RU2303594C2 - Organosilicon compound and their using - Google Patents

Abstract

FIELD: chemistry of organosilicon compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds and their using in therapy. Invention describes compounds of the formula (I):

wherein alternate values are given in the invention claim. These substances are claimed as compounds possessing antagonistic activity with respect to GnRH, and pharmaceutical composition comprising these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 ex

Description

Field of Invention

This invention relates to compounds and their use in therapy.

The background of the invention.

Gonadotropin-releasing hormone (GnRH) plays a key role in reproduction biology. GnRH is also known as luteinizing hormone releasing hormone (LH-RH).

The decapeptide GnRH (pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Art-Pro-Gly-NH ₂ or p-EHWSYGLRPG-NH ₂ ) is formed in neurons of the middle basal hypothalamus from a larger precursor as a result of enzymatic processing. The peptide is pulsedly released into the pituitary-circulating system, where GnRH interacts with high affinity receptors (receptors associated with 7-transmembrane G-proteins) in the anterior pituitary gland located at the base of the brain. Here, GnRH triggers the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), both of which are gonadotropic hormones (gonadotropins). LH stimulates the production of testosterone and estradiol in the testes and ovaries, respectively, while FSH stimulates follicle growth in women and sperm formation in men. When properly functioning, pulsating release and levels of GnRH concentration are critical for maintaining gonadal steroidogenesis and for normal reproductive function associated with growth and sexual development.

The pituitary response to GnRH varies greatly throughout life. GnRH and gonatropins first appear in the womb during pregnancy for about ten weeks. Sensitivity to GnRH decreases prior to puberty. There is, however, a brief rise during the first three months after birth. Before puberty, the FSH response to GnRH is higher than the LH response. After the onset of puberty, sensitivity to GnRH increases, and as a result, pulsed secretion of LH occurs. Later, during puberty and during the reproductive period, the pulsating release of GnRH occurs throughout the day, with the LH response becoming higher than the FSH reaction. The pulsed release of GnRH leads to a pulsed release of LH and FSH, and thus testosterone and estradiol are released from the gonads. After menopause, the concentration of FSH and LH increases and postmenopausal FSH levels are higher than the level of LH.

Long-term use of GnRH agonists and antagonists leads to reduced levels of circulation of both LH and FSH. GnRH agonists are compounds that mimic endogenous GnRH, stimulating receptors on the pituitary gland and leading to the release of LH and FSH. After a temporary increase in the production of gonadal hormone (“flashing” response), prolonged use of GnRH agonists leads to a downregulation of GnRH receptors. Such downregulation and deactivation lead to a decrease in circulating levels of LH and FSH. Despite the existing symptom-exacerbating hormonal outbreak, GnRH agonists were the preferred treatment for sex steroid-dependent pathophysiology. GnRH agonists were used to reduce testosterone production, thereby reducing prostate volume in benign prostatic hyperplasia (BPH) and slowing tumor growth in prostate cancer. Such compounds have also been used in the treatment of breast and ovarian cancer.

In recent years, GnRH antagonists have become available for clinical evaluation, and it has been shown that they have a direct effect on the pituitary gland, but without the observed outbreak associated with agonists. The use of GnRH antagonists for the treatment of ovarian, breast and prostate cancers has been reported.

Other antagonist uses include the treatment of diseases such as endometriosis (including endometriosis with pain), uterine fibroids, cystic diseases of the ovaries and mammary glands (including polycystic ovarian diseases), prostatic hypertrophy, amenorrhea (e.g., secondary amenorrhea), and premature puberty. These compounds can also be used to symptomatically relieve premenstrual syndrome (PMS). Antagonists may also be useful for regulating gonadotropins in male mammals to stop spermatogenesis (for example, as a contraceptive for men) and for treating male sexual dysfunctions. It has been shown that GnRH antagonists and agonists can be used for treatment in which a reversible suppression of the sex gland-pituitary system is desirable.

The presence of GnRH receptors on the anterior pituitary cells and the cells of certain types of tumors opens up the possibility of developing drugs that act on receptors for the treatment of both hormone-dependent and hormone-independent cancers.

Typically, androgen reduction was the most effective systematic treatment for metastatic prostate carcinoma. The prostate needs androgens for normal growth, maintenance and functioning. Prostate cancer and benign prostatic hyperplasia, however, are common in men and develop under conditions of continuous exposure to androgen. The use of a GnRH antagonist to interrupt the pituitary gland system reduces androgen production and modulates tumor growth.

GnRH antagonists can have a direct effect on tumor growth by blocking receptors on tumor cells. For cancers of those types that respond both to sex hormones and directly to GnRH, antagonists must be effective in slowing tumor growth by two mechanisms. Because GnRH receptors are present on many cancer cells in the prostate and mammary glands, it has recently been suggested that GnRH antagonists may also be effective in the treatment of hormone-independent tumors. Recent literature examples indicate that GnRH receptors are present on a variety of cancer cell lines, in particular cancer cells of the prostate, ovary and mammary gland (see, for example, Montagnaniet al., Arch. Ital, Urol. Androl., 1997, 69 (4 ), 257-263; Jungwirth et al., Prostate, 1997, 32 (3), 164-172; Srkalovic et al., Int. J. Oncol., 1998, 12 (3), 489-498; Kottler et al ., Int. J. Cancer, 1997, 71 (4), 595-599).

Available GnRH antagonists are primarily represented by peptide analogues of GnRH (see, for example, W093 / 03058). Peptide antagonists of peptide hormones are somewhat effective, but the use of currently existing peptide antagonists is often problematic because peptides are degraded by physiological enzymes and are often poorly distributed in the body being treated. Thus, they have limited activity as medicines.

