ZA200305318B - Therapeutic chroman compounds. - Google Patents

Description

THERAPEUTIC CHROMAN COMPOUNDS

. Field of the Invention

This invention relates to novel 8-amino derivatives, methods for their preparation, v 5 pharmaceutical compositions containing them and their use in therapy.

Background of the Invention

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, cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. Serotonin receptors have been subdivided into at least 14 subtypes, see Bamnes 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 related receptors. This family includes the 5-HT;g and 5-HTp receptor subtypes.

Compounds that interact with the 5-HT, family are known to have therapeutic potential in the above mentioned disorders and diseases. In particular, compounds that are SHT 5 and SHTp antagonist have been known to be antidepressant and anxiolytic agents. Compounds that are 5HTg and 5HTp agonists have been used in the treatment of migraine.

Summary of the Invention

Provided herein is a compound having the formula (I): E

R®

R! o 0 y~

R2 wherein : R! is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, , thiomethoxy, -NHA, -NA,, -NHC(=0)A, aminocarbonyl, ' -C(=0)NHA, -C(=0)NA; halogen, hydroxy, -OA, cyano or aryl;

A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R? is represented by (i), (ii), (iii), or (iv) below: 4 N EIA \ Co og Sp —FK Ne : R3 : “(1 (ii) (iii) iv)

R’ is independently at each position represented by —H, optionally substituted C,.¢alkyl, optionally substituted Casalkenyl, optionally substituted C;.salkynyl, optionally substituted

Csigcycloalkyl or AOH;- : nis 2, 3 or 4; oo

P is a heterocyclic ring; ‘R% is -H or methyl;

Y is -C(=O)NH-, -C(=0)NA-, -C(=0)N(A)-, -NHC(=0)-, -C(=S)NH-, -CH,NH-, -C(=0)-, -C(=0)CH;-, -CH,C(=0)-, -C(=O)-piperazine-, , -NAC(=0)-, -C(=S)N(A)-, CHzNA,

NACH; or a S-membered heterocyclic.

R7 is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from R®-R°® and R'°; wherein R” is connected to Y either by a single bond or by a ring fusion; :

R%is -CH,-, -C(=0)-, -SO»-, - SO,NH-, -C(=0)NH-, -O-, -S-, -S(=0)-, a single bond as tether from R” to R’, or a five membered heterocyclic connected to R by either a single bond or by ring fusion;

R’ is optionally substituted heterocycle, optionally substituted aryl, optionally substituted : piperazinyl-R11, optionally substituted morpholinyl-R11 or optionally substituted ~ 20 thiomorpholinyl- or -C(=0)A; : oo

R! is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH,-, methylthio, -NHA, -NA,, -NHC(=0)A, C(=0)NHA, C(=0)NA,, or

OA; :

R'is -H, alkyl, AOH, -SO,A, -SO;NHa, -SO;NHA, -SO;NA,, -SO;NHAR’, -C(=O)R’, -alkylR®, C(=0)A, C(=0)NH,, C(=0)NHA, C(=0)NA; or -C(=0)OA; or a pharmaceutically ’ acceptable salt of said compound.

The term “hydrocarbyl” refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.

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. . 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. ' 5 The term “alkynyl” refers to straight or branched chain hydrocarbyl radicals having at ~ least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.

The term “cycloalkyl” refers to ring-containing hydrocarbyl radicals comprising at least 3 up to about 12 carbon atoms.

The term “cycloalkenyl” refers to ring-containing hydrocarbyl radicals having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms. © 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. - The term “aromatic” refers to hydrocarbyl radicals having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 6 up to about 14 carbon atoms.

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.

The term “alkylene” refers to divalent alkyl moieties, wherein said moiety serves to link two structures together.

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 saturated or unsaturated, containing one or more double bonds, and heterocyclic moieties may contain more than one ring. : The term “heteroaryl” refers to heterocyclic monovalent and divalent radicals having ) aromatic character.

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, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-

dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-1/4-azepine homopiperazine, 1,3- dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide. In addition heterocyclic moieties include heteroaryl rings such as: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, . thienyl, furyl, pyrroly}, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 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, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. oo

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 both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

The term “halo” or “halogen” refers to fluorine, chlorine, bromine and iodine radicals.

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, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy..

The term amine or amino refers to radicals of the general formula -NRR’, wherein R - and R’ are independently selected from hydrogen or a hydrocarby radical.

Detailed Description of the Invention

In a further aspect of the invention, A, R! and R3, each independently, as an alkyl, alkenyl, alkynyl and as a cycloalkyl, may optionally be substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carboxamido, amidino, carbamoyl, mercapto, sulfamoyl, C,4 alkyl, C4 alkenyl, C,4 alkynyl, Cj. cycloalkyl, Cs. cycloalkenyl, C).4 alkoxy, Cy.4 alkanoyl, C;.4 alkanoyloxy, N~(C;4 alkyl), N(Ci.4 alkyl),, C14 alkanoylamino, . ) (Cia alkanoyl);amino, N-(C;4 alkyl)carbamoyl, N,N-(C;4 alkyl),carbamoyl, (Ci4)S, (C14 alkyl)S(O), (Ci4alky)S(0)2, (C14) alkoxycarbonyl, N-(C4 alkyl)sulfamoyl, N,N-C4 . alkyl)sulfamoyl, C;.4 alkylsolfonylamino, and heterocyclic. :

Examples of optional substituents for aryl and heterocyclic groups, when not otherwise defined, are halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy,

carboxamido, amidino, carbamoyl, mercapto, sulfamoyl, C;_4 alkyl, C,4 alkenyl, C,4 alkynyl,

Cs. cycloalkyl, Cs. cycloalkenyl, C,.4 alkoxy, C4 alkanoyl, C4 alkanoyloxy, N-(C,4 alkyl), . N(C,4 alkyl);, C14 alkanoylamino, (C4 alkanoyl),amino, N-(C4 alkyl)carbamoyl, N,N-(C14 alkyl),carbamoyl, (C;4)S, (C4 alkyl)S(0O), (C 1-4alkyl)S(O),, (C,.4) alkoxycarbonyl, N-(Ci4 ' 5 alkyl)sulfamoyl, N,N-Cj.4 alkyl)sulfamoyl, C;.4 alkylsolfonylamino, and heterocyclic.

A, R! and R? each independently as an alkyl, alkenyl or alkynyl may be straight or branched, preferably having 1-6 carbon atoms. A, R' and R® preferably have 3-6 atoms when each are independently a cyclic alkyl. Other preferable values for A, R! and R® when each . are an alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, neopentyl and cyclohexyl. Preferable values for R' when R! is a halogen are fluorine, chlorine, and bromine. Other preferable values for R! when R! is at position 6 on the "bicyclic ring are methyl, ethyl, ethoxy and methoxy. Preferable values for R' when R'is at position 5 on the bicyclic ring are —H, methyl, ethyl and methoxy. When R' is at position 5- on the bicyclic ring, R! is more preferably -H. When R' is at position 7- on the bicyclic ring,

R'is preferably —H.

