JP2009507072A - PI3K inhibitors for the treatment of endometriosis - Google Patents

Abstract

  The present invention relates to a method for treating and / or preventing endometriosis comprising administering a PI3K inhibitor. A PI3K inhibitor can also be administered in combination with a hormone inhibitor. The invention further relates to the treatment of endometriosis-related infertility.

Description

  Endometriosis is one of the most frequent diseases in female reproductive life. It is characterized by the presence of endometrial tissue outside the uterine cavity, which histologically consists of glands and stroma. The most affected anatomical sites are the ovary, uterine sacral ligament, pelvic peritoneum, rectal vaginal septum, cervix, vagina, fallopian tube and vulva.

  Endometriosis is considered a benign disease, but endometrial lesions are sometimes malignant. Like other types of malignancies, the development of endometriosis-derived neoplasms is a concomitant event and is accompanied by altered control of growth factors and / or oncogenes (Kyama et al. 2003). Furthermore, endometriosis is believed to be a major cause of infertility (Giudice et al. 2004).

  Current treatment of endometriosis consists of hormone therapy and / or surgery. Hormone therapy includes high doses of progestogens, oral contraceptives (a combination of estrogen and progesterone), danazol (androgenic derivative of etisterone) and recently a GnRH agonist. These hormonal therapies are effective for pelvic pain and can induce objective regression of the lesion, but have some warnings. Since estrogen cannot respond to progesterone, it can stimulate and cause the growth of endometrial tissue (Dawood et al, 1993). Luteinizing hormone drugs can cause irregular bleeding with depression, weight gain and fluid retention. Danazol can improve symptoms in about 66-100% of patients suffering from pain, but the recurrence rate by 4 years is about 40-50%. Other disadvantages of danazol treatment are weight gain and androgenic side effects. GnRH analogs are more potent and longer effective than native GnRH, which acts by eliminating estrogen stimulation on the growth of all estrogen sensitive tissues. Side effects of GnRH analogues, such as a decrease in bone density, occur primarily due to severe hypoestremia, with a recurrence rate of up to 50% after 5 years (Waller et al.,). 1993).

  Surgical intervention is conservative and can lead to removal of the uterus, ducts and ovaries in severe disease if fertility is required. In any case, even limited surgical procedures result in a significant decrease in fertility.

  Although endometriosis exists as one of the most studied diseases in gynecology, the current understanding of the pathophysiology of this disease is still elusive. According to the preferred theory, endometrial lesions develop by orthotopic endometrial cells away from the primary site or by retrograde menstruation and transplantation at the remote site, followed by host tissue. Continues to infiltration and proliferation. Furthermore, endometriosis appears to be an invasive and metastatic disease. Although endometrial cells proliferate to some extent, they are not neoplastic because they are typically found in carcinomas. Clearly, endometrial cells become senescent, apoptotic and necrotic. Inflammatory responses induced or accompanied by lesion formation ultimately lead to fibrosis and scar formation.

  The survival of ectopic grafts is presumed to be due to decreased cell death (apoptosis) of these grafts and to increased expression of live cell signaling pathways. Proteins or certain small molecule compounds that induce target-specific cell death of ectopic endometrial cells without affecting the orthotopic endometrium or other normal cells are useful for the elimination of endometriosis Can be used as a treatment. In this regard, the effect of PI3K inhibitors on the ability to induce cell death of endometrial cells, immortalized human epithelial endometrial cells was investigated.

  PI3K (phosphoinositide 3-kinase) is an important signaling in cell proliferation, cell viability, angiogenesis, membrane transport, glucose transport, neurite outgrowth, cell membrane rippling, superoxide production, actin reorganization and chemotaxis (Cantley (2000) and Vanhaesebroeck (2001)). PI3K consists of two subunits, a catalytic P110 subunit and a control and localization subunit P85. The main catalytic function of PI3K is the P110 subunit that acts to phosphorylate inositol phospholipids (PIP2: phosphatidylinositol 4,5 bis-phosphate) in the plasma membrane at position 3 in the inositol sugar ring. Exists. The intracellular signaling pathway of inositol phospholipids (phosphoinositides) is a G protein incorporated into the plasma membrane by signaling molecules (extracellular ligands), stimuli, receptor dimerization, heterologous receptors (eg receptor tyrosine kinases) It begins with transactivation to a bound transmembrane receptor. PI3K converts the membrane phospholipid PIP (4,5) 2 to PIP (3,4,5) 3, which is another 3 'phosphorylation of phosphoinositide by a 5'-specific phosphoinositide phosphatase. Thus, the enzymatic activity of PI3K directly or indirectly leads to the generation of two 3′-phosphoinositide subtypes that function as second messengers in intracellular signaling. To bring.

  Evolutionary conserved isoforms P110α and β are ubiquitously expressed, while δ and γ are more specifically expressed in hematopoietic cell lines, smooth muscle cells, muscle cells and endothelial cells. (Vanhaesebroeck 1997). Their expression can also be controlled in an inductive manner depending on the cell type, tissue type and stimulus and disease status.

  To date, eight mammalian PI3Ks have been identified and divided into three major classes (I, II, and III) based on sequence homology, structure, binding partner, activation mode, and substrate selection in vitro. It was.

Two compounds, LY294992 and waltomannin, are known PI3 kinase inhibitors. These compounds are non-selective PI3K inhibitors.

  Azolidinone-vinyl benzene derivatives (described in WO 04/007491) and 2-imino-azolidinone-vinyl fused benzene derivatives (described in WO 05/011686) are PI3K kinase inhibitors, specifically It is said to be PI3K kinase gamma. These compounds may be used to treat autoimmune and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial infections, viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injury and / or It is said to be useful for prevention.

  The invention described herein shows the unexpected result that inhibition of PI3K by a PI3K inhibitor reduces endometriosis. Since normalization of genital structure has a positive effect on implantation rate, reduction of endometrial lesions using PI3K inhibitors can also improve the birth rate.

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

  The present invention further provides treatment of endometriosis by treatment with a PI3K inhibitor in combination with a hormone inhibitor (eg, GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor modulator, estrogen receptor modulator). Or relates to a method for preventing.

  The present invention also relates to a method of treating endometriosis-related infertility in a woman comprising administering a therapeutically effective amount of a PI3K inhibitor alone or in combination with other ovulation-inducing agents.

  The present invention finally relates to a pharmaceutical composition comprising a PI3K inhibitor, a hormone inhibitor and a pharmaceutically acceptable excipient.

DESCRIPTION OF THE INVENTION The following paragraphs provide definitions for the various chemical moieties that make up the compounds of the present invention, and throughout the specification and claims, unless the definitions explicitly provided provide a broader definition. It is intended to be applied in the same way.

  “Aryl” represents an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl). Preferred aryls include phenyl, naphthyl, phenanthrenyl and the like.