Non-peptide GnRH analogues are described in WO00 / 20358.

Silicon-substitution (C / Si-exchange) of drugs is a relatively new approach for the search for organosilicon compounds that have useful biological properties. The approach includes replacing certain carbon atoms with silicon and controlling the change in the biological properties of the compounds. A review of the data for this approach is published by Tacke and Zilch, Endeavor, New Series, 10, 191-197 (1986).

Summary of the invention

A first aspect of the invention relates to a compound of formula (I) or formula (II):

Where

A and C are the same or different, and each represents a bond, - (CH ₂ ) _n -, -C (R ^b ) ₂ -, -Si (R ^c ) ₂ -, -O-, -S (O) _m -, -N =, -N (R ^b ) -, -N (R ^e ) C (= X) - or -C (= X) -;

B represents - (CH ₂ ) _n -, -O-, -C (R ^b ) ₂ -, -Si (R ^c ) ₂ -, -C (R ^b ) = C (R ^b ) -, C (R ^b ) =, - (CH ₂ ) _n C (R ^g ) ₂ -, -C (R ^g ) ₂ (CH ₂ ) _n - or -CH (R ^b ) CH (R ^b ) -;

where any of A, B and C is optionally substituted with —Si (R ^c ) ₃ ;

D represents - (CH ₂ ) _n -, -C (= X) -, -O-, -S (O) _m -, -C (= X) N ( ^Re ) -, -C (R ^b ) ₂ -, -C (R ^b ) = C (R ^b ) -, -CH (R ^b ) CH (R ^b ) -;

E is optionally present and is - (CH ₂ ) _n -, -N (R ^d ) -, - (CH ₂ ) _n N (R ^d ) - or -N (R ^d ) (CH ₂ ) _n -;

F is —C (═X) - or —N (R ^d ) -;

G represents - (CH ₂ ) _n -, -N (R ^d ) -, - (CH ₂ ) _n N (R ^d ) - or -N (R ^d ) (CH ₂ ) _n ;

J is optionally present and is —O—, —N (R ^c ) C (= X) -, —C (= X) N (R ^c ) -, —S (O) _m -, —N (R ^c ) S (O) _m -, -S (O) _m N (R ^c ) - or -N (R ^e ) -;

K is optionally present and is alkylene optionally substituted with R ^b ; or K is cycloalkylene, cycloalkenylene, arylene, heterocycloalkylene or heteroarylene, any of which may optionally be substituted with R ^a ;

L is hydrogen, halogen, —N (R ^f ) ₂ , cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, any of which is optionally substituted with R ^a , —C (= X) OR ^d , —OH, —OR ^c , -C (= X) N (R ^b ) (R ^c ), -S (O) _m N (R ^b ) (R ^c ) or -CN;

each of R ^a is the same or different and represents hydrogen, halogen, alkyl, aryl, hydroxy, alkoxy, alkoxy- (CH ₂ ) _n C (O) ₂ R ^b , -O-aryl, -C (= X) R ^s , -NO ₂ , -CN, -N (R ^c ) C (= X) R ^c , -C (= X) N (R ^c ) ₂ , -S (O) ₂ N (R ^c ) ₂ or - N (R ^e ) ₂ ;

each of R ^b is the same or different and represents hydrogen or alkyl;

each of R ^c is the same or different and represents alkyl, cycloalkyl, -alkyl-aryl, -alkyl-cycloalkyl or aryl, optionally substituted with R ^a ;

each of R ^d is the same or different and represents hydrogen, alkyl or aryl, optionally substituted with R ^a ;

each of R ^e is the same or different and represents hydrogen or alkyl; or R ^e is aryl or heteroaryl, each of which is optionally substituted with R ^a ;

each of R ^f is the same or different and represents hydrogen or alkyl; or R ^f —NR ^f taken together form heterocycloalkyl, heterocycloalkenyl or heteroaryl;

R ^g —CR ⁹ taken together form heterocyclyl;

each X is the same or different and represents oxygen or sulfur;

rings 1 and 2 are the same or different, and each of them is arylene or heteroarylene, each of which is optionally substituted with R ^a ;

each m is the same or different and is equal to 0, 1 or 2; and

each n is the same or different and is 0, 1, 2 or 3;

provided that at least one of A, B, and C includes a silicon atom; each of A and C is not a bond; and the compounds do not include a Si-Si bond, a single N-N bond, a Si-O bond, a Si-N bond or an N-O-N bond; or a pharmaceutically acceptable salt thereof.

The compounds of the invention can act as GnRH antagonists and, as a result, can find therapeutic applications in the treatment of cancer, for the treatment or prevention of endometriosis, uterine fibroids, ovarian disease, cystic breast disease, prostatic hypertrophy, amenorrhea, premature puberty, premenstrual sex steroid-dependent syndrome, pathophysiology, benign prostatic hyperplasia, Alzheimer's disease, HIV infection, AIDS or disease caused by of improper functioning of the thyroid gland, or to stop spermatogenesis.

Accordingly, a second aspect of the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment of cancer or for the treatment or prevention of endometriosis, uterine fibroids, ovarian disease, cystic breast disease, prostate hypertrophy, amenorrhea, premature puberty, premenstrual syndrome, dependent from a sex steroid pathophysiology, benign prostatic hyperplasia, Alzheimer's disease, HIV infection, AIDS or disease, you caused by improper functioning of the thyroid gland, or to stop spermatogenesis.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

Description of the invention

Certain compounds and combinations of substituents are preferred, in particular see the claims.

The term “alkyl,” as used herein, refers to an optionally substituted linear or branched alkyl moiety containing from one to six carbon atoms. The term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. The substituents may be the same or different at each appearance and are selected from halogen and the like. The term “C _1-6 alkyl” has the same meaning. The term “alkylene” refers to a similar divalent group.

