KR20080052641A - Pi3k inhibitors for the treatment of endometriosis - Google Patents

Abstract

This invention relates to a method of treating and/or preventing endometriosis comprising administering a P13K inhibitor. The P13K inhibitor can also be administered combined with a hormonal suppressor. The invention further relates to the treatment of endometriosis-related infertility.

Description

PI3K inhibitor for the treatment of endometriosis {PI3K INHIBITORS FOR THE TREATMENT OF ENDOMETRIOSIS}

The present invention relates to a method of treating and / or preventing endometriosis comprising the step of administering a PI3K inhibitor. In addition, the PI3K inhibitor may be administered with a hormonal suppressor. Moreover, the present invention relates to the treatment of endometriosis-related infertility.

Endometriosis is one of the most common diseases of women in their reproductive life. Endometriosis is characterized by the presence of endometrial tissue outside the uterine cavity, constituting the histology of the gland and stroma. The most commonly affected anatomical sites are the ovary, uterosacral ligament, pelvic peritoneum, rectovaginal septum, cervix, vagina, fallopian tube And vulva.

Endometriosis is considered to be a benign disease, but endometrial lesions sometimes turn malignant. As in other malignancies, the development of endometriosis-induced neoplasms is associated with changes in growth factor and / or oncogene regulation and is due to concurrent events (Kyama et al., 2003). Moreover, endometriosis is considered a major cause of infertility (Giudice et al., 2004).

Current treatment of endometriosis is through hormonal therapy and / or surgery. Hormone therapy includes progestogen, oral contraceptive (along with estrogen and progesterone), danazol (androgenic derivative of ethisterone) and the most recent GnRH. Excessive administration of an agonist. These hormone therapies are effective for pelvic pain and can lead to degeneration of the target of the lesion, but have a serious caveat. Since estrogens cannot respond to progesterone, they can cause proliferation of endometrial tissues (Dawood et al., 1993). Progesterone factor can cause depression, weight gain, and fluid retention with irregular bleeding. Danazol improves symptoms in about 66-100% of patients suffering from pain, but relapses about 40-50% after up to four years. Other drawbacks of danazol therapy are weight gain and androgenic side effects. GnRH analogs are more effective and work longer than native GnRH, which acts by removing all estrogen sensitive tissues for growth estrogen stimulation. Side effects of GnRH analogues are primarily secondary to severe hypoestrogeniemia, such as a decrease in bone density, with relapse rates up to 50% after 5 years (Waller et al., 1993).

Surgery is the traditional method if fertility is needed, but in the case of severe illness, surgery can also remove the uterus, ducts and ovaries. In severe cases, even limited surgical treatment significantly reduces fertility.

Although endometriosis is one of the most studied diseases in gynecology, it is still difficult to understand the pathophysiology of the disease at present. According to a preferred theory, ectopic endometrial cells leaving the initial site of endometriosis lesions, possibly retrograde menstruation, and by distant grafts, followed by invasion and proliferation of host tissues Endometrial lesions develop. Endometriosis also appears to be an invasive and metastatic disease. Although endometrial cells proliferate to some extent, they are not neoplastics typically found in carcinoma. It is clear that endometrial cells are senescent, apoptotic and necrotic. Inflammatory responses induced or accompanied by lesion formation eventually lead to fibrosis and scar formation.

The reason that ectopic grafts survive is presumably because cell death (apoptosis) of these grafts is reduced and expression of viable cell signaling pathways is increased. Proteins or specific small molecule compounds that induce target-specific cell death of ectopic endometrial cells without affecting ectopic endometrium or other normal cells can be used as therapeutics to eliminate endometriosis. In this regard, the effect on the ability of PI3K inhibitors to induce cell death of endometrial cells, immortalized human epithelial endometrial cells was investigated.

PI3Ks (phosphoinositide 3-kinase) are used for cell proliferation, cell survival, vascularization, membrane trafficking, glucose transport, neurite outgrowth, and membrane vibrational movements. ruffling, superoxide formation, actin reconstitution and chemotaxis ( Cantley (2000) and Vanhaesebroeck (2001)). PI3K consists of two sub-units, the catalytic P110 subunit and the regulating and localizing subunit. The main catalytic function of PI3K is to phosphorylate the inositol phospholipid (PIP2: phosphatidyl inositol 4,5 bis-phosphate) of the plasma membrane at three positions in the inositol sugar ring. It is in a P110 subunit that acts to phosphorylate. The inositol phospholipids (phosphoinositide) intracellular signal transduction pathways are characterized by signal transduction molecules (extracellular ligands, stimulation, receptor dimerization, heterologous receptors (eg, receptor tyrosine). Transactivation by kinase] and binding of G-protein coupled transmembrane receptors integrated into the plasma membrane. PI3K transforms the membrane phospholipid PIP (4,5) 2 into PIP (3,4,5) 3, which is transformed by 5'-specific phosphoinositide phosphatase As it can be further modified into another 3 'phosphorylated form of phosphinositide, PI3K enzymatic activity results in two 3'-phosphoises that function as secondary messengers in intracellular signal transduction. Nocitide subtypes are generated either directly or indirectly.

Evolutionary conserved isoforms P110α and β are expressed everywhere, while δ and γ are hematopoetic cell systems, smooth muscle cells, myocytes and endothelial cells. It is more specifically expressed in Vanhaesebroeck (1997) . In addition, their expression may be regulated in different inducible ways depending on the cell-, tissue type and stimulation as well as the disease context.

To date, eight mammalian PI3Ks have been identified and based on sequence homology, structure, binding partner, mode of activation, and in vitro substrate preference, three major classes (I, II, And III).

Two compounds, LY294002 and wortmannin, are known as PI3-kinase inhibitors. The compounds are nonspecific PI3K inhibitors.

Azolidinone-vinyl benzene derivatives described in WO04 / 007491 and 2-imino-azolinone-vinyl fused-benzene derivatives described in WO05 / 011686 are the PI3 kinase inhibitors. , In particular as inhibitors of PI3 kinase gamma. Such compounds are said to be useful in the treatment and / or prevention of autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney disease, platelet aggregation, cancer, graft rejection or lung diseases.

The present invention described herein clearly shows the unexpected result that PI3K inhibition by PI3K inhibitors reduces endometriosis. In addition, reduction of endometrial lesions with PI3K inhibitors can increase fertility rate, since normalization of the genital structure has a positive effect on the implantation rate.

Summary of the Invention

The present invention relates to a method for treating and / or preventing endometriosis in an individual, comprising administering a therapeutically effective amount of a PI3K inhibitor.

The invention also provides for the treatment and / or prophylaxis of endometriosis through a combination treatment of PI3K inhibitors and hormone inhibitors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators). It is about a method.

Moreover, the present invention relates to a method for treating endometriosis-related infertility in women, comprising administering a therapeutically effective amount of a PI3K inhibitor alone or in combination with another fertility drug.

Finally, the present invention relates to pharmaceutical compositions comprising PI3K inhibitors, hormone inhibitors and pharmaceutically acceptable excipients.

Detailed description of the invention

The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply equally throughout this specification and claims, unless the clearly stated definition provides a broader definition. .

"Aryl" means an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms with only one ring (eg phenyl) or multiple condensed rings (eg naphthyl). Aryl preferably includes phenyl, naphthyl, phenantrenyl and the like.

"C ₁ -C ₆ -alkyl aryl" means a C ₁ -C ₆ -alkyl group having an aryl substituent, including benzyl, phenethyl, and the like.

"Heteroaryl" means a monocyclic heteroaromatic, or bicyclic or tricyclic fused-ring heteroaromatic group. In particular, examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, 1,3,4-oxa Diazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothier Neil, Indolyl, Isoindoleyl, 3H-Indolyl, Benzimidazolyl, Imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl, quinazolinyl, phthala Genyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, Quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, furinyl, fr Piperidinyl, carbazolyl, and the like is greater chrysanthemate carbonyl or benzo-quinolyl.

"C ₁ -C ₆ - alkyl heteroaryl" C ₁ -C ₆ having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2- (1H- indol-3-yl) ethyl -Means an alkyl group.

"C ₂ -C ₆ -alkenyl" means an alkenyl group which preferably has 2 to 6 carbon atoms and has at least one or two alkenyl unsaturated sites. The alkenyl group preferably contains ethenyl (-CH = CH ₂ ), n-2-propenyl [allyl, -CH ₂ CH = CH ₂ ], and the like.

"C ₂ -C ₆ -alkenyl aryl" means a C ₂ -C ₆ -alkenyl group having an aryl substituent, including 2-phenylvinyl and the like.

"C ₂ -C ₆ -alkenyl heteroaryl" means a C ₂ -C ₆ -alkenyl group having a heteroaryl substituent, including 2- (3-pyridinyl) vinyl and the like.

