JP2002544278A - Imidazo and pyrrolo [1,2-a] pyrimid-4-ones as gonadotropin releasing hormone receptor antagonists - Google Patents

Abstract

SUMMARY A GnRH receptor antagonist is disclosed which has utility in the treatment of various sex hormone-related conditions in both men and women. The compounds of the present invention have structural formula (I) and include stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein Ar, B, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and m are defined herein. The present invention also provides a method for treating lupus erythematosus, irritable bowel syndrome, premenstrual syndrome, hirsutism, short stature or sleep disorder in a subject in need of treatment.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention generally relates to gonadotropin releasing hormone (GnRH) receptor antagonists and the treatment of disorders by administering such antagonists to warm-blooded animals in need of such treatment. On how to do.

BACKGROUND OF THE INVENTION Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), plays a key role in human reproduction and is a decapeptide (pGlu-His-). Trp-Ser-Tyr-Gly-Leu
_{-Arg-Pro-Gly-NH 2} ) it is. GnRH is released from the hypothalamus and acts on the pituitary to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH released from the pituitary is responsive to regulation of gonadal steroidogenesis in both males and females, while FSH regulates spermatogenesis in males and vesicle development in females. Adjust

[0003] Due to their biological importance, synthetic antagonists and agonists for GnRH have received considerable attention, particularly in view of prostate cancer, breast cancer, endometriosis, uterine smooth muscle species, and precocious puberty. It was the point of concentration. For example, peptide Gn
RH agonist (for example, leuprorelin (pGlu-His-Trp)
-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt)) has been used to treat such conditions. Such agonists appear to function by binding to the pituitary gonadotropin GnRH receptor, thereby inducing gonadotropin synthesis and release. Chronic administration of a GnRH antagonist consumes gonadotropin and subsequently down-regulates its receptor, and after some period of time (eg, 2-3 weeks after the start of chronic administration) On the order), resulting in suppression of steroid hormones.

[0004] In contrast, GnRH antagonists are thought to suppress the production of gonadotropins, and thus have received the most attention over the past two decades. To date, some of the major obstacles to the clinical use of such antagonists have been the adverse side effects caused by their relatively low bioavailability and histamine release. However, although some peptidic antagonists with low histamine release properties have been reported, they are still subject to sustained routes of delivery (eg, subcutaneous injection or intranasal spray) due to limited bioavailability. Must be delivered via

[0005] In view of the limitations on peptidic GnRH antagonists, a number of non-peptidic compounds have been proposed. For example, Cho et al. (J. Med. Chem. 4)
1: 4190-4195, 1998) disclose thieno [2,3-b] pyridin-4-ones for use as GnRH receptor antagonists; U.S. Patent Nos. 5,780,437 and 5; , 849, 764 teach substituted indoles as GnRH receptor antagonists (published PCT WO 97/21704, 98/55479, 98/55470, 98/551).
16, 98/55119, 97/21707, 97/21703 and 97/2
Published PCT WO 96/38438 discloses tricyclic diazepines as GnRH receptor antagonists; published PC
T WO 97/14682, 97/14697 and 99/09033 are Gn
Disclose derivatives of quinoline and thienopyridine as RH antagonists; published PCT WO 97/44037, 97/44041, 97/443.
21 and 97/44339 teach substituted quinolin-2-ones as GnRH receptor antagonists; and published PCT WO 99 /
33831 discloses certain phenyl-substituted fused ring nitrogen-containing bicyclic compounds as GnRH receptor antagonists.

[0006] Although significant progress has been made in this area, there remains a need in the art for effective small molecule GnRH receptor antagonists. There is also a need for pharmaceutical compositions comprising such GnRH receptor antagonists, as well as methods relating to the use of the compositions, for example, for the treatment of sex hormone related conditions. The present invention fulfills these needs, and provides other related advantages.

SUMMARY OF THE INVENTION Briefly, the present invention generally relates to gonadotropin releasing hormone (GnRH) receptor antagonists, and methods for their preparation and use, and pharmaceutical compositions containing them.

More specifically, the GnRH receptor antagonist of the present invention has the following general formula (I):

[0009]

Embedded image (Including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof), wherein Ar, B, R ₁ , R ₂ , R _3a , R _3b , R ₄ , R ₅ , R ₆ and m are as defined below.

[0010] The GnRH receptor antagonists of the present invention have utility over a wide range of therapeutic applications and are useful in both men and women, as well as in general mammals (also referred to herein as "subjects"). ) Can be used to treat various sex hormone related conditions. For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, reproductive steroid dependent neoplasia (eg, prostate, breast and uterine cancer), gonadotropes Pituitary adenoma, sleep apnea,
Irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (eg,
Assisted reproductive therapy, such as in vitro fertilization). The compounds of the present invention are also useful as adjuncts for the treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosus. The compounds are also useful in the treatment of endometriosis, fibroids, and in contraception, in combination with androgens, estrogens, progesterone, and antiestrogens and antiprogestogens, and angiotensin converting enzyme inhibitors, angiotensin, Useful for the treatment of uterine fibroids in combination with a II receptor antagonist, or a renin inhibitor. In addition, the compounds may be used for the treatment and / or prevention of disorders of calcium degradation, phosphate and bone metabolism, in combination with biological phosphonates and other agents, and with estrogen, progesterone and / or androgen Bone loss or pituitary symptoms (eg, hot flashes during treatment with a GnRH antagonist)
Can be used for prevention or treatment.

[0011] The method of the invention comprises the step of administering an effective amount of a GnRH receptor antagonist, preferably in the form of a pharmaceutical composition, to a mammal in need thereof.
Thus, in a still further embodiment, a pharmaceutical composition is disclosed that contains one or more GnRH receptor antagonists of the present invention in combination with a pharmaceutically acceptable carrier and / or diluent.

[0012] These and other aspects of the invention will become apparent with reference to the following detailed description. To this end, various references are set forth herein, which describe in more detail specific background information, procedures, compounds and / or compositions, each of which is incorporated herein in its entirety. Incorporated by reference in the book.

DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention generally relates to gonadotropin-releasing hormone (GnRH)
)) Compounds useful as receptor antagonists. The compounds of the present invention
The following structure (I):

[0014]

Embedded image And including its stereoisomers, prodrugs and pharmaceutically acceptable salts, wherein: m is an integer from 1 to 6: R ₁ is hydrogen, alkyl, substituted alkyl, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, aryl (CR _3c R _3d ) _n
, Substituted aryl (CR _3c R _{3d) n,} heteroaryl (CR _3c R _{3d) n} or substituted heteroaryl _{(CR 3c R 3d) n;} R 2 is hydrogen, or an alkyl or substituted alkyl; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring; R _3a , R _3b , R _3c and R _3d are the same or Different, and independently in each case, hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, thioalkyl, amino, alkylamino, dialkylamino, cyano, halogen,
Is —C (＝ O) OR ₇ or —C (＝ O) OR ₇ R ₈ ; or R _3a and R _3b , or R _3c and R _3d together with the carbon atom to which they are attached, Forms a carbocyclic or substituted carbocyclic ring; or R _3a and R ₁ together with the carbon and nitrogen atoms to which they are attached, respectively, form a heterocyclic or substituted heterocyclic ring formed; R ₄ 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 monoalkyl or dialkyl amine; R ₆ is water , Alkyl, substituted alkyl, aryl, substituted aryl, heterocycle,
Substituted _{heterocycle, -OR 7, -SR 7, -SOR} 7, -SO 2 R 7, -OSO 2 R 7, -S
_{O 2 OR 7, -SO 2 NR} 7 R 8, -NR 9 SO 2 R 7, -C (= O) R 7, -C (= O
_{) OR 7, -OC (= O} ) R 7, -NR 7 R 8, -C (= O) NR 7 R 8, -OC (=
_{O) NR 7 R 8, -NR} 9 C (= O) R 7, -NR 9 C (= O) NR 7 R 8, -NR 8 C
(＝ O) OR ₇ or —C (OH) R ₇ R ₈ ; R ₇ , R ₈ and R ₉ are the same or different and are independently hydrogen,
Is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or R ₇ and R ₈ are the nitrogen atoms to which they are attached And to form a heterocyclic or substituted heterocyclic ring; n is an integer from 1 to 6; and B and Ar are as follows: Ar is heteroaryl or substituted hetero When R is aryl and R ₁₀ is hydrogen, B is nitrogen or CR ₁₀ ; or Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R ₁₀ is halogen, cyano , Nitro, amino, monoalkylamino or dialkylamino, or alkyl In some cases, B is CR _10.

As used herein, the above terms have the following meanings: “Alkyl” means linear or branched, acyclic or cyclic, unsaturated or saturated, An aliphatic hydrocarbon containing ８8 carbon atoms is meant, while the term “lower alkyl” has the same meaning as alkyl, but contains 1-4 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl,
Examples of n-pentyl, n-hexyl and the like; on the other hand, examples of saturated branched alkyl 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 "alkenyl" or "alkynyl," respectively). Representative linear 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 typical 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” refers to an aryl moiety (eg, benzyl, — (CH ₂ ) ₂ —
Phenyl, — (CH ₂ ) ₃ phenyl, —CH (phenyl) _2, etc.) means alkyl having at least one alkyl hydrogen atom.

“Heteroaryl” is a 5- to 10-membered ring and has at least one heteroatom selected from nitrogen, oxygen, and sulfur and contains at least one carbon atom, and is a monocyclic ring Aromatic heterocyclic rings are meant to include both system 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, cinnonyl, cinnonylyl It is quinazolinyl.

“Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety (eg, —CH ₂ pyridinyl, —CH ₂ pyrimidinyl, and the like).

“Heterocycle” means a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring, wherein the heterocyclic ring is any of saturated, unsaturated, or aromatic. And comprises 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and The atoms can be optionally quaternized ammoniumated, and the heterocycle includes a bicyclic ring in which any of the above heterocycles is fused to a benzene ring. Heterocycles may be linked via any heteroatom or carbon atom. Heterocycle includes heteroaryl as defined above. Accordingly, in addition to the heteroaryls listed above, heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl , Tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

“Heterocyclealkyl” means an alkyl having at least one alkyl hydrogen atom substituted with a heterocycle (eg, —CH ₂ morpholinyl, and the like).