The term “alkoxy,” as used herein, refers to an optionally substituted linear or branched alkoxy group containing up to six carbon atoms. The term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. The substituents may be the same or different at each appearance and are selected from halogen and the like. The term “C _1-6 alkoxy” has the same meaning.

The term “halogen,” as used herein, refers to F, Cl, Br, or I.

The term “aryl,” as used herein, refers to optionally substituted aromatic ring systems comprising six to ten ring atoms and optionally substituted polycyclic ring systems having two or more cyclic rings, among which at least one is aromatic. The term includes, for example, phenyl and naphthyl. The group may optionally be substituted with the same or different substituents selected from R ^a and the like. The term “arylene” refers to a similar divalent group.

The term “cycloalkyl,” as used herein, refers to a saturated alicyclic moiety having from three to six carbon atoms. The term includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group may optionally be substituted with any substituent described herein. The term “cycloalkylene” refers to a similar divalent group.

The term “cycloalkenyl,” as used herein, refers to an alicyclic moiety containing from three to six carbon atoms and having, in addition, at least one double bond. The term includes, for example, cyclopentenyl, cyclohexenyl and the like. The group may optionally be substituted with any substituent described herein. The term “cycloalkenylene” refers to a similar divalent group.

The term “heterocycloalkyl,” as used herein, refers to a saturated heterocyclic moiety containing from three to seven carbon atoms and one or more heteroatoms selected from the group N, O, S, P and Si. The term includes, for example, azetidinyl pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The group may optionally be substituted with any substituent described herein. The term “heterocycloalkylene” refers to a similar divalent group.

The term “heteroaryl,” as used herein, refers to an aromatic ring system of five to ten atoms, where at least one atom is selected from O, N and S. The term includes, for example, furanyl, triophenyl, pyridyl, indolyl, quinolyl and the like. The group may optionally be substituted with R ^a and the like substituents. The term “heteroarylene” refers to a similar divalent group.

The term “heterocyclyl,” as used herein, refers to a saturated or unsaturated heterocyclic ring containing from three to seven carbon atoms and one or more heteroatoms selected from N, O, S, P and Si. The term includes, for example, piperidinyl, pyrrolidinyl, morpholinyl and the like. The group may be polycyclic (for example, a fused ring system), a group comprising two or more rings, at least one of which includes a heteroatom.

Preferred compounds of the invention include:

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide ;

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide;

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazin-1 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N-dimethylamino ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan -2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl ) furan-2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6 dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4 -methylpiperazin-1-yl) propylamino] -4,6-trimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N , N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholine -4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide ;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan -2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl ) furan-2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6 dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4 -methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N , N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholine -4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

(5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (6-chloro-1,1-dimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-chloro-1,1-dimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (6-chloro-1,1-dimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide ;

5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1, 3-pyrimidin-5-yl} furan-2-carboxamide;

5- (4,4,6-trimethyl-4-strength-chroman-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3- pyrimidin-5-yl} furan-2-carboxamide;

5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy-1,3- pyrimidin-5-yl} furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N-2- [3- (N, N-dimethylamino) propylamino] -4 , 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide ;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2-methylamino-4,6-dimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (4-methylpiperazin-1 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (N, N-dimethylamino ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (morpholin-4-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2 - [(pyridin-2-yl) methylamino] -4,6- dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide ;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5-yl) furan-2 β-carboxamide;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6-dimethoxy- 1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1, 3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy-1, 3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl) furan-2 β-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5-yl) furan -2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6- dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy- 1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy- 1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- {2- [3- (morpholin-4 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide ;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2 - [(pyridin-2-yl) methylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yl) methyl] -N- {2- [3- (4- methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yl) methyl] -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yl) methyl] -N- {2- [3- (morpholine- 4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,6-dimethoxyphenyl) furan- 2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,4,6-trimethoxy- 1,3-pyrimidin-5-yl) furan-2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2-methylamino-4,6- dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- {2- [3- (4- methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- {2- [3- (morpholin- 4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2,4,6-trimethoxy-1,3-pyrimidine- 5-yl) furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2-methylamino-4,6-dimethoxy-1,3- pyrimidin-5-yl) furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2 - [(pyridin-2-yl) methylamino] -4 , 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5 - [(1,1,5-trimethyl-1-force-2,3-dihydroinden-6-yl) methyl] -N- (4-chloro-2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,3,4,4,6-hexamethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [2- (morpholin-4-yl ) ethylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,4,4,6-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalene-5-hydroxy) -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide;

5- (7'-hydroxy-1,1,1 ', 1', 6,6'-hexamethyl-3,3'-spiro-1,1'-disyl-4,4'-dioxo-1,1 ' 2,2 ', 3,3', 4,4'-octahydrodinaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- [1,1,2,6-tetramethyl-3- (2-propyl) -1-force-2,3-dihydroinden-5-yloxy] -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide;

5- (1,1,3,4,4-pentamethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide;

5- (1,1,5-trimethyl-1-force-2,3-dihydroinden-6-yloxy) -N- (4-chloro-2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,3,3,5-pentamethyl-1-force-2,3-dihydroinden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (1,1,3,3,6-pentamethyl-1-strength-2,3-dihydroinden-5-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide;

5- (8-methoxy-1,1,4,4,6-pentamethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4 -yl) -N-propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide;

5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4-dimethoxypyridin-3-yl) furan-2-carboxamide;

5- (1,1,3,4,4,6-hexamethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide and

5- (1,1,3,4,4,6-hexamethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- [2- (2-N, N-dimethylaminoethyl) -4,6-trimethoxy-1,3-pyrimidin-5-yl] furan-2-carboxamide;

the corresponding structures of which are presented below, respectively (in order from left to right):

The compounds of the invention may be chiral. They can be in the form of a single enantiomer, or diastereomer, or racemate.

