Compounds for treating cancer

Abstract

The present invention relates to quinazoline carboxamide azetidine compounds, as well as pharmaceutical combinations and compositions comprising such compounds, preferably together with at least one separate therapeutic agent, preferably an anti-cancer agent, and methods for treating diseases, preferably cancer, more preferably estrogen receptor positive (ER) diseases, particularly in subjects resistant to endocrine therapy. + ) its use for treating cancer.

Description

[Technical Field]

[0001] The present invention relates to the field of oncology. More particularly, the present invention relates to quinazolinecarboxamide doazetidine compounds, as well as pharmaceutical combinations and compositions comprising such compounds, preferably together with at least one separate therapeutic agent, preferably an anti-cancer agent, and the treatment of diseases, preferably cancers, more preferably estrogen receptor positive (ER) (ERP)-positive (ER) (ERG)-positive (ERG ... + ) its use for treating cancer. [Background technology]

[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 all breast cancer cases worldwide.

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

[0004] Approximately 81% of breast cancers are invasive, or penetrating, i.e., metastatic. In other words, abnormal cells break through the walls of the gland or duct where they originate and grow into surrounding tissue. While historically referred to as a single disease, breast cancer is now considered a group of diseases consisting of four major molecular subtypes and at least 21 distinct histological subtypes (types of tissue from which the cancer originates) that differ in risk factors, presentation, response to treatment, and outcome. For example, approximately 5-10% of breast cancer patients present with metastatic disease at the time of diagnosis, the incidence of breast cancer brain metastasis ("BCBM") in estrogen receptor-positive breast cancer is 14%, and the median overall survival after the development of brain metastasis is 9-10 months (Brosnan et al., 2018).

[0005] The importance and role of the estrogen receptor (ER) pathway is well understood in both the development and progression of breast cancer. The standard of care (SOC) treatment of choice for estrogen receptor-positive breast cancer is endocrine therapy (also called "hormone therapy," "hormonal therapy," or "hormonal treatment"), commonly consisting of: selective estrogen receptor modulators ("SERMs"), such as tamoxifen and "tamoxifen-like" compounds, e.g., 4 Hydroxytamoxifen, endoxifene, 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 amsenestrant, azenosertib (ZN-c5), borestrant, brilantrant (b rilanestrant), camizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lintodestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927, or SHR9549; full estrogen receptor antagonists (CERANs), such as OP-1250; and luteinizing hormone-releasing hormone (LHRH) and / or gonadotropin-releasing hormone (GnRH) agonists, such as buserelin, cetrorelix, degarelix, gonadorelin, goserelin, leuprolide, triptorelin, and triptorelix.

[0006] Unfortunately, resistance develops in 30–50% of patients treated with endocrine therapy due to sophisticated and sometimes redundant molecular interactions between growth factors, ERs, and downstream cell signaling pathways. Several mechanisms of resistance to endocrine therapy have been described, including alterations in the ER and / or ER pathway, 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)), alterations in the cell cycle, alterations in the ubiquitin-proteasome pathway, or increased activity of protein bromodomains and / or extracellular domains (Patel et al., 2018). 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, deregulated activation of the PI3K / Akt / mTOR pathway, which under normal conditions plays a key role in proliferation and survival, may be an adaptive mechanism of treatment resistance in ER+ breast cancer and correlate with poorer outcomes in patients treated with endocrine therapy. Indeed, PI3K, Akt, and downstream effectors of mTOR can phosphorylate and activate ER in the absence of estrogen, thereby conferring resistance to endocrine therapy. Furthermore, some studies suggest a reciprocal relationship between PI3K activation and ER expression. Indeed, gain-of-function mutations in PI3K occur in over 30% of ER+ breast cancers, highlighting the role of this pathway in this setting. These findings support the use of endocrine / hormonal agents, more preferably inhibitors of the PI3K / Akt / mTOR pathway, e.g., SERDs such as fulvestrant or AIs such as exemestane, e.g., buparlisib (BKM120), pilaralisib (XL147, SAR245408), pictilisib (GDC-0941), sonolicib (PX-866), dactolisib (BEZ235), sapanisertib (INK128, MLN0128), voxtalisib (XL76 5, SAR245409), ceravelisib (MLN1117), alpelisib (BYL719), perifosine (KRX-0401), MK2206, ipatasertib (GDC0068), GSK690693, temsirolimus (CCI-779), ridaforolimus (MK8669, deforolimus), sirolimus (rapamycin), everolimus (RAD001), AZD-8055, or OSI-027 (ASP7486).