As used herein, the term “substituted” refers to any of the above groups wherein at least one hydrogen atom is replaced with a substituent (ie, alkyl, aryl, arylalkyl, heteroaryl , Heteroarylalkyl, heterocycle and heterocyclealkyl). In the case of a keto substituent ("C = O"), two hydrogen atoms are replaced. Substituents include: halogen, hydroxy, alkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -N
R'R ", -NR '" C (= O) R', -NR '"C (= O) NR'R'
', -NR''' C ( = O) OR ', - NR''' SO 2 R ', - C (= O) R
'-C (= O) OR', -C (= O) NR'R ", -OC (= O) R ', -O
C (= O) OR ', - OC (= O) NR'R'' or -NR''' SO ₂ R '
Wherein R ′ and R ″ are the same or different and are independently hydrogen, amino, alkyl, halogenated alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclic, substituted heterocyclic, heterocyclic, Ring alkyl or substituted heterocyclic alkyl, or R ′ and R ″, together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring.

“Halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” means an alkyl having at least one hydrogen atom replaced with a halogen (eg, trifluoromethyl and the like).

“Alkoxy” is an alkyl moiety attached through an oxygen bridge (ie, —
O-alkyl) (eg, methoxy, ethoxy, etc.).

“Aryloxy” means an aryl moiety attached through an oxygen bridge (ie, —O-aryl) (eg, phenoxy and the like).

“Thiol” refers to —SH.

“Thioalkyl” refers to an alkyl moiety attached through a sulfur bridge (ie, —S-alkyl) (eg, —SCH ₃ , —SCH ₂ CH _3, etc.).

“Thioaryl” means an aryl moiety attached through a sulfur bridge (ie, —S-aryl) such as, for example, —S-phenyl.

“Monoalkylamine or dialkylamine” means —NH (alkyl) or —NH (alkyl) (alkyl), respectively.

“Sulfonylalkyl” means an alkyl moiety attached through a sulfonyl bridge (ie, —SO ₂ -alkyl) (eg, —SO ₂ CH ₃ , —SO ₂ CH ₂ CH _3, etc.).

“Sulfonylaryl” means an aryl moiety (ie, —SO ₂ -aryl) attached through a sulfonyl bridge (eg, —SO ₂ -phenyl and the like).

Depending on the choice of the B moiety of structure (I), the compounds of the invention have the following structure (II) when B is nitrogen and the following structures when B is CR ₁₀ Structure (I
II).

[0034]

Embedded image In structure (II), Ar is heteroaryl or substituted heteroaryl. Similarly, when R ₁₀ is hydrogen in structure (III), Ar is heteroaryl or substituted heteroaryl. However, when R ₁₀ in structure (III) is halogen, cyano, nitro, amino, monoalkylamino or dialkylamino or alkyl, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

In one embodiment, R ₆ is —C (＝ O) OR ₇ and a representative compound of the invention has the following structure (IV):

[0036]

Embedded image Having.

In another embodiment, R ₆ is —C (＝ O) NR ₇ R ₈ , and a representative compound of the invention has the structure (V)

[0038]

Embedded image Having.

In another embodiment, R ₆ is —C (＝ O) R ₇ , —C (OH) R ₇ R ₈ or —OR ₇ , and a representative compound of the invention has the structure: (VI), (VI
I) and (VIII)

[0040]

Embedded image Respectively.

In a still further embodiment, R ₆ is hydrogen, alkyl, substituted alkyl, hydroxy, thioalkyl or sulfonylalkyl, and representative compounds of the invention have the following structures (IX)-(XIV), respectively:

[0042]

Embedded image Having.

In one embodiment of structure (I), R ₁ and R ₂ together with the nitrogen atom to which they are attached, have the following structure (XV):

[0044]

Embedded image To form a heterocyclic ring represented by

Similarly, in more particular embodiments of structure (V), R ₇ and R ₈ together with the nitrogen atom to which they are attached, form a heterocyclic or substituted heterocyclic ring represented by the following structure (XVI) Formed and optionally combined with R ₁ and R ₂ to form the following structure (X
VII):

[0046]

Embedded image To form a heterocyclic or substituted heterocyclic ring represented by

In another embodiment of structure (I), R ₁ is heteroaryl (CR _3c R _3d ) _n or substituted heteroaryl (CR _3c R _3d ) _n . In one aspect of this embodiment, the heteroaryl portion of the heteroaryl (CR _3c R _{3d) n} moiety is pyridinyl (e.g., pyridin-2-yl), and the compound of the present invention have the following structure (XVIII ):

[0048]

Embedded image Wherein R _e and R _f are the same or different and represent optional substituents independently selected from hydrogen, alkyl, alkoxy, dialkylamino, halo and cyano.

In a still further embodiment of structure (I), the (CR _3a R _3b ) _m moiety has the following structure (XIX):

[0050]

Embedded image Wherein the alkylidene is a divalent alkyl group (eg, a divalent linear alkyl (eg, methylene (ie, —CH ₂ —), ethylene (ie, —CH ₂ CH ₂ — )Such)
Divalent branched alkyl _{(e.g., -CH (CH 3) -,} - C (CH 3) 2 - , etc.),
And divalent cycloalkyl (including, for example, cyclohexylene).

In a more particular embodiment of the present invention, the Ar moiety has the following structure (XX):

[0052]

Embedded image Wherein A ₁ , A ₃ and A ₄ are the same or different and are independently nitrogen or CH
A ₂ is oxygen, sulfur, NH, N = N or N = CH; and R _a , R _b , R _c and R _d are optional substituents, 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, monoalkylamino, dialkylamino, monoarylamino, diarylamino, -COOalkyl, -COOaryl, -CONHalkyl, -CONHaryl, -CON
(Alkyl) ₂ , -CON (aryl) ₂ , -NHCOalkyl, -NHCOaryl, -N (alkyl) COalkyl, -N (alkyl) COaryl, -NH
SO ₂ alkyl, -NHSO ₂ aryl, N (alkyl) SO ₂ alkyl, -N (
Or alkyl) SO ₂ aryl, —NHCONHalkyl or —NHCONHaryl; or R _a and R _b together with the atom to which they are attached form aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Thus, depending on the choice of A ₁ , A ₂ , A ₃ and A ₄ of structure (XX), the heterocycle containing A ₁ , A ₂ , A ₃ and A ₄ is a heteroaryl :

[0054]

Embedded image including.

In addition to the above heteroaryls, the present invention also includes heteroaryls in which R _a and R _b form an aryl or heteroaryl with the atoms to which they are attached, including benzofuranyl, isobenzoyl Furanyl, thionaphthenyl, isothionaphthenyl, indoyl (ind
oyl), purinyl, quinolinyl, isoquinolinyl, pyrano [3,4-b] pyrrolyl, indoxazinyl, benzoxazolyl, anthranyl, cinnolinyl,
Quinazolinyl, naphthyridinyl, pyrido [3,4-b] pyridinyl, pyrido [3
, 2-b] pyridinyl, pyrido [4,3-b] pyridinyl and the like, but are not limited thereto.

The compounds of the present invention can be prepared by known organic synthesis techniques,
Examples include methods described in more detail. However, in general, compounds of structure (II) can be produced by the following reaction schemes A and B, and
) Can be produced according to Schemes C and D. Reaction Schemes EM show additional synthetic procedures that are generally applicable to compounds of structure (I). In the following reaction schemes, all substituents are as defined above unless otherwise indicated.

(Reaction Scheme A)

[0058]

Embedded image As shown in Reaction Scheme A, imidazolo [1,2-a] pyrimidone (i
va) can be prepared from an α-bromoheteroaryl ketone (R = alkyl). Thus, bromoketone (ia) can be prepared by combining acetylguanidine with a suitable solvent (eg,
Cyclization in dimethylformamide) at a temperature of 25-120 ° C. for 1-72 hours gives 2-acetamidoimidazole (iia), which is reacted in a suitable solvent (eg water or ethanol) at 60-120 ° C. Hydrolysis with an acid such as sulfuric acid at a temperature for 2 to 24 hours may produce 2-aminoimidazole (iiiia). 2-
Aminoimidazole (iiiia) is substituted with a substituted acrylate and an inert solvent (eg,
Modification by cyclization in methanol (dioxane or phenyl ether) at a temperature of 60-260 ° C. for 0.5-16 hours can produce imidazolo [1,2-a] pyrimidone (iva).

(Reaction Scheme B)

[0060]

Embedded image Alternatively, imidazolo [1,2-a] pyrimidone (iva) is a base (eg, sodium hydride, tetrabutylammonium fluoride) of 2-aminopyrimidine (viia) and an α-bromoheteroaryl ketone (ia). , Potassium carbonate) in an inert solvent (eg, DME, dimethylformamide, ethanol) at a temperature of 25-100 ° C for 12-24 hours.

(Reaction Scheme C)

[0062]

Embedded image In Reaction Scheme C, amidine hydrochloride (ib) is reacted with a bis-electrophile (eg, diethylethoxymethylene malonate) in an organic solvent (eg, ethanol) in the presence of sodium ethoxide at a temperature of 25-100 ° C. The cyclization is preferably carried out at reflux temperature in ethanol for 2 to 12 hours to produce the corresponding pyrimidone (iib). Pyrimidone (iib) is an inert solvent (eg,
Treatment with a base (eg, tetrabutylammonium fluoride, sodium hydride, or sodium ethoxide) in 0,25 ° C for 30 minutes in 1,2-dimethoxyethane, tetrahydrofuran, or a mixture thereof. And then treated with α-bromoketone at 0 to 25 ° C. for 12 to 24 hours to obtain an alkylated pyrimidone (iiib)
Generate Pyrimidone (iiib) forms a ring when treated with a strong base (eg, sodium ethoxide, sodium hydride or LiN (SiMe ₃ ) ₂ ) in an inert solvent (eg, ethanol) at 25-80 ° C. for 2-4 hours. Pyrrolo [1
, 2-a] pyrimidone (ivb).

(Reaction Scheme D)

[0064]

Embedded image In Reaction Scheme D, a heteroaryl ketone (vb) is combined with a brominating reagent (eg, copper (II) bromide, bromine, etc.) in an organic solvent (eg, chloroform, ethyl acetate, ether or mixtures thereof). 2 to 12 hours, 2
Converted by treatment (preferably refluxing in a mixture of chloroform and ethyl acetate) at a temperature of 5 ° C to 100 ° C to give the corresponding α-bromoketone (vib)
Get. Alternatively, treating the heteroaryl ketone (vb) at reflux with N-bromosuccinamide or bromine in an inert solvent such as carbon tetrachloride or chloroform containing a radical initiator such as AIBN. By the above, bromoketone (vib) can be obtained. The bromoketone (vib) can be combined with an azide salt such as sodium azide, potassium azide, etc. in an inert solvent (e.g., DMF, tetrahydrofuran, ether, water, or a mixture thereof) between 0 <0> C and 5 <0> C.
Replace by treating at 0 ° C. for 2-12 hours. To produce the aminoketone hydrochloride (viib), the azide group is dissolved in a suitable solvent (eg, ethanol or ethanol with hydrochloric acid) and (a) palladium on carbon or Raney nickel is added as a catalyst to the solution. The mixture is reacted under a hydrogen atmosphere at room temperature for 1 to 12 hours, or (b) triethyl phosphate (tr
When the mixture is allowed to react at 0 ° C. to 25 ° C. for 1 to 24 hours, the azido group is converted to an amino group. The amino ketone (viib) is treated with malononitrile using a malononitrile treated with a strong base (eg, sodium or potassium hydroxide) in an inert solvent (eg, acetonitrile, water, ethanol or a mixture thereof).
By performing a catalytic reaction at 5 to 100 ° C. for 2 to 24 hours, aminopyrrole (viii
Obtain b). The aminopyrrole (viiib) is treated with a bis electrophile (eg, diethylethoxymethylene malonate) in an inert solvent (ethanol or dioxane) at a temperature of 25 ° C to 100 ° C for 12 to 24 hours. Condensation and then in a high binding solvent (e.g., phenyl ether)
The catalyst is reacted at 5 ° C. for 0.5 to 2 hours, and pyrrolo [1,2-a] pyrimidone (
ixb).