R? is preferably represented by Formula i. Preferably R? is represented by formula i, wherein n equals 2. Most preferably R? is represented by N-methyl piperazinyl.

R?is preferably represented by hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. R® is most preferably represented by methyl.

R* is preferably represented by hydrogen, methyl, ethyl, n-propyl, isopropyl and trimethylsilanyl-ethoxymethoxy. R* is most preferably represented by methyl.

RS is preferably represented by H. :

Y represents a linking group. Y is preferably -C(=0)N(CH;)-, when Y is -C(=O)N(A)-. Y may also be ~C(=0)-piperazine. When Y represents a five-membered 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.

More preferably, Y is ~-C(=O)NH-. . 30 Examples of R’ 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;

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. .

R’ may also be represented by the Formula (v):

IAN

[pee ¥)

P ~

R!0

R” may further be represented by the Formula (vi): x : —_RS—R® (vi)

Ce.

When the values for R” are as set forth above, R® may be a single bond as tether, -C(=0)-, ~~ -CHs-, -C(=0)-~, ~-S0;-, -S(=0)-, -S-, -0-, -C(=0)NH-, -SO,NH-, or a five membered heterocycle connected to R” by single bond or by a ring fusion; and R’ may represent an aryl, heterocyclic or heteroaryl each independently optionally substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C; alkyl,

Cs.alkenyl, C4 alkynyl, Cs.6 cycloalkyl, Cs. cycloalkenyl, C;4 alkoxy, C;4 alkanoyl, C4 : alkanoyloxy, N-(C,4 alkyl), N(Ci4 alkyl), C14 alkanoylamino, (C4 alkanoyl)>amino, N-(C,. salkyl)carbamoyl, N,N-(C;4),carbamoyl, C14)S, C143(0), (Ci4alkyl)S(=0),, (Ci) alkoxycarbonyl, N-(C,.4 alkyl)sulfamoyl, N,N-C, 4 alkyl)sulfamoyl, C,.4 alkylsolfonylamino, or heterocyclic. Preferably R’ is an optionally substituted heterocyclic moiety.

More preferably R’ represents piperazine, thiomorpholine or morpholine each independently optionally substituted on carbon with at least one substituent selected from A.

R® may be a five membered heterocycle, incorporating at least one heteroatom selected from

N, O, or S and it may be connected to R’ by a ring fusion, preferably when R is phenyl.

When R® is a single bond as tether, R’ is preferably methoxy, cyano, a five-membered heterocycle optionally substituted with at least one substituent represented by A or R'! for oe example compounds represented by the Formulas (vii), (viii) and (ix):

N N—RT (ii)

. N o—RU! (viii) ’

SN

N s—R! (vii) s

When R® is represented by a 5-membered heterocyclic comprising N and further when it is connected to R’ by a ring fusion, R’ is preferably -C(=0)A attached at the nitrogen atom.

R? is most preferably —C(=0)CH,CH; .

When R’ is phenyl or a 6-membered heterocyclic ring, R’, is attached via the R® tether at the 2-, 3- or 4-position of the phenyl or a 6-membered heterocyclic ring. Preferably, R'is attached via the R® tether at the 3- or 4-position of the phenyl or a 6-membered heterocyclic ring. More preferably, R’ is attached via the RS tether at the 4 position of the phenyl or a 6- membered heterocyclic ring.

R'® may be represented by alkyl or cycloalkyl each independently optionally substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C4 alkyl, C,4alkenyl, C14 alkynyl, Ci cycloalkyl, Cs. cycloalkenyl, ‘C4 alkoxy, C).4 alkanoyl, C4 alkanoyloxy, N-(C;.4 alkyl), N(C, alkyl), C14 -alkanoylamino, (C;_4 alkanoyl);amino, N-(Ci.4alkyl)carbamoyl, N,N-(C;.4),carbamoyl, C;.4)S,

C1.45(0), (C14alkyl)S(O),, (C14) alkoxycarbonyl, N-(C,4 alkyl)sulfamoyl, N,N-C;4 alkyl)sulfamoyl, C4 alkylsulfonylamino, or heterocyclic. R'? is preferably a halogen, - preferably chlorine or fluorine, cyano, or ~OCH;. When R'is a halogen it is preferably chlorine or fluorine. When Risa phenyl or 6-membered heteroaromatic ring, RY is attached at the 2-, 3- or 4-position of the phenyl or a 6-membered heterocyclic ring. : Preferably, R'? is attached at the 2- or 3-position of the phenyl or a 6-membered heterocyclic ring when R® is attached via the R® tether at the 4-position of the phenyl or a 6-membered heterocyclic ring. More preferably, R'® is attached at the 3-position of the phenyl or a 6- membered heterocyclic ring when R’ is attached via the R® tether at the 4-position of the phenyl or a 6-membered heterocyclic ring.

When R? is represented by a single bond as tether, R’ 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 R attached to the tether, with a substituent represented by RY (see e.g., Formulas (vii), (viii) and (ix). The preferred heterocyclic compounds for R8 “are piperazine, morpholine, or Ct thiomorpholine

When R!! represents SO,A it is preferably represented by an alkylsufonyl, more preferably -SO,CHj, -SO;,CH,CH;, SO2-n-C3Hy, SO4-i-C3Hy, SO2-n-CyHig, -SO,-i-C4H),, or -

SO,-t-C4H}o. When R'! represent C(=0)A, it is preferably represented by an alkylcarbonyl ~ 10 more preferably ~C(=0)CHs, ~C(=0)CH;CHj;, C(=0)-n-C4H,g, -C(=0)-i-C4Hjj, -C(=0)-t-

C4Hjo, or ~C(=0)C;3H;.- When R!! is represented by C(=0)NHA or C(=0)NA, it is preferably an alkyl or dialkyl carbamoyl more preferably C(=0)NCH,CHs, C(=O)NH-cycloCgHj,, or

C(=0)NH-cycloCsH,q,. When R'is represented by C(=0)R’ it is preferably —C(=0)- pyrrolidine, or ~C(=0)-morpholine. When RY is represented by SO;NA,; it is preferably

SO,N(CH;);, . When R!! is represented by AOH, it is preferably represented by, CH,CH,0H or -C(=0)CH,CH,OH. R!! may also be represented by —C(=0)OCH,o.

In preferred embodiments, when Y is represented by —C(=0)NH: (a R'is halogen or methoxy, most preferably fluorine, at the 6™ position of the bicyclic ring, and is preferably hydrogen, methyl, ethyl or methoxy at the 5% position of the bicyclic ring, and is hydrogen at the 7 position on the bicyclic ring; (b) R?is methyl piperazine; : (c) Reis hydrogen; * (@ Ris phenyl substituted with R8-R9 (e) R%isa single bond as tether; (f) R’isa heterocyclic moiety, preferably morpholine or piperazine attached to R® by + nitrogen and optionally substituted on the other nitrogen (for piperazine) with R'! or optionally substituted on the oxygen with R'' when R’ is morpholine; . . (2) R'is AOH or —S0,A wherein A is represented by methyl or ethyl. ~The compounds provided herein are useful in the form as a free base, but may alsobe - 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:

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 pharmaceutically-acceptable salts of compounds of the present invention include for y 5 example hydrochloride, sulfate, pyrosulfate, bisulfate, bisulfite, nitrate, and phosphate.

