochloride (Reference Example 2) (3.0g, 8.5 mmol), TBTU (5.5g, 17 mmol), 1-hydroxybenztriazole (2.6g, 17 mmol), 4-dimethylaminopyridine (0.05g, catalytic) and commercially available 4-moipholin-4-yl-aniline (1.66g, 9.3 mmol) were dissolved in dimethylformamide (100 mL). Triethylamine (3.5 mL, 25 mmol was added and this mixture 10 stirred at room temperature for 17 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between chloroform (400 mL) and saturated aqueous sodium bicarbonate' (50 mL). The organic layer was separated, dried (Na2S04), vacuum-filtered and concentrated under vacuum. The residue was purified by chromatography on silica eluted with 2-5% methanol in chloroform and then triturated with ether to yield a yellow powder. (1.6 g = 39%) 15 LCMS - m/z = 479.5 mp = 234-236 °C. <br><br> Example 32 <br><br> .0 <br><br> N <br><br> ■v <br><br> 0**0 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]-amide. <br><br> 20 This compound was prepared from 6-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 4-(4-methanesulfonyl- <br><br> WO 02/055014 <br><br> -92- <br><br> PCT/SE02/00070 <br><br> piperazin-1 -yl)-phenylamine (Reference Example 12) as prepared in example 1, yielding a yellow solid. GC/MS (EI, M+) m/z = 556 Example 33 <br><br> CI N <br><br> 5 6-Methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 3-chloro-4-moipholin-4-yl-phenylamine (Maybridge) as prepared in Example 12, 10 yielding a yellow solid. (45mg = 31%) LCMS -m/z = 513.5 Example 34 <br><br> O <br><br> 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide. <br><br> 15 This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 3-fluoro-4-morpholin-4-yl-phenylamine (Reference Example 16) as prepared in Example 12, yielding a yellow solid. (55mg = 61%), LCMS - m/z = 497.5 <br><br> WO 02/055014 <br><br> -93- <br><br> PCT/SE02/00070 <br><br> Example 35 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 2-methoxy-4-morpholin-4-yl-phenylamine (SALOR) as prepared in Example 12, yielding a yellow solid. (55mg = 38%), LCMS - m/z = 510.5 Example 36 <br><br> thiomorpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 4-thiomorpholin-4-yl-phenylamine (Reference Example 13) as prepared in Example 12, yielding a yellow solid. (99mg = 71%),LCMS-m/z = 495.5 <br><br> PCT/SE02/00070 <br><br> -94- <br><br> O <br><br> V^°Vn <br><br> SJ V <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(2,6-dimethyl-moipholin-4-yl)-phenyl]-amide. <br><br> 5 This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 4-(2,6-dimethyl-morpholin-4-yl)-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow solid. (70mg = 49%), LCMS - m/z = 507.5 Example 38 <br><br> 4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-methoxy-8 -(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 3-morpholin-4-yl-15 phenylamine (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (80mg = 60%), LCMS - m/z = 479.5 <br><br> WO 02/055014 <br><br> Example 37 <br><br> WO 02/055014 <br><br> -95- <br><br> PCT/SE02/00070 <br><br> Example 39 <br><br> 6-Methoxy-8-(4-methyl-piperazin4-yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(2-hydroxy-ethyl)-piperazin-l -yl] -phenyl} -amide. <br><br> 5 This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H- <br><br> . chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 2-[4-(4-amino-phenyl)-piperazin-l-yl]-ethanol (Reference Example 19) as prepared in Example 12, yielding a yellow solid. (80mg = 60%). mp = 211.5-212.2 (dec.), MS - base peak at m/z =492 by positive ion and m/z =490 by negative ion CI 10 Example 40 <br><br> I 0 <br><br> (X <br><br> 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid[4-(l-iaorpholin-4-yl-methanoyl)-phenyl]-amide. <br><br> . This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-l-yl)-4-oxo-4H-15 chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 1 -(4-amino-phenyl)-1 -morpholin-4-yl-methanone (Reference Example 14) as prepared in Example 12, yielding a yellow solid. (170mg = 80%), LCMS - m/z = 507.5 <br><br> WO 02/055014 <br><br> -96 - <br><br> PCT/SE02/00070 <br><br> Example 41 <br><br> 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano-4-moipholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as prepared in Example 12, yielding a yellow solid. (120mg = 57%), LCMS - m/z = 504.5 Example 42 <br><br> 10 <br><br> N <br><br> 4-[4-({l-[6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl3-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. <br><br> The 6-methoxy-8-(4-methyi-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) (1.04 g, 2.93 mmol) was placed in a 250 ml 3-neck 15 flask under nitrogen and it was dissolved in 50 ml of DMF. The solution was treated with triethylamine (1.22 mL, 8.79 mmol) followed by HOBT hydrate (0.90 g, 5,9 mmol) followed by TBTU (1.88 g, 5.9 mmol) and then followed by DMAP (0.056 g, 0.46 mmol). The mixture was stirred for 10 minutes and.then it was treated with 4-(4-Amino-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (Reference Example 17) (0.81 g, 2.9 mmol). The mixture was 20 stirred for 15 minutes and then it was treated with triethylamine (0.41 mL, 2.9 mmol). The mixture was stirred at room temperature for 18 hours and then it was concentrated (1 mm Hg <br><br> WO 02/055014 <br><br> -97- <br><br> PCT/SE02/00070 <br><br> pressure, 45 C bath) to give a dark liquid. The concentrate was treated with 80 mL of saturated aqueous sodium bicarbonate and extracted with ethyl acetate forming a suspended yellow solid in the organic layer. The solid was filtered off, washed with diethyl ether, <br><br> washed with water, and vacuum dried (0.1mm Hg pressure @ 25C) to give 0.36 gram of a 5 yellow solid, M.P. = 232.3-232.8 C. <br><br> Proton NMR and CI mass spectral analyses were consistent for the desired product (m/e = 578 by positive ion CI and m/e = 576 by negative ion CI). <br><br> The aqueous layer was extracted twice with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated to give 1.35 gram of a dark semisolid. It was triturated with diethyl 10 ether and allowed to stand at room temperature as a solid formed. The solid was filtered off, washed with diethyl ether, and vacuum dried at room temperature to give 0.4816 gram of a yellow solid. CI mass spectral analyses was consistent for the desired product (M/Z = 578 BY positive ion CI AND M/Z = 576 by negative ion CI). <br><br> WO 02/055014 <br><br> -98- <br><br> PCT/SE02/00070 <br><br> Example 43 <br><br> 6-Methoxy-8-(4-methyi-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide. <br><br> 5 The 4-[4-({ 1 -[6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]- <br><br> methanoyl}-amino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester (Example 42) (0.792 gram, 1.37 nimol) was placed in a 50 ml round flask under nitrogen and it was dissolved in 15 ml of methylene chloride. The solution was treated with 15 ml of trifluoroacetic acid (195 mmol) to give a dark solution and it was stirred at room temperature for 18 hours. It was 10 concentrated to give a brown foam. The foam was treated with 30 ml of saturated aqueous sodium bicarbonate and it was stirred at room temperature as a yellow solid formed. The solid was filtered off, washed several times with water, air dried and dried under high vacuum (0.1 mm Hg pressure) to give 0.493 gram.of a yellow solid, M.P. = 203.6-204.7 C. <br><br> Proton NMR and CI mass spectral analyses were consistent for the desired product 15 (m/z = 478 by positive ion CI and m/z = 476 by negative ion CI). <br><br> Example 44-54 <br><br> The following examples were prepared in parallel by acylation of 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide (Example 43) in an Argonaut Quest synthesizer. <br><br> 20 The piperazine side chain was derivatized in parallel fashion using eleven different commercially available acylating and sulfonating reagents. The resins used were Argonaut Tech polystyrene amine resins. Each 5 