"C ₂ -C ₆ -alkynyl" means an alkynyl group, preferably having 2 to 6 carbon atoms and having at least one to two alkynyl unsaturated moieties. To ethynyl alkynyl group and the like (-C≡CH), propargyl (-CH ₂ C≡CH) it is preferred.

"C ₂ -C ₆ -alkynyl aryl" means a C ₂ -C ₆ -alkynyl group having an aryl substituent, including phenylethynyl and the like.

"C ₂ -C ₆ -alkynyl heteroaryl" means a C ₂ -C ₆ -alkynyl group having a heteroaryl substituent, including ₂ -thienylethynyl, and the like.

"C ₃ -C ₈ -cycloalkyl" refers to a saturated carbo of 3 to 8 carbon atoms with only one ring (eg cyclohexyl) or multiple condensed rings (eg norbornyl) Means cyclic group. Cycloalkyl preferably includes cyclopentyl, cyclohexyl, norbornyl, and the like.

"Heterocycloalkyl" means a C ₃ -C ₈ -cycloalkyl group according to the above definition, wherein from one to three carbon atoms are O, S, NR, where R is defined as hydrogen or methyl Substituted by a selected heteroatom. Heterocycloalkyl preferably includes pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.

"C ₁ -C ₆ -alkyl cycloalkyl" means a C ₁ -C ₆ -alkyl group having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.

“C ₁ -C ₆ -alkyl heterocycloalkyl” includes heterocyclo, including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl, and the like C ₁ -C ₆ -alkyl group having an alkyl substituent.

"Carboxy" means a -C (O) OH group.

"C ₁ -C ₆ -alkyl carboxy" means a C ₁ -C ₆ -alkyl group having a carboxy substituent, including 2-carboxyethyl and the like.

"Acyl" refers to the group -C (O) R, wherein R is "C ₁ -C ₆ -alkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl" or "C ₁ -C ₆ -alkyl heteroaryl ".

"C ₁ -C ₆ -alkyl acyl" means a C ₁ -C ₆ -alkyl group having an acyl substituent, including 2-acetylethyl and the like.

"Aryl acyl" means an aryl group having an acyl substituent, including 2-acetylphenyl and the like.

"Heteroaryl acyl" means a heteroaryl group having an acyl substituent, including 2-acetylpyridyl and the like.

"C ₃ -C _8- (hetero) cycloalkyl acyl" means a 3-8 membered cycloalkyl or heterocycloalkyl group having an acyl substituent.

"Acyloxy" refers to the group -OC (O) R, wherein R is H, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl " , "C ₂ -C ₆ - alkenyl aryl", "C ₂ -C ₆ - alkenyl heteroaryl", "C ₂ -C ₆ - alkynyl aryl", "C ₂ -C ₆ - alkynyl heteroaryl" , “C ₁ -C ₆ -alkyl cycloalkyl”, “C ₁ -C ₆ -alkyl heterocycloalkyl”.

"C ₁ -C ₆ - alkyl acyloxy" is C ₁ -C ₆ having, an acyloxy substituent, including 2- (acetyloxy) ethyl-refers to an alkyl group.

"Alkoxy" means a -OR group, where R is "C ₁ -C ₆ -alkyl", "aryl", "hetero-aryl", "C ₁ -C ₆ -alkyl aryl" or "C ₁ -C ₆ -Alkyl heteroaryl It is preferable that the alkoxy group contains, for example, methoxy, ethoxy, phenoxy, and the like.

"C ₁ -C ₆ -alkyl alkoxy" means a C ₁ -C ₆ -alkyl group having an alkoxy substituent, including 2-ethoxyethyl and the like.

"Alkoxycarbonyl" means a -C (O) OR group, where R is "C ₁ -C ₆ -alkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl" or " C ₁ -C ₆ -alkyl heteroaryl ”.

"C ₁ -C ₆ - alkyl alkoxycarbonyl" is 2- (benzyloxycarbonyl) C ₁ -C ₆ has a containing, such as ethyl, alkoxycarbonyl substituents - refers to an alkyl group.

"Aminocarbonyl" refers to the group -C (O) NRR 'wherein each R, R' is independently hydrogen, "C ₁ -C ₆ -alkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl hetero-aryl ".

"C ₁ -C ₆ - alkyl aminocarbonyl" are C ₁ -C ₆ having, aminocarbonyl substituent, including 2- (dimethylamino-carbonyl) ethyl-refers to an alkyl group.

"Acylamino" refers to the group -NRC (O) R 'wherein R and R' are independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ -Alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ - alkyl acylamino" is C ₁ -C ₆ having, acylamino substituent, including 2- (propionylamino) ethyl-refers to an alkyl group.

"Ureido" refers to the group -NRC (O) NR'R '' wherein each R, R ', R''is independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C _1- C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C ₂ -C ₆ -Alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ", wherein R 'and R '' May optionally form a 3-8 membered heterocycloalkyl ring with the nitrogen atom to which they are attached.

"C ₁ -C ₆ - alkyl ureido" is C ₁ -C ₆ having a ureido substituent, including 2- (N'- methyl ureido) ethyl-refers to an alkyl group.

"Carbamate" refers to the group -NRC (O) OR 'wherein each R, R' is independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", " C ₂ -C ₆ -alkynyl ”,“ C ₃ -C ₈ -cycloalkyl ”,“ heterocycloalkyl ”,“ aryl ”,“ heteroaryl ”,“ C ₁ -C ₆ -alkyl aryl ”or“ C ₁ -C ₆ - alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ - C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"Amino" refers to the group -NRR 'wherein each R, R' is independently hydrogen, "C ₁ -C ₆ -alkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl Aryl "," C ₁ -C ₆ -alkyl heteroaryl "," cycloalkyl "," heterocycloalkyl "wherein R and R 'together with the nitrogen atom to which they are attached are 3-8 membered heterocycloalkyl Rings may optionally be formed.

"C ₁ -C ₆ -alkyl amino" means a C ₁ -C ₆ -alkyl group having an amino substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Ammonium" means -N ⁺ RR'R "positive charge, wherein each R, R ', R" is independently hydrogen, "C ₁ -C ₆ -alkyl", "aryl", "heteroaryl" , "C ₁ -C ₆ -alkyl aryl", "C ₁ -C ₆ -alkyl heteroaryl", cycloalkyl "," heterocycloalkyl ", wherein R and R 'together with the nitrogen atom to which they are attached, It may optionally form a 3 to 8 membered heterocycloalkyl ring.

"C ₁ -C ₆ -alkyl ammonium" means a C ₁ -C ₆ -alkyl group having an ammonium substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Halogen" means fluoro, chloro, bromo and iodo atoms.

"Sulfonyloxy" is to mean a group -OSO ₂ -R, where R is H, "C ₁ -C ₆ - alkyl," substituted by halogen - for "C ₁ -C ₆ alkyl", e -OSO ₂ -CF ₃ group, "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "hetero Aryl "," C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl " , "C ₂ -C ₆ -alkynyl aryl", "C ₂ -C ₆ -alkynylheteroaryl", "C ₁ -C ₆ -alkyl cycloalkyl", "C ₁ -C ₆ -alkyl heterocycloalkyl" Is selected from.

"C ₁ -C ₆ -alkyl sulfonyloxy" means a C ₁ -C ₆ -alkyl group having a sulfonyloxy substituent, including 2- (methylsulfonyloxy) ethyl and the like.

"Alkylsulfonyl" is "-SO ₂ -R" group, where R is H, "aryl", "heteroaryl", to mean "C ₁ -C ₆ - alkyl", the "C ₁ -C ₆ optionally substituted by halogen -Alkyl ", for example -SO ₂ -CF ₃ group," C ₂ -C ₆ -alkenyl "," C ₂ -C ₆ -alkynyl "," C ₃ -C ₈ -cycloalkyl "," hetero Cycloalkyl "," aryl "," heteroaryl "," C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ -C ₆ - alkynyl heteroaryl "," C ₁ -C ₆ - alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ -alkyl sulfonyl" means a C ₁ -C ₆ -alkyl group having a sulfonyl substituent, including 2- (methylsulfonyl) ethyl and the like.

"Sulfinyl" is "-S (O) -R" to mean a group, wherein R is H, "C ₁ -C ₆ - alkyl," substituted by halogen - for "C ₁ -C ₆ alkyl", for example, -SO ₂ -CF ₃ group, "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl" , "Heteroaryl", "C ₁ -C ₆ -alkyl aryl" or "C ₁ -C ₆ -alkyl heteroaryl", "C ₂ -C ₆ -alkenyl aryl", "C ₂ -C ₆ -alkenyl Heteroaryl "," C ₂ -C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl hetero Cycloalkyl ".

