Compounds for treatment of cancer

Abstract

The present invention relates to quinazoline carboxamide azetidine compounds, and to pharmaceutical combinations and compositions comprising such compounds, preferably with at least one different therapeutic agent, preferably an anti-cancer agent, and to the use thereof for the treatment of diseases, preferably cancer, even more preferably estrogen receptor positive (ER +) cancer, in particular for the treatment of estrogen receptor positive (ER +) cancer. In particular in subjects resistant to endocrine therapy.

Description

[0001] The present invention relates to the field of oncology. More specifically, to quinazolinecarboxamide azetidine compounds, and to pharmaceutical combinations and compositions comprising such compounds (preferably together with at least one different therapeutic agent, preferably an anticancer agent), and to their use in the treatment of diseases, preferably cancer, and even more preferably estrogen receptor positive (ER positive) + ) cancer, particularly in subjects resistant to hormone therapy, even more preferably in subjects with breast cancer resistant to hormone therapy. Background Art

[0002] Breast cancer is the most prevalent cancer worldwide, with 2.3 million new diagnoses and 685,000 deaths worldwide in 2020. Hormone receptor-positive (HR+) breast cancer is the most common subtype of breast cancer, accounting for approximately 70% of the global breast cancer population.

[0003] Approximately 80% of HR+ breast cancers in women are estrogen receptor positive ("ER+" or "ER-positive") and / or progesterone receptor positive ("PR+" or "PgR-positive"). Likewise, 90% of breast cancers in men are ER-positive.

[0004] Approximately 81% of breast cancers are invasive or infiltrating (i.e., metastatic). In other words, the abnormal cells have broken through the wall of the gland or duct from which they originated and have grown into the surrounding tissue. Although breast cancer has historically been referred to as a single disease, it is now considered a group of diseases consisting of four major molecular subtypes and at least 21 different histological subtypes (the type of tissue from which the cancer originates) that differ in risk factors, presentation, response to treatment, and outcome. For example, approximately 5% to 10% of breast cancer patients will present with metastatic disease at the time of diagnosis, and the incidence of breast cancer brain metastases (“BCBMs”) in estrogen receptor-positive breast cancer is 14%, with a median overall survival of 9–10 months following the appearance of brain metastases (Brosnan et al., 2018).

[0005] The importance and role of the estrogen receptor (ER) pathway in the development and progression of breast cancer are well recognized. The standard of care (SOC) treatment of choice for estrogen receptor-positive breast cancer is endocrine therapy (also known as “hormone therapy”, “hormonal The term "hormone therapy" refers to "selective estrogen receptor modulators ("SERMs"), such as tamoxifen and "tamoxifen-like" compounds, such as 4-hydroxytamoxifen, endoxifen, toremifene, droloxifene, idoxifene, raloxifene, arzoxifene, bazedoxifene, pipindoxifene, or lasofoxifene; aromatase inhibitors ("AIs"), such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, vorozole, or AZD9496; selective estrogen receptor degraders or downregulators ("SERDs"), such as amcenestrant, azenosertib (ZN-c5), borestrant, brilanestrant, camizestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927 or SHR9549; complete estrogen receptor antagonists (CERAN) such as OP-1250; and luteinizing hormone-releasing hormone (LHRH) and / or gonadotropin-releasing hormone (GnRH) agonists such as buserelin, cetrorelix, degarelix, gonadorelin, goserelin, leuprorelin, triptorelin and triptorelix.

[0006] Unfortunately, resistance develops in 30-50% of patients treated with endocrine therapy due to complex and sometimes redundant interferences at the molecular level between growth factors, ERs, and downstream cell signaling pathways. Several mechanisms of resistance to endocrine therapy have been described (Patel et al., 2018), such as alterations in the ER and / or ER pathways, activation of the PI3K / Akt / mTOR (“PAM”) pathway, activation of growth factor receptor pathways [involving epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin growth factor receptor (IGFR), and / or vascular endothelial growth factor receptor (VEGFR)], cell cycle alterations, alterations in the ubiquitin proteasome pathway, or increased activity of bromodomains and / or super-terminal domains of proteins. These multiple mechanisms of resistance to endocrine therapy make strategies for treating refractory disease challenging and dependent on the patient's condition.

[0007] For example, dysregulated activation of the PI3K / Akt / mTOR pathway, which plays a key role in proliferation and survival under normal conditions, is an adaptive mechanism of therapy resistance in ER+ breast cancer and can be associated with a poor outcome in patients treated with endocrine therapy. Indeed, downstream effectors of PI3K, Akt, and mTOR can phosphorylate and activate ER in the absence of estrogen, conferring resistance to endocrine therapy. Moreover, several studies have demonstrated an inverse relationship between PI3K activation and ER expression. Indeed, gain-of-function mutations in PI3K occur in more than 30% of ER+ breast cancers, underscoring the role of this pathway in this setting. These findings have led to combination strategies including the administration of endocrine / hormonal agents, more preferably SERDs (e.g., fulvestrant) or AIs (e.g., exemestane), and PI3K / Akt / mTOR pathway inhibitors, such as buparlisib (BKM120), pilaralisib (XL147, SAR245408), pictilisib (GDC-0941), sonolisib (PX-866), dactolisib (BEZ235), sapanisertib (INK128, MLN012 8), voxtalisib (XL765, SAR245409), serabelisib (MLN1117), apellisib (BYL719), perifosine (KRX-0401), MK2206, ipatasertib (GDC0068), GSK690693, temsirolimus (CCI-779), deforolimus (MK8669; deforolimus), sirolimus (rapamycin), everolimus (RAD001), AZD-8055 or OSI-027 (ASP7486).

[0008] Another example is the alteration of the cell cycle. During the quiescent state, the tumor suppressor retinoblastoma (Rb) protein remains hypophosphorylated and binds to the transcription factor E2F, preventing E2F from promoting the transcription of genes involved in the G1-S phase of the cell cycle. Under growth factor stimulation, Rb is phosphorylated by cyclin-dependent kinases 4 and 6 (CDK4 / 6) complexed with cyclin D, resulting in the release of E2F and progression through the cell cycle. There are several lines of evidence linking these cell cycle regulators to the ER pathway, including the observation that CDK4 / 6 is often overactivated. These findings have led to a combination strategy including endocrine agents, more preferably SERDs such as fulvestrant, and CDK4 / 6 (CDK4 / 6i) inhibitors, such as palbociclib (PD0332991), ribociclib (LEE011) or abemaciclib (LY2835219).

[0009] A further example is that activation of growth factor receptor pathways, such as by overexpression or amplification of human epidermal growth factor receptor-2 (Her2), which is a member of the epidermal growth factor receptor (EGFR) family, can confer resistance to endocrine agents. The addition of dual EGFR / Her2 targeted agents (e.g., lapatinib (GW572016)) to SERDs (e.g., fulvestrant) has been evaluated in patients with ER+ advanced breast cancer, but a statistically relevant clinical treatment effect has not been observed in ER+ / HER2+ patients (Burstein et al., 2014).

[0010] Tumor responses were enhanced with adjuvant therapy including an mTORCl inhibitor (everolimus), a CDK4 / 6 inhibitor (palbociclib / ribociclib / abesiclib), and an alpha isoform-specific PI3K inhibitor (apellisib).

[0011] However, approximately 25% of patients with ER+ breast cancer who have primary disease and nearly all patients who have metastatic disease will develop or eventually become endocrine resistant.

[0012] Several studies have demonstrated that ER and more particularly functional estrogen receptor 1 ("ESR1") are key drivers of endocrine resistance during ER+ breast cancer progression. For example, ER expression is positively correlated with tamoxifen results, and changes in ER and ER pathways have been described as leading to treatment resistance to SERMs such as tamoxifen or SERDs such as fulvestrant. In addition, ER loss via epigenetic silencing via DNA methylation or histone deacetylation has been described as a mechanism of resistance to these two compounds (Fan et al., 2006; Parl, 2003; Yang, Phillips, Ferguson et al., 2001). In particular, ER loss has been described as being highly correlated with de novo resistance and acquired resistance to tamoxifen, emphasizing the importance of early target engagement and inhibition in this case. Some clinical trials are investigating the combination of endocrine therapy with epigenetic modifiers, such as mutations in the ligand binding domain (LBD) of the ERa protein (estrogen receptor α) encoded by the estrogen receptor 1 gene (identified herein as ESR1). These mutations in the gene encoding ERa alter the conformation of the ERa protein, increasing its interaction with its co-activators, promoting a constitutively active form of the receptor in the absence of hormones and helping tumor cells evade hormone therapy.

[0013] In general, there were no detectable ESR1 mutations in patients with treatment-naive disease, and there was a correlation between the frequency of patients with tumors harboring these mutations and the number of endocrine therapy sessions received, suggesting that under selective treatment pressure, clonal expansion of rare mutant clones occurs, leading to resistance.

[0014] Fifty-five next-generation endocrine agents are in clinical development for the treatment of ER+ breast cancer (Maxwell R. Lloyd et al., 2022), such as CERAN agents, which are tetrahydro-1H-pyrido[3,4-b]indole compounds, as described in WO2017059139. However, several other candidate compounds that showed preclinical anti-tumor activity were also stopped at various stages of clinical trials, such as brinostran (GDC0810), an oral SERD described in US20150258080 and US2015258099, which was removed from development after Phase II clinical trials and failed to show efficacy comparable to or better than fulvestrant.

[0015] There is a need to develop novel, principle-based treatment strategies for patients who develop resistance to endocrine therapy to make them responders to endocrine therapy again.

[0016] The novel quinazolinecarboxamide azetidine compound 4-[(S)-2-azetidine-l-yl-l-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) was previously described in WO201269146 as an effective, orally bioavailable, selective inhibitor of p70S6K, AKT1, and AKT3, which affects tumor growth in mouse cancer models and crosses the blood-brain barrier (Machl et al., 2016). M2698 treatment is well tolerated in patients with ER+ and HER2+ breast cancer as a monotherapy and in combination with trastuzumab or tamoxifen, respectively. Overall, the efficacy of M2698 monotherapy in this patient population is moderate (Tsimberidou et al., 2021).

[0017] The inventors now reveal for the first time that administration of quinazolinecarboxamide azetidine compounds, preferably 4-[(S)-2-azetidin-l-yl-l-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, can resensitize ER+ cancerous tumors that have been identified as resistant to endocrine therapy to cancer treatment (including endocrine therapy), thereby significantly improving treatment outcomes. Summary of the invention

[0018] Endocrine therapy (also known as "hormone therapy," "hormonal therapy," or "hormonal treatment") has successfully improved patients' progression-free survival ("PFS") and overall survival ("OS") . However, the emergence of resistance to endocrine and / or ER therapy remains an obstacle for ER+ cancers, especially breast cancer. Intrinsic resistance to endocrine therapy explains that only 30% of patients with metastatic disease see initial tumor regression with endocrine therapy, while almost all patients eventually develop resistance and tumors often recur. In addition, more than 20% of patients with early breast cancer develop endocrine resistance throughout the course of treatment. Resistance to endocrine therapy has been associated with mutations in the estrogen receptor 1 (ESR1) gene, alterations in receptor tyrosine kinases (e.g., HER2), and alterations in signaling pathways (e.g., MAPK pathways).

[0019] Therefore, there is a need to develop new therapeutic strategies that are effective in treating, in particular, estrogen receptor-positive (ER+) tumors, particularly tumors that are resistant to endocrine therapy, preferably tumors carrying mutations in the estrogen receptor 1 (ESR1) gene encoding the estrogen receptor alpha (ERα, ERa or ESR1) protein, in patients, and in particular breast cancer patients, who have developed resistance to endocrine therapy or are at risk of developing endocrine resistance (Sung Qwe Ahn et al., 2022).

[0020] The present invention now provides such a new and advantageous therapeutic strategy.

[0021] The inventors describe quinazolinecarboxamide azetidine compounds in more detail herein, and relate to a combination of at least two compounds, particularly a combination consisting of at least two compounds, wherein one compound is a quinazolinecarboxamide azetidine compound, or a composition, particularly a pharmaceutical composition, comprising a quinazolinecarboxamide azetidine compound and a pharmaceutically acceptable carrier. In addition to the quinazolinecarboxamide azetidine compound, the combination or composition preferably further comprises different therapeutic agents, preferably anticancer agents, more preferably antitumor agents and / or signal transduction inhibitors. The inventors also describe the combination or composition as a drug, preferably for treating hormone-dependent diseases in subjects in need, and even more preferably for treating cancer, particularly for treating estrogen receptor positive (ER+) cancer.

[0022] The quinazolinecarboxamide azetidine compound is advantageously a quinazolinecarboxamide azetidine compound of formula (I):

[0023]

[0024] and / or its pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer, including mixtures thereof in all ratios, wherein:

[0025] R 1 is H or LA;

[0026] R 2 is Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH2 or A;

[0027] R 3 '、R 3 ” is independently H, LA or Hal;

[0028] Ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2, 3 or 4 N, O and / or S atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONH(Art), CONA2, NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH2, NHSO2A, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, and wherein the ring N atoms may be substituted by O atoms to form N oxide groups, and wherein in the case of a bicyclic aromatic ring, one of the two rings may be partially saturated;

[0029] Ar1 is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2 or 3 N, O and / or S atoms and 5 or 6 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), CHO, CO(LA), SO2NH2, SO2(LA) and / or SO2Hal;

[0030] A is an unbranched or branched, straight-chain or cyclic alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and / or -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, and in which 1 to 3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN;

[0031] LA is an unbranched or branched linear alkyl group having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; and

[0032] Hal is F, Cl or Br, preferably F or Cl, most preferably F;

[0033] or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, or any mixtures thereof in all ratios.

[0034] The quinazolinecarboxamide azetidine compound is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (also referred to herein as "M2698") or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all ratios.

[0035] The anti-tumor agent is preferably a hormone therapy agent or a chemotherapeutic agent.

[0036] The chemotherapeutic agent can be selected from, for example, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, taxanes, topoisomerase inhibitors, and vinca alkaloids.

[0037] The anti-tumor agent is preferably a hormone therapy agent (also referred to herein as "hormonal therapy agent" or "endocrine therapy agent"), and even more preferably an anti-estrogen agent. For example, it is selected from selective ER down-regulator degraders (SERDs), selective ER modulators (SERMs), aromatase inhibitors (AIs), complete estrogen receptor antagonists (CERANs), luteinizing hormone-releasing hormone (LHRH), gonadotropin-releasing hormone (GnRH) agonists, and any mixtures thereof.

[0038] In certain embodiments, the therapeutic agent or signal transduction inhibitor is not a HER2 inhibitor, a HER3 inhibitor, or a HER3 Nanobody.

[0039] In certain aspects, the HER2 inhibitor is not lapatinib or trastuzumab.

[0040] In certain aspects, the HER3 inhibitor is not MM-121 [i.e., a fully humanized anti-Her3 antibody that specifically blocks the binding of HRG1- (neuregulin-1 type I polypeptide) to Her3], MM-11 [a bispecific antibody that binds to two different target proteins: ErbB2 and ErbB3], or U3-1287 (also known as AMG888, the first fully humanized Her3 monoclonal antibody).

[0041] In a specific embodiment, the combination or composition of the present invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all ratios, (b) a different therapeutic agent, and optionally (c) an anticancer agent, provided that if one of compounds (b) or (c) is a HER2 inhibitor, then the HER2 inhibitor is not lapatinib or trastuzumab.

[0042] In a specific embodiment, the combination or composition of the present invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all ratios, (b) a different therapeutic agent, and optionally (c) an anticancer agent, provided that if one of compounds (b) or (c) is a HER3 inhibitor, the HER3 inhibitor is not MM-121, MM-11 or U3-1287.

[0043] The signal transduction inhibitor is preferably a cyclin-dependent protein kinase (CDK) inhibitor, for example selected from CDK 1, 2, 4, 5, 6 and / or 7 inhibitors and any mixture thereof, more preferably a CDK4 / 6 inhibitor.

[0044] Treatment may involve the administration of an additional anti-cancer agent, which is for example selected from anti-angiogenesis agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or (functional) fragments thereof (including single chain antibodies), antibody-drug conjugates, small molecules, growth factor receptor agents, antisense molecules and any mixtures thereof.

[0045] In a particular embodiment, the combination or composition of the present invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all proportions, and at least one anticancer agent, provided that the anticancer agent is not a MEK inhibitor, in particular a MEK inhibitor selected from trametinib, cobimetinib, selumetinib, refametinib and pimasertib. Preferably, the MEK inhibitor is not pimasertib.

[0046] In another specific embodiment, the combination or composition of the present invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all proportions, and at least one anticancer agent, provided that the anticancer agent is not an EGFR inhibitor, in particular an EGFR inhibitor selected from gefitinib, erlotinib, afatinib, brigatinib, icotinib, osimertinib and cetuximab. Preferably, the EGFR inhibitor is not cetuximab.

[0047] In a further specific embodiment, the combination or composition of the present invention comprises: (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all ratios (b) a different therapeutic agent, and optionally (c) an anticancer agent, provided that if the different therapeutic agent (b) or anticancer agent (c) ) is a MEK inhibitor, such as trametinib, cobimetinib, selumetinib, rifatinib or pimasertib, in particular pimasertib, then the other (b) or (c) compound is not an EGFR inhibitor, such as gefitinib, erlotinib, afatinib, brigatinib, icotinib, osimertinib or cetuximab, in particular cetuximab, or if the different therapeutic agent (b) or the anticancer agent (c) is an EGFR inhibitor, such as cetuximab, then the other (b) or (c) compound is not a MEK inhibitor, such as pimasertib.

[0048] In a particular embodiment, the combination or composition of the invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer or any mixture thereof in all ratios, and (b) a different therapeutic agent selected from an anti-tumor agent and a signal transduction agent, and optionally (c) another different anti-cancer agent.

[0049] In a more specific embodiment, the combination or composition of the present invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all ratios, (b) a different therapeutic agent selected from an antineoplastic agent, a hormonal therapeutic agent (e.g. selected from SERDs, SERMs, AIs, CERANs, LHRH and GnRH agonists), preferably a SERD, such as amcenestrant, azenosertib (ZN-c5), borestrant, brinstrant, camizestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant AZD9496, D-0502, LY3484356, GDC-0927 or SHR9549, and optionally (c) another different anticancer agent.

[0050] In particular aspects, the inventors describe herein (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, including any mixtures thereof in all ratios; and (b) a selective ER downregulator degrader (SERD), preferably elastomeric or a combination of pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, and compositions comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0051] Also described herein are methods of treating a hormone-dependent disease in a subject, wherein the method comprises administering to the subject (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a selective ER downregulator degrader (SERD), preferably elastomeric or a combination of pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, thereby treating the subject.

[0052] Further described herein are kits comprising, in separate containers, (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a selective ER downregulator degrader (SERD), preferably elastomeric or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, and materials for administering M2698 and / or the SERD or for administering the composition.

[0053] In a more specific embodiment, the combination or composition of the present invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all ratios, and (b) a different therapeutic agent selected from signal transduction inhibitors, preferably cyclin-dependent kinase (CDK) inhibitors, such as CDK4 / 6 inhibitors, such as abemaciclib, palbocilcib and ribociclib, and optionally (c) a further different anticancer agent.

[0054] In another specific aspect, the inventors describe herein a combination of (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, including any mixtures thereof in all ratios, and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, preferably abemaciclib or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0055] Also described herein is a method for treating a hormone-dependent disease in a subject, wherein the method comprises administering to the subject (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, preferably abemaciclib or a combination of pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, thereby treating the subject.

[0056] Further described herein is a kit comprising, in separate containers, (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, preferably abemaciclib or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, as well as materials for administering M2698 and / or a CDK4 / 6 inhibitor or for administering the composition.

[0057] The diseases targeted in the context of the present invention are preferably hormone-dependent diseases, whether malignant or non-malignant. Hormone-dependent diseases are preferably pre-malignant ( / precancerous) diseases or malignant diseases, i.e. cancer. They are usually hormone receptor positive (HR +) cancer, for example, selected from brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer (e.g., type I endometrial cancer), uterine cancer, bladder cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, and any other known HR + Cancer of cancer.

[0058] In a preferred aspect, hormone receptor positive (HR + ) cancer is estrogen receptor positive (ER + )cancer.

[0059] The estrogen receptor positive (ER+) cancer is preferably selected from breast cancer, in particular metastatic breast cancer, typically metastatic breast cancer that is resistant and / or refractory to standard of care treatment, ovarian cancer and type I endometrial cancer.

[0060] A subject in need thereof is preferably a subject who has been treated with a drug used in endocrine (hormonal / hormone) therapy and may still be treated with a drug used in endocrine (hormonal / hormone) therapy, such as a selective ER modulator (SERM), a selective ER downregulator degrader (SERD), an aromatase inhibitor (AI) inhibitor, a CERAN inhibitor, a hormone, a luteinizing hormone releasing hormone (LHRH) agonist, a gonadotropin releasing hormone (GnRH) agonist, a progestin, an anti-androgen, a CYP17 inhibitor, an anti-adrenergic agent; a cyclin-dependent kinase (CDK) inhibitor; a PI3K / AKT / mTOR ("PAM") pathway inhibitor; or any combination thereof, in particular a combination of a CDK inhibitor and a hormonal therapeutic agent, or a combination of a CDK inhibitor, a hormonal therapeutic agent and a PI3K / AKT / mTOR ("PAM") pathway inhibitor. The drugs used in endocrine therapy can be selected from selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and complete estrogen receptor antagonists (CERANs).

[0061] In a preferred embodiment, ER+ breast cancer is characterized by a mutated estrogen receptor 1 (ESR1) cancerous tumor, wherein the mutation (including, for example, an addition, deletion, substitution, or frameshift mutation) occurs in the ligand binding domain ("LBD") of the ERa sequence of SEQ ID NO: 1. In a particular aspect, the LBD mutant form of ER favors the agonist conformation of the receptor, thereby mediating constitutive transcription leading to clinical resistance. Preferred ERa mutants include at least one of the following mutations: E380Q, V392I, F404fs, V422del, S463P L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, D538G, even more preferably Y537S and / or D538G mutations.

[0062] In a specific embodiment, the quinazolinecarboxamide azetidine compound according to the present invention or a composition comprising a quinazolinecarboxamide azetidine compound is used for anti-cancer treatment, which anti-cancer treatment further involves (co-)administering to the subject a drug selected from a selective ER modulator (SERM), a selective ER downregulator (SERD), an aromatase inhibitor (AI), a complete estrogen receptor antagonist (CERAN), an inhibitor of the cell cycle, a PI3K / Akt / mTOR ("PAM") pathway inhibitor and / or a growth factor receptor inhibitor.

[0063] In a further preferred embodiment, the quinazolinecarboxamide azetidine compound according to the present invention or a composition comprising a quinazolinecarboxamide azetidine compound is used for anti-cancer treatment, which anti-cancer treatment further involves (co-)administering to the subject a drug selected from anti-tumor agents (e.g., selective ER modulators (SERMs), selective ER downregulators (SERDs), aromatase inhibitors (AIs) and / or complete estrogen receptor antagonists (CERANs)), signal transduction inhibitors such as CDK inhibitors and PI3K / Akt / mTOR ("PAM") pathway inhibitors. DETAILED DESCRIPTION OF THE INVENTION

[0065] The present invention provides novel therapeutic compounds, combinations of compounds and pharmaceutical compositions comprising such compounds, and their use in human medicine, preferably in oncology.