[0008] Another example is alterations in the cell cycle. During dormancy, the tumor suppressor retinoblastoma (Rb) protein remains hypophosphorylated and bound to the transcription factor E2F, preventing E2F from promoting the transcription of genes involved in progression through the G1-S phase of the cell cycle. Upon growth factor stimulation, Rb is phosphorylated by cyclin-dependent kinases 4 and 6 (CDK4 / 6) in complex with cyclin D, leading to the release of E2F and progression through the cell cycle. Several lines of evidence, including the observation that CDK4 / 6 are often hyperactivated, link these cell cycle regulators to the ER pathway. These discoveries have led to combination strategies involving endocrine agents, more preferably SERDs, such as fulvestrant, and CDK4 / 6 inhibitors (CDK4 / 6i), such as palbociclib (PD0332991), ribociclib (LEE011), or abemaciclib (LY2835219).

[0009] A further example is the activation of growth factor receptor pathways, for example, through overexpression or amplification of human epidermal growth factor receptor-2 (Her2), a member of the epidermal growth factor receptor (EGFR) family, which can confer resistance to endocrine agents. The addition of dual EGFR / Her2-targeting agents such as lapatinib (GW572016) to a SERD such as fulvestrant was evaluated in patients with ER+ advanced breast cancer, but no statistically relevant clinical benefit was observed for ER+ / HER2+ patients (Burstein et al., 2014).

[0010] Tumor responses are enhanced with adjuvant therapy including mTORC1 inhibitors (everolimus), CDK4 / 6 inhibitors (palbociclib / ribociclib / abemaciclib), and α-isoform-specific PI3K inhibitors (alpelisib).

[0011] However, approximately 25% of ER+ breast cancer patients with primary disease and nearly all patients with metastases present with or eventually develop endocrine resistance.

[0012] Several studies have demonstrated that ER, and more specifically functional estrogen receptor 1 ("ESR1"), is a major driver of endocrine resistance during the progression of ER+ breast cancer. For example, ER expression is positively correlated with tamoxifen outcome, and alterations in the ER and ER pathway have been described as conferring treatment resistance to SERMs such as tamoxifen or SERDs such as fulvestrant. Furthermore, loss of ER through epigenetic silencing via DNA methylation or histone deacetylation has been described as a mechanism of resistance to both compounds (Fan et al., 2006; Parl, 2003; Yang, Phillips, Ferguson et al., 2001). In particular, loss of ER has been described to be significantly correlated with de novo versus acquired resistance to tamoxifen, highlighting the importance of early target engagement and inhibition in this setting. Several 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 alpha), which is 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 coactivators and facilitating a constitutively active form of the receptor in the absence of hormone, helping tumor cells evade hormone treatment.

[0013] In general, the absence of detectable ESR1 mutations in patients with treatment-naive disease and the correlation between the frequency of patients with tumors harboring these mutations and the number of endocrine treatments they have received suggests 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-stage development for managing ER+ breast cancer (Maxwell R. Lloyd et al., 2022), including the CERAN agents, which are tetrahydro-1H-pyrido[3,4-b]indole compounds, as described in WO2017059139. However, several other candidate compounds showing preclinical antitumor activity have also been discontinued during various stages of clinical trials, such as brilanstrant (GDC0810), an oral SERD described in US20150258080 and US2015258099, which was withdrawn from development after Phase II clinical trials and failed to demonstrate comparable or superior efficacy to fulvestrant. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] WO2017059139 No. [Patent Document 2] No. US20150258080 [Patent Document 3] No. US2015258099 [Patent Document 4] WO201269146 No. [Patent Document 5] WO2022 / 170060 issue [Patent Document 6] WO2022 / 018596 issue [Patent Document 7] WO19 / 241231 [Patent Document 8] U.S. Patent No. 6,106,864 [Patent Document 9] WO2000 / 035298 No. [Patent Document 10] WO2021 / 007146 issue [Non-patent literature]

[0016] [Non-Patent Document 1] "Remington's Pharmaceutical Sciences", 19th edition (Mack Publishing Company, 1995)

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[0017] For patients who develop endocrine treatment resistance, there is a need to develop rationale-based novel therapeutic strategies to make them responders to endocrine treatment again. [Means for solving the problem]

[0018] The novel quinazoline carboxamide azetidine compound, 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (M2698), was previously described in WO201269146 as a potent, orally bioavailable, selective inhibitor of p70S6K, AKT1, and AKT3 that affected tumor growth in mouse models of cancer and crossed the blood-brain barrier (Machl et al., 2016). M2698 treatment was well tolerated as monotherapy and in combination with trastuzumab or tamoxifen in patients with ER+ and HER2+ breast cancer, respectively. Overall, the efficacy of M2698 monotherapy was modest in this patient population (Tsimberidou et al., 2021).