"C ₁ -C ₆ -alkyl sulfinyl" means a C ₁ -C ₆ -alkyl group having a sulfinyl substituent, including 2- (methylsulfinyl) ethyl and the like.

"Sulfanyl" is to mean a group -SR where R is H, "C ₁ -C ₆ - alkyl," substituted by halogen "C ₁ -C ₆ - alkyl", for example, -SO-CF ₃ group, "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₃ -C ₈ -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C ₁ -C ₆ -alkyl aryl "or" C ₁ -C ₆ -alkyl heteroaryl "," C ₂ -C ₆ -alkenyl aryl "," C ₂ -C ₆ -alkenyl heteroaryl "," C _2- C ₆ -alkynyl aryl "," C ₂ -C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ". The sulfanyl group preferably contains methylsulfanyl, ethylsulfanyl and the like.

"C ₁ -C ₆ -alkyl sulfanyl" means a C ₁ -C ₆ -alkyl group having a sulfanyl substituent, including 2- (ethylsulfanyl) ethyl and the like.

"Sulfonylamino" refers to the group -NRSO ₂ -R 'wherein each R, R' is independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", " C ₂ -C ₆ -alkynyl ”,“ C ₃ -C ₈ -cycloalkyl ”,“ heterocycloalkyl ”,“ aryl ”,“ heteroaryl ”,“ C ₁ -C ₆ -alkyl aryl ”or“ C ₁ -C ₆ - alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ - C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ -alkyl sulfonylamino" means a C ₁ -C ₆ -alkyl group having a sulfonylamino substituent, including 2- (ethylsulfonylamino) ethyl and the like.

"Aminosulfonyl" refers to the group -SO ₂ -NRR 'wherein each R, R' is independently hydrogen, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", " C ₂ -C ₆ -alkynyl ”,“ C ₃ -C ₈ -cycloalkyl ”,“ heterocycloalkyl ”,“ aryl ”,“ heteroaryl ”,“ C ₁ -C ₆ -alkyl aryl ”or“ C ₁ -C ₆ - alkyl heteroaryl "," C ₂ -C ₆ - alkenyl aryl "," C ₂ -C ₆ - alkenyl heteroaryl "," C ₂ -C ₆ - alkynyl aryl "," C ₂ - C ₆ -alkynylheteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl ".

"C ₁ -C ₆ - alkyl aminosulfonyl" is C ₁ -C ₆ having, aminosulfonyl substituent, including 2- (cyclohexyl-amino-sulfonyl) ethyl-refers to an alkyl group.

"Substituted or unsubstituted": Unless limited to the definition of an individual substituent, the above-described functional groups such as "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl", etc. Optionally substituted with 1 to 5 substituents selected from the group consisting of: “C ₁ -C ₆ -alkyl”, “C ₂ -C ₆ -alkenyl”, “C ₂ -C ₆ -alkynyl”, “ Cycloalkyl "," heterocycloalkyl "," C ₁ -C ₆ -alkyl aryl "," C ₁ -C ₆ -alkyl heteroaryl "," C ₁ -C ₆ -alkyl cycloalkyl "," C ₁ -C ₆ -alkyl heterocycloalkyl "," amino "," ammonium "," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," ureido "," aryl " , "Carbamate", "heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy, mer Capto, nitro etc. Alternatively, the substitution may also include the situation in which the ring of neighboring substituents is closed, especially when adjacent functional substituents are involved, resulting in, for example, lactam, lacton, cyclic In addition to forming anhydrides, it forms acetals, thioacetals, and aminals formed by ring closure in an effort to obtain protecting groups.

"Pharmaceutically acceptable cationic salts or complexes" include alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg calcium or magnesium) , Aluminum salts, ammonium salts, and methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, N-Me-D-glucamine, N, N'-bis (phenylmethyl) -1,2 Ethanediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, piperidine, benzatin (N, N'-dibenzylethylenediamine), choline, ethylene-diamine, meglumine (N- Methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethanemin (2-amino-2-hydroxymethyl-1,3-propanediol), procaine For defining salts such as organic amine salts such as amines of the formula -NR, R'R ", wherein R, R ', R " are independently hydrogen, alkyl or benzyl to be. Particularly preferred salts are the sodium and potassium salts.

“Pharmaceutically acceptable salts or complexes” means salts or complexes of the following-identified compounds of the invention that possess desirable biological activity. Examples of such salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like. Acid addition salts; And acetic acid, oxalic acid, tartari acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid , Benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, And salts formed with organic acids such as poly-galacturonic acid. The compounds also may be administered in pharmaceutically acceptable quaternary salts known by those skilled in the art, in particular, the formula -NR, R ', R'' + Z - { wherein R, R', R '' are independently hydrogen, Alkyl, or benzyl, "C ₁ -C ₆ -alkyl", "C ₂ -C ₆ -alkenyl", "C ₂ -C ₆ -alkynyl", "C ₁ -C ₆ -alkyl aryl", "C ₁ -C ₆ -alkyl heteroaryl "," cycloalkyl "," heterocycloalkyl ", Z is chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, Or carboxylates (e.g. benzoate, succinate, acetate, glycorate, maleate, maleate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandello Quaternary ammonium salts, including mandeloate and diphenylacetate].

"Pharmaceutically active derivative" means any compound which, upon administration to a recipient, can provide the activity disclosed herein directly or indirectly.

The "tautomers" of the compounds according to formula (I) are only themselves (where R ² and / or R ⁰ are hydrogen) and represent formulas (Ia) and (Ib).

"Enantiomeric excess" (ee) refers to asymmetric synthesis, that is, synthesis or at least one enantioselective involving a non-racemic starting material and / or a reagent. Means a product obtained by the synthesis comprising a step). This produces one enantiomer surplus at least about 52% ee.

"Aromatase inhibitor" means a drug that inhibits the enzyme aromatase and thereby lowers the level of estradiol. Aromatase inhibitors preferably include, for example, anastrozole, letrozole, vorozole and exemestane.

"Estrogen receptor modulator (SERM)" means a drug that blocks the action of estrogen by occupying the estrogen receptor in the cell. SERMS also includes estrogen receptor beta antagonists and estrogen receptor beta agonists. SERMs preferably include, for example, Tamoxifen, Raloxifen.

"GnRH antagonist" refers to a synthetic GnRH analog that is a drug that competitively blocks the pituitary GnRH receptor, which is located in the plasma membrane of gonadotrophin. This results in rapid and reversible induction of gonadotropin secretion. GnRH antagonists preferably include, for example, cetrorelix, Ganirelix.

"GnRH agonist" refers to a decapeptide variant of the natural hormone GnRH, which is a drug that desensitizes the GnRH receptor of the pituitary gland upon continued exposure, thereby reducing the pituitary-ovary axis It causes an initial stimulus, followed by a decrease in circulating serum gonadotropin concentrations and inhibition of ovarian function. GnRH agonists preferably include, for example, Buserelin acetate, Nafarelin, Reuprolide, Triptorelin, Goserelin.

"PI3K-inhibitor" means a compound, peptide or protein that inhibits the activity of phosphatoinositide 3-kinase (PI3K). When the PI3K enzyme is inhibited, PI3K cannot exert its enzymatic, biological and / or pharmacological effects. In one embodiment, the activity of PI3K alpha is inhibited. In another embodiment, the activity of PI3K beta is inhibited. In another embodiment, the activity of PI3K gamma is inhibited. In another embodiment, the activity of the PI3K delta is inhibited. In a preferred embodiment, the activity of PI3K gamma is inhibited. The inhibitory activity can be measured by assays or animal models that are well known in the art. In one embodiment, the PI3K inhibitor is a compound selected from the group consisting of Formulas (I), (II), (III), (IV), (V), (VI), (VII) and (VIII).

"Progesterone Receptor Modulators (SPRMs)": One of the superfamily members of nuclear receptors, the progesterone receptor is a receptor for progesterone that plays an important role in female reproduction. Selective progesterone receptor modulators are drugs that may have different agonist, antagonist or partial (mixed) agonist / antagonist activity depending on the site of action. The SPRM preferably comprises asoprisnil, for example.

A first aspect of the invention is to provide a method for treating and / or preventing endometriosis in an individual, comprising administering a therapeutically effective amount of a PI3K inhibitor. In a preferred embodiment, the individual is a human female.

In a second aspect, the invention provides treatment of endometriosis via sequential or mixed treatment of hormone inhibitors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) with PI3K inhibitors, and And / or preventive measures.

The second or continuous administration of a therapeutically effective amount may be carried out at a dose that is less than or more than or equal to the initial or previous dose administered to the individual. A second or continuous administration may be performed during or prior to the relapse of endometriosis or related symptoms. The term "relapse" or "reoccurrence" is defined to include the appearance of one or more symptoms of endometriosis.