(Reaction Scheme E)

[0066]

Embedded image As shown in Reaction Scheme E, intermediate (ix) was converted to an inert solvent (DMF,
In the presence of a base (eg, tetrabutylammonium fluoride, sodium hydride, or silver (I) oxide) in DME, THF, etc., with an alkyl halide at 25-80 ° C. for 1-72 hours. Converted to the corresponding 4-substituted intermediate (x)
Get. Alternatively, compound (x) also comprises a starting material (ix) comprising an alcohol in an inert solvent (eg, tetrahydrofuran, benzene or ether) and a binder (eg, a mixture of dimethylazocarboxylate and triphenylphosphine). Can be prepared by a Mitsunobu coupling reaction at a temperature of 0 to 100 ° C for 1 to 24 hours.

(Reaction Scheme F)

[0068]

Embedded image As shown in Reaction Scheme F, intermediate (x) (R is an alkyl group)
With a brominating reagent such as N-bromosuccinamide in an inert solvent (e.g., carbon tetrachloride, chloroform) in the presence of a radical initiator (e.g., AIBN or benzoyl peroxide) at 25C to 100C. 1 to 24 at a temperature in the range
Treatment with time affords the corresponding bromoalkyl intermediate (xi) m, which can be combined with a primary or secondary amine (1-5 equivalents) at 0-50 ° C.
For 0.5 to 16 hours to obtain a compound (xii). The reaction is carried out in a suitable solvent (eg, dimethylformamide, acetonitrile, ethanol,
It can be carried out with stirring in tetrahydrofuran, chloroform or carbon tetrachloride). In this reaction, if necessary, a base such as triethylamine, DBU or pyridine can be used.

(Reaction Scheme G)

[0070]

Embedded image As shown in Reaction Scheme G, intermediate (xa) can be prepared by reacting an amine (eg, an alkylamine or dialkylamine) and an aldehyde (eg, formaldehyde, para Formaldehyde or acetaldehyde) together with 25-10
It can be modified by treating at a temperature of 0 ° C. for 0.5 to 16 hours, and the amine analog (xi
ia).

(Reaction Scheme H)

[0072]

Embedded image As shown in Reaction Scheme H, the ethyl ester of intermediate (xiii) was
Inert solvent (e.g., dioxane, tetrahydrofuran or dimethylformamide) or containing, or excess alcohol (R ₇ OH) with a strong base which does not include (e.g., butyl lithium, LiN (SiMe _{3) 2,} LDA, or potassium t- butoxide ) Can be converted to another ester (xiv) by treating at a temperature of 25-100 ° C for 0.5-16 hours. The ethyl ester group of compound (xiii) can be prepared by dissolving the starting material in a suitable solvent (eg, dichloromethane or dichloroethane) and adding a primary or secondary amine (R ₇ R ₈ NH) with triethyl aluminum or dibutyl. The amide analog (xv) can be converted to an amide group by adding it to a mixture with aluminum hydride and reacting the mixture at 20 to 100 ° C. for 1 to 12 hours under a nitrogen atmosphere. .
The starting material inert solvent (e.g., tetrahydrofuran, ether, hexane or mixtures thereof) suitable organometallic reagent in (e.g., an alkyllithium (R ₇
When reacted with Li), an alkyl magnesium halide or an organozinc) at a temperature of 0 to 25 ° C. for 1 to 165 hours, the ester group of compound (xiii) can also be converted to ketone (xvi). Further, a further organometallic reagent (R ₈ Li
) Is used to react the ketone (xvi) with the corresponding alcohol (xvi).
vii) is obtained.

(Reaction Scheme I)

[0074]

Embedded image Treat with an oxidizing agent such as m-chloroperbenzoic acid in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, ethyl acetate, etc.) for 1-16 hours or until the starting material is consumed, as shown in Reaction Scheme I. By doing so, the ketone derivative of the compound (xvi) can be oxidized to obtain the carboxylate analog (xviii). This ester (xviii) can be combined with a base (eg, sodium hydroxide, lithium hydroxide, etc.) in a suitable solvent (ethanol, water, tetrahydrofuran, or mixtures thereof) at 25-100 ° C. for 2-24 hours.
Time treatment can hydrolyze to the corresponding hydroxy compound (xix).
This ether derivative (xx) is combined with an alkyl halide (R ₇ X) and a base (potassium carbonate or sodium hydroxide) in an inert organic solvent (eg, acetone, dimethylformamide or DMSO) at 25-100 ° C. ~ 72 hours, (
xix) to give the product (xx).

(Reaction Scheme J)

[0076]

Embedded image As shown in Reaction Scheme J, to obtain the amino compound (xxii),
Starting compound (xxi) is converted to a suitable solvent (eg, ethanol or methanol)
And (a) adding a catalyst (e.g., palladium carbon or Raney nickel) to the solution and reacting the mixture under a hydrogen atmosphere at room temperature for 1 to 12 hours, or
Or (b) iron powder and hydrochloric acid are added to the solution, and the mixture
When reacted for 12 hours, a nitro group can be converted to an amino group as a substituent. A monoalkylamino analog (xxiii) or a dialkylamino analog (xxiv) can be prepared by combining an aldehyde and a reducing agent (eg, sodium cyanoborohydride, sodium borohydride) in a suitable solvent (acetic acid, ethanol, acetonitrile, water, or a mixture thereof). ) Together with reductive amination of the amino compound (xxii) at a temperature of 0 to 100 ° C. for 1 to 24 hours. Alternatively, (xxiii) and (xxiv) can be combined with an alkyl halide and a base (eg, sodium hydride, potassium carbonate, or sodium methoxide) in an inert solvent (tetrahydrofuran, dimethylformamide or DMSO) at 25-100 ° C. By treating (xxii) at a temperature of from 2 to 24 hours.

The urea derivative (xxv) is converted to a carbamoyl chloride (R) in an inert solvent (eg, dichloromethane, chloroform, tetrahydrofuran or a mixture thereof).
'YCOX, Y = NR', X = Cl) or an isocyanate reagent and an amine base (for example, pyridine, triethylamine, diisopropylethylamine, N-
Methyl morpholine) at a temperature of 0-65 ° C. for 1-72 hours,
It can be prepared by treating xii). Compound (xxii) is converted to an amine base (for example, pyridine, triethylamine, diisopropylethylamine, N-
Bis (electrophilic) reagent (in an inert solvent (dichloromethane, chloroform, tetrahydrofuran, etc.)) with or without added methyl morpholine)
For example, phosgene, triphosgene, 1,1'-carbonyldiimidazole, N '
, N'-disuccinimidyl carbonate, etc.) at a temperature of -20 to 0 ° C for 0.5 to 16 hours. The reaction mixture is then combined with the appropriate mono- or disubstituted amine at -20 to 25 ° C for 1 to 1
By treating for 6 hours, a urea analog (xxv) is obtained.

The amino analog (xxii) can be modified by acylation under various conditions. For example, acid chlorides (R'YC) in an inert solvent (dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or mixtures thereof)
_{OX, Y = CH 2, X} = Cl), an acid anhydride, an activated ester or an alkyl chloroformate, (R'YCOX, Y = O, X = Cl) and an amine base (e.g., triethylamine, diisopropylamine, pyridine ) At 0 ° C. to room temperature for 1 to 12 hours to give the corresponding amide / urethane derivative (xxv). Alternatively, (xxii) can be prepared by adding a dehydrating reagent (e.g., 1,3 -Dichlorohydroxylcarbodiimide (DC
C) or a carboxylic acid promoted by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC)) and 2-24 at room temperature.
Coupling over time to produce the corresponding amide (xxv).

The amino compound (xxii) can also be used with an appropriate sulfonyl chloride or sulfamyl chloride, including an amine base (eg, pyridine or triethylamine) in an inert solvent (dichloromethane, chloroform or tetrahydrofuran), for example, from -20 to Modification by treating at a temperature of 25 ° C. for 0.5 to 12 hours gives the corresponding N-sulfonamide or N-sulfamylamide derivative (xxvi).

(Reaction Scheme K)

[0081]

Embedded image As shown in Scheme K, a benzyloxy analog (xxvii) was prepared under a hydrogen atmosphere using a catalyst (eg, palladium on carbon or Raney nickel) in an inert solvent (ethanol, methanol, ethyl acetate or mixtures thereof).
By treating at room temperature for 1 to 24 hours, the hydroxy compound (xxvii)
i). The hydroxyl compound (xxviii) is converted into an inert solvent (
For example, dichloromethane, chloroform, ethyl acetate or tetrahydrofura)
Acid chlorides, acid anhydrides, alkyl chloroformates, mono-alkylaminocarbonyl chlorides or dialkylaminocarbonyl chlorides with an amine base (e.g., triethylamine, pyridine, or N-methylmorpholine) from 0 to
Further conversion to another analog (xxix) by treatment at 65 [deg.] C for 1-12 hours gives (xxix). Further, the hydroxy compound (xxviii) is
With an alkyl or substituted halide and a base (eg, potassium carbonate) in an inert solvent (acetone, acetonitrile, or dimethylformamide), 2
It can be converted to ether (xxx) by treating at 5-100 ° C for 12-72 hours.

(Reaction Scheme L)

[0083]

Embedded image As shown in Scheme L, the ethyl ester (xxxi) is converted to a base (eg, sodium hydroxide, lithium hydroxide, or potassium carbonate) in an aqueous solvent (eg, ethanol, methanol, tetrahydrofuran, water, or a mixture thereof). ) Can be hydrolyzed to the corresponding acid analog (xxxii) by treating the ester (xxxi) at 0-100 <0> C for 1-24 hours. This acid (x
xxii) can be converted to diethyl azidophosphoate in an inert solvent such as toluene, dioxane or dimethylformamide.
phosphate (DPPA) and a base (eg, triethylamine)
To give in the presence of an alcohol (R ₇ OH), obtained modified by 1 to 24 hours at a temperature of 25 to 120 ° C., carbamate (xxxiii).