[0066] Specifically, the inventors describe herein a combination of (a) a quinazolinecarboxamide azetidine compound and (b) a different therapeutic agent preferably selected from the following anticancer agents: an anti-angiogenic agent, a signal transduction inhibitor, an anti-tumor agent, a therapeutic antibody or a (functional) fragment thereof (including, for example, a single-chain antibody), an antibody-drug conjugate, a small molecule, a growth factor receptor agent, an antisense molecule, and any combination thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0067] The present application also describes quinazolinecarboxamide azetidine compounds, more specifically compounds of formula (I):

[0068]

[0069] alone or in the form of any mixture with a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof (or any mixture thereof in all ratios), wherein:

[0070] R 1 is H or LA;

[0071] R 2 is Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH2 or A;

[0072] R 3’ , R 3” are independently H, LA or Hal;

[0073] Ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2, 3 or 4 N, O and / or S atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONH(Art), CONA2, NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH2, NHSO2A, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, wherein the ring N atoms may be substituted by O atoms to form N-oxide groups and wherein, in the case of a bicyclic aromatic ring, one of the two rings may be partially saturated;

[0074] Ar1 is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2 or 3 N, O and / or S atoms and 5 or 6 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), CHO, CO(LA), SO2NH2, SO2(LA) and / or SO2Hal;

[0075] A is an unbranched or branched, straight-chain or cyclic alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and / or -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, and in which 1 to 3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN;

[0076] LA is an unbranched or branched linear alkyl group having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; and

[0077] Hal is F, Cl or Br, preferably F or Cl, most preferably F.

[0078] The inventors also describe a combination involving at least two compounds, in particular a combination consisting of at least two compounds, one of which is a quinazolinecarboxamide azetidine compound, or a composition, in particular a pharmaceutical composition comprising a quinazolinecarboxamide azetidine compound and a pharmaceutically acceptable carrier.

[0079] The preferred combination is the following combination: (a) quinazolinecarboxamide azetidine compound of formula (I):

[0080]

[0081] and / or any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, wherein:

[0082] R 1 is H or LA;

[0083] R2 is Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH2 or A;

[0084] R 3’ , R 3” are independently H, LA or Hal;

[0085] Ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2, 3 or 4 N, O and / or S atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONH(Art), CONA2, NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH2, NHSO2A, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, and wherein the ring N atoms may be substituted by O atoms to form N oxide groups, and wherein in the case of a bicyclic aromatic ring, one of the two rings may be partially saturated;

[0086] Ar1 is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2 or 3 N, O and / or S atoms and 5 or 6 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), CHO, CO(LA), SO2NH2, SO2(LA) and / or SO2Hal;

[0087] A is an unbranched or branched, straight-chain or cyclic alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and / or -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, and in which 1 to 3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN;

[0088] LA is an unbranched or branched linear alkyl group having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; and

[0089] Hal is F, Cl or Br, preferably F or Cl, most preferably F, and

[0090] (b) anticancer agents, preferably antitumor agents and / or signal transduction inhibitors.

[0091] Preferred compositions comprise a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0092] The inventors also describe a combination or composition as described herein for use as a medicament.

[0093] In a preferred aspect, the combined quinazolinecarboxamide azetidine compounds of (a) and (b) and a different therapeutic agent, preferably an anticancer agent, even more preferably an antitumor agent and / or a signal transduction inhibitor, are formulated for simultaneous, concurrent or sequential administration, preferably oral administration.

[0094] Preferably, the combination or composition is for use in preventing or treating a hormone-dependent disease, preferably cancer, in a subject in need thereof, and even more preferably for preventing or treating estrogen receptor-positive (ER-positive) + ) cancer, in particular breast cancer, or any mixture thereof in all proportions.

[0095] In a preferred aspect, in addition to the administration of the quinazolinecarboxamide azetidine compound, the treatment further comprises a step involving the administration of an anticancer agent, preferably an antitumor agent and / or a signal transduction inhibitor, even more preferably an endocrine therapeutic agent, for example selected from the group consisting of selective ER modulators ("SERMs"), selective ER downregulators / degraders ("SERDs"), aromatase inhibitors ("AIs"), complete estrogen receptor antagonists (CERANs), inhibitors of the cell cycle, inhibitors of the PI3K / Akt / mTOR ("PAM") pathway, and / or inhibitors of growth factor receptors; more preferably selected from the group consisting of SERDs, selective ER modulators ("SERMs"), aromatase inhibitors ("AIs"), complete estrogen receptor antagonists (CERANs), inhibitors of the cell cycle, inhibitors of the PI3K / Akt / mTOR ("PAM") pathway, and / or inhibitors of growth factor receptors; (CDK) inhibitors and any combination thereof; most preferably selected from selective ER modulators ("SERMs"), selective ER downregulators / degraders ("SERDs"), aromatase inhibitors ("AIs"), complete estrogen receptor antagonists (CERANs) and cyclin-dependent kinase (CDK) inhibitors, PI3K / Akt / mTOR ("PAM") pathway inhibitors and any combination thereof; the quinazolinecarboxamide azetidine compound is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or any mixture thereof in all proportions.

[0096] In another specific aspect, the composition comprises (c) another agent, preferably an anticancer agent. This other agent is preferably selected from anti-angiogenic agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates and / or antisense molecules (except quinazoline carboxamide azetidine compounds, anti-tumor agents and / or signal transduction inhibitors). The other agent (c) is preferably selected from anti-angiogenic agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents and / or antisense molecules (except quinazoline carboxamide azetidine compounds, anti-tumor agents and / or signal transduction inhibitors).

[0097] Also described herein is a corresponding method of treatment, which includes administering to a subject in need thereof a quinazolinecarboxamide azetidine compound or a combination or (drug) composition comprising a quinazolinecarboxamide azetidine compound and a pharmaceutically acceptable carrier, preferably (a) a quinazolinecarboxamide azetidine compound and (b) a different therapeutic agent, preferably an anticancer agent, even more preferably an antitumor agent and / or a signal transduction inhibitor, and possible (c) another different therapeutic agent, preferably another anticancer agent, as further described below. Another different therapeutic agent, preferably an anticancer agent (c) can be, for example, selected from anti-angiogenic agents, signal transduction inhibitors, antitumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates and / or antisense molecules. In a particular aspect, another different therapeutic agent, preferably an anticancer agent (c), can be selected from, for example, anti-angiogenic agents, signal transduction inhibitors, antitumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents and / or antisense molecules.

[0098] Combination of M2698 and SERD:

[0099] In a more preferred aspect, the treatment comprises a step involving administration of an anticancer agent, preferably a selective ER downregulator / degrader ("SERD"), preferably selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, camizestrant, elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, in addition to the quinazolinecarboxamide azetidine compound. AZD9496, D-0502, LY3484356, GDC-0927 and SHR9549, more preferably elastomeric, the quinazolinecarboxamide azetidine compound is preferably 4-[(S)-2-azetidin-l-yl-l-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer, or any mixture thereof in all proportions.

[0100] In a particular aspect, the inventors describe herein a combination of (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a selective ER downregulator degrader (SERD), preferably, the SERD is selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, ca mizestrant (AZD9833), elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing, including any mixtures thereof in all ratios, even more preferably elastrant, and a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0101] In a specific aspect, M2698 and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof is present in the combination or composition at a dosage of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg.

[0102] In another specific aspect, M2698 and / or its pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer is present in the combination or composition at a dose of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg, and elastostat is present in the combination or composition at a dose of about 150 mg or 200 mg to about 500 mg, e.g. 172 mg, 258 mg or 345 mg, preferably about 300 mg to about 400 mg, more preferably about 340 mg or 350 mg.

[0103] In another specific aspect, M2698 and the SERD are formulated for simultaneous, concurrent or sequential administration, preferably for oral administration.

[0104] In another specific aspect, the combination or composition further comprises (c) one or several different therapeutic compounds, in particular an anti-cancer agent selected from anti-angiogenesis agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents, antisense molecules, and any combination thereof.

[0105] Also described herein is a method of treating a hormone-dependent disease, preferably cancer, in a subject, wherein the method comprises administering to the subject a combination of (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a selective ER downregulator degrader (SERD), preferably elastomeric, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, thereby treating the subject.

[0106] If the hormone-dependent disease is cancer, the cancer may be selected from brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, uterine cancer, bladder cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer. The cancer is preferably breast cancer, for example selected from primary cancer, advanced or metastatic cancer, human epidermal growth factor receptor 2 positive (HER2+) cancer, human epidermal growth factor receptor 2 negative (HER2-) cancer, human epidermal growth factor receptor 2 low (HER2 low) cancer and cancer characterized by wild-type estrogen receptor alpha (ERα, ERa or ESR1) cancerous tumors. In a specific aspect, breast cancer is a cancer characterized by mutated estrogen receptor alpha (ERα, ERa or ESR1) cancerous tumors.

[0107] The method of treating a hormone-dependent disease in a subject may comprise administering a combination or composition of the invention in combination with (c) one or more different therapeutic compounds as described herein. If the hormone-dependent disease is cancer, the one or more different therapeutic compounds may be an anticancer agent, for example selected from anti-angiogenic agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents, antisense molecules, and any combination thereof.

[0108] Further described herein are kits comprising (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a selective ER downregulator degrader (SERD), preferably elastomeric, in separate containers, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, and materials for administering M2698 and / or the SERD or for administering the composition.

[0109] Combination of M2698 with cyclin-dependent kinase (CDK) 4 / 6 inhibitors:

[0110] In another more preferred aspect, in addition to administering the quinazolinecarboxamide azetidine compound, the treatment includes a step involving administering an anticancer agent, preferably a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor, more preferably a CDK4 / 6 selected from abemaciclib, palbociclib or ribociclib, and the quinazolinecarboxamide azetidine compound is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0111] In another specific aspect, the inventors describe herein a combination of (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, the cyclin-dependent kinase (CDK) 4 / 6 inhibitor being a combination of The CDK4 / 6 inhibitor is preferably selected from abemaciclib, palbociclib, ribociclib and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing, including any mixture thereof in all ratios, and even more preferably abemaciclib or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0112] In a specific aspect, M2698 and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof is present in the combination or composition at a dosage of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg.

[0113] In another specific aspect, M2698 and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof is present in the combination or composition at a dose of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg, and wherein abemaciclib is present in the combination or composition at a dose of about 100 mg to about 500 mg, preferably about 150 mg to about 400 mg, more preferably about 300 mg.

[0114] In another specific aspect, M2698 and the CDK4 / 6 inhibitor are formulated for simultaneous, concurrent or sequential administration, preferably for oral administration.

[0115] In another specific aspect, the combination or composition further comprises (c) one or several different therapeutic compounds, in particular an anticancer agent selected from anti-angiogenesis agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents, antisense molecules and any combination thereof.

[0116] If the hormone-dependent disease is cancer, the cancer may be selected from brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, uterine cancer, bladder cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer. The cancer is preferably breast cancer, for example selected from primary cancer, advanced or metastatic cancer, human epidermal growth factor receptor 2 positive (HER2+) cancer, human epidermal growth factor receptor 2 negative (HER2-) cancer, human epidermal growth factor receptor 2 low (HER2 low) cancer and cancer characterized by wild-type estrogen receptor alpha (ERα, ERa or ESR1) cancerous tumors. In a specific aspect, breast cancer is a cancer characterized by mutated estrogen receptor alpha (ERα, ERa or ESR1) cancerous tumors.

[0117] Also described herein are methods of treating a hormone-dependent disease (preferably cancer) in a subject, wherein the method comprises administering to the subject (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a cyclin-dependent kinase (CD The invention relates to a combination of (a) and (b) 4 / 6 inhibitors, wherein the cyclin-dependent kinase (CDK) 4 / 6 inhibitor is preferably selected from abemaciclib, palbociclib, ribociclib and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing, and even more preferably abemaciclib or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, thereby treating a subject.

[0118] Further described herein is a kit comprising: (a) 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, preferably selected from Abbe, in separate containers. An inhibitor of cilifari, palbociclib, ribociclib and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing, even more preferably abemaciclib or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, as well as materials for administering M2698 and / or a CDK4 / 6 inhibitor or for administering the composition.

[0119] definition

[0120] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently disclosed subject matter belongs.

[0121] The following definitions are useful in understanding the embodiments presented herein.

[0122] The term "hormone-dependent disease" refers to any disease caused directly or indirectly by a hormonal disorder as a result of an imbalance of hormones affecting hormone-producing glands or organs, such as the brain, breast, endometrium, ovaries, pancreas, prostate, testicles, thyroid, and bone tissue.

[0123] The hormone-dependent disease may be, for example, cancer, primary amenorrhea, polycystic ovary syndrome (PCOS) or anovulation.

[0124] Unless otherwise indicated, the terms "cancer", "cancerous tumor", "malignant tumor", "tumor", "neoplasia", "cancer disease" or "proliferative disease" are used interchangeably herein. These terms refer to or describe a physiological condition that is generally characterized by unregulated cell growth in mammals. As used herein, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. As used herein, "cancer" refers to solid tumors named after the type of cells that form them, as well as cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemias, lymphomas, and myelomas. The term "cancer" includes, but is not limited to, primary cancers that originate in a specific part of the body. The term cancer also includes cancers that have metastasized, i.e., cancers that have spread from where they began to other parts of the body, such as to the central nervous system (CNS), particularly the brain, or to the bones, lungs, or liver; recurrence of the original primary cancer after remission, and a second primary cancer, which is a new primary cancer in a person with a previous history of cancer of a different type than the latter.

[0125] In the context of the present invention, "tumor cells" are cells obtained from a tumor or tissue of a subject suffering from cancer, in particular cells obtained from at least one of the cancers identified herein (preferably breast cancer), and exhibit well-known cancer cell characteristics, such as maintaining proliferation signaling, escaping growth inhibitors, resisting cell death, achieving replicative immortality, inducing angiogenesis, and activating invasion and metastasis. It should be understood that the expression "tumor cell" used to identify cells obtained from a subject's tumor is also used in this specification to identify circulating tumor cells, cells obtained from liquid tumor biopsies, cells obtained from tumor beds, or cells obtained from metastases.

[0126] The cancer is preferably a hormone receptor positive (HR+) cancer. The cancer can be selected from, for example, brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, uterine cancer, bladder cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

[0127] In some embodiments, the cancer, such as breast cancer, is hormone receptor positive (HR+), i.e., the cancer is estrogen receptor positive (ER+) and / or progesterone receptor positive (PR+). In some embodiments, the cancer is hormone receptor negative (HR-), i.e., the cancer is estrogen receptor negative (ER-) and progesterone receptor negative (PR-).

[0128] Estrogen receptor alpha, also referred to herein as "ERα" or "ERa" or "ESR1", also referred to as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is a nuclear receptor activated by the sex hormone estrogen. More specifically, it is one of the two major estrogen receptor subtypes (α, ERα and β, ERβ) that make up the estrogen receptor (ER). Breast cancer shows abundant levels of Erα and ERβ, while only ERα expression is present in the advanced stages of the disease, and ERβ has been lost. The human wild-type ERa protein amino acid sequence is identified herein as SEQ ID NO:1. Human ERα is encoded by the gene ESR1 (estrogen receptor 1) of SEQ ID NO:3. Alternative splicing produces several ESR1 mRNA transcripts that differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.

[0129] Estrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding and transcriptional activation.

[0130] As used herein, a "mutant ERa protein" is a non-wild-type ERa protein containing at least one amino acid mutation (including, for example, addition, deletion, substitution or frameshift mutation) relative to the wild-type (the protein may also be referred to as "ESR1WT").

[0131] "Wild-type" or "WT" ESR1 or ESR1 refers to the predominant form in which a nucleotide or amino acid sequence, respectively, is present. The predominant form can be identified in a sample from a subject and / or determined based on the predominant form of the nucleotide or amino acid sequence observed in a population of subjects (e.g., a human population). For example, if 80% of the nucleotide sequences in a human population contain an adenosine base at a particular position and the remainder of the sequence contains cytosine, thymine, or guanine at that position, the wild-type is said to have adenosine at that position. Similarly, if 80% of the protein sequences in a human population have a glycine residue at a particular position and the remainder of the sequence contains some other amino acid residues, the glycine is said to be the wild-type residue.

[0132] As used herein, "ESR1 mutation" or "ESR1 mutant" or "mutant ERa protein" refers to a non-wild-type ERa protein containing at least one amino acid mutation relative to the wild type (the mutant protein may also be referred to as mutant "Era"). As used herein, "ESR1 mutant" refers to at least one mutation in the ESR1 gene encoding the ERa protein. In some embodiments, the wild-type ESR1 gene is SEQ ID NO: 3, and the amino acid sequence of the wild-type ERa protein is SEQ ID NO: 1. Those skilled in the art will recognize that different ESR1 mutations can result in different ERa proteins with various mutations, including, for example, one or more of the following amino acid sequence mutations: E380Q, V392I, F404fs, V422del, S463PL536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, and D538G.

[0133] As used herein, a "constitutively active mutant" is a non-wild-type protein that is active without the need for ligand binding, for example, an ERa protein that is active even in the absence of estrogen.

[0134] The cancer is preferably a cancer that is conventionally treated with hormone ( / endocrine) therapy, i.e., a hormone receptor positive (HR + ) cancer (cancerous tumor), preferably an estrogen receptor positive (ER+) cancer. In a preferred embodiment, the ER+ cancer is selected from breast cancer, ovarian cancer and type I endometrial cancer. Even more preferably, the cancer is breast cancer, in particular metastatic and / or advanced breast cancer.

[0135] In particular aspects, the cancer (typically a HR+ cancer, preferably an ER+ cancer) is a human epidermal growth factor receptor 2-positive (HER2+) cancer.

[0136] In another specific aspect, the cancer (typically a HR+ cancer, preferably an ER+ cancer) is a human epidermal growth factor receptor 2 negative (HER2- or HER2neg) cancer.

[0137] In another specific aspect, the cancer (typically a HR+ cancer, preferably an ER+ cancer) is a human epidermal growth factor receptor 2 low (HER2 low) cancer.

[0138] In particular aspects, the tumor is a HR+ tumor, particularly an ER+ tumor, and a "mutated ESR1" or a "mutated ERa" tumor.

[0139] The tumor may also be a HR+, particularly ER+, mutated ESR1 (or mutated ERa) and HER2- / HER2neg tumor. In some such aspects, HR+ / HER2-cancer, particularly breast cancer, is refractory to conventional treatments for cancer therapy as defined below, and is preferably refractory to anti-tumor agents, preferably endocrine therapy agents, such as those selected from selective ER modulators (SERMs), selective ER downregulators degraders (SERDs), aromatase inhibitors (AI) inhibitors, CERAN, hormones, particularly luteinizing hormone releasing hormone (LHRH) agonists, gonadotropin releasing hormone (GnRH) agonists, cyclin dependent kinase (CDK) inhibitors, such as CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib or abemaciclib) and pharmaceutically acceptable salts thereof. In some such embodiments, HR+ / HER2- breast cancer is resistant to treatment with an endocrine therapy selected from, for example, a selective ER modulator (SERM), a selective ER downregulator degrader (SERD), an aromatase inhibitor (AI) inhibitor, CERAN, a hormone, in particular a luteinizing hormone releasing hormone (LHRH) agonist, a gonadotropin releasing hormone (GnRH) agonist, a cyclin dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib or abemaciclib), and pharmaceutically acceptable salts thereof. In some embodiments, HR+ / HER2- breast cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

[0140] In some other aspects, HR+ / HER2- cancer, particularly breast cancer, is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some aspects of each of the aforementioned aspects, HR+ / HER2- cancer is advanced or metastatic HR+ / HER2- breast cancer.

[0141] In some other aspects, cancer is HR- / HER2+, particularly HR- / HER2+ breast cancer.In some embodiments where cancer is HER2+, methods described herein, combinations and purposes further include other anticancer agents, wherein other anticancer agents are HER2 targeting agents (e.g., trastuzumab emtansine, fam-trastuzumab deruxtecan, hand tuzumab, lapatinib, neratinib or tucatinib), or agents targeting PI3K / AKT molecular pathways (e.g., ipatasertib).

[0142] In another specific aspect, the tumor is a HR+, particularly an ER+, mutated ESR1 (or mutated ERa), and HER2+ / HER2pos tumor.

[0143] In another specific aspect, the tumor is HR+, particularly ER+, mutated ESR1 (or mutated ERa), and HER2 low tumor.

[0144] In some aspects, breast cancer is associated with the BRCA1 or BRCA2 gene.

[0145] In another aspect, the breast cancer is triple negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR-, and HER2-. In certain aspects, TNBC is refractory to treatment with an endocrine therapy agent selected from, for example, a selective ER modulator (SERM), a selective ER downregulator degrader (SERD), an aromatase inhibitor (AI) inhibitor, CERAN, a hormone, in particular a luteinizing hormone releasing hormone (LHRH) agonist, a gonadotropin releasing hormone (GnRH) agonist, a cyclin dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and pharmaceutically acceptable salts thereof. In some aspects, TNBC is resistant to treatment with endocrine therapeutic agents, which are selected from, for example, selective ER regulators (SERMs), selective ER downregulators degraders (SERDs), aromatase inhibitors (AI) inhibitors, CERAN, hormones, particularly luteinizing hormone-releasing hormone (LHRH) agonists, gonadotropin-releasing hormone (GnRH) agonists, cyclin-dependent kinase (CDK) inhibitors, preferably CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib or abemaciclib), and pharmaceutically acceptable salts thereof. In some aspects, TNBC is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some such aspects, TNBC is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some aspects, TNBC is locally recurrent / late or metastatic TNBC. In some aspects, TNBC is late or metastatic TNBC.

[0146] In certain embodiments, the breast cancer is an advanced or metastatic breast cancer characterized by a mutated estrogen receptor alpha (ERα, ERa or ESR1) cancerous tumor, wherein the mutation occurs in the ligand binding domain of the ERa wild-type sequence of SEQ ID NO: 1, and / or wherein the mutated ERa is characterized by a change in the conformation of its ligand binding domain.

[0147] In a preferred embodiment, the mutation occurs in at least one residue selected from residues 380, 392, 404, 422, 463, 536, 537 and 538, and even more preferably is an amino acid substitution selected from the group consisting of E380Q, V392I, F404fs, V422del, S463P, L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, D538G, and even more preferably Y537S and / or D538G.

[0148] In some aspects of each of the aforementioned aspects, the cancer (particularly breast cancer) is refractory or resistant to treatment with one or more standard of care agents.

[0149] In some such embodiments, breast cancer is refractory or resistant to treatment with anti-tumor agents (preferably endocrine / hormonal therapeutic agents, such as AIs, CERAN, SERD or SERM). In some embodiments, cancer (particularly breast cancer) is refractory or resistant to treatment with cyclin-dependent kinase (CDK) inhibitors (preferably CDK4 / 6 inhibitors). For example, in some embodiments, breast cancer is refractory or resistant to treatment with palbociclib, ribociclib or abemaciclib or any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof. In other embodiments, breast cancer is refractory or resistant to treatment with anti-tumor chemotherapeutics (e.g., platinum agents, taxanes, anthracyclines or antimetabolites), or progress has been made in treatment with anti-tumor chemotherapeutics (e.g., platinum agents, taxanes, anthracyclines or antimetabolites).