ml Quest tube was charged with 0.010 gram (0.021 mmol) of the starting N-H piperazine and 3ml of methylene chloride followed by 4 equivalents (0.08 mmol) of PS-DIEA resin (diisopropylbenzylamine PS resin) to scavenge 25 HCI. Each tube was then treated with an acyl chloride, sulfonyl chloride, or isocyanate (2 . equivalents of each) followed by a little more methylene chloride. The tubes were sealed under nitrogen, and stirred fot 3 hours at room temperature. The mixtures were then opened <br><br> WO 02/055014 <br><br> -99- <br><br> PCT/SE02/00070 <br><br> and treated with about 4 equivalents (0.08 mmol) of PS-trisamine resin (primary amine PS resin) to scavenge any excess acylating or sulfonating reagent. The mixtures were sealed and stirred for 1.5 hours and then filtered directly into vials and concentrated to give the products. The products were characterized by HPLC mass spectral analysis and were found to be 5 greater than 90% pure by HPLC. The compounds were submitted to the 5-HTlb binding assay for determination of 5-HT receptor binding affinities and selectivities. <br><br> Example 44 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yI)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-10 propionyl-piperazin-l-yl)-phenyl]-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazm-l-yl-phenyl)-amide (Example 43) and commercially available propionyl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =534 by positive ion CI 15 Example 45 <br><br> O <br><br> Vx o <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethane sulfonyl-piperazin-l-yl)-phenyl]-amide. MS - base peak at m/z =570 by positive ion CI <br><br> WO 02/055014 <br><br> -100- <br><br> PCT/SE02/00070 <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) and commercially available ethanesulfonyl chloride (Aldrich) via the parallel synthesis described, above. Example 46 <br><br> N <br><br> N / <br><br> No-Nv <br><br> ° O <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-dimethyl sulfamoyl-piperazin-l-yl)-phenyl]-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Exathple 43) and commercially 10 available dimethylsulfamoyl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =585 by positive ion CI Example 47 <br><br> O <br><br> .0. <br><br> 4-[4-({ 1 -[6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-methanoyl} -15 amino)-phenyl]-piperazine-1 -carboxylic acid dimethylamide. <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) and commercially available dimethylcarbamyl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =549 by positive ion CI <br><br> WO 02/055014 <br><br> -101- <br><br> PCT/SE02/00070 <br><br> Example 48 <br><br> 4-[4-({l-[6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid ethylamide. <br><br> This compoimd was prepared from 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide (Example 43) and commercially available ethyl isocyanate (Aldrich) via the parallel synthesis described above. <br><br> MS - base peak at m/z =549 by positive ion CI. <br><br> Example 49 <br><br> 0' <br><br> 1° <br><br> 4-[4-({l-[6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid cyclohexylamide. <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperaziu-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) and commercially 15 available cyclohexyl isocyanate (Aldrich) via the parallel synthesis described above. MS -base peak at m/z =603 by positive ion CI <br><br> WO 02/055014 <br><br> -102- <br><br> PCT/SE02/00070 <br><br> Example 50 <br><br> 4-[4-( {1 - [6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl] -methanoyl} -amino)-phenyl]-piperazine-1-carboxylic acid cyclopentylamide. <br><br> 5 This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H- <br><br> cbromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) and commercially available cyclopentanecarbonyl chloride (Aldrich) via the parallel synthesis described above. <br><br> . MS - base peak at m/z =574 by positive ion CI. <br><br> Example 51 <br><br> 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(l-' pyrrolidin-1-yl-methanoyl)-piperazin-1-yl]-phenyl }-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l -yl-phenyl)-amide (Example 43) and commercially 15 available 1-pyrrolidinecarbonyl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =575 by positive ion CI. <br><br> WO 02/055014 PCT/SE02/00070 <br><br> -103- <br><br> Example 52 <br><br> 6-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-[4-(prqpane-2-sulfonyl)-piperazin-1 -yl]-phenyl} -amide. <br><br> 5 This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid (4-piperazin- l-yl-phenyl)-amide (Example 43) and commercially available isopropylsulfonylonyl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =584 by positive ion CI. <br><br> Example 53 <br><br> O <br><br> ^Os <br><br> 10 1 ° <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(2-methyl-propanoyl)-piperazin-l-yl]-phenyl}-amide. <br><br> This compound was prepared from 6-methoxv-8-(4-methyl-piperazin-1 -yI)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) and commercially 15 available isobutyryl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =548 by positive ion CI. <br><br> WO 02/055014 <br><br> -104- <br><br> PCT/SE02/00070 <br><br> Example 54 <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-( 1 -moipholin-4-yl-methanoyl)-piperazin-lryl]-phenyl}-amide. <br><br> This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) and commercially available moipholine-4-carbonyl chloride (Aldrich) via the parallel synthesis described above. MS - base peak at m/z =591 by positive ion CI. <br><br> Example 55 <br><br> Q <br><br> F„ <br><br> 10 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 3) and 4-moipholin-4-yl-15 phenylamine (Reference Example 20) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 467 <br><br> WO 02/055014 <br><br> -105- <br><br> PCT/SE02/00070 <br><br> Example 56 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid' [4-(4-methanesulfonyl-piperazm-l-yl)-phenyl]-amide. <br><br> 5 This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid hydrochloride (Reference Example 3) and 4-(4-me£hanesulfonyl-piperazin-l-yl)-phenylamine -(Reference Example 12) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 544 Example 57 <br><br> F <br><br> N <br><br> Nr <br><br> 10 0 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl]-amide. <br><br> This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboXylic acid hydrochloride (Reference Example 3) and l-[4-(4-amino-15 phenyl)-piperazin-l-yl]-ethanone (Reference Example 11) as prepared in Example 1, yielding a yellow solid. MS (M+H) m/z = 508 <br><br> WO 02/055014 <br><br> -106 - <br><br> PCT/SE02/00070 <br><br> Example 58 <br><br> O <br><br> F <br><br> 6-Fluoro-8-(4-methyl-piperazin--l -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-chloro-4-morpholin-4-yl-phenyl)-amide. <br><br> hydrochloride (Reference Example 3) (150 mg, 0.43 mmol), 1-hydroxybenzotriazole (140 mg, 0.9 mmol), 0-(lH-Benzotriazol-l-yl)-N,N,N',N'-pentamethylene-uromum tetrafluoroborate (290 mg, 0.9 mmol), 4-(dimethylaxnino)pyridine (10 mg, catalytic), triethylamine (0.2 mL, 1.5 mmol), and commercially available 3-chloro-4-morpholin-4-yl-10 phenylamine (Maybridge) were dissolved in dimethylformamide (2.5 mL) and stirred at room temperature overnight. At 17 h, water (20 mL) was added and the resulting mixture was stirred for 15-30 min. The mixture was vacuum-filtered and the residue washed with water and air-dried to yield a yellow powder (220 mg = quantitative yield). LC/MS - m/z = 501.5 Example 59 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (3-fluoro-4-moipholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride' (Reference Example 3) and 3-fluoro-4-morpholin- <br><br> 20 4-yl-phenylamine (Reference Example 16) as prepared in Example 58, yielding a yellow solid (210mg = 99%). LC/MS-m/z = 485.5 <br><br> 5 