The compounds of the invention may be prepared as a racemic mixture or as individual enantiomers by racemic synthesis or resolution, as will be appreciated by those skilled in the art. Compounds, for example, can be resolved into enantiomers by standard methods, such as the formation of diastereomeric pairs using salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. Alternatively, the enantiomers of the new compounds can be resolved by HPLC using a chiral column.

Some compounds having the presented formula may exist in various tautomeric forms, which are also included in the scope of this invention.

The compound of the invention may be in the form with a protected amino group, or a protected hydroxyl group, or a protected carboxyl group. The terms “protected amino group”, “protected hydroxyl group” and “protected carboxyl group”, as used herein, refer to amino, hydroxyl or carboxyl groups that are protected by a method known to those skilled in the art. For example, the amino group may be protected by benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or the like, or be in the form of a phthalimido or the like. The carbonyl group may be protected by an easily cleavable ester group, such as a methyl, ethyl, benzyl or tert-butyl ester group.

Some compounds having the presented formula may exist in the form of solvates, for example hydrates, which are also included in the scope of this invention.

The compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, inorganic or organic acid addition salts. Such inorganic acid addition salts include, for example, hydrobromic acid, hydrochloric acid, nitric acid, phosphoric and sulfuric acids. Additive salts of organic acids include, for example, salts of acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, 2- (4-chlorophenoxy) -2-methylpropionic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid ( EDTA), fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, N-glucolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2- (4-hydroxybenzoyl) benzoic acid, 1-hydroxy-2-naphthoic acid, 3-hydro hydroxy-2-naphthoic acid, 2-hydroxyethanesulfonic acid, lactobionic acid, n-dodecyl sulfuric acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, methyl sulfuric acid, mucous acid, 2-naphthalenesulfonic acid, pamic acid, pantothenic acid, phosphanilic acid acids ((4-aminophenyl) phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulfonic acid, 10-undecenoic acid oty and the like. It should be understood that such salts, provided that they are pharmaceutically acceptable, can be used in therapy. Such salts may be prepared by the usual reaction of a compound with a suitable acid.

The compound of the invention can be prepared by any suitable method known in the art and by the following methods:

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

It should be understood that the methods described above are presented solely for the purpose of illustrating the invention, and should not be construed as limiting the invention. To obtain the compounds according to the invention, you can also use the method in which use similar or similar reagents and / or conditions known to specialists in this field.

Any resulting mixtures of end products or intermediates can be separated by known methods based on differences in the physicochemical properties of their constituent components into pure end products or intermediates, for example, by chromatography, distillation, fractional crystallization, or salt formation, if appropriate or possible in the circumstances.

The activity and selectivity of the compounds can be determined using any suitable assay method known in the art.

The compounds of the invention can be used to treat numerous ailments, conditions and diseases, including, but not limited to, cancer, endometriosis, uterine fibroids, ovarian disease, cystic breast disease, prostate hypertrophy, amenorrhea, premature puberty, premenstrual syndrome, dependent from sex steroid pathophysiology, benign prostatic hyperplasia, Alzheimer's disease, HIV infection, AIDS and diseases caused by improper functioning thyroid gland, or to stop spermatogenesis.

The term “cancer,” as used herein, refers to any disease or condition characterized by uncontrolled, abnormal cell growth, and includes all known types of cancer, such as cancer of the bladder, breast, colon, brain, bone, head, blood, eyes, neck, skin, lungs, ovaries, prostate and rectum; digestive system, gastrointestinal, endometrial, hematological, AIDS-related, musculoskeletal, neurological and gynecological types of cancer; lymphomas, melanomas, and leukemia.

In therapeutic use, the active compounds can be administered orally, rectally, intravaginally, parenterally, by inhalation (pulmonary delivery), in an external (local) manner, by ocular route, nasally or buccally. Oral administration is preferred. Thus, the compositions of the present invention can be in the form of any known pharmaceutical composition intended for such a method of administration. By methods known to those skilled in the art, compositions can be prepared resulting in controlled release, for example, rapid release or delayed release, of the compounds of the present invention.

Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of the active compound. The compositions of the invention are usually prepared in unit dosage form. Preferably, a unit dose contains the active ingredient in an amount of 1-500 mg. Excipients used in the preparation of these compositions are excipients known in the art.

Suitable dosage levels may be determined by any suitable method known to one skilled in the art. However, it should be understood that the specific dosage level for any particular patient will depend on many factors, including the activity of the particular compound used, age, body weight, general health, gender, diet, administration time, route of administration, excretion rate, drug combination and the severity of the disease being treated.

Compositions for oral administration are preferred compositions of this invention and are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. A pharmaceutical composition containing the active ingredient may be presented in a form suitable for oral administration, for example, in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, or elixirs. Compositions intended for oral use may be prepared according to any methods known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorings and preservatives, for creating pleasing drugs that are pharmaceutically superior in quality. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin, gum arabic, microcrystalline cellulose or polyvinylpyrrolidone; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known methods to inhibit degradation and absorption in the gastrointestinal tract and, therefore, provide a long-lasting effect over a longer period of time. To slow down in time, a material such as glyceryl monostearate or glyceryl distearate can be used.

Oral formulations may also be presented in the form of hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredient is mixed with water or an oil medium, for example with peanut butter, liquid paraffin or olive oil.