Processes for the manufacture of the compounds of Formula 1 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 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

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): £0, | : 7 XH

Halogen

Via ®R', R? R? and R’ are as defined for Formula I unless otherwise specified and X is represented by 0), with for example a compound represented by::

ROC —==—COR , wherein R’ is represented by alkyl, preferably lower alkyl (e.g.,

C,-Cs) most preferably methyl or ethyl, to form a precursor compound of Formula (VIb):

a COR’ : 7

RT 1 SE

Ay 7 COR

Halogen :

Vib : :

R'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. : : Further provided herein is a process for the preparation of a precursor compound comprising hydrolyzing the esters of compound (VIb) to form intermediate (VIc):

CO,H

CY

Ri——

ZF X CO,H : . ‘Halogen :

Vic .

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 oo preparation of an intermediate by the cyclization of compound (VIc) to form intermediate (VId)

0]

N

" : Ry—— = OR"

X

. Halogen 0 :

Vid

Intermediate compound (VId) may be formed by refluxing a compound of Formula (VIc) with a strong acid (e.g., H,SO) and further refluxed with heat and an alkyl alcohol for example ROH wherein R*’ is C;-C, alkyl, preferably ethyl.

In an additional aspect of the invention, a process is provided for the preparation of an intermediate by reacting a compound of Formula (VId) with an amine of R%in the presence of a catalyst and a base to form intermediate Formula (Vie): 8) . 10 hd

R = | "

X OR

OR? 0

Vie

In a further embodiment of the invention, a compound of Formula (VId) is reacted with a catalyst selected from the group consisting of nickel and palladium. Preferably the palladium i 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. "Further provided herein is an acid hydrochloride of a compound of Formula (VIe) which is intermediate Formula (VIf):

’

Oo

SPI x

R= JP

Lo X OH

R? oO

HCI

. Vif

The intermediate Formula (VIf) may be formed for example by heating a compound of

Formula (VIe) in the presence of an acid and water (e.g., HCL/H,0).

In another aspect of the invention provided is intermediate Formula (VIg):

O .

R= a

R 0

HCI

Vig

Thus, in another aspect of the invention, a leaving group is added to the carboxylate of a compound of Formula (VIf). 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 (VIf) with ) 5 thionyl chloride (SOCl,).

Provided herein is a compound of Formula (VIh):

Oo 1] os

N

FF x “NRT R2 © - Vih

Methods for reacting amines with acid chlorides may be used to prepare compounds of - formula I such as a compound of Formula (VIh) For example, a method for the preparation of (VIh) may include reacting a compound of Formula (VIg) with H,N-R’ in the presence of

DIPEA.

Alternatively, compounds of Formula (VIh) may also be prepared by reacting a compound of Formula (VIf) with HoN-R’ in the presence for example 1- hydroxybenzotriazole (HOBT), O-(1H-Benzotriazol-1-yl)-N,N,N’N’-pentamethylene- . uronium tetrafluorborate (TBTU), and (dimethylamino)pyridine, preferably in that order.

Compounds of Formulas (VIe), (VIf), and (VIg), and (V1h) may also comprise a : pharmaceutically acceptable salt of said compounds.

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.

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): 5 . : 7 XH

Halogen : : Via Co (R, Rr? R®, and R” are as defined for Formula I unless otherwise specified and X is represented by O), with for example a compound represented by:

R'O,C ——— =——CO,R’ . . » Wherein R is represented by alkyl, preferably lower alkyl (e. g,

C,-Cs) most preferably methyl or ethyl, to form a precursor compound of Formula (VIb): ~~ CO5R' ee) Lo

Halogen

Vib

R'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.

Further provided herein is a process for the preparation of a precursor compound comprising hydrolyzing the esters of compound (VIb) to form intermediate (VIc):

CO,H

Ri—— a x CO,H

Halogen

Vic

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 (VId) 0)

Xx

Rr | OR"

X

: Halogen 0

Vid

Intermediate compound (VI1d) may be formed by refluxing a compound of Formula (VIc) with a strong acid (e.g., H>SO) and further refluxed with heat and an alkyl alcohol for ’ example R’°’OH wherein R’’ is C;-C4 alkyl, preferably ethyl. :

In an additional aspect of the invention, a process is provided for the preparation ofan intermediate by reacting a compound of Formula (VId) with an amine of R? in the presence of a catalyst and a base to form intermediate Formula (Ve):

0 : NN 1 I

RTC | . : X OR

R? 6)

Ve

In a further embodiment of the invention, a compound of Formula (VId) is reacted with a catalyst selected from the group consisting of nickel and palladium. Preferably the palladium is provided in the presence ofa 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.

Further provided herein is an acid hydrochloride of a compound of Formula (Ve) . which is intermediate Formula (VIF): : . 'e) ° ) 1 l :

RET]

OX OH

R? o)

HCI

Vif

" The intermediate Formula (VIf) may be formed for example by heating a compound of

Formula (VIe) in the presence of an acid-and water (e.g., HCL/H,0).

In another aspect of the invention provided is intermediate Formula (VIg): o fT : | | X L

R? 0 : HCI

Vig :

Thus, in another aspect of the invention, a leaving group is added to the carboxylate of a compound of Formula (VIf). Lis 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 (VIf) with thionyl chloride (SOCl,). ‘Provided herein is a compound of Formula (VIh):

0 soo¥ a

AF X NY

R2 O | E

Co Vih

Methods for reacting amines with acid chlorides may be used to prepare compounds of formula I such as a compound of Formula (VIh) For example, a method for the preparation of (VIh) may include reacting a compound of Formula (Vig) with H,N-R’ in the presence of

DIPEA. .

Alternatively, compounds of Formula (VIh) may also be prepared by reacting a compound of Formula (VIf) with H;N-R’ in the presence for example 1- hydroxybenzotriazole (HOBT), O-(1H-Benzotriazol-1-yl)-N,N,N"N’-pentamethylene- uronium tetrafluorborate (TBTU), and (dimethylamino)pyridine, preferably in that order.

Compounds of Formulas (VIe), (VIf), and (VIg), and (VIh) may also comprise a pharmaceutically acceptable salt of said compounds. ‘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.