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid <br><br> 15 <br><br> WO 02/055014 <br><br> -107- <br><br> PCT/SE02/00070 <br><br> Example 60 <br><br> 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (3-cyano-4-morpholin-4-yl-phenyl)-ainide. <br><br> 5 This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid hydrochloride (Reference Example 3) and 5-amino-2-moipholin-4-yl-benzonitrile (Reference Example 15) as prepared in Example 58, yielding a yellow solid (210 mg = 99%). LC/MS - m/z = 492.5 Example 61 <br><br> 10 <br><br> 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(l-morpholin-4-yl-methanoyl)-phenyl]-amide. <br><br> This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 3) and l-(4-amino-phenyI)-l-15 morpholin-4-yl -methanone (Reference Example 14) as prepared in Example 58, yielding a yellow solid (220 mg = quantitative yield). LC/MS - m/z = 495.5 Example 62 <br><br> 0 <br><br> H,Cv <br><br> WO 02/055014 <br><br> -108- <br><br> PCT/SE02/00070 <br><br> 6-Methyl-8-(4-metiiyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-Methyl-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 4) and 4-morpholin-4-yl-5 phenylamine (Reference Example 20) as prepared in Example 1, yielding a yellow solid. LCMS - m/z = 463.6 Example 63 <br><br> 6-Methyl-8-(4-methyl-piperazin- l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(l-10 morpholin-4-yl-methanoyl)-phenyl]-amide. <br><br> This compound was prepared from 6-Methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 4) and 1-(4-amino-phenyl)-1-morpholin-4-yl-methanone (Reference Example 14) as prepared in Example 1, yielding a yellow solid. LCMS - m/z = 491.6 15 Example 64 <br><br> morpholin-4-yl-phenyl)-amide. <br><br> This compound was prepared from 6-Methyl-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-20 chromene-2-carboxylic acid hydrochloride (Reference Example 4) and 3-fluoro-4-morpholin- <br><br> WO 02/055014 <br><br> -109- <br><br> PCT/SE02/00070 <br><br> 4-yl-phenylamine (Reference Example 16) as prepared in Example 1, yielding a yellow solid. LCMS-m/z = 504.5 Example 65 <br><br> yl^phenyl)-amide. <br><br> This compound was prepared from 6-chloro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 5) and 4-moipholin-4-yl-phenylamine (Reference Example 20) as prepared in Example 1, yielding a yellow solid. 10 LCMS-m/z = 483.3 Example 66 <br><br> yl-phenyl)-amide. <br><br> 15 This compound was prepared from 5-methyl-8-(4-methyl-piperazin-l -yl)-4-oxo-4H- <br><br> chromene-2-carboxylic acid hydrochloride (Reference Example 6) and 4-morpholin-4-yl-phenylamine (Reference Example 20) as prepared in Example 1, yielding a yellow solid (116 mg = 84%) LCMS- m/z = 463.5 <br><br> WO 02/055014 <br><br> -110- <br><br> PCT/SE02/00070 <br><br> Example 67 <br><br> 5-Methoxy-8-(4-methyl-piperazin-l -yi)-4-oxo-4H-chromene-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide. <br><br> 5 This compound was prepared from 5-methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H- <br><br> chromene-2-carboxyIic acid hydrochloride (Reference Example 7) and 4-morpholin-4-yl-phenylamine (Reference example 20) as prepared in Example 1, yielding a yellow solid (149 mg = 50%) LCMS -m/z = 479.4 <br><br> 10 The following additional examples incorporate 4-substituted piperazine-1 -yl-phenyl amides similar in structure to Examples 44-54 Example 68 <br><br> I 0 <br><br> O. <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4- [4-(3-15 hydroxy-propanoyl)-piperazin-l-yl]-phenyl}-amide. <br><br> 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide (Example 43) (1.5 gram, 2.12 mmol) was placed in a 100 mL flask with 50 mL of CH2CI2. This suspension was treated with triethylamine (4 equivalents, 1.2 mL, 8.5 mmol) and (3-propionylactone (0.2 mL, 3.2 mmol) and the reaction stirred at room 20 temperature for 2 hours, then heated to 50°C for 2 hours. Then 0.8 mL more of b-propionylactone was added and the reaction heated for 4 hours more. The reaction was <br><br> WO 02/055014 <br><br> -111- <br><br> PCT/SE02/00070 <br><br> allowed to cool to room temperature and then concentrated (1 mm Hg pressure). The concentrate was treated with saturated aqueous sodium bicarbonate and the resulting solid collected by vacuum filtration. The residue was purified by chromatography on silica eluting with 2% methanol in chloroform, then concentrated (1mm Hg pressure). Then triturated with 5 either to yield a yellow powder with was dried under high vacuum for 48 h at 50°C (100 mg) LCMS-m/z 550, mp = 195-197°C. <br><br> Example 69 <br><br> O <br><br> F <br><br> 4-[4-({l-[6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-10 phenyl]-piperazine-1-carboxylic acid tert-butyl ester. <br><br> This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 3) and 4 -(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-bwty\ ester (Reference Example 17) according to the method . of Example 42 to yield (1.65 grams, 64%) of a yellow powder LCMS - m/z = 556; mp = 15 219-220°C. <br><br> Example 70 <br><br> 0 <br><br> F, <br><br> 4-[4-({ l-[6-Fluoro-8-(4-m'ethyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide. <br><br> 20 This compound was prepared from 4-[4-({1 -[6-Fluoro-8-(4-methyl-piperazin-1 -yI)-4- <br><br> oxo-4H-chromen-2-yl]-methanoyl} -amino)-phenyl]-piperazine-1 -carboxylic acid tert-butyl <br><br> WO 02/055014 <br><br> -112- <br><br> PCT/SE02/00070 <br><br> ester, as prepared in Example 69, using the method of Example 43 to yield a yellow solid LCMS -m/z =466. <br><br> Example 71 <br><br> 5 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-ethane sulforiyl-piperazin-l-yl)~phenyl]-amide. <br><br> 4-[4-( {1 -[6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin- l-yl-phenyl)-amide ditrifluoroacetate (the free acid of which was prepared as in Example 70) (4.0 grams, 5.77 mmol) was placed in a flask with 50 mL of CH2CI2 and 10 triethylamine (3.2 mL and 23 mmol) and ethylsulfonyl chloride was added (0.6 mL, 6.35 mmol) portionwise (0.1 mL at a time) over 15 minutes and allowed to stir at room temperature for 20 hours. The reaction was concentrated (1 mm Hg pressure) and then saturated aqueous sodium bicarbonate was added and extracted with CHCI3. The organic fractions were combined, washed with saturated sodium chloride, dried (MgSO^) 15 concentrated (1 mm Hg pressure) to give a yellow solid which was recrystallized from methanol to give 1.33 grams of product LCMS - m/z = 558, mp = 233-234°C. <br><br> Example 72 <br><br> 0 <br><br> F. <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-20 piperazin-l-yl)-phenyl]-amide. <br><br> 4-[4-({ 1 - [6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-l-yl-phenyl)-amide ditrifluoroacetate (the free acid of which was prepared as in <br><br> WO 02/055014 <br><br> -113- <br><br> PCT/SE02/00070 <br><br> Example 70) (0.69 grams, 1,00 mmol) was placed in a flask with 25 mL of CH2CI2 and triethylamine (0.56 mL and 4 mmol) and propionyl chloride was added (0.95 mL, 1.1 mmol) and the reaction allowed to stir at room temperature for 20 hours. The residue was purified by chromatography on silica eluting with 2% methanol in chloroform, then concentrated (1mm 5 Hg pressure). The residue was triturated with either then digested with CHCI3 and the CHCI3 concentrated to yield a yellow powder which was dried under high vacuum for 48 h at 45°C (260 mg) LCMS - m/z = 522. <br><br> Example 73 <br><br> 10 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid {4-[4-(3-hydroxy-propanoyl)-piperazin-l-yl]-phenyl}-amide. <br><br> This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin- l-yl-phenyl)-amide and p-propionylactone using the ' method described above in Example 68 to yield 65 mg of a yellow powder LCMS - m/z = 15 538, mp = 195-199°C. <br><br> The following exemplifies a. substituted chromene-2-"reverse amide" (or substituted chromene-2-yl-benzamide). <br><br> Example 74 <br><br> O <br><br> F <br><br> O <br><br> O <br><br> 20 N-[8-(4-Methyl-piperazin-1 -yl)-4-oxo-4H-chromen-2-yl]-4-morpholin-4-yl-benzamide. <br><br> 8-(4-Methyl-piperazin-l -yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride Reference Example 1 (227 mg, 0.69 mmol), triethylamine (2 equivalents, 1.389 mmol, 0.193 <br><br> WO 02/055014 <br><br> -114- <br><br> PCT/SE02/00070 <br><br> mL) and diphenylphosphoryl azide (0.69 mmol, 0.15 mL) were stirred in toluene (10 mL) at 65°C for 30 minutes. The reaction was allowed to cool to 22°C and 4-mprpholinobenzonoic acid (0.7 mmol, 145 mg), more triethylamine (0.051 mL, 0.7mmol), and CH3CN (5 mL) were added and the reaction heated to reflux for 1 hour. The reaction was concentrated (1 mm Hg 5 pressure) the residue was partitioned between IN methanesufonic acid and ether. The acid layer was then basified with solid K2CO3 and the product extracted in to CHCI3. The organic layer was dried (MgS04) and concentrated under reduced pressure to leave a yellow solid which was further purified with silica chromatography using CHCI3 to 4% CH3OH in CHC13. Concentration of the fractions containing product yielded 13 mg of product LC/MS - m/z = 10 449. <br><br> Enantiomers of 8-(4-Methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> t <br><br> Example 75 <br><br> amide. <br><br> racemic-8-(4-Methyl-l-piperazin-l-yl)-chroman-2-carboxylic acid hydrochloride (Example 75a) (1.04 mmol) was dissolved in anhydrous jV^iV-dimethylformamide (40 ml) and the following were added in order: HOBt (0.17 g, 1.14 mmol), TBTU (0.37 g, 1.14 mmol) 20 then triethylamine (0.6 ml, 4.2 mmol). After stirring for 5 min at' room temperature, 4-(4-morpholinyl)aniline (reference example 20) (0.185 g, 1.14 mmol) was added and the reaction stirred overnight at room temperature. <br><br> The solution was concentrated in vacuo, the remains were partitioned between chloroform / saturated sodium bicarbonate, extracted (x3) with chloroform, dried (MgS04) and 25 concentrated in vacuo to give the crude product. <br><br> The crude product was chromatographed on a Waters Delta Prep 4000 using 1 PrepPak cartridge (Porasil 37-55125 A) eluting with 2.5 % methanol / chloroform. The product was collected to give a yellow oil. Ethyl acetate was added to the oil. The solution was <br><br> WO 02/055014 <br><br> -115- <br><br> PCT/SE02/00070 <br><br> refluxed then cooled the yellow solid was filtered to give 55 mg (12% yield) of racemic-8-(4-methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (mp 215-216 °C). The mother liquor contained 76 mg that was used in the chiral separation described below. LC/MS (M+l) m/z = 437. <br><br> 5 Example 75a racemic-8-(4-MethyI-1 -piperazin-1 -yl)-chroman-2-carboxylic acid hydrochloride. <br><br> Ethyl, 8-(4-methyl-1 -piperazin-1 -yl)-4-oxo-4H-chromen-2-carboxylate (Reference Example 1) (0.74 g, 2.3 mmol) was dissolved in glacial acetic acid (50 ml) and 10 % palladium on carbon (80 mg) was added. The mixture was hydrogenated on a Paar apparatus 10 (50 psi) at 70 °C for 3 h. Then, concentrated HCI and 10 % palladium on carbon (100 mg) were added and the mixture was again subjected to hydrogenation (50 psi) at 70 °C for lh. The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. Toluene was repeatedly added and the solution concentrated to give racemic-8-(4-. Methyl-1-piperazin-l-yl)-chroman-2-carboxylic acid hydrochloride as a foam that was used 15 without further purification in the next reaction. LC/MS (M+1) m/z = 277. <br><br> Example 76 <br><br> 20 <br><br> (+)-8-(4-Methyl-piperazin-1 -yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> The-snantiomers of racemic-8-(4-Methyl-piperazin-l-yl)-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Example 75) (0.52 g, 1.19 mmol) were separated by the use of a chiral column (ChiralPak AD, 5 cm X 50 cm, 20 |x). The faster (+) isomer (example 76) was eluted with 45 % isopropanol / hexane and the slower (-)isomer (example 77) was eluted with 75 % isopropanol / hexane. <br><br> 25 The faster (+) isomer (example 76) was obtained as a white solid (250 mg, mp 206- <br><br> 207 °C, ocd + 92.66 in dichloromethane). LC/MS (M+l) m/z = 437. <br><br> WO 02/055014 <br><br> -116- <br><br> PCT/SE02/00070 <br><br> Example 77 <br><br> (-)-8-(4-Methyl-piperazin-l-yl)-chroman-2-carboxylicacid(4-morpholin-4-yl-phenyl)-amide. <br><br> The enantipmers ofracemic-8-(4-Methyl-piperazin-l-yl)-chroman-2-carboxylic acid 5 (4-niorpholin-4-yl-phenyl)-amide (Example 75) (0.52 g, 1.19 mmol) were separated by the use of a chiral column (ChiralPak AD, 5 cm X 50 cm, 20 jj,). The faster (+) isomer (example 76) was eluted with 45 % isopropanol / hexane and the slower (-)isomer (example 77) was eluted with 75 % isopropanol / hexane. <br><br> The slower (-) isomer (example 77) was obtained as obtained as a light purple solid 10 (260 mg, mp 205.5-207 °C, aD - 91.08 in dichloromethane). LC/MS (M+.l) m/z = 437. ' <br><br> Enantiomers of 8-(4-methyl-piperazin-1 -yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> Example 78 <br><br> 15 &lt;:- <br><br> racemic-8-(4-methyl-piperazin-1 -yl)-4-oxo-chrpman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> Racemic-8-(4-methyl-1 -piperazin-1 -yl)- 4-oxo-chroman-2-carboxylic acid hydrochloride (Example 78a) (1.04 mmol) was dissolved in anhydrous N,N-20 dimethylformamide (40 ml) and the following were added in order: HOBt (0.17 g, 1.14 mmol), TBTU (0.37 g, 1.14 mmol) then triethylamine (0.6 ml, 4,2 mmol). After stirring for 5 min at room temperature, 4-(4-morpholinyl)aniline (reference example 20) (0.185 g, 1.14 mmol) was added and the reaction stirred overnight at rPom temperature. <br><br> WO 02/055014 <br><br> -117- <br><br> PCT/SE02/00070 <br><br> The solution was concentrated in vacuo, the remains were partitioned between chloroform / saturated sodium bicarbonate, extracted (x3) with chloroform, dried (MgS04) and concentrated in vacuo to give the crude product. <br><br> The crude product was chromatographed on a Waters Delta Prep 4000 using 1 5 PrepPak cartridge (Porasil 37-55|am 125A) eluting with 2.5 % methanol / chloroform. The product was collected to give a yellow oil. Ethyl acetate was added to the oil. .The solution was refluxed then cooled the yellow solid was filtered to give 55 mg (12% yield) of racemic-8-(4-methyl-piperazin-1 -yl)-4-oxo-chroman-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide (mp 215-216 °C). The mother liquor contained 76 mg that was used in the chiral 10 separation described below. LC/MS (M+l) m/z = 451. <br><br> Example 78a racemic-8-(4-Methyl-l-piperazin-1-yl)- 4-oxo-chroman-2-carboxylic acid hydrochloride. <br><br> racemic-Ethyl-8-(4-methyl-1 -piperazinyl)- 4-oxo-chroman-2-carboxylate (Example 78b) (0.33 g, 1.04 mmol) was dissolved in 6 M HCI (20 ml) and heated to 100 °C for 1.5 h. 15 The reaction was allowed to cool. The solution was concentrated in vacuo and anhydrous toluene was added (x3) and the solution was again concentrated in vacuo to give racemic-8-• (4-Methyl-l-piperazin-1-yl)- 4-oxo-chroman-2-carboxylic acid hydrochloride as a yellow foam (0.44 g, quantitative yield) that was used as is in the next reaction. LC/MS (M+l) m/z = 291. <br><br> 20 Example 78b racemic-Ethyl-8-(4-methyl-1 -piperazin-1 -yl)- 4-oxo-chroman-2-carboxylate. <br><br> Racemic-Ethyl-8-(4-methyl-l-piperazin-l-yl)-4-hydroxy-chroman-2-carboxylate (Example 78c) (0.43 g, 1.3 mmol) was dissolve in anhydrous dichloromethane (35 ml) and manganese dioxide (1.2 g, 13 mmol) was added. The reaction stirred at room temperature 25 overnight. <br><br> The reaction was filtered through diatomaceous earth and the solvent was removed in vacuo to give racemic-Ethyl-8-(4-methyl-l-piperazin-l-yl)- 4-oxo-chroman-2-carboxylate as a white solid (0.37 g, 86 % yield) that was used as is in the next reaction. GC/MS (EI, M+) m/z = 318. <br><br> 30 Example 78c racemic-Ethyl-8-(4-methyl-l-piperazin-l-yl)- 4-hydroxy-chroman-2-carboxylate. <br><br> Ethyl 