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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators

Definitions

• This invention relates generally to gonadotropin-releasing hormone 5 (GnRH) receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof.
• GnRH gonadotropin-releasing hormone 5
• GnRH Gonadotropin-releasing hormone
• LHRH luteinizing hormone-releasing hormone
• GnRH luteinizing hormone
• FSH follicle-stimulating hormone
• GnRH GnRH agonists
• peptidic GnRH agonists such as leuprorelin (pGlu-His-Trp-Ser-
• GnRH antagonists are believed to suppress gonadotropins from the onset, and thus have received the most attention over the past two decades.
• some of the primary obstacles to the clinical use of such antagonists have been their relatively low bioavailability and adverse side effects caused by histamine release.
• several peptidic antagonists with low histamine release properties have been reported, although they still must be delivered via sustained delivery routes (such as subcutaneous injection or intranasal spray) due to limited bioavailability.
• this invention is generally directed to gonadotropin-releasing hormone (GnRH) receptor antagonists, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same.
• GnRH gonadotropin-releasing hormone
• GnRH receptor antagonists of this invention are compounds having the following general structure (I):
• the GnRH receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of sex-hormone related conditions in both men and women, as well as a mammal in general (also referred to herein as a "subject").
• such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization).
• the compounds of this invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.
• the compounds are also useful in combination with androgens, estrogens, progesterones, and antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids, and in contraception, as well as in combination with an angiotensin-converting enzyme inhibitor, an antiotensin H-receptor antagonist, or a renin inhibitor for the treatment of uterine fibroids.
• the compounds may be used in combination with bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with a GnRH antagonist.
• the methods of this invention include administering an effective amount of a GnRH receptor antagonist, preferably in the form of a pharmaceutical composition, to a mammal in need thereof.
• a GnRH receptor antagonist preferably in the form of a pharmaceutical composition
• pharmaceutical compositions are disclosed containing one or more GnRH receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
• the present invention is directed generally to compounds useful as gonadotropin-releasing hormone (GnRH) receptor antagonists.
• the compounds of this invention have the following structure (I):
• m is an integer from 1 to 6;
• Ri is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, aryl(CR 3c R 3 d) n , substituted aryl(CR 3c R 3d ) ;!
• R 2 is hydrogen, alkyl or substituted alkyl; or R] and R 2 taken together with the nitrogen atom to which they are attached form a heterocycle ring or a substituted heterocycle ring;
• R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• R 5 is hydrogen, halogen, cyano, alkyl, substituted alkyl, hydroxy, alkoxy, thioalkyl or mono- or di-alkylamine;
• B is nitrogen or CRio when Ar is heteroaryl or substituted heteroaryl and Rin is hydrogen;
• Alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 8 carbon atoms, while the term “lower alkyl” has the same meaning as alkyl but contains from 1 to 4 carbon atoms.
• Representative saturated straight chain alkyls include methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
• Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
• Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl", respectively).
• Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- methyl-1 butynyl, and the like.
• Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl.
• Arylalkyl means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl, -(CH ) 2 phenyl, -(CH ) 3 phenyl, -CH(phenyl) , and the like.
• Heteroaryl means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
• Representative heteroaryls are pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
• Heteroarylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with a
• Heterocycle means a 5- to 7-membered monocyclic, or 7- to 10- membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
• the heterocycle may be attached via any heteroatom or carbon atom.
• Heterocycles include heteroaryls as defined above.
• heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH 2 morpholinyl, and the like.
• substituted means any of the above groups (i.e., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent.
• two hydrogen atoms are replaced.
• Halogen means fluoro, chloro, bromo and iodo.
• Haloalkyl means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
• Alkoxy means an alkyl moiety attached through an oxygen bridge (i.e., -O-alkyl) such as methoxy, ethoxy, and the like.
• Aryloxy means an aryl moiety attached through an oxygen bridge (i.e.,
• -O-alkyl such as phenoxy and the like.
• Thioalkyl means an alkyl moiety attached through a sulfur bridge (i.e., -S-alkyl) such as -SCH 3 , -SCH 2 CH 3 and the like.
• Thioaryl means an aryl moiety attached through a sulfur bridge (i.e.,
• -S-aryl such as -S-phenyl and the like.
• “Mono- or dialkylamine” means -NH(alkyl) or -N(alkyl)(alkyl), respectively.
• “Sulfonylalkyl” means an alkyl moiety attached through a sulfonyl bridge (i.e. , -SO 2 -alkyl) such as - SO 2 CH 3 , - SO 2 CH 2 CH 3 and the like.
• “Sulfonylaryl” means an aryl moiety attached through a sulfonyl bridge (i.e., -SO 2 -aryl) such as - SO -phenyl and the like.
• compounds of this invention have the following structure (H) when B is nitrogen, and the following structure (HI) when B is CR 10 :
• Ar is heteroaryl or substituted heteroaryl.
• Rio when Rio is hydrogen in structure (HI), Ar is heteroaryl or substituted heteroaryl.