Aqueous suspensions contain the active substances in admixture with excipients suitable for preparing aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabian gum; dispersing agents or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylene ethoxy ketanol, or products of condensation of non-ethylene fatty acids acids, for example polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those mentioned above and flavorings may be added to provide a pleasant oral preparation. These compositions can be stabilized by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent and one or more preservatives. Suitable sweetening, flavoring and coloring agents may also be present.

The pharmaceutical compositions of the invention can also be formulated as oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or a mixture thereof. Suitable emulsifying agents can be natural gums, for example gum arabic or tragacanth gum, natural phosphatides, for example soybeans, lecithin and esters or partial esters derived from fatty acid anhydrides and hexitol, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.

Syrups and elixirs can be formulated together with sweeteners, for example glycerin, propylene glycol, sorbitol, or sucrose. Such preparations may also contain a painkiller, preservative and flavoring and coloring agents. The pharmaceutical compositions may be sterile injectable aqueous or oleaginous suspensions. Such a suspension can be obtained in accordance with methods known in the art using such suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injection or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Suitable carriers and solvents that can be used in this case include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as a solvent or suspension preparation medium. For this purpose, any soothing fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids are used for injectable formulations.

The compounds of the invention can also be administered as suppositories for rectal administration of a drug. These compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at ordinary temperature but liquid at rectal temperature and therefore will melt in the rectum, releasing the drug. Such substances are cocoa butter and polyethylene glycols.

Compositions for external (local) administration are also suitable for the purposes of the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream can be obtained by incorporating the active compound into an external carrier, such as light liquid paraffin dispersed in an aqueous medium using surfactants. An ointment can be prepared by mixing the active compound with an external carrier, such as mineral oil or wax. The gel can be obtained by mixing the active compound with a carrier for external use, including a gelling agent. Topically administered compositions may also include a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that they are held in contact with the skin for transdermal administration of the compounds.

The following examples illustrate the invention.

In the examples, all syntheses were carried out in an atmosphere of dry nitrogen. Tetrahydrofuran (THF), diethyl ether, dichloromethane, toluene and m-xylene were dried and purified in accordance with standard methods and stored under nitrogen. The term "light petroleum ether" refers to the fraction with so Kip. 40-60 ° C. Thin layer chromatography was performed on silica gel plates (SiO ₂ ). ¹ H NMR spectra were recorded at 400 MHz in a solution of CDCl ₃ , unless otherwise indicated.

Intermediate 1: Bis (chlorodimethylsilyl) methane.

This compound was synthesized in accordance with the method described by Greber et al., Makromol. Chem., 1962, 52, 174-183.

Intermediate 2: Bis (ethynyldimethylsilyl) methane

This compound was synthesized in accordance with the procedure described by Kusumoto et al., Chem. Lett., 1988, 1149-1152.

Intermediate 3: Methyl 5- (but-2-ynyl) 2-furoate

This compound was synthesized in accordance with the method described in WO-A-04/045625.

Intermediate 4: Methyl 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -2-furoate

A solution of cyclopentadienyl cobalt dicarbonyl [CpCo (CO) ₂ ; 328 mg, 1.82 mmol] in m-xylene (90 ml) was added dropwise over 14 hours to a stirred boiling mixture of bis (ethynyldimethylsilyl) methane (Intermediate 2, 2.02 g, 11.2 mmol) and methyl- 5- (but-2-ynyl) -2-furoate (Intermediate 3, 2.00 g, 11.2 mmol) in m-xylene (20 ml). (In order to prevent heating of the CpCo (CO) ₂ solution before addition, the dropping funnel containing this catalyst was separated from the boiling reaction mixture by a glass tube (20 cm long), through which the CpCo (CO) ₂ solution freely dropped into the boiling mixture). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography [(column size 60 × 3.5 cm; 300 g silica gel (32-63 μm, ICN 02826); eluent n-hexane / ethyl acetate (95: 5)]. The desired fractions (control by gas chromatography) were combined, the solvent was removed under reduced pressure, and the residue was dried in vacuo (15 mbar, 20 ° C, 30 min) to obtain 2.62 g of a yellowish oil, which was crystallized from boiling n-hexane (17 ml, crystallization at -20 ° C, for 3 days). The product was recrystallized under the same conditions and the obtained t the verdant was separated by decantation, washed with cold (20 ° C) hexane (8 ml) and dried in vacuo (0.001 mbar, 20 ° C, 2 hours) to give the title compound as a colorless crystalline substance (1.78 g, 44 %); mp 111 ° C. Elemental analysis. Calculated for C ₁₉ H ₂₆ O ₃ Si ₂ : C, 63.64; H, 7.31. Found: C, 63.7; H, 7.2 .

Intermediate 5: 2,4,6-trimethoxyaniline hydrochloride

This compound was synthesized in accordance with the method described in WO-A-04/045625.

Intermediate 6: oct-2-in-4-ol

To a solution of 1-propynylmagnesium bromide (0.5 M in THF, 100 ml) was added valeraldehyde (5.84 ml, 1.1 molar equivalent) in dry THF (100 ml) at room temperature with stirring for 30 minutes. The reaction mixture was allowed to stir for an additional 3 hours at room temperature, after which the reaction was quenched with a mixture of ice and a saturated aqueous solution of ammonium chloride (1: 1, 120 ml). The organic phase was separated and the aqueous portion was extracted with light petroleum ether (3 × 100 ml), after which the combined organic phases were dried (magnesium sulfate) and concentrated in vacuo. The resulting light yellow oil (7.28 g) was substantially uniform and was used in the next step without further purification. Rf 0.19 (10% diethyl ether-light petroleum ether). ¹ H NMR δ _H 0.92 (3H, t, J = 7.1 Hz), 1.31-1.49 (4H, m), 1.65-1.79 (2H, m), 1.86 (3H, s); and 4.34 (1H, broad s).