[0150] In the context of the present invention, "conventional treatment for cancer" (also referred to herein as "standard of care treatment" or "main form of cancer therapy") can be an anticancer agent selected from, for example, endocrine ( / hormone) therapeutic agents, anti-angiogenesis agents, signal transduction inhibitors, anti-tumor agents, small molecules, antibodies or fragments thereof (including single-chain antibodies), antibody-drug conjugates (ADC) and antisense molecules, preferably selected from anti-angiogenesis agents, signal transduction inhibitors, anti-tumor agents, small molecules, growth factor receptor agents, antibodies or fragments thereof (including single-chain antibodies), antibody-drug conjugates (ADC) and antisense molecules.

[0151] Conventional treatments for cancer are, for example, selected from hormone therapy, immunotherapy, therapy based on specific kinase inhibitors, therapy based on anti-angiogenic agents, antibody-based therapy (particularly monoclonal antibody-based therapy, particularly antibody-drug conjugate-based therapy), chemotherapy, radiotherapy and surgery.

[0152] The term "conventionally" means that the therapy is applied, or if not conventionally applied, is appropriate and at least recommended by health authorities. "Conventional" treatment is selected by an oncologist depending on the specific cancer to be prevented or treated. The term "adjuvant therapy" refers to additional therapy given after the primary mode of therapy.

[0153] In the context of cancer, a conventional method of treatment for cancer is chemotherapy. The chemotherapeutic agent may, for example, be selected from alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, taxanes, topoisomerase inhibitors and vinca alkaloids.

[0154] In cancer, especially hormone receptor-positive (HR + In the context of HR+ cancer (e.g., breast cancer), conventional treatment of cancer is hormonal therapy, which involves administration of drugs selected from selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and complete estrogen receptor antagonists (CERANs). In particular aspects, conventional treatment of such HR+ cancers involves the use of anti-tumor agents and / or signal transduction inhibitors.

[0155] Conventional treatment of cancer preferably involves cyclin-dependent kinase (CDK) inhibitors, endocrine therapeutic agents, for example selected from selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitor (AI) inhibitors, CERAN, hormones, in particular luteinizing hormone-releasing hormone (LHRH) agonists, gonadotropin-releasing hormone (GnRH) agonists, progestogens or antiandrogens, CYP17 inhibitors, antiadrenergic agents; PI3K / AKT / mTOR ("PAM") pathway inhibitors, and any combination thereof, in particular a combination of a CDK inhibitor with a hormonal therapeutic agent, a combination of a CDK inhibitor with a SERD and / or a SERM, or a combination of a CDK inhibitor, a SERD and a PI3K / AKT / mTOR ("PAM") pathway inhibitor.

[0156] Specific conventional treatments for cancer involve the administration of a drug selected from the group consisting of an inhibitor of a compound of the ER pathway, an inhibitor of a compound of the PI3K / Akt / mTOR ("PAM") pathway, an inhibitor of a compound of the growth factor receptor pathway (involving epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin growth factor receptor (IGFR) and / or vascular endothelial growth factor receptor (VEGFR)), an inhibitor of a compound of the cell cycle, an inhibitor of a compound of the ubiquitin-proteasome pathway, or an inhibitor of a compound of the bromodomain and / or super-terminal domain of a protein. Preferably, the drug is a cell cycle inhibitor or an inhibitor of the PI3K / AKT / mTOR ("PAM") pathway, or a targeted agent, typically an anti-hormone receptor targeted agent, such as a HER-2 targeted agent.

[0157] Other conventional treatments for cancer, particularly adjuvant therapy, include surgery, radiation therapy (also referred to herein as "radiotherapy"), chemotherapy, immunotherapy, endocrine therapy, and targeted therapy (particularly targeted therapy focused on specific genes or proteins in the tumor).

[0158] In certain aspects, the conventional treatment is not an EGFR inhibitor, in particular the treatment is not an EGFR inhibitor selected from gefitinib, erlotinib, afatinib, brigatinib, icotinib, osimertinib and cetuximab. In certain aspects, the treatment is not cetuximab.

[0159] The term "anti-angiogenic agent" refers in particular to VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiogenin inhibitors, PKCf3 inhibitors, cyclooxygenase II (COX-2) inhibitors, integrins (α-v / β-3), matrix metalloproteinase 2 (MMP-2) inhibitors or matrix metalloproteinase 9 (MMP-9) inhibitors. The anti-angiogenic agent can be selected from, for example, gefitinib, cilengitide, Ziv-aflibercept and any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer form of any of the foregoing. It is preferably selected from Cilengitide, Ziv-Aflibercept and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomeric forms of any of the foregoing.

[0160] The term "signal transduction inhibitor" specifically refers to kinase inhibitors [e.g., inhibitors of tyrosine kinases, serine / threonine kinases, including, for example, p21-activated kinase 1 (PAK1), cyclin-dependent kinases or members of the HER family of tyrosine kinases, such as epidermal growth factor receptor-2 (HER2) or receptor-3 (HER3)], proteasome inhibitors, isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, neurotrophin receptor kinase (NTRK) inhibitors, Hedgehog pathway inhibitors, PARP inhibitors, B-cell lymphoproliferative disorder inhibitors, inhibitors, BCL2 inhibitors, EZH2 inhibitors, FGFR pathway inhibitors, rearrangement during transfection (RET) inhibitors, Notch inhibitors, selective inhibitors of nuclear export (SINE), SRC3 inhibitors, MYC inhibitors, BET bromodomain inhibitors, farnesyl transferase inhibitors, HMG-CoA reductase inhibitors, PI3K / AKT / mTOR ("PAM") pathway inhibitors, RAS / RAF / MEK / ERK ("MAPK") pathway inhibitors, S6K inhibitors, eIF4A / E inhibitors or CDK inhibitors.

[0161] The kinase inhibitor can be selected from, for example, abivertinib, acalabrutinib, afatinib, alectinib, ametinib, azenosertib (ZN-c5), axitinib, bemetinib (Mektovi or ARRY-162), bosutinib, brigatinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, conafenib, epertinib, erlotinib, gefitinib, gilteritinib, ibrutinib, icotinib, imatinib, lapatinib, larotinib, lazertinib, lifirafenib, lorlatinib, rlatinib), midostaurin, mobocertinib, naquotinib, nazartinib, neratinib, nilotinib, omotinib, osimertinib, pazopanib, pimasertib, ponatinib, poziotinib, pyrotinib, rifatinib, regorafenib, ruxolitinib, saputinib, selatinib, sirotinib, tepotinib, tesevatinib, trametinib, tucatinib, varlitinib, vemurafenib, Yinlitinib, zanubrutinib, zorifertinib, ABP-1119, ABP-1130, AG-101, AI-6802, AM-105, AMX-3009, APL-1898, ASK-120067, AST-2818, BAY-2476568, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BI-4020, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711C-005, DS-2087b, CK-101, CLM- 29. CLM-3, CMAB-017, CR-13626, CSHEGF-29, D-0316, DBPR-112, DGD-I202, DTRMWXHS-12, DZD-9008, EO-1001, ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, FmAb-2, GB-263, GC-1118A, HA-12128, HMPL-309, HMPL-813, HS-627, IPA3, JMT-101, JRF-103, JS-111, JZB-29, KBP-5209, KNP-501, KU-004,LL-191, MCLA-129, MCLA-158, MDC-22, MP 0274, mRX-7, MTX-211, MVC-101, NRC-2694, NT-004, NT-113, OBX-1012, ORIC-114, PB-357, PF-07799 54. QL-1105, QL-1203, RXDX-105, SAH-EJ1, SCT-200, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, TGRX-360, TQB-3804, UBP-1215, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, YZJ-0318, ZNE-4, ZR-2002, ZSP-0391, ZW49, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0162] The p21-activated kinase 1 (PAK1) inhibitor may be, for example, IPA3 or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0163] In certain embodiments, the signal transduction inhibitor is not a kinase inhibitor.

[0164] The proteasome inhibitor can be selected from, for example, bortezomib, carfilzomib, ixazomib, marizomib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0165] The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitor may be, for example, enasidenib, ivosidenib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.

[0166] The neurotrophin receptor kinase (NTRK) inhibitor may be selected from, for example, entrectinib, sunitinib, M074-2865, PF-07265028, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0167] The Hedgehog pathway inhibitor can be selected from, for example, glasdegib, sonidegib, vismodegib, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.

[0168] The PARP inhibitor can be selected from, for example, niraparib, olaparib, rucaparib, talazoparib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0169] The B-cell lymphoma 2 (BCL2) inhibitor can be, for example, venetoclax or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0170] The EZH2 inhibitor can be, for example, tazemetostat or PF-06821497, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0171] The FGFR pathway inhibitor can be selected from, for example, lucitanib, dovitinib, AZD4547, erdafitinib, infigratinib (BGJ398), BAY-1163877, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

[0172] The rearrangement during transfection (RET) inhibitor can be selected from, for example, vandetanib, cabozantinib, lenvatinib, sorafenib, selpercatinib, pralsetinib, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

[0173] The Notch inhibitor can be, for example, MK-0752, [(s,s)-2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine-3-yl)-propionamide or 11-endo-N-(5,6,7,8,9,10-hexahydro-6,9-methanobenzo[9][8]annulene-11-yl)-thiophene-2-sulfonamide, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0174] The selective inhibitor of nuclear export (SINE) can be, for example, selinexor or eltanexor (KPT-8602), or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0175] The SRC3 inhibitor may be, for example, SI-2 or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0176] The MYC inhibitor may be, for example, omomyc or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0177] The BET bromodomain inhibitor can be selected from, for example, JQ1, I-BET762, OTX015, I-BET151, RVX-208, MS417, ABBV-075, ABBV-744, SJ432, AZD5153, INCB054329, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0178] The farnesyl transferase inhibitor may be, for example, lonafarnib or tipifarnib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0179] The HMG-CoA reductase inhibitor may be, for example, atorvastatin (Caduet, Lipitor, Lypqozet) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0180] PI3K / AKT / mTOR ("PAM") pathway inhibitors refer to compounds designed to inhibit phosphoinositide 3-kinase (PI3K) and / or protein kinase B (Akt) and / or mammalian target of rapamycin (mTOR). It is, for example, a phosphoinositide 3-kinase (PI3K) pathway inhibitor, an ATP competitor, a dual inhibitor of class I PI3K and mTORC1 / 2; a "pan-PI3K" inhibitor that inhibits all four isoforms of class I PI3K (α, β, δ, γ); an isoform-specific inhibitor of any of the various PI3K isoforms (e.g., class II PI3K (PI3K-C2α, PI3K-C2β and PI3K-C2γ) or class III PI3K); an allosteric and catalytic inhibitor of AKT; an ATP-competitive inhibitor of only mTOR (and therefore mTORC1 and mTORC2), or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.The PAM pathway inhibitor can be selected from, for example, an mTOR inhibitor, such as bimiralisib, dactolisib tosylate, detorsertib, everolimus, monepantel, omipalisib, onatasertib, defostiolimus, sapanisertib, sirolimus, Streptomyces OA293, temsirolimus, vitusertib, AL-5880S, AL-58922, AUM-302, CA-102, CA-103, CC-115, CC-223, CT-365, DFN- S29, DHM-ZS, FP-208, FT-IS18, HEC-68498, LXI-15029, ME-344, NSC-765844, OSI-027, OSU-53, OT-043, PQR-514, PTX-367, QR-213, RMC-5552, SN-202, SPR-965 or TAM-03, WXFL-10030390 or XP-105; AKT / PDK1 inhibitors, such as afuresertib, borussertib, capivasertib (AZD5363), celecoxib or celecoxib derivatives, dordaviprone (ONC-201), enzastaurin, ipatasertib, miransertib, uprosertib (GSK2141795), ALM-301, ARQ-751, AT-13148, AZD8055, BAY-1125976, BX795, BX912, COTI-2, DC-120, FXY-1, GSK470, JRP-890, JX06, KS-99, LY-2503029, MK-2206, NISC-6, OSU-03012, PHT-427, PTX-200, RX-0201, RX-0301, SBF1 or TAS-117; PI3K inhibitors, such as apellisib, buparlisib (BKM120), copanlisib, duvelisib, idelalisib, paxalisib, pictilisib (GDC0941) or sonalisib; and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing. PAM inhibitors can also be selected from AZD8055, GDC0941, selumetinib and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.The PAM pathway inhibitor is preferably selected from buparlisib, pilaralisib, pictilisib, sonolisib, dactolisib, sapacerti, voxtalisib, serabelisib, apellisib, perifosine, MK2206, pataserti, GSK690693, temsirolimus, rifolimus, sirolimus, everolimus, AZD8055, OSI-027 and any pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing, or any mixtures thereof in all ratios.

[0181] RAS / RAF / MEK / ERK ("MAPK") pathway inhibitors can be selected from, for example, VS-6766, TNO-155, SHP099, RMC-4550, RMC-4630, RMC-5845, 1ACS-13909, JAB-3068, JAB-3312, RLY-1971, BBP-398, ERAS-601, HBI-2376, ICP-189, BR790, ETS-001, PF-07284892, RX-SHP2i, SH3809, TAS-ASTX, X-37-SHP2, BMS-SCH, BAY-293, BI-3406, BI-1701963, SDGR -5, AZ6197, BIERKi, CC-90003, ERAS-007, HMPL-295, IPN-ERK, KO-947, LTT462, SCH772984, TK216, ASTX-029, HH-2710, LY-3214996, selumetinib, trametinib, uritinib, ASN-007, ATG-017, BPI-27336, JSI-1187, MK-8353, JRP-890, JRF-108, dual RAF / MEK inhibitors identified in WO2022 / 170060, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0182] In certain aspects, the MAPK pathway inhibitor is not a MEK inhibitor.

[0183] In certain aspects, the MEK inhibitor is not trametinib, cobimetinib, selumetinib, rifatinib or pimasertib. Preferably, the MEK inhibitor is not pimasertib.

[0184] The S6K inhibitor can be selected from, for example, LY2584702, a piperazinyl pyrimidine derivative (e.g., PF-4708671 or PF-4708671), A77 1726 (an active metabolite of leflunomide), FS-115, FL772, LY2780301, LYS6K2, AD80 / AD81, gingerol, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0185] The eIF4A / E inhibitor may be selected from, for example, a rapamycin analog, ribavirin, zotatifin, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0186] The cyclin-dependent kinase (CDK) inhibitor is selected from, for example, CDK 1, 2, 4, 5, 6 and / or 7 inhibitors, and in particular may be, for example, abemaciclib (also known as LY2835219), AG024322, aloisine A, aloisine B, ateporone, aminopurvalanol, AT7519, AZD-5438, AZD5597, BLU-222, BMS-387032, pyroximate (XZP3287), bohemine, butyrolactone, CYC065, dalpiciclib (SHR-6390), dinaciclib, ETH-155008, flavopiridol, FCN-437c, GLR2007, indirubin, indirubin-3'-monoxime, JNJ-7706621, kemperolone, lerociclib (also known as G1T38), meriolin 3. milciclib, narazaciclib (ON123300), NVP-LCQ19, olomoucin, olomoucin II, palbociclib (also known as Ibrance, PD-0332991 or PF-00080665), PF-07220060, PF-07104091, PF-06873600, PHA-793887, purvalanol A, purvanol B, R-CR8, RGB-286638, RGB286147, ribociclib (also known as LEE-011), riviciclib hydrochloride (P276-00), roniciclib, R-roscovitine, Ro4584820, SRX-3177, TG02, TQB3303, trilaciclib (also known as GTI128), voruciclib, xylocydin, ZK304709, 10Z-membrane alkaloids (10Z-Hymenialdisine), 5-iodo-indirubin-3'-monoxime, (1R, 3S)-3-[3-(([3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl)amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing. A specific example of a CDK7 inhibitor is samuraciclib (also known as CT7001 or ICE0942).

[0187] Other examples of CDK inhibitors are described in WO2022 / 018596. The CDK inhibitor is preferably a CDK4 / 6 inhibitor, such as abemaciclib, palbocilcib, ribociclib and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0188] The term "anti-neoplastic agent" refers in particular to chemotherapeutic agents and hormonal ( / endocrine) therapeutic agents.

[0189] The term "chemotherapeutic agent" refers in particular to an alkylating agent, a platinum coordination complex, a cytotoxic antibiotic, an antimetabolite, a biological response modifier, a histone deacetylase (HDAC) inhibitor, a growth factor inhibitor, a taxane, a topoisomerase inhibitor or a vinca alkaloid. The term also encompasses other compounds such as asparaginase (pegaspargase), bexarotene, eribulin, eribulin mesylate, fosbretabulin, hydroxyurea, ixabepilone, lenalidomide, mitotane, omacetin, pomalidomide, tagraxofusp, telotristat, thalidomide and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates and tautomers of any of the foregoing.

[0190] In a preferred aspect, the chemotherapeutic agent is selected from capecitabine, cyclophosphamide, docetaxel, doxorubicin, epirubicin, eribulin mesylate, fluorouracil, 5-fluorouracil, gemcitabine, liposomal doxorubicin, paclitaxel, vinorelbine, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

[0191] The alkylating agent can be selected from, for example, apaziquone, altretamine, bendamustine, busulfan, carboquinone, carmustine, chlorambucil, mechlorethamine, cyclophosphamide, dacarbazine, fotemustine, glufosfamide, ifosfamide, improsulfan tosylate, lomustine, mechlorethamine, melphalan, dibromomannitol, dibromodulcitol, nimustine, palifosfamide, pipobroman, procarbazine, ranimustine, streptozotocin, temozolomide, N,N'N'-triethylenethiophosphoramide (ThioTEPA), trabectedin, trooxsulfan, trolofosamide, uramustine, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0192] The platinum coordination complex can be selected from, for example, carboplatin, cisplatin, epplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0193] The cytotoxic antibiotic can be selected from, for example, aclarubicin, bleomycin, dactinomycin, daunomycin, doxorubicin, epirubicin, levamisole, idarubicin, miltefosine, mitomycin, mitoxantrone, plicamycin, valrubicin, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0194] The antimetabolite can be selected from, for example, antifolates (e.g., methotrexate, pemetrexed, pralatrexate or trimetrexate); purine analogs (e.g., azathioprine, cladribine, fludarabine, mercaptopurine or thioguanine); pyrimidine analogs (e.g., azacitidine, capecitabine, cytarabine, decitabine, floxuridine, fluorouracil, 5-fluorouracil, gemcitabine or trifluridine / tipracil) and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0195] The biological response modifier may be selected from, for example, aldesleukin (IL-2), denileukin diftitox, and interferon gamma.

[0196] The histone deacetylase (HDAC) inhibitor may be selected from, for example, belinostat, panobinostat, vorinostat, romidepsin, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0197] The taxane can be selected from, for example, cabazitaxel, docetaxel, paclitaxel (eg, paclitaxel albumin-stabilized nanoparticle formulation), tesetaxel, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0198] The topoisomerase inhibitor is selected from, for example, etoposide, irinotecan, teniposide, topotecan, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0199] The vinca alkaloid is selected from, for example, vinblastine, vindesine, vincristine, vinflunine, vinorelbine, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0200] The term "hormonal ( / endocrine) therapeutic agent" refers in particular to antiandrogens, such as abiraterone (abiraterone acetate), apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide and nilutamide; hormones, such as luteinizing hormone-releasing hormone (LHRH) agonists or gonadotropin-releasing hormone (GnRH) agonists, such as buserelin, cetrorelix, gonadorelin, lanreotide, octreotide, somatostatine (pasireotide), degarelix, goserelin, leuprolide or triptorelin or triptorelix; progestogens, such as medroxyprogesterone acetate or megestrol acetate; CYP17 inhibitors, such as abiraterone or ketoconazole; antiadrenergic agents, such as mitotane; antiestrogens; and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0201] The anti-estrogen can be selected from, for example, selective ER downregulators or selective ER degraders ("SERDs"), selective ER modulators ("SERMs"), aromatase inhibitors ("AIs"), and complete estrogen receptor antagonists ("CERANs").

[0202] The term "selective ER modulator ("SERM")" refers to an anti-estrogen compound that is designed to compete with estrogen for ER binding and exhibits mixed agonist / antagonist capabilities in a tissue-specific manner. SERMs are typically selected from triphenylethylene, benzothiophene, phenylindole, tetralin, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0203] The triphenylethylene is preferably tamoxifen or a "tamoxifen-like" compound, such as 4-hydroxytamoxifen, afexifen, endoxifen, toremifene, droloxifene or idoxifene; the benzothiophene is preferably raloxifene or arzoxifene; the phenylindole is preferably bazedoxifene or pipindoxifene; and the tetralin is preferably lasofoxifene.

[0204] The term "selective ER downregulator or selective ER degrader ("SERD")" refers to an anti-estrogen compound that is intended to create an unstable protein complex that induces ER protein degradation via the proteasome. The SERD is preferably selected from fulvestrant, alastrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also known as RAD-1901], amcenestrant [(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, also known as SAR439859], brilanestrant [(E)-3 -(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, also known as ARN-810 or GDC-0810], camizestrant [N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine, also known as AZD9833], giredestrant [3-((1R,3R) -1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, also known as RG6171 or GDC9545], rintodestrant[(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, also known as G1T48], AZD9496[(E)-3-[3,5-difluoro-4- [(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(l,l-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also known as LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, and any of the foregoing pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers. In another preferred aspect, the SERD compound is elastomeric or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0205] In a particularly preferred embodiment, the SERD is selected from amcenestrant [(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, also known as SAR439859], azenosertib (ZN-c5) [1-[(7R)-7-ethyl-7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one], borestrant [(7a,17b)-7 -[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol-1,3,5(10)-triene-3,17-diol-3-boronic acid], brinostrant [(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, also known as ARN-810 or GDC-0810], camizestrant [N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridine -3-amine, also known as AZD9833], ellastrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also known as RAD-1901], fulvestrant [(7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol-1,3,5(10)-triene-3,17-diol], giredestrant [3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro -2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, also known as RG6171 or GDC9545], imlunestrant[(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol], rintodestrant[(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, also known as G1T48], AZD9496[(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(l,l-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also known as LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing. In a preferred aspect, the SERD compound is selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, camizestrant, elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927 or SHR9549, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers of any of the foregoing.

[0206] The term "aromatase inhibitor ("AI")" refers to a compound that reduces systemic levels of estrogen. The aromatase inhibitor can be a steroidal aromatase inhibitor or a non-steroidal aromatase inhibitor. For example, the one or more aromatase inhibitors can be selected from aminoglutethimide, exemestane (steroidal aromatase inhibitor), testolactone (steroidal aromatase inhibitor), anastazole (non-steroidal aromatase inhibitor), letrozole (non-steroidal aromatase inhibitor), fadrozole (non-steroidal aromatase inhibitor), formestane (steroidal aromatase inhibitor), vorozole (non-steroidal aromatase inhibitor) and AZD9496 (non-steroidal aromatase inhibitor), including any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing. The AI ​​is preferably selected from aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, vorozole, AZD9496, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

[0207] The term "complete estrogen receptor antagonist ("CERAN")" refers to a compound that potently and completely inactivates the estrogen receptor (ER). CERAN is preferably OP-1250, ARV-471 ((3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione), H3B-6545 ((E)-N,N-dimethyl-4-[2-[5 -[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide), or N-(2-(4-(adamantan-2-ylidene(4-hydroxyphenyl)methyl)phenoxy)ethyl)-adamantane-1-carboxamide, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing. Additional examples of similar CERAN compounds are described in WO19 / 241231.