[0019] The present inventors have now shown for the first time that administration of a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, makes it possible to resensitize ER+ cancerous tumors identified as resistant to endocrine therapy to cancer treatment, including endocrine therapy, thereby substantially improving treatment outcome. DETAILED DESCRIPTION OF THE INVENTION

[0020] Endocrine therapy (also called "hormone therapy," "hormonal therapy," or "hormone treatment") has been successful in improving patients' progression-free survival ("PFS") and overall survival ("OS"). However, the development of resistance to endocrine and / or ER treatment remains an obstacle in ER+ cancers, particularly breast cancer. Intrinsic resistance to endocrine therapy explains why only 30% of patients with metastatic disease experience initial tumor regression with endocrine therapy, with resistance eventually developing in nearly all patients and frequent tumor recurrence. Furthermore, more than 20% of patients with early-stage breast cancer develop endocrine resistance throughout treatment. Resistance to endocrine therapy has been associated with mutations in the estrogen receptor 1 (ESR1) gene, alterations in receptor tyrosine kinases such as HER2, and alterations in signaling pathways such as the MAPK pathway.

[0021] Therefore, there is a need to develop new therapeutic strategies that are effective for treating estrogen receptor-positive (ER+) tumors, particularly tumors that are resistant to endocrine therapy, preferably tumors harboring mutations in the estrogen receptor 1 (ESR1) gene, which encodes the estrogen receptor alpha (ERα, ERa, or ESR1) protein, in patients who have developed or are at risk of developing endocrine resistance to endocrine therapy, particularly breast cancer patients (Sung Qwe Ahn et al., 2022).

[0022] The present invention now provides such a new and advantageous therapeutic strategy.

[0023] More specifically, the present inventors describe herein a quinazolinecarboxamide doazetidine compound, a combination comprising, in particular consisting of, at least two compounds, one of which is a quinazolinecarboxamide doazetidine compound, or a composition, in particular a pharmaceutical composition, comprising a quinazolinecarboxamide doazetidine compound and a pharmaceutically acceptable carrier. In addition to the quinazolinecarboxamide doazetidine compound, the combination or composition preferably further comprises a separate therapeutic agent, preferably an anticancer agent, more preferably an anti-neoplastic agent and / or a signal transduction inhibitor. The present inventors also describe said combination or composition for use as a medicine, preferably for treating a hormone-dependent disease, more preferably for treating cancer, in particular for treating estrogen receptor-positive (ER+) cancer, in a subject in need thereof.

[0024] The quinazolinecarboxamide doazetidine compound is advantageously a quinazolinecarboxamide doazetidine compound of formula (I): [ka] and / or its pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers (including mixtures thereof in any ratio), wherein: R 1 is H or LA, R 2 is Hal, O(LA), N(LA)(LA)′, CONH(LA), Ar, CONH, or A; R 3' , R 3'' are independently H, LA, or Hal; Ar is a monocyclic or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3, or 4 N, O, and / or S atoms and 5, 6, 7, 8, 9, or 10 skeletal atoms, which is unsubstituted or, independently of one another, is selected from the group consisting of 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, NHSOA, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, the N atoms of the rings may be replaced by O atoms to form N-oxide groups, and in the case of bicyclic aromatic rings, one of the two rings may be partially saturated, Ar1 is a monocyclic aromatic homo- or heterocycle having 0, 1, 2, or 3 N, O, and / or S atoms and 5 or 6 skeletal atoms, which may be unsubstituted or mono-, di-, or tri-substituted, independently of one another, by Hal, LA, OH, SH, O(LA), NH, NH(LA), N(LA), NO, CN, OCN, SCN, COOH, COO(LA), CONH, CONH(LA), CON(LA), NHCO(LA), CHO, CO(LA), SON, NH, SO(LA), and / or SOHal; A is unbranched or branched, straight-chain or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH groups may be replaced by O or S atoms and / or by -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, in which one to three H atoms may be replaced by Hal, in which one or two CH groups may be replaced by OH, SH, NH, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN, L A is unbranched or branched straight-chain alkyl having 1, 2, 3 or 4 C atoms, in which 1, 2 or 3 H atoms may be replaced by Hal, such as methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, Hal is F, Cl, or Br, preferably F or Cl, most preferably F; or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, or any mixture thereof in any ratio.

[0025] The quinazolinecarboxamide azetidine compound is preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (also identified herein as "M2698"), or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, or any mixture thereof in any ratio.

[0026] The anti-neoplastic agent is preferably a hormonal therapy or chemotherapeutic agent.

[0027] The chemotherapeutic agent can be selected from, for example, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, taxanes, topoisomerase inhibitors, and vinca alkaloids.

[0028] The anti-neoplastic agent is preferably a hormone therapeutic agent (also identified herein as a "hormone therapeutic agent" or "endocrine therapeutic agent"), more preferably an anti-estrogen agent, such as selected from a selective ER downregulator degrader (SERD), a selective ER modulator (SERM), an aromatase inhibitor (AI), a complete estrogen receptor antagonist (CERAN), a luteinizing hormone-releasing hormone (LHRH), a gonadotropin-releasing hormone (GnRH) agonist, and any mixture thereof.

[0029] In certain embodiments, the therapeutic agent or signaling inhibitor is not a HER2 inhibitor, a HER3 inhibitor, or a HER3 nanobody.