Intermediate 7: oct-2-in-4-one

To a solution of oct-2-in-4-ol (intermediate 6, 2.41 g) in acetone (30 ml) was added dropwise over 3 hours a mixture of chromium trioxide (1.91 g), concentrated sulfuric acid (1, 62 ml) and water (20 ml). After stirring at room temperature for an additional 30 minutes, the reaction mixture was diluted further with water (50 ml), and the product was isolated by extraction with ether (3 × 30 ml), drying (magnesium sulfate) and concentration. The target substance was purified by distillation in vacuo (mp. 61-63 ° C at 8 mbar, 1.54 g). ¹ H NMR (CDCl ₃ ) δ _H 0.96 (3H, t, J = 7.3 Hz), 1.27-1.41 (2H, m), 1.61-1.69 (2H, m) 2.05 (3H, s) and 2.56 (2H, t, J = 7.3 Hz).

Intermediate 8: 1- (1,3,6-trimethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) pentanone

To a mixture of bis (ethynyldimethylsilyl) methane (intermediate 2, 1.40 g, 7.78 mmol), oct-2-in-4-one (intermediate 7, 0.96 g, 7.78 mmol) and dry xylene (100 ml) while refluxing, a solution of CpCo (CO) ₂ (0.25 mol equiv., 0.241 ml) in dry xylene (40 ml) was added dropwise over approximately 3 hours. The mixture was allowed to warm at reflux overnight, after which a solution of CpCo (CO) ₂ (0.25 mol equiv., 0.241 ml) in dry xylene (40 ml) was additionally added. The mixture was again heated to a boil and left under reflux overnight. After cooling, the volatiles were removed in vacuo and the residue was purified by column chromatography (SiO ₂ , 10% dichloromethane in light petroleum ether) to give the desired compound (748 mg, 32%). LC-Macc spectrum: m / z = 305 (M + H ⁺ ). ¹ H NMR δ _H 0.03 (2H, s), 0.32 (6H, s), 0.33 (6H, s), 0.97 (3H, t, J = 7.3 Hz), 1, 38-1.47 (2H, m), 1.68-1.75 (2H, m), 2.48 (3H, s), 2.93 (2H, t, J = 7.32 Hz), 7 42 (1H, s) and 7.72 (1H, s).

Intermediate 9: 1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-ol

To a solution of 1- (1,3,6-trimethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) pentanone (intermediate 8, 250 mg, 0.82 mmol) in dichloromethane ( 5 ml) 3-chloroperoxybenzoic acid (mCPBA, 190 mg; 0.82 mmol, approximately 71% mCPBA) was added. The next day, an additional portion of mCPBA (190 mg; 0.82 mmol) was added to the reaction mixture, which was then heated under reflux overnight.

The next day, the colorless precipitate was removed by filtration, after which the mother liquor was evaporated in vacuo, dissolved in methyl alcohol (10 ml) and treated with sodium methoxide (25% by weight in methyl alcohol, 0.822 mol). After stirring at room temperature for 2.5 hours, the mixture was concentrated, placed in water (10 ml) and acidified with hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (3 × 25 ml) and the combined extracts were dried (magnesium sulfate) and concentrated. The target phenol was obtained in a homogeneous state when purified by column chromatography (SiO ₂ , 10% to 25% diethyl ether in light petroleum ether) as an off-white solid (10 mg). Rf = 0.43 (25% diethyl ether in light petroleum ether). ¹ H NMR (CDCl ₃ ) δ _H 0.05 (2H, s), 0.29 (12H, s), 2.29 (3H, s), 4.75 (1H, s, broad), 6, 96 (1H, s) and 7.35 (1H, s).

Intermediate 10: 1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-ol

This compound was prepared according to the methods described for the preparation of intermediate 9. Rf 0.36 (10% diethyl ether in light petroleum ether). ¹ H NMR δ _H 0.200 (6H, s), 0.203 (6H, s), 0.97 (4H, s), 2.25 (3H, s), 4.70 (1H, s), 6.89 ( 1H, s) and 7.25 (1H, s).

Example 1: 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,4,6 -trimethoxyphenyl) furan-2-carboxamide

A solution of trimethylaluminium (115 mg, 1.60 mmol) in toluene (5 ml) was added dropwise at -30 ° C over 10 minutes to a stirred suspension of 2,4,6-trimethoxyaniline hydrochloride (351 mg, 1.60 mmol) in toluene (5 ml) (dissolution of 2,4,6-trimethoxyaniline hydrochloride followed by the formation of a precipitate). The stirred mixture was heated to 0 ° C for 1 hour, and then to 20 ° C for an additional 1 hour (dissolution of the precipitate), and the resulting solution was then added dropwise at 0 ° C over 10 minutes to a stirred solution of methyl 5- [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -2-furoate (intermediate 4, 359 mg, 1, 00 mmol) in dichloromethane (10 ml). The resulting mixture was stirred at 0 ° C for 30 minutes and then at 20 ° C for 3 days [almost quantitative conversion (HPLC control) color change from colorless to black], followed by the addition of a half-saturated aqueous solution of ammonium acetate (20 ml) (formation draft). The precipitate was filtered off and washed with ethyl acetate (10 ml), the filtrate and the solution after washing were combined, and the organic layer was separated and washed with water (20 ml). The resulting aqueous solutions (A and B) were extracted with ethyl acetate (2 × 20 ml) as follows. The first aqueous solution (A) obtained by washing was extracted with ethyl acetate (20 ml), the obtained extract was then used to extract the second aqueous solution (B) obtained by washing, and the organic extract was separated, and then a second extraction of solutions A and B was carried out. obtained by washing with a fresh portion of ethyl acetate (20 ml) using the same protocol as described for the first extraction sequence. All organic extracts were combined and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography [column size 60 × 3.5 cm; silica gel, 300 g (32-63 μm, ICN 02826); eluent, ethyl acetate / n-hexane (55:45)]. The desired fractions (TLC control) were combined and the solvent was removed under reduced pressure. The residue was crystallized at 20 ° C by diffusion of n-pentane vapor (200 ml) into a solution of the crude substance in diethyl ether (10 ml) for 7 days. The product was recrystallized under the same conditions, and the resulting solid was isolated by decantation, washed with n-pentane (5 ml) and dried in vacuo (0.001 mbar, 20 ° C, 2 hours) to give the title compound in 70% yield as a colorless crystalline solid (357 mg, 0.700 mmol); so pl. 105 ° C. Elemental analysis. Calculated for C ₂₇ H ₃₅ NO ₅ Si ₂ : C, 63.62; H, 6.92; N, 2.75. Found: C, 63.6; H, 6.9; N, 2.8.