• Rio of structure (HI) is halogen, cyano, nitro, amino, mono- or di- alkylamino or alkyl, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
• representative compounds of this invention have the following structure (IV):
• representative compounds of this invention have the following structure (V):
• representative compounds of this invention have the following structures (VI), (VH) and (VEH), respectively:
• R is hydrogen, alkyl, substituted alkyl, hydroxy, thioalkyl or sulfonylalkyl, and representative compounds of this invention have the following structures (IX) through (XTV), respectively:
• Ri and R 2 taken together with the nitrogen atom to which they are attached, form a heterocycle ring as presented by the following structures (XV):
• R 7 and R 8 taken together with the nitrogen atom to which they are attached, form a heterocycle ring or substituted heterocycle ring as represented by the following structure (XVI), optionally in combination with Ri and R 2 forming a heterocycle ring or substituted heterocycle ring as represented by the following structure (XVH):
• Ri is heteroaryl (CR 3c R 3d ) sanction or substituted heteroaryl (CR 3c R 3d ) whatsoever.
• the heteroaryl portion of the heteroaryl (CR 3c R 3d ) prison moiety is pyridinyl (e.g, pyridin-2-yl), and the compounds of this invention have the following structure (XVTH):
• R e and R f are the same or different and represent optional substituents independently selected from hydrogen, alkyl, alkoxy, dialkyamino, halo and cyano.
• the (CR 3a R 3b ) ffl moiety is an alkilidene moiety, as represented by the following structure (XIX):
• alkylidene means a bivalent alkyl radical, including bivalent straight chain alkyls such as methylene (i.e., -CH 2 -), ethylene (i.e., -CH CH -), and the like, bivalent branched alkyls such as -CH(CH 3 )-, -C(CH 3 ) 2 -, and the like, and bivalent cycloalkyls such as cyclohexylene, and the like.
• bivalent straight chain alkyls such as methylene (i.e., -CH 2 -), ethylene (i.e., -CH CH -), and the like
• bivalent branched alkyls such as -CH(CH 3 )-, -C(CH 3 ) 2 -, and the like
• bivalent cycloalkyls such as cyclohexylene, and the like.
• the Ar moiety is a heteroaryl moiety, as represented by the following structure (XX):
• Ai, A 3 and A are the same or different and independently nitrogen or
• R a , R b , R c and R d are optional substituents that are the same or different and independently halogen, nitro, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, hydroxy, alkoxy, aryloxy, thiol, thioalkyl, thioaryl, sulfonylalkyl, sulfonylaryl, amino, mono- or di-alkylamino, mono- or di-arylamino,
• -NHCOalkyl -NHCOaryl, -N(alkyl)COalkyl, -N(alkyl)COaryl, -NHSO 2 alkyl, -NHSO 2 aryl, N(alkyl)SO 2 alkyl, -N(alkyl)SO 2 aryl, -NHCONHalkyl or -NHCONHaryl; or R a and R b taken together with the atoms to which they are attached form aryl, substituted aryl, heteroaryl or substituted heteroaryl.
• the heterocyclic ring containing Ai, A 2 , A 3 and A 4 includes the following heteroaryls:
• this invention also includes heteroaryls wherein R a and R b taken together with the atoms to which they are attached form aryl or heteroaryl, including (but not limited to) benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indoyl, purinyl, quinolinyl, isoquinolinyl, pyrano[3,4-b]pyrrolyl, indoxazinyl, benzoxazolyl, anthranyl, cinnolinyl, quinazolinyl, naphthyridinyl, prido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, pyrido[4,3-b]pyridinyl, and the like.
• benzofuranyl isobenzofuranyl, thionaphthenyl, isothionaphth
• the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. In general, however, the compounds of structure (H) may be made by the following Reaction Schemes A and B, and the compounds of structure (LU) by Reaction Schemes C and D. Reaction Schemes E through M illustrate further synthetic procedures applicable to compounds of structure (I) generally. In the following reaction schemes, all substituents are as defined above unless indicated otherwise.
• ia bromoketone
• acetyl guanidine in an appropriate solvent such as dimethylformamide at a temperature of 25-120°C for a period of 1-72 hours
• 2- acetamidoimidazole (iia) which can be hydrolyzed with an acid such as sulfuric acid in an appropriate solvent such as water or ethanol at a temperature of 60-120°C for a period of 2-24 hours to give 2-aminoimidazole (iiia).
• 2-Aminoimidazole (iiia) can be modified by cyclization with substituted acrylate in an inert solvent such as methanol, dioxane or phenylether at a temperature of 60-260°C for a period of 0.5-16 hours to give imidazolo[l,2-a]pyrimidone (iva).
• an inert solvent such as methanol, dioxane or phenylether
• imidazolo[l,2-a]pyrimidone may be prepared according to Reaction Scheme B by condensation of 2-aminopyrimidine (viia) with the alpha-bromoheteroaryl ketone (ia) in the presence of a base such as sodium hydride, tetrabutylammonium fluoride, potassium carbonate in a inert solvent such as DME, dimethylformamide, ethanol at a temperature of 25-100°C for a period of 12-24 hours.
• a base such as sodium hydride, tetrabutylammonium fluoride, potassium carbonate
• a inert solvent such as DME, dimethylformamide, ethanol
• the pyrimidone (iib) may be alkylated by treatment with a base such as tetrabutylamonium fluoride, sodium hydride, or sodium ethoxide in an inert solvent such as 1,2-demethoxyethane, tetrahydrofuran, or mixtures thereof at 0- 25°C for a period of 30 minutes, followed by an alpha-bromoketone at 0-25°C for 12-24 hours to provide the alkylated pyrimidone (iiib).