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: | -

AN CO,R' CO,R'

R'— =z A XC

ZF OH Br R'—- P

Halo" © OR

R' = CH3, C,Hj5 J ogen ’ Halogen = Cl, Br (R')q = -OCHj, F, CHa. Cl, OE, H. Vib

Via | | | NaOH (@]

B CO,H

Ril | 1. HySO, We TE

Ll Off =—— RT 0) a CO,H een 2. EtOH, reflux 0 2

Hal®d 0 Hal°9e"

Vid H

N, Vie ( (CH2)n ( Or precursor amines for (ii) or 0)

N structural variations of R? ‘3

Pd catalyst phosphine ligand cesium carbonate o °

IAN r-L | HOMO pil hd

Zo OEt — —~ a OH

AN o ~~ N 0 (lpr (pn

N . : N, HCI

R R3

Vie vif

Scheme 1: Preparation of chromone-2-carboxylic acids as intermediates in the synthesis of : compounds of the present invention.

Alternatively, the chromone-2-carboxylic acid may be converted to the acid chloride and reacted immediately with an appropriate amine, as depicted in Scheme 2, below:

0 Oo

AN

RI soc, Ne

C RI 1] ——— 0 OH cl ae

N_ Oo :

N N Oo (CH), . N CH / HCl {Fri

N N HCI

R® \_3 vin ©

Vig N80 AN ——R°R DIPEA| = | —Rr®R®

HNT Z

’ 2 HoN ‘

TBTU, HOBT o

DMF, DIPEA 6

Ri— | H

P= N 0 - N_ 0 PF { (FHz)n

N - \ . Vii rR”

Scheme 2. Amide synthesis via acid chloride intermediate.

Additional functional group manipulations include, but are not limited to, O- dealkylation and N-dealkylation (Scheme 3).

® 0 o :

He” HO

H BBr: k] H

IOS CURL IES Gb 8 6

N [o) ’ Ls Ls \ Example 31 N Example 86

CHa dn, 1-chloroethyl chloroformate . 64% : 0 0.

Hee” SE

N

0 .

TCL

( ) NY .

N Example 85 (LS ;

H

Scheme 3: Functional group manipulation with compounds of the present invention includes, but is not limited to, N- and O- dealkylation

Quinoline and quinolone compounds of the present invention are prepared and derivatized via synthetic routes similar to those employed for synthesis of the chromone-2- carboxamides described above and in Schemes 1-3. These synthetic routes to quinoline and quinolone compounds of the present invention are depicted in Scheme 4, infia.

MeO. _.0O 0 methanol H 1 + reflux OMe

R oe on oo

NH, N © :

Br MeO” SO Br 0 0

R= OCH, or F : 230°C : . 0 No SCH); 0

NaH’ 1 os -~ R

R P OMe 2-(trimethylsilyl)ethoxy- N OMe

N methyl chloride 2 H L!

Br 0 r ’ amine, Pd | ’ oo SiCH); 0 ]! 0

R .

R' ES : amine ——— ——

R 0 - THF/MeOH/H,0 R> H 0 R2 0

OMe

OMe - i PN RL ' : —- OMe NaH

R a n CH,1

ZZ pz OH -—— | _ OM -— A nt

N LiOH ZN € amine, Pd P OMe

R® O THF/MeOH/H,O ge S N . : Br 0] amine i oy | THF/MOH/H )

HOB cOH/H,

OMe 7 R! § xX 1 ~ R’ Be Ed

R P NHAr Ni Cl oxalyl chloride N OH

N

R2 0 Br eo] Br H o 1) amine . 4

RN, -R 4 4 cl N RNR

EN 1 x: amine, Pd XN rR! — R —_— R!

NZ NHAT amine NZ HAT 2A __NHAr

A, 60 psi , N : Br 0 Br oO R o amine ic TBTU 0 oo , 0 No SH Hj)g o HOBE . R R

Rr! ES NaH : NHAr —~=—— ©

N amine, Pd Nd NHAr } N NPAr

Rr? H 0 2-(trimethylsilyl)ethoxy- H

Br O methyl chloride Br o

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 stereoisomeric forms, or mixtures thereof, which forms 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. ’

Compounds of Formula I have been found to be 5-HT,p and 5SHTp 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 salt of said compound. : 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.

The invention further provides a pharmaceutical composition suitable for the treatment 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.

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. "All compounds described herein demonstrate binding affinities (observed Ki values), in an assay described below, of less than about 10uM. Further, compounds of the present invention not only demonstrate SHT),g antagonist activity by reversing SHT,p 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 SHT)p antagonist activity in a dosage range of 0.006-5.5 mg/kg. In 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 agonism (low percentages) to antagonism (high percentages).

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 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 ofa suppository. The compounds described herein may also be administered parentally, for example by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion.

The compounds may be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally or sublingually.

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, sweetening, flavoring and/or preservative agents.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon 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 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 SHT;p and SHTp :

The utility of the compounds for example to treat depression may be 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 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 L X 16 W X 21 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 shocks. Induction is conducted for 2 consecutive days.

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 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 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. “Avoidance training, 45-min in duration, is conducted on 2 consecutive days, beginning 48 hr after the final induction session. Seventy subjects are assigned to 1 of 6 groups of 11-12 animals. The groups are as follows: 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; 2) Induction vehicle control group; 3) Imipramine 17.8 mg/kg; 4) 0.3 mg/kg compounds; 5) 1 mg/kg compounds; and . : 6) 5 mg/kg compounds.

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 . avoidance training session. :

Compounds of the present invention may be administered in a volume of ImL/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.

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. © Other assays that may be used to measure for example affinity of compounds of the present invention for SHTg and SHT)p 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-HT 5 receptors and 5-HT)p receptors are thawed rapidly, briefly vortexed, and diluted in assay buffer (AB) containing 50 mM Tris-HCI, 4 mM MgCl,, 4mM CaCl,, 1 mM EDTA, and adjusted to pH 7.4 with NaOH. Final protein concentrations are - 0.185 mg/ml for 5-HT)s, and 0.4 mg/ml for 5-

HTp membranes. Test compounds are evaluated in competition assays using ["H]-GR125743 (Amersham). The ligand concentration In both assays was 0.27nM. Kd for [’H]-GR125743 - may vary from 0.15 nM to 0.25 nM. The 5-HT;p and 5-HTp assays are performed 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 pl compound/nonspecific; 100 pi membranes; 100 pl [3H]}-GR125743; and 790 pl AB. Specific binding is defined by using 10 SE 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 > 2 hrs. in PEI) using a Packard Filtermate 196. Filters are washed 2x with 1 ml ice-cold wash buffer (5 mM Tris-HCI - pH7.4 with NaOH). After the filters are dried, 35 pl 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

J potency, and selectivity for 5-HT,g over 5-HT,p receptors.

A method that may be used to determine a compound’s affinity for 5-HT pz and SHTip 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 and homogenized in 50 mM Tris-HCI, 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. "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: [PH]GR125743 saturation studies are tested in duplicate with 3-4 mg w.w. per tube in 5 mL buffer (50 mM Tris, 4 mM CaCl2, 4 mM MgCl2 and | 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 4 hours at 30°C and terminated by rapid filtration through Whatman GF/B filters (pretreated with 0.1% polyethyleneimine) using a Brande! 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 K4 values obtained from the saturation studies are used in the calculation of the Ki values by the LIGAND program. The

Ka value of ["H]JGR125743 may result in a measurement of 46 +4 pM and the Bin a measurement of 4.9 + 0.2 pmol/g w.w.