[0030] In certain embodiments, the HER2 inhibitor is not lapatinib or trastuzumab.

[0031] In certain embodiments, 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 (AMG888, also identified as the first fully humanized Her3 monoclonal antibody).

[0032] In certain embodiments, a combination or composition of the invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-acetidin-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 any ratio; (b) a separate therapeutic agent; and optionally (c) an anticancer agent, with the proviso that if one of compounds (b) or (c) is a HER2 inhibitor, then said HER2 inhibitor is not lapatinib or trastuzumab.

[0033] In certain embodiments, a combination or composition of the invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-acetidin-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 any ratio; (b) a separate therapeutic agent; and optionally (c) an anticancer agent, with the proviso that if one of compounds (b) or (c) is a HER3 inhibitor, then said HER3 inhibitor is not MM-121, MM-11, or U3-1287.

[0034] The signalling inhibitor is preferably a cyclin dependent kinase (CDK) inhibitor, more preferably a CDK4 / 6 inhibitor, for example selected from CDK1, 2, 4, 5, 6 and / or 7 inhibitors and any mixtures thereof.

[0035] The treatment may include, for example, the administration of an additional anti-cancer agent selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or (functional) fragment thereof (including single chain antibodies), an antibody-drug conjugate, a small molecule, a growth factor receptor agent, an antisense molecule, and any mixture thereof.

[0036] In certain embodiments, 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-acetidin-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 any ratio, and at least one anticancer agent, with the proviso that the anticancer agent is not a MEK inhibitor, particularly a MEK inhibitor selected from trametinib, cobimetinib, selumetinib, refametinib, and pimasertib. Preferably, the MEK inhibitor is not pimasertib.

[0037] 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-acetidin-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 any ratio, and at least one anticancer agent, with the proviso 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.

[0038] In a further 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-acetidin-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 any ratio; (b) a separate therapeutic agent; and optionally (c) an anticancer agent, with the proviso that When (c) is a MEK inhibitor, for example, trametinib, cobimetinib, selumetinib, refametinib, or pimasertib, particularly pimasertib, the other (b) or (c) compound is not an EGFR inhibitor, for example, gefitinib, erlotinib, afatinib, brigatinib, icotinib, osimertinib, or cetuximab, particularly cetuximab; or when the separate therapeutic agent (b) or anti-cancer agent (c) is an EGFR inhibitor, for example, cetuximab, the other (b) or (c) compound is not a MEK inhibitor, for example, pimasertib.

[0039] In certain embodiments, the combination or composition of the invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-acetidin-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 any ratio; (b) a separate therapeutic agent selected from an anti-neoplastic agent and a signal transduction agent; and, optionally, (c) an additional separate anti-cancer agent.

[0040] In more particular embodiments, 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-acetidin-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 any ratio; and (b) an anti-neoplastic agent, such as a SERD, SERM, A, or a pharmaceutically acceptable salt thereof. a separate therapeutic agent selected from a hormone therapy agent selected from I, CERAN, LHRH, and GnRH agonists, preferably a SERD, e.g., amsenestrant, azenosertib (ZN-c5), bolestrant, brilantrant, camizestrant, elacestrant, fulvestrant, gildestrant, imrunestrant, lintodestrant, AZD9496, D-0502, LY3484356, GDC-0927, or SHR9549, and optionally (c) an additional separate anti-cancer agent.

[0041] In certain aspects, we describe herein a combination of (a) 4-[(S)-2-acetidin-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 any ratio), and (b) a selective ER downregulator degrader (SERD), preferably elacestrant, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, as well as compositions comprising the combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0042] Also described herein is a method of treating a hormone-dependent disease in a subject, comprising administering to the subject a combination of (a) 4-[(S)-2-acetidin-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 any ratio), and (b) a selective ER downregulator degrader (SERD), preferably elacestrant, 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 the subject.

[0043] Further described herein is a kit comprising (a) 4-[(S)-2-acetidin-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 any ratio), and (b) a selective ER downregulator degrader (SERD), preferably elacestrant, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, 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 a SERD or for administering the composition.

[0044] In more particular embodiments, the combination or composition of the invention comprises (a) a quinazolinecarboxamide azetidine compound, preferably a compound of formula (I), such as 4-[(S)-2-acetidin-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 any ratio; (b) a separate therapeutic agent selected from a signal transduction inhibitor, preferably a cyclin-dependent kinase (CDK) inhibitor, e.g., selected from a CDK4 / 6 inhibitor, e.g., abemaciclib, palbocilcib, and ribociclib; and, optionally, (c) an additional separate anticancer agent.

[0045] In another specific aspect, we describe herein a composition comprising: (a) 4-[(S)-2-acetidin-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 any ratio); 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 combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0046] Also described herein are methods for treating a hormone-dependent disease in a subject, comprising administering to the subject a combination of (a) 4-[(S)-2-acetidin-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 any ratio), 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, thereby treating the subject.