[0208] The term cell cycle inhibitor refers to compounds designed to slow down or stop cell cycle progression through various mechanisms. Cell cycle arrest can be induced at different stages, thereby reducing the rate of cell division and the number of actively cycling cells.

[0209] The cell cycle inhibitor is preferably selected from palbociclib, ribociclib, abemaciclib and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

[0210] The term "growth factor receptor agent" refers to compounds designed to target the epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin growth factor receptor (IGFR) and / or vascular endothelial growth factor receptor (VEGFR).

[0211] The term "targeted agent" refers to inhibitors of the cell cycle, inhibitors of the PI3K / Akt / mTOR pathway or inhibitors of growth factor receptors; and / or compounds that target pathway alterations in the ubiquitin-proteasome; and / or compounds that increase the activity of the bromodomain and / or super-terminal domain of a protein.

[0212] The targeting agent is preferably selected from palbociclib, ribociclib, abemaciclib, buparlisib, pilaralisib, pictilisib, sonolisib, dactolisib, sabasert, voxtalisib, serabelisib, apellis, perifosine, MK2206, patasert, GSK690693, temsirolimus, rufolimus, sirolimus, everolimus, AZD-8055, OSI-027, lapatinib and any of the foregoing pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers. The targeting agent is even more preferably palbociclib, ribociclib, abemaciclib and / or any of the foregoing pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers.

[0213] The term "small molecule" specifically refers to a small molecule compound, such as tipiracil, vistonuridine (uridine triacetate), zoledronic acid, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any of the foregoing.

[0214] In the context of the present invention, the term "antibody" (or "immunoglobulin") refers to any type of antibody, such as a monoclonal antibody, a multispecific antibody (i.e. an antibody comprising a first antigen binding site and at least one second, different antigen binding site; e.g. a bispecific antibody) or a single-chain antibody. The term also encompasses any (functional) fragments thereof.

[0215] Typical antibodies are composed of glycoproteins that include at least two heavy (H) chains and two light (L) chains that are interconnected by disulfide bonds. Each heavy chain includes a heavy chain variable region (or domain) (abbreviated herein as VH) and a heavy chain constant region (hereinafter referred to as CH). The heavy chain is classified as γ, μ, α, δ or ε, and the subtypes of the antibody are defined as IgG, IgM, IgA, IgD and IgE, respectively. The heavy chain constant region of immunoglobulins IgG, IgD and IgA (γ, δ and α chains, respectively) includes three domains (CH1, CH2 and CH3) and a hinge region for increasing flexibility, while the heavy chain constant region of immunoglobulins IgM and IgE contains 4 domains (CH1, CH2, CH3 and CH4). The antibody of the present invention can be IgG, IgM, IgA, IgD, IgE subtypes according to the different structures of its heavy chain. However, in a preferred embodiment, the antibody of the present invention is an IgG subtype, that is, its heavy chain is a γ (γ) type.

[0216] IgG antibodies are classified into four different subtypes in order of their abundance in serum, namely IgG1, IgG2, IgG3 and IgG4 (IgG1 being the most abundant). The structure of the hinge region in the γ chain gives each of these subtypes its unique biological properties (although there is about 95% similarity between their Fc regions, the structure of the hinge region is relatively different).

[0217] The antibodies of the invention may be of the IgG1, IgG2, IgG3 or IgG4 subtype. However, in a preferred embodiment, the antibodies of the invention are of the IgG1 subtype.

[0218] Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region CL comprising only one domain. There are two types of light chains in mammals: a kappa (κ) chain encoded by the immunoglobulin kappa locus on chromosome 2 and a lambda (λ) chain encoded by the immunoglobulin lambda locus on chromosome 22. In a preferred embodiment, the antibodies of the present invention have a kappa light chain. The VH and VL regions can be further subdivided into regions of hypervariability, called "complementarity determining regions" (CDRs), which are primarily responsible for binding to the epitope of the antigen and are interlaced with more conserved regions, called "framework regions (FRs)". Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The functional ability of an antibody to bind to a specific antigen depends on the variable regions of each light chain / heavy chain pair and is largely determined by the CDRs.

[0219] The variable region of the heavy chain differs in antibodies produced by different B cells but is identical for all antibodies produced by a single B cell or B cell clone (or hybridoma).

[0220] In contrast, the constant regions of the antibodies mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.

[0221] As used herein, the term "antibody fragment" is intended to mean Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, single-chain antibodies, dimers, minibodies, nanobodies, diabodies and multimers thereof and bispecific antibody fragments. Antibodies can be fragmented using conventional techniques. Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments are obtained by proteolytic digestion of intact antibodies. For example, F(ab')2 fragments can be produced by treating antibodies with pepsin. The resulting F(ab')2 fragments can be treated to reduce disulfide bonds to produce Fab' fragments. Papain digestion can result in the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, dsFv, ds-scFv, dimers, minibodies, nanobodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant technology.

[0222] Typically, the antibody fragments of the invention are functional fragments, ie, antibody fragments that are capable of binding and preferably inhibiting or neutralizing the activity of a molecule of interest, like the antibody from which they are derived.

[0223] In another specific embodiment, the antibody of the invention is a monoclonal antibody.

[0224] As used herein, "monoclonal antibody" refers to an antibody produced by a colony of almost homogeneous antibodies. More specifically, the antibodies of a given subject are identical except for a few possible naturally occurring mutations that can be found in minimal proportions. In other words, monoclonal antibodies are composed of homogeneous antibodies produced by the growth of single cell clones (e.g., hybridomas, eukaryotic host cells transfected with DNA molecules encoding homogeneous antibodies, prokaryotic host cells transfected with DNA molecules encoding homogeneous antibodies, etc.), and are generally characterized by one and only one subtype and subtype of heavy chain, and only one type of light chain. In addition, compared with the preparation of polyclonal antibodies, each monoclonal antibody is directed against a single epitope of an antigen.

[0225] In order to produce monoclonal antibodies, cells (lymphocytes) producing antibodies can be harvested from immune animals as described above, and fused with myeloma cells by standard somatic cell fusion procedures, so that these cells are immortalized and hybridoma cells are produced. Such technology is well known in the art (e.g., hybridoma technology initially developed by Kohler and Milstein (1975)), and other technologies, such as human B cell hybridoma technology, EBV hybridoma technology for producing human monoclonal antibodies, and screening of combinatorial antibody libraries. Hybridoma cells can be subjected to immunochemical screening to produce antibodies that specifically react with the target polypeptide, so as to separate only the monoclonal antibodies combined with the polypeptide.

[0226] The antibodies or fragments thereof of the present invention may be human, chimeric, humanized, mouse, CDR-grafted, phage-displayed, bacterially displayed, yeast-displayed, produced by transgenic mice, mutagenized or randomized antibodies or fragments.

[0227] Chimeric antibodies are molecules in which different portions are derived from different animal species, such as those having variable regions derived from a mouse monoclonal antibody (mAb) and human immunoglobulin constant regions.

[0228] The humanized form of the antibody of the present invention is a chimeric antibody, which contains the minimum sequence derived from non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (receptor antibodies), wherein the residues from the hypervariable region of the receptor are replaced by the hypervariable region residues from non-human species (donor antibodies) such as mice, rats, rabbits or non-human primates with desired specificity, affinity and ability. In some cases, the skeleton region (FR) residues of human immunoglobulins (receptor antibodies) are replaced by the corresponding non-human residues of donor antibodies. In addition, humanized antibodies may be included in residues not found in receptor antibodies or donor antibodies. In general, humanized antibodies may include substantially all at least one, usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to the hypervariable loops of non-human immunoglobulins (donor antibodies with desired specificity, affinity and ability), and all or substantially all of the FRs are the FRs of human immunoglobulin sequences. The method for humanizing non-human antibodies has been described in the art. Preferably, humanized antibodies have one or more amino acid residues introduced therein from non-human sources. These non-human amino acid residues are generally referred to as "import" residues, which are generally taken from the "import" variable domain. Humanization can be carried out substantially by replacing the corresponding sequence of a human antibody with a hypervariable region sequence. Therefore, such humanized antibodies are chimeric, wherein substantially less than a complete human variable domain has been replaced by a corresponding sequence from a non-human species. In fact, humanized antibodies are generally human antibodies, in which some hypervariable region residues and possible FR residues are replaced by residues from similar sites in rodent antibodies. Other methods generally involve conferring donor CDR binding affinity to an antibody receptor variable region skeleton. One method involves simultaneously transplanting and optimizing the binding affinity of variable region binding fragments. Another method involves optimizing the binding affinity of antibody variable regions.

[0229] The antibodies or fragments thereof of the invention may be administered in their "naked" or unconjugated form, or may have other agents conjugated thereto, such as drugs, toxins, or radioactive atoms.

[0230] An “antibody” is, for example, alemtuzumab, amelimumab, amivantamab, atezolizumab, avelumab, besozumab, bevacizumab, blinatumomab, brentuximab, catumaxomab, cemiplimab, cetuximab, dalotuzumab, daratumumab, denosumab, dinutuximab, durvalumab, elotuzumab, elranatamab, epratuzumab, farletuzumab, gemtuzumab, inotuzumab, ozogamicin), ipilimumab, matuzumab, mogamulizumab, moxetumomab, pasudotox, nimotuzumab, PF-07260437, PF-07257876, PF-07062119, necituzumab, nivolumab, obinutuzumab, ocaratuzumab, onartuzumab, ofatumumab, olaratumumab aratumab), ogavuzumab, panitumumab, pembrolizumab, pertuzumab, racotumomab, ramucirumab, rilotumumab, rituximab, siltuximab, tabalumab, tocilizumab, tomucotuximab, tositumomab, trastuzumab, zalutumumab, zanolimumab, or zenocutuzumab.

[0231] The term "antibody-drug conjugate" ("ADC") refers in particular to ADC compounds, such as trastuzumab enamivir, trastuzumab dexamethasone, and trastuzumab seroquel. Trastuzumab duocarmazine, disitamab vedotin, laditratumab vedotin (also known as SGN-LIV1A), depatuxizumab mafodotin, SN-38, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any one of the foregoing.

[0232] The term "antisense molecules" refers in particular to several classes of oligonucleotide molecules that contain sequence complementarity with a target RNA molecule (e.g., mRNA, viral RNA, or other RNA species) and inhibit the function of its target RNA after sequence-specific binding. Antisense molecules can be selected from antisense oligodeoxynucleotides (ODNs), i.e., single-stranded DNA molecules, small interfering RNA (siRNA) molecules, ribozymes, DNA enzymes, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0233] In the context of the present invention, "non-responder" or "resistance" refers to the phenotype of a subject who does not respond to cancer treatment, particularly conventional treatments for cancers as identified herein, i.e., there is no substantial reduction in tumor volume, or no alleviation of cancer symptoms in the subject, or the cancer progresses, such as an increase in tumor volume and / or local or distant metastasis of the tumor. The term "non-responder" or "resistance" also refers to the phenotype of a subject who will die from cancer.

[0234] In the context of the present invention, "responder" or "sensitive" refers to the phenotype of a patient who responds to cancer treatment, in particular to conventional treatments for cancer as defined herein, i.e., the tumor size is reduced, at least one of his symptoms is alleviated, or the progression of the cancer is stopped or slowed.

[0235] In the sense of the present invention, a subject who responds to a cancer treatment is one who generally has a much longer chance of disease-free survival ("DFS") or metastasis-free survival ("MFS") than a patient who has not been determined (using the methods described herein) to be sensitive to a cancer treatment. In a preferred embodiment, a subject who responds to a cancer treatment is one who will be completely treated (cured), i.e., one who will survive the cancer [the parameter detected or measured (e.g., the gene expression product disclosed herein) has a beneficial effect on "overall survival" (OS)].

[0236] In the context of the present invention, the term pathological complete response ("pCR") refers to a dramatic reduction in tumor size under anticancer treatment, usually following neoadjuvant hormonal therapy, and then becoming operable (possibly with surgery) or becoming undetectable.

[0237] In the context of the present invention, the term "progressive disease" means that the size of the tumor or the spread of the tumor has increased by at least 20% since the start of treatment. In other words, if the size of the tumor in the scan is 20% larger than the initial measurement, it will be called progressive disease.

[0238] The terms "primary endocrine resistance" or "primary hormone resistance" used to characterize patients refer to relapse in patients who have received adjuvant hormonal therapy within the first 2 years, or progressive disease within the first 6 months of first-line hormonal therapy in the metastatic setting.

[0239] The terms "secondary endocrine resistance" or "secondary hormone resistance" used to characterize patients refer to relapse in patients receiving adjuvant hormonal therapy after 2 years, relapse in patients within the first 12 months of completing adjuvant therapy, or progressive disease 6 months after initiation of endocrine therapy in the metastatic setting.

[0240] The term “early relapse” is defined as relapse occurring less than 12 months after adjuvant endocrine therapy.

[0241] The term “late relapse” was defined as relapse occurring more than 12 months after adjuvant therapy.

[0242] The term "sample" refers to a material or material mixture containing one or more components of interest. A sample from a subject refers to a sample obtained from a subject, including a sample of a biological tissue or liquid source obtained, reached or collected in vivo or in situ. The sample can be obtained from a region containing precancerous or cancerous cells or tissues of a subject or from another tissue or fluid in the subject. Such samples can be, but are not limited to, organs, tissues, fractions and cells separated from mammals. Exemplary samples include lymph nodes, whole blood, partially purified blood, serum, plasma, bone marrow and peripheral blood mononuclear cells ("PBMCs"). Samples can also be tissue biopsies. Exemplary samples also include cell lysates, cell cultures, cell lines, tissues, organs, biological fluids, blood samples, urine samples, etc.

[0243] The sample preferably includes tumor cells or tumor nucleic acids, such as DNA or RNA. Tumor DNA can be, for example, cell-free DNA ("cfDNA") or circulating tumor DNA ("ctDNA"). cfDNA can be found, for example, in a blood sample of a subject. ctDNA can be found, for example, in a plasma sample of a subject.

[0244] A sample from a subject may have multiple copies of the ESR1 gene. These copies may encode wild-type and / or mutant ERa proteins. As used herein, a sample from a subject with an ESR1 mutation may also have one or more copies of a wild-type ESR1 gene and / or a wild-type ERa protein.

[0245] The term "about" used to modify a numerically defined parameter means that the parameter can vary up to 10% above or below the numerical value of the parameter. For example, a dosage of "about 5 mg" means 5 mg ± 10%, i.e., the dosage can vary between 4.5 mg and 5.5 mg.

[0246] As used herein, an "effective dose" or "effective amount" of a compound, combination or composition is an amount sufficient to affect any one or more beneficial or desired outcomes of a disease, including biochemical, histological and / or behavioral symptoms, its complications, and intermediate pathological phenotypes occurring during the course of the disease.

[0247] As used herein, an "effective dose" or "effective amount" of a compound or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired outcomes of a disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes occurring during the course of the disease.

[0248] For therapeutic uses, a "therapeutically effective amount" means an amount of a compound or combination administered that will alleviate to some extent one or more symptoms of the disorder being treated. For cancer treatment, a therapeutically effective amount means an amount that has the following effects: (1) reduces tumor size, (2) inhibits (i.e., slows to some extent, preferably stops) tumor metastasis, (3) inhibits (i.e., slows to some extent, preferably stops) tumor growth or tumor invasiveness, (4) alleviates to some extent (preferably eliminates) one or more signs or symptoms associated with cancer, (5) reduces the dosage of other drugs required to treat the disease, and / or (6) enhances the effect of another drug, and / or (7) delays the progression of the disease in the patient.

[0249] The effective dose can be administered in one or more administrations. For purposes of the present invention, the effective dose of a drug, compound, combination, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a preventive or therapeutic treatment. As understood in a clinical context, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, combination, or pharmaceutical composition.

[0250] As used herein, "pharmaceutically acceptable carrier" refers to a carrier, excipient or diluent that does not cause significant irritation to an organism and does not eliminate the biological activity and characteristics of an active compound or therapeutic agent. A pharmaceutically acceptable carrier may include any conventional pharmaceutical carrier or excipient. The selection of carriers and / or excipients depends to a large extent on factors such as the specific mode of administration, the effect of excipients on solubility and stability, and the nature of the dosage form. Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents (e.g., hydrates and solvates). If desired, the pharmaceutical composition may contain additional ingredients, such as flavoring agents, adhesives, excipients, etc. Therefore, for oral administration, tablets containing various excipients (e.g., citric acid) can be used with various disintegrants (e.g., starch, alginic acid, and certain complex silicates) and with adhesives (e.g., sucrose, gelatin, and gum arabic). Examples of excipients (not limited to) include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. In addition, lubricants (such as magnesium stearate, sodium lauryl sulfate and talc) can generally be used for tableting purposes. Similar types of solid compositions can also be used for soft and hard filled gelatin capsules. Therefore, non-limiting examples of materials include lactose (lactose) or milk sugar (milk sugar) and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are needed for oral administration, the active compound therein can be combined with various sweeteners or flavorings, coloring agents or dyes and (if necessary) emulsifiers or suspending agents and diluents (such as water, ethanol, propylene glycol, glycerol or a combination thereof).

[0251] As used herein, the term "combination" or "combination therapy" means that each therapeutic agent in the combination therapy of the invention is administered separately or sequentially, concurrently or simultaneously in the form of a pharmaceutical composition or medicament.

[0252] As used herein, the term "sequentially" or "sequentially" refers to each therapeutic agent of the combination therapy of the present invention administered alone or one after another in a medicament, wherein each therapeutic agent can be administered in any order. Sequential administration may be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and / or the agents are administered according to different dosing schedules, for example, one agent is administered daily and the second agent is administered less frequently, for example, weekly.

[0253] As used herein, the term "concurrently" refers to administration of each therapeutic agent in the combination therapy of the present invention separately or in different drugs, the second therapeutic agent is administered immediately after the first therapeutic agent, and the therapeutic agents are administered in any order. In a preferred embodiment, the therapeutic agents are administered concurrently.

[0254] As used herein, the term "simultaneously" refers to administration of each therapeutic agent of the combination therapy of the invention in the same drug. It will be appreciated by those skilled in the art that the combination therapy can be effectively administered to a subject during different phases of its treatment.

[0255] In some embodiments of each of the methods, combinations, and uses herein, the combination therapy is administered to a previously untreated (ie, treatment naive) subject.

[0256] In some preferred embodiments of each of the methods, combinations, and uses herein, the combination therapy is administered to a subject who has failed to achieve a sustained response following at least one prior therapy with an anticancer agent identified herein, ie, a treatment-experienced subject.

[0257] Quinazolinecarboxamide azetidine compounds

[0258] The quinazolinecarboxamide azetidine compounds used in the context of the present invention, in particular for the treatment of hormone-dependent diseases, in particular the cancers described herein, preferably breast cancer, are compounds defined by formula (I):

[0259]

[0260] and / or any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, wherein:

[0261] R 1 is H or LA;

[0262] R 2 is Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH2 or A;

[0263] R 3’ , R 3” are independently H, LA or Hal;

[0264] Ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2, 3 or 4 N, O and / or S atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONH(Art), CONA2, NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH2, NHSO2A, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, and wherein the ring N atoms may be substituted by O atoms to form N oxide groups, and wherein in the case of a bicyclic aromatic ring, one of the two rings may be partially saturated;

[0265] Ar1 is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2 or 3 N, O and / or S atoms and 5 or 6 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), CHO, CO(LA), SO2NH2, SO2(LA) and / or SO2Hal;

[0266] A is an unbranched or branched, straight-chain or cyclic alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and / or -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, and in which 1 to 3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN;

[0267] LA is an unbranched or branched linear alkyl group having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; and

[0268] Hal is F, Cl or Br, preferably F or Cl, most preferably F.

[0269] A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2.2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1.3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.

[0270] A further preferably represents alkyl as defined above, in which one or two CH2 groups may be replaced by O or S atoms and / or NH, N(LA), CONH, NHCO or -CH=CH- groups, and / or a further 1 to 3 H atoms may be replaced by F and / or Cl, for example trifluoromethyl, pentafluoroethyl, 1,1-difluoromethyl, 1,1,1-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0271] In a preferred embodiment, the novel quinazolinecarboxamide azetidine compounds are further defined by formula (II):

[0272]

[0273] and / or any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, wherein:

[0274] R 4 , R 5 , R 6 , R 7 , R 8 are independently H, Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), NHCONH(LA), NHCONH2, NHS02(LA)(CO(LA), SO2NH2, SO2(LA) or SO2Hal,

[0275] R 5 , R 6 Together with the phenyl groups to which they are attached, they can form a 9- or 10-membered bicyclic ring system, wherein 1 or 2 non-phenyl carbon atoms can be independently replaced by NH, O or S, wherein R 5 and R 6The formed ring may be unsubstituted or mono- or di-substituted by Hal or LA,

[0276] R 5 , R 6 , R 7 One of can be AM, O(Ar1), NH(A), CONH(Arl), NHCO(Arl), NHCONH(Arl), NHSO2(Ar1), CO(Ar1) or SO2(Ar1), and R 5 , R 6 , R 7 The other two are not Ar1, O(Ar1), NH(Ar1), CONH(A), NHCO(Ar1), NHCONH(Ar1), NHSO2(Ar1), CO(Ar1) or SO2(Ar1), and the remaining substituents have the meanings shown in formula (I).

[0277] In more preferred embodiments of formula (I) and (II), the stereochemistry at the central chiral carbon atom is as shown in formula (I') and (II'):

[0278]

[0279] In general, all residues which occur more than once may be identical or different, ie independent of one another. Above and below, unless expressly stated otherwise, residues and parameters have the meanings indicated in formula (I), formula (II), formula (I') and formula (II")

[0280] Further preferred are compounds of sub-formulae 1 to 12 of the formulae (II) and (II′), wherein in sub-formula 1:

[0281] R 4 , R 5 , R 6 , R 7 , R 8 are independently H, F, Cl, Br, OH, LA, O(LA), CN, C(Hal)3, OC(Hal)3

[0282] In Subformula 2:

[0283] R 1 , R 2 H

[0284] In Subformula 3:

[0285] R 3’ , R 3” are independently H, OH or F

[0286] In Subformula 4:

[0287] R 4 , R 8 are independently H, F or Cl

[0288] In Subformula 5:

[0289] R 5 , R 7 are independently H, F, Cl, Br, CN, methoxy or CF3

[0290] In Subformula 6:

[0291] R 5 , R 6 Together with the phenyl groups to which they are attached they form benzo-1,2-dioxolyl, in which the carbon atom bridging the two oxygen atoms may be unsubstituted or mono- or di-substituted by F or methyl.

[0292] In Subformula 7:

[0293] R 6 H, F, CI or CF3

[0294] In Subformula 8:

[0295] R 5 , R 6 are independently H, F, Cl, Br, methyl, CHF2 or CF3

[0296] In Subformula 9:

[0297] R 1 , R 2 , R 3’ , R 3” , R 4 , R 7 , R 8 H

[0298] In Subformula 10:

[0299] R 1 , R 2 , R 3’ , R 3” , R 4 , R 7 , R 8 For H,

[0300] R 5 , R 6 are independently H, F, Cl, Br, methyl, CHF2 or CF3

[0301] In Subformula 11:

[0302] R 1, R 2 , R 3’ , R 3” , R 4 , R 8 For H,

[0303] R 5 is Br, methyl, CHF2 or CF3,

[0304] R 6 is F, Cl or CF3,

[0305] R 7 H or F

[0306] In Subformula 12:

[0307] R 1 , R 2 , R 4 , R 8 For H,

[0308] R 3’ is F or methyl,

[0309] R 3” For H,

[0310] R 5 is Br, methyl, CHF2 or CF3,

[0311] R 6 is F, Cl or CF3,

[0312] R 7 is H or F,

[0313] And the remaining residues have the meanings as shown in formula (I).