• a base such as tetrabutylamonium fluoride, sodium hydride, or sodium ethoxide in an inert solvent such as 1,2-demethoxyethane, tetrahydrofuran, or mixtures thereof at 0- 25°C for a period of 30 minutes, followed by an alpha-bromoketone at 0-25°C for 12-24 hours to provide the alkylated pyrimidone (iiib).
• the pyrimidone (iiib) may be cyclized upon treatment with a strong base such as sodium ethoxide, sodium hydride or LiN(SiMe 3 ) in an inert solvent such as ethanol at 25-80°C for 2-4 hours to give the pyrrolo[l,2-a]pyrimidone (ivb).
• a strong base such as sodium ethoxide, sodium hydride or LiN(SiMe 3 ) in an inert solvent such as ethanol at 25-80°C for 2-4 hours to give the pyrrolo[l,2-a]pyrimidone (ivb).
• heteroaryl ketone (vb) is modified by treatment with a brominating reagent such as copper(H) bromide, bromine, or the like in an organic solvent such as chloroform, ethyl acetate, ether or mixture thereof at a temperature of 25-100°C, preferably at reflux in a mixture of chloroform and ethyl acetate, for a period of 2-12 hours gives the corresponding alpha-bromoketon (vib).
• a brominating reagent such as copper(H) bromide, bromine, or the like
• organic solvent such as chloroform, ethyl acetate, ether or mixture thereof
• heteroaryl ketone (vb) may be treated with N-bromosuccinamide, or bromine in an inert solvent such as carbon tetrachloride or chloroform with a radical initiator such as AD3N, at reflux to give the bromoketone (vib).
• the bromoketone (vib) is substituted by treatment with a azide salt such sodium azide, potasium azide or the like in an inert solvent such as DMF, tetrahydrofuran, ether, water or mixture thereof at 0-50°C for a period of 2-12 hours.
• the azido group is converted to an amino group when it is dissolved in an appropriate solvent, such a ethanol or methanol with hydrochloric acid, and (a) to the solution is added palladium-carbon or Raney Nickel as the catalyst and the mixture is reacted at room temperature for one to 12 hours under hydrogen atmosphere, or (b) to the solution is added triethyl phorsphite and the mixture is reacted at 0-25°C for 1-24 hours to provide the amino ketone hydrochloride (viib).
• an appropriate solvent such as a ethanol or methanol with hydrochloric acid
• the amino ketone (viib) is cyclized with malononitrile upon treatment with a strong base such as sodium hydroxide or potassium hydroxide in an inert solvent such as acetonitrile, water, ethanol or mixture thereof at 25-100°C for 2-24 hours to give the aminopyrrole (viiib).
• a strong base such as sodium hydroxide or potassium hydroxide
• an inert solvent such as acetonitrile, water, ethanol or mixture thereof at 25-100°C for 2-24 hours to give the aminopyrrole (viiib).
• the aminopyrrole (viiib) is condensed with a biselectrophilic reagent such as diethyl ethoxymethylenemalonate in an inert solvent such as ethanol or dioxane at a temperature of 25-100°C for 12-24 hours, then cyclized in a high boiling solvent such as phenyl ether at 200-265°C for 0.5 -2 hours to provide pyrrolo[l,2- ajpyrimidone (ixb).
• a biselectrophilic reagent such as diethyl ethoxymethylenemalonate
• an inert solvent such as ethanol or dioxane
• a high boiling solvent such as phenyl ether
• intermediate (ix) can be modified by treatment with an alkyl halide in the presence of a base such as tetrabutylamonnium fluoride, sodium hydride or silver(I) oxide in an inert solvent such as DMF, DME, THF or the like at 25-80°C for a period of 1-72 hours to give the corresponding 4-substituted intermediate (x).
• a base such as tetrabutylamonnium fluoride, sodium hydride or silver(I) oxide
• an inert solvent such as DMF, DME, THF or the like
• compound (x) can also be prepared by a Mitsunobu coupling reaction of the starting material (ix) with an alcohol and a coupling reagent such as a mixture of diethyl azodicarboxylate and triphenylphosphine in an inert solvent such as tetrahydrofuran, benzene or ether at a temperature of 0-100°C for 1-24 hours.
• a coupling reagent such as a mixture of diethyl azodicarboxylate and triphenylphosphine in an inert solvent such as tetrahydrofuran, benzene or ether at a temperature of 0-100°C for 1-24 hours.
• intermediate (x) (R is an alkyl group) can be modified by treatment with a brominatmg reagent such as N- bromosuccmnamide, in the presence of a radical initiator such as ALBN or benzoyl peroxide, in an inert solvent such as carbon tetrachlo ⁇ de, chloroform at temperature ranging from 25 to 100°C for a pe ⁇ od of 1-24 hours to give the co ⁇ espondmg bromoalkyl intermediate (x ⁇ )m which is reacted with a p ⁇ mary or secondary amine (1-5 eq) at a temperature ranging from 0 to 50°C for a pe ⁇ od of 0.5 to 16 hours to give compound (xn).