(Reaction Scheme M)

[0085]

Embedded image As shown in Reaction Scheme M, compounds of structure (II) can be made by conversion of the appropriate acetoheteroaryl to bromoacetyl (xxxiv)
This is then 2-amino-5-bromo-6-methylpyrimidin-4-ol (x
xxxv) to give the corresponding imidazolopyrimidin-4-ones (xxxvi). Next, the compound (xxxvi) is converted to an R ₄ -substituted compound (xxxvii)
And subsequently converted to an R ₆ -substituted compound (xxxviii), which is then utilized to form compound (xxxvix). This reaction can also be utilized for compounds of structure (III) after formation of the corresponding intermediate (xxxvi) via reaction scheme C.

Representative GnRH receptor antagonists of the present invention include the following compounds (a)
(A) 2- (2,5-dimethylfuran-3-yl) -3- [N-methyl- (
2-pyridylethyl)] aminomethyl-5- (3-pentoxycarbonyl) -7
-(2-fluorobenzyl) imidazolo [1,2-a] pyrimid-4-one; (b) 2- (1-methylpyrrol-3-yl) -3- {N- [2- (2-pyridyl) Ethyl] -N-methylaminomethyl {-5- (3-methoxyphenyl)
-6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a]
(C) 2- (thiophen-2-yl) -3- {N- [2- (2-pyridyl)
Ethyl] -N-methylaminomethyl} -5- (3-methoxyphenyl) -6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a] pyrimid-4-one; (d) 2 -(2,5-Dimethylfur-3-yl) -3- (N- [2- (2-
Pyridyl) ethyl] -N-methylaminomethyl {-5- (3-methoxyphenyl) -6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a
] Pyrimid-4-one; (e) 2- (pyrid-3-yl) -3- {N- [2- (2-pyridyl) ethyl] -N-methylaminomethyl} -5- (3-methoxyphenyl ) -6-Methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a] pyrimido-4
-F; 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2- (
2,5-dimethylfuran-3-yl) -4- (2-fluorobenzyl) -6- (
(G) 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2- (3-pentoxycarbonyl) pyrrolo [1,2-a] pyrimid-7-one;
4-methoxyphenyl) -3-cyano-4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; (h) 1- (N-benzyl-N-methyl ) Aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; (i) 1- ( N-benzyl-N-methyl) aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2-cyanobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one (J) 1- (N-benzyl-N-methyl) aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2-methoxybenzyl) -6-ethoxycarbonylpyrrolo [1,2- a] Limid-7-one; (k) 1- (N-benzyl-N-methyl) aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2,4-difluorobenzyl) -6-ethoxy Carbonylpyrrolo [1,2-a] pyrimid-7-one; (l) 1- (N-benzyl-N-methyl) aminomethyl-2- (4-isobutoxyphenyl) -3-cyano-4- (2 -Fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; (m) 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2- (
2,5-dimethylfuran-3-yl) -4- (2-fluorobenzyl) -6- (
3-pentoxycarbonyl) pyrrolo [1,2-a] pyrimid-7-one; (n) 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2- (
2,5-dimethylfuran-3-yl) -4- (2-fluorobenzyl) -6- (
3-pentoxycarbonyl) imidazolo [1,2-a] pyrimid-7-one; (o) 1- (N-benzyl-N-methyl) aminomethyl-2- (4-isobutoxyphenyl) -3-fluoro -4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; and (p) 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2 − (
4-isobutoxyphenyl) -3-fluoro-4- (2-fluorobenzyl)-
6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one.

The compounds of the present invention can generally be used as a free base. Alternatively, the compounds of the present invention can be used in the form of an acid addition salt. The acid addition salts of the free amino compounds of the present invention can be prepared by methods well known in the art, and can be formed from organic and inorganic acids. Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, propionic acid,
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. Thus, the term "pharmaceutically acceptable salt" of structure (I) is intended to include any and all acceptable salt forms.

In addition, prodrugs are also included within the context of the present invention. A prodrug is any covalently bonded carrier that releases a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying the functional group in such a way that the modification is cleaved, either by conventional procedures or in vivo, to give the parent compound. As a prodrug,
Examples include compounds of the present invention, wherein a hydroxy, amine or mercapto group is attached to any group, which is cleaved off when administered to a patient with hydroxy,
Forms an amine or mercapto group. Thus, representative examples of prodrugs include, but are not limited to: acetate, formate and benzoate derivatives of the alcohol and amine functions of the compounds of structure (I). Further, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters and the like may be utilized.

With respect to stereoisomers, compounds of structure (I) may have chiral centers and occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers. All such isomeric forms, including mixtures thereof, are included in the present invention. Furthermore, some of the crystalline forms for 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 also included within the scope of the present invention.

The potency of a compound as a GnRH receptor antagonist can be determined by various assay methods. Suitable GnRH antagonists of the present invention include GnR
H can inhibit specific binding of H to its receptor and antagonize activity for GnRH. For example, inhibition of GnRH-stimulated LH release in immature rats has been described by Vilchez-Martinez (Endocrinology 9).
6: 1130-1134, 1975). Briefly, 25-day-old male Sprague-Dawley rats are administered a GnRH antagonist in saline or other suitable formulation by oral gavage, subcutaneous injection, or intravenous injection . This is followed by a subcutaneous injection of 200 ng GnRH in 0.2 mL saline. Thirty minutes after the last injection, the animal is decapitated and body blood is collected. After centrifugation, the separated plasma is
Stored at -200 C until LH and FSH were determined by radioimmunoassay. Other techniques for determining the activity of a GnRH receptor antagonist are well known in the art, for example, using cultured pituitary cells to measure GnRH activity (Vale et al., Endocrinology 91: 562-57).
2, 1972), and techniques for measuring radiolabel binding to rat pituitary membrane (Perrin et al., Mol. Pharmacol. 23: 44-51, 198).
3).

The activity of a GnRH receptor antagonist is typically measured as the concentration of compound required to displace 50% of the radiolabeled ligand from the GnRH receptor.
Calculated from IC ₅₀ and the following formula:

[0092]

(Equation 1) Is reported as a "K _i" value calculated by a affinity of radioligand for where L = radioligand and K _D = receptor, (Cheng and Prusoff, Biochem.Pharmacol.22: 3099,1
973). The GnRH receptor antagonist of the present invention has a K _{i of} 10 μM or less.
Having. In a preferred embodiment of the invention, the GnRH receptor antagonist has a K _i of less than 1 μM, and more preferably less than 100 nM.

The compounds of the present invention are more resistant to metabolic enzymes, provide increased bioavailability and longer duration of action, and are more absorbed, more potent than existing GnRH receptor antagonists. It is strong and / or has increased solubility properties. As GnRH receptor antagonists, the compounds of the present invention have utility over a wide range of therapeutic uses, and can be used to treat various sex hormone-related conditions in both men and women, as well as normal animals. . For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonad steroid-dependent neoplasia (
Prostate, breast and ovarian cancers), gonadotrophic pituitary adenoma, sleep apnea,
Irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (eg,
Adjuvant reproductive therapy, such as in vitro fertilization).

The compounds of the present invention are also useful as an adjunct for the treatment of growth hormone deficiency and short stature, as well as for the treatment of systemic lupus erythematosus.

In addition, the compounds are useful for the treatment of endometriosis, fibroids, and contraception, in combination with androgens, estrogens, progesterone, and antiestrogens and antiprogestogens, and for the treatment of uterine fibroids. For treatment, an angiotensin converting enzyme inhibitor, angiotensin (antiotin)
ensin) II-receptor antagonists, or useful in combination with renin inhibitors. The compounds may also be used in combination with bisphosphonates and other drugs, and for treating bone loss or hypogonadism (eg, GnRH) for the treatment and / or prevention of disorders of calcium, phosphate and bone metabolism. It may be used in combination with estrogens, progesterone and / or androgens for the prevention or treatment of hot flashes during therapy with antagonists.

[0096] In another embodiment of the present invention, a pharmaceutical composition comprising one or more GnRH receptor antagonist is disclosed. For the purpose of administration, the compounds of the invention may be formulated as pharmaceutical compositions. A pharmaceutical composition of the invention comprises a GnRH receptor antagonist of the invention, and a pharmaceutically acceptable carrier and / or diluent. The GnRH receptor antagonist is present in the composition in an amount effective to treat the particular disorder, ie, in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably has a patient-acceptable toxicity. . Typically, the pharmaceutical compositions of the present invention contain 0 per dose, depending on the route of administration.
. GnRH in an amount of 1 mg to 250 mg, and more typically 1 mg to 60 mg.
It may include a receptor antagonist. Appropriate concentrations and dosages can be readily determined by one skilled in the art.

[0097] Pharmaceutically acceptable carriers and / or diluents are well known to those skilled in the art. For compositions formulated as a liquid solution, acceptable carriers and / or
Or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other conventional additives. The composition also comprises Gn
It can be formulated as a pill, capsule, granule, or tablet, which contains, in addition to the RH receptor antagonist, diluents, dispersants, and surfactants, binders, and lubricants. One skilled in the art will appreciate the appropriate manner, and generally accepted practice (eg, Remington's Pharmaceutical Sciences)
, Gennaro eds., Mack Publishing Co. , Easton
GnRH receptor antagonists may be further formulated according to the procedures disclosed in US Pat.

[0098] In another embodiment, the invention provides a method for treating a sex hormone-related condition as discussed above. Such methods include administering a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. “Treatment” in the present context includes prophylactic administration. Such a method may be performed by a GnRH receptor antagonist of the invention (preferably in the form of a pharmaceutical composition as discussed above).
Systemically administered. As used herein, systemic administration includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions of a GnRH receptor antagonist include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions. These compositions may also contain flavoring, preserving, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the invention may contain, in addition to the GnRH receptor antagonist, an aqueous injection which may contain buffers, antioxidants, bacteriostats, and other additives commonly used in such solutions. It can be prepared in solution.

The compounds of the present invention can be evaluated as GnRH receptor antagonists according to the following techniques.