[0047] Further described herein is a kit comprising: (a) 4-[(S)-2-acetidin-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 any ratio); and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, preferably abemaciclib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, 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 CDK4 / 6 inhibitor or for administering the composition.

[0048] In the context of the present invention, the target disease is preferably hormone-dependent disease, whether malignant or non-malignant.Hormonal-dependent disease is preferably pre-malignant ( / pre-cancerous) disease or malignant disease, i.e. cancer.It is typically selected from hormone receptor positive (HR+) cancer, such as brain cancer, breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer (for example, 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.

[0049] In a preferred embodiment, the hormone receptor positive (HR+) cancer is estrogen receptor positive (ER+) + ) cancer.

[0050] 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 therapeutic treatment, ovarian cancer, and type I endometrial cancer.

[0051] The subject in need is preferably one who has been treated, and optionally is still being treated, with a drug used in endocrine (hormonal / hormonal) 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 antiandrogen, a CYP17 inhibitor, an antiadrenergic agent; a cyclin-dependent kinase (CDK) inhibitor; a PI3K / AKT / mTOR ("PAM") pathway inhibitor; or any combination thereof, particularly a combination of a CDK inhibitor and a hormone therapy agent, or a combination of a CDK inhibitor, a hormone therapy agent and a PI3K / AKT / mTOR ("PAM") pathway inhibitor. 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).

[0052] In a preferred embodiment, the ER+ breast cancer is characterized by a mutated estrogen receptor 1 (ESR1) cancer tumor, and 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 certain aspects, the LBD-mutant form of ER supports an agonist conformation of the receptor, thereby mediating constitutive transcription and resulting in 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, more preferably a Y537S and / or D538G mutation.

[0053] In certain embodiments, the quinazolinecarboxamide doazetidine compound, or a composition comprising a quinazolinecarboxamide doazetidine compound, according to the invention is for use in anti-cancer treatment further comprising (co)administration to a subject of a drug selected from a selective ER modulator (SERM), a selective ER downregulator (SERD), an aromatase inhibitor (AI), a complete estrogen receptor antagonist (CERAN), a cell cycle inhibitor, a PI3K / Akt / mTOR ("PAM") pathway inhibitor, and / or an inhibitor of a growth factor receptor.

[0054] In a further preferred embodiment, the quinazolinecarboxamide doazetidine compound, or a composition comprising a quinazolinecarboxamide doazetidine compound, according to the present invention is for use in anti-cancer treatment further comprising the (co)administration to a subject of a drug selected from an anti-neoplastic agent (such as a selective ER modulator (SERM), a selective ER downregulator (SERD), an aromatase inhibitor (AI), and / or a complete estrogen receptor antagonist (CERAN)), a signal transduction inhibitor such as a CDK inhibitor, and a PI3K / Akt / mTOR ("PAM") pathway inhibitor.

[0055] Detailed Description The present invention provides novel therapeutic compounds, combinations of compounds, and pharmaceutical compositions containing such compounds, as well as their use in human medicine, preferably oncology.

[0056] In particular, we describe herein a combination of (a) a quinazolinecarboxamide doazetidine compound and (b) a separate therapeutic agent, preferably an anti-cancer agent selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or (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.

[0057] The present inventors have also discovered quinazolinecarboxamide azetidine compounds, more particularly compounds of formula (I): [ka] Also described are the forms of said compound alone or in any mixture with its pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers, or any mixture thereof in any ratio, wherein: R 1 is H or LA, R 2 is Hal, O(LA), N(LA)(LA)′, CONH(LA), Ar, CONH, or A; R 3' , R 3'' are independently H, LA, or Hal; Ar is a monocyclic or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3, or 4 N, O, and / or S atoms and 5, 6, 7, 8, 9, or 10 skeletal atoms, which is unsubstituted or, independently of one another, is selected from the group consisting of 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, NHSOA, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, the N atoms of the rings may be replaced by O atoms to form N-oxide groups, and in the case of bicyclic aromatic rings, one of the two rings may be partially saturated, Ar1 is a monocyclic aromatic homo- or heterocycle having 0, 1, 2, or 3 N, O, and / or S atoms and 5 or 6 skeletal atoms, which may be unsubstituted or mono-, di-, or tri-substituted, independently of one another, by Hal, LA, OH, SH, O(LA), NH, NH(LA), N(LA), NO, CN, OCN, SCN, COOH, COO(LA), CONH, CONH(LA), CON(LA), NHCO(LA), CHO, CO(LA), SON, NH, SO(LA), and / or SOHal; A is unbranched or branched, straight-chain or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH groups may be replaced by O or S atoms and / or by -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, in which one to three H atoms may be replaced by Hal, in which one or two CH groups may be replaced by OH, SH, NH, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN, L A is unbranched or branched straight-chain alkyl having 1, 2, 3 or 4 C atoms, in which 1, 2 or 3 H atoms may be replaced by Hal, such as methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, Hal is F, Cl, or Br, preferably F or Cl, most preferably F].