8-(4-methyl-1 -piperazin-1 -yl)-4-ox:o-4H-chroman-2-carboxylate (reference example 1) (0.48 g, 1.5 mmol) was dissolved in glacial acetic acid (50 ml) and 10 % <br><br> WO 02/055014 <br><br> -118- <br><br> PCT/SE02/00070 <br><br> palladium on carbon (100 mg) was added. The mixture was hydrogenated on a Paar apparatus (50 psi) at 70 °C for 3 h. <br><br> The reaction was allowed to cool, the catalyst was filtered and the solution was concentrated in vacuo. Ethyl acetate / saturated sodium bicarbonate was added to the remains 5 and the mixture was extracted (x3) with ethyl acetate, dried (MgSO,*) and stripped to give racemic-Ethyl-8-(4-methyl-l-piperazin-l-yl)- 4-hydroxy-chroman-2-carboxylate (0.43 g, 90 % yield) as a yellow oil. GC/MS (EI, M+) m/z = 320. <br><br> Example 79 <br><br> 10 8-(4-Methyl-piperazin-1 -yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (faster running isomer). <br><br> The enantiomers of the racemic-8-(4-methyl-piperazin-l-yl)-4-oxo-chroman-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide (Example 78) (100 mg, 0.22 mmol) were separated by the use of a chiral column (ChiralPak AD, 5 cm X 50 cm, 20 |i). The isomers 15 were eluted with a gradient of 3 5-5 5 % isopropanol / hexane. The faster isomer was obtained as a light yellow solid (40 mg, mp 216 °C dec.) LC/MS (M+l) m/z = 451. <br><br> Example 80 <br><br> 8-(4-Methyl-piperazin-1 -yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-20 amide (slower running isomer). <br><br> The enantiomers of the racemic-8-(4-methyl-piperazin-l-yl)-4-oxo-chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide(100 mg, 0.22 mmol) were separated by the use of a chiral column (ChiralPak AD, 5 cm X 50 cm, 20 |i). The isomers were eluted with a o <br><br> O <br><br> WO 02/055014 <br><br> -119- <br><br> PCT/SE02/00070 <br><br> gradient of 35-55 % isopropanol / hexane. The slower isomer was obtained as an off white solid (32 mg, mp 215 °C dec.) LC/MS (M+1) m/z = 451. <br><br> Example 81 <br><br> F <br><br> N <br><br> Nk <br><br> T <br><br> 5 4-[4-({l-[6-Fhioro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-amino)-phenyl]-piperazine-1 -carboxylic acid ethylamide: <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide (Example 71) (150 mg, 0.216 mmol) was placed in a 50 mL flask with 10 mL of CH2C12- This suspension was treated with triethylamine (0.1 mL, 0.67 mmol) and 10 ethylisocyanate (0.21 mL, 18.7 mg, 0.26 mmol) and the reaction stirred at rpom temperature for 18 hours. The reaction was concentrated (1 mm Hg pressure) and the concentrate purified by chromatography on silica eluting with 1% methanol in chloroform, then concentrated (1mm Hg pressure). Then triturated with either to yield a yellow powder with was dried under high vacuum for 48. h at 50°C (79 mg) LCMS - AP+ 537.4, mp = 23.6-238°C. 15 Example 82 <br><br> 6-Methoxy-8-(4-methyl-[ 1,4] diazepan-1 -yl)-4-oxo-4if-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide: <br><br> Into a 100 mL round bottom flask equipped with a nitrogen inlet and magnetic stirrer 20 is added 327 mg (0.89 mmol, 1.0 equiv.) of 6-Methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride salt (Reference Example 23). This <br><br> WO 02/055014 <br><br> -120- <br><br> PCT/SE02/00070 <br><br> material is dissolved in 20 mL of DMF and then 189 mg (1.06 mmol, 1.2 equiv.) of 4-• moipholinoaniline is added. To the stirred solution is quickly added simultaneously added • 568 mg (1.77 mmol, 2.0 equiv.) of TBTU and 239 mg (1.77 mmol, 2.0 equiv.) of HOBT. At this point 457 mg, 577 jliL (25.2 mmol, 4.0 equiv.) is added via syringe over 5 minutes. The 5 reaction is allowed to stir at room temperature for 18 hrs, then is concentrated on a rotary evaporator under high vacuum in order to remove the DMF. The residue is triturated with methanol and the crude solids are recovered by filtration. These residues are then purified by flash chromatography using a gradient of 5-10% methanol in methylene chloride as eluent. The eluted material, which is obtained from chromatography, is concentrated, dried under 10 high vacuum, suspended in methylene chloride, dried over K2CO3, concentrated, then crystallized from methanol to give the free base of the pure product as 345 mg (79%) of a yellow solid. Mass Spec.: calc. for [C27H32FN405+H]+ Theor. m/z = 393; Obs. = 393 Example 83 <br><br> O <br><br> 15 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4Jf-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide: <br><br> Into a 100 mL flask equipped with a nitrogen inlet and magnetic stirrer is placed 133 mg (.748 mmol, 1.1 equiv.) of 4-morpholinoaniline, which is then dissolved in 20 mL of methylene chloride. To this mixture is then added 290 mg, 367 jiL (2.24 mmol, 3.3 equiv.) of, 20 ethyldiisopropyl amine, followed by addition of a solution of 250 mg (0.68 mmol, 1.0 equiv.) of 6-ethoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-4flr-chromene-2-carbonyl chloride (Reference Example 23) which has been dissolved in 10 ml of methylene chloride. The reaction is allowed to stir for 4 hr, after which no further formation of product was seen by LC/MS. The crude reaction was concentrated on a rotary evaporator, then triturated with 10 mL of 25 methanol. The crude solids were collected by filtration, then subjected to flash chromatography using a gradient of from 2 to 20% methanol in methylene chloride. <br><br> WO 02/055014 <br><br> - 121 - <br><br> PCT/SE02/00070 <br><br> Recrystallization from methylene chloride and hexanes afforded 55 mg (16%) of the pure product as a yellow solid. <br><br> Mass Spec.: calc. for [C27H32N4C&gt;5+H]+ Theor. m/z = 493; Obs. = 493 Example 84 <br><br> O <br><br> 5 O <br><br> 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4i?-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide: <br><br> This compound was prepared from 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4.flr-chromene-2-carbonyl chloride (Reference Example 23) and 10 175 mg (0.748 mmol, 1.1 equiv.) of l-[4-(4-Amino-phenyl)-piperazin-l-yl]-propan-l-one by an analogous procedure to that used to prepare the 4-morpholino aniline derivative, to give 45 mg (12%) of the desired product as a yellow solid. <br><br> Mass Spec.: calc. for [CsoH^NsOs+H]"1" Theor. m/z = 548; Obs. - 548 Example 85 <br><br> O <br><br> ,0. <br><br> 15 <br><br> 6-Methoxy-4-oxo-8-piperazin-1 -yl-4#-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide: <br><br> Into a 50 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 50 mg (0.115 mmol, 1.0 equiv.) of 6-Methoxy-8-(4-methyl-20 piperazin-l-yl)-4-oxo-4i/-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Example 31) and 10 mL of 1, 2 dichloroethane. To this solution is then added via syringe 49 mg, 37 (J,L (0.345 mmol, 3.0 equiv.) of 1-chloroethyl chloroformate. A precipitate forms, <br><br> WO 02/055014 <br><br> -122- <br><br> PCT/SE02/00070 <br><br> indicating formation of an intermediate. The reaction is heated to reflux for 3 days, whereupon an analysis of an aliquot by LC/MS indicates only a trace of product has formed. At this time 52 mg (0.345 mmol, 3.0 equiv.) of sodium iodide are added to the refluxing reaction. LC/MS analyses then progressively show formation of demethylated product over 5 5 additional days. The reaction is then cooled, concentrated on a rotary evaporator, then dried over K2CO3 as a suspension in methylene chloride containing methanol, removal of solids by filtration, followed by flash chromatography of the solution, using a gradient of 5 to 20% methanol in methylene chloride, gives 34 mg (64%) of the pure product as a reddish solid. Mass Spec.: calc. for [C25H28N405+H]+ Theor. m/z = 465; Obs. = 465 10 Example 86 <br><br> 4-yl-phenyl)-amide: <br><br> Into a 50 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and 15 magnetic stirrer is placed 50 mg (0.115 mmol, 1.0 equiv.) of 6-Methoxy-8-(4-methyl-piperazin-1 -yl)-4-oxo-4if-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Example 31) and 20 mL of methylene chloride. To this solution is added 1 mL of a IN solution of boron tribromide in methylene chloride. The reaction is stirred at room temperature for 2.5 days at which time it is complete by LC/MS. The reaction is concentrated 20 on a rotary evaporator, then methanol is added. The methanol is concentrated and readded 5 times, until the BBr3 is removed as HBr and trimethyl borate. The solid hydrobromide salt residue, which is obtained, is &gt;85% pure product by LC/MS. Mass Spec.: calc. for [C25H28N405+H]+ Theor. m/z = 465; obs. = 465 <br><br> WO 02/055014 <br><br> -123- <br><br> PCT/SE02/00070 <br><br> Example 87 (Method 1) <br><br> N <br><br> 6-Methoxy-8-(4-methyl-[ 1,4] diazepan-1 -yI)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide. <br><br> 5 . To a solution of 6-methoxy-8-(4-methyl-[l,4]diazepan-l-yl)-4-oxo-l,4-dihydro- <br><br> quinoline-2-carboxylic acid (2.10 mmol) (Reference Example 25b) and diisopropylethyl amine (1.4 mL, 8.6 mmol) in 34 mL dimethylformamide was added TBTU (1.40 g, 4.36 mmol) and HOBt (0.588 g, 4.35 mmol) followed by the addition of 4-morpholinoaniline (0.463 g, 2.60 mmol). The resulting dark brown solution was stirred' at room temperature 10 under nitrogen for 19 hours. The reaction was concentrated in vacuo and the resulting crude product was taken up in methylene chloride/methanol. Filtration of the resulting mixture afforded some product as a yellow solid. The filtrates were concentrated and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated sodium bicarbonate, dried (MgS04), and concentrated under 15 vacuum to afford a brown solid. This was suspended in methanol and filtered to afford the desired product as a yellow solid (0.714 g, 69%). !H NMR (300 MHz, DMSO, cU) 8 9.97 (bs, 1 H,NH), 7.67 (d, 2 H, J0= 8.8 Hz, ArHr&amp;JfcO. 7.47(bs, 1 H, ArHs), 7.00 (s, 1 H, C=CH), 6.99 (d, 2 H, JQ= 8.8 Hz, Arfij'&amp;jisO. 6.71 (bs, 1 H, ArH7), 3.85 (s, 3 H, OCH3), 3.75 (t, 4 H, J= 4.6 Hz, OCH2CH2N), 3.70 (bs, 2 H, ArNCHaCHaCHjNCHs), 3.55 (bs, 2 H, 20 ArNCH2CH2NCH3), 3.09 (t, 4 H, /= 4.6 Hz, OCH2CH2N), 2.95 (bs, 2 H, <br><br> ArNCH2CH2NCH3), 2.73 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.36 (s, 3 H, NCH3), 2.07 (bs, 2 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C27H33N504+H]+ Theor. m/z = 492; Obs. 492. <br><br> WO 02/055014 <br><br> -124 - <br><br> PCT/SE02/00070 <br><br> Example 87 (Method 2) <br><br> O <br><br> / <br><br> 6-Methoxy-8 -(4-methyl-[ 1,4] diazepan-1 -yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> ethoxymethoxy)-quinoline-2-carboxylic acid (4-moipholin-4-yl-phenyl)-amide (Reference Example 27d) (0.989 g, 1.59 mmol) in 20 mL methanol was poured into 300 mL 0.05 N hydrochloric acid. The clear dark yellow solution became cloudy within 5 minutes. The mixture was stirred at room temperature for 45 minutes and then adjusted to pH 7 with 10% 10 sodium hydroxide. The resulting yellow precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the desired product as a yellow solid (0.629 g, <br><br> 80%). !H NMR (300 MHz, DMSO, dg) 8 9.97 (bs, 1 H,C(0)NH), 7.67 (d, 2 H, /&lt;,= 8.8 Hz, ArHr&amp;Hg-), 7.47 (bs, 1 H, ArHs), 7.00 (s, 1 H, C=CH), 6.99 (d, 2H, J0= 8.8 Hz, ArHj-&amp; HsO, 6.71 (bs, 1 H, ArH7), 3.85 (s, 3 H, OCH3), 3.75 (t, 4 H, J= 4.6 Hz, OCH2CH2N), 3.70 15 (bs, 2 H, ArNCH2CH2CH2NCH3), 3.55 (bs, 2 H, ArNCH2CH2NCH3), 3.09 (t, 4 H, J= 4.6 Hz, OCH2CH2N), 2.95 (bs, 2 H, ArNCH2CH2NCH3), 2.73 (bs, 2 H, ArNCHaCHaCJ&amp;NCHs), 2.36 (s, 3 H, NCH3), 2.07 (bs, 2 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for • [C27H33Ns04+H]+ Theor. m/z = 492; Obs. = 492. Analysis for C27H33N504.1.0eqHCl. 0.3eqH20: Calculated C 60.79 H 6.54 N 13,13. Found C 60.82 H 6.53 N 13.17. <br><br> 20 Example 88 <br><br> 5 A solution of 6-methoxy-8-(4-methyl-[ 1,4]diazepan-1 -yl)-4-(2-trimethylsilanyl- <br><br> O <br><br> WO 02/055014 <br><br> -125- <br><br> PCT/SE02/00070 <br><br> 6-Methoxy-8-(4-methyl-piperazin-l -yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> The title compoimd was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according 5 to the procedures described in Reference Example 25a and in Example 87 (Method 1). A ' yellow solid was obtained. Mass Spec.: calc. for [C26H3iNs04+H]+ Theor. m/z = 478; Obs. 478. ' <br><br> Example 89 <br><br> 10 6-Methoxy-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)-phenyl]-amide. <br><br> The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method 1), except 15 that the amide was formed from l-[4-(4-amino-phenyl)-piperazin-l-yl]-propan-l-one. A yellow solid was obtained. Mass Spec.: calc. for [C29H36N604+H]+ Theor. m/z = 533; Obs. 533. <br><br> Example 90 <br><br> 6-Fluoro-8-(4-methyl-piperazin-1 -yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide <br><br> O <br><br> O <br><br> 20 <br><br> WO 02/055014 <br><br> -126- <br><br> PCT/SE02/00070 <br><br> The title compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid hydrochloride salt (Reference Example 26) using the procedure described in Example 87 (Method 1). After chromatography, it is then crystallized from methanol to give the pure product as 150 mg (55%) of a yellow solid. Mass Spec.: calc. <br><br> 5 for [C25H28FNs03+H]+ Theor. m/z = 466; Obs. = 466. <br><br> Example 91 <br><br> 0 <br><br> F« <br><br> 6-Fluoro-8-(4-methyl-piperazm-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid [4-(4-10 propionyl-piperazin-l-yl)-phenyl]-amide. <br><br> The title compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid hydrochloride salt (200 mg, 0.59 mmol) (Reference Example 26) using the procedure described in Example 87 (Method 1). 31% yield. Mass Spec.: calc. for [C2sH33FN603+H]+ Theor. m/z = 521; Obs. = 521. <br><br> 15 Example 92 <br><br> 8-[(2-Dimethylamino-ethyl)-methyl-amino]-6-methoxy-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> 20 The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl- <br><br> ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method <br><br> WO 02/055014 <br><br> -127- <br><br> PCT/SE02/00070 <br><br> 2), using N,N,N'-trimethyl ethylenediamine for the Pd catalysed coupling. A yellow solid was obtained. Mass Spec.: calc. for [C26H33Ns04+H]+ Theor. m/z = 480; Obs. = 480. Example 93 <br><br> carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method 10 2), using NjNjN'-trimethyl-1 ,3 -propanediamine for the Pd catalysed coupling. A yellow solid was obtained. Mass Spec.: calc. for [C27H3sN504+H]+ Theor. m/z = 494; Obs. = 494. <br><br> Example 94 <br><br> 8-((3R)-(+)-3-Dimethylamino-pyrrolidin -l-yl)-6-methoxy-4-oxo-l,4-dihydto-quinoline-2-15 caiboxylic acid (4rmoxpholin-4-yl-phenyl)-amide. <br><br> The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method 2), using (3R)-(+)-3-(dimethylamino)pyrrolidine for the Pd catalysed coupling. A yellow solid was 20 obtained. Mass Spec.: calc. for [C27H33Ns04+H]+ Theor. m/z = 492; Obs. = 492. <br><br> WO 02/055014 <br><br> PCT/SE02/00070 <br><br> -128- <br><br> Example 95 <br><br> O <br><br> N <br><br> \ <br><br> 8-((3S)-(-)-3-Dimethylamino-pyrrolidin -1 -yl)-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-caiboxylic acid (4-moipholm4-yl-phenyl)-amide. <br><br> The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method 2), using (3S)-(-)-3-(dimethylamino)pyrrolidine for the Pd catalysed coupling. A yellow solid was obtained. Mass Spec.: calc. for [C27H33Ns04+H]+ Theor. m/z = 492; Obs. = 492. <br><br> Example 96 <br><br> 6-Methoxy-8-[methyl-(l-methyl-pyrrolidin-3-yl)-amino]-4-oxo-l,4-dihydro-quinoline-2-carboxylic acid (4-morpholm-4-yl-phenyl)-amide. <br><br> The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method 2), using N,N'-dimethyl-3-aminopyrrolidine for the Pd catalysed coupling. A yellow solid was obtained. Mass Spec.: calc. for [C27H33N504+H]* Theor. m/z = 492; Obs. = 492. <br><br> O <br><br> \ <br><br> WO 02/055014 <br><br> -129- <br><br> PCT/SE02/00070 <br><br> Example 97 <br><br> carboxylic acid (4-morpholin~4-yl-phenyl)-amide. <br><br> 5 The title compound was prepared from 8-bromo-6-methoxy-4-(2-trimethylsilanyl- <br><br> ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (Reference Example 24c) according to the procedures described in Reference Example 25a and in Example 87 (Method 2), using 3-diethylaminopyrrolidine for the Pd catalyzed coupling. A yellow solid was obtained. Mass Spec.: calc. for [C29H37N504+H]+ Theor. m/z = 520; Obs. = 520. <br><br> 10 Example 98 <br><br> 4-Dimethylamino-6-methoxy-8-(4-methyl-piperazin-l-yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> To a suspension of 8-bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid 15 (4-morpholin-4-yI-phenyl)-amide (Reference Example 28b) (139.9 mg, 0.288 mmol), N-methylpiperazine (48 (XL, 0.43 mmol), and 4 A sieves in 15 mL anhydrous toluene was added Pda (dba)2 (15.3 mg, 16.7 p,mol), BINAP (63.0 mg, 0.101 mmol) and cesium carbonate (0.436 g, 1.345 mmol). The resulting wine colored mixture was heated at reflux under nitrogen for 20 hours. The reaction mixture was cooled to room temperature and 20 concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol to afford the desired product as a <br><br> WO 02/055014 <br><br> -130- <br><br> PCT/SE02/00070 <br><br> yellow solid (96.9 mg, 67%). ]H NMR (300 MHz, DMSO, d6) 810.06 (s, 1H, C(O)NH), 7.69 (d, 2H, J"0= 9.0Hz, ArH2-&amp;Hg-), 7.58 (s, 1 H, ArHs), 7.58 (d, 2H, Jd=9.0Hz, ArHs'&amp;HsO, 6.95 (d, 1 H, Jm= 2.7 Hz, ArHs), 6.76 (d, 1 H, Jm= 2.7 Hz3ArH7), 3.90 (s, 3 H, OCHs), 3.75 (t, 4 H, J= 4.8 Hz, OCHzCHaN), 3.37 (bs, 4 H, ArNC&amp;CHzN), 3.10 (t, 4 H, J= 4.8 Hz, 5 OCH2CH2N), 3.01 (s, 6 H, N(CH3) 2), 2.71 (bs, 4 H, ArNCHaCHjN), 2.35 (s, 3 H, R2NCH3); Mass Spec.: calc. for [C28H36N6O3+H]4" Theor. m/z = 505; Obs. = 505.5. <br><br> Example 99 <br><br> 10 morpholin-4-yl-phenyl)-amide. <br><br> The title compound was prepared from 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27b) according to the procedure described for Example 98 using N-methyl amine to prepare 8-bromo-4-methylamino-6-methoxy-' quinoline-2-carboxylic acid (4-morpholin-4-yl~phenyl)-amide. A glassy orange solid was 15 obtained. Mass Spec.: calc. for [C27H34N603+H]+ Theor. m/z = 491; Obs. = 491.5. <br><br> Example 100 <br><br> 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1 -yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. <br><br> 20 Into a 250 mL round bottom flask equipped with a nitrogen inlet and magnetic stirrer is added 2.01g (6.3 mmol, 1.0 equiv.) of 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-l-yl)- <br><br></p> </div>

Claims (2)

<div class="application article clearfix printTableText" id="claims"> <p lang="en"> WO 02/055014<br><br> -131-<br><br> PCT/SE02/00070<br><br> quinoline-2-carboxylic acid hydrochloride salt.. This material is dissolved in 20 mL of DMF and then 1.35 g (7.56 mmol, 1.2 equiv.) of 4-morpholinoaniline is added. To the stirred solution is quickly added simultaneously added 4.05g (12.6 mmol, 2.0 equiv.) of TBTU (2-(lH-benzotriazole-l-yl)-l,l,3,3tetramethyluroniumtetrafluoroborate) and 1.7 g (12.6 mmol, 5 2.0 equiv.) of HOBT (1-hydroxybenzotriaole hydrate). At this point 3.25 g, 4.11 mL (25.2 mmol, 4.0 equiv.) is added via syringe over 5 minutes. The reaction is allowed to stir at room temperature for 18 hrs, then is concentrated on a rotary evaporator under high vacuum in. order to remove the DMF. The residue is triturated with methanol and the crude solids are recovered by filtration. The material is then dissolved in methylene chloride and extracted 10 with 10% sodium bicarbonate solution. The organic layer is dried and then concentrated. These residues are then purified by flash chromatography using a gradient of 5-10% methanol in methylene chloride as eluent. The material which is obtained from chromatography, is then crystallized from methanol to give the pure product as 2.83g (93%) of a yellow solid.<br><br> Mass Spec.: calc. for [C26H3oFN503+H]+ Theor. m/z = 480; Obs. = 480 15 Example 101<br><br> 6-Fluoro-4-oxo-8-piperazin-1 -yl-4i7-chromene-2-carboxylic acid (4-moipholin~4-yl-phenyI)-amide: made according to the general method of Howarth et. al. Tetrahedron, 1998,54, 10899-10914.<br><br> Dry 6-flouro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-20 propionyl-piperazin-l-yl)-phenyl]-amide (Example 72)(1 g 1.9 mmol) was added to 100 mL of rigorously dried 1,2-dichloroethane in a flask under N2 atmosphere and magnetic stirring. The mixture was cooled to 06C and freshly distilled 1-chloroethyl chloroformate (650 ul, 858 mg, 6 mmol, 3 eq) was added drop wise. The reaction was then heated under reflux for 5 hours at which time LC/MS revealed complete consumption of starting material. Nal (lg, 25 leq) was added and heating continued for 2 days more. The reaction was then allowed to cool and filtered and evaporated to dryness under reduced pressure. MeOH (100 mL) was added and heated to reflux for 4h, filtered hot and evaporated to dryness. The product was isolated by chromatography using silica gel and CHC13/5% MeOH as an eluent. This gave 700 mg of the product HCI salt as a yellow solid. LCMS - m/z = 508.<br><br> WO 02/055014<br><br> -132-<br><br> PCT/SE02/00070<br><br> 5<br><br> I<br><br> O<br><br> Y<br><br> wherein<br><br> R! is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, thiomethoxy, -NHA, -NA2, -NHC(=0)A, aminocarbonyl, -10 C(=0)NHA, -C(=0)NA2, halogen, hydroxy, -OA, cyano or aryl;<br><br> A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;<br><br> R2 is represented by (i), (ii), (iii), or (iv) below:<br><br> 15 R3 is independently at each position represented by -H, optionally substituted C^aUqd, optionally substituted C2^alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3_6cycloalkyl or AOH;<br><br> n is 2, 3 or 4;<br><br> FH's a heterocyclic ring;<br><br> 20 R6 is -H or methyl;<br><br> Y is -C(=0)NH-, -C(=0)NA-, -C(=0)N(A)-, -NHC(=0)-, -C(=S)NH-, -CH2NH-, -C(=0&gt; -C(=0)CH2-, -CH2C(=0)-, -C(=0)-piperazine-, , -NAC(=0)-, -C(=S)N(A)-, CH2NA, NACH2 or a 5-membered heterocyclic.<br><br> (i)<br><br> R3 (iii)<br><br> (iv)<br><br> WO 02/055014<br><br> -133-<br><br> PCT/SE02/00070<br><br> R7 is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R8-R9 and R10; wherein R7 is connected to Y either by a single bond or by a ring fusion;<br><br> R8 is -CHr, -C(=0)-, -SO2-, - S02NH-,-C(=0)NH-, -0-, -S-, -S(=0)-, a single bond as tether 5 from R7 to R9, 5-membered heterocycle connected to R7 by a ring fusion or a single bond as tether;<br><br> R9 optionally substituted heterocycle, optionally substituted aryl, optionally substituted ■ piperazinyl-Rl 1, optionally substituted moipholinyl-Rl 1, optionally substituted thiomoipholinyl, or -C(=0)A;<br><br> 10 R10 is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH2-, methylthio, -NHA, -NA2, -NHC(=0)A, C(=0)NHA, C(=0)NA2&gt; or OA;<br><br> R" is -H, alkyl, AOH, -S02A, -S02NH2) -S02NHA, -S02NA2, -S02NHAR9, -C(=0)R9, -alkylR9, C(=0)A, C(=0)NH2, C(=0)NHA, C(=0)NA2 0r-C(=0)0A; or a phannaceutically 15 acceptable salt of said compound.<br><br> 2. A compound recited in claim 1 for use in the treatment of migraine in a human or animal in need of such therapy.<br><br> 3. . The use of the compound recited in claim 1 in the preparation of a medicament for the 25 treatment of migraine.<br><br> 4. A pharmaceutical composition comprising a compound as recited in Claim 1 or a phannaceutically acceptable salt thereof and a phannaceutically acceptable carrier.<br><br> 5. A compound of the Formula (Vie):<br><br> INTELLECTUAL PROPERTY OFFICE!<br><br> OF N.Z<br><br> 17 JAN 2005 —RECEIVED<br><br> WO 02/055014<br><br> -134-<br><br> PCT/SE02/00070<br><br> Vie wherein Rl is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA2, -NHC(=0)A,-5 aminocarbonyl, -C(=0)NHA, -C(=0)NA2, halogen, hydroxy, -OA, cyano or aryl;<br><br> A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;<br><br> • R2 is represented by (i), (ii), (iii), or (iv) below:<br><br> R<br><br> S (CH2)n ' N<br><br> anjuv<br><br> (CH2)n<br><br> \<br><br> ,N.<br><br> R<br><br> R<br><br> R<br><br> (0<br><br> (ii)<br><br> R3 (iii)<br><br> N<br><br> -R3<br><br> (iv)<br><br> 10<br><br> wherein R3 is independently at each position represented by -H, optionally substituted Ci^alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl or -AOH;<br><br> n is 2, 3 or 4;<br><br> P is a heterocyclic ring;<br><br> K is represented by O;<br><br> R" is C1-C4 alkyl; or a pharmaceutically acceptable salt of said compound.<br><br> The compound of Formula (VIfl):<br><br> INTELLECTUAL PROPERTY OFFICE OF W.Z<br><br>