Rat Anterior Pituitary Cell Culture Assay of GnRH Antagonists Anterior pituitary glands were collected from 7-week-old female Sprague-Dawley rats, and the collected glands were analyzed using collagenase in dispersion flasks. 1 at 37 ° C
. Digest for 5 hours. After collagenase digestion, the glands were washed with neuraminidase for 37 hours.
Digest further at 9 ° C for 9 minutes. The digested tissue was then replaced with 0.1% BSA
/ McCoy's 5A medium and wash the washed cells with 3% FBS /
Suspend in 0.1 BSA / McCoy's 5A medium and pour into a 96-well tissue culture plate at a density of 40,000 cells per well in 200 μl medium.
The cells are then incubated at 37 ° C. for 3 days. One pituitary gland
Normally given one 96-well plate of cells, this can be used to assay three compounds. For assays of GnRH antagonists, the incubated cells were first washed once with 0.1% BSA / McCoy's 5A medium, followed by 200 μl 0.1% BSA / Mc
Add test sample and 1 nM GnRH in Coy's 5A medium. Each sample was assayed at 5 dose levels and GnRH stimulated LH and / or FS
A dose-response curve is generated for determining its potential for inhibiting H release. 3
After a 4 hour incubation at 7 ° C., the medium was collected and LH and / or
Alternatively, the level of FSH is secreted into the medium as determined by RIA.

LH and FSH RIA For determination of LH levels, each sample medium was assayed twice and all dilutions were made in RIA buffer (0.01 M sodium phosphate buffer / 0. 15 M NaCl / 1% BSA / 0.01% NaN, pH 7.5) and run the assay kit with NIDDK-supported National Hormon.
e and obtained from the Pituitary Program. In a 12 × 75 mm polyethylene tube, 100 μl of 1: 5 diluted rLH standard in sample medium or RIA buffer and 100 μl of [125I] labeled rLH (（30,00)
0 cm) and 100 μl of 1: 187,500 diluted rabbit anti-rLH antibody and 100 μl of RIA buffer. The mixture is incubated overnight at room temperature. The following day, 100 μl of 1:20 diluted goat anti-rabbit IgG and 100 μl of 1: 1000 diluted normal rabbit serum are added, and the mixture is incubated at room temperature for another 3 hours. The incubated tubes are then centrifuged at 3,000 rpm for 30 minutes and the supernatant is removed by suction. The remaining pellet in the tube is counted with a gamma counter. FSH RIA is 1
: Performed in a similar manner to the assay for LH with displacement of LH antibody by FSH antibody diluted to 30,000 and labeled rLH by labeled rFSH.

Radioiodination of GnRH Peptides GnRH analogs are labeled by the chloramine T method. 20 μl of 0.5
10 μg of peptide in M sodium phosphate buffer (pH 7.6)
i of Na125I is added, followed by 22.5 μg of chloramine-T and the mixture is vortexed for 20 seconds. The reaction was stopped by the addition of 60 μg of sodium metabisulfite and free iodine was removed from the iodinated mixture by C-8Sep-P.
ak cartridge (Millipore Corp., Milford, MA)
Through it. The peptide is eluted with a small volume of 80% acetonitrile / water. The recovered labeled peptide was purified by V-on a Beckman 334 gradient HPLC system using an acetonitrile gradient in 0.1% TFA.
ydac C-18 analytical column (The Separations Group
(P, Hesperia, CA). The purified radioactive peptide was added to 0.1% BSA / 20% acetonitrile / 0.1
Store at -800C in% TFA and can be used for up to 4 weeks.

GnRH Receptor Membrane Binding Assay Cells stably or transiently transfected with a GnRH receptor expression vector are collected, resuspended in 5% sucrose, and polytron homogenizer (2 × 15). Second). The nuclei were centrifuged (300
Oxg, 5 min) and the supernatant centrifuged (20,000 xg, 4
C. for 30 minutes) and collect the membrane fraction. The final membrane preparation was prepared using binding buffer (10 mM Hepes (pH 7.5), 150 mM NaCl, and 0.1% BSA.
) And store at -70 ° C. The binding reaction was performed using a Millipore MultiS with GF / C membrane coated with polyethyleneimine.
Run in a clean 96-well fraction plate assembly. This reaction,
Start by adding 50 μl of [ ¹²⁵ I] -labeled GnRH peptide (about 100,000 cpm) and 20 μl of membrane (40 μg protein in binding buffer) at a concentration varying to competitor. The reaction is terminated after 90 minutes by applying vacuum and washing with phosphate buffered saline (2 ×). Bound radioactivity was measured using a 96-well scintillation counter (Packard T).
opcount) or remove the filtrate from the plate and measure by direct gamma counter. The Ki value is stored in the Prism software package (G
Calculated from competitive combined data using non-linear least squares regression using the RoughPad Software.

The following examples are provided for illustrative purposes, but not for limitation.

EXAMPLES In summary, the following examples disclose the synthesis of representative compounds of the present invention. Such compounds can be evaluated for activity as GnRH receptor antagonists according to the methods described above.

Examples 1 to 20 (3-cyano-6- (3-ethoxycarbonyl) -4- (2-fluorobenzyl) -2- (4-methoxyphenyl) -1-methylpyrrolo
[1,2-A] pyrimid-7-one)

[0107]

Embedded image (Step A) (4′-Methoxy-2-bromopropiophenone) In a flask containing a mixture of CHCl ₃ (200 mL) and ethyl acetate (200 mL), 4′-methoxypropyrophenone (32.8 g, 0.1 mL) was added. 2mol)
Was added, followed by copper (II) bromide (89.4 g, 0.4 mol) in portions. The mixture was then refluxed for 1 hour and stirred at room temperature overnight. This solid was filtered and washed with ethyl acetate (2 × 100 mL). The filtrate was then washed with water (2 × 100 mL) and dried over Na ₂ SO ₄ . Concentration gave a brown oil, which was then dissolved in ether (300 mL) and stored at 0 ° C. for 1 day. Crystals formed and were filtered, washed with a mixture of ether / hexane (1: 1, 2 × 100 mL), air dried,
The title compound (35.5 g, 73%) was obtained; proton NMR (CDCl ₃ ) δ:
8.02 (2H, d, J = 9 Hz), 6.95 (2H, d, J = 9 Hz), 5.
27 (1H, q, J = 6.6 Hz), 3.88 (3H, s), 1.89 (3H,
d, J = 6.6 Hz).

(Step B) (4′-Methoxy-2-aminopropiophenone hydrochloride) 4′-methoxy-2-bromopropiophenone (10 g, 41 mmol) was
Dissolved in a mixture of THF (100 mL) and water (20 mL), followed by the addition of sodium azide (6.5 g, 0.1 mol). The slurry was stirred vigorously for 5 hours and TLC showed complete conversion to 4'-methoxy-2-azidopropiophenone. The aqueous phase is then removed and the organic phase is replaced with ethanol (2
(00 mL). Concentrated hydrochloride (5 mL, about 60 mmol
l) and palladium on carbon (10%, 2 g) are added and the hydrogenation is
Run for 1 hour at 20 psi using an arr apparatus. The product which precipitated during the hydrogenation was redissolved by the addition of methanol (100 mL). After filtration to remove the catalyst, the solution was concentrated to form a solid. This is ether (30
0 mL) and the solid was filtered and dried under vacuum at 50 ° C. overnight to give the title compound (8.8 g, 100%); MS: 180 (MH +), 16
2 (M-NH3), Proton _{NMR (DMSO-d 6) δ} : 7.96 (2H, b
rs), 7.79 (2H, d, J = 8.4 Hz), 6.87 (2H, d, J = 8)
. 4 Hz), 4.49 (1H, brs), 1.17 (2H, d, J = 6.9 Hz)
).

(Step C) (3-cyano-6-ethoxycarbonyl-2- (4-methoxyphenyl) -1-methyl-4H-pyrrolo [1,2-a] pyrimid-7-one) Ethanol and water ( 7/3) in a refluxing solution (150 mL) was added NaOH (2.
2 g, 55 mmol) and malononitrile (
(2.64 g, 40 mmol) was added. Then 4'-methoxy-2-aminopropyrophenone hydrochloride (5.9 g, 27.2 mmol) was added in portions. After refluxing the solution for 30 minutes, additional malonitrile (1.3
g, 20 mmol) and NaOH (1.1 g, 27.5 mmol). Refluxed for an additional 30 minutes, then poured into water (100 mL), which caused a precipitate. It was then filtered and washed with water until the color was not rinsed off. The solid was then dried at 50 ° C. under vacuum overnight and 2-amino-3-cyano-4- (
4-Methoxyphenyl) -5-methylpyrrole (3.9 g, 63%) was obtained; M
S: 228 (MH +).

Next, 2-amino-3-cyano-4- (4-methoxyphenyl) -5-methylpyrrole was added to diethylethoxymethylene malonate (2.75 g, 12.7 m).
(mol) in ethanol for 24 hours and concentrated to a deep brown oil. This oil was mixed with Dowtherm (20 mL) and then at 240 ° C.
For 30 minutes. After cooling to room temperature, it was diluted with ether (200 mL) to produce a precipitate. The precipitate was filtered, washed with ether (2 × 100 mL) and air dried to give the title compound (2.8 g, 63%) as a yellow powder; proton NMR (DMSO-d ₆ ) δ: 8.08 (1H, s), 7.09 (
2H, d, J = 8.1 Hz), 6.84 (2H, d, J = 8.1 Hz), 3.9
7 (2H, q, J = 6.9 Hz), 3.57 (3H, s), 2.36 (s, 3H)
), 1.03 (3H, t, J = 6.9 Hz); MS: 352 (MH +).

(Step D) (3-cyano-6-ethoxycarbonyl-4- (2-fluorobenzyl) -2- (4-methoxyphenyl) -1-methylpyrrolo [1,2-a] pyrimid-7-one ) 3-Cyano-6-ethoxycarbonyl- ₂ in dry DMF (5 mL) under N2
-(4-Methoxyphenyl) -1-methyl-4H-pyrrolo [1,2-a] pyrimid-7-one (351 mg, 1.0 mmol) was treated with 2-fluorobenzyl bromide (473 mg, 2.5 mmol) and oxidized. Silver (I) (924 mg, 4 mm
ol) was added. The slurry was stirred at room temperature for 2 days and poured into water (10 mL). The crude product was extracted from water with ethyl acetate (50mL). The organic layer was then concentrated and purified by silica gel chromatography (ethyl acetate / hexane) to give a pure product. Crystallize from ethyl / ethyl acetate to give the title compound (31
0 mg, 52%) were obtained as off-white crystals; proton NMR (DMSO
_{-D 6): 8.67 (1H,} s), 7.45-7.80 (6H, m), 7.00
(2H, d, J = 7.8), 5.70 (2H, s), 4.18 (2H, q, J =
6.6 Hz), 3.74 (3H, s), 2.56 (3H, s), 1.23 (3H, s)
, T, J = 6.6 Hz); MS: 460 (MH +).