A GTPyS binding assay may used to determine whether a compound is a SHT;p or )

A 5HT)p 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-HT receptors are purchased for example from Unisyn, Hopkinton, MA. Frozen membranes are thawed, briefly sonicated, and diluted to 167g/ml protein in assay buffer containing 20 mM

HEPES, 100 mM NaCl, 1mM MgCL; and 1uM GDP, pH adjusted to 7.4 with NaOH.

Diluted membranes are briefly homogenized with a Polytron and allowed to equilibrate at room temperature for at least 15 minutes before ise. Serial dilutions (10 uM 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 quadruplicate in 96-well, deep-well plates and consisted of 180 pL. of membranes (30 pug | : protein) and 40 LL of compound with or without 5-HT. After an incubation period of 15 minutes at room temperature, 20 uL of [* S]GTPYS (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

Beckman GF/B glass fiber filters using a 96-well Packard cell harvester. Filters are 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 [*SIGTPYS binding is defined in the presence of 100nM 5-HT. Basal [**S]GTPYS binding is defined in buffer alone. IC50 values are defined as the concentration of compound at which 50% of the 100nM 5-HT response [was] obtained. Maximal intrinsic activity (IA) of a compound is defined as the percent maximal 5-HT-induced stimulation by 10 pM compound in the absence of 5-HT. As an inter-assay standard, a concentration response curve of 5-HT 1 uM to 1pM final) in the absence of compounds was included in each assay and an ECsq was determined.

Preferred compounds of the present invention include, but are not limited to, the . following compositions listed in Table 1 on the following pages. :

Table 1: Compounds.

EP ET PL Lo NE : 1 9 8-(4-methyl-1-piperazinyl)-N-[4-(4- : morpholinyl)phenyl]-4-ox0-4H-

N chromene-2-carboxamide

RAG

N. 0

NY

(J @ 2 0 2-{1-[4-(2-Methoxy-phenyl)- q piperazin-1-yl]-methanoyl }-8-(4- $ methyl-piperazin-1-yl)-chromen-4- o N _0 one . ™ 0

N

3 0 2-{1-[4-(1-Acetyl-2,3-dihydro-1H-

JN indol-6-yl)-piperazin-1-yl]- ) = methanoyl}-8-(4-methyl-piperazin- o N ° 1-yl)-chromen-4-one ® 0

N

: o cl 2-Chloro-5-(4-{1-[8-(4-methy]-

JQ piperazin-1-yl)-4-0xo0-4H-chromen- ) CN 2-yl]-methanoyl}-piperazin-1-yl)- : o N benzonitrile

SE

N : o ow 2-{1-[4-(4-Methoxy-phenyl)- ir piperazin-1-yl}-methanoyl }-8-(4- : ) methyl-piperazin-1-yl)-chromen-4- 0 N | one

SI

N

O 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (5-

N ° furan-2-yl-1H-pyrazol-3-yl)-amide 0 N

A J

N

= 0 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (4- o | N imidazol-1-yl-phenyl)-amide ’

NTN

(J 5 : N

Jo} s—N, 8-(4-Methyl-piperazin-1-yl)-4-oxo- ~~ 4H-chromene-2-carboxylic acid (4- \ [1,2,3]thiadiazol-5-yl-phenyl)- o} amide ) o .

AN

9 0 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid 4-

A | [1,2,3]thiadiazol-5-yl-benzylamide : N oC 0 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid [4- : | N (4-acetyl-piperazin-1-yl)-phenyl]- 0 TL amide

SERA §

N

N

T oo 1 9 8-(4-Methyl-piperazin-1-yl)-4-oxo- : 4H-chromene-2-carboxylic acid [4- |} : N (4-methanesulfonyl-piperazin-1-yl)- fe TL phenyl]-amide

Helihae o 0 . 12 Q 8-(4-Methyl-piperazin-1-yl)-4-oxo- 0” : 4H-chromene-2-carboxylic acid (2- | ’

N methoxy-4-morpholin-4-yl-phenyl)- 0 amide

SINGS

13 Q 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (3- ] | N ci chloro-4-morpholin-4-yl-phenyl)- 0 TIL amide : ) 0) NY

Lo

N

14 Q 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (4- ° | N thiomorpholin-4-yl-phenyl)-amide

ATM

Ls

N

0 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid

N o_- (2,5-diethoxy-4-morpholin-4-yl- © 1X phenyl)-amide

LO YO pp (Lo

N

1 16 0 8-(4-Methyl-piperazin-1-yl)-4-oxo- : 4H-chromene-2-carboxylic acid (4- “ | N cyanomethyl-phenyl)-amide east ( ) CN

N

17 9 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid : N (1H-indol-5-yl)-amide 0 A\

SE

N

18 Q 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid [4-

N (1-morpholin-4-yl-methanoyl)- 0 SW (To phenyl]-amide . N lo} Ne (J

N

19 0 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid [4- : | (2,6-dimethyl-morpholin-4-y1)- 0 TL phenyl]-amide ) o NY ) 20 0 8-(4-Methyl-piperazin-1-yl)-4-oxo- . 4H-chromene-2-carboxylic acid [4-

N FE (4-fluoro-phenoxy)-phenyl]-amide (J ©

N

21 0 8-(4-Methyl-piperazin-1-yl)-2-(6-

N © morpholin-4-yl-benzooxazol-2-yl)-

N

I —/ chromen-4-one : 0 0

SN

N

22 0 8-(4-Methyl-piperazin-1-yl)-4-oxo-

OH 4H-chromene-2-carboxylic acid (2-

N hydroxy-4-morpholin-4-yl-phenyl)- 0 amide ’ ) Oo NY i Ld _ 23 9 8-(4-Methyl-piperazin-1-yl)-4-oxo-

CLL 4H-chromene-2-carboxylic acid (5-

Ne _s ethoxy-benzothiazol-2-yl)-amide 6) [28 ® oO N . 0

I \ 24 9 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (4- . | “OL bromo-pheny!)-amide ) 0} NY ’

Lo

N

9 8-(4-Methylpiperazin-1-yl)-4-oxo- . 4H-chromene-2-carboxylic acid

N methyl-(4-morpholin-4-yl- i 0 TL | phenyl)amide . . S 0 N ™ ~ 26 : 9 8-(4-Methyl-piperazin-1-yl)-4-oxo-

Mo 4H-chromene-2-carboxylic acid (3- |. morpholin-4-yl-phenyl)-amide

ENG Ne Ip yl-phenyl)

SI

27 9 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (3-

ON oN cyano-4-morpholin-4-yl-phenyl)- o) TI amide

SIRS ® \ L_o 28 Q 8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid (3-

N " fluoro-4-morpholin-4-yl-phenyl)- 0 Tr amide oIRas : L_o 29 9 4-[4-({1-[8-(4-Methyl-piperazin-1- yl)-4-ox0-4H-chromen-2-yl]-

N methanoyl }-amino)-phenyl]}- o TL piperazine-1-carboxylic acid tert-

SQ 0 NY butyl ester

N Sy 0 0 8-(4-Methyl-piperazin-1-y1)-4-oxo- 4H-chromene-2-carboxylic acid (4- o | N piperazin-1-yl-phenyl)-amide

Feline ; NP ’

31 o) 6-Methoxy-8-(4-methyl-piperazin- _o 1-y1)-4-0x0-4H-chromene-2- .