“C ₁ -C ₆ -alkyl aryl” refers to C ₁ -C ₆ -alkyl groups having an aryl substituent, such as benzyl, phenethyl and the like.

  “Heteroaryl” represents a monocyclic heteroaromatic or bicyclic or tricyclic fused-ring heteroaromatic group. Specific 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-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, isoindolyl, 3H-indolyl, benzimidazolyl, imidazol [1,2-a] pyridyl, benzothiazolyl, benzo Oxazolyl, quinolidinyl Quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, 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, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

"C ₁ -C ₆ - alkyl heteroaryl", C ₁ -C ₆ having heteroaryl substituent, such as 2-furylmethyl, 2-thienylmethyl, and the like 2- (1H-indol-3-yl) ethyl - Represents an alkyl group.

“C ₂ -C ₆ -alkenyl” represents an alkenyl group preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH ₂ ), n-2-propenyl (allyl, —CH ₂ CH═CH ₂ ), and the like.

“C ₂ -C ₆ -alkenyl aryl” refers to C ₂ -C ₆ -alkenyl groups having an aryl substituent, such as 2-phenylvinyl.

“C ₂ -C ₆ -alkenyl heteroaryl” refers to C ₂ -C ₆ -alkenyl groups having a heteroaryl substituent, such as 2- (3-pyridinyl) vinyl and the like.

“C ₂ -C ₆ -alkynyl” refers to an alkynyl group having preferably 2 to 6 carbon atoms and having at least 1 to 2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (— C≡CH), propargyl (—CH ₂ C≡CH) and the like.

“C ₂ -C ₆ -alkynyl aryl” refers to C ₂ -C ₆ -alkynyl groups having an aryl substituent, such as phenylethynyl and the like.

“C ₂ -C ₆ -alkynyl heteroaryl” refers to C ₂ -C ₆ -alkynyl groups having a heteroaryl substituent, such as 2-thienylethynyl and the like.

“C ₃ -C ₈ -cycloalkyl” represents a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (eg, cyclohexyl) or multiple condensed rings (eg, norbornyl). Preferred cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

“Heterocycloalkyl” represents a C ₃ -C ₈ -cycloalkyl group as defined above, wherein 1 to 3 carbon atoms are represented by a heteroatom selected from the group consisting of O, S, NR. substituted, R represents is defined as hydrogen or C ₁ -C ₆ alkyl. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.

“C ₁ -C ₆ -alkyl cycloalkyl” refers to C ₁ -C ₆ -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.

“C ₁ -C ₆ -alkyl heterocycloalkyl” has heterocycloalkyl substituents including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl, and the like. It represents an alkyl group - C ₁ -C _6.

  “Carboxy” refers to the group —C (O) OH.

“C ₁ -C ₆ -alkyl carboxy” refers to C ₁ -C ₆ -alkyl groups having a carboxy substituent, such as 2-carboxyethyl and the like.

“Acyl” refers to the group —C (O) R, where R is H, “C ₁ -C ₆ -alkyl”, “aryl”, “heteroaryl”, “C ₁ -C ₆ — “Alkylaryl” or “C ₁ -C ₆ -alkylheteroaryl”.

“C ₁ -C ₆ -alkyl acyl” refers to C ₁ -C ₆ -alkyl groups having an acyl substituent, such as 2-acetylethyl and the like.

  “Aryl acyl” refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

  “Heteroaryl acyl” refers to heteroaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.

"C ₃ -C ₈ - (hetero) cycloalkyl acyl" refers to a 3-8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.

“Acyloxy” refers to the group —OC (O) R, where 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 “Aryl”, “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” refers to C ₁ -C ₆ -alkyl groups having an acyloxy substituent, such as 2- (acetyloxy) ethyl and the like.

“Alkoxy” refers to the group —O—R, where R is “C ₁ -C ₆ -alkyl” or “aryl” or “heteroaryl” or “C ₁ -C ₆ -alkyl aryl” or “C ₁ -C ₆ -alkyl heteroaryl” may be mentioned. Preferred alkoxy groups include methoxy, ethoxy, phenoxy and the like.

“C ₁ -C ₆ -alkyl alkoxy” refers to C ₁ -C ₆ -alkyl groups having an alkoxy substituent, such as 2-ethoxyethyl.

“Alkoxycarbonyl” represents a group —C (O) OR, where R is H, “C ₁ -C ₆ -alkyl” or “aryl” or “heteroaryl” or “C ₁ -C _6”. - include alkyl heteroaryl "- alkyl aryl" or "C ₁ -C _6.

“C ₁ -C ₆ -alkyl alkoxycarbonyl” refers to C ₁ -C ₆ -alkyl groups having an alkoxycarbonyl substituent, such as 2- (benzyloxycarbonyl) ethyl and the like.

“Aminocarbonyl” refers to the group —C (O) NRR ′, where each R, R ′ is independently hydrogen or “C ₁ -C ₆ -alkyl” or “aryl” or “heteroaryl”. Or “C ₁ -C ₆ -alkyl aryl” or “C ₁ -C ₆ -alkyl heteroaryl”.

“C ₁ -C ₆ -alkylaminocarbonyl” refers to C ₁ -C ₆ -alkyl groups having an aminocarbonyl substituent, such as 2- (dimethylaminocarbonyl) ethyl and the like.

“Acylamino” refers to the group —NRC (O) 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 ” - alkynyl heteroaryl "," C ₁ -C ₆ - alkyl cycloalkyl "," C ₁ -C ₆ - alkyl heterocycloalkyl ".

“C ₁ -C ₆ -alkyl acylamino” refers to C ₁ -C ₆ -alkyl groups having an acylamino substituent, such as 2- (propionylamino) ethyl and the like.

“Ureido” represents 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 -alkynyl heteroaryl”, “C ₁ -C ₆ -alkyl cycloalkyl”, “C ₁ -C ₆ -alkyl heterocycloalkyl”, wherein R ′ and R ″ are Optionally with 3-8 membered heterocycloalkyl together with the nitrogen atom to which it is attached. It can form a ring.

“C ₁ -C ₆ -alkyl ureido” refers to C ₁ -C ₆ -alkyl groups having a ureido substituent, such as 2- (N′-methylureido) ethyl and the like.

“Carbamate” represents 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 ” - heteroaryl alkynyl "," C ₁ -C ₆ - is a heterocycloalkyl alkyl "- alkylcycloalkyl", "C ₁ -C _6.

“Amino” refers to the group —NRR ′ where each R, R ′ is independently hydrogen or “C ₁ -C ₆ -alkyl” or “aryl” or “heteroaryl” or “C ₁ — “C ₆ -alkyl aryl” or “C ₁ -C ₆ -alkyl heteroaryl” or “cycloalkyl” or “heterocycloalkyl”, wherein R and R ′ are optionally combined with the nitrogen atom to which they are attached. A 3-8 membered heterocycloalkyl ring can be formed.