[0314] Compounds of formula (I), formula (II), formula (I') and formula (II') may have one or more chiral centers. Therefore, they may exist in various enantiomeric forms and are racemic or optically active forms. Therefore, the present invention also relates to optically active forms (stereoisomers), enantiomers, racemates and diastereomers of these compounds. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the present invention may be different, it may be desirable to use enantiomers. In these cases, the final product or even the intermediate can be separated into enantiomeric compounds by chemical or physical measures known to those skilled in the art, or even used as is in the synthesis.

[0315] In the case of racemic amines, diastereomers are formed from the mixture by reacting with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. It is also advantageous to perform chromatographic enantiomer separation with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivative methacrylate polymers fixed on silica gel). Eluents suitable for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile, for example in a ratio of 82:15:3. A mild method for resolving racemates containing ester groups (e.g., acetyl esters) is to use enzymes, particularly esterases.

[0316] The compound of the present invention can be in the form of a prodrug compound. "Prodrug compound" refers to in vivo under physiological conditions, such as by oxidation, reduction, hydrolysis, etc. (each of which is enzymatically carried out, or without enzyme participation), converted into a derivative of the bioactive compound according to the present invention. The example of a prodrug is such a compound: wherein the amino group in the compound of the present invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino; or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into boric acid ester, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy; or wherein the carboxyl group is esterified or amidated, or wherein the sulfhydryl group forms a disulfide bond with a carrier molecule (such as a peptide), which selectively delivers the drug to the target and / or the cytosol of the cell. These compounds can be prepared by the compound of the present invention according to well-known methods. Further examples of prodrugs are compounds in which a carboxylic acid ester in a compound of the invention is converted, for example, into an alkyl-, aryl-, choline-, amino-, acyloxymethyl or linolenoyl ester.

[0317] Metabolites of the compounds of the present invention are also within the scope of the present invention.

[0318] When the compounds of the present invention or their prodrugs may exhibit tautomerism, such as keto-enol tautomerism, the individual forms, such as keto or enol forms, are claimed separately and together as mixtures in any ratio. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, conformers, etc.

[0319] If desired, isomers may be separated by methods well known in the art, for example by liquid chromatography. The same applies to enantiomers, for example by using a chiral stationary phase. In addition, enantiomers may be separated by converting the enantiomers into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of the compounds of the invention may be obtained by stereoselective synthesis using optically pure starting materials.

[0320] The compounds of the present invention may be in the form of pharmaceutically acceptable salts or solvates.

[0321] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including an inorganic base or acid and an organic base or acid). In the case where the compound of the present invention contains one or more acidic or basic groups, the present invention also includes its corresponding pharmaceutically or toxicologically acceptable salt, particularly its pharmaceutically available salt. Therefore, the compound of the present invention containing an acidic group can exist in the form of a salt and can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt or an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or an organic amine (e.g., ethylamine, ethanolamine, triethanolamine or an amino acid). The compound of the present invention containing one or more basic groups (i.e., a protonated group) can exist in the form of a salt and can be used according to the present invention in the form of an addition salt with an inorganic or organic acid. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compound of the present invention contains both acidic and basic groups in the molecule, in addition to the salt forms mentioned, the present invention also includes inner salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in solvents or dispersions, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention, which are not directly suitable for use in medicines due to low physiological compatibility, but can be used as, for example, intermediates for chemical reactions or for preparing pharmaceutically acceptable salts.

[0322] The term "pharmaceutically acceptable solvate" refers to an addition form with a pharmaceutically acceptable solvent containing a stoichiometric or non-stoichiometric amount of the solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, such as a monohydrate or a dihydrate. If the solvent is an alcohol, the solvate formed is an alcoholate, such as a methanolate or an ethanolate. If the solvent is an ether, the solvate formed is an etherate, such as diethyl etherate.

[0323] Therefore, the following technical solutions are also in line with the present invention:

[0324] a) all stereoisomers or tautomers of the compounds, including mixtures thereof in all ratios,

[0325] b) prodrugs of the compounds, or stereoisomers or tautomers of these prodrugs,

[0326] c) pharmaceutically acceptable salts of the compounds and pharmaceutically acceptable salts of the technical solutions mentioned in (a) and (b),

[0327] d) Pharmaceutically acceptable solvates of the compounds and pharmaceutically acceptable solvates of the technical solutions mentioned in (a), (b) and (c).

[0328] It should be understood that all references to compounds above and below are intended to include these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable solvates of pharmaceutically acceptable salts thereof.

[0329] In the context of the present invention, the preferred quinazolinecarboxamide azetidine compound is 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (also referred to herein as "M2698").

[0330] The quinazolinecarboxamide azetidine compounds used in the present invention, such as the compounds of formula (I), (II), (I') and (II') as defined above, and preferably M2698, are further described in the international patent application WO2012 / 69146 "Quinazolinecarboxamide azetidine". Those skilled in the art can refer to the patent application to synthesize these quinazolinecarboxamide azetidine compounds.

[0331] The present invention also provides a composition comprising a quinazolinecarboxamide azetidine compound, preferably M2698. In a specific embodiment, the composition comprises a quinazolinecarboxamide azetidine compound, preferably M2698, and a pharmaceutically acceptable excipient, carrier or diluent.

[0332] Additional therapeutic agents, preferably anticancer agents

[0333] As taught above, in a preferred aspect, the combination or composition comprises, in addition to the quinazolinecarboxamide azetidine compound, in particular in addition to 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, at least one different therapeutic agent, preferably an anticancer agent.

[0334] In a preferred embodiment, at least one of the different therapeutic agents (preferably anticancer agents) is an anti-tumor agent, a signal transduction inhibitor, or a mixture thereof, as described in the "Definitions" section herein.

[0335] The combinations or compositions of the present invention may comprise one or more additional different therapeutic agents, preferably anti-cancer agents (also identified herein as agent (c)), such as, in particular, endocrine / hormonal therapeutic agents, anti-angiogenic agents, signal transduction inhibitors, anti-tumor agents, small molecules, antibodies or fragments thereof, antibody-drug conjugates (ADCs) and antisense molecules as described herein in the "Definitions Section", preferably anti-angiogenic agents, signal transduction inhibitors, anti-tumor agents, small molecules, growth factor receptor agents, antibodies or fragments thereof, antibody-drug conjugates (ADCs) or antisense molecules as described herein, wherein the amounts together are effective for treating cancer.

[0336] In some embodiments, the additional anticancer agent is selected from abemaciclib (LY2835219), abiraterone, abiraterone acetate, avitinib, acalabrutinib, aclarubicin, aldesleukin (IL-2), ado-trastuzumab emtansine, afatinib bismaleate, afifexifen, afuresertib, alectinib, alemtuzumab, hexamethylmelamine, ametinib, aloisine A, aloisine B. Apellis, atepolone, amifostine, amcenestrant (SAR439859), amelimumab, aminoglutethimide, aminopurvalanol, anastrozole, ervantumab, apalutamide, apaziquinone, aprepitant, arsenic trioxide, arzoxifene, asparaginase (pegaspargase), atezolizumab, atorvastatin (Caduet, Lipitor, Lypqozet), avapritinib, avelumab, axicabtagene ciloleucel), axitinib, azacytidine, azathioprine, azenosertib (ZN-c5), bazedoxifene, belinostat, bendamustine hydrochloride, bevacizumab, bexarotene, bicalutamide, bimiralisib, bemetinib (Mektovi or ARRY-162), birociclib (XZP3287), bleomycin sulfate, blinatumomab, bohemine, borestrant, bortezomib, borussertib, bosutinib, brentuximab vedotin, brigatinib, brinostane (GDC-0810), buparlisib (BKM120), busulfan, butyrolactone, cabazitaxel, cabozantinib-s-malate, calaspargase pegol-mknl, camizestrant (AZD9833), capecitabine, capacitinib (AZD5363), caplacizumab-yhdp, capmatinib hydrochloride, carboquinone, carboplatin, carfilzomib, carmustine, cemiprilimab-rwlc, celecoxib, celecoxib derivatives, cemiprilimab, ceritinib, cetuximab, chlorambucil, nitrogen mustard, cilengitide cisplatin, cladribine, clofarabine, cobimetinib, clopancilcept hydrochloride, crizotinib, cyclophosphamide, cyproterone, cytarabine, dabrafenib mesylate, dacarbazine, dacomitinib,Dactinomycin, dactolisib mesylate, dactolisib (SHR-6390), daratumumab, daratumumab and hyaluronidase-fihj, darbepoetin alfa, darolutamide, dasatinib, daunomycin hydrochloride, decitabine, defibrotide sodium, degarelix, denileukin, depertuzumab-mafudotin, detorsertib, diftitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dichloroethene acid salt, dinaciclib, dactuximab, vedicizumab (RC48-ADC), docetaxel, dordaviprone (ONC-201), dovitinib, doxorubicin hydrochloride, droloxifene, durvalumab, duvelithel, elastatin, elotuzumab, eltanexor, eltrombopag, enantuzumab, emapalumab-Izsg, eltanexor (KPT-8602), enasidenib mesylate (enasidenib mesylate), conafenib, enfortumab vedotin-ejfv, endoxifen, entrectinib, enzalutamide, enzastaurin, apetinib, epirubicin hydrochloride, epoetin alpha, epoetin platinum, erdafitinib, eribulin mesylate, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, fadrozoles, fedratinib hydrochloride, flavopiridol, floxuridine, fludarabine phosphate, fluorouracil, 5-fluorouracil, flutamide, formestane, forbreib, fostamatinib disodium, fotemustine, fulvestrant, gefitinib, gemcitabine hydrochloride, gemtuzumab ozogamicin, gingerol, gilteritinib fumarate, giredestrant (GDC9545), gradib maleate, glucarpidase, glufosfamide, goserelin acetate, granisetron, granisetron hydrochloride, histrelin, hydroxyurea, ibintumomab tiuxetan tiuxetan), ibrutinib, icotinib, idarubicin hydrochloride, idelalisib, idoxifene, ifosfamide, imatinib mesylate, imiquimod, improsulfan tosylate, indirubin, indirubin-3'-monoxime, infigratinib (BGJ398), oliguriazumab, interferon alpha-2b recombinant, interferon gamma, iobenguanidine I-131, patasertib, ipilimumab, irinotecan hydrochloride, isatuximab-irfc, ivosidenib, ixabepilone, ixazomib citrate, kenpaullone, ketoconazole, vedilatuzumab (also known as SGN-LIV1A), acetoin Lanreotide acid, lapatinib ditosylate, vedilatuzumab (SGN-LIV1A), larotrectinib sulfate, lerlotinib, larotrectinib, lasofoxifene, lazertinib, lenalidomide, lenvatinib mesylate, letrozole, leroxilimib (G1T38), folinic acid, leuprolide acetate, levamisole, lifirafenib, lobaplatin, lomustine, lonafarnib, lorlatinib, delitinib, lurbinectedin, luteinizing hormone-releasing hormone (LHRH) agonists, marizomib, meclofenamic acid, medroxyprogesterone acetate, megestrol acetate, melphalan, melphalan hydrochloride, mercaptopurine, meriolin3. Methotrexate, midostaurin, milciclib, miltefosine, dibromomannitol, dibromodole, mitoxantrone hydrate, miransertib, mitomycin, mitotane, mitoxantrone hydrochloride, mobotinib, moglizumab, moglizumab-kpkc, monepantel, pasitumomab-tdfk, naquotinib, narazaciclib (ON123300), naza tinib, necituzumab, nedaplatin, nelarabine, neratinib maleate, nilotinib, nilutamide, nimotuzumab, nimustine, niraparib mesylate monohydrate, nivolumab, obotuzumab, octreotide, ofatumumab, olaparib, olaramumab, omotinib, olomoucin, olomoucin II, omacetaxineomepesuccinate, omilimab, omomyc, ondansetron hydrochloride adenosine, onatasertib, osimertinib mesylate, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, palbociclib (Ibrance, PD-0332991 or PF-00080665), palifermin, palifosfamide, palonosetron hydrochloride, pamidronate disodium, panitumumab, panobinostat, paxalisib, pazopanib hydrochloride, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pemigatinib, pertuzumab, pesedatinib hydrochloride, pictilisib (GDC0941), pimasertib, piperazine pyrimidine derivatives (PF-4708671, PF-4708671), plerixafor, picoplatin, pipoxifene, pipobroman, plicamycin, polatuzumab vedotin-piiq, pomalidomide, ponatinib hydrochloride, pralidinib, poziotinib, pralatrexate, prednisone, pralidinib, procarbazine hydrochloride, propranolol hydrochloride, purvalanol A, purvalanol B, radium 223 dichloride, pyrotinib, raloxifene hydrochloride, ramucirumab, ranimustine, rapamycin analogs, rasburicase, ravulizumab-cwvz, recombinant interferon α-2b, refactinib, regorafenib, ribavirin, ribociclib (LEE-011), rifolimus, rintodestrant, ripretinib, rituximab, rolapitant, riviciclib hydrochloride (P276-00), roniciclib, romidepsin, romiprotinib, R-roscovitine, rucaparib camphorsulfonate, ruxolitinib phosphate, gosatuzumab (sacituzumabgovitecan-hziy), sapacerti, sabutinib, saplatin, ceritinib, ceritinib, selenisol, selpatinib, selumetinib sulfate, Streptomyces OA293, streptozotocin, selutuximab, sipruset-t, sonalisib, sonidegi, sirolimus, ceritinib, somatostatin (pasireotide), sorafenib tosylate, Streptomyces OA293, streptozotocin, sunitinib, tagraxofusp-erzs, talazopanib tosylate, talimogene laherparepvec, tamoxifen, tazemestat hydrobromide, terostat, temozolomide, temsirolimus, teniposide, tepotinib, tesifatinib, tesetaxel, testolactone, thalidomide, thioguanine, ThioTEPA (N,N'N'-triethylenethiophosphoramide), tipifarnib, tipracil, tisagenlecleucel, tocilizumab, tometuximab, topotecan hydrochloride, toremifene, tositumomab, trabectedin, trametinib, trastuzumab, detrastuzumab Trastuzumab polycarbazine (SYD985), trastuzumab and hyaluronidase-oysk (Herceptin Hylecta TM ), trastuzumab enmetuzumab, treoxazole, treracisib (GTI128), trifluridine and tipiracil hydrochloride, trimetrexate, triptorelin, trolofosamide, tucatinib, uritinib, eupressor (GSK2141795), uracil nitrogen mustard valrubicin, vandetanib, varlitinib, vemurafenib, venetoclax, vinblastine, vinblastine sulfate, vindesine, vincristine sulfate, vinflunine, vinorelbine tartrate, vismodegib, vistonuridine (uridine triacetate), vitusertib, vorinostat, voruzole, voruciclib, xylocydin, inlitinib, zanubrutinib, ziv-aflibercept, zetuzumab, ziv-aflibercept zotatifin, zoledronic acid, zolitinib, zotatifin, A77 1726 (active metabolite of leflunomide), ABBV-075, ABBV-744, ABP-1119, ABP-1130, AD80 / AD81, AG024322, AG-101, AI-6802, AL-5880S, AL-58922, ALM-301, AM-105, AMX-3009, APL-1898, ARQ-751, ARV-471, ASK-120067, ASN-007, AST-2818, ASTX-029, AT-13148, AT7519, ATG-017, AUM-302, AZ6197, AZD4547, AZD5153, AZD5438, AZD5597, AZD8055, AZD9496, BAY-1125976, BAY-1163877, BAY-24765 68. BAY-293, BBP-398, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BI-1701963, BI-3406, BI-4020, BIERKi, BLU-222, BLU-4810, BMS-387032, BMS-SCH, BMX-002, BO-1978, BPI-15086, BPI-27336, BPI-7711, BR790, BX795, BX912, C-005, CA-102 , CA-103, CC-115, CC-223, CC-90003, CK-101, CLM-29, CLM-3, CMAB-017, COTI-2, CR-13626, CSHEGF-29, CT-365, CYC065, D-03 16. D-0502, DBPR-112, DC-120, DFN-S29, DGD-I202, DHM-ZS, DS-2087b, DTRMWXHS-12, DZD-9008, EO-1001, ERAS-007, ERAS-60 1. ES-072, ETH-155008, ETS-001, FCN-411, FCN-437c, FHND-9041, FL772, FLAG-001, FLAG-003, FmAb-2, FP-208, FS-115, FT-IS18、FXY-l、GB-263、GC-1118A、GDC-0927、GLR2007、GSK470、HA-12128、HBI-2376、HEC-68498、HH-2710、HMPL-295、HMPL-309、HMPL-813、HS-627、H3B-6545、IACS-13909、I-BET151、I-BET762、ICP-189、INCB054329、IPA3、IPN-ERK、JAB-3068、JAB-3312、JMT-101、JNJ-7706621、JQ1、JRF-103、JRF-108、JRP-890、JRP-890、JS-111、JSI-1187、JX06、JZB-29、KBP-5209、KNP-501、KO-947、KS-99、KU-004、LL-191、LSZ102、LTT462、LXI-15029、LY2503029、LY2584702、LY2780301、LY3214996、LY3484356、LYS6K2、M074-2865、MCLA-129、MCLA-158、MDC-22、ME-344、MK-0752、MK-2206、MK-8353、MP 0274、mRX-7、MS417、MTX-211、MVC-101、NISC-6、NRC-2694、NSC-765844、NT-004、NT-113、NVP-LCQ19、OBX-1012、OP-1250、ORIC-114、OSI-027、OSU-03012、OSU-53、OT-043、OTX015、PB-357、PF-06821497、PF-06873600、PF-07062119、PF-07104091、PF-07220060、PF-07257876、PF-07260437、PF-07265028、PF-07284892, PF-0779954, PF-4708671, PHA-793887, PHT-427, PQR-514, PTX-200, PTX-367, QL-1105, QL-120 3. QR-213, R-CR8, RG6171, RGB286147, RGB-286638, RLY-1971, RMC-4550, RMC-4630, RMC-5552, RMC- 5845, Ro4584820, RVX-208, RX-0201, RX-0301, RXDX-105, RX-SHP2i, SAH-EJ1, SBF1, SCH772984, SCT -200, SDGR-5, SH3809, SHP099, SHR9549, SI-2, SJ432, SKLB-1028, SKLB-1206, SN-202, SN-38, SPH-1 18811, SPR-965, SRX-3177, SYN-004, TAM-03, TAS-117, TAS-6417, TAS-ASTX, TG02, TGRX-360, TK216 , TNO-155, TQB3303, TQB-3804, UBP-1215, VRN-071918, VRN-6, VS-6766, WBP-297, WJ-13404, WSD-09 22, WXFL-10030390, X-37-SHP2, XP-105, XZP-5809, YZJ-0318, ZK304709, ZNE-4, ZR-2002, ZSP-0391, ZW49, 10Z-membrane alkaloids, 5-iodo-indirubin-3'-monoxime or free base, and any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer form of any of the foregoing or any combination thereof. The additional anticancer agent may also be samuraciclib (also known as CT7001 or ICE0942).

[0337] In a preferred aspect, the additional anticancer agent is selected from the group of compounds listed above, wherein said list excludes afatinib bismaleate, brigatinib, cetuximab, erlotinib hydrochloride, gefitinib, icotinib, simertinib, pimasertib and / or tepotinib.

[0338] Pharmaceutical compositions and combinations

[0339] "Pharmaceutical composition" refers to a mixture of one or more therapeutic agents described herein or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, tautomers, hydrates or prodrugs thereof as active ingredients and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0340] Therefore, "pharmaceutical composition" generally refers to one or more active ingredients, and one or more inert ingredients that constitute the carrier, and any product produced directly or indirectly by the combination, complexation or aggregation of any two or more ingredients, or any product produced by the dissociation of one or more ingredients, or any product produced by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention covers any composition made by mixing a compound of the present invention (usually in a therapeutically effective amount), preferably at least (a) a quinazolinecarboxamide azetidine compound of formula (I), such as 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (or its pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer, including any mixture thereof in all proportions) and (b) a different therapeutic agent, preferably an anti-tumor agent and / or a signal transduction inhibitor, and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may additionally comprise one or more other compounds as active ingredients, for example one or more additional therapeutic agents of the present invention, preferably anticancer agents ("(c)"), or prodrug compounds or other substances known to be active against hormone-dependent diseases, preferably cancer.

[0341] The (pharmaceutical) combinations or pharmaceutical compositions of the present invention include combinations and compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and the nature of the active ingredients. They may conveniently be presented in unit dosage form and prepared by any method well known in the pharmaceutical art.

[0342] The (drug) combination or pharmaceutical composition may be, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions or suspensions, in a form suitable for parenteral injection, such as sterile solutions, suspensions or emulsions, in a form suitable for topical administration, such as ointments or creams, or in a form suitable for rectal administration, such as suppositories.

[0343] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if necessary.

[0344] The combination or pharmaceutical composition may be in unit dosage form suitable for single administration of precise amounts.

[0345] Combinations or pharmaceutical compositions of therapeutic agents suitable for delivery of the combination therapies of the present invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

[0346] The therapeutic agents of the combination therapy of the present invention can be administered orally. Oral administration can include swallowing so that the therapeutic agent enters the gastrointestinal tract, or buccal or sublingual administration can be used, through which the therapeutic agent enters the blood directly from the mouth.

[0347] Formulations suitable for oral administration include solid preparations such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid-filled), chewables, multi- and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesives), ovules, sprays, and liquid preparations.

[0348] Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations can be used as fillers in soft or hard capsules and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstitution of solids (e.g., from a sachet).

[0349] The therapeutic agents of the combination therapies of the invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described by Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11(6), 981-986, the disclosure of which is incorporated herein by reference in its entirety.

[0350] For tablet dosage forms, the therapeutic agent may account for 1wt% to 80wt% of the dosage form, more typically 5wt% to 60wt% of the dosage form. In addition to the active agent, the tablet usually contains a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, low alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Typically, the disintegrant may account for 1wt% to 25wt% of the dosage form, preferably 5wt% to 20wt%.

[0351] Binders are generally used to impart adhesion properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0352] Tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the amount of surfactant is typically 0.2 wt% to 5 wt% of the tablet, and the glidant is typically 0.2 wt% to 1 wt% of the tablet.

[0353] Tablets also typically contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants are typically present in an amount of 0.25wt% to 10wt%, preferably 0.5wt% to 3wt% of the tablet.

[0354] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets may contain up to about 80 wt % active agent, about 10 wt % to about 90 wt % binder, about 0 wt % to about 85 wt % diluent, about 2 wt % to about 10 wt % disintegrant and about 0.25 wt % to about 10 wt % lubricant.

[0355] Tablet blends can be compressed directly or by rollers to form tablets. Tablet blends or portions of blends can alternatively be wet, dry or melt granulated, melt congealed or extruded prior to tableting. The final formulation can include one or more layers and can be coated or uncoated; or encapsulated.

[0356] The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[0357] Solid dosage forms for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0358] Suitable modified release formulations are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies (e.g., high energy dispersions and osmotic and coated particles) can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 2000 / 035298. The disclosures of these references are incorporated herein by reference in their entirety.