• a brominatmg reagent such as N- bromosuccmnamide
• a radical initiator such as ALBN or benzoyl peroxide
• an inert solvent such as carbon tetrachlo ⁇ de
• reaction can be earned out under stir ⁇ ng in an approp ⁇ ate solvent such as dimethylformamide, acetonit ⁇ le, ethanol, tetrahydrofuran, chloroform or carbon tetrachlo ⁇ de.
• an approp ⁇ ate solvent such as dimethylformamide, acetonit ⁇ le, ethanol, tetrahydrofuran, chloroform or carbon tetrachlo ⁇ de.
• a base such t ⁇ ethylam e, DBU or py ⁇ d e may be used.
• intermediate (xa) can be modified by treatment with an amine such as alkylamine or dialkylamine and an aldehyde such as formaldehyde, paraformaldehyde or acetaldehyde in an appropriate solvent such as ethanol, chloroform, dioxane, acetic acid, or acetonitrile, at a temperature of 25-100°C for a period of 0.5-16 hours to give the amine analog (xiia).
• an amine such as alkylamine or dialkylamine and an aldehyde such as formaldehyde, paraformaldehyde or acetaldehyde in an appropriate solvent such as ethanol, chloroform, dioxane, acetic acid, or acetonitrile
• the ethyl ester of intermediate (xiii) can be converted to another ester (xiv) by treatment with an excess of alcohol (R OH) and a strong base such as butyllithium, LiN(SiMe 3 ) 2 , LDA or potassium t-butoxide with or without an inert solvent such as dioxane, tetrahydrofuran or dimethylformamide, at a temperature of 25-100°C for a period of 0.5-16 hours.
• R OH alcohol
• a strong base such as butyllithium, LiN(SiMe 3 ) 2 , LDA or potassium t-butoxide with or without an inert solvent such as dioxane, tetrahydrofuran or dimethylformamide
• the ethyl ester group of compound (xiii) can also be converted to an amide group by dissolving the starting material in an appropriate solvent (e.g., dichloromethane or dichloroethane) and adding to a mixture of a primary or secondary amine (R 7 R 8 NH) and triethylaluminum or dibutylaluminum hydride, and the mixture reacted at 20-100°C for 1-12 hours under nitrogen atmosphere to give amide analog (xv).
• an appropriate solvent e.g., dichloromethane or dichloroethane
• the ester group of compound (xiii) can also be converted to ketone (xvi) when the starting material is reacted with an appropriate organometallic reagent such as alkyl lithium (R 7 Li), alkylmagnesiumhalide or organozinc, in an inert solvent such as tetrahydrofuran, ether, hexanes or mixture thereof at a temperature of 0-25°C for a period of 1-16 hours. Furthermore, when more organometalic reagent (R 8 Li) is used to react with ketone (xvi), the co ⁇ esponding alcohol (xvii) is obtained.
• organometallic reagent such as alkyl lithium (R 7 Li), alkylmagnesiumhalide or organozinc
• the ketone derivative of compound (xvi) may be oxidized to provide the carboxylic ester analog (xviii), by treatment with an oxidation reagent such as m-chloroperbenzoic acid in an appropriate solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like for a period of 1-16 hours or until the starting material has been consumed.
• an oxidation reagent such as m-chloroperbenzoic acid in an appropriate solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like for a period of 1-16 hours or until the starting material has been consumed.
• the ester (xviii) can hydrolyzed to the corresponding hydroxy compound (xix) by treatment with a base such as sodium hydroxide, lithium hydroxide or the like in an appropriate solvent such as ethanol, water, tetrahydrofuran, or mixture thereof at a temperature of 25-100°C for a period of 2-24 hours.
• a base such as sodium hydroxide, lithium hydroxide or the like in an appropriate solvent such as ethanol, water, tetrahydrofuran, or mixture thereof at a temperature of 25-100°C for a period of 2-24 hours.
• the ether derivative (xx) can be prepared by treatment of (xix) with an alkyl halide (R 7 X) and a base such as potassium carbonate or sodium hydroxide in an inert organic solvent such as acetone, dimethylformamide or DMSO at a temperature of 25-100°C for a period of 1-72 hours to give product (xx).
• the nitro group as the substituent can be converted to an amino group when the starting compound (xxi) is dissolved in an appropriate solvent, (e.g. ethanol or methanol), and (a) to the solution is added a catalyst such as palladium-carbon or Raney nickel, and the mixture is reacted at room temperature for one to 12 hours under hydrogen atmosphere, or (b) to the solution is added iron powder and hydrochloric acid, and the mixture is reacted a t room temperature for one to 12 hours, to give the amino compound (xxii).
• an appropriate solvent e.g. ethanol or methanol
• a catalyst such as palladium-carbon or Raney nickel
• iron powder and hydrochloric acid iron powder and hydrochloric acid
• Mono- or dialkylamino analogs (xxiii and xxiv) can be prepared by reductive amination of amino compound (xxii) with an aldehyde and a reducing agent such as sodium cyanoborohydride, sodium borohydride in an appropriate solvent such as acetic acid, ethanol, acetonitrile, water or mixture thereof at a temperature of 0-100°C for a period of 1-24 hours.
• a reducing agent such as sodium cyanoborohydride, sodium borohydride in an appropriate solvent such as acetic acid, ethanol, acetonitrile, water or mixture thereof at a temperature of 0-100°C for a period of 1-24 hours.