1 7 JAN 2005 RECEIVED<br><br> -135-<br><br> Vlf1<br><br> wherein R1 is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA2, -NHC(=0)A, aminocarbonyl, -C(=0)NHA, -C(=0)NA2, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;<br><br> R2 is represented by (i), (ii), (iii), or (iv) below:<br><br> WLTb i<br><br> (CH2)0<br><br> -N \<br><br> I<br><br> OJWU<br><br> I<br><br> ^ (CH2)n<br><br> -N.,<br><br> R<br><br> R<br><br> R<br><br> (i)<br><br> (ii)<br><br> anjw&lt;<br><br> N<br><br> R-<br><br> R3<br><br> (iy)<br><br> wherein R3 is independently at each position represented by -H, optionally substituted C1-6 alkyl, optionally substituted C2-e alkenyl, optionally substituted C2-e alkynyl, optionally substituted C3-6 cycloalkyl or -AOH;<br><br> n is 2, 3 or 4;<br><br> P is a heterocyclic ring;<br><br> and X is represented by O, S, or N, or a phannaceutically acceptable salt thereof. 7. A compound of Formula (VIgl)<br><br> Vlg1<br><br> HCI<br><br> INTELLECT UAL^HUPERTY OFF/CT t 7 JAN 2005<br><br> WO 02/055014<br><br> -136-<br><br> PCT/SE02/00070<br><br> wherein R1 is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA2, -NHC(=0)A, aminocarbonyl, -C(=0)NHA, -C(=0)NA2, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted 5 alkenyl or optionally substituted alkynyl;<br><br> L represents a leaving group.<br><br> R2 is represented by (i), (ii), (iii), or (iv) below:<br><br> I<br><br> .N<br><br> -WW<br><br> f (CH2)n<br><br> \ M<br><br> ,N.<br><br> (CH2)n<br><br> \<br><br> (0<br><br> ■<br><br> R3 R3<br><br> (ii)<br><br> -R3<br><br> onjvA/<br><br> N<br><br> R;<br><br> (iv)<br><br> R3<br><br> R3 is independently at each position represented by -H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-6 cycloalkyl or -AOH;<br><br> n is 2, 3 or 4;<br><br> P is a heterocyclic ring;<br><br> and X is represented by O; or a pharmaceutically acceptable salt of said compoimd.<br><br> 8. A compound of Formula (Vlh)<br><br> Vlh1<br><br> wherein R1 is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA2, -NHC(=0)A, aminocarbonyl, -C(=0)NHA, -C(s=0)NA2, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;<br><br> R7 is as defined in claim 1;<br><br> R2 is represented by (i), (ii), (iii), or (iv) below:<br><br> INTELLECTUAL PROPERTY OFFICE OF NZ<br><br> 17 JAN 2005<br><br> RECEIV £ D<br><br> -137-<br><br> f (CH2)n<br><br> \ JsJ<br><br> \<br><br> .N,<br><br> R<br><br> R<br><br> R<br><br> (i)<br><br> (CH2)n (ii)<br><br> *R<br><br> 'VnjxAy<br><br> N<br><br> 'to<br><br> R3<br><br> (iv)<br><br> R is independently at each position represented by -H, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-C6 alkynyljoptionally substituted C3.6 cycloalkyl or -AOH;<br><br> n is 2, 3 or 4; and P is a heterocyclic ring;<br><br> and X is represented by 0; or a pharmaceutically acceptable salt of said compound.<br><br> 9. A process for preparing a compound of Formula (Vie) as recited in Claim 5 comprising reacting a compound of Formula (Vld):<br><br> OR"<br><br> with HR2 in the presence of a catalyst and a base.<br><br> 10. A process for preparing a compound of Formula (Vlfl) as recited in Claim 6 comprising heating a compound of Formula (Vie) as recited in Claim 5 in the presence of an acid and water to form a mixture wherein the mixture is hydrogenated using a catalyst.<br><br> 11. The process as recited in Claim 10 wherein the catalyst is palladium.<br><br> 12. A process for preparing a compound of Formula (VIgl) as recited in Claim 7 comprising replacing the hydroxyl group of the carboxylate moiety of Formula (VIg) with a leaving group.<br><br> WO
02/055014<br><br> -138-<br><br> PCT/SE02/00070<br><br> 13. A process for preparing a compound of Formula (Vlhl) as recited in Claim 8<br><br> comprising reacting a compound of (Vlfl) as recited in Claim 7 with H2R7, wherein R7 is a 5 monocyclic or bicyclic aromatic ring or a heterocycle, optionally substituted by one or more substituents selected from R8-R9 and R10; wherein R7 is connected to Y either by a single bond or by a ring fusion;<br><br> R8 is -CH2-, -C(=0)-, -SOr, - S02NH-, -C(=0)NH-, -0-, -S-, -S(=0&gt;, a five membered heterocyclic connected to R7 by a ring fusion or single bond as tether;<br><br> 10 R9 is morpholine optionally substituted with at least one substituent selected from A,<br><br> thiomoipholine, piperazin-R11, optionally substituted aryl, optionally substituted heterocyclic, or -C(=0)CA;<br><br> R10 is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH2-, methylthio, -NHA, -NA2, -NHC(=0)A, -C(=0)NHA, -C(=0)NA2) or 15 OA;<br><br> Rn is -H, alkyl, AOH, -S02A, -S02NH2, -S02NHA, -S02NA2, -S02NHAR9, -C(=0)R9, -alkylR9, C(=0)A, C(=0)NH2, C(=0)NHA, C(=0)NA2 0r-C(=0)0A.<br><br> 14. A process for preparing a compoimd of Formula (Vlhl) as recited in Claim 8<br><br> 20 comprising reacting a compound of Formula (VIgl) with H2R7 wherein R7 is a monocyclic or bicyclic aromatic ring or a heterocycle, optionally substituted by one or more substituents selected from R8-R9 and R10; wherein R7 is connected to Y either by a single bond or by a ring fusion;<br><br> R8 is -CH2-, -C(=0&gt;, -SO2-, - S02NH-, -C(=0)NH-, -0-, -S-, -S(=0)-, a five membered 25 heterocyclic connected to R7 by a ring fusion or single bond as tether;<br><br> R9 is morpholine optionally substituted with at least one substituent selected from A, thiomoipholine, piperazin-R1optionally substituted aryl, optionally substituted heterocyclic, or -C(=0)CA;<br><br> R10 is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, 30 halogen, -C(=0)NH2-, methylthio, -NHA, -NA2, -NHC(=0)A, -C(=0)NHA, -C(=0)NA2, or OA;<br><br> R11 is -H, alkyl, AOH, -S02A, -S02NH2, -S02NHA, -S02NA2, -S02NHAR9 -C(=0)R9, -alkylR9, C(=0)A, C(=0)NH2, C(=0)NHA, C(=0)NA2 or -C(=0)0A.<br><br> -139 -<br><br> 15. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to Claim 1 substantially as herein described with reference to any example thereof.<br><br> 16. A pharmaceutical composition according to Claim 4 substantially as herein described with reference to any example thereof.<br><br> 17. A compound of the Formula (Vie) according to Claim 5 or a pharmaceutically acceptable salt thereof substantially as herein described with reference to any example thereof.<br><br> 18. A compound of the Formula (Vlfl) according to Claim 6 or a phannaceutically acceptable salt thereof substantially as herein described with reference to any example thereof.<br><br> 19. A compound of the Formula (VIgl) according to Claim 7 or a pharmaceutically acceptable salt thereof substantially as herein described with reference to any example thereof.<br><br> 20. A compound of Formula (Vlh) according to Claim 8 or a pharmaceutically acceptable salt thereof substantially as herein described with reference to any example thereof.<br><br> 21. A process according to Claim 9 for preparing a compound of Formula (Vie) substantially as herein described with reference to any example thereof.<br><br> END OF CLAIMS<br><br> INTELLECTUAL PROPERTY OFFICE OF l\LZ.<br><br> 17 JAN 2005 RECEIVED<br><br> 100093857J.DOC<br><br> </p> </div>
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