Example 2: 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (morpholine- 4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide

This compound can be prepared from 4,6-dimethoxy-N ² - (3-morpholinopropyl) pyrimidine-2,5-diamine (which can be synthesized according to the methods described in WO-A-02/098363) and intermediate 9 using the methods illustrated in scheme 5 of this description.

Example 3: 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy-N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide

This compound can be prepared from 4,6-dimethoxy-N ² - [3- (4-methylpiperazin-1-yl) propyl] pyrimidin-2,5-diamine (which can be synthesized according to the methods described in WO- A-02/098363) and intermediate 10 in accordance with the methods illustrated in scheme 6 of the present description.

Claims (26)

1. The compound of formula (I)

where A and C are the same and each represents-Si (R ^c ) ₂ -, where R ^c represents C ₁ -C ₆ alkyl; B represents - (CH ₂ ) _n- , where n = 1,2; D represents - (CH ₂ ) _n- , —O—; E is absent in the compound; ring 1 is heteroarylene consisting of five atoms, where one of the atoms is O; F is —C (= X) -, where X is O; G represents —N (R ^d ) -, where R ^d represents hydrogen; ring 2 is phenyl or six-membered heteroaryl containing 2 nitrogen atoms, which is optionally substituted with R ^a ; J is optionally present or is —N (R ^e ) -, where R ^e is hydrogen; K is optionally present and is alkylene; L is heterocycloalkyl containing 6 atoms, where two atoms are heteroatoms selected from O and N; each of R ^a represents hydrogen, alkyl or alkoxy; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where A and C are —Si (R ^c ) ₂ -. 3. The compound according to claim 2, where each of R ^c represents C ₁ -C ₆ alkyl. 4. The compound according to claim 1, where B represents - (CH ₂ ) _n -. 5. The compound according to claim 1, where D is —O—, or —CH ₂ -. 6. The compound according to claim 1, where E is absent. 7. The compound according to claim 1, where F is —C (O) -. 8. The compound according to claim 1, where G is —N (R ^d ) -. 9. The compound of claim 8, where R ^d represents hydrogen. 10. The compound according to claim 1, where J and K are absent, and L is heterocycloalkyl containing 6 atoms, where two atoms are heteroatoms selected from O or N. 11. The compound according to claim 1, where J is —NH—, K is alkylene, and L is heterocycloalkyl containing 6 atoms, where two atoms are heteroatoms selected from O or N. 12. The compound according to claim 1, where ring 1 is heteroarylene consisting of five atoms, where one of the atoms is O. 13. The compound of claim 12, wherein ring 1 is furanylene. 14. The compound according to claim 1, where ring 2 is phenyl, pyrimidinyl or pyridinyl, any of which may optionally be substituted. 15. The compound of claim 14, wherein ring 2 is substituted 1, 2, or 3 times, wherein the substituents are the same or different at each occurrence and are selected from an alkoxyl group. 16. The compound according to claim 1, selected from 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide ; 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide; 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazin-1 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N-dimethylamino ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,7-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,2,4,4,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholin-4 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan -2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl ) furan-2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6 dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4 -methylpiperazin-1-yl) propylamino] -4,6-trimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N , N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (morpholine -4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide ; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (8-methoxy-1,1,6-trimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,4,4,5,7-hexamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yloxy) -N-2- {3- (morpholin-4- il) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan -2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl ) furan-2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6 dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4 -methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N , N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-methoxy-1,1,4,4,8-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholine -4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-2-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N -dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-chloro-1,1,4,4-tetramethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- (3-morpholin-4- il) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (6-chloro-1,1-dimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide ; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1, 3-pyrimidin-5-yl} furan-2-carboxamide; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3- pyrimidin-5-yl} furan-2-carboxamide; 5- (4,4,7-trimethyl-4-strength-chroman-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy-1,3- pyrimidin-5-yl} furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,2,3,4-tetrahydro-4,4,7-trimethyl-4-strength-quinolin-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide ; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- (2-methylamino-4,6-dimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (4-methylpiperazin-1 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (N, N-dimethylamino ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (morpholin-4-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yloxy) -N- {2 - [(pyridin-2-yl) methylamino] -4,6- dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl ) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-2,3-dihydro-1H-inden-5-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide ; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5-yl) furan-2 β-carboxamide; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6-dimethoxy- 1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1, 3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-1H-inden-6-yloxy) -N-2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy-1,3 -pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5-yl) furan-2 β-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidin-5-yl) furan -2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6- dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- {2- [3-N, N-dimethylamino) propylamino] -4,6-dimethoxy-1 , 3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] -4,6-dimethoxy- 1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2,6-dimethoxyphenyl) furan-2 β-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2,4,6-trimethoxyphenyl) furan -2-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2,4,6-trimethoxy-1 , 3-pyrimidin-5-yl) furan-2-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- (2-methylamino-4,6-dimethoxy -1,3-pyrimidin-5-yl) furan-2-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- {2- [3- (4-methylpiperazine -1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- {2- [3-N, N- dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- [1,1,6-trimethyl-3- (2-propyl) -1-force-2,3-dihydro-1H-inden-5-yloxy] -N- {2- [3- (morpholin-4 -yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-chloro-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide ; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl ) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-chloro-1,1,7-trimethyl-1-strength-2,3-dihydro-1H-inden-4-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidin-5 -yl) furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- (2-methylamino-4,6-dimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (4-methylpiperazin-1-yl) propylamino ] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (N, N-dimethylamino) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2- [3- (morpholin-4-yl) propylamino] - 4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (5-methoxy-1,1-dimethyl-1-strength-2,3-dihydro-1H-inden-6-yloxy) -N- {2 - [(pyridin-2-yl) methylamino] -4, 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yl) methyl] -N- {2- [3- (4- methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yl) methyl] -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,4,4,7-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalen-6-yl) methyl] -N- {2- [3- (morpholine- 4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,6-dimethoxyphenyl) furan- 2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2,4,6-trimethoxy- 1,3-pyrimidin-5-yl) furan-2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- (2-methylamino-4,6- dimethoxy-1,3-pyrimidin-5-yl) furan-2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- {2- [3- (4- methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,3,3,6-pentamethyl-1,3-disyl-2,3-dihydro-1H-inden-5-yl) methyl] -N- {2- [3- (morpholin- 4-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2,4,6-trimethoxyphenyl) furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2,4,6-trimethoxy-1,3-pyrimidine- 5-yl) furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- (2-methylamino-4,6-dimethoxy-1,3- pyrimidin-5-yl) furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2- [3- (4-methylpiperazin-1-yl) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2- [3- (N, N-dimethylamino) propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- [2- (3-morpholinopropylamino) -4,6-dimethoxy- 1,3-pyrimidin-5-yl] furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydro-1H-inden-6-yl) methyl] -N- {2 - [(pyridin-2-yl) methylamino] -4 , 6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5 - [(1,1,5-trimethyl-1-force-2,3-dihydroinden-6-yl) methyl] -N- (4-chloro-2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,3,4,4,6-hexamethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N - {[2- (2- (morpholin-4- il) ethylamino) -4,6-dimethoxy-1,3-pyrimidin-5-yl] furan-2-carboxamide; 5- (1,1,4,4,6-pentamethyl-1,4-disyl-1,2,3,4-tetrahydronaphthalene-5-hydroxy) -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide; 5- (7'-hydroxy-1,1,1 ', 1', 6,6'-hexamethyl-3,3'-spiro-1,1'-disyl-4,4'-dioxo-1,1 ' 2,2 ', 3,3', 4,4'-octahydrodinaphthalen-7-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- [1,1,2,6-tetramethyl-3- (2-propyl) -1-force-2,3-dihydroinden-5-yloxy] -N- (2,4,6-trimethoxyphenyl) furan-2 β-carboxamide; 5- (1,1,3,4,4-pentamethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3-pyrimidine -5-yl) furan-2-carboxamide; 5- (1,1,5-trimethyl-1-force-2,3-dihydroinden-6-yloxy) -N- (4-chloro-2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,3,3,5-pentamethyl-1-strength-2,3-dihydroinden-6-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (1,1,3,3,6-pentamethyl-1-strength-2,3-dihydroinden-5-yloxy) -N- (2,6-dimethoxyphenyl) furan-2-carboxamide; 5- (8-methoxy-1,1,4,4,6-pentamethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- {2- [3- (morpholin-4 -yl) -N-propylamino] -4,6-dimethoxy-1,3-pyrimidin-5-yl} furan-2-carboxamide; 5- (1,1,6-trimethyl-1-force-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4-dimethoxypyridin-3-yl) furan-2-carboxamide; 5- (1,1,3,4,4,6-hexamethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- (2,4,6-trimethoxy-1,3 -pyrimidin-5-yl) furan-2-carboxamide and 5- (1,1,3,4,4,6-hexamethyl-1-strength-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N- [2- (2-N, N-dimethylaminoethyl) -4,6-trimethoxy-1,3-pyrimidin-5-yl] furan-2-carboxamide. 17. The compound according to claim 1 in the form of a single enantiomer or diastereomer or tautomer. 18. The compound according to claim 1, having antagonistic activity against GnRH. 19. A pharmaceutical composition having antagonistic activity against GnRH, comprising a compound according to any one of claims 1-17, and a pharmaceutically acceptable diluent or carrier. 20. The use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment of cancer. 21. The use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment or prevention of endometriosis, uterine fibroids, ovarian disease, cystic breast disease, prostatic hypertrophy, amenorrhea, premature puberty, premenstrual syndrome, dependent on a sex steroid pathophysiology or benign prostatic hyperplasia or to stop spermatogenesis. 22. The use according to item 21 for the treatment or prevention of endometriosis associated with pain, polycystic ovarian disease or secondary amenorrhea. 23. The use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease. 24. The use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment or prevention of HIV infection or AIDS. 25. The use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment or prevention of a disease caused by malfunctioning of the thyroid gland. 26. The use of claim 25 for the treatment or prevention of multiple sclerosis, rheumatoid arthritis or type 1 diabetes.