• (xxiii) and (xxiv) can be prepared by treatment of (xxii) with an alkyl halide and a base such as sodium hydride, potassium carbonate or sodium methoxide in an inert solvent such as tetrahydrofuran, dimethylformamide or DMSO for a temperature of 25-100°C for a period of 2-24 hours.
• a base such as sodium hydride, potassium carbonate or sodium methoxide
• an inert solvent such as tetrahydrofuran, dimethylformamide or DMSO
• an isocyanate regent such as pyridine, triethylamine, diisopropylethylamine, N- methylmorpholine or the like
• an inert solvent such as dichloromethane, chloroform, tetrahydrofuran or mixture thereof at a temperature of
• Compound (xxii) can also be modified by treatment with a bis(electrophilic) reagent such as phosgene, triphosgene, lj'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or the like with or without the addition of an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine in an inert solvent such as dichloromethane, chloroform, terahydrofuran, or the like at a temperature of -20 to 0°C for a period of 0.5-16 hours. After this time, the reaction mixture is treated with an appropriate mono- or disubstituted amine at -20 to 25°C for a period of 1-16 hours to give the urea analog (xxv).
• a bis(electrophilic) reagent such as phosgene, triphosgene, lj'-carbonyldiimid
• the amino analog (xxii) can also be modified by acylation under a variety of conditions.
• Alternatively (xxii) may be coupled with carboxylic acid promoted by a dehydrating reagent such as 1,3- dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), with or without a tertiary amine base such as pyridine or diisopropylethylamine in an inert solvent such as dichloromethane, chloroform, demethylformamide, or the like at room temperature for a period of 2-24 hours to provides the co ⁇ esponding amide (xxv).
• a dehydrating reagent such as 1,3- dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
• DCC 1,3- dicyclohexylcarbodiimide
• EDC
• the amino compound (xxii) can also be modified by treatment with appropriate sulfonyl chloride or sulfamyl chloride with an amine base such as pyridine or triethylamine in an inert solvent such as dichloromethane, chloroform or tetrahydrofuran at a temperature of -20 to 25°C for a period of 0.5 to 12 hours to give the co ⁇ esponding N-sulfonamide or N-sulfamylamide derivatives (xxvi).
• an amine base such as pyridine or triethylamine
• an inert solvent such as dichloromethane, chloroform or tetrahydrofuran
• the benzyloxy analog (xxvii) can be converted to the hydroxy compound (xxviii) by treatment with a catalyst such as palladium-carbon or Raney nickel in an inert solvent such as ethanol, methanol or ethyl acetate, on mixture thereof under hydrogen atmosphere at room temperature for a period of 1-24 hours.
• a catalyst such as palladium-carbon or Raney nickel
• an inert solvent such as ethanol, methanol or ethyl acetate
• the hydroxy compound (xxviii) can be further modified to another analog (xxix) by treatment with an acid chloride, acid anhydride, alkyl chloroformate, mono-alkyl or dialkylamino carbonyl chloride and an amine base such as triethylamine, pyridine, or N-methylmorpholine in an inert solvent such as dichloromethane, chloroform, ethyl acetate, or tetrahydrofuran at 0 to 65°C for a period of 1-12 hours to give (xxix).
• an acid chloride, acid anhydride, alkyl chloroformate, mono-alkyl or dialkylamino carbonyl chloride and an amine base such as triethylamine, pyridine, or N-methylmorpholine in an inert solvent such as dichloromethane, chloroform, ethyl acetate, or tetrahydrofuran at 0 to 65°C for a period of 1-12 hours to give
• the hydroxy compound (xxviii) can also be modified to ether (xxx) by treatment with an alkyl or substituted halide and a base such as potassium carbonate in an inert solvent such as acetone, acetonitrile, or dimethylformamide at 25-100°C for a period of 12-72 hours.
• a base such as potassium carbonate
• an inert solvent such as acetone, acetonitrile, or dimethylformamide
• the ethyl ester (xxxi) can be hydrolyzed to the co ⁇ esponding acid analog (xxxii) by treatment of the ester (xxxi) with a base such as sodium hydroxide, lithium hydroxide or potassium carbonate in an aqueous solvent such as ethanol, methanol, tetrahydrofuran, water or mixture thereof at 0-100°C for 1-24 hours.
• a base such as sodium hydroxide, lithium hydroxide or potassium carbonate
• an aqueous solvent such as ethanol, methanol, tetrahydrofuran, water or mixture thereof at 0-100°C for 1-24 hours.
• the acid (xxxii) can be modified by treatment with diethyl azido phosphorate (DPPA) and a base such as triethylamine in the presence of an alcohol (R 7 OH) in an inert solvent such as toluene, dioxane or dimethylformamide at a temperature of 25- 120°C for a period of 1-24 hours to give the carbamate (xxxiii).
• DPPA diethyl azido phosphorate
• R 7 OH an inert solvent
• toluene, dioxane or dimethylformamide at a temperature of 25- 120°C for a period of 1-24 hours
• compounds of structure (H) may be made by conversion of the appropriate acetoheteroaryl to bromoacetal (xxxiv), which is then reacted with 2-amino-5-bromo-6-methylpyrimidin-4-ol (xxxv) to give the co ⁇ esponding imidazolopyrimid-4-one (xxxvi).