In a third aspect, the present invention relates to a method for treating endometriosis-related infertility in women, comprising administering a therapeutically effective amount of a PI3K inhibitor alone or in combination with other infertility treatment drugs.

In one embodiment, the sequential or mixed treatment regimen minimizes the disease by inhibiting endocrine-dependent cells.

A fourth aspect of the present invention provides a pharmaceutical composition comprising a PI3K inhibitor, a hormone inhibitor (eg, a GnRH antagonist, a GnRH agonist, an aromatase inhibitor, a progesterone receptor modulator, an estrogen receptor modulator) and a pharmaceutically acceptable excipient. Is made of.

A fifth aspect of the invention consists in the use of a PI3K inhibitor in the manufacture of a medicament for the treatment and / or prophylaxis of endometriosis.

As used herein, the term "prevention" should be understood to partially, completely prevent, inhibit, alleviate, or reverse one or more symptoms or causes of endometriosis.

Models designed for the progression of endometrial disease predict lesion progression from benign inflammatory lesions in response to endocrine intervention to partially or completely hormonally unresponsive lesions involved in upregulated survival pathways other than the inflammatory pathway. do.

Thus, in one embodiment, the PI3K inhibitor may interfere with the survival path of endometriosis.

A sixth aspect of the invention provides a method of preparing a medicament for the treatment and / or prophylaxis of endometriosis, comprising hormone suppressors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) and The use of a PI3K inhibitor in combination with a pharmaceutically acceptable carrier.

PI3K inhibitors used in combination with hormone inhibitors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) can be used sequentially or in combination with the hormone inhibitors.

A seventh aspect of the invention relates to the use of a PI3K inhibitor, alone or in combination with other drugs, in the manufacture of a medicament for the treatment of endometriosis-related infertility.

An eighth aspect of the invention relates to the use of a PI3K inhibitor for the treatment of endometriosis.

In particular, when treating or curing endometriosis-related infertility, drugs for treating infertility, such as biologically active human chorionic gonadotrophin (hCG), luteinizing hormone (LH) or follicles Follicle stimulating hormone (FSH) can be administered in natural, highly purified or recombinant form. Such molecules and their production methods are described in European Patent Applications EP 160,699, EP 211,894 and EP 322,438.

The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More generally, however, the composition is presented in unit dosage form to facilitate precise administration. The term "unit dosage form" refers to a form that is physically separated into suitable units as a single dosage for human subjects and other mammals, each unit form being calculated to obtain the desired therapeutic effect in connection with a suitable pharmaceutical excipient. A predetermined amount of the active substance. Typical unit dosage forms include prefilled or measured ampoules or syringes for liquid compositions, or pills, tablets, capsules and the like for solid compositions. In such compositions, the PI3K inhibitor is generally a minor component (about 0.1 to 50% by weight or preferably about 1 to 40% by weight), with the remainder being various carriers or carriers and auxiliaries useful for forming the preferred dosage forms.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers such as buffers, suspensions and dispersants, colorants, flavors and the like.

Solid forms can include, for example, the following components or compounds having similar properties: binders such as microcrystalline cellulose, gum tragacanth or gelatine; Excipients such as starch or lactose; Disintegratimg agents such as alginic acid, Primogel, or corn starch; Lubricants such as magnesium stearate; Glidants, such as colloidal silicon dioxide; Sweetening agents such as sucrose or saccharin; Or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

Injectable compositions are generally based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known to those skilled in the art. As mentioned above, in such compositions the PI3K inhibitor is generally a minor component, often within 0.05 to 10% by weight, with the remainder being the injectable carrier and the like.

The ingredients for oral administration or injectable compositions described above are merely representative. This where the pharmaceutical sciences of Leamington incorporated by reference to such statements, as well as other materials processing technology (Remington's Pharmaceutical Sciences , 20 th Edition , 2000, Marck Publishing Company , Easton , Pennsylvania ) .

The compounds of the present invention can also be administered in sustained release form or in a sustained release drug delivery system. In addition, delayed action of the exemplary materials are described in pharmaceutical science Leamington (Remington's Pharaceutical Sciences ) .

The definition of “pharmaceutically acceptable” means to include a carrier that does not interfere with the effectiveness of the biological activity of the active ingredient and which does not endow the host to which it is administered. For example, for parenteral administration, the PI3K inhibitor can be formulated in a single dosage form for infusion with carriers such as saline, dextrose solution, serum albumin and Ringer's solution.

For parenteral (eg, intravenous, subcutaneous, intramuscular) administration, the PI3K inhibitor is a pharmaceutically acceptable parenteral carrier (eg, water, saline, dextrose solution), and isotonicity. It may be formulated as a solution, suspension, emulsion or lyophilized powder, with additives that maintain [eg, mannitol] or chemical stability (eg, preservatives and buffers). The formulation is sterilized by conventional techniques.

A therapeutically effective amount of a PI3K inhibitor may be a function of many variables, including the type of inhibitor, the affinity of the inhibitor to PI3K, the residual cytotoxic activity seen by the PI3K inhibitor, the route of administration, or the clinical condition of the patient. Can be.

A "therapeutically effective amount" is the extent to which a PI3K inhibitor can inhibit the biological activity of PI3K when administered. Dosages administered to individuals in single or multiple doses will depend on a variety of factors, including: PI3K inhibitor pharmacokinetic properties, route of administration, patient condition and characteristics (sex, age, weight, health, height) , Degree of symptoms, concurrent treatment, frequency of treatment and desired effect. In vitro and in vivo methods of measuring individual PI3K inhibition, as well as the adjustment and control of a set dosage range, are well within the ability of those skilled in the art.

The PI3K inhibitor may be a compound of Formula (I):

Such compounds are described in WO 04/007491 (Applied Research Systems ARS Holding NV), in particular autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney disease, Compounds for treating platelet aggregation, cancer, transplant complications, graft rejection or lung injury are described.

The PI3K inhibitor is not only a compound according to formula (I) but also optically active such as its geometrical isomer, its enantiomer, diastereomer and racemate forms. Forms, pharmaceutically acceptable salts thereof and pharmaceutically active derivatives thereof.

Substituents in formula (I) are defined as follows:

A is an unsubstituted or substituted 5-8 membered heterocyclic group or an unsubstituted or substituted carbocyclic group.

The carbocyclic group may be fused to unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocycloalkyl.

The heterocyclic or carbocyclic group is phenyl, phenanthrenine, cyclopentyl, cyclohexyl, norbornyl, pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, pyrrolyl, furanyl, Thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadia Zolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, Benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindoleyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3,4-b ] Pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl, iso Nolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, putridinyl, carbazolyl, xanthenyl or benzoquinolyl And aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

Examples of another heterocyclic or carbocyclic group A include: unsubstituted or substituted dioxoles, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted ( Dihydro) furanyl, unsubstituted or substituted (dihydro) oxazinyl, unsubstituted or substituted oxazinoyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted isoxazolyl, unsubstituted or Substituted oxazolyl, unsubstituted or substituted (dihydro) naphthalenyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyra Genyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted oxadiazolyl.

X is S, O or NH, preferably S.

Y ¹ and Y ² are independently from each other selected from the group consisting of S, O or —NH, preferably O.

Z is S or O, preferably O.

R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted C _1- C ₆ -alkyl aminocarbonyl, acylamino, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl ureido, amino, unsubstituted Or substituted C ₁ -C ₆ -alkyl amino, ammonium, sulfonyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonyloxy, sulfonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfes Ponyl, sulfinyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfinyl, sulfanyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfanyl, sulfonylamino, unsubstituted or substituted C _1- C ₆ -alkyl Sulfonylamino and carbamate. In a specific embodiment, R ¹ is H.

R ² is H, halogen, acyl, amino, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alky Unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aminocarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, unsubstituted or substituted C _1- C ₆ -alkyl ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl carbamate, unsubstituted or substituted C ₁ -C ₆ -alkyl amino, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, Unsubstituted or substituted C ₁ -C ₆ -alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfinyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonylaminoaryl, Unsubstituted or substituted aryl, unsubstituted or substituted C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₂ -C _6- Alkenyl-aryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl, carboxy, cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl And sulfonyl.

n is an integer selected from 0, 1 or 2, preferably n is O or 1, more preferably n is 0.

According to a specific embodiment of the invention, R ¹ And R ² are both H.

In another specific embodiment of the invention, X is S and Y ¹ And Y ² are both O and R ¹ And R ² is as defined above and n is O.

In one embodiment, the PI3K inhibitor is a thiazolidinedione-vinyl fusion-benzene derivative of formula (II):

A is unsubstituted or substituted dioxol, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (dihydro) furanyl, unsubstituted or substituted (dihydro) oxazinyl Unsubstituted or substituted oxazinoyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted (dihydro) naphthalenyl, unsubstituted Or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted thiadiazolyl, non It is selected from the group consisting of a ring or substituted oxadiazolyl.