[0359] Kits as described herein may be particularly suitable for administering different dosage forms, such as oral and parenteral, for administering a single active (particularly therapeutic) agent of a combination or composition at different dosage intervals, or for titrating the active (particularly therapeutic) agents of a combination or composition to each other. In order to help compliance, the kit typically includes instructions for administration, and memory aids may be provided. The kit may further include other materials that may be used to administer the drug, such as diluents, filters, IV bags and lines, needles and syringes, etc. The kit may further include any other materials that may be used to stratify the prognosis of metastatic breast cancer by identifying a tumor (e.g., PCR test) that has evolved resistance to endocrine therapy.

[0360] A specific kit comprises i) (a) a quinazolinecarboxamide azetidine compound, which is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) different therapeutic agents as described herein, such as anti-tumor agents and / or signal transduction inhibitors, in different containers, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, and ii) materials for administering compounds (a) and / or (b).

[0361] A more specific kit comprises i) (a) a quinazolinecarboxamide azetidine compound, which is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) different therapeutic agents as described herein, such as anti-tumor agents, such as selective ER modulators ("SERMs"), selective ER downregulators / degraders ("SERDs"), aromatase inhibitors ("AIs"), complete estrogen receptor antagonists (CERAN), or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, and ii) materials for administering compounds (a) and / or (b).

[0362] Even more specific kits comprise i) (a) a quinazolinecarboxamide azetidine compound, which is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) different therapeutic agents as described herein, such as a selective ER downregulator / degrader ("SERD"), for example selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, camizestrant, elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, in different containers. AZD9496, D-0502LY3484356, GDC-0927 and SHR9549, and even more preferably elastomeric, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, and ii) a material for administering compounds (a) and / or (b).

[0363] Another specific kit comprises i) (a) a quinazolinecarboxamide azetidine compound, which is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) a different therapeutic agent as described herein, such as a signal transduction inhibitor, such as a cyclin-dependent kinase (CDK) inhibitor or a PI3K / Akt / mTOR ("PAM") pathway inhibitor, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, in different containers, and ii) materials for administering compounds (a) and / or (b).

[0364] Another specific kit comprises i) (a) a quinazolinecarboxamide azetidine compound, which is preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, including any mixture thereof in all ratios, and (b) different therapeutic agents as described herein, such as cyclin-dependent kinase (CDK) inhibitors, preferably CDK 4 / 6 inhibitors, such as abemaciclib, palbocilcib, ribociclib, even more preferably abemaciclib, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, and ii) materials for administering compounds (a) and / or (b).

[0365] When quinazolinecarboxamide azetidine compounds, particularly M2698, are used to treat or prevent cancers mentioned herein, satisfactory results are generally obtained when the compound is administered at a daily dose of about 15 milligrams (mg) to about 800 mg, about 50 mg to about 800 mg, or about 15 milligrams (mg) to about 400 mg (possibly given as a single dose). The daily dose of M2698 administered to a subject is, for example, about 60 milligrams to about 300 milligrams, preferably about 80 milligrams to about 280 or 300 milligrams, and even more preferably about 160 milligrams to about 240 milligrams.

[0366] In a specific aspect, the quinazolinecarboxamide azetidine compound of formula (I) is 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide ("M2698"), and the compound is present in the combination or composition at a dosage of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg.

[0367] In a particular embodiment, the antineoplastic agent is elastomeric, which is present in the combination or composition at a dosage of about 200 mg to about 500 mg, preferably about 300 mg to about 400 mg, and more preferably about 350 mg. Elastomeric may be present in the combination or composition as a specific active ingredient, and another different active ingredient also present in the combination or composition is 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide ("M2698") (used as the quinazolinecarboxamide azetidine compound).

[0368] Other examples of therapeutically effective amounts of elastomeric or a solvate (e.g., hydrate) or salt thereof for use in the methods disclosed herein include, but are not limited to, about 150 to about 1500 mg, about 200 to about 1500 mg, about 250 to about 1500 mg, or about 300 to about 1500 mg dose qd for subjects with resistant ER-driven tumors or cancers; about 150 to about 1500 mg, about 200 to about 1000 mg, or about 250 to about 1500 mg dose qd for subjects with wild-type ER-driven tumors and / or cancers and resistant tumors and / or cancers; and for subjects with (predominantly) wild-type ER-driven tumors and / or cancers, about 300 to about 500 mg, about 300 to about 550 mg, about 300 to about 600 mg, about 250 to about 500 mg, about 250 to about 550 mg, about 250 to about 600 mg, about 200 to about 500 mg, about 200 to about 550 mg, about 200 to about 600 mg, about 150 to about 500 mg, about 150 to about 550 mg, or about 150 to about 600 mg qd. In certain embodiments, the dosage of the antitumor agent (e.g., elastomeric) disclosed herein or its polymorph, enantiomer, stereoisomer, salt, solvate or tautomer can be about 150 mg, 170 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 30 mg to 2000 mg, 100 mg to 1500 mg or 150 mg to 1500 mg, and any amount therebetween, such as 172 mg, 258 mg or 345 mg, po, qd for an adult subject. The daily dose can be achieved by single administration or multiple administrations.

[0369] The effective dose of anticancer agents (particularly small molecule inhibitors) is usually in a single dose or divided dose in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day. For a 70 kg human subject, this will be equivalent to about 0.01 to about 7 g / day, preferably about 0.02 to about 2.5 g / day, and more preferably about 0.02 to about 1.0 g / day. In some cases, the dosage level at the lower limit of the above range may be more than enough, and in other cases, a larger dose can still be used without causing any harmful side effects, provided that such a larger dose is first divided into several small doses for full-day administration. The dosage can be used as a single dose (QD), or optionally can be subdivided into smaller dosages, suitable for BID (twice a day), TID (three times a day) or QID (four times a day) administration.

[0370] The therapeutically effective amount of compound depends on many factors, including, for example, the age and body weight of animals, the exact illness and the severity thereof, the properties and the administration method of the preparation, and is finally determined by the treating doctor or veterinarian. However, the effective amount range of the compound according to the present invention is generally 0.1 to 100mg / kg of recipient (mammalian subject) body weight every day, and usually especially in the range of 1 to 10mg / kg of body weight every day. Therefore, the actual amount of an adult mammal of body weight 70kg every day is usually between 70 and 700mg, wherein the amount can be used as a single dose every day or usually with a series of partial doses every day (for example, twice, three times, four times, five times or six times) to apply so that the total daily dose is the same. The effective amount of its salt, solvate, polymorph, tautomer, enantiomer or stereoisomer can be determined according to the fraction of the effective amount of the compound of the present invention itself.

[0371] In some embodiments, the CDK inhibitor or its pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer is administered at a daily dose of about 1 mg to about 1000 mg per day. In some embodiments, the compound or its pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer is administered at a daily dose of about 10 mg to about 500 mg per day. In some embodiments, it is administered at a dose of about 25 mg to about 300 mg per day. In some embodiments, it is present in an amount of about 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 Doses of 0, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 260, 270, 275, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475 or 500 mg are administered on a QD, BID, TID or QID schedule.

[0372] In certain embodiments, the signal transduction inhibitor is a cyclin-dependent kinase (CDK) inhibitor, which is selected from, for example, CDK 1, 2, 4, 5, 6 and / or 7 inhibitors and any mixtures thereof, more preferably a CDK4 / 6 inhibitor, and is, for example, palbociclib, ribociclib or abemaciclib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, which is orally administered at a daily dose of about 25 mg to about 600 mg per day, and sometimes at a dose of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg per day. In other embodiments, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, which is orally administered at a daily dose of about 100 mg to about 300 mg per day; or the CDK4 / 6 inhibitor is palbociclib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, which is orally administered at a daily dose of about 75 mg to about 125 mg per day; or the CDK4 / 6 inhibitor is ribociclib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, which is orally administered at a daily dose of about 200 mg to about 600 mg per day.

[0373] This dosage regimen can be adjusted by the oncologist to provide the best therapeutic response for the patient.

[0374] In a specific example, the quinazolinecarboxamide azetidine compound, particularly M2698, can be formulated as an active compound of a combination or pharmaceutical composition, for example, administered orally at 80 mg per dose, once or several times a day, preferably several times a day, to obtain the desired therapeutic effect. In a preferred aspect of the invention, the patient receives 240 mg / day of M2698.

[0375] Alternatively, acceptable (drug) combinations or compositions described herein can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the active compound of the present application with a suitable non-irritating excipient or carrier, which is solid at room temperature, but liquid at body (e.g., rectal or vaginal) temperature, and will therefore melt in the rectum or vaginal cavity to release the active compound. Such materials include, for example, cocoa butter, suppository waxes (e.g., beeswax) and / or polyethylene glycol.

[0376] In actual use, the compound of the present invention can be used as an active ingredient, and is closely mixed with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques to combine. As explained above, the carrier can take a variety of forms, depending on the form of the desired preparation for administration, such as oral or parenteral (including intravenous).

[0377] Pharmaceutically acceptable combinations and compositions described herein can be orally administered in any oral acceptable dosage form (including but not limited to capsules, tablets, aqueous suspensions or solutions). In this solid dosage form, the active compound can be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). According to conventional practice, this dosage form can also include additional substances other than inert diluents, such as lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. When an aqueous suspension is needed for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavoring agents or coloring agents can also be added.

[0378] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and / or sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and / or glyceryl monostearate, h) absorbents such as kaolin and / or bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and any mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.The active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.

[0379] Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings (i.e., buffers) and other coatings well known in the field of pharmaceutical formulation. They may optionally contain opacifiers and may also be compositions that release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0380] Tablets and capsules represent the most advantageous oral dosage unit forms due to their ease of administration, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent (%) of active compound. Of course, the percentage of active compound in these compositions may vary, and may conveniently be between about 2% to about 80% of the weight of the unit, such as 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective (i.e. therapeutic) dose will be obtained. Active compound may also be administered intranasally, for example, by drops or sprays.

[0381] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and any mixture thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0382] The compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water with appropriate mixing with a surfactant (e.g., hydroxypropylcellulose). Dispersions may also be prepared in oils in glycerol, liquid polyethylene glycols, and mixtures thereof. Under ordinary storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0383] The pharmaceutical form suitable for injection includes sterile aqueous solution or dispersion and sterile powder for preparing sterile injection solution or dispersion extemporaneously. In all cases, the form must be sterile and must be a fluid that is easy to injectable (syringability). It must be stable under manufacturing and storage conditions and must be preserved for the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol and liquid polyethylene glycol) and vegetable oil or any suitable mixture thereof.

[0384] Any suitable route of administration can be used to provide an effective dose of the compounds of the present invention to mammals, particularly humans. For example, oral, rectal, topical, parenteral, ocular, pulmonary and / or nasal routes, etc., can be used. Dosage forms include tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Preferably, the compounds of the present invention are administered orally.

[0385] The effective dosage of any active ingredient described herein may vary depending on the specific compound used, the mode of administration, the treatment condition and the severity of the condition being treated. Such dosages can be readily determined by a person skilled in the art (usually an oncologist).

[0386] Subjects

[0387] As explained above, in the context of the present invention, the term "patient" or "subject" refers to any single subject, including human and mammalian veterinary patients, in need of therapy or participating in a clinical trial, epidemiological study or used as a control.

[0388] A "subject" or "patient" is typically a mammal. The subject can be a human or a non-human mammal, such as a rodent, such as a mouse or rat, a rabbit, a primate, such as a monkey, a dog, a cat, a bovine, an equine, such as a horse, or a transgenic species thereof.

[0389] In certain aspects, the mammal is a human, regardless of age or sex.

[0390] In some embodiments, the subject is an adult human subject. The subject is preferably a female.

[0391] In some such embodiments, the subject is a postmenopausal female or male.

[0392] In some such embodiments, the subject is a premenopausal or perimenopausal woman.

[0393] In some such embodiments, the subject is a premenopausal or perimenopausal woman being treated with a luteinizing hormone releasing hormone (LHRH) and / or gonadotropin releasing hormone (GnRH) agonist (e.g., buserelin, cetrorelix, gonadorelin, goserelin, leuprolide, triptorelin, or triptorelix).

[0394] In some such embodiments, the subject is a male. In some such embodiments, the subject is a male treated with a luteinizing hormone-releasing hormone (LHRH) and / or gonadotropin-releasing hormone (GnRH) agonist (e.g., goserelin, leuprolide, triptorelin, and degarelix).

[0395] In some embodiments, the subject is a human child between the ages of birth and 18 years.

[0396] The subject is typically a subject suffering from a hormone-dependent disease, preferably cancer. Unless otherwise specified in the present disclosure, cancer is characterized by malignant tumors and / or metastases preferably present in the brain, bone, lung or liver.

[0397] In certain aspects, the subject is a child between the ages of birth and 15 years with pediatric cancer.

[0398] The subject is preferably a subject or patient with a hormone receptor positive ["HR+", such as estrogen receptor+ ("ER+") and / or progesterone receptor+ ("PgR+")] benign, premalignant or malignant tumor, preferably an estrogen receptor positive (ER+) premalignant or malignant tumor.

[0399] In certain aspects, the subject has a malignancy that is ER+, regardless of his / her epidermal growth factor receptor-2 status (the tumor or the subject may be "HER2-positive," "HER2-negative," or "HER2-low").

[0400] In a preferred embodiment, the subject suffers from breast cancer, preferably advanced breast cancer, particularly metastatic advanced breast cancer.

[0401] In typical aspects, the patient has histologically and / or cytologically confirmed breast cancer with hormone receptor positive status (ER and / or PgR positive). The patient may also additionally have epidermal growth factor receptor 2 negative ("HER2-") status, epidermal growth factor receptor 2 positive ("HER2+") status, or epidermal growth factor receptor 2 low ("HER2 low") status, as defined by Bergeron A et al., 2023 and Peiffer D. et al., 2023.

[0402] In a specific and preferred embodiment of the present invention, the subject is a subject who is undergoing cancer treatment, in particular conventional treatment for cancer, preferably hormonal treatment for cancer, or a subject who has undergone such treatment.

[0403] This means that, usually before assessing the sensitivity of the subject to a specific cancer treatment, or before treating the subject with a compound, combination or composition according to the present invention, the subject has been exposed to the specific cancer treatment. The subject may have been exposed to a complete conventional treatment regimen or a part of a complete conventional treatment regimen, such as being exposed to at least one cycle of a total planned treatment regimen. In a preferred embodiment, the subject has been treated with a drug used in a hormone therapy defined herein or exposed to a drug used in a hormone therapy defined herein, such as a drug selected from a selective ER regulator (SERM), a selective ER down-regulator degrader (SERD), an aromatase inhibitor (AI) and a complete estrogen receptor antagonist ("CERAN") .

[0404] In a specific aspect, the subject is a subject who has been treated with a drug selected from, for example, a drug used in hormone ( / endocrine) therapy, a CDK inhibitor, a PI3K / AKT / mTOR ("PAM") pathway inhibitor, or any combination thereof, in particular a combination of a CDK inhibitor and hormone ( / endocrine) therapy, a combination of a CDK inhibitor and a SERD, or a combination of a CDK inhibitor, a SERD and a PI3K / AKT / mTOR ("PAM") pathway inhibitor.

[0405] The subject can be one who has exhausted all standard acceptable treatment options, has measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria (EA Eisenhauer, Eur J Cancer. 2009 Jan;45(2):228-47) and a biopsy accessible tumor.

[0406] The above-mentioned subject herein is preferably a subject or patient suffering from a breast cancer tumor, and even more preferably a breast cancer tumor expressing estrogen receptor α (ERα) protein (encoded by the ESR1 gene).

[0407] In a preferred aspect, the subject's ESR1 mutation status is determined on circulating tumor deoxyribonucleic acid (ctDNA) in the blood prior to or during any treatment with the combination or composition of the invention using methods known to those skilled in the art (e.g., Guardant360 CDx assay) to monitor the progression of the disease or the subject's response to treatment. Preferably, the ESR1 mutation status is limited to ESR1 missense mutations in the ligand binding domain (between codons 310 to 547).

[0408] Treatment of patients with the combinations or compositions of the invention is preferred when disease progression and / or unacceptable therapy-induced toxicity is observed following a different previously applied therapy (or detected, for example, by analysis of ESR1 mutation status).

[0409] The subject may be a subject with de novo resistance to hormone therapy.

[0410] The subject is preferably a subject with acquired resistance to hormone therapy.

[0411] In a preferred aspect of the invention, the subject is a subject who has developed (acquired) endocrine resistance during or after hormone / endocrine therapy and whose tumor is characterized by mutated estrogen receptor alpha (ERa). Mutations in ERA are often responsible for ER-independent growth of cancer cells or tumors.

[0412] In a preferred aspect, a cancer sample or cell obtained from a subject has a genetic change, typically a mutation that affects the sequence of a translated protein, and results in, for example, a loss (deletion) of one or more amino acids in the estrogen receptor 1 (ESR1) gene of SEQ ID NO:3 responsible for the expression of the mutated Era, an increase in one or more amino acids, and / or substitution of at least one amino acid by another amino acid. In a preferred aspect, the mutation (including, for example, an increase, deletion, substitution, or frameshift mutation) occurs in the ligand binding domain of the wild-type sequence of the ERa protein of SEQ ID NO:1. In a specific aspect, the tumor is characterized by a change in the conformation of the ligand binding domain (SEQ ID NO:2) of the ERa protein responsible for the constitutive activation of the ER receptor, even in the absence of estrogen.

[0413] The subject may be a subject suffering from a pre-existing mutation in the ESR1 gene (typically a mutation responsible for expression of a mutant Era) which is responsible for constitutive activation of the ER receptor even in the absence of estrogen.

[0414] The estrogen receptor 1 (ESR1) or ERa protein status of a patient can be determined by detecting mutations in the ESR1 gene or ERa protein.

[0415] Those skilled in the art will recognize that various methods and techniques can be used to determine ESR1 or ERa status, including sequencing techniques well known in the art, such as next generation sequencing (NGS) and droplet digital PCR (ddPCR). For example, one useful tool is Guardant360 TM , a highly sensitive next generation sequencing platform (Guardant Health, USA). This diagnostic test can detect any ESR1 mutation with a low sensitivity limit of 0.05%. This tool is used, for example, in the experimental section for testing performed on liquid tumor biopsies.

[0416] Another useful tool is Inostics Liquid Biopsy (ONCOBEAM TM) ctDNA biomarker standard test (see www.sysmex-inostics.com; https: / / cdn2.hubspot.net / hubfs / 5871980 / OncoBEAM_ctDNA_Testing_in_Clinic al_Practice_NSCLC_web.pdf. Further description and use of this assay can be found in Oxnard, GR et al. J. Clin. Oncol. 34(28):3375-3382 (2016); Wu, YL et al. MA08.03 J. Thorac. Oncol. 12, S386 (2017); Mok, TS et al. N. Engl. J. Med. 376, 629-640 (2017); and Thress K. et al. Poster presented at: European Society for Medical Oncology 2014 Congress; 2014 Sep 26-30; Madrid, Spain; #1270P; 25. Murtaza M. et al. Nature. 497, 108-112 (2013). This diagnostic test can detect any ESR1 mutation with a low level sensitivity limit of 0.05%.

[0417] In a preferred aspect of the invention, ER+ breast cancer is characterized by a mutated estrogen receptor alpha (ERa) cancerous tumor, wherein the mutation occurs in the ligand binding domain of the ERa wild-type sequence of SEQ ID NO: 1 (i.e., in SEQ ID NO: 2), characterized by a change in the conformation of the ligand binding domain of the ERa protein (SEQ ID NO: 2), and / or characterized in that ERa is expressed in a constitutively active form, which does not require the presence or binding of its hormone ligand to be active.

[0418] In another preferred aspect of the present invention, an ERa mutation can be confirmed by determining that the first mutant allele frequency ("MAF") value of the first ERa mutant is equal to or greater than (≥) 0.5% and / or the second MAF value of the second ERa mutant value is less than (<) 0.5%. Mutant allele frequency or "MAF" is a ratio that represents the number of individual genetic reads carrying a specific mutation relative to the wild-type sequence at a specific position divided by the decimal of the total number of individual genetic reads covering the same locus. For example, for a specific sequence position, if the total sequencing depth is 10,000, of which adenine (A) bases account for 9,900 different occurrences, the remaining different sequencing occurrences may include, for example, 23 occurrences of thymine (T) bases at the same position, 42 occurrences of cytosine (C) bases at the same position, and the remaining 35 occurrences of guanine (G) bases at the same position. Because the vast majority of sequences have adenine bases in this position (thus assigning adenine in this position as " wild type " base), therefore the mutant allele frequency with thymine (T) base is calculated as (T) / (T+C+G+A), or 23 / 10000=0.0023 here.Because those skilled in the art understand that genetic code is redundant, the mutant allele frequency can also be calculated according to the codon encoding of specific amino acids in specific protein sequence.Therefore, the MAF value reflecting amino acid mutation will group all nucleotide sequences encoding the same mutation.It is also understood by those skilled in the art that single gene can encode the amino acid mutation at different positions.Therefore, the MAF value of multiple amino acid mutations at different positions in single gene can be calculated.

[0419] In a preferred embodiment, the mutation occurs at at least one residue selected from 380, 392, 404, 422, 463, 536, 537 and 538 of SEQ ID NO: 1, and is preferably an amino acid substitution selected from the group consisting of E380Q, V392I, F404fs, V422del, S463P L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, D538G, even more preferably Y537S and / or D538G mutations.

[0420] Those skilled in the art will recognize that different ESR1 mutations can result in ERa proteins with various mutations, including, for example, one or more of the following amino acid sequence mutations: E380Q, V392I, F404fs, V422del, S463P, L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, and D538G. In particular aspects, mutations at specific positions in the ERa protein sequence are evaluated in the methods disclosed herein, particularly mutations at amino acid positions 537 and / or 538 in SEQ ID NO: 1 (as opposed to ESRI genetic mutations in codons at those positions that have altered nucleic acid sequences but still encode wild-type amino acid residues at given positions within the ERa protein).

[0421] In a preferred aspect, the patient is a patient who has been treated with (exposed to) a drug for treating cancer or is still being treated with a drug for treating cancer, particularly a drug for hormone therapy, such as a selective ER and modulator (SERM), a selective ER down-regulator degrader (SERD), an aromatase inhibitor (AI) and / or a complete estrogen receptor antagonist ("CERAN"), a luteinizing hormone releasing hormone (LHRH) and / or a gonadotropin releasing hormone (GnRH) agonist, such as a selective ER and modulator (SERM), a selective ER down-regulator degrader (SERD), an aromatase inhibitor (AI) and / or a complete estrogen receptor antagonist ("CERAN"), as further exemplified below. The patient is preferably a subject who is unresponsive to hormone therapy (or in other words a patient who is resistant).