“C ₁ -C ₆ -alkylamino” refers to C ₁ -C ₅ -alkyl groups having an amino substituent, such as 2- (1-pyrrolidinyl) ethyl and the like.

“Ammonium” represents a positively charged group —N ⁺ RR′R ″, where each R, R ′, R ″ is independently “C ₁ -C ₆ -alkyl” or “C ₁ -C ₆ - alkyl aryl "or" C ₁ -C ₆ - alkyl heteroaryl "or" cycloalkyl "or" heterocycloalkyl ", R and R ', together with the nitrogen atom to which they are attached, Optionally, a 3-8 membered heterocycloalkyl ring can be formed.

“C ₁ -C ₆ -alkyl ammonium” refers to C ₁ -C ₆ -alkyl groups having an ammonium substituent, such as 2- (1-pyrrolidinyl) ethyl and the like.

  “Halogen” represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

"Sulfonyloxy" refers to a group -OSO ₂ -R, wherein, R represents, H, "C ₁ -C ₆ - alkyl" substituted with halogens "C ₁ -C ₆ - alkyl", for example, —OSO 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”, Selected from “C ₂ -C ₆ -alkynyl aryl”, “C ₂ -C ₆ -alkynyl heteroaryl”, “C ₁ -C ₆ -alkyl cycloalkyl”, “C ₁ -C ₆ -alkyl heterocycloalkyl” The

“C ₁ -C ₆ -alkylsulfonyloxy” refers to C ₁ -C ₅ -alkyl groups having a sulfonyloxy substituent, such as 2- (methylsulfonyloxy) ethyl and the like.

“Sulfonyl” refers to the group “—SO ₂ —R”, where R is H, “aryl”, “heteroaryl”, “C ₁ -C ₆ -alkyl”, “C” substituted with halogen. 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 -alkynyl heteroaryl”, “C ₁ -C ₆ -alkyl cycloalkyl”, “C ₁ -C” ₆ - selected from alkyl heterocycloalkyl " It is.

“C ₁ -C ₆ -alkyl sulfonyl” refers to C ₁ -C ₅ -alkyl groups having a sulfonyl substituent, such as 2- (methylsulfonyl) ethyl and the like.

"Sulfinyl" denotes the group "-S (O) -R", wherein, R represents, H, "C ₁ -C ₆ - alkyl" substituted with halogens "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 -alkynyl heteroaryl ”,“ C ₁ -C ₆ -alkyl cycloalkyl ”,“ C ₁ -C ₆ -alkyl heterocycloalkyl ” Selected.

“C ₁ -C ₆ -alkyl sulfinyl” refers to C ₁ -C ₅ -alkyl groups having a sulfinyl substituent, such as 2- (methylsulfinyl) ethyl and the like.

"Sulfanyl" refers to the group -S-R, wherein, as the R, H, "C ₁ -C ₆ - alkyl" substituted with halogens "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 Examples include “ _2- C ₆ -alkynyl aryl”, “C ₂ -C ₆ -alkynyl heteroaryl”, “C ₁ -C ₆ -alkyl cycloalkyl”, and “C ₁ -C ₆ -alkyl heterocycloalkyl”. Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl and the like.

“C ₁ -C ₆ -alkyl sulfanyl” refers to C ₁ -C ₅ -alkyl groups having a sulfanyl substituent, such as 2- (ethylsulfanyl) ethyl and the like.

“Sulfonylamino” refers to the group —NRSO ₂ —R ′, where 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 - alkynyl heteroaryl "," C ₁ -C ₆ - alkyl cycloalkyl "," C ₁ -C ₆ - alkyl heterocycloalkyl "and the like.

“C ₁ -C ₆ -alkylsulfonylamino” refers to C ₁ -C ₅ -alkyl groups having a sulfonylamino substituent, such as 2- (ethylsulfonylamino) ethyl and the like.

“Aminosulfonyl” refers to the group —SO ₂ —NRR ′ where 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 - alkynyl heteroaryl "," C ₁ -C ₆ - alkyl cycloalkyl "," C ₁ -C ₆ - alkyl heterocycloalkyl "and the like.

“C ₁ -C ₆ -alkylaminosulfonyl” refers to C ₁ -C ₆ -alkyl groups having an aminosulfonyl substituent, such as 2- (cyclohexylaminosulfonyl) ethyl and the like.

“Substituted or unsubstituted”: unless otherwise restricted by the definition of individual substituents, groups such as “alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” “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”, “sulfiyl” Optionally selected from 1 to 5 substituents selected from the group consisting of "Lu", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy, mercapto, nitro Can be substituted. Alternatively, this substitution also includes situations in which adjacent substituents undergo ring closure, particularly when adjacent functional substituents are involved, thereby providing, for example, lactams, lactones, cyclic anhydrides, and, for example, protecting groups. Acetals, thioacetals, and aminals formed by the ring closure of

  “Pharmaceutically acceptable salts or complexes” include alkali metal salts (eg, sodium and potassium), alkaline earth metal salts (eg, calcium or magnesium), aluminum salts, ammonium salts, and organic amines such as methylamine. , Dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, N-Me-D-glucamine, N, N′-bis (phenylmethyl) -1,2-ethanediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, Piperidine, benzathine (N, N'-dibenzylethylenediamine), chlorin, ethylene-diamine, meglumine (N-methylglucamine), venetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethami (2-amino-2-hydroxymethyl-1,3-propanediol), procaine and an amine of formula —NR, R ′, R ″ where R, R ′, R ″ are independently hydrogen , Alkyl or benzyl) is intended to define the salts. Sodium and potassium salts are particularly preferred.

“Pharmaceutically acceptable salt or complex” refers to a salt or complex of a compound of formula I identified below that retains the desired biological activity. Examples of such salts include acid addition salts formed with inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (eg, acetic acid, oxalic acid, tartaric acid, A salt formed by succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamonic acid, alginic acid, polyglutamic acid, naphthalene-sulfonic acid, naphthalene-disulfonic acid, and polygalacturonic acid) For example, but not limited to. This compound can also be administered as a pharmaceutically acceptable quaternary salt known by those skilled in the art, specifically a quaternary ammonium of the formula —NR, R ′, R ″ ⁺ Z ⁻ . Salt, 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 a counter ion such as chlorine, bromine, iodine, —O-alkyl, toluenesulfonate , Methyl sulfonate, sulfonate, phosphate, or carboxylate (eg, benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citric acid Salt, tartrate, ascorb Salt, a Shinamoeto (Cinnamoate), Manderoeto (Mandeloate), and diphenyl acetate salts).

  “Pharmaceutically active derivative” refers to any compound capable of providing the activity disclosed herein, directly or indirectly, upon administration to a recipient.

The only “tautomers” of the compounds of formula I are those wherein R ² and / or R ⁰ are hydrogen, which represents formulas (Ia) and (Ib).