• Compound (xxxvi) is then converted to the R 4 -substituted compound (xxxvii) followed by R 6 -substituted compound (xxxviii), which is then utilized to form compound (xxxvix).
• This reaction may also be employed for compounds of structure (HI), after formation of the co ⁇ esponding intermediate (xxxvi) via Reaction Scheme C.
• GnRH receptor antagonists of this invention include the following compounds (a) through (p):
• the compounds of the present invention may generally be utilized as the free base.
• the compounds of this invention may be used in the form of acid addition salts.
• Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
• Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
• pharmaceutically acceptable salt of structure (I) is intended to encompass any and all acceptable salt forms.
• prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
• Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
• representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I).
• esters may be employed, such as methyl esters, ethyl esters, and the like.
• the compounds of structure (I) may have chiral centers and may occur as recemates, reacemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention. The effectiveness of a compound as a GnRH receptor antagonist may be determined by various assay methods.
• Suitable GnRH antagonists of this invention are capable of inhibiting the specific binding of GnRH to its receptor and antagonizing activities associated with GnRH.
• inhibition of GnRH stimulated LH release in immature rats may be measured according to the method of Vilchez -Martinez (Endocrinology 96:1130-1134, 1975). Briefly, twenty-five day old male Spraque- Dawley rats are administered an GnRH antagonist in saline or other suitable formulation by oral gavage, sub-cutaneous injection, or intravenous injection. This is followed by sub-cutaneous injection of 200 ng GnRH in 0.2 mL saline. Thirty minutes after the last injection, the animals are decapitated and trunk blood collected.
• GnRH receptor antagonists are well known in the field, such as the use of cultured pituitary cells for measuring GnRH activity (Vale et al., Endocrinology 91 :562-572, 1972), and a technique for measuring radioligand binding to rat pituitary membranes (Perrin et al., Mol. Pharmacol. 23:44-51, 1983). Activity of GnRH receptor antagonists are typically calculated from the
• IC o concentration of a compound necessary to displace 50% of the radiolabeled ligand from the GnRH receptor, and is reported as a "K,” value calculated by the following equation:
• GnRH receptor antagonists of this invention have a K ⁇ of 10 ⁇ M or less. In a preferred embodiment of this invention, the GnRH receptor antagonists have a K, of less than 1 ⁇ M, and more preferably less than 100 nM.
• the compounds of this invention are more resistant to metabolic enzymes, provide increased bioavailability and longer duration of action, are better absorbed, are more potent, and/or have enhanced solubility properties compared to existing GnRH receptor antagonists.
• GnRH receptor antagonists the compounds of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of sex-hormone related conditions in both men and women, as well as mammals in general.
• such conditions include endometriosis, uterine fibroids, polycysic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization).
• endometriosis uterine fibroids
• polycysic ovarian disease hirsutism
• precocious puberty gonadal steroid-dependent neoplasia
• gonadotrophe pituitary adenomas sleep apnea
• sleep apnea irritable bowel syndrome
• premenstrual syndrome benign prostatic hypertrophy
• contraception and infertility e.
• the compounds of this invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.
• the compounds are useful in combination with androgens, estrogens, progesterones, and antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids, and in contraception, as well as in combination with an angiotensin-converting enzyme inhibitor, an antiotensin H-receptor antagonist, or a renin inhibitor for the treatment of uterine fibroids.
• the compounds may also be used in combination with bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with a GnRH antagonist.
• compositions containing one or more GnRH receptor antagonists are disclosed.
• the compounds of the present invention may be formulated as pharmaceutical compositions.
• Pharmaceutical compositions of the present invention comprise a GnRH receptor antagonist of the present invention and a pharmaceutically acceptable carrier and/or diluent.
• the GnRH receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably with acceptable toxicity to the patient.
• the pharmaceutical compositions of the present invention may include a GnRH receptor antagonist in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
• compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
• the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a GnRH receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants.
• GnRH receptor antagonist diluents, dispersing and surface active agents, binders, and lubricants.
• One skilled in this art may further formulate the GnRH receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
• the present invention provides a method for treating sex-hormone related conditions as discussed above.
• Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition.
• "treat” includes prophylactic administration.
• Such methods include systemic administration of a GnRH receptor antagonist of this invention, preferably in the form of a pharmaceutical composition as discussed above.
• systemic administration includes oral and parenteral methods of administration.
• suitable pharmaceutical compositions of GnRH receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions.
• compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
• the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the GnRH receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
• the compounds of this invention may be evaluated as GnRH receptor antagonists according to the following techniques.
• One pituitary gland normally yields one 96-well plate of cells, which can be used for assaying three compounds.
• the incubated cells are first washed with 0.1% BS A/McCoy's 5A medium once, followed by addition of the test sample plus InM GnRH in 200 ⁇ l 0.1% BS A/McCoy's 5 A medium in triplicate wells. Each sample is assayed at 5-dose levels to generate a dose-response curve for determination of its potency on the inhibition of GnRH stimulated LH and/or FSH release. After 4-hr incubation at 37°C, the medium is harvested and the level of LH and/or FSH secreted into the medium determined by RIA.