R ² is H, halogen, acyl, amino, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alky Unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aminocarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, unsubstituted or substituted C _1- C ₆ -alkyl ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl carbamate, unsubstituted or substituted C ₁ -C ₆ -alkyl amino, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, Unsubstituted or substituted C ₁ -C ₆ -alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfinyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonylaminoaryl, Unsubstituted or substituted aryl, unsubstituted or substituted C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₂ -C _6- Alkenyl-aryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl, carboxy, cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl And sulfonyl.

In another embodiment, the PI3K inhibitor is an optical agent such as a thiazolidinone-vinyl fusion-benzene derivative of formula (II ′), as well as its geometric isomers, its enantiomers, diastereomers and racemate forms. Active forms, pharmaceutically acceptable salts thereof and pharmaceutically active derivatives thereof:

Wherein Y ¹ , Z, R ¹ , R ² are as defined above and n is O or 1.

Compounds of formula (II)-(VI) as well as methods for their synthesis are described in detail in WO 04/007491 (Applied Research Systems ARS Holding N.V.).

In specific embodiments, R ¹ is unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted aryl, unsubstituted or substituted C _3- C ₈ -cycloalkyl or -heterocycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl aryl, substituted or substituted C ₂ -C _6- Alkynyl aryl.

In another preferred embodiment, Y ¹ is O.

In another embodiment, the PI3K inhibitor is optically active, such as the thiazolidinone-vinyl fusion-benzene derivative of formula (III), as well as its geometric isomers, its enantiomers, diastereomers and racemate forms Forms, pharmaceutically acceptable salts thereof and pharmaceutically active derivatives thereof:

Where R ¹ And R ² is as defined above (dotted line in the figure indicates selective presence of double bond).

In another embodiment, the PI3K inhibitor is a compound of Formula (IV), (V) and (VI).

R ¹ is selected from the group consisting of hydrogen, halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, acyl and alkoxy carbonyl, while R ² is as defined above. In specific embodiments, R ² is an amino moiety.

In another embodiment, the PI3K inhibitor is a compound of Formula (I ′) wherein R ¹ And Y ¹ is as defined above and W is O, S or —NR ³ Wherein R ³ is H or an unsubstituted or substituted C ₁ -C ₆ -alkyl group. In a preferred embodiment, R ¹ Is an unsubstituted or substituted C ₁ -C ₄ -alkyl group or an unsubstituted or substituted C ₁ -C ₅ -alkenyl group, carboxy, cyano, C ₁ -C ₄ -alkoxy, nitro, acylamino, ureido.

In particular, the compounds of the present invention include compounds of the group consisting of:

5- (1,3-benzodioxol-5-ylmethylene) -1,3-thiazolidine-2,4-dione,

5- (1,3-benzodioxol-5-ylmethylene) -2-thioxo-1,3-thiazolidin-4-one,

5- (2,3-dihydro-1,4-benzodioxin-6-ylmethylene) -1,3-thiazolidine-2,4-dione,

5- (2,3-dihydro-1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione,

5-[(7-methoxy-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-[(9,10-dioxo-9,10-dihydroanthracen-2-yl) methylene] -1,3-thiazolidine-2,4-dione,

(5-[(2,2-difluoro-1,3-benzodioxol-5-yl) methylene] -1,3-thiazolidine-2,4-dione,

(5Z) -5- (1,3-dihydro-2-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione,

5- (1-benzofuran-5-ylmethylene) -1,3-thiazolidine-2,4-dione,

5-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5- (1,3-benzodioxol-5-ylmethylene) -2-imino-1,3-thiazolidin-4-one,

5-quinolin-6-ylmethylene-thiazolidine-2,4-dione,

5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one,

2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one,

5- (3-methyl-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione,

5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione,

5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione,

5-[(4-aminoquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-[(4-piperidin-1-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-[(4-morpholin-4-ylquinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-{[4- (benzylamino) quinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-{[4- (diethylamino) quinazolin-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-({4-[(pyridin-2-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

5-({4-[(pyridin-3-ylmethyl) amino] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-3-carboxylate,

Ethyl 1- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} piperidine-4-carboxylate,

tert-butyl 1- {6-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] quinazolin-4-yl} -L-prolinate,

5-{[4- (4-methylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-{[4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-({4- [4- (4-fluorophenyl) piperidin-1-yl) quinazolin-6-yl] methylene) -1,3-thiazolidine-2,4-dione,

5-{[4- (4-benzylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-({4- [4- (2-phenylethyl) piperidin-1-yl] quinazolin-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

5-{[4- (4-methylpiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-{[4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-4-carboxylic acid,

1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-3-carboxylic acid,

1- [6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl] -piperidine-2-carboxylic acid,

5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione,

5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2,4-dione,

2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidine-4-dione,

2-imino-5- (4-piperidine-quinazolin-6-ylmethylene) -thiazolidine-4-dione,

2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-4-dione,

5- (2-methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione,

5- (3-methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2,4-dione,

5- (3-ethyl-3H-benzoimidazol-5-ylmethylene) -thiazolidine-2,4-dione,

5-{[1- (4-phenylbutyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-[(1-prop-2-yn-1-yl-1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-[(1- {2- [4- (trifluoromethyl) phenyl] ethyl} -1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-({1- [2- (4-hydroxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

Methyl 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylate,

5-({1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4 Dion,

5-({1-[(1-methyl-1H-pyrazol-4-yl) methyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione ,

5-({1- [2- (3,4-dimethoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

5-({1- [2- (4-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

5-({1- [4- (trifluoromethyl) benzyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazol-1-yl} cyclohexanecarboxylic acid,

5-[(1-isobutyl-1H-benzimidazol-6-yl) methylene] -1,3-thiazolidine-2,4-dione,

5-({1- [2- (1,3-benzodioxol-4-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4- Dion,

5-({1- [2- (2-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione,

5-{[1- (3,3-diphenylpropyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-{[1- (2-methoxybenzyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-{[1- (3-furylmethyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-[(1-propyl-1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione,

5-quinoxaline-6-ylmethylene-thiazolidine-2,4-dione,

5-quinoxaline-6-ylmethylene-2-thioxo-thiazolidin-4-one,

2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one,

5-benzothiazol-6-ylmethylene-thiazolidine-2,4-dione,

5- (3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione,

5- (2-bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione,

5- (3-bromo-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione,

3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid ethyl ester,

3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -acrylic acid,

3- [3- (3-oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene] -thiazoli-dine-2,4-dione,

Methyl 1- (3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl Prolineate,

Methyl 1-((3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-eno Yl) -D-prolinate,

(5-({3-[(3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3- Thiazolidine-2,4-dione,

(5-({3- [3-morpholin-4-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazoli Din-2,4-dione,

Methyl 1- (3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl ) -L-prolinate,

N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} -N-methylacrylamide ,

3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-ethyl-N- (2-hydr Oxyethyl) acrylamide,

N-cyclobutyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide,

5-({3- [3-azetidin-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3- Thiazolidine-2,4-dione,

5-({3- [3- (1,3-morpholin-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl } Methylene) -1,3-thiazolidine-2,4-dione,

5-({3- [3-Azepan-1-yl-3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1,3-thiazolidine -2,4-dione,

3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N-piperidin-1-ylacrylic amides,

3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} -N- (pyridin-3-ylmethyl) Acrylamide,

N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide,

5-({3- [3- (4-methylpepyrazin-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} methylene) -1, 3-thiazolidine-2,4-dione,

N-cycloheptyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide,

5-({3- [3- (2,5-Dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl] -1-benzofuran-5-yl} Methylene) -1,3-thiazolidine-2,4-dione,

N-cyclopentyl-3- {5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide,

3- [5- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid ethyl ester,

3- [5- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -benzofuran-3-yl] -propionic acid,

5- [3- (3-oxo-3-piperidin-1-yl-propyl) -benzofuran-5-ylmethylene] -thiazole-idin-2,4-dione,

6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -2,3-dihydro-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester,

5- (3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione,

5- (4-benzoyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione,

5- (4-acetyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine-2,4-dione,

6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester,

[6- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] -oxazin-4-yl] -methyl acetate ester,

N-benzyl-2- [6- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazine-4- General] -acetamide,

5- (4-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazoli-dine-2,4-dione,

5- (4-benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thia-zolidine-2,4-dione,

5- (2-chloro-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione,

5- (3-amino-benzo [d] isoxazol-5-ylmethylene) -thiazolidine-2,4-dione,

5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2,4-dione,

5-benzo [1,2,5] thiadiazol-5-ylmethylene-thiazolidine-2,4-dione,

5-benzo [1,2,5] oxadiazol-5-ylmethylene-thiazolidine-2,4-dione,

5- (2-methyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione,

5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione,

5- (3-bromo-2-fluoro-2,3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione,

5- (2-Fluoro-benzofuran-6-ylmethylene) -thiazolidine-2,4-dione.