The following compounds were also prepared by the above procedure;

[0113]

Embedded image (Examples 21 to 37) (3-cyano-6-ethoxycarbonyl-4- (2-fluorobenzyl) -2
-(4-methoxyphenyl) -1- [N-methyl-N- [2- (2-pyridyl)
Ethyl] aminomethylpyrrolo [1,2-A] pyrimid-7-one]

[0114]

Embedded image 3-cyano-6-ethoxycarbonyl-4- (2-fluorophenyl) -2-
(4-methoxyphenyl) -1-methylpyrrolo [1,2-a] pyrimidone (4
60 mg, 1.0 mmol) (from Example 1 above) at reflux CCl ₄ (30 m
To L), three particles of NBS (235 mg, 1.4 mmol) and benzoyl peroxide were added. This was refluxed for 30 minutes and cooled to room temperature. Triethylamine (
1 mL) and acetonitrile (2 mL) and 2- (N-methylaminoethyl) pyridine were added. Then, the mixture was stirred at room temperature for 30 minutes. Concentration gave an oil which was collected on a Prep-TLC plate (CHCl ₃ / MeOH / NH ₄ OH).
= 200/50/1) to give the title compound (220 mg, 37%) as a pure product. Proton NMR (CDCl ₃ ) δ: 8.23 (1H, d, J
= 4.5 Hz), 8.19 (1H, s), 7.53-7.11 (9H, m), 6
. 95 (2H, d, J = 8.4 Hz), 5.51 (2H, s), 4.34 (2H
, Q, J = 7.2 Hz), 4.17 (2H, brs), 3.84 (3H, s),
2.95-2.75 (4H, m), 2.15 (3H, s), 1.34 (3H, t)
, J = 7.2 Hz); MS: 594 (MH +).

Following the above procedure, the following compounds were also prepared:

[0116]

Embedded image (Examples 38 to 47) 3-cyano-6- (3-pentyloxycarbonyl) -4- (2-fluorobenzyl) -2- (4-methoxyphenyl) -1- [N-methyl-N- [2 -(2
-Pyridyl) ethyl] aminomethylpyrrolo [1,2-A] pyrimid-7-one
]

[0117]

Embedded image 3-cyano-6-ethoxycarbonyl-4- (2-fluorophenyl) -2-
(4-Methoxyphenyl) -1- [N-methyl-N- [2- (2-pyridyl) ethyl] aminomethylpyrrolo [1,2-a] pyrimidone] (59 mg, 0.1 m
mol) in a dry THF solution (2 mL) under a nitrogen atmosphere under a nitrogen atmosphere.
0.5 mL) and a toluene solution of KN (TMS) ₂ (0.5 M, 3 mL, 1.M).
5 mmol) was added. The mixture was stirred for 30 minutes and ethyl acetate (30 m
L) and HCl (2N, 10 mL). The organic phase was separated, concentrated and purified by Prep-TLC to give the title compound (18 mg, 28
%). Proton NMR (CDCl ₃ ) δ: 8.43 (1H, d, J = 5.
1 Hz), 8.16 (1H, s), 7.54-6.96 (9H, m), 6.98
(2H, d, J = 8.7 Hz), 5.62 (2H, s), 5.00-4.92 (
1H, m), 4.12 (2H, s), 3.87 (3H, s), 2.90-2.8
0 (2H, m), 2.80-2.70 (2H, m), 2.11 (3H, s), 1
. 70-1.61 (4H, m), 0.92 (6H, t, J = 7.2 Hz); MS
: 636 (MH +) By the above procedure, the following compound was also prepared:

[0118]

Embedded image Examples 48-63 The following compounds were made by the procedures described in the preceding examples.

[0119]

Embedded image Example 64 (3-Cyano-6- (3-pentyloxycarbonyl) -4- (2-fluorobenzyl) -2- [4- (3-pentyl) oxyphenyl] -1- {N-methyl- N- [2- (2-pyridyl) ethyl] aminomethylpyrrolo [1,2-A] pyrimid-7-one)

[0120]

Embedded image (Step A) (3-Cyano-6- (3-hydroxycarbonyl) -4- (2-fluorobenzyl) -2- (4-hydroxyphenyl) -1- [N-methyl-N-
[2- (2-pyridyl) ethyl] aminomethylpyrrolo [1,2-a] pyrimido-
7-one) in N ₂ atmosphere under -78 ° C. dry DCM (2 mL) solution of 3-cyano-6- (3
-Ethoxycarbonyl) -4- (2-fluorobenzyl) -2- (4-methoxyphenyl) -1-methylpyrrolo [1,2-a] pyrimid-7-one (230 mg)
, 0.5 mmol) to the stirred solution of boron tribromide (4 mL, 1 M in DCM). After the addition was completed, the cooling bath was removed and the mixture was warmed to room temperature and stirred for 5 hours. Then it was poured into stirring water (10 mL) to give a precipitate. The precipitate was filtered, washed with water (2 × 20 mL), ether (10 mL) and dried to give the title compound (150 mg, 72%). MS: 418 (M
H +), 400 (M-OH) ^<+> .

(Step B) (3-Cyano-6- (3-pentoxycarbonyl) -4- (2-fluorobenzyl) -2- [4- (3-pentoxyphenyl] -1-methylpyrrolo [
l, 2-a] pyrimido-7-one) 3-cyano-6- (3-hydroxycarbonyl in dry DMF (5 mL) in N ₂ atmosphere under) -4- (2-fluorobenzyl) -2- (4 -Hydroxyphenyl) -1-methylpyrrolo [1,2-a] pyrimid-7-one (83 mg, 0.1 mg).
Potassium carbonate (500 mg, 3.6 mmol) was added to a stirred solution of 2 mmol), followed by 3-bromopentane (0.5 mL, 4.0 mmol.). The slurry was heated at 90 ° C. overnight and ethyl acetate (20 mL) water (
20 mL). The organic layer was separated and a silica gel pad (10 g)
And washed with ethyl acetate. It was then concentrated to give the title compound (essentially pure by TLC) (85 mg, 76%). MS: 5
58 (MH ^<+> ).

(Step C) (3-Cyano-6- (3-pentoxycarbonyl) -4- (2-fluorobenzyl) -2- [4- (3-pentoxy) phenyl] -1- [N-methyl -N- [2- (2-pyridyl) ethyl] aminomethylpyrrolo [l, 2-a] pyrimid-7-one) 3-cyano-6- (3-pentoxycarbonyl) -4- (2-fluorobenzyl ) -2- [4- (3-Pentoxyphenyl] -1-methylpyrrolo [1,2-a
] Pyrimid-7-one (85 mg, 0.15 mmol), carbon tetrachloride (5
mL) of the refluxing solution was added NBS (43 mg, 1.5 eq) and 3 particles of benzoyl peroxide at once. It was refluxed for 1 hour to obtain a brominated compound. The solution was then equally divided into four parts. While stirring one part, add a drop of 2- (
(N-methylethyl) pyridine was added. After stirring for 5 minutes, it was separated by preparative TLC
Purified by plate (CHCl ₃ / MEOH / NH ₄ OH = 500/50/1)
The pure title compound was obtained as an oil (9.0 mg, 35%). NMR (C
DCL ₃ , 8): 8.42 (1H, d, J = 3.9 Hz), 8.14 (1H, s)
), 7.52-6.92 (11H, m), 5.60 (2H, s), 4.96-4.
. 89 (1H, m), 4.16-4.11 (2H, m), 2.90-2.70 (
4H ,, m), 2.13 (3H, s), 1.75-1.59 (8H, m), 1.
00-0.87 (12H, m). MS: 678 (MH ^<+> ).

Examples 65 to 75 (2- (2,5-dimethyl-3-furyl) -3- {N-methyl-N- [2- (
2-pyridyl) ethyl] aminomethyl} -5- (3-methoxyphenyl) -6
Methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-A] -pyrimid-4-one)

[0124]

Embedded image (Step A) (3- (bromoacetyl) -2,5-dimethylfuran) Copper bromide (17.9 g, 2.0 equiv.) Was added to EtOAc / CHC13 (1: 1,50).
mL) to a solution of 2,5 dimethyl 3-acetofuran (5.52 g, 40 mmol). The mixture was refluxed for 2.5 hours, at which time the starting material was almost completely exhausted. It was then cooled and filtered to remove copper residues. The green filtrate was concentrated to give an oil, which was diluted with ether and filtered again to further remove some black insoluble residue. The filtrate was then concentrated to give an oil (6.5 g) as the desired product, which was used directly in the next step.

(Step B) (2- (2,5-Dimethyl-3-furyl) -5-bromo-6-methylimidazolo [1,2-a] pyrimid-4-one) suspended in DMF 2-Amino-5-bromo-6-methylpyrimidin-4-ol (2.04 g, 10 mmol) was treated carefully with NaH (60%, 520 mg, 1.3 eq). A large amount of foam was generated. The mixture was stirred at room temperature for 30 minutes. 3- (Bromoacetyl) -2,5-dimethylfuran dissolved in DMF was added dropwise. The brown solution was stirred at room temperature for 3 hours. Then it was ice-cooled 1
Transferred into N HCl. The precipitate formed was filtered and washed with water, ether and dried to give a solid as the desired product (2.8 g); MS m /
e 324 (M + H).

(Step C) (2- (2,5-dimethyl-3-furyl) -5-bromo-6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a] pyrimido-4
-One) 2- (2,5-dimethyl-3-furyl) -6-methylimidazolo [1,2-a
] Pyrimid-4-one (1 g, 3.1 mmol) was suspended in DME (6 mL) and treated with TBAF (1 M in THF, 4.65 mL, 1.5 equiv) to give a clear solution, 2-Fluorobenzyl bromide was added. The mixture was stirred at room temperature for 3 hours, the resulting precipitate was filtered and water (50 mL), ether (
(50 mL) to give a white solid (203 mg); MS: m / e 430 (M + H).

(Step D) (2- (2,5-dimethyl-3-furyl) -5- (3-methoxyphenyl) -6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,
2a] pyrimid-4-one) 2- (2,5-dimethyl-3-furyl) -5-bromo-6-methyl-7- (2
-Fluorophenylmethyl) -imidazolo [1,2-a] pyrimid-4-one (
200 mg, 0.466 mmol), boronic acid (74 mg, 1.05 eq), P
d (OAc) ₂ (5.2 mg, 0.05 eq), PPh ₃ (12 mg, 0.1 eq), K ₂ CO ₃ (129 mg, 2.0 eq) were charged into a reaction flask and degassed. And protected under N ₂ atmosphere. Followed by the addition of toluene (4 mL) and H ₂ O (1mL). The mixture was refluxed at 110 ° C. for 6 hours. MS showed that about 1/4 of the bromide remained unchanged. The reaction was stopped by filtering the Pd catalyst. The filtrate was partitioned between EtOAc and water. The organic layer was concentrated to give a pale yellow solid as crude product, which was used directly in the next step without further purification (200 mg); MS: m / e 458 (M + H).