[0422] In an even more preferred aspect, the patient is a patient who has been treated with (exposed to) a drug for treating cancer or is still being treated with a drug for treating cancer, in particular a drug selected from drugs used in hormone ( / endocrine) therapy, CDK inhibitors, PI3K / AKT / mTOR ("PAM") pathway inhibitors and any combination thereof, in particular:

[0423] -i) Combinations of: CDK inhibitors [e.g., abemaciclib (also known as LY2835219), AG024322, aloisine A, aloisine B, atepolone, aminopurvalanol, AT7519, AZD-5438, AZD5597, BLU-222, BMS-387032, birociclib (XZP3287), bohemine, butyrolactone, CYC065, dalsil (SHR-6390), dinaciclib, ETH-155008, flavopiridol, FCN-437c, GLR2007, indirubin, indirubin-3'-monoxime, JNJ-7706621, kemperolone, lelociclib (also known as G1T38), meriolin 3. milciclib, narazaciclib (ON123300), NVP-LCQ19, olomoucin, olomoucin II, palbociclib (also known as Ibrance, PD-0332991 or PF-00080665), PF-07220060, PF-07104091, PF-06873600, PHA-793887, Purvalanol A, Purvanol B, R-CR8, RGB-286638, RGB286147, ribociclib (also known as LEE-011), riviciclib hydrochloride (P276-00), roniciclib, R-roscovitine, Ro4584820, samuraciclib (also known as CT7001 or ICE0942), SRX-3177, TG02, TQB3303, triraciclib (also known as GTI128), voruciclib, xylocydin, ZK304709, 10Z-membrane alkaloids, 5-iodo-indirubin-3'-monoxime, and (1R,3S )-3-[3-(([3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl)amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate; and related compounds as described in WO2022 / 018596)], and ii) a hormonal therapeutic agent [e.g., a selective ER modulator (SERM), a selective ER downregulator degrader (SERD), an aromatase inhibitor (AI) inhibitor, or CERAN, a hormone, a luteinizing hormone releasing hormone (LHRH) agonist, a gonadotropin releasing hormone (GnRH) agonist, a progestin, an antiandrogen, a CYP17 inhibitor, and an antiadrenergic agent], or

[0424] -i) a CDK inhibitor, such as any of the CDK inhibitors described above, and ii) a SERD [e.g., fulvestrant, elastrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also known as RAD-1901], amcenestrant [(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene- 3-carboxylic acid, also known as SAR439859], brinostran [(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, also known as ARN-810 or GDC-0810], camizestrant [N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine, also known as AZD9833], giredestrant [3-((lR,3R)-l-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, also known as RG6171 or GDC9545], rintodestrant [(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, Also known as G1T48], AZD9496 [(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(l,l-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also known as LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, D0502. In another aspect, the SERD can be, for example, amcenestrant [(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, also known as SAR439859], azenosertib (ZN-c5) [1-[(7R)-7-ethyl-7-hydroxy-5,6-dihydrocyclopentadienyl[b]pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one], borestrant[(7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol-1,3,5(10)-triene-3,17-diol-boronic acid], bulinstrant[(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, also known as ARN-810 or GDC-0810], camizestrant[N-[1 -(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine, also known as AZD9833], ellastrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also known as RAD-1901], fulvestrant [(7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol-1,3,5(10)-triene-3,17-diol] 、giredestrant [3-((lR,3R)-l-(2,6-difluoro-4-((l-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, also known as RG6171 or GDC9545]、imlunestrant [(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol]、rintodestrant [(E)-3-(4-((2-(4-fluoro- 2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thien-3-yl)oxy)phenyl)acrylic acid, also known as G1T48], AZD9496 [(E)-3-[3,5-difluoro-4-[(lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-l,3,4,9-tetrahydropyrido[3,4-b]indol-l-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(l,l-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thien-3-yl)oxy)phenyl)acrylic acid (also known as LSZ102), D-0502, LY3484356, GDC-0927 or SHR9549], or,

[0425] -i) a CDK inhibitor, such as any of the CDK inhibitors described above, ii) a SERD, such as any of the SERDs described above, and iii) a PI3K / AKT / mTOR ("PAM") pathway inhibitor, such as bimiralisib, dactolisib tosylate, ditosertib, everolimus, monepantel, omilisib, onatasertib, rufoslimus, sapacerti, sirolimus, Streptomyces sp. OA293, temsirolimus, vitusertib, AL-5880S, AL-58922, AUM-302, CA-102, CA-103, CC-115, CC-223, CT-365, DFN-S29, DHM-ZS, FP-208, FT-I S18, HEC-68498, LXI-15029, ME-344, NSC-765844, OSI-027, OSU-53, OT-043, PQR-514, PTX-367, QR-213, RMC-5552, SN-202, SPR-965 or TAM-03, WXFL-10030390 or XP-105; furesertib, borussertib, capasertinib (AZD5363), celecoxib or celecoxib derivatives, dordaviprone (ONC-201), enzastaurin, patasertib, miransertib, eupressant (GSK2141795), ALM-301 , ARQ-751, AT-13148, AZD8055, BAY-1125976, BX795, BX912, COTI-2, DC-120, FXY-1, GSK470, JRP-890, JX06, KS-99, LY-2503029, MK-2206, NISC-6, OSU-03012, PHT-427, PTX-200, RX-0201, RX-0301, SBF1 or TAS-117, apellisib, buparlisib (BKM120), copanlisib, duvilisib, idelalisib, paxalisib, pictilisib (GDC0941) and sonalisib].

[0426] The patient is preferably a subject who has not responded to (or in other words is resistant to) treatment.

[0427] In a particular aspect, the patient is one who has been exposed or is still exposed to standard of care treatment with an anti-cancer agent and more preferably with an anti-tumor agent and / or a signal transduction inhibitor.

[0428] In another specific aspect, the patient is one who has been exposed or is still exposed to a combination of a SERD compound (e.g., borestrant, camizestrant, and / or fulvestrant) and a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib, and / or ribociclib).

[0429] In another specific aspect, the patient is one who has been exposed or is still exposed to a combination of a SERD compound (eg, camizestrant) and a CDK4 / 6 inhibitor (eg, palbociclib).

[0430] In another specific aspect, the patient is a patient who has been exposed or is still exposed to a combination of a SERD compound (e.g., borestrant, camizestrant, elastrant and / or fulvestrant) with a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib and / or ribociclib) and a PI3K / AKT / mTOR ("PAM") pathway inhibitor (e.g., apellis, capasitinib and / or everolimus).

[0431] In another specific aspect, the patient is a patient who has been exposed or is still exposed to a combination of a SERD compound (e.g., fulvestrant) with a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib, and / or ribociclib) and a PI3K / AKT / mTOR ("PAM") pathway inhibitor (e.g., capasitinib)

[0432] Treatment can occur in the neoadjuvant setting (ie, before surgery) or outside of the neoadjuvant setting (ie, after surgery).

[0433] In particular aspects, the patient is a postmenopausal patient with advanced ER+ breast cancer who has been exposed to a SERM (e.g., tamoxifen) or to a SERD compound (e.g., borestrant, camizestrant, elastrant and / or fulvestrant), to an AI (e.g., letrozole) or to a CERAN (e.g., OP-1250), preferably to a SERD compound, in particular to fulvestrant.

[0434] In another specific aspect, the patient has been exposed or is still exposed to a hormonal agent, preferably a SERD compound (e.g., borestrant, camizestrant, elastrant and / or fulvestrant), an AI (e.g., letrozole), a CERAN (e.g., OP-1250), or a PI3K / Akt / mTOR ("PAM") pathway inhibitor.

[0435] In further specific aspects, the patient has been exposed or is still exposed to a hormonal therapeutic agent, preferably a SERD compound (e.g., borestrant, camizestrant, elastrant and / or fulvestrant), an AI compound (e.g., letrozole), a CERAN compound (e.g., OP-1250), and a CDK4 / 6i (e.g., palbociclib (PD0332991), ribociclib (LEE011) and / or abemaciclib (LY2835219)).

[0436] In further specific aspects, the patient has been exposed or is still exposed to a hormonal therapeutic agent, such as fulvestrant, letrozole or lapatinib, preferably a compound such as borestrant, fulvestrant, camizestrant, elastrant, letrozole and / or lapatinib.

[0437] In another specific aspect, the patient is a premenopausal patient with advanced ER+ breast cancer who has been exposed to ovarian ablation or neutralization (by oophorectomy, radiation therapy, or by administration of a luteinizing hormone-releasing hormone antagonist) and hormonal therapy involving administration of a SERM (eg, tamoxifen).

[0438] In another specific aspect, the patient has been exposed or is still exposed to an anti-estrogen in combination with a targeted agent or in other words, an inhibitor of the cell cycle, an inhibitor of the PI3K / Akt / mTOR pathway, an inhibitor of a growth factor receptor; a compound that targets alterations in the ubiquitin-proteasome pathway; or a compound that increases the activity of the bromodomain and / or super-terminal domain of a protein.

[0439] In a further specific aspect, the patient has been continuously exposed to the same or different hormone therapies, preferably different (distinct) independent therapies, in a continuous treatment sequence / treatment line (from 1 to 12 lines of treatment, with a median of 6 lines of treatment). A specific hormone therapy may occur several times, i.e. be used in several sequences of a continuous treatment sequence.

[0440] cancer

[0441] As explained above (see "Definitions" section), unless the disclosure specifies otherwise, a cancer or tumor is a pre-malignant or malignant tumor.

[0442] In a preferred aspect of the invention, the cancer is an estrogen receptor positive (ER+) precancerous tumor, a cancerous tumor, a premalignant tumor, or a malignant tumor.

[0443] In certain aspects, the premalignant tumor or malignant tumor is an ER+ and "mutated ESR1" or "mutated ERa" tumor. The tumor may also be ER+, mutated ESR1 (or mutated ERa), regardless of HER2- tumor status (which may be positive, low or negative).

[0444] In certain aspects, the tumor may further have a confirmed or potential alteration (mutation) in the BRCA1 and / or BRCA2 gene or protein.

[0445] In another specific aspect, the tumor has a confirmed or potential alteration (mutation) in any of the following genes or proteins: IRS1, PTEN, PIK3CA, AKT1, AKT2, AKT3, mTOR, TSC1, TSC2, EGFR, or KRAS.

[0446] In a preferred aspect of the invention, the cancer is characterized by malignant tumors and / or metastases, preferably metastases to the brain, bones, lungs or liver, and more particularly to the brain.

[0447] Methods of patient selection

[0448] Also described herein are methods for selecting / identifying subjects (typically patients) who are most likely to be sensitive or more responsive to cancer treatment, particularly after having shown resistance to hormone therapy, and then become sensitive or more responsive to hormone therapy again. These subjects are most likely to benefit from the administration of the compounds or compositions of the present invention.

[0449] The method can be performed in vitro, ex vivo or in vivo, and generally includes the steps of determining whether the subject's tumor is an HR+ tumor, particularly an ER+ tumor, preferably an ER+ and mutated ESR1 tumor (regardless of the HER2 status of the tumor), and, if confirmed, selecting a subject who may again be sensitive to cancer treatment, particularly hormonal treatment for cancer.

[0450] The sensitivity or susceptibility of a subject to a cancer treatment indicates whether the subject is a "responder" or a "non-responder", in other words, whether the subject will or will not be at least partially treated (tumor growth arrest or regression), preferably completely treated (cured) by said anti-cancer treatment, as already explained above.

[0451] The methods for selecting patients described herein are predictive methods, i.e. methods capable of assessing the ability of a subject to respond in the context of an anti-cancer treatment as defined herein, and not merely prognostic methods, capable of merely indicating whether a subject will survive or die from cancer.

[0452] Cancer treatment

[0453] The inventors herein advantageously describe quinazolinecarboxamide azetidine compounds, combinations of compounds comprising quinazolinecarboxamide azetidine compounds and preferably anti-tumor agents and / or signal transduction inhibitors, and pharmaceutical compositions comprising quinazolinecarboxamide azetidine compounds, preferably together with anti-tumor agents and / or signal transduction inhibitors, and optionally a pharmaceutically acceptable carrier, for use as a medicament, preferably for use in a subject in need thereof (as described above) for the treatment of hormone-dependent diseases, particularly cancer, preferably estrogen receptor-positive (ER-positive) . + ) cancer (as described above). In a preferred embodiment, the cancer is breast cancer as described above, and the subject is preferably a subject as described above.

[0454] The products described herein (compounds of the invention, combinations or compositions comprising such compounds) are preferably used to treat ER+ breast cancer in subjects who have not responded to endocrine therapy.

[0455] Embodiments relate to therapeutic uses in oncology, and corresponding methods of treating cancer, preferably breast cancer, in a subject as described herein, preferably in a patient with a breast cancer tumor expressing an estrogen receptor alpha (ERα) protein (encoded by the ESR1 gene). The ERα protein may be a wild-type or mutant version of ERα.

[0456] Particular therapeutic uses or cancer treatments involve the use (usually administration) of a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, or a pharmaceutical composition comprising the quinazolinecarboxamide azetidine compound, and further the use (usually administration) of a drug selected from the group consisting of an anti-tumor agent, a signal transduction inhibitor, Agents and any combination thereof, such as selective ER modulators (SERMs) as described herein, selective ER downregulators (SERDs) as described herein, aromatase inhibitors (AIs) as described herein, complete estrogen receptor antagonists ("CERANs") as described herein, cell cycle inhibitors as described herein, PI3K / Akt / mTOR ("PAM") pathway inhibitors as described herein, or growth factor receptor inhibitors as described herein, preferably drugs selected from SERDs, cyclin-dependent kinase (CDK) inhibitors, SERMs, AIs, and CERANs. In a preferred aspect, the drug is selected from selective ER modulators (SERMs) as described herein, selective ER downregulators (SERDs) as described herein, aromatase inhibitors (AIs) as described herein, complete estrogen receptor antagonists ("CERANs") as described herein, cyclin-dependent kinase (CDK) inhibitors as described herein, and PI3K / Akt / mTOR ("PAM") pathway inhibitors as described herein.

[0457] In a specific aspect of the invention, the compound or composition is administered to a subject following a first-line (therapeutic) treatment step of hormone therapy and prior to any subsequent, typically second-line, treatment involving administration to the subject of a different therapeutic compound for treating cancer, typically a HR+ cancer, preferably breast cancer.

[0458] The first step may further comprise administering, for example, a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, or abemaciclib.

[0459] Subsequent steps may include administering to the subject a therapeutic compound selected from the group consisting of: a SERD agent (e.g., elastrant and / or fulvestrant); an AI (e.g., exemestane); a PI3K / Akt / mTOR ("PAM") inhibitor (e.g., apellisor or everolimus), a CERAN (e.g., OP-1250); or a combination of a SERD agent and a PI3K / Akt / mTOR inhibitor, e.g., a combination of everolimus and exemestane.

[0460] In another specific aspect, the inventors disclose herein a therapeutic use or method for treating a subject with a hormone-dependent disease (preferably cancer) characterized by a mutation in estrogen receptor 1 (ESR1), wherein the mutation is an activating mutation as described above (i.e., it is responsible for constitutive activation of ESR1). The use / method comprises the step of administering to the subject a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, optionally in combination with one or more different compounds, such as any of the drugs described herein, such as, but not limited to, selected from tamoxifen, 4-hydroxy ... SERM compounds selected from the group consisting of amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant (ARN-810), camizestrant, elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927 or SHR9549, in particular elastodestrant, for example selected from amcenestrant, AZD9496, brinostrant (ARN-810), camizestrant, D-0502, elastodestrant (RAD-1901), fulvestrant, preferably elastodestrant, GDC-0927, giredestrant, LY3484356 and rintodestrant; AI inhibitors selected from aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole and vorozole; and CERAN compounds, such as OP-1250;A CDK inhibitor selected from the group consisting of abemaciclib (also known as LY2835219), AG024322, aloisine A, aloisine B, atepolone, aminopurvalanol, AT7519, AZD-5438, AZD5597, BLU-222, BMS-387032, birociclib (XZP3287), bohemine, butyrolactone, CYC065, dalsil (SHR-6390), dinaciclib, ETH-155008, flavopiridol, FCN-437c, GLR2007, indirubin, indirubin-3'-monoxime, JNJ-7706621, kemperolone, lelociclib (also known as G1T38), meriolin 3. milciclib, narazaciclib (ON123300), NVP-LCQ19, oromiacin, oromiacin II, palbociclib (also known as Ibrance, PD-0332991, or PF-00080665), PF-07220060, PF-07104091, PF-06873600, PHA-793887, purvalanol A, purvanol B, R-CR8, RGB-286638, RGB286147, ribociclib (also known as LEE-011), riviciclib hydrochloride (P276-00), roniciclib, R-roscovitine, Ro4584820, samuraciclib (also known as CT7001 or ICE0942), SRX-3177, TG02, TQB3303, triclasiclib (also known as GTI128), vor uciclib, xylocydin, ZK304709, 10Z-membrane alkaloids, 5-iodo-indirubin-3'-monoxime, (1R,3S)-3-[3-(([3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl)amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate, preferably selected from a CDK4 / 6 inhibitor selected from palbocociclib, ribociclib and abemaciclib;and / or a PI3K / Akt / mTOR ("PAM") pathway inhibitor selected from buparlisib (BKM120), pilaralisib (XL147, SAR245408), pictilisib (GDC-0941), sonolisib (PX-866), dactolisib (BEZ235), sabasiloti (INK128, MLN0128), voxtalisib (XL765, SAR 245409), serabelisib (MLN1117), apellisib (BYL719), perifosine (KRX-0401), MK2206, patasertib (GDC0068), GSK690693, temsirolimus (CCI-779), deforolimus (MK8669; deforolimus), sirolimus (rapamycin), everolimus (RAD001), AZD-8055, and OSI-027 (ASP7486). In a specific aspect, the SERD is selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, camizestrant, elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant AZD9496, D-0502, LY3484356, GDC-0927 or SHR9549; the cyclin-dependent protein kinase (CDK) inhibitor is preferably a CDK4 / 6 inhibitor such as abemaciclib, palbocociclib or ribociclib; the SERM is selected from tamoxifen and lasofoxifene; the AI ​​is selected from anastrozole and letrozole; or the CERAN is OP-1250. ;

[0461] In a further specific aspect, the therapeutic use or method comprises the step of administering to a subject a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, wherein the amount of a composition comprising M2698 administered to the subject once daily is from about 160 mg to about 240 mg, and the composition is preferably in the form of a capsule, tablet, solution or suspension.

[0462] In yet a further specific aspect, the therapeutic use or method treats a subject suffering from a hormone-dependent disease, preferably cancer, even more preferably a cancer selected from breast cancer, ovarian cancer, endometrial cancer (especially type I endometrial cancer), and / or a cancer that has preferably metastasized to the brain, bone, lung or liver.

[0463] In another specific aspect, the inventors disclose herein a therapeutic use or method for treating a subject suffering from a hormone-dependent disease (preferably cancer) characterized by a mutation in estrogen receptor 1 (ESR1) as described herein, comprising the step of administering a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, wherein the patient has a first ERa equal to or greater than (≥) 0.5%. A (first) mutant allele frequency ("MAF") value of a mutant, which is, for example, detected on cfDNA in a biological sample (e.g., a blood sample) obtained from a patient, wherein the first ERa mutant is preferably Y537S or D538G, and / or the (second) MAF value of the ERa mutant is lower than (<) 0.5%, wherein the (second) ERa mutation is preferably D538G, L536H, L536P, L536Q, L536R, Y537C, Y537N, Y537D, Y537S, S463P, E380Q, V392I, F404fs or V422del.

[0464] In a further specific aspect, the inventors also disclose herein a therapeutic use or method of treating a subject suffering from a hormone-dependent disease (preferably cancer) characterized by a mutation in estrogen receptor 1 (ESR1) as described herein, comprising the step of administering a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, wherein the subject has a PgR and / or ER positive status.

[0465] The present disclosure also encompasses the advantageous therapeutic use of quinazolinecarboxamide azetidine compounds, preferably 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698) or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, for the treatment of metastatic cancer, such as cancer that has spread to the brain, bones, lungs, liver or central nervous system.

[0466] As shown in Table A below, in contrast to active fulvestrant (which is unable to penetrate the blood-brain barrier), M2698 was able to cross the blood-brain barrier ("BBB") when orally administered at 25 mg / kg of subject body weight (i.e., in an amount similar to the amount of compound 1 as defined in WO2021 / 007146 as an active compound for cancer that has metastasized to the brain).

[0467] Table A:

[0468] Matrix molecular dose Dosage Unit Concentration (ng / ml) plasma M2698 25 mg / kg 1600 plasma Compound 1 10 mg / kg 1919 plasma Compound 1 30 mg / kg 5558 brain Fulvestrant 5 mg 501 brain Compound 1 10 mg / kg 2147 brain Compound 1 30 mg / kg 9708 brain M2698 25 mg / kg 4000

[0469] Thus, the present disclosure provides therapeutic uses or methods for treating a subject suffering from a hormone-dependent disease, preferably a cancer that has preferably metastasized to the brain, bone, lung, liver or central nervous system, comprising administering a quinazolinecarboxamide azetidine compound of Formula I:

[0470] As defined herein,

[0471] or a quinazolinecarboxamide azetidine compound of formula II:

[0472] As defined in this article

[0473] Preferred is 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide ("M2698") or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

[0474] In some embodiments, the cancer subject in need of treatment has one or more CNS metastatic tumors, such as brain metastases, and optionally additionally has bone, lung, or liver metastases.

[0475] All references cited in this specification are incorporated into this application by reference.Other features and advantages of the present invention are presented in the following examples and figures, which are for illustrative purposes only and not for limiting purposes. BRIEF DESCRIPTION OF THE DRAWINGS

[0476] Figure 1 .Combination of M2698 and elastatin.

[0477] The graph shows the evolution of the calculated mean volume and standard deviation (SD) of MCF7 tumors over time (up to 40 days) in each group: vehicle (n=8 mice); elastomeric alone (n=8 mice); M2698 alone (n=8 mice) and M2698 plus elastomeric (n=6 mice).

[0478] Figure 2.M2698 combined with abemaciclib

[0479] The graph shows the evolution of the calculated mean volume and SD of MCF7 tumors over time (up to 40 days) in each group: vehicle (n=8 mice); abemaciblib alone (n=8 mice); M2698 alone (n=8 mice) and M2698 plus abemaciblib (n=6 mice).

[0480] Figure 3 .Combination of M2698 and elastatin.

[0481] The graph shows the evolution of the calculated mean volume and standard deviation (SD) of MCF7 tumors over time (up to 60 days) in each group: vehicle (n=8 mice); elastostat alone (n=8 mice); M2698 alone (n=8 mice) and M2698 plus elastostat (n=6 mice). ****p<0.0001, Tukey range test.

[0482] Figure 4 .M2698 combined with abemaciclib

[0483] The graph shows the evolution of the calculated mean volume and SD of MCF7 tumors over time (up to 60 days) in each group: vehicle (n=8 mice); abemaciclib alone (n=8 mice); M2698 alone (n=8 mice) and M2698 plus abemaciclib (n=6 mice). ****p<0.0001, Tukey range test. Example

[0484] The following non-limiting examples are provided to further illustrate certain teachings provided by the present disclosure. Those skilled in the art will appreciate from this application that various changes may be made to the specific embodiments described in the examples without departing from the spirit and scope of the present teachings.

[0485] Example 1

[0486] Materials and Methods

[0487] Patient group criteria

[0488] Female patients aged >18 years with advanced metastatic breast cancer classified as hormone receptor positive (HR+, ER+ and / or PgR+) and epidermal growth factor receptor 2 negative (HER2-negative or HER2-), whose tumors have confirmed alterations or potential alterations in the PAM pathway (PAM+: e.g., PTEN, PIK3CA, AKT1, AKT3, mTOR, TSC1, or TSC2), who have exhausted all standard, acceptable treatment options, have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST1.1) criteria (EA Eisenhauer, Eur J Cancer. 2009 Jan;45(2):228-47) and biopsyable tumors.