Methods of synthesizing compounds of formulas (I)-(VI) are described in detail in WO 04/007491.

In another embodiment, the PI3K inhibitor is a compound of Formula (VII):

A and X are as defined above. In a preferred embodiment, A is a heterocyclic moiety.

X is S, O or -NR ³ , preferably S. R ³ is H or optionally substituted C ₁ -C ₆ -alkyl.

Y is S or O, preferably O.

R ¹ is H, CN, carboxy, acyl, optionally substituted C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, unsubstituted Or substituted C ₁ -C ₆ -alkyl aminocarbonyl, acylamino, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl ureido, Amino, unsubstituted or substituted C ₁ -C ₆ -alkyl amino, ammonium, sulfonyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonyloxy, sulfonyl, unsubstituted or substituted C ₁ -C _{6-alkylsulfonyl,} sulfinyl, unsubstituted or substituted C ₁ -C ₆ - alkyl sulfinyl, sulfanyl, an unsubstituted or substituted C ₁ -C ₆ -alkyl sulfanyl, sulfonyl, amino, unsubstituted or Hwandoen C ₁ -C ₆ - is selected from the group consisting of alkylsulfonylamino, and carbamates. It is preferable that R ¹ is H.

R ² is H, halogen, acyl, amino, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alky Unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyl, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aminocarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, unsubstituted or substituted C _1- C ₆ -alkyl ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl carbamate, unsubstituted or substituted C ₁ -C ₆ -alkyl amino, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, Unsubstituted or substituted C ₁ -C ₆ -alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfinyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfonylaminoaryl, Unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or Substituted C ₁ -C ₆ -alkyl heteroaryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl-aryl or -heteroaryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl or -heteroaryl , Carboxy, cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl and sulfonyl. It is preferable that R ² is H. In a specific embodiment, R ¹ And R ² are both H.

G is unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, unsubstituted or substituted heteroaryl Unsubstituted or substituted C ₁ -C ₆ -alkyl aryl, unsubstituted or substituted C ₁ -C ₆ -alkyl heteroaryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl-aryl or -heteroaryl, Unsubstituted or substituted C ₂ -C ₆ -alkynyl aryl or -heteroaryl, unsubstituted or substituted C ₁ -C ₆ -alkoxy, cyano, unsubstituted or substituted C ₁ -C ₆ -acyl and sulfonyl Selected from the group consisting of moieties.

In a preferred embodiment, G is selected from the group consisting of unsubstituted or substituted C ₁ -C ₆ -alkoxy, cyano and unsubstituted or substituted sulfonyl moieties.

In another preferred embodiment, G is unsubstituted or substituted C ₁ -C ₆ -alkyl including propyl and methyl; C ₂ -C ₆ -alkenyl; It is selected from the group consisting of C ₁ -C ₆ -alkyl aryl including C ₂ -C ₆ -alkynyl and phenyl methyl.

In another preferred embodiment, G is phenyl sulfonyl, 4-methylphenyl sulfonyl, methyl sulfonyl, ethyl sulfonyl, 6-chloropyridine-3-sulfonyl, thiophene-2-carboxylic acid methyl ester-3-sul Phonyl, 5-chloro-1,3-dimethyl-1H-pyrazole-4 sulfonyl, 3-chlorophenyl sulfonyl, 2-chlorophenyl sulfonyl, quinoline-8-sulfonyl, biphenyl-2-sulfonyl, Optionally substituted sulfonyl moiety, including pyridine-3-sulfonyl, a cyano group, and a substituted or unsubstituted C ₁ -C ₆ -alkoxy.

In one embodiment, G is a sulfonyl moiety of the formula -SO ₂ -R ⁴ , wherein R ⁴ is H, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ -alkynyl, unsubstituted or substituted C ₁ -C ₆ -alkyl carboxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acyl, unsubstituted or Substituted C ₁ -C ₆ -alkyl alkoxycarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl aminocarbonyl, unsubstituted or substituted C ₁ -C ₆ -alkyl acyloxy, unsubstituted or substituted C ₁ -C ₆ -alkyl acylamino, unsubstituted or substituted C ₁ -C ₆ -alkyl ureido, unsubstituted or substituted C ₁ -C ₆ -alkyl carbamate, unsubstituted or substituted C ₁ -C _6- Alkyl amino, unsubstituted or substituted C ₁ -C ₆ -alkyl alkoxy, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ -alkyl sulfinyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonyl, Beach Or substituted C ₁ -C ₆ - alkylsulfonylamino, aryl, heteroaryl, unsubstituted or substituted C ₃ -C ₈ - cycloalkyl or heterocycloalkyl, unsubstituted or substituted C ₁ -C ₆ - alkyl Aryl, unsubstituted or substituted C ₁ -C ₆ -alkyl heteroaryl, unsubstituted or substituted C ₂ -C ₆ -alkenyl-aryl or -heteroaryl, unsubstituted or substituted C ₂ -C ₆ -alkynyl Aryl or -heteroaryl, carboxy, hydroxyl, C ₁ -C ₆ -alkoxy, acylamino and sulfonylamino.

In one embodiment, R ⁴ is selected from the group consisting of unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C ₁ -C ₃ -alkyl.

In a specific embodiment, X is S; Y is O; R ¹ And R ² is H; A is selected from the group consisting of dioxolenyl, pyridinyl or pyrazinyl moieties, preferably dioxolenyl and pyridinyl moieties.

Compounds of formula (VII) can be obtained as E / Z isomer mixtures or as essentially pure E-isomers or Z isomers. The E / Z isomerism preferably refers to a vinyl moiety connecting the phenyl and azolidinon moieties. In a specific embodiment, the compound of formula (I) is a Z-isomer.

In one embodiment, the PI3K inhibitor is selected from the group consisting of:

N- (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -2-chloro-benzenesulfonamide;

Ethanesulfonic acid (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -amide;

N- (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -3-chloro-benzenesulfonamide;

5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -amide ;

3- (5-Benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidenesulfamoyl) -thiophene-2-carboxylic acid methyl ester;

6-chloro-pyridine-3-sulfonic acid (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -amide;

Quinoline-8-sulfonic acid (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -amide;

N- (5-Benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -benzenesulfonamide;

N- (5-Benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -4-methyl-benzenesulfonamide;

N- (5-Benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -methanesulfonamide;

N- [5- (2,2-Difluoro-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene] -benzenesulfonamide;

N- [5- (2,2-Difluoro-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene] -4-methyl-benzenesulfonamide;

N- [5- (2,2-Difluoro-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene] -methanesulfonamide;

Biphenyl-2-sulfonic acid (5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -amide;

Pyridine-3-sulfonic acid (5-benzo [l, 3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene) -amide;

3- (4-oxo-5-quinolin-6-ylmethylene-thiazolidine-2-ylidenesulfamoyl) -thiophene-2-carboxylic acid methyl ester;

2-Chloro-N- (4-oxo-5-quinolin-6-ylmethylene-thiazolidine-2-ylidene) -benzenesulfonamide;

3- (5-Benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidenesulfamoyl] -thiophene-2-carboxylic acid;

5-benzo [1,3] dioxol-5-ylmethylene-4-oxo-thiazolidine-2-ylidene-cyanamide;

5-benzo [1,3] dioxol-5-ylmethylene-thiazolidine-2,4-dione 2- (O-methyl-oxime);

4-oxo-5-quinoxalin-6-ylmethylene-thiazolidine-2-ylidene-cyanamide;

5-benzo [1,3] dioxol-5-ylmethylene-2-benzylimino-thiazolidin-4-one;

2-benzylimino-5-quinolin-6-ylmethylene-thiazolidin-4-one;

2-propylimino-5-quinolin-6-ylmethylene-thiazolidin-4-one;

5-benzo [1,3] dioxol-5-ylmethylene-2-propylimino-thiazolidin-4-one;

5- (4-dimethylamino-quinazolin-6-ylmethylene) -2-methylamino-thiazol-4-one.

In another embodiment, the PI3K inhibitor may be a compound shown in Formula (VIII) (WO 04/17950, Piramed):

The invention will now be illustrated by the following examples, which are not intended to be limiting in any way.

Example  1: Endometriosis Model

The effect of PI3K inhibitors was measured in both in vitro and in vivo models of endometriosis. The efficacy of the drug treatment in inhibiting endometriosis was tested in two in vivo models, i) mice without thymic gland and ii) mouse model.