[0058] We also describe combinations comprising, and in particular consisting of, at least two compounds, one of which is a quinazolinecarboxamide doazetidine compound, or compositions, in particular pharmaceutical compositions, comprising a quinazolinecarboxamide doazetidine compound and a pharmaceutically acceptable carrier.

[0059] A preferred combination is (a) a quinazolinecarboxamide azetidine compound of formula (I): [ka] and / or any pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers thereof (including any mixtures thereof in any ratio), wherein: R 1 is H or LA, R 2 is Hal, O(LA), N(LA)(LA)′, CONH(LA), Ar, CONH, or A; R 3' , R 3'' are independently H, LA, or Hal; Ar is a monocyclic or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3, or 4 N, O, and / or S atoms and 5, 6, 7, 8, 9, or 10 skeletal atoms, which is unsubstituted or, independently of one another, is selected from the group consisting of 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, NHSOA, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, the N atoms of the rings may be replaced by O atoms to form N-oxide groups, and in the case of bicyclic aromatic rings, one of the two rings may be partially saturated, Ar1 is a monocyclic aromatic homo- or heterocycle having 0, 1, 2, or 3 N, O, and / or S atoms and 5 or 6 skeletal atoms, which may be unsubstituted or mono-, di-, or tri-substituted, independently of one another, by Hal, LA, OH, SH, O(LA), NH, NH(LA), N(LA), NO, CN, OCN, SCN, COOH, COO(LA), CONH, CONH(LA), CON(LA), NHCO(LA), CHO, CO(LA), SON, NH, SO(LA), and / or SOHal; A is unbranched or branched, straight-chain or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH groups may be replaced by O or S atoms and / or by -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, in which one to three H atoms may be replaced by Hal, in which one or two CH groups may be replaced by OH, SH, NH, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN, L A is unbranched or branched straight-chain alkyl having 1, 2, 3 or 4 C atoms, in which 1, 2 or 3 H atoms may be replaced by Hal, such as methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, Hal is F, Cl, or Br, preferably F or Cl, most preferably F; (b) an anti-cancer agent, preferably an anti-neoplastic agent and / or a signal transduction inhibitor; It is a combination of

[0060] A preferred composition comprises a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0061] We also describe a combination or composition as described herein for use as a medicament.

[0062] In a preferred embodiment, the quinazoline carboxamide azetidine compound of the combination of (a) and (b) and the separate therapeutic agent, preferably an anti-cancer agent, more preferably an anti-neoplastic agent and / or a signal transduction inhibitor, are formulated for simultaneous, concurrent, or sequential administration, preferably oral administration.

[0063] Preferably, the combination or composition is used to prevent or treat a hormone-dependent disease, preferably cancer, in a subject in need thereof, more preferably an estrogen receptor positive (ER) disease. + ) or any mixture thereof in any ratio for use in preventing or treating cancer, particularly breast cancer.

[0064] In a preferred embodiment, the treatment comprises the administration of a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-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 any ratio, in addition to an anti-cancer agent, preferably an anti-neoplastic agent, and / or a signal transduction inhibitor, more preferably, for example, a selective ER modulator ("SERM"), a selective ER downregulator / degrader ("SERD"), an aromatase inhibitor ("AI"), a complete estrogen receptor antagonist (CERAN), a cell cycle inhibitor, a PI3K / Akt inhibitor, or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof, or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof, in addition to an anti-cancer agent, preferably an anti-neoplastic agent, and / or a signal transduction inhibitor, more preferably, for example, a selective ER modulator ("SERM"), a selective ER downregulator / degrader ("SERD"), an aromatase inhibitor ("AI"), a complete estrogen receptor antagonist (CERAN), a cell cycle inhibitor, a PI3K / Akt inhibitor, or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof, in any ratio. and / or inhibitors of growth factor receptors, more preferably selected from a SERD, a selective ER modulator ("SERM"), an aromatase inhibitor ("AI"), a complete estrogen receptor antagonist (CERAN), a cyclin-dependent kinase (CDK) inhibitor, and any combination thereof, and most preferably selected from a selective ER modulator ("SERM"), a selective ER downregulator / degrader ("SERD"), an aromatase inhibitor ("AI"), a complete estrogen receptor antagonist (CERAN), a cyclin-dependent kinase (CDK) inhibitor, a PI3K / Akt / mTOR ("PAM") pathway inhibitor, and any combination thereof.