N carboxylic acid (4-morpholin-4-yl- 0 TL phenyl)-amide

SEA § (Lo 32 [of 6-Methoxy-8-(4-methyl-piperazin- _O 1-y1)-4-ox0-4H-chromene-2-

N carboxylic acid [4-(4- : 0 TL methanesulfonyl-piperazin-1-yl)- ) © | NY phenyl]-amide

Lone p

N EN ’ oo 33 o 6-Methoxy-8-(4-Methyl-piperazin- 0 1-yl)-4-0x0-4H-~chromene-2- :

N cl carboxylic acid (3-chloro-4- 0 Tr morpholin-4-yl-phenyl)-amide

SHG

L_o

N . . ! 34 O 6-Methoxy-8-(4-methyl-piperazin- 0 1-yI)-4-ox0-4H-chromene-2-

N E carboxylic acid (3-fluoro-4- o Tr morpholin-4-yl-phenyl)-amide

I ) 0] x NY

Lo 1g : 6-Methoxy-8-(4-methyl-piperazin- 0 0” 1-y1)-4-ox0-4H-chromene-2-

N carboxylic acid (2-methoxy-4- ° morpholin-4-yl-phenyl)-amide 0) o NT ]

Lo 36 Q 6-Methoxy-8-(4-methyl-piperazin- 0 1-yl)-4-0x0-4H-chromene-2- :

N carboxylic acid (4-thiomorpholin-4- "0 TL yl-phenyl)-amide ) 0] NY

Ls \ . i

37 0 6-Methoxy-8-(4-methyl-piperazin- 0 1-y1)-4-ox0-4H-chromene-2- _

I : carboxylic acid [4-(2,6-dimethyl- 0 TL morpholin-4-yl)-phenyl]-amide : . @ 0 NY

No

N

38 9 6-Methoxy-8-(4-methyl-piperazin- 0 No 1-yl)-4-oxo0-4H-chromene-2-

N N carboxylic acid (3-morpholin-4-yl- 0° phenyl)-amide

SRN

N

39 1 6-Methoxy-8-(4-methyl-piperazin- 0 1-yl)-4-0x0-4H-chromene-2-

N carboxylic acid {4-[4-(2-hydroxy- © TL ethyl)-piperazin-1-yl]-phenyl }- ) 0 NT amide

N Lh, 40 0 6-Methoxy-8-(4-methyl-piperazin- o 1-yl)-4-oxo-4H-chromene-2- : N carboxylic acid {4-(1-morpholin-4- 0 rr 0 yl-methanoyl)-phenyl]-amide 1 N 0 Ne (J I

N

41 9 6-Methoxy-8-(4-methyl-piperazin- 0 1-yl)-4-0x0-4H-chromene-2-

N carboxylic acid (3-cyano-4- 0 morpholin-4-yl-phenyl)-amide @ ° NN

N CN L_o 42 Q. 4-[4-({1-[6-Methoxy-8-(4-methyl- ) 0 piperazin-1-yl)-4-oxo-4H-chromen-

N 2-yl]-methanoyl}-amino)-phenyl]- 0 TL piperazine-1-carboxylic acid ters- . | ™ 0 iP butyl ester “_N.__0 : N ry

C#m TE ee Ee 43 0 6-Methoxy-8-(4-methyl-piperazin- pe) 1-yl)-4-0x0-4H-chromene-2- : N carboxylic acid (4-piperazin-1-yl- 0 TL phenyl)-amide . @ oO NY .

X LA

44 0. 6-Methoxy-8-(4-methyl-piperazin- _0 1-y1)-4-0x0-4H-chromene-2- : N carboxylic acid [4-(4-propionyl- 0 TL piperazin-1-yl)-phenyl]-amide

N le} NY i : J Lon :

I

45 | a 6-Methoxy-8-(4-methyl-piperazin- 0 : 1-yl)-4-ox0-4H-chromene-2- o N carboxylic acid [4-(4-ethane \ ! TL sulfonyl-piperazin-1-yl)-phenyl]- ( ) NY amide

N Lon, og 7 6-Methoxy-8-(4-methyl-piperazin- 0 1-yl)-4-oxo0-4H-chromene-2- ln carboxylic acid [4-(4-dimethy] oo a! TL sulfamoyl-piperazin-1-y1)-phenyl}-

N amide (J hy | B

A | 3 AN . a7 0 4-[4-({1-[6-Methoxy-8-(4-methyl- : 0 : piperazin-1-yl)-4-oxo-4H-chromen-

N 2-yl]-methanoyl }-amino)-phenyl]- 0 TL piperazine-1-carboxylic acid

N (e] di .

N imethylamide olihaol

J

48 0 4-[4-({1-[6-Methoxy-8-(4-methyl- 0 piperazin-1-yl)-4-0x0-4H-chromen- :

N 2-yl]-methanoyl } -amino)-phenyl]- 0 TL piperazine-1-carboxylic acid i @ Ee) i ethylamide

N

. N N

I

49 0 4-[4-({1-[6-Methoxy-8-(4-methyl-

AO piperazin-1-yl)-4-oxo-4H-chromen-

IN 2-yl]-methanoyl }-amino)-phenyl]- © TL piperazine-1-carboxylic acid . ) © ) cyclohexylamide , 0 50 0 4-[4-({1-[6-Methoxy-8-(4-methyl- 0 piperazin-1-yl)-4-0x0-4H-chromen-

N 2-yl}-methanoyl}-amino)-phenyl}- 0 TL piperazine-1-carboxylic acid 0) © NY cyclopentylamide ~ )

N d od 51 o 6-Methoxy-8-(4-methyl-piperazin- 0 1-yl)-4-oxo-4H-chromene-2-

I carboxylic acid {4-[4-(1-pyrrolidin- 0 TL 1-yl-methanoyl)-piperazin-1-yl]- ) 0 7) phenyl }-amide

N

N N i 52 0 6-Methoxy-8-(4-methyl-piperazin- 0 1-y1)-4-oxo-4H-chromene-2-

N carboxylic acid {4-[4-(propane-2- o TL sulfonyl)-piperazin-1-yl]-phenyl}- ; @® © NY amide : o 0 53 a 6-Methoxy-8-(4-methyl-piperazin-

AO 1-yl)-4-oxo0-4H-chromene-2- lL carboxylic acid {4-[4-(2-methyl- 0 TL propanoyl)-piperazin-1-yl}-phenyl}-

N lo ;

N amide () Oh

N : : 0 54 Q 6-Methoxy-8-(4-methyl-piperazin- : 0 1-yl)-4-ox0-4H-chromene-2-

I carboxylic acid {4-[4-(1-morpholin- 0 3 4-yl-methanoyl)-piperazin-1-yl]- ) N ° N phenyl }-amide

CJ !