  “Enantiomeric excess” (ee) refers to a product obtained by asymmetric synthesis, ie, a synthesis method comprising non-racemic starting materials and / or reagents, or a synthesis method comprising at least one enantioselective step. Thereby producing an excess of one enantiomer on the order of at least about 52% ee.

  “Aromatase inhibitor” refers to an agent that inhibits the enzyme aromatase and reduces the concentration of estradiol. Preferred aromatase inhibitors include, for example, anastrozole, letrozole, borozole and exemestane.

  “Estrogen receptor modulator (SERM)” refers to an agent that blocks the action of estrogen by occupying the estrogen receptor on the cell. SERMs also include estrogen receptor beta antagonists and estrogen receptor beta agonists. Preferred SERMs include, for example, tamoxifen and raloxifene.

  “GnRH antagonist” refers to a synthetic GnRH analog. It is an agent that competitively blocks the pituitary GnRH receptor, is located on the plasma membrane of gonadotropin-secreting cells, and induces rapid and reversible suppression of gonadotropin secretion. Preferred GnRH antagonists include, for example, cetro relics and ganirelix.

  “GnRH agonist” refers to a decapeptide modification of the natural hormone GnRH. It is a drug that desensitizes the pituitary GnRH receptor on continuous exposure, causing an initial stimulation of the pituitary-ovarian axis and subsequently reducing circulating serum gonadotropin levels and inhibiting ovarian function To do. Preferred GnRH agonists include, for example, buserelin acetate, nafarelin, leuprolide, triptorelin, goserelin.

  “PI3K inhibitor” refers to a compound, peptide or protein that inhibits the activity of phosphatoinositide 3-kinase (PI3K). If 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 yet another embodiment, the activity of PI3K delta is inhibited. In a preferred embodiment, the activity of PI3K gamma is inhibited. Such inhibitory activity can be measured by tests or animal models well known in the art. In one embodiment, the PI3K inhibitor is selected from the group consisting of formulas (I), (II), (III), (IV), (V), (VI), (VII) and (VII) A compound.

  “Progesterone Receptor Modulator (SPRM)”: Progesterone receptors (members of the nuclear receptor superfamily) are receptors for progesterone that play an important role in female reproduction. Selective progesterone receptor modulators are agents that can have agonist, antagonist or partial (mixed) agonist / antagonist activity depending on the site of action. A preferred SPRM is, for example, asoprisnil.

  A first aspect of the present invention is to provide a method of 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 present invention provides a continuous or combined treatment of hormone inhibitors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) with a PI3K inhibitor, The present invention relates to a method for treating and / or preventing endometriosis.

  Administration of the second or subsequent therapeutically effective amount can be performed at a dose that is the same, less than or greater than the dose initially or previously administered to the individual. A second or subsequent administration can be administered during or before the recurrence of endometriosis or related symptoms. The terms “relapse” or “relapse” are defined to encompass the appearance of one or more symptoms of endometriosis.

  In a third aspect, the present invention treats endometriosis-related infertility in females comprising administering a therapeutically effective amount of a PI3K inhibitor alone or in combination with other ovulation-inducing agents. Regarding the method.

  In one embodiment, this sequential or combined treatment method minimizes disease by inhibiting endocrine dependent cells.

  A fourth aspect of the invention includes a PI3K inhibitor, a hormone inhibitor (eg, GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor modulator, estrogen receptor modulator) and a pharmaceutically acceptable excipient A pharmaceutical composition consisting of

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

  As used herein, the term “prophylaxis” is to be understood as partially or totally preventing, inhibiting, reducing, or opposing one or more symptoms or causes of endometriosis. is there.

  Proposed models for the progression of endometrial disease are those in which the lesion is partially or completely hormonally related from an inflammatory lesion responsive to endocrine intervention to an upregulated survival pathway in addition to the inflammatory pathway. Expect to progress to non-responsive lesions.

  Thus, in one embodiment, PI3K inhibitors can interfere with survival pathways in endometriosis.

  The sixth aspect of the present invention relates to hormone inhibitors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptors) in the manufacture of a medicament for the treatment and / or prevention of endometriosis. Body modulators) and the use of PI3K inhibitors together with pharmaceutically acceptable carriers.

  Use of PI3K inhibitors in combination with hormone inhibitors (eg, GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators, estrogen receptor modulators) is a sequential or combined use of PI3K inhibitors and hormone inhibitors Can be.

  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.

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

  Specifically, when intended to treat or cure endometriosis-related infertility, agents for the treatment of infertility, such as natural highly purified or recombinant biology Active human chorionic gonadotropin (hCG), luteinizing hormone (LH) or follicle stimulating hormone (FSH) can be administered. Such molecules and methods for their production are described in European patent applications EP160,699, EP211,894 and EP322,438.

  The pharmaceutical compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More generally, however, the composition can be present in unit dosage forms that facilitate accurate administration. The term “unit dosage form” refers to physically discrete units suitable for unit dosage for human subjects and other animals, each unit together with suitable pharmaceutical excipients to produce the desired therapeutic effect. Contains a predetermined amount of active substance calculated. Typical unit dosage forms include ampoules or syringes pre-filled and measured with liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the PI3K inhibitor is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and the desired A processing aid useful in forming dosage forms.

  Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous vehicles with buffer solutions, suspending and dispersing agents, coloring agents, flavoring agents, and the like.

  The solid form can contain, for example, any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants, For example, alginic acid, primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange Flavoring.

  Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As noted above, PI3K inhibitors in such compositions are typically minor components, often in the range of 0.05 to 10% by weight, with the remainder being injectable carriers and the like.

  The above components for oral administration or injectable compositions are merely representative. Additional materials and processing techniques etc. are described in Part 5 of Remington's Pharmaceutical Sciences, 20th Edition, 2000, Markck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. .

  The compounds of the present invention can also be administered in sustained release formulations or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in samples incorporated into Remington's Pharmaceutical Sciences.

  The definition of “pharmaceutically acceptable” is intended to encompass any carrier that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the host to which it is administered. For example, for parenteral administration, PI3K inhibitors can be formulated in unit dosage forms for injection in vehicles such as saline, dextrose solution, serum albumin and Ringer's solution.

  For parenteral (eg, intravenous, subcutaneous, intramuscular) administration, PI3K inhibitors are pharmaceutically acceptable parenteral vehicles (eg, water, saline, dextrose solution) and additives that retain isotonicity. (E.g., mannitol) or additives that retain chemical stability (e.g., preservatives and buffers) may be formulated as solutions, suspensions, emulsions or lyophilized powders. This formulation is sterilized by commonly used techniques.

  A therapeutically effective amount of a PI3K inhibitor can be a function of many variables, such as the type of inhibitor, the affinity of the inhibitor for JNK, any residual cytotoxicity exhibited by the PI3K inhibitor, the route of administration or the clinical symptoms of the patient. there will be.