• each sample medium is assayed in duplicates and all dilutions are done with RIA buffer (0.01M sodium phosphate buffer/0.15M NaCl/1% BSA/0.01% NaN3, pH 7.5) and the assay kit is obtained from the National Hormone and Pituitary Program supported by NLDDK.
• RIA buffer 0.01M sodium phosphate buffer/0.15M NaCl/1% BSA/0.01% NaN3, pH 7.5
• the assay kit is obtained from the National Hormone and Pituitary Program supported by NLDDK.
• To a 12x75 mm polyethylene test tube is added 100 ⁇ l of sample medium diluted 1:5 or rLH standard in
• the mixture is incubated at room temperature over-night.
• 100 ⁇ l of goat anti-rabbit IgG diluted 1:20 and 100 ⁇ l of normal rabbit serum diluted 1:1000 are added and the mixture incubated for another 3 hr at room temperature.
• the incubated tubes are then centrifuged at 3,000 rpm for 30 min and the supernatant removed by suction. The remaining pellet in the tubes is counted in a gamma-counter.
• RIA of FSH is done in a similar fashion as the assay for LH with substitution of the LH antibody by the FSH antibody diluted 1:30,000 and the labeled rLH by the labeled rFSH.
• GnRH Peptide Radio-iodination of GnRH Peptide
• the GnRH analog is labeled by the chloramine-T method.
• the reaction is stopped by the addition of 60 ⁇ g sodium metabisulfite and the free iodine is removed by passing the iodinated mixture through a C-8 Sep-Pak cartridge (Millipore Corp., Milford, MA).
• the peptide is eluted with a small volume of 80% acetonitrile/water.
• the recovered labeled peptide is further purified by reverse phase HPLC on a Vydac C- 18 analytical column (The Separations Group, Hesperia, CA) on a Beckman 334 gradient HPLC system using a gradient of acetonitrile in 0.1% TFA.
• the purified radioactive peptide is stored in 0.1% BS A/20% acetonitrile/0.1% TFA at -800C and can be used for up to 4 weeks.
• Cells stably, or transiently, transfected with GnRH receptor expression vectors are harvested, resuspended in 5% sucrose and homogenized using a polytron homogenizer (2x15 sec). Nucleii are removed by centrifugation (3000 x g for 5 min.), and the supernatant centrifuged (20,000 x g for 30 min, 4°C) to collect the membrane fraction. The final membrane preparation is resuspended in binding buffer (lOmM Hepes (pH 7.5), 150 mM NaCl, and 0.1% BSA) and stored at -70°C.
• binding buffer pH 7.5
• 150 mM NaCl 150 mM NaCl
• BSA 0.1% BSA
• Binding reactions are performed in a Millipore MultiScreen 96-well filtration plate assembly with polyethylenimine coated GF/C membranes.
• the reaction is initiated by adding membranes (40 ug protein in 130 ul binding buffer) to 50ul of [ 125 I]-labeled GnRH peptide (-100,000 cpm), and 20ul of competitor at varying concentrations.
• the reaction is terminated after 90 minutes by application of vacuum and washing (2X) with phosphate buffered saline.
• Bound radioactivity is measured using 96-well scintillation counting (Packard Topcount) or by removing the filters from the plate and direct gamma counting. K; values are calculated from competition binding data using nonlinear least squares regression using the Prism software package (GraphPad Software).
• Step C 3-Cyano-6-ethoxycarbonyl-2-(4-methoxyphenyl)-l -methyl -4H- pyrrolo ⁇ ,2-alpyrimid-7-one
• a refluxing solution 150 mL
• ethanol and water 7/3
• NaO ⁇ 2.2 g, 55 mmol
• malononitrile 2.64 g, 40 mmol
• 4'-methoxy-2- aminopropiophenone hydrochloride (5.9 g, 27.2 mmol) was added in several portions. After the solution was refluxed for 30 minutes., additional malonitrile (1.3 g, 20 mmol) and NaO ⁇ (1.1 g, 27.5 mmol) were added.
• 2-amino-3-cyano-4-(4-methoxyphenyl)-5-methylpy ⁇ ole was then refluxed with diethyl ethoxymethylene malonate ( 2.75 g, 12.7 mmol ) in ethanol for 24 hours and concentrated to a deep brown oil.
• the oil was mixed with Dowtherm (20 mL) and then heated at 240°C for 30 minutes. After cooling down to room temperature, it was diluted with ether (200 mL) resulting in a precipitation.
• Step D 3-Cyano-6-ethoxycarbonyl-4-(2-fluorobenzyl)-2-(4-methoxyphenyl)-l- methylpy ⁇ olo
• Step B 3-Cyano-6-(3-pentoxycarbonyl)-4-(2-fluorobenzyl)-2-r4-(3- pentox yphenyl] - 1 -methylpy ⁇ olo ⁇ 1 ,2-alpyrimid-7-one
• 3-Cyano-6-(3-hydroxycarbonyl)-4-(2- fluorobenzyl)-2-(4-hydroxyphenyl)- l-methylpy ⁇ olo[l,2-a]pyrimid-7-one 83 mg, 0.2 mmol
• dry DMF 5 mL
• potassium carbonate 500 mg, 3.6 mmol.