Example  1.1: In endometrial cells Cell death  ( cell - death ) Judo

Glandular and stromal tissues of the ectopic endometrium are well transplanted to the isosite to induce endometriosis. It is presumed that ectopic grafts survive because of reduced cell death (apoptosis) and increased expression of viable cell signaling pathways. Proteins or specific small molecule compounds that induce target-specific cell death of ectopic endometrial cells without affecting ectopic endometrium or other normal cells can be used as therapeutics to eliminate endometriosis. In this regard, PI3K inhibitor-1 (5-quinoxaline-6-ylmethylene-thiazolidine-2) that induces cell death of endometrial cells (12Z cells), immortalized human epithelial endometrial cells , 4-dione) was investigated (Zeitvogel et al. 2001). The cells grow in culture and secrete cytokines in response to TNFα, which has been reported to be increased in the peritoneal fluid of endometriosis patients. The 12Z cells were treated with PI3K inhibitor-1 for 24 hours, and cell death was measured by crystal violet staining. Since the ascites contained increased concentrations of TNFα, the inhibitor was also tested in the presence of this cytokine. Killed cells were separated from the tissue culture plates and washed off during staining with crystal violet. The color concentration will determine the amount of viable cells present in the plate. PI3K inhibitor-1 was tested in these cells and was found to reduce the amount of live cells in culture, either alone or in the presence of TNFα. The EC 50 of the inhibitors are shown in Table 1 below. The extent of cell death induced by the inhibitor was greater in the presence of TNFα. TNFα alone had no effect on cell viability (data not shown).

The concentration of PI3K inhibitor-1 required to induce 50% cell death (EC50 at μM) of human endometrial cells. Cells were incubated for 24 hours with varying inhibitor-1 concentrations alone or in the presence of 15ng / ml of TNFα and cell viability was measured using crystal violet staining. Alone [μM]  + TNFα [μM] Inhibitor-1 > 10 6.40

Example 1 .2 Breastless  Mouse model

Human endometrial tissue was injected into ovarectomized thymus-free mice to cause disease (Bruner-Tran et al., 2002). Briefly, endometrial biopsies obtained from normal volunteers or endometrial patients were cut into small pieces and incubated in the presence of estradiol for 24 hours. Treated tissues were injected subcutaneously or intraperitoneally in ovarian resected thymus-free mice implanted with estradiol. Within 2-4 days of injection, ectopic endometrial lesions developed in the mice. Treatment began with progesterone or PI3K inhibitor-1 10 days after tissue injection. Compounds were administered for 28 days at doses of 10 mg / kg and 30 mg / kg / animal. In previous experiments using this model, progesterone treatment was found to prevent disease progression, so it was used as a control. After terminating treatment, mice were killed and lesions developed from transplanted tissue found at subcutaneous and intraperitoneal sites (both size and number).

Table 2 below shows the study constructs performed on thymus-free mice. PI3K inhibitors at doses of 10 mg / kg and 30 mg / kg were effective in regressing the disease causing about 53% and 80%, respectively, compared to progesterone treatment. Mean lesion size was also reduced by about 10% and 30%, respectively, by treatment. The results are important because this model measures the growth / degeneration of human endometrial tissue and therefore has a direct relevance for treating human disease. PI3K inhibitor treatment did not have any effect on the uterine size and weight of the mice.

Effect of PI3K Inhibitor-1 on the Regression of Endometrial Lesions in a Mouse Xenograft Model without Thyroid Gland cure Lesions (% progesterone) compared to groups treated with progesterone Lesion size PI3K Inhibitor-1 10 mg / kg x 28 days 53% reduction 10% reduction PI3K Inhibitor-1 30 mg / kg x 28 days 80% reduction 30% reduction

Example  1.3: rat model

As described above, endometriosis was induced in mice (D'Antonio et al., 2000). In brief, autologous uterine horn segments were implanted onto the inner surface of the rat dominant wall. Three weeks after transplantation, the size and viability of the transplanted tissues were measured. One week after confirmation of adhesion of the tissue, treatment was started. Only vehicle was injected into the control group. The PI3K inhibitor-1 was administered orally at a single dose of 30 mg / kg per day. After 9 days of treatment with the PI3K inhibitor, the rats were anesthetized 2 hours after the last treatment, and blood samples were collected. The surface area of endometriosis-like lesions was measured. Endometrial-like lesions were removed for histology.

Inhibitor-1 induced significant regression (64%) of established endometrial lesions. Treatment with anide (for comparison) showed about 94% regression (data not shown). Results from the in vitro and in vivo models show that the activity of the molecule directly affects the endometrial tissues. Another important difference in the rat model is that intact myometrial and endometrial tissues are surgically dissected into experimental rats.

Taken together, in vitro studies and two in vivo model system studies show that kinase inhibitors targeting the PI3K pathway are effective drugs for the treatment of endometriosis.

Reference list

Bruner-Tran et al. (2002) Ann NY Acad Sci., 955: 328-339

Cantley, 2000, Science, 296, 1655-1657

D'Antonio et al. (2000) J. Reprod Immuno. 48: 81-98

Dawood, M. Y et al. (1993) Int. J. Gynaecol. Obstet. 40 (Suppl.), 29-42

Giudice et al. (2004) Lancet 364, 1789-99

Kyama et al. (2003) Reprod Biol Endocrinol. 1, 123

Vanhaesebroeck et al., 2001, Annu. Rev. Biochem., 70, 535-602

Waller et al. (1993) Fertil. Steril. 59, 511-515

Zeitvogel et al. (2001) Am. J. Pathol. 159, 1839-52

EP 160, 699

EP 211, 894

EP 322, 438

WO 04/17950

WO 04/007491

WO 05/011686

Claims (28)

A method of treating and / or preventing endometriosis in an individual, comprising administering a pharmaceutically effective amount of a PI3K inhibitor. The method of claim 1, wherein the PI3K inhibitor is administered in combination with a hormone suppressor. The method of claim 1 or 2, wherein said hormone inhibitor is selected from the group consisting of GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators and estrogen receptor modulators. . 4. The method of claim 1, wherein the PI3K inhibitor is administered alone or in combination with an endometriosis-related infertility treatment drug. The method according to any one of claims 1 to 4, wherein the PI3K inhibitor is not only a compound according to formula (I), but also optical such as its geometric isomers, its enantiomers, diastereomers and racemic forms. A method for treating and / or preventing endometriosis, characterized in that it is an active form, a pharmaceutically acceptable salt thereof and a pharmaceutically active derivative thereof:

Wherein A is a 5-8 membered heterocyclic group or a carbocyclic group which can be fused to aryl, heteroaryl, cycloalkyl or heterocycloalkyl; X is S, O or NH; Y ¹ and Y ² are each independently selected from the group consisting of S, O or -NH; Z is S or O; R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, acylamino, C ₁ -C ₆ -alkyl acylamino, ureido , C ₁ -C ₆ -alkyl ureido, amino, C ₁ -C ₆ -alkyl amino, ammonium, sulfonyloxy, C ₁ -C ₆ -alkyl sulfonyloxy, sulfonyl, C ₁ -C ₆ -alkyl sulfonate Selected from the group consisting of fonyl, sulfinyl, C ₁ -C ₆ -alkyl sulfinyl, sulfanyl, C ₁ -C ₆ -alkyl sulfanyl, sulfonylamino, C ₁ -C ₆ -alkyl sulfonylamino and carbamate Become; R ² is H, halogen, acyl, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl acylamino, C _1- C ₆ -alkyl ureido, C ₁ -C ₆ -alkyl amino, C ₁ -C ₆ -alkyl alkoxy, C ₁ -C ₆ -alkyl sulfanyl, C ₁ -C ₆ -alkyl sulfinyl, C ₁ -C ₆ -Alkyl sulfonyl, C ₁ -C ₆ -alkyl sulfonylaminoaryl, aryl, C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, C ₁ -C ₆ -alkyl aryl, C ₂ -C ₆ -alkenyl- Aryl, C ₂ -C ₆ -alkynyl aryl, carboxy, cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, C ₁ -C ₆ -alkyl carbamate, sulfonylamino, Selected from the group consisting of sulfanyl and sulfonyl; n is 0, 1 or 2. 6. The method of claim 5, wherein Y ¹ and Y ² are both O. The compound of claim 5 or 6, wherein n is 1 or 2; A method for treating and / or preventing endometriosis, wherein R ¹ and R ² are both H. 8. A compound according to any one of claims 5 to 7, wherein X is S; Y ¹ and Y ² are both O; A method for treating and / or preventing endometriosis, wherein R ¹ and R ² are as defined above and n is zero. The method according to any one of claims 1 to 4, wherein the PI3K inhibitor is not only a compound according to formula (I '), but also its geometric isomers, its enantiomers, diastereomers and racemic forms A method of treating and / or preventing endometriosis, which is an optically active form, a pharmaceutically acceptable salt thereof and a pharmaceutically active derivative thereof:

Wherein R ¹ , Y ¹ are as defined above and W is selected from O, S, —NR ³ , wherein R ³ is H or an unsubstituted or substituted C ₁ -C ₆ -alkyl group. The method according to any one of claims 1 to 4, wherein the PI3K inhibitor is not only a compound according to formula (II), but also optical such as its geometric isomers, its enantiomers, diastereomers and racemic forms. A method for treating and / or preventing endometriosis, characterized in that it is an active form, a pharmaceutically acceptable salt thereof, and a pharmaceutically active derivative thereof:

Wherein A is dioxol, dioxin, dihydrofuran, (dihydro) furanyl, (dihydro) oxazinyl, pyridinyl, isoxazolyl, oxazolyl, (dihydro) naphthalenyl, pyrimidinyl, Triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl and oxdiazolyl; R ² is H, halogen, acyl, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl acylamino, C _1- C ₆ -alkyl ureido, C ₁ -C ₆ -alkyl carbamate, C ₁ -C ₆ -alkyl amino, C ₁ -C ₆ -alkyl alkoxy, C ₁ -C ₆ -alkyl sulfanyl, C ₁ -C ₆ -Alkyl sulfinyl, C ₁ -C ₆ -alkyl sulfonyl, C ₁ -C ₆ -alkyl sulfonylaminoaryl, aryl, C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, C ₁ -C ₆ -alkyl aryl , C ₂ -C ₆ -alkenyl-aryl, C ₂ -C ₆ -alkynyl aryl, carboxy, cyano, hydroxy, C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, It is selected from the group consisting of sulfanyl and sulfonyl. 5. The method according to claim 1, wherein the PI3K inhibitor is not only a compound according to formula (II ′), but also a geometric isomer thereof, enantiomer, diastereomer and racemic form. A method of treating and / or preventing endometriosis, which is an optically active form, a pharmaceutically acceptable salt thereof and a pharmaceutically active derivative thereof:

Wherein Z, Y ¹ , R ¹ , R ² are as defined above and n is O or 1. 12. The method of claim 11, wherein Y ¹ is O. 13. A compound according to claim 11 or 12, wherein R ¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyl aryl, aryl, C ₃ -C ₈ -cycloalkyl, heterocycloalkyl, C ₁ -C ₆ A method for treating and / or preventing endometriosis, which is selected from the group consisting of -alkyl aryl, C ₂ -C ₆ -alkenyl aryl and C ₂ -C ₆ -alkynyl aryl. The method according to any one of claims 1 to 4, wherein the PI3K inhibitor is not only a compound according to formula (III), but also optical such as its geometric isomers, its enantiomers, diastereomers and racemate forms. A method for treating and / or preventing endometriosis, characterized in that it is an active form, a pharmaceutically acceptable salt thereof and a pharmaceutically active derivative thereof:

Wherein R ¹ and R ² are as defined above. 5. The method according to claim 1, wherein said PI3K inhibitor is a compound according to any one of formulas (IV), (V) and (VI).

16. The method of claim 15, wherein the PI3K inhibitor is 5-quinoxalin-6-ylmethylene-thiazolidine-2,4-dione. 5. The optical composition according to claim 1, wherein the PI3K inhibitor is not only a compound according to formula (VII) but also an optical form such as its geometric isomers, enantiomers, diastereomers and racemate forms. A method for treating and / or preventing endometriosis, characterized in that it is an active form, a pharmaceutically acceptable salt thereof and a pharmaceutically active derivative thereof:

Wherein A is a 5-8 membered heterocyclic group or a carbocyclic group which can be fused to aryl, heteroaryl, cycloalkyl or heterocycloalkyl; X is S, O or -NR ³ ; Y is S or O; R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl alkoxy, alkoxycarbonyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, acylamino, C ₁ -C ₆ -alkyl acylamino, ureido , C ₁ -C ₆ -alkyl ureido, amino, C ₁ -C ₆ -alkyl amino, ammonium, sulfonyloxy, C ₁ -C ₆ -alkyl sulfonyloxy, sulfonyl, C ₁ -C ₆ -alkyl sulfonate Selected from the group consisting of fonyl, sulfinyl, C ₁ -C ₆ -alkyl sulfinyl, sulfanyl, C ₁ -C ₆ -alkyl sulfanyl, sulfonylamino, C ₁ -C ₆ -alkyl sulfonylamino and carbamate Become; R ² is H, halogen, acyl, amino, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, C ₁ -C ₆ -alkyl aminocarbonyl, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl acylamino, C _1- C ₆ -alkyl ureido, C ₁ -C ₆ -alkyl carbamate, C ₁ -C ₆ -alkyl amino, C ₁ -C ₆ -alkyl alkoxy, C ₁ -C ₆ -alkyl sulfanyl, C ₁ -C ₆ -Alkyl sulfinyl, C ₁ -C ₆ -alkyl sulfonyl, C ₁ -C ₆ -alkyl sulfonylaminoaryl, aryl, heteroaryl, C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, C ₁ -C ₆ -Alkyl aryl, C ₁ -C ₆ -alkyl heteroaryl, C ₂ -C ₆ -alkenyl-aryl or -heteroaryl, C ₂ -C ₆ -alkynyl aryl or -heteroaryl, carboxy, cyano, hydroxy , C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl and sulfonyl; G is C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl aryl, cyano and sulfonyl Selected from the group consisting of moieties; R ³ is H or C ₁ -C ₆ -alkyl. 18. The compound of claim 17, wherein A is 2H- (benzo-1,3-dioxolanyl), 2H, 3H-benzo-1,4-dioxanyl, 2,3-dihydrobenzofuranyl, anthraquinonyl, 2,2-difluorobenzo-1,3-dioxolenyl, 1,3-dihydrobenzofuranyl, benzofuranyl, 4-methyl-2H-benzo-1,4-oxazine-3-onyl, A method for treating and / or preventing endometriosis, characterized in that it is selected from the group consisting of pyridinyl, pyrazinyl, 4-methyl-2H and 3H-benzo-1,4-oxazinyl. 19. The method for treating and / or preventing endometriosis according to claim 17 or 18, wherein A is a dioxolenyl or pyridinyl moiety. 20. The method of any one of claims 17-19, wherein R ¹ and / or R ² is H. 21. The method of any one of claims 17-20, wherein G is selected from the group consisting of C ₁ -C ₆ -alkoxy, cyano or sulfonyl moieties. 22. The compound of any one of claims 17-21, wherein G is a sulfonyl moiety of the formula -SO ₂ -R ⁴ , wherein R ⁴ is H, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -Alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkyl carboxy, C ₁ -C ₆ -alkyl acyl, C ₁ -C ₆ -alkyl alkoxycarbonyl, C ₁ -C ₆ -alkyl amino Carbonyl, C ₁ -C ₆ -alkyl acyloxy, C ₁ -C ₆ -alkyl acylamino, C ₁ -C ₆ -alkyl ureido, C ₁ -C ₆ -alkyl carbamate, C ₁ -C ₆ -alkyl Amino, C ₁ -C ₆ -alkyl alkoxy, C ₁ -C ₆ -alkyl sulfanyl, C ₁ -C ₆ -alkyl sulfinyl, C ₁ -C ₆ -alkyl sulfonyl, C ₁ -C ₆ -alkyl sulfonyl Aminoaryl, aryl, heteroaryl, C ₃ -C ₈ -cycloalkyl or heterocycloalkyl, C ₁ -C ₆ -alkyl aryl, C ₁ -C ₆ -alkyl heteroaryl, C ₂ -C ₆ -alkenyl-aryl or - heteroaryl, C ₂ -C ₆ - alkynyl-aryl or-heteroaryl, carboxy, hydroxy, C ₁ -C ₆ - alkoxy, acylamino, and the group consisting of alcohol -5- Endometriosis treatment and / or prevention method according to claim selected from. The method of claim 22, wherein R ⁴ is selected from the group consisting of aryl, heteroaryl, and C ₁ -C ₆ -alkyl. The compound of any one of claims 17-23, wherein X is S; Y is O; A method for treating and / or preventing endometriosis, wherein R ¹ and R ² are H and A is a dioxolenyl or pyridinyl moiety. A pharmaceutical composition comprising a PI3K inhibitor, a hormonal inhibitor and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 25, wherein said hormone inhibitor is selected from the group consisting of GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators and estrogen receptor modulators. 27. The pharmaceutical composition of claim 25 or 26, wherein the PI3K inhibitor is a compound as defined by any one of claims 5 to 24. 28. The pharmaceutical composition of any one of claims 25 to 27, wherein the PI3K inhibitor is 5-quinoxalin-6-ylmethylene-thiazolidine-2,4-dione.