  A “therapeutically effective amount” is one in which, when administered, a JNK inhibitor results in inhibition of the biological activity of JNK. The dose administered to an individual as a single or multiple dose depends on various factors such as PI3K inhibitor pharmacokinetic properties, route of administration, patient symptoms and characteristics (sex, age, weight, health status, size), symptoms Will vary depending on the extent of treatment, the combination treatment, the frequency of treatment and the desired effect. Adjustment and manipulation of established dose ranges and in vitro and in vivo methods for measuring inhibition of PI3K in an individual are well within the ability of those skilled in the art.

The PI3K inhibitor can be of formula (I)

  This compound is disclosed in WO 04/007491 (Applied Research Systems ARS Holding NV), in particular, autoimmune and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial infections, viral infections, kidneys It has been described for the treatment of disease, platelet aggregation, cancer, transplant complications, transplant rejection or lung injury.

  In compounds of formula (I) and geometric isomers thereof, their optically active forms, such as enantiomers, and their racemic forms, and their pharmaceutically acceptable salts and pharmaceutically active derivatives.

  The substituents in formula (I) are defined as follows:

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

  The carbocyclic group can be fused with unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl.

  The heterocyclic or carbocyclic group is aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, such as phenyl, phenanthrenyl, 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-oxadiazolyl, 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, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, quinolidinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, 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, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

  Further exemplary heterocyclic groups or carbocyclic groups A include unsubstituted or substituted dioxoles, unsubstituted or substituted dioxins, unsubstituted or substituted dihydrofurans, 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, unsubstituted or substituted oxadiazolyl.

  X is S, O or NH, preferably S.

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

  Z is either 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 - alkylaminocarbonyl, 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 -alkylamino, sulfonyloxy, unsubstituted or a substituted C ₁ -C ₆ - alkyl sulfonyloxy, sulfonyl, unsubstituted or substituted C ₁ -C ₆ - alkyl Sulfonyl, sulfinyl, an unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, sulfanyl, an unsubstituted or substituted C ₁ -C ₆ - alkyl sulfanyl, sulfonylamino, an unsubstituted or substituted C ₁ -C ₆ - alkylsulfonylamino and carbamates Selected from the group consisting of 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 -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 amino carbonyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acyloxyalkyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acylamino, an 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 - alkylamino, unsubstituted or substituted C ₁ -C ₆ - alkyl alkoxy, unsubstituted or substituted C ₁ -C ₆ - alkylsulfanyl , Unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonylamino aryl, unsubstituted or substituted aryl, unsubstituted or a 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, are independently selected from the group consisting of sulfanilic and sulfonyl.

  n is an integer selected from 0, 1 or 2, and preferably n is 0 or 1. Even more preferably, n = 0.

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

In a more specific embodiment of the invention, X is S, Y ¹ and Y ² are both O, R ¹ and R ² are the same as defined above, and n is 0. .

In one embodiment, the PI3K inhibitor is a thiazolidinedione-vinyl fused-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 oxazolyl, 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 Selected from the group consisting of substituted thiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted 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 -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 amino carbonyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acyloxyalkyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acylamino, an 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 - alkylamino, unsubstituted or substituted C ₁ -C ₆ - alkyl alkoxy, unsubstituted or substituted C ₁ -C ₆ - alkylsulfanyl , Unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonylamino aryl, unsubstituted or substituted aryl, unsubstituted or a 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, is selected from the group consisting of sulfanilic and sulfonyl.

並びに、その幾何異性体、エナンチオマー、ジアステレオマーのようなその光学活性型、及びそのラセミ型、並びにその医薬として許容される塩及び医薬として活性な誘導体（ここで、Ｙ¹、Ｚ、Ｒ¹、Ｒ²は上記で定義したものと同じであり、ｎは０又は１である）。 In another embodiment, the PI3K inhibitor is a thiazolidinone-vinyl fused-benzene derivative of formula (II ′). Compounds of formula (II)-(VI) and their synthesis are described in WO 04/007491 (Applied Research Systems ARS Holding NV):

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein Y ¹ , Z, R ¹ , R ² is the same as defined above, and n is 0 or 1.

In a specific embodiment, R ¹ is unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₁ -C ₆ -alkylaryl, 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 - at alkynyl aryl - aryl, unsubstituted or substituted C ₂ -C ₆ is there.

In another preferred embodiment, Y ¹ is O.

並びに、その幾何異性体、エナンチオマー、ジアステレオマーのようなその光学活性型、及びそのラセミ型、並びにその医薬として許容される塩及び医薬として活性な誘導体である。ここで、Ｒ¹及びＲ²は、上記で定義したものと同じである（点線は、二重結合の任意の存在を表す）。 In another embodiment, the PI3K inhibitor is a thiazolidinone-vinyl fused-benzene derivative of formula (III):

And their optically active forms such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof. Here, R ¹ and R ² are the same as defined above (the dotted line represents any presence of a 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 alkoxycarbonyl, while R ² is the same as defined above. It is. In a specific embodiment, R ² is an amino moiety.

In another embodiment, the PI3K inhibitor is a compound of formula (I ′), wherein R ¹ , Y ¹ are the same 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 preferred embodiments, 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 It is.

The compounds of the present invention specifically include those in 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-thiazolidine-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-benzo Oxol-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-thiazolidine-4-one 2-imino-5-quinolin-6-ylmethyle -Thiazolidine-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-dio So-1,3-thiazolidine-5-ylidene) methyl] quinazolin-4-yl} -L-prolinato 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] quinazoline- 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] -pyrrolidine-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-quinazoline-6 -Ylmethylene) -thiazolidine-4-one 2-imino-5- (4-piperidin-quinazolin-6-ylmethylene) -thiazolidine-4-one 2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -Thiazolidine-4-one 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-benzimidazol-5-ylmethylene) -thio Zolidine-2,4-dione 5-{[1- (4-phenylbutyl) -1H-benzimidazol-6-yl] methylene} -1,3-thiazolidine-2,4-dione 5-[(1-prop 2-In-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-benzimidazole- 6-yl} methylene) -1,3-thiazolidine-2,4-dione methyl 4- {6-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1H-benzimidazole -1-yl} cyclohexanecarboxylate 5-({1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3- Thiazolidine-2,4-dione 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-dione 5-({1 -[2- (2-phenoxyphenyl) ethyl] -1H-benzimidazol-6-yl} methylene) -1,3-thiazolidine-2,4-dione 5-{[1- (3,3-diphe Rupropyl) -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-quinoxalin-6-ylmethylene-thiazolidine-2,4-dione 5-quinoxaline-6 Ilmethylene-2-thioxo-thiazolidin-4-one 2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one 5-benzo Azol-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 5- [3- (3-oxo-3- Piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene] -thiazolidine-2,4-dione methyl 1 ((3- {5-[(2,4-Dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl) prolinate methyl 1-((3- {5-[(2,4-Dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl) -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-thiazolidine-2,4-dione methyl 1- (3- {5-[(2,4-Dioxo 1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} prop-2-enoyl) -L-prolinate N-cyclohexyl-3- {5-[(2,4-dioxo-1, 3-thiazolidine-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-hydroxyethyl) acrylamide N-cyclobutyl-3- {5-[(2,4-dioxo-1,3-thiazolidine-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-dihydro-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-ylacrylamide 3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1- Benzofuran-3-yl} -N- (pi Gin-3-ylmethyl) acrylamide N-cyclohexyl-3- {5-[(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] -1-benzofuran-3-yl} acrylamide 5-({ 3- [3- (4-Methylpiperazin-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-thiazolidine-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- ON N-cyclopentyl-3- {5-[(2,4-dioxo-1,3-thiazolidine-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] -thiazolidine-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] -acetic acid methyl ester N-benzyl-2- [6- (2,4-dioxo-thiazolidine-5-i Denmethyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl] -acetamide 5- (4-butyl-3-oxo-3,4-dihydro-2H-benzo [1, 4] Oxazin-6-ylmethylene) -thiazolidine-2,4-dione 5- (4-Benzyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-ylmethylene) -thiazolidine- 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] thiadiazole-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.