[0065] In another specific embodiment, the composition comprises (c) an additional agent, preferably an anti-cancer agent. This additional agent is preferably selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or fragment thereof, an antibody-drug conjugate, and / or an antisense molecule (in addition to the quinazolinecarboxamide doazetidine compound, an anti-neoplastic agent, and / or a signal transduction inhibitor). This additional agent (c) is preferably selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or fragment thereof, an antibody-drug conjugate, a small molecule, a growth factor receptor agent, and / or an antisense molecule (in addition to the quinazolinecarboxamide doazetidine compound, an anti-neoplastic agent, and / or a signal transduction inhibitor).

[0066] Also described herein is a corresponding method of treatment comprising administering to a subject in need thereof a quinazolinecarboxamide doazetidine compound, or a combination or (pharmaceutical) composition comprising a quinazolinecarboxamide doazetidine compound and a pharmaceutically acceptable carrier, preferably (a) a quinazolinecarboxamide doazetidine compound, (b) a separate therapeutic agent, preferably an anti-cancer agent, more preferably an anti-neoplastic agent and / or a signal transduction inhibitor, and optionally also (c) an additional separate therapeutic agent, preferably an additional anti-cancer agent, as further identified herein below. The additional separate therapeutic agent, preferably the anti-cancer agent (c), may be selected from, for example, an anti-angiogenesis agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or fragment thereof, an antibody-drug conjugate, and / or an antisense molecule. In certain embodiments, the additional separate therapeutic agent, preferably an anti-cancer agent (c), may be selected from, for example, an anti-angiogenic agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or fragment thereof, an antibody-drug conjugate, a small molecule, a growth factor receptor agent, and / or an antisense molecule.

[0067] Combination of M2698 and SERD In a more preferred embodiment, the treatment comprises the administration of a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-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 any ratio, in addition to, preferably, amsenestrone, azetidine. The method includes administering an anti-cancer agent, preferably a selective ER downregulator / degrader ("SERD") selected from nosertib (ZN-c5), bolestrant, brilantrant, camizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lintodestrant, AZD9496, D-0502, LY3484356, GDC-0927, and SHR9549, more preferably elacestrant.

[0068] In certain aspects, the inventors herein describe a compound comprising (a) 4-[(S)-2-acetidin-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 any ratio, and (b) a selective ER downregulator degrader (SERD), preferably amsenestrant, azenosertib (ZN-c5), borestrant, brilantrant, or camizestrant. and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing (including any mixture thereof in any ratio), more preferably elacestrant; and compositions comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier.

[0069] In certain embodiments, 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.

[0070] In another specific embodiment, 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 elacestrant 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, and more preferably about 340 mg or 350 mg.

[0071] In another particular embodiment, M2698 and SERD are formulated for simultaneous, concurrent, or sequential administration, preferably oral administration.

[0072] In another particular embodiment, the combination or composition further comprises (c) one or several distinct therapeutic compounds, in particular anti-cancer agents selected from anti-angiogenic agents, signal transduction inhibitors, anti-neoplastic agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents, antisense molecules, and any combination thereof.

[0073] Also described herein is a method of treating a hormone-dependent disease, preferably cancer, in a subject, comprising administering to the subject a combination of (a) 4-[(S)-2-acetidin-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 any ratio), and (b) a selective ER downregulator degrader (SERD), preferably elacestrant, or a composition comprising a combination of (a) and (b) and a pharmaceutically acceptable carrier, thereby treating the subject.

[0074] When 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, for example, breast cancer, 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 tumor. In a specific embodiment, the breast cancer is a cancer characterized by mutated estrogen receptor alpha (ERα, ERa, or ESR1) cancerous tumor.

[0075] The method for treating a hormone-dependent disease in a subject may comprise administering the combination or composition of the present invention, as described herein, in combination with (c) one or several separate therapeutic compounds. When the hormone-dependent disease is cancer, the one or several separate therapeutic compounds may be, for example, an anti-cancer agent selected from an anti-angiogenesis agent, a signal transduction inhibitor, an anti-neoplastic agent, a therapeutic antibody or fragment thereof, an antibody-drug conjugate, a small molecule, a growth factor receptor agent, an antisense molecule, and any combination thereof.

[0076] Further described herein is a kit comprising (a) 4-[(S)-2-acetidin-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 any ratio), and (b) a selective ER downregulator degrader (SERD), preferably elacestrant, 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 a SERD or for administering the composition.

[0077] Combination of M2698 with a cyclin-dependent kinase (CDK) 4 / 6 inhibitor In another more preferred embodiment, the treatment comprises a step comprising administration of an anti-cancer agent, preferably a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor, more preferably a CDK4 / 6 inhibitor selected from abemaciclib, palbociclib, or ribociclib, in addition to administration of a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-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.

[0078] In another specific aspect, the inventors herein disclose a compound comprising (a) 4-[(S)-2-acetidin-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 any ratio; and (b) preferably abemaciclib, palbociclib, ribociclib, and any of the foregoing. and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor selected from a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the above (a) and (b), including any mixture thereof in any ratio, 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.