55 9 6-Fluoro-8-(4-methyl-piperazin-1- } - F y)-4-0x0-4H-chromene-2- lo carboxylic acid (4-morpholin-4-yl- fo TL phenyl)-amide } (Lo :

N : : : : 56 9) 6-Fluoro-8-(4-methyl-piperazin-1-

F yD-4-0x0-4H-chromene-2-

N carboxylic acid [4-(4- o TL methanesulfonyl-piperazin-1-yl)- ® lo] NN phenyl]-amide

N Note B 00 57 [* : | 6-Fluoro-8~(4-methyl-piperazin-1-

F yl)-4-oxo-4H-chromene-2-

I carboxylic acid [4-(4-acetyl- 0} TL piperazin-1-yl)-phenyl]-amide . 0) (e} NY

N Not o 58 Q 6-Fluoro-8-(4-methyl-piperazin-1-

F yl)-4-oxo-4H-chromene-2-

NL al carboxylic acid (3-chloro-4- © TL morpholin-4-yl-phenyl)-amide

Bela e @

N . - 59 Q : 6-Fluoro-8-(4-methyl-piperazin-1-

F yD-4-oxo-4H-chromene-2-

N Ce carboxylic acid (3-fluoro-4- \% Tr : morpholin-4-yl-phenyl)-amide

Eee @ : N

Q 6-Fluoro-8-(4-methyl-piperazin-1-

F yl)-4-oxo-4H-chromene-2- ’

N CN carboxylic acid (3-cyano-4- o TX morpholin-4-yl-phenyl)-amide

SIMS

Lo

0 6-Fluoro-8-(4-methyl-piperazin-1-

F yl)-4-ox0-4H-chromene-2- ) | N carboxylic acid [4-(1-morpholin-4- 0 a © yl-methanoyl)-phenyl}-amide a. J (J I

N

62 0 6-Methyl-8-(4-methyl-piperazin-1-

H,C yl)-4-oxo0-4H-chromene-2-

N carboxylic acid (4-morpholin-4-yl- o phenyl)-amide

N fo oleae , Lo

N

63 0 6-Methy!-8-(4-methyl-piperazin-1-

H,C yl)-4-ox0-4H-chromene-2-

J carboxylic acid [4-(1-morpholin-4-

So” CL 3 yl-methanoyl)-phenyl}-amide

N 0 N

CJ - 64 0 6-Methyl-8-(4-methyl-piperazin-1-

H,C yl)-4-oxo0-4H-chromene-2-

N r carboxylic acid (3-fluoro-4-

Nn 0 I morpholin-4-yl-phenyl)-amide

CO C0 : | : Lo .

N

65 9 6-Chloro-8-(4-methyl-piperazin-1- cl yl)-4-ox0-4H-chromene-2-

N carboxylic acid (4-morpholin-4-yl- o TL phenyl)-amide

IRS ®

Lo.

CH; © 5-Methyl-8-(4-methyl-piperazin-1- . yl)-4-oxo0-4H-chromene-2-

N carboxylic acid (4-morpholin-4-yl- 0 TL phenyl)-amide olihaol (_o )

67 ~ o 5-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-0x0-4H-chromene-2- carboxylic acid (4-morpholin-4-yl-

N . o TL phenyl)-amide ™ 0 N ~ | , 0 6-Methoxy-8-(4-methyl-piperazin- 0 1-yl)-4-ox0-4H-chromene-2-

N carboxylic acid {4-[4-(3-hydroxy- 07 TL propanoyl)-piperazin-1-yl]-phenyl}- () © NY amide

N No 0 69 a 4-[4-({1-[6-Fluoro-8-(4-methyl- -

F piperazin-1-yl)-4-ox0-4H-chromen- 2-yl]-methanoyl}-amino)-phenyl]- © TL : piperazine-1-carboxylic acid terz-

N 0 butyl este : ( ) ig utyl ester

N Nod 3 70 Q 4-[4-({1-[6-Fluoro-8-(4-methyl- :

F piperazin-1-yl)-4-oxo-4H-

N chromene-2-carboxylic acid (4- © TL piperazin-1-yl-phenyl)-amide eRe s ; L_nH 71 | 1" 6-Fluoro-8-(4-methyl-piperazin-1-

F y1)-4-oxo-4H-chromene-2-

N “carboxylic acid [4-(4-ethane ° TL sulfonyl-piperazin-1-yl)-phenyl]- 0) © NY amide

N NPN

* 7 \ 00 72 2 6-Fluoro-8-(4-methyl-piperazin-1-

F : y1)-4-0x0-4H-chromene-2-

N : carboxylic acid [4-(4-propionyl- 0] TL piperazin-1-yl)-phenyl]-amide

SERA’

N

: N

I

Claims (21)

CLAIMS We claim:

1. A compound represented by the formula (D: CR 1 R} 7 (8) v7 oo | ka wherein : R! is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, thiomethoxy, -NHA, -NA,, -NHC(=0)A, aminocarbonyl, - C(=0)NHA, -C(=0)NA;, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl; R? is represented by (i), (ii), (iii), or (iv) below: :

a. A N N (Gr B77 (CH, p vd EE EN

\ . 3 ~g? —R3 - Rr : R3 (® (ii) (iif) (iv) R® is independently at each position represented by —H, optionally substituted C,_galkyl, optionally substituted C.ealkenyl, optionally substituted C,.salkynyl, optionally substituted

Cs.ecycloalkyl or AOH; nis 2,3 or4, ’ Pisa heterocyclic ring; RS is -H or methyl; . Y is -C(=0)NH-, -C(=O)NA-, -C(=0)N(A)-, -NHC(=0)-, -C(=S)NH-, -CH,NH-, -C(=0)- -C(=0)CHa-, -CH,C(=0)-, -C(=0)-piperazine-, , -NAC(=0)-, -C(=S)N(A)-, CH;NA, NACH, or a 5-membered heterocyclic.

-133- PCT/SE02/00070 R’ is a monocyclic or bicyclic aromatic ring or a heterocycle optionally substituted by one or more substituents selected from RS R® and R10. wherein rR’ is connected to Y either by a single bond or by a ring fusion; RS is -CH,-, -C(=0)-, -SO5-, -SOyNH-, -C(=0O)NH-, -O-, -S-, -S(=0)-, a single bond as tether from R’ to RY, 5-membered heterocycle connected to R’ by a ring fusion or a single bond as tether; R® optionally substituted heterocycle, optionally substituted aryl, optionally substituted piperazinyl-R11, optionally substituted morpholinyl-R11, optionally substituted thiomorpholinyl, or -C(=0)A; R10 is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH,-, methylthio, -NHA, -NA,, -NHC(=0)A, C(=0)NHA, C(=0)NA,, or OA; RI is -H, alkyl, AOH, -SO,A, -SO,NH,, -S0,NHA, -SO,NA,, -SO,NHAR?, -C(=0)R?, -alkyIR?, C(=0)A, C(=0)NH,, C(=O0)NHA, C(=O)NA, or -C(=0)OA; or a pharmaceutically acceptable salt of said compound.