[0489] Patients’ estrogen receptor 1 (ESR1) status was defined by detection of any mutations (including any deletions and / or frameshifts) in the ESR1 gene in liquid tumor biopsies, specifically at study entry via Guardant360 TM (Highly sensitive next-generation sequencing platform (Guardant Health, USA)) as a retrospective analysis.

[0490] Patients with confounding EGFR, KRAS, and AKT2 alterations were excluded.

[0491] Patients with asymptomatic brain metastases that were stable for >4 weeks after treatment were eligible.

[0492] To be eligible, all patients underwent cardiac function testing.

[0493] The 26 patients had histologically and / or cytologically confirmed breast cancer with hormone receptor-positive status (ER and / or PgR-positive) and HER2-negative ("HER2-") status, with prior exposure to tamoxifen and / or aromatase inhibitors and / or aromatase inhibitors plus palbociclib. Prior treatment with tamoxifen in the neoadjuvant setting was allowed but had to have been stopped for at least 1 year before the first dose.

[0494] Patients were enrolled at 10 centers in the United States and provided written informed consent before any study procedures. This study was conducted in accordance with the ethical principles of the International Committee on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable local regulations.

[0495] Drug Substance:

[0496] -4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-ethylamino]-quinazoline-8-carboxylic acid amide ("M2698" - CAS n°1379545-95-5) capsule dosage is 80 mg / capsule.

[0497] -2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethylamine (Tamoxifen - CAS n°10540-29-1) tablet dosage is 20 mg / tablet.

[0498] A list of examples of prior endocrine anticancer therapies (ETs) that may be administered to a patient is described in Table 1 below.

[0499] Table 1:

[0500]

[0501] ET: Endocrine therapy specifically includes aromatase inhibitors (AIs), such as letrozole, exemestane, and anastrozole, and selective estrogen receptor degraders or modulators (SERD / Ms), such as tamoxifen and fulvestrant.

[0502] Everolimus is the only mTOR inhibitor (“mTORi”) approved for the treatment of recurrent metastatic ER+ breast cancer.

[0503] Palbociclib is one of 3 CDK4 / 6 kinase (CDK4 / 6i) inhibitors approved for treatment-naïve advanced ER+ breast cancer. Ribociclib and abemaciclib can be used similarly. Detrastuzumab is an anti-HER2 ADC (antibody drug conjugate).

[0504] Estrogen Receptor 1 (ESR1) Status:

[0505] Peripheral blood samples were collected from patients at the start of the study. Plasma was separated from 20 ml of whole blood, 20 ng of DNA was extracted, and genomic analysis of circulating tumor DNA (ctDNA) based on hybridization capture was performed in a CLIA-certified / CAP-accredited laboratory (Guardant Health, USA) to identify substitutions, short insertions / deletions, rearrangements / fusions, and amplifications of the ESR1 gene as part of the multigene panel of the Guardant 360 assay.

[0506] Study Design and Dosing Schedule

[0507] Both drug substances were administered orally at the same time, once daily, by swallowing the tablet whole with a full glass of water (approximately 200 mL / 8 fl oz). Participants took the total assigned dose (one to three capsules of 80 mg of 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-ethylamino]-quinazoline-8-carboxylic acid amide and 20 mg of tamoxifen) at the same time each morning. Participants were instructed to fast for at least 2 hours before and 1 hour after dosing.

[0508] Statistical analysis

[0509] Progression-free survival (PFS) refers to the time between the start of treatment and tumor progression or death from any cause based on investigator assessment. Disease progression is defined by the response evaluation criteria in solid tumors (RECIST) as an increase of at least 20% in the sum of the maximum tumor diameters, the appearance of any new lesions, or a significant increase in unmeasurable malignant disease (EA Eisenhauer, Eur J Cancer. 2009 Jan; 45 (2): 228-47) and biopsy accessible tumors. PFS was estimated using the Kaplan-Meier method.

[0510] result

[0511] In 26 patients with recurrent ER+HER2- metastatic breast cancer treated with M2698 + tamoxifen:

[0512] - 1 patient received only 1 day of M2698 and was not evaluable for treatment duration or PFS analysis

[0513] - 6 patients had non-evaluable ESR1 status (results were questionable due to suspected sample contamination or lack of data).

[0514] - 19 patients had evaluable ESR1 gene mutation status at study entry.

[0515] *9 patients showed one or more mutations (Y537D and D538G, accounting for about 90%)

[0516] *10 patients had unmutated wild-type (WT) ESR1 gene sequence.

[0517] Table 2:

[0518]

[0519] Both ESR1 mutant and ESR1 WT patients had very advanced cancer with an unfavorable prognosis: both groups had failed a median of ∼6 prior anticancer therapies. Both groups were considered to have exhausted all available therapeutic options to treat their disease.

[0520] Patients with mutated ESRI genes stayed on the M2698+tamoxifen combination treatment about twice as long as those with WT ESR1: the median duration of treatment was 6 months and 3.17 months, respectively, meaning that in the subgroup of patients with ESR1 mutations, half of them had disease stabilization lasting more than 6 months, while in the subgroup with ESR1 WT, half of them had disease stabilization lasting more than just 3.17 months.

[0521] The median progression-free survival (PFS) in the ESR1 mutation subgroup was nearly twice as long as in the ESR1 WT group. This means that M2698+tamoxifen delayed disease recurrence longer in the group of patients with ESR1 mutations compared to ESR1 WT: half of the patients in the ESR1 mutation group experienced cancer recurrence after 5.5 months of treatment, while the ESR1 WT group experienced cancer recurrence after only 2.65 months.

[0522] Table 2 provided illustrates that patients with ER+ breast cancer with ESR1 mutations fail to respond to and have developed resistance to all available therapies, regardless of drug class and mode of action. Despite this, they were able to achieve significant clinical benefit (in terms of duration of disease stabilization and time to disease recurrence) when treated with M2698+tamoxifen.

[0523] in conclusion

[0524] Mutations in the ESR1 gene are markers of acquired resistance to all classes of endocrine therapy. They are associated with worse clinical outcomes and shorter survival.

[0525] The use of the M2698 compound in combination with tamoxifen or the use of M2698 in combination with any other endocrine therapy selected from those described herein provides a favorable therapeutic benefit to relapsed / refractory ER+ breast cancer patients whose tumors display mutations in the ESRI gene.

[0526] The M2698 compound can be safely combined with endocrine therapy selected from the group consisting of selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and complete estrogen receptor antagonists (CERANs).

[0527] The M2698 compound can be more specifically safely combined with a selective ER downregulator degrader (SERD) selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, camizestrant, elastodestran, fulvestrant, giredestrant, imlunestrant, rintodestrant AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927 and SHR9549, and even more specifically with elastodestran.

[0528] In addition, the M2698 compound can be safely combined with endocrine therapeutic compounds as described above, as well as compounds that function in the ER pathway, the PI3K / Akt / mTOR pathway, the growth factor receptor pathway [involving the epidermal growth factor receptor (EGFR), the fibroblast growth factor receptor (FGFR), the insulin growth factor receptor (IGFR), or the vascular endothelial growth factor receptor (VEGFR)], the cell cycle, the ubiquitin-proteasome pathway, or the bromodomains and / or super-terminal domains of proteins.

[0529] The M2698 compound is able to restore the sensitivity of ER+ tumors to endocrine therapy, which is the basis of treatment for ER+ cancers (e.g., breast cancer, ovarian cancer, and type I endometrial cancer, especially ER+ breast cancer). ER+ tumors also include any ER+ tumors that have metastasized to the brain, bone, lung, or liver, and more specifically to the brain.

[0530] In addition, the M2698 compound can restore the sensitivity of ESR1-mutated ER+ tumors to endocrine therapy, which is the basis for the treatment of ER+ cancers (e.g., breast cancer, ovarian cancer, and type I endometrial cancer), preferably ESR1-mutated ER+ breast cancer. ESR1-mutated ER+ tumors also include any ESR1-mutated ER+ tumors that have metastasized to the brain, bone, lung, or liver, and more specifically to the brain.

[0531] Example 2

[0532] Evaluation of the antitumor efficacy of anticancer compounds in a SCID-CB17 mouse xenograft model implanted with MCF7 cells and substrate phosphorylation.

[0533] Materials and Methods

[0534] Experimental design

[0535] MCF7 cells were expanded in vitro in complete medium before implantation. 24 h before cell injection, mice were implanted with estrogen pellets (Innovative Research of America, 0.18 mg / pellet).

[0536] On the day of injection, cells were harvested, counted with the aid of trypan blue viability dye (acceptable cutoff ≥ 80% viability), and resuspended at the appropriate concentration in 50:50 PBS:Matrigel. Within 30 minutes of harvest, 120 mice were inoculated with 5.10% PBS:Matrigel in 200 μL PBS: 6 Cells were injected subcutaneously into the right flank.

[0537] When the tumor reaches 100 (+ / - 25) mm 3 The mice (female mice, 5 weeks old, strain: SCID-CB17, average body weight 20 g (range 18-22 g) were randomly divided into 8 groups (a total of 100 mice). After implantation, all mice were observed to detect any toxic effects of the product. Endpoints were defined by animal ethics. They included the evaluation of tumor diameter >18 mm (1600 mm 3 ), significant weight loss or change in the animal's health.

[0538] To assess the effectiveness of compounds on tumorigenesis, tumor volume was measured twice a week for 8 weeks, and mice were weighed once a week for 8 weeks.

[0539] The size of the primary tumor was measured with a caliper and the tumor volume (TV) was extrapolated into a sphere by calculating the mean radius of the two measurements using the formula TV = 4 / 3π x r3.

[0540] treat

[0541] Mice were randomized at the time of tumor uptake and treated daily for 5 weeks with the treatments shown in Table 3 below:

[0542] Table 3 :

[0543]

[0544]

[0545] After 4 days of treatment, tumors of 3 satellite mice at 4 h after the last treatment and 3 satellite mice at 8 h after the last treatment in 6 groups (Group 1; Group 4; Group 5; Group 6; Group 7; Group 8) were sampled for Western blot analysis (a total of 36 mice).

[0546] Western blot assays will be performed on 3x2 tumor samples from 6 satellite mice from 6 groups for semi-quantification of the following proteins:

[0547] The entire operation was performed on ice.

[0548] Using FastPrep (Bio101) Protein extraction. Tumors were placed in Lysing Matrix D tubes with 100 μL of RIPA lysis buffer and shaken at 6.5 m / sec for 12 s. Then, after incubation for 1 h, they were centrifuged. The supernatant was recovered for quantification.

[0549] The lysates were quantified using the Bradford protein assay and adjusted to 50 μg in each sample. Each sample was then heated at 95°C for 5 min and loaded onto a precast gel ( After electrophoresis, use a PVDF Mini Stacks 2 (Thermofisher) to transfer proteins.

[0550] Statistical analysis

[0551] Statistical analyses were performed with the aid of GraphPad Prism software, which combines scientific graphing, comprehensive curve fitting, and easy-to-understand statistics and data organization.

[0552] Unless otherwise specified, tumor volume values ​​(mm 3 ) were subjected to Mann-Whitney t test (unpaired, two-tailed test).

[0553] result

[0554] The results are presented by tumor growth curves.

[0555] Figure 1 and Figure 3 The graphs show the evolution of the calculated mean volume and standard deviation (SD) of MCF7 tumors over time (up to 40 days and up to 60 days, respectively) in each group: vehicle (n=8 mice); elastomeric alone (n=8 mice); M2698 alone (n=8 mice) and M2698 plus elastomeric (n=6 mice).

[0556] Elastran (50 mg / kg / day) weakly inhibited MCF7 tumor growth, while M2698 (20 mg / kg / day) showed strong antitumor efficacy. The combination of M2698 and alastrant was significantly more effective than M2698 alone.

[0557] Figure 2 and Figure 4 The graphs of Figure 4 show the evolution of the calculated mean volume and SD of MCF7 tumors over time (up to 40 days and up to 60 days, respectively) in each group: vehicle (n = 8 mice); abemaciclib alone (n = 8 mice); M2698 alone (n = 8 mice); and M2698 plus abemaciclib (n = 6 mice).

[0558] M2698 (20 mg / kg / day) strongly inhibits tumor growth and is as effective as abemaciclib alone (40 mg / kg / day). The combination of M2698 and abemaciclib is significantly more effective than each compound alone.

[0559] Sequence Listing

[0560] SEQ ID NO:1

[0561] (Seq:ESR1:P03372|ESR1_human–htpps: / / www.uniprot.org / uniprotkb / P03372 / history):

[0562] MTMTLHTKAS GMALLHQIQG NELEPLNRPQ LKIPLERPLGEVYLDSSKPA VYNYPEGAAYEFNAAAAANA QVYGQTGLPYGPGSEAAAFG SNGLGGFPPL NSVSPSPLML LHPPPQLSPFLQPHGQQVPYYLENEPSGYT VREAGPPAFY RPNSDNRRQGGRERLASTND KGSMAMESAK ETRYCAVCNDYASGYHYGVWSCEGCKAFFK RSIQGHNDYM CPATNQCTID KNRRKSCQACRLRKCYEVGM MKGGIRKDRRGGRMLKHKRQ RDDGEGRGEVGSAGDMRAAN LWPSPLMIKR SKKNSLALSL TADQMVSALLDAEPPILYSEYDPTRPFSEA SMMGLLTNLA DRELVHMINWAKRVPGFVDL TLHDQVHLLE CAWLEILMIGLVWRSMEHPGKLLFAPNLLL DRNQGKCVEG MVEIFDMLLA TSSRFRMMNLQGEEFVCLKS IILLNSGVYTFLSSTLKSLE EKDHIHRVLD KITDTLIHLMAKAGLTLQQQ HQRLAQLLLI LSHIRHMSNKGMEHLYSMKCKNVVPLYDLL LEMLDAHRLH APTSRGGASV EETDQSHLATAGSTSSHSLQ KYYITGEAEGFPATV

[0563] SEQ ID NO:2 (Sequence of the ligand-binding domain "LBD" of ERa):

[0564] KNSLALSLTA DQMVSALLDA EPPILYSEYD PTRPFSEASMMGLLTNLADR ELVHMINWAKRVPGFVDLTL HDQVHLLECAWLEILMIGLV WRSMEHPGKL LFAPNLLLDR NQGKCVEGMVEIFDMLLATSSRFRMMNLQG EEFVCLKSII LLNSGVYTFL SSTLKSLEEKDHIHRVLDKI TDTLIHLMAK AGLTLQQQHQ

[0565] SEQ ID NO:3 (Sequence of the ESR1 gene):

[0566]

Claims

1. A combination of (a) a quinazolinecarboxamide azetidine compound and (b) a different therapeutic agent, preferably an anticancer agent, wherein the therapeutic agent is selected from anti-angiogenesis agents, signal transduction inhibitors, anti-tumor agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, antisense molecules, small molecules, growth factor receptor agents, and any combination thereof, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

2. The combination or composition according to claim 1, wherein the quinazolinecarboxamide azetidine compound is a compound of formula (I): in: R 1 is H or LA; R 2 For Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH2 or A; R 3’ , R 3” are independently H, LA or Hal; Ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2, 3 or 4 N, O and / or S atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONH(Art), CONA2, NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH2, NHSO2A, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, and wherein the ring N atoms may be substituted by O atoms to form N oxide groups, and wherein in the case of a bicyclic aromatic ring, one of the two rings may be partially saturated; Ar1 is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2 or 3 N, O and / or S atoms and 5 or 6 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), CHO, CO(LA), SO2NH2, SO2(LA) and / or SO2Hal; A is an unbranched or branched, straight-chain or cyclic alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and / or by -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, and in which 1 to 3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN; LA is an unbranched or branched linear alkyl group having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; and Hal is F, Cl or Br, preferably F or Cl, most preferably F, and / or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, including any mixtures thereof in all ratios, and The different therapeutic agent (b) is an anti-tumor agent and / or a signal transduction inhibitor.

3. A combination or composition according to claim 1 or 2, wherein the quinazolinecarboxamide azetidine compound of formula (I) is 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

4. The combination or composition according to claim 1 or 2, wherein the different therapeutic agent is an anti-tumor agent, and the anti-tumor agent is a hormonal therapeutic agent or a chemotherapeutic agent.

5. The combination or composition of claim 4, wherein the hormone therapy agent is selected from a selective ER downregulator degrader (SERD), a selective ER modulator (SERM), an aromatase inhibitor (AI) and a complete estrogen receptor antagonist (CERAN).

6. The combination or composition of claim 5, wherein the SERD compound is selected from amcenestrant, azenosertib (ZN-c5), borestrant, brinostrant, camizestrant, elastrant, fulvestrant, giredestrant, imlunestrant, rintodestrant AZD9496, D-0502, LY3484356, GDC-0927 and SHR9549.

7. The combination or composition according to claim 6, wherein the SERD compound is elastomeric and any pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

8. The combination or composition of claim 4, wherein the chemotherapeutic agent is selected from the group consisting of alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, taxanes, topoisomerase inhibitors and vinca alkaloids.

9. The combination or composition of claim 4, wherein the chemotherapeutic agent is selected from capecitabine, cyclophosphamide, docetaxel, doxorubicin, epirubicin, eribulin mesylate, fluorouracil, 5-fluorouracil, gemcitabine, liposomal doxorubicin, paclitaxel, vinorelbine, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

10. The combination or composition according to claim 1 or 2, wherein the signal transduction inhibitor is a cyclin-dependent kinase (CDK) inhibitor.

11. The combination or composition according to claim 10, wherein the CDK inhibitor is a CDK4 / 6 inhibitor selected from abemaciclib, palbociclib, ribociclib and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer of any one of the foregoing.

12. A combination or composition according to any one of claims 1 to 11 for use as a medicament.

13. The combination of claim 12, wherein the quinazolinecarboxamide azetidine compound, the anti-tumor agent and / or the signal transduction inhibitor are formulated for simultaneous, concurrent or sequential administration.

14. A combination or composition according to any one of claims 1 to 13 for use in treating a hormone-dependent disease in a subject.

15. The combination or composition for use according to claim 14, wherein the hormone-dependent disease is hormone receptor positive (HR + ) cancers, especially those that are estrogen receptor-positive (ER + )cancer.

16. The combination or composition for use according to claim 15, wherein the cancer is selected from brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, uterine cancer, bladder cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

17. The combination or composition for use according to claim 16, wherein the cancer is a human epidermal growth factor receptor 2 positive (HER2+) cancer or a human epidermal growth factor receptor 2 negative (HER2-) cancer or a human epidermal growth factor receptor-2-low ("HER2-low") cancer.

18. The combination or composition for use according to any one of claims 15 to 17, wherein the cancer is breast cancer, in particular metastatic breast cancer.

19. The combination or composition for use according to any one of claims 15-17, wherein the cancer is breast cancer, in particular metastatic breast cancer that is resistant and / or refractory to standard of care treatment.

20. The combination or composition for use according to any one of claims 15 to 20, wherein the treatment involves administration of an anti-cancer agent selected from an anti-angiogenesis agent, a signal transduction inhibitor, an anti-tumor agent, a therapeutic antibody or fragment thereof, an antibody-drug conjugate, a small molecule, a growth factor receptor agent and / or an antisense molecule.

21. The combination or composition for use according to any one of claims 14 to 21, wherein the subject has been treated with a drug selected from the group consisting of a drug used in hormone therapy, a CDK inhibitor, a PI3K / AKT / mTOR ("PAM") pathway inhibitor, or any combination thereof, in particular a combination of a CDK inhibitor and a hormone therapy agent, a combination of a CDK inhibitor and a SERD, or a combination of a CDK inhibitor, a SERD, and a PI3K / AKT / mTOR ("PAM") pathway inhibitor.

22. A combination or composition for use according to any one of claims 14 to 22, wherein the quinazolinecarboxamide azetidine compound of formula (I) is 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof, and the compound is present in the combination or composition in a dosage of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg.

23. The combination or composition for use according to claim 23, wherein the anti-tumor agent is elastomeric, and elastomeric is present in the combination or composition in a dosage of about 200 mg to about 500 mg, preferably about 300 mg to about 400 mg, more preferably about 350 mg.

24. A quinazolinecarboxamide azetidine compound, or a pharmaceutical composition comprising a quinazolinecarboxamide azetidine compound and a pharmaceutically acceptable carrier, for use in treating estrogen receptor positive (ER+) cancer in a subject in need thereof.

25. A composition according to claim 24, wherein the quinazolinecarboxamide azetidine compound is a compound of formula (I): in: R 1 is H or LA; R 2 For Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH2 or A; R 3’ , R 3” are independently H, LA or Hal; Ar is a monocyclic or bicyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2, 3 or 4 N, O and / or S atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA2, NO2, CN, OCN, SCN, COOH, COOA, CONH2, CONHA, CONH(Art), CONA2, NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH2, NHSO2A, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, and wherein the ring N atoms may be substituted by O atoms to form N oxide groups, and wherein in the case of a bicyclic aromatic ring, one of the two rings may be partially saturated; Ar1 is a monocyclic aromatic homocyclic or heterocyclic ring having 0, 1, 2 or 3 N, O and / or S atoms and 5 or 6 backbone atoms, which may be unsubstituted or, independently of one another, mono-, di- or tri-substituted by Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2, CN, OCN, SCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), CHO, CO(LA), SO2NH2, SO2(LA) and / or SO2Hal; A is an unbranched or branched, straight-chain or cyclic alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and / or -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, and in which 1 to 3 H atoms may be replaced by Hal, and in which one or two CH3 groups may be replaced by OH, SH, NH2, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN; LA is an unbranched or branched linear alkyl group having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal, for example methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; and Hal is F, Cl or Br, preferably F or Cl, most preferably F, and / or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates or tautomers thereof, including any mixtures thereof in all ratios.

26. A composition according to claim 24 or 25, wherein the quinazolinecarboxamide azetidine compound of formula (I) is 4-[(S)-2-azetidine-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate or tautomer thereof.

27. The composition for use according to claims 24 to 26, wherein the cancer is selected from brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer, uterine cancer, bladder cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

28. The composition for use according to claims 24 to 26, wherein the cancer is a human epidermal growth factor receptor 2 positive (HER2+) cancer or a human epidermal growth factor receptor 2 negative (HER2-) cancer or a human epidermal growth factor receptor 2 low (HER2-low) cancer.

29. The composition for use according to any one of claims 28, wherein the cancer is breast cancer, in particular metastatic breast cancer.

30. The composition for use according to any one of claim 29, wherein the cancer is breast cancer, in particular metastatic breast cancer that is resistant and / or refractory to standard of care treatment.

31. A composition for use according to any one of claims 24 to 26 for treating ER+ breast cancer in a subject unresponsive to hormone therapy.

32. The composition for use according to any one of claims 24 to 26, wherein the ER+ breast cancer is characterized by a mutated estrogen receptor alpha (ERα, ERa or ESR1) cancerous tumor, wherein the mutation occurs in the ligand binding domain of the ERa wild-type sequence of SEQ ID NO: 1, and / or wherein the mutated ERa is characterized by a change in the conformation of its ligand binding domain.

33. The composition for use according to claim 32, wherein the mutation occurs in at least one residue selected from residues 380, 392, 404, 422, 463, 536, 537 and 538, and is preferably an amino acid substitution selected from the group consisting of E380Q, V392I, F404fs, V422del, S463P, L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, D538G, and even more preferably Y537S and / or D538G.

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