• Step C 3-Cvano-6-(3-pentoxycarbonyl)-4-(2-fluorobenzyl)-2-r4-(3- pentox v)phenyll - 1 - ( N-meth yl-N- [2-(2- pyridyl)ethyl1aminomethylpyHolori,2-alpyrimid-7-one
• N-meth yl-N- [2-(2- pyridyl)ethyl1aminomethylpyHolori,2-alpyrimid-7-one To a refluxing solution of carbon tetrachloride (5 mL) containing 3- cyano-6-(3-pentoxycarbonyl)-4-(2-fluorobenzyl)-2-[4-(3-pentoxyphenyl]-l- methylpy ⁇ olo[l,2-a]pyrimid-7-one (85 mg, 0.15 mmol), NBS (43 mg, 1.5 eq) and 3 particles of
• Step A 3-(Bromoacetyl)-2,5-dimethylfuran Copper bromide (17.9g, 2.0eq) was added to a solution of the 2,5- dimethyl 3-acetofuran (5.52g, 40 mmol) in EtOAc/CHC13 (1:1, 50 mL). The mixture was refluxed for 2.5 hours, at which time the starting material was almost totally consumed. It was then cooled down and filtered to remove the copper residue. The green filtrate was concentrated to yield an oil which was diluted with ether, filtered again to further remove some black insoluble residue. The filtrate was then concentrated to yield an oil (6.5g) as the desired product, which was directly used in the next step.
• Step B 2-(2,5-dimethyl-3-furyl)-5-bromo-6-methylimidazolo[l,2-alpyrimid-4- one
• Step D 2-(2,5-Dimethyl-3-furyl)-5-(3-methoxyphenyl)-6-methyl-7-(2- fluorophenylmethyl)imidazoloIl,2-alpyrimid-4-one 2-(2,5-Dimethyl-3-furyl)-5-bromo-6-methyl-7-(2-fluorophenylmethyl)- imidazolo[l,2-a]pyrimid-4-one (200mg, 0.466 mmol) , boronic acid (74 mg, 1.05 eq.), Pd(OAc) 2 (5.2 mg, 0.05eq), PPh 3 (12 mg, O.leq), K 2 CO 3 (129mg, 2.0eq) were charged into the reaction flack, degassed and protected under N 2 atmosphere.
• Step E 2-(2,5-dimethyl-3-furyl)-3-(N-methyl-N-r2-(2- pyridyl)ethyllaminomethyl ⁇ -5-(3-methoxyphenyl)-6-methyl-7-(2- fluorophenylmethyl)imidazolori.2-alpyrimid-4-one 2-(2,5-Dimethyl-3-furyl)-5-(3-methoxyphenyl)-6-methyl-7-(2- fluorophenylmethyl)imidazolo[l,2-a]pyrimid-4-one (30 mg) obtained above as suspended in acetic acid and treated with 2 drops of amine followed by 2 drops of the formaldehyde (37% water solution). The reaction was stirred at room temperature for 1 hour. HO Ac was evaporated and the residue was diluted with DCM and purified by prep-TLC to yield the desired product, which was characterized by proton NMR and mass spectra.
• Step A l-I2-(2.5-Dimethyl-3-furyl)-2-oxoethyll-2-methyl-5- ethoxycarbonylpyrimid-6-one 5-Ethoxycarbonyl-2-methylpyrimid-4-one (3.5g, 19 mmol) was dissolved in DME (110 mL) and TBAF (28.5 mL, 1 M solution in THF, 28.5 mmol) added dropwise at 0°C. The resulting solution was stirred ten minutes and a solution of 3-bromoacetyl-2,5-dimethylfuran (4.3 g, 20 mmol) in DME (10 mL) was added dropwise. The reaction was sti ⁇ ed at room temperature overnight.
• Step C 2-(2.5-Dimethyl-3-furyl)-6-ethoxycarbonyl-4-(2- fluorophenylmethyl)pyrrolori,2-alpyrimid-7-one
• 2-(2,5-Dimethyl-3-furyl)-4H-6-ethoxycarbonylpyrrolo[l,2-a]pyrimid-7- one (1.83 g, 6.1 mmol) was suspended in DME (10 mL), followed by addition of TBAF (12.2 mL, IM solution in T ⁇ F, 12.2 mmol), and then 2-fluorobenzyl bromide. The solution was stirred at room temperature overnight. A solid precipitate was collected by filtration and washed with Et 2 O to yield the product; MS: 409 (M+H) and 363.
• Step D 2-(2.5-Dimethyl-3-furviy 1 - ( N-methyl-N- .2-(2- pyridyl)ethvHaminomethyl r-6-ethoxycarbonyl-4-(2- fluorophenylmethyPpyrrolof 1 ,2-a1pyrimid-7-one 2-(2,5-Dimethyl-3-furyl)-6-ethoxycarbonyl-4-(2-fluorophenylmethyl)- py ⁇ olo[l,2-a]pyrimid-7-one (50mg, 122umol) was added into a solution of formaldehyde (5 ⁇ L, 184 ⁇ mol) and a secondary amine (184 ⁇ mol) in acetic acid (2 mL).
• Step E Ethyl-2-fluoroethyl-3-r4-(2-methylpropyloxy)phenyllcarbonylmethyl-6-

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