(Step E) (2- (2,5-dimethyl-3-furyl) -3- {N-methyl-N
-[2- (2-Pyridyl) ethyl] aminomethyl} -5- (3-methoxyphenyl) -6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a]
Pyrimid-4-one) 2- (2,5-dimethyl-3-furyl) -5- (3-methoxyphenyl) -6-methyl-7- (2-fluorophenylmethyl) imidazolo obtained as above [1,2-a] Pyrimid-4-one (30 mg) was suspended in acetic acid and treated with 2 drops of amine followed by 2 drops of formaldehyde (37% aqueous solution). The reaction was stirred at room temperature for 1 hour. HOAc was evaporated and the residue was DCM
And purified by preparative TLC to give the desired product. The compound was characterized by proton NMR and mass spectroscopy.

Following a procedure similar to the above, the compounds listed below were also prepared.

[0130]

Embedded image (Examples 76 to 77) (2- (2,5-dimethyl-3-furyl) -1- {N-methyl-N- [2- (
2-pyridyl) ethyl] aminomethyl} -6-ethoxycarbonyl-4- (2-
Fluorophenylmethyl) pyrrolo [1,2-A] pyrimid-7-one)

[0131]

Embedded image (Step A) (1- [2- (2,5-dimethyl-3-furyl) -2-oxoethyl] -2-methyl-5-ethoxycarbonylpyrimid-6-one) 5-ethoxycarbonyl-2-methylpyrimido -4-one (3.5 g, 19 m
mol) was dissolved in DME (110 mL) and TBAF (28.5 mL,
A 1 M solution in THF, 28.5 mmol) was added dropwise at 0 ° C. The resulting solution is
Stir for 0 min and 3-bromoacetyl-2,5- in DME (10 mL)
A solution of dimethylfuran (4.3 g, 20 mmol) was added dropwise. The reaction was stirred overnight at room temperature. Then the solution was concentrated under reduced pressure and partitioned between saturated aqueous NH ₄ Cl and EtOAc. The EtOAc layer was separated and concentrated.
The product is purified by flash silica chromatography (EtOA).
Purified using c / hexanes (2: 8 to 8: 2) (O-alkylated by-product eluted at 4: 6 and desired N-alkylated product at 8: 2) Eluted). The N-alkylated product was dried and isolated as a yellow solid in 31% yield; MS: 319 (M + H) and 273.

(Step B) (2- (2,5-dimethyl-3-furyl) -4H-6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one) 1- [2- (2 5-dimethyl-3-furyl) -2-oxoethyl] -2-methyl-5-ethoxycarbonyl-pyrimid-6-one (1.94 g, 6.1 mm)
The ol) was dissolved in EtOH, and is prepared in situ by dissolving sodium (280 mg) in dry EtOH under N ₂ (70 mL) NaO
It was added dropwise to the Et solution. The mixture was stirred at room temperature for 1 hour, concentrated and acidified to pH = 5 with 6N HCl. This produces a yellow-brown solid,
This was collected by filtration and dried to give the product as a medium brown solid; MS: 301 (M + H) and 255.

(Step C) (2- (2,5-dimethyl-3-furyl) -6-ethoxycarbonyl-4- (2-fluorophenylmethyl) pyrrolo [1,2-a] pyrimid-7-one) 2- (2,5-Dimethyl-3-furyl) -4H-6-ethoxycarbonylpyrrolo [1,2-a] pyrimido-7one (1.83 g, 6.1 mmol) was added to DME (
10 mL) and then TBAF (12.2 mL, 1 M solution in THF, 12 mL).
. 2 mmol) was added, followed by 2-fluorobenzyl bromide. The solution was stirred overnight at room temperature. Collect the solid precipitate by filtration and add Et ₂
Washed with O to give the product; MS: 409 (M + H) and 363.

(Step D) (2- (2,5-dimethyl-3-furyl) -1- {N-methyl-N
-[2- (2-pyridyl) ethyl] aminomethyl} -6-ethoxycarbonyl-
4- (2-fluorophenylmethyl) pyrrolo [1,2-a] pyrimid-7-one) 2- (2,5-dimethyl-3-furyl) -6-ethoxycarbonyl-4- (
2-fluorophenylmethyl) -pyrrolo [1,2-a] pyrimid-7-one (
50 mg, 122 μmol) was added to formaldehyde (5 μL) in acetic acid (25 ml).
, 184 μmol) and a secondary amine (184 μmol). The resulting solution was stirred at room temperature for 10 minutes and then at 50 ° C. for another for 10 minutes. The HOAc was evaporated and the residue was diluted with DCM and purified by preparative TLC (MeOH / DCM-1: 9) to give the desired product. The product was characterized by proton NMR and mass spectroscopy.

The following compounds were prepared according to the procedure described above.

[0136]

Embedded image (Examples 78 to 84) (1- {N-methyl-N- [2- (2-pyridyl) ethyl] aminomethyl-3 "
-Fluoro-4- (2-fluorobenzyl) -2- [4- (2-methylpropoxy) phenyl] -6- (ethyloxycarbonyl) pyrrolo [1,2-A] pyrimid-7-one)

[0137]

Embedded image (Step A) (fluoroacetamidine)

[0138]

Embedded image HCl gas was bubbled into fluoroacetonitrile (11 g, 186 mmol) at 0-20 ° C. until the reaction mixture solidified. Pre-cooled EtOH (40
mL) was added to the solid at -50 C and the reaction was allowed to warm to room temperature overnight. Ether (200 mL) was added and the solid product i was filtered and washed with ether to give a total of 15.72 g of a white solid (yield = 75%).

(Step B) (Ethyl- (2-fluoromethylpyrimidin-4-one) -5-carboxylate)

[0140]

Embedded image Sodium hydroxide (4.0 g, 100 mmol) was added to EtOH (250 mL)
Amidine i (5.63 g, 50 mmol) and ester ii (11.1 m
L, 55 mmol). The suspension was heated at reflux for 7 hours. After cooling to room temperature, the mixture was poured into water and acidified with 10% HCl solution. After extraction with EtOAc, evaporation and trituration with ether gave pyrimidone iii as a solid (2.59 g, 26% yield).

(Step C) (4 ′-(2-methylpropyloxy) acetophenone)

[0142]

Embedded image 4'hydroxyacetophenone iv (6.81 g, 50 mmol) was added to EtOH
In (170 mL). Potassium carbonate (13.8 g, 100 mmol) and 1-bromo-2-methylpropane (6 mL, 55 mmol) were added and the reaction was refluxed for 50 hours. Water (500 mL) was added and then extracted with EtOAc. After evaporation of the organic layer and washing with 1 M sodium hydroxide and brine, v was obtained as an amber oil (3.95 g, 41% yield).

(Step D) (2-bromo-4 ′-(2-methylpropyloxy) acetophenone)

[0144]

Embedded image Acetophenone v (3,3 in chloroform / EtOAc (1: 1, 35 mL)
5 g, 18.2 mmol) and CuBr ₂ (8.14 g, 36.5 mmol)
Was heated at reflux for 2 hours. After filtration, the organic layer was washed, dried, filtered and evaporated to give the α-bromoketone vi (4.4 g, 89% yield).

(Step E) (Ethyl-2-fluoroethyl-3- [4- (2-methylpropyloxy) phenyl] carbonylmethyl-6- (ethyloxycarbonyl) pyrimid-4-one-5-carboxylate)

[0146]

Embedded image Tetrabutylammonium fluoride in THF (9.0 mL, 1.0 M) was added to a suspension of iii (1.0 g, 5 mmol) in dimethoxyethane (30 mL). After 30 minutes, bromoketone vi (1.49 g, 5.30 g) in DME (2 mL).
5 mmol) was added and the reaction mixture was stirred at room temperature overnight. Hexane /
Column chromatography using ethyl acetate gave isomer v as eluent
ii (794 mg, 41% yield) and product viii (434 mg, 22%)
I got

(Step F) (3-Fluoro-2- [4- (2-methylpropyloxyphenyl)]
-6- (ethyloxycarbonyl) pyrrolo [1,2-a] pyrimid-7-one)

[0148]

Embedded image The pyrimidone ester viii (430 g, 1.1 mmol) was added to a solution of sodium etoside (63 mg Na in 14 mL EtOH) and the reaction mixture was stirred at room temperature for 4 hours. Acidification of the reaction mixture with 10% HCl resulted in a fine precipitate. The precipitate was filtered and combined with an EtOAc wash to give solid ix (410 mg, 99% yield).

(Step G) (3-Fluoro-4- (2-fluorobenzyl) -2- [4- (2
-Methylpropyloxy) phenyl] -6- (ethyloxycarbonyl) pyrrolo [
1.2-a] pyrimid-7-one)

[0150]

Embedded image 1.0 M solution of tetrabutylammonium fluoride in THF (1.21 mL
) Was added to a suspension of ix (410 mg, 1.1 mmol) in DME (8 mL). The resulting solution was stirred for 30 minutes. 2-Fluorobenzyl bromide (0.
16 mL, 1.3 mmol) was added and the reaction mixture was stirred for 19 hours. A workup that included extraction with EtOAc, aqueous washing of the EtOAc layer and chromatography with EtOAc / hexanes provided x (116 mg, 22%).

(Step H) (1- {N-methyl-N- [2- (2-pyridyl) ethyl] aminomethyl-3-fluoro-4- (2-fluorobenzyl) -2- [4- (2 -Methylpropyloxy) phenyl] -6 (ethyloxycarbonyl) pyrrolo [1,2-
a] Pyrimid-7-one)

[0152]

Embedded image Pyrrolopyrimidone ester x (30 mg, 0.0625 mmol) glacial acetic acid (1
mL), formaldehyde (2 drops) and 2- (2-methylaminoethyl) pyridine (2 drops). After 1 h, extracted with EtOAc, CHC1 ₃ / MeOH
Purification by preparative TLC using / NH ₄ OH and trituration with ether gave the title compound 71 as a white solid (10 mg, 26%).

According to a procedure similar to the one described above, the compounds listed below were also prepared.