  Details of the synthesis of the compounds of formula (I)-(VI) are described in WO 04/007491.

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

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

X is any one of S, O, and —NR ³ , preferably S. R ³ is either H or optionally substituted C ₁ -C ₆ -alkyl.

  Y is either 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 -alkylcarboxy, unsubstituted or substituted C ₁ -C ₆ - alkyl acyloxyalkyl, 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 - alkylaminocarbonyl, acylamino, unsubstituted or substituted C ₁ -C ₆ - alkyl acylamino, ureido, an unsubstituted or substituted C ₁ -C ₆ - alkyl ureido, amino, an unsubstituted or substituted C ₁ -C ₆ - alkylamino, ammonium, sulfonyloxy, an unsubstituted or substituted C ₁ -C ₆ - alkyl sulfonyloxy, sulfonyl, non換又is substituted C ₁ -C ₆ - alkylsulfonyl, sulfinyl, an unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, sulfanyl, an unsubstituted or substituted C ₁ -C ₆ - alkyl sulfanyl, sulfonylamino, an unsubstituted or substituted C Selected from the group consisting of _1- C ₆ -alkylsulfonylamino and carbamate. Preferably 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 -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 amino carbonyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acyloxyalkyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acylamino, an 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 - alkylamino, unsubstituted or substituted C ₁ -C ₆ - alkyl alkoxy, unsubstituted or substituted C ₁ -C ₆ - alkylsulfanyl , Unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonylamino aryl, 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 - alkylheteroaryl, non 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, Selected from the group consisting of acylamino, ureido, sulfonylamino, sulfanyl and sulfonyl. Preferably R ² is H. In a specific embodiment, R ¹ and R ² are both H.

G is substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C ₂ -C ₆ -alkynyl, substituted or unsubstituted heteroaryl, unsubstituted or substituted C ₁ -C ₆ - alkyl aryl, unsubstituted or substituted C ₁ -C ₆ - alkylheteroaryl, unsubstituted or substituted C ₂ -C ₆ - alkenyl - aryl or - heteroaryl, unsubstituted or substituted C ₂ -C ₆ - alkynyl aryl or - heteroaryl, substituted or unsubstituted C ₁ -C ₆ - is selected from the group consisting of acyl and sulfonyl moiety - alkoxy, cyano, a substituted or unsubstituted C ₁ -C _6.

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

In another preferred embodiment, G is a substituted or unsubstituted C ₁ -C ₆ - alkyl, such as propyl and methyl; C ₂ -C ₆ - alkenyl; C ₂ -C ₆ - alkynyl and C ₁ -C ₆ - alkyl Selected from the group consisting of aryl, for example phenylmethyl.

In another preferred embodiment, G is an optionally substituted sulfonyl moiety such as phenylsulfonyl, 4-methylphenylsulfonyl, methylsulfonyl, ethylsulfonyl, 6-chloropyridine-3-sulfonyl, methyl thiophene-2-carboxylate. Ester-3-sulfonyl, 5-chloro-1,3-dimethyl-1H-pyrazole-4sulfonyl, 3-chlorophenylsulfonyl, 2-chlorophenylsulfonyl, quinoline-8-sulfonyl, biphenyl-2-sulfonyl, 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 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, an 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 - alkylaminocarbonyl, unsubstituted or substituted C ₁ -C ₆ - alkyl acyloxyalkyl, 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 alcohol Alkoxy, unsubstituted or substituted C ₁ -C ₆ - alkyl sulfanyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfinyl, unsubstituted or substituted C ₁ -C ₆ - alkylsulfonyl, unsubstituted 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 - alkylheteroaryl, 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 - Selected from the group consisting of 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 are H; and A is selected from the group consisting of a dioxolenyl, pyridinyl or pyrazinyl moiety; Preferred are dioxolenyl and pyridinyl moieties.

  The compounds of formula (VII) can be obtained as E / Z isomer mixtures or essentially pure E-isomers or Z-isomers. The E / Z isomerism preferably represents a vinyl moiety that joins the azolidinone moiety with phenyl. In a specific embodiment, the compound of formula (I) is the 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 [1,3] dioxole- 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.

  Details of the method for synthesizing the compound of formula (VII) are described in WO05 / 011686 (Applied Research Systems, ARS Holding NV).

In another embodiment, the PI3K inhibitor can be a compound of formula (VIII) (WO 04/17950, Piramed):

  The present invention is illustrated by examples, which are not intended to be limiting in any way.

Example 1: Model for Endometriosis The effects of PI3K inhibitors were evaluated in both in vitro and in vivo models of endometriosis. The effectiveness of drug treatment to inhibit endometriosis was tested in two in vivo models, i) nude mouse model and ii) rat model.

Example 1.1: Induction of cell death in endometrial cells It is well documented that glandular tissue and stromal tissue from ectopic orthotopic endometrial transplantation leads to endometriosis. Some of the ectopic transplants are speculated to be due to the decreased cell death (apoptosis) of these transplants and to increased expression of viable cell signaling pathways. Proteins or certain small molecule compounds that induce target-specific cell death of ectopic endometrial cells without affecting the orthotopic endometrium or other normal cells eliminate endometriosis Can be used as a treatment. In this regard, we determined that PI3K inhibitor-1 (5-quinoxalin-6-ylmethylene-thiazolidine-2,4-dione) endometrial cells (12Z cells), immortalized human epithelial endometrial cell death The effect on the ability to induce thrombosis was tested (Zeitvogel et al. 2001). These cells secrete cytokines that respond to TNFα that have been reported to grow in medium and rise in the ascites of endometrial patients. 12Z cells were treated with PI3K inhibitor-1 for 24 hours and cell death was measured by crystal violet staining. Ascites fluid contained elevated concentrations of TNFα, so inhibitors were also tested in the presence of this cytokine. Dead cells were separated from tissue culture plates and washed away while stained with crystal violet. The intensity of the color determines the extent of living cells present in the plate. PI3K inhibitor-1 was tested in these cells and found to reduce the number of living cells, alone or in the presence of TNFα. The EC50 for this inhibitor is shown in Table 1. The degree of cell death induced by this inhibitor was greater in the presence of TNFα. Single TNFα had no cell viability effect (data not shown).

Table 1: PI3K inhibitor-1 concentration required to induce 50% cell death (EC50 (μM)) of human endometrial cells. Cells were incubated with various concentrations of inhibitor-1 alone or in the presence of 15 ng / ml TNFα for 24 hours and cell viability was measured using crystal violet staining.

Example 1.2: Nude mouse model Human endometrial tissue was injected into ovariectomized nude mice to establish disease (Bruner-Tran et al 2002). In general, endometrial biopsies obtained from normal volunteers or endometrial patients were cut into small pieces and cultured in the presence of estradiol for 24 hours. Treated tissues were injected subcutaneously or intraperitoneally into ovariectomized nude mice with estradiol injection. Within 2-4 days of injection, ectopic endometrial lesions developed in the animals. Treatment with either progesterone or PI3K inhibitor-1 was started 10 days after tissue injection. This compound was administered for 28 days at doses of 10 mg / kg and 30 mg / kg / animal. Early implementations using this model established that progesterone treatment prevented disease progression and therefore was used as a control. After completion of the treatment, the animals were sacrificed and lesions developed from the transplanted tissue found in both subcutaneous and intraperitoneal sites were measured (both size and number).

  Table 2 below shows the results of tests performed on nude mice. The 10 mg / kg and 30 mg / kg doses of PI3K inhibitors were effective in reducing established disease by 53% and 80%, respectively, compared to progesterone treatment. The average lesion size was also reduced by 10% and 30%, respectively, with this treatment. These results are striking because this model measures the growth / degeneration of human endometrial tissue and has a direct relevance to the treatment of human disease. Treatment with a PI3K inhibitor did not affect the weight and size of the animal's uterus.

Table 2: Effect of PI3K inhibitor-1 on degeneration of endometrial lesions in a xenograft nude mouse model.

Example 1.3: Rat model Endometriosis was induced in rats as previously described (D'Antonio et al 2000). Briefly, autologous uterine horn fragments were implanted on the inner surface of the rat abdominal wall. Three weeks after transplantation, the size and survival rate of the transplanted tissue was measured. The treatment was started one week after confirmation of tissue binding. The control group received vehicle and received PI3K inhibitor-1 orally (po) at a dose of 30 mg / kg per day. Treatment with this inhibitor was carried out for 9 days, and animals were anesthetized 2 hours after the last treatment and blood samples were collected. The surface area of the endometrial lesion was measured. Endometrial lesions were removed for histology.

  Inhibitor-1 significantly induced regression of established endometrial lesions (64%). Treatment with antide (for comparison) caused 94% regression (data not shown). These results from in vitro and in vivo models suggest an important activity of this molecule directly on endometrial tissue. Another important feature of the rat model is that myometrial and endometrial tissues are surgically excised in laboratory animals.

  A summary of in vitro studies and results from one of these in vivo model systems indicates that kinase inhibitors target the PI3K pathway and are effective agents for the treatment of endometriosis.

Claims (28)

  A method of treating and / or preventing endometriosis in an individual comprising administering a therapeutically effective amount of a PI3K inhibitor.   2. The method of claim 1, wherein the PI3K inhibitor is administered in combination with a hormone inhibitor.   The method according to claim 1 or 2, wherein the hormone inhibitor is selected from the group consisting of a GnRH antagonist, a GnRH agonist, an aromatase inhibitor, a progesterone receptor modulator, and an estrogen receptor modulator.   4. The method according to any one of claims 1 to 3, wherein the PI3K inhibitor is administered alone or in combination with an agent for the treatment of endometriosis-related infertility. A PI3K inhibitor is a compound of formula (I):

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
A is a 5- to 8-membered heterocyclic group or carbocyclic group, wherein the carbocyclic group can be fused with 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 either S or O; and R ¹ is H, CN, carboxy, acyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy, acyloxy, C ₁ -C ₆ -alkylcarboxy, C ₁ -C ₆ - alkyl acyloxyalkyl, C ₁ -C ₆ - alkyl alkoxy, alkoxycarbonyl, C ₁ -C ₆ - alkyl alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ - alkylaminocarbonyl, acylamino, C ₁ -C ₆ - alkyl acylamino, ureido, C ₁ -C ₆ - alkyl ureido, amino, C ₁ -C ₆ - alkylamino, ammonium, sulfonyloxy, C ₁ -C ₆ - alkyl sulfonyloxy, sulfonyl, C ₁ -C ₆ - alkyl sulfonyl, sulfinyl, C ₁ -C ₆ - alkylsulfinyl, sulfanyl, C ₁ -C ₆ - A Kirusurufaniru, sulfonylamino, C ₁ -C ₆ - is selected from the group consisting of alkylsulfonylamino, and carbamates;
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 -alkylcarboxy, C ₁ -C ₆ - alkyl acyl, C ₁ -C ₆ - alkyl alkoxycarbonyl, C ₁ -C ₆ - alkylaminocarbonyl, C ₁ -C ₆ - alkyl acyloxyalkyl, C ₁ -C ₆ - alkyl acylamino, C ₁ -C ₆ - alkyl ureido, C ₁ -C ₆ - alkylamino, C ₁ -C ₆ - alkyl alkoxy, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfinyl, C ₁ -C ₆ - alkylsulfonyl, C ₁ - C ₆ - alkylsulfonylamino, 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, from the group consisting of sulfanyl, and sulfonyl And n is 0, 1 or 2;
The method as described in any one of Claims 1-4. The method of claim 5, wherein Y ¹ and Y ² are both O. The method according to claim 5 or 6, wherein n is 1 or 2, and R ¹ and R ² are both H. X is S, is O Y ¹ and Y ² are both the same as those ^of R ¹ and R ² are as defined above, n is 0, any one of claims 5-7 The method described in 1. A compound of formula (I ′) wherein the PI3K inhibitor is:

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein R ¹ , Y ¹ 5 is the same as defined above, W is selected from O, S, —NR ³ and R ³ is H or an unsubstituted or substituted C ₁ -C ₆ -alkyl group. The method as described in any one of. A compound of formula (II) wherein the PI3K inhibitor is:

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
A is selected from the group consisting of dioxol, dioxin, dihydrofuran, (dihydro) furanyl, (dihydro) oxazinyl, pyridinyl, isoxazolyl, oxazolyl, (dihydro) naphthalenyl, pyrimidinyl, triazolyl, imidazolyl, pyrazinyl, thiazolyl, thiadiazolyl and oxadiazolyl ;
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 -alkylcarboxy, C ₁ -C ₆ - alkyl acyl, C ₁ -C ₆ - alkyl alkoxycarbonyl, C ₁ -C ₆ - alkylaminocarbonyl, C ₁ -C ₆ - alkyl acyloxyalkyl, C ₁ -C ₆ - alkyl acylamino, C ₁ -C ₆ - alkyl ureido, C ₁ -C ₆ - alkyl carbamate, C ₁ -C ₆ - alkylamino, C ₁ -C ₆ - alkyl alkoxy, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfinyl, C ₁ - C ₆ - alkylsulfonyl, C ₁ -C ₆ - alkylsulfonylamino, 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, the group consisting of sulfanyl, and sulfonyl Selected from the
The method as described in any one of Claims 1-4. A PI3K inhibitor is a compound of formula (II ′):

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
Z, Y ¹ , R ¹ , R ² are the same as defined above, and n is 0 or 1.
The method as described in any one of Claims 1-4. The method of claim 11, wherein Y ¹ is O. R ¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylaryl, aryl, C ₃ -C ₈ -cycloalkyl, heterocycloalkyl, C ₁ -C ₆ -alkylaryl, C ₂ -C ₆ - alkenyl aryl and C ₂ -C ₆ - is selected from the group consisting of alkynyl aryl, a method according to claim 11 or claim 12. A PI3K inhibitor is a compound of formula (III):

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
R ¹ and R ² are the same as defined above,
The method as described in any one of Claims 1-4. The PI3K inhibitor is a compound of any of formulas (IV), (V) and (VI):

The method according to any one of claims 1 to 4, wherein   16. The method of claim 15, wherein the PI3K inhibitor is 5-quinoxalin-6-ylmethylene-thiazolidine-2,4-dione. A PI3K inhibitor is a compound of formula (VII):

And optically active forms thereof such as geometric isomers, enantiomers, diastereomers, and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein
A is a 5- to 8-membered heterocyclic group or carbocyclic group, wherein the carbocyclic group can be fused with aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
X is S, O or NR ³ ;
Y is either 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 - alkylaminocarbonyl, acylamino, C ₁ -C ₆ - alkyl acylamino, ureido, C ₁ -C ₆ - alkyl ureido, amino, C ₁ -C ₆ - alkylamino, ammonium, sulfonyloxy, C ₁ -C ₆ - alkyl sulfonyloxy, sulfonyl, C ₁ -C ₆ - alkylsulfonyl, sulfinyl, C ₁ -C ₆ - alkylsulfinyl, sulfanyl, C ₁ -C ₆ - alkyl sulfanyl, sulfonylamino C ₁ -C ₆ - is selected from the group consisting of alkylsulfonylamino, and carbamates;
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 -alkylcarboxy, C ₁ -C ₆ - alkyl acyl, C ₁ -C ₆ - alkyl alkoxycarbonyl, C ₁ -C ₆ - alkylaminocarbonyl, C ₁ -C ₆ - alkyl acyloxyalkyl, C ₁ -C ₆ - alkyl acylamino, C ₁ -C ₆ - alkyl ureido, C ₁ -C ₆ - alkyl carbamate, C ₁ -C ₆ - alkylamino, C ₁ -C ₆ - alkyl alkoxy, C ₁ -C ₆ - alkyl sulfanyl, C ₁ -C ₆ - alkylsulfinyl, C ₁ - C ₆ - alkylsulfonyl, C ₁ -C ₆ - alkylsulfonylamino, 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, Selected from the group consisting of C ₁ -C ₆ -alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl and sulfonyl;
G is, C ₁ -C ₆ - consisting of alkyl aryl, cyano and sulfonyl moiety - alkoxy, C ₁ -C ₆ - alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₁ -C ₆ Selected from the group; and R ³ is either H or C ₁ -C ₆ -alkyl.
The method as described in any one of Claims 1-4.   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, pyridinyl, pyrazinyl, 4-methyl-2H and 3H-benzo- The method of claim 17, wherein the method is selected from the group consisting of 1,4-oxazinyl.   19. A method according to claim 17 or 18, wherein A is either a dioxolenyl or pyridinyl moiety. The method according to any one of claims 17 to 19, wherein R ¹ and / or R ² is H. G is, C ₁ -C ₆ - alkoxy, it is selected from the group consisting of cyano or sulfonyl moiety, A method according to any one of claims 17 to 20. G is a sulfonyl moiety of formula —SO ₂ —R ⁴ , where 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 - alkylaminocarbonyl, C ₁ -C ₆ - alkyl acyloxyalkyl, C ₁ -C ₆ - alkyl acylamino, C ₁ -C ₆ - alkyl ureido, C ₁ -C ₆ - alkyl carbamate, C ₁ -C ₆ - alkylamino, C ₁ -C ₆ - alkyl alkoxy, C ₁ -C ₆ - alkyl sulfanyl , C ₁ -C ₆ - alkylsulfinyl, C ₁ -C ₆ - alkylsulfonyl, C ₁ -C ₆ - alkylsulfonylamino, aryl, heteroaryl, C ₃ -C ₈ - cycloalkyl addition Alkylaryl, C ₁ -C ₆ - - alkylheteroaryl, C ₂ -C ₆ - heterocycloalkyl, C ₁ -C ₆ alkenyl - aryl or - heteroaryl, C ₂ -C ₆ - alkynyl aryl or - heteroaryl , carboxy, hydroxyl, C ₁ -C ₆ - alkoxy, is selected from the group consisting of acylamino and sulfonylamino a method according to any one of claims 17 to 21. R ⁴ is aryl, selected from the group consisting of heteroaryl and C ₁ -C ₆ alkyl, The method of claim 22. X is S, Y is O, R ¹ and R ² is H, A is either benzodioxol-enyl or pyridinyl moiety according to any one of claims 17 to 23 Method.   A pharmaceutical composition comprising a PI3K inhibitor, a hormone inhibitor, and a pharmaceutically acceptable excipient.   26. The pharmaceutical composition according to claim 25, wherein the hormone inhibitor is selected from the group consisting of GnRH antagonists, GnRH agonists, aromatase inhibitors, progesterone receptor modulators and estrogen receptor modulators.   27. A pharmaceutical composition according to claim 25 or 26, wherein the PI3K inhibitor is a compound as defined by any one of claims 5-24.   28. The pharmaceutical composition according to any one of claims 25 to 27, wherein the PI3K inhibitor is 5-quinoxalin-6-ylmethylene-thiazolidine-2,4-dione.