[0079] In certain embodiments, 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.

[0080] In another specific embodiment, 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 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, and more preferably about 300 mg.

[0081] In another particular embodiment, M2698 and the CDK4 / 6 inhibitor are formulated for simultaneous, concurrent, or sequential administration, preferably for oral administration.

[0082] In another particular embodiment, the combination or composition further comprises (c) one or several distinct therapeutic compounds, in particular anti-cancer agents selected from anti-angiogenic agents, signal transduction inhibitors, anti-neoplastic agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents, antisense molecules, and any combination thereof.

[0083] When 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, for example, breast cancer, 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 tumor. In a specific embodiment, the breast cancer is a cancer characterized by mutated estrogen receptor alpha (ERα, ERa, or ESR1) cancerous tumor.

[0084] (a) 4-[(S)-2-acetidin-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 any ratio; and (b) preferably abemaciclib, palbociclib, ribociclib, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer of any of the foregoing. Also described herein are methods for treating a hormone-dependent disease, preferably cancer, in a subject, comprising administering to the subject a combination of (a) and (b) with a cyclin-dependent kinase (CDK) 4 / 6 inhibitor selected from the group consisting of a bemaciclib, a cyclin-dependent kinase (CDK) 4 / 6 inhibitor ...

[0085] (a) 4-[(S)-2-acetidin-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 any ratio, and (b) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, preferably abemaciclib, palbociclib, ribociclib, and any of the foregoing, in separate containers. Further described herein are kits comprising an inhibitor selected from a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of them, 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, and materials for administering the M2698 and / or CDK4 / 6 inhibitor or for administering the composition.

[0086] definition Unless otherwise defined, 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 subject matter disclosed herein belongs.

[0087] The following definitions may be useful for understanding the embodiments presented herein.

[0088] The term "hormone-dependent disease" refers to any disease caused directly or indirectly by a hormonal disorder that is the result of a hormonal imbalance affecting hormone-producing glands or organs, such as the brain, breast, endometrium, ovaries, pancreas, prostate, testes, thyroid, and bone tissue.

[0089] The hormone-dependent disease can be, for example, cancer, primary amenorrhea, polycystic ovary syndrome (PCOS), or anovulation.

[0090] Unless otherwise specified, the terms "cancer," "cancerous tumor," "malignant tumor," "tumor," "neoplasia," "cancerous disease," or "proliferative disorder" are used interchangeably herein. These terms refer to or describe the physiological condition in mammals typically characterized by uncontrolled cell growth. 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 for the type of cell that forms them, and 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, leukemia, lymphoma, and myeloma. The term "cancer" includes, but is not limited to, primary cancers originating in a particular site within the body. The term cancer also includes cancer that has metastasized, i.e., spread from where it began to other parts of the body, such as the central nervous system (CNS), especially the brain, or to the bones, lungs, or liver; recurrence of the original primary cancer after remission; and second primary cancers, which are new primary cancers of a different type in people with a history of previous cancer.

[0091] In the context of the present invention, a "tumor cell" is a cell obtained from a tumor or tissue of a subject suffering from cancer, particularly from at least one of the cancers identified herein, preferably breast cancer, and which exhibits well-known characteristics of cancer cells, such as sustained proliferation signaling, evasion of growth suppressors, resistance to cell death, ability to replicate, induction of angiogenesis, and activation of 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 herein to identify circulating tumor cells, cells obtained from a liquid tumor biopsy, cells obtained from a tumor bed, or cells obtained from a metastasis.

[0092] The cancer is preferably a hormone receptor positive (HR+) cancer. The cancer may 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.

[0093] In some embodiments, the cancer, e.g., 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-).

[0094] Estrogen receptor alpha, also identified herein as "ERα" or "ERa" or "ESR1," and also known 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 two major estrogen receptor subtypes (alpha, ERα, and beta, ERβ) that make up the estrogen receptor (ER). While breast cancers exhibit abundant levels of ERα and ERβ, advanced stages of the disease only express ERα, with ERβ being lost. The amino acid sequence of the human wild-type ERa protein is identified herein as SEQ ID NO: 1. Human ERα is encoded by the gene ESR1 (estrogen receptor 1), SEQ ID NO: 3. Alternative splicing results in several ESR1 mRNA transcripts that differ primarily in their 5' untranslated regions. The translated receptor exhibits less variability.

[0095] The estrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and transcriptional activation.

[0096] As used herein, a "mutant ERa protein" is a non-wild-type ERa protein that contains at least one amino acid mutation (including, for example, an addition, deletion, substitution, or frameshift mutation) compared to the wild-type (which protein may also be referred to as "ESR1 WT").

[0097] "Wild-type" or "WT" ESR1 or ESR1 refers to the predominant form of a nucleotide or amino acid sequence present, respectively. 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 subject population, 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 sequences contain 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 sequences contain some other amino acid residue, glycine is said to be