Embedded image

[0154]

Embedded image While particular embodiments of the present invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, it is understood that the invention is not limited except as by the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 15/02 A61P 15/02 15/12 15/12 17/00 17/00 25/20 25/20 35 / 00 35/00 37/02 37/02 (31) Priority claim number 09 / 405,286 (32) Priority date September 23, 1999 (September 23, 1999) (33) Priority claim country United States (US) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, M D, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventors Wilcoxen, Keith M. United States California 92104, San Diego, 31 Estee Street-2015 (72) Inventor Struthers, Earl. Scott United States California 92024, Encinitas, Avenida Esteban 1161 (72) Inventor Tseng, Tzen United States of America 92129, San Diego, Spellen Avenue 13922 (72) Inventor Connors, Patrick Jr. United States of America 92014, San Diego, Illinois Street 4201 ( 72) Inventor Gao, Inhon United States of America California 92122, San Diego, Camino Trunk 7856 (72) Inventor Tuchy, Fabio United States of America 92121, San Diego, Science Center Drive 105550 F-term (reference) 4C050 AA01 BB04 BB05 CC08 EE02 EE03 FF03 FF05 GG03 HH02 HH04 4C086 AA01 CB05 MA01 MA04 ZA05 ZA66 ZA81 ZA89 ZB05 ZB26 ZC03

Claims (38)

[Claims] 1. A compound having the following structure: And stereoisomers, prodrugs and pharmaceutically acceptable salts thereof,
Where: m is an integer from 1 to 6: R ₁ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted hetero Arylalkyl, aryl (CR _3c R _3d ) _n
, Substituted aryl (CR _3c R _{3d) n,} heteroaryl (CR _3c R _{3d) n} or substituted heteroaryl _{(CR 3c R 3d) n;} R 2 is hydrogen, or an alkyl or substituted alkyl; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring; R _3a , R _3b , R _3c and R _3d are the same or Different, and independently in each case, hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, thioalkyl, amino, alkylamino, dialkylamino, cyano, halogen,
Is —C (＝ O) OR ₇ or —C (＝ O) OR ₇ R ₈ ; or R _3a and R _3b , or R _3c and R _3d together with the carbon atom to which they are attached, Forms a carbocyclic or substituted carbocyclic ring; or R _3a and R ₁ together with the carbon and nitrogen atoms to which they are attached, respectively, form a heterocyclic or substituted heterocyclic ring formed; R ₄ 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 monoalkyl or dialkyl amine; R ₆ is water , Alkyl, substituted alkyl, aryl, substituted aryl, heterocycle,
Substituted _{heterocycle, -OR 7, -SR 7, -SOR} 7, -SO 2 R 7, -OSO 2 R 7, -S
_{O 2 OR 7, -SO 2 NR} 7 R 8, -NR 9 SO 2 R 7, -C (= O) R 7, -C (= O
_{) OR 7, -OC (= O} ) R 7, -NR 7 R 8, -C (= O) NR 7 R 8, -OC (=
_{O) NR 7 R 8, -NR} 9 C (= O) R 7, -NR 9 C (= O) NR 7 R 8, -NR 8 C
(＝ O) OR ₇ or —C (OH) R ₇ R ₈ ; R ₇ , R ₈ and R ₉ are the same or different and are independently hydrogen,
Is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or R ₇ and R ₈ are the nitrogen atoms to which they are attached And to form a heterocyclic or substituted heterocyclic ring; n is an integer from 1 to 6; and B and Ar are as follows: Ar is heteroaryl or substituted hetero When R is aryl and R ₁₀ is hydrogen, B is nitrogen or CR ₁₀ ; or Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R ₁₀ is halogen, cyano , Nitro, amino, monoalkylamino or dialkylamino, or alkyl In some cases, B is CR _10, compound. 2. The compound of claim 1, wherein B is nitrogen or CR ₁₀ ; R ₁₀ is hydrogen; and Ar is heteroaryl or substituted heteroaryl. Compound. 3. The compound according to claim 1, wherein B is CR ₁₀ ; R ₁₀ is halogen, cyano, nitro, amino, monoalkylamino or dialkylamino or alkyl; And wherein Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl. 4. The compound according to claim 2, wherein B is nitrogen and Ar is heteroaryl. 5. A compound according to claim 4, having the following structure: Wherein A ₁ , A ₃ , and A ₄ are the same or different and are independently nitrogen or CH; A ₂ is oxygen, sulfur, NH, N = N or N = CH; And R _a , R _b , R _c and R _d are the same or different and are 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, monoalkylamino or dialkylamino, monoarylamino or diarylamino,- COO alkyl,-
COO aryl, -CONH-alkyl, -CONH aryl, -CON (alkyl) _2, -CON (aryl) _2, -NHCO alkyl, -NHCO aryl, -
N (alkyl) CO-alkyl, -N (alkyl) CO aryl, -NHSO ₂ alkyl, -NHSO ₂ aryl, N (alkyl) SO ₂ alkyl, -N (alkyl) SO ₂ aryl, in -NHCONH alkyl or -NHCONH aryl Or _a certain substituent; or R _a and R _b together with the atom to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl. 6. B is CR_TenAr is heteroaryl, and R _Ten Is a compound of claim 2, wherein is hydrogen. 7. The following structure: The compound of claim 6, having the formula: 8. The compound according to claim 3, wherein B is CR ₁₀ and Ar is heteroaryl. 9. The following structure: 9. The compound according to claim 8, having the formula: 10. The compound according to claim 1, wherein R ₁ is arylalkyl, substituted arylalkyl or heteroarylalkyl. 11. The compound according to claim 10, wherein aralkyl is benzyl and substituted arylalkyl is substituted benzyl. 12. The heteroarylalkyl is —CH ₂ (heteroaryl)
Or -CH ₂ CH ₂ (heteroaryl), compound of claim 10. 13. The compound according to claim 1, wherein R ₂ is alkyl. 14. The compound according to claim 13, wherein the alkyl is methyl. 15. The compound of claim 1, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle. 16. The compound according to claim 1, wherein R _3a is hydrogen. 17. The compound according to claim 1, wherein R _3b is hydrogen. 18. The compound according to claim 16, wherein R _3b is hydrogen. 19. The compound according to claim 1, wherein m is 1. 20. The compound according to claim 1, wherein R ₄ is arylalkyl or substituted arylalkyl. 21. The compound of claim 14, wherein said arylalkyl or substituted arylalkyl is benzyl or substituted benzyl. 22. The compound according to claim 1, wherein R ₅ is hydrogen. 23. The compound according to claim 1, wherein R ₆ is —C (＝ O) OR ₇ . 24. The compound according to claim 23, wherein R ₇ is alkyl. 25. The compound of claim 1, wherein R ₆ is —C (＝ O) NR ₇ R ₈ . 26. The compound of claim 13, wherein R ₇ and R ₈ are the same or different and are independently alkyl or substituted alkyl. 27. The compound according to claim 25, wherein R ₇ and R ₈ together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle. 28. A compound according to any one of claims 5, 7 or 9, wherein: Wherein said heteroaryl moiety has the following structure: A compound having one of the following: 29. The compound according to claim 1, wherein R ₁₀ is halogen or cyano. 30. The compound according to claim 1, wherein the compound is: 2- (2,5-dimethylfuran-3-yl) -3- [N-methyl- (2-pyridylethyl)] Aminomethyl-5- (3-pentoxycarbonyl) -7- (2-
Fluorobenzyl) imidazolo [1,2-a] pyrimid-4-one; 2- (1-methylpyrrol-3-yl) -3- {N- [2- (2-pyridyl)
Ethyl] -N-methylaminomethyl {-5- (3-methoxyphenyl) -6-methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a] pyrimid-4-one; 2- (thiophene -2-yl) -3- {N- [2- (2-pyridyl) ethyl]
-N-methylaminomethyl} -5- (3-methoxyphenyl) -6-methyl-7
-(2-Fluorophenylmethyl) imidazolo [1,2-a] pyrimid-4-one; 2- (2,5-dimethylfur-3-yl) -3- (N- [2- (2-pyridyl) [Ethyl] -N-methylaminomethyl} -5- (3-methoxyphenyl) -6
Methyl-7- (2-fluorophenylmethyl) imidazolo [1,2-a] pyrimid-4-one; 2- (pyrid-3-yl) -3- {N- [2- (2-pyridyl) ethyl] -N
-Methylaminomethyl} -5- (3-methoxyphenyl) -6-methyl-7- (
2-fluorophenylmethyl) imidazolo [1,2-a] pyrimid-4-one; 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2- (4-methoxyphenyl) -3-cyano- 4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; 1- [N-methyl- (2-pyridylethyl)] aminomethyl-2 (2,5- Dimethylfuran-3-yl) -4- (2-fluorobenzyl) -6- (3-pentoxycarbonyl) pyrrolo [1,2-a] pyrimid-7-one; 1- (N-benzyl-N-methyl ) Aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; 1- (N-benzyl -N- 1- (N-methyl) aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2-cyanobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; Benzyl-N-methyl) aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2-methoxybenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; -(N-benzyl-N-methyl) aminomethyl-2- (4-methoxyphenyl) -3-cyano-4- (2,4-difluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimido 1- (N-benzyl-N-methyl) aminomethyl-2- (4-isobutoxyphenyl) -3-cyano-4- (2-fluorobenzyl) -6-ethoxycarbonyl Lolo [1,2-a] pyrimido-7-one; 1-[N-methyl - (2-pyridylethyl)] aminomethyl-2- (2,5
1- [N-methyl- (2-dimethylfuran-3-yl) -4- (2-fluorobenzyl) -6- (3-pentoxycarbonyl) pyrrolo [1,2-a] pyrimid-7-one; Pyridylethyl)] aminomethyl-2- (2,5-
Dimethylfuran-3-yl) -4- (2-fluorobenzyl) -6- (3-pentoxycarbonyl) imidazolo [1,2-a] pyrimid-7-one; 1- (N-benzyl-N-methyl ) Aminomethyl-2- (4-isobutoxyphenyl) -3-fluoro-4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimid-7-one; or 1- [N -Methyl- (2-pyridylethyl)] aminomethyl-2- (4-isobutoxyphenyl) -3-fluoro-4- (2-fluorobenzyl) -6-ethoxycarbonylpyrrolo [1,2-a] pyrimido- A compound which is 7-one. 31. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 32. A method for antagonizing a gonadotropin-releasing hormone in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of claim 1. A method comprising the step of: 33. A method for treating a sex hormone-related condition in a subject in need of treatment, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 31. A method comprising the step of: 34. The method of claim 33, wherein said sex hormone-related condition is cancer, benign prostatic hyperplasia or uterine fibroids. 35. The method of claim 34, wherein said cancer is prostate cancer, uterine cancer, breast cancer or pituitary gonadotropin adenoma. 36. The method of claim 33, wherein said sex hormone-related condition is endometriosis, polycystic ovarian disease, uterine fibroids or precocious puberty. 37. A method for preventing pregnancy in a subject in need thereof, comprising the step of administering to the subject an effective amount of the pharmaceutical composition of claim 31. Including, methods. 38. A method for treating lupus erythematosus, irritable bowel syndrome, premenstrual syndrome, hirsutism, short stature or sleep disorder in a subject in need of treatment, the method comprising: Administering to the subject an effective amount of the described pharmaceutical composition.