2. A compound recited in claim 1 for use in the treatment of migraine in a human or animal in need of such therapy.

3 A substance or composition for use in a method of treatment of a human or animal suffering from migraine, said substance or composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound, and said method comprising administering to such animal an effective amount of said substance or composition.

4. The use of the compound recited in claim 1 in the preparation of a medicament for the treatment of migraine.

5. A pharmaceutical composition comprising a compound as recited in Claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. A compound of the Formula (VIe): AMENDED SHEET

Oo 1 I R— _I_ X OR R? 0 Vie wherein R' is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA,, -NHC(=0)A, aminocarbonyl, -C(=0)NHA, -C(=0)NA,, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl; R%is represented by (i), (ii), (iii), or (iv) below: & a N N _ ZN (CH,), R’ (CHa), p RS ! !

\., Rp —® ke R : R3 ® (if) (iii) iv) and X is represented by O; or a pharmaceutically acceptable salt of said compound.

7. The compound of Formula (VIfl):

R J Ay OH R® o) HCl : VIf1 wherein R' is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA,, -NHC(=0)A, aminocarbonyl, -C(=O)NHA, -C(=0)NA,, halogen, hydroxy, -OA, cyano er aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl; R? is represented by (i), (ii), (iii), or (iv) below: a & N N ’ ~ SU / (Cade R’ (Hn P R} I

N. N — TR? Ne Rr’ PN Rr} R Ne 6 ® (ii) (iif) (iv) and X is represented by O, S, or N, or a pharmaceutically acceptable salt thereof.

8. A compound of Formula (VIgl) CD R'— PP X L R2 0 HCI Vig1 wherein R' is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA,, -NHC(=0)A, aminocarbonyl, -C(=0)NHA, -C(=0)NA,, halogen, hydroxy, -OA, cyano or aryl; A is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl; ‘ L represents a leaving group. Ris represented by (i), (ii), (iii), or (iv) below: i 1 [ N N NN UNS (Go TE “0 N N \_, RT OR —R Ne R3 1) (ii) (ii) (iv) and X is represented by O; or a pharmaceutically acceptable salt of said compound.

9. A compound of Formula (VIh) ON R'—— ~ H = N X NY . R2 Oo : Vih1 wherein R' is, at each position, independently represented by hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, methoxy, thiomethoxy, -NHA, -NA;, -NHC(=0)A, aminocarbonyl, -C(=0)NHA, -C(=0)NA; halogen, hydroxy, -OA, cyano or aryl; Ais optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted : alkenyl or optionally substituted alkynyl; R? is represented by (i), (ii), (iii), or (iv) below: )

y \ © NN N ~ SS id . ( (CH, R’ (CHa), r) R ( N N \ oN —r AN rR? R3 ® (ii) (iii) (iv) and X is represented by O; or a pharmaceutically acceptable salt of said compound.

10. A process for preparing a compound of Formula (VIe) as recited in Claims 6 comprising reacting a compound of Formula (VId): O x Ri—— JP | OR" X Halogen ®) Vid with HR? in the presence of a catalyst and a base.

11. A process for preparing a compound of Formula (VIf1) as recited in Claim 7 comprising heating a compound a of Formula (VIe) as recited in Claim 6 in the presence of an acid and water to form a mixture wherein the mixture is hydrogenated using a catalyst. ) 20

12. The process as recited in Claim 11 wherein the catalyst is palladium. © } -

13. A process for preparing a compound of Formula (VIg1) as recited in Claim 8 : comprising replacing the hydroxyl group of the carboxy! ate moiety of Formula (Vig) with a leaving group.

14. A process for preparing a compound of Formula (VIh1) as recited in Claim 9 > comprising reacting a compound of (VIf1) as recited in Claim 7 with HR’, wherein R” is a monocyclic or bicyclic aromatic ring or a heterocycle, optionally substituted by one or more substituents selected from R-R”® and RY: wherein R” is connected to Y either by a single bond or by a ring fusion; R%is -CHy-, -C(=0)-, -SO,-, - SO,NH-, -C(=0)NH-, -O-, -S-, -5(=0)-, a five membered heterocyclic connected to R” by a ring fusion or single bond as tether; Ris morpholine optionally substituted with at least one substituent selected from A, thiomorpholine, piperazin-R'’, optionally substituted aryl, optionally substituted heterocyclic, or -C(=0)CA,; Ris optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH,-, methylthio, -NHA, -NA,, -NHC(=0)A, -C(=O)NHA, -C(=0)NA, or OA; oo R'is -H, alkyl, AOH, -SO,A, -SO,NH,, -SO,NHA, -SO;NA,, -SO,NHAR’, -C(=0)R’, -alkylR’, C(=0)A, C(=0)NH,, C(=O)NHA, C(=0)NA; or —C(=0)OA..

15. A process for preparing a compound of Formula (VIh1) as recited in Claim 9 comprising reacting a compound of Formula (VIgl) with H,R’ wherein R’ is a monocyclic or bicyclic aromatic ring or a heterocycle, optionally substituted by one or more substituents selected from RR’ and R'®; wherein R7 is connected to Y either by a single bond or by a ring fusion; R%is -CHs-, -C(=0)-, -SO;-, - SO,NH~, -C(=0)NH-, -O-, -S-, -S(=0)-, a five membered heterocyclic connected to R’ by a ring fusion or single bond as tether; R’ is morpholine optionally substituted with at least one substituent selected from A, thiomorpholine, piperazin-R'’, optionally substituted aryl, optionally substituted heterocyclic, or -C(=0)CA,; . RY is optionally substituted alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano, halogen, -C(=0)NH,-, methylthio, -NHA, -NA,, -NHC(=0)A, -C(=0)NHA, -C(=0O)NA,, or ° OA; R'is -H, alkyl, AOH, -SO,A, -SO,NH,, -SO,NHA, -SO,NA,, -SO.NHAR’, -C(=O)R’, -alkylR®, C(=0)A, C(=0)NH,, C(=0)NHA, C(=0)NA, or —C(=0)OA.

-139- PCT/SE02/00070

16. A compound according to any one of claims 1, 2 or 6 to 9, substantially as herein described and illustrated.

17. A substance or composition for use in a method of treatment according to claim 2 or claim 3, substantially as herein described and illustrated.

18. Use according to claim 4, substantially as herein described and illustrated.

19. A composition according to claim 5, substantially as herein described and illustrated.

20. A process according to any one of claims 10 to 15, substantially as herein described and illustrated.

21. A new compound, a substance or composition for a new use in a method of treatment, a new use of a compound as claimed in claim 1, a new composition, or a new process for preparing a compound, substantially as herein described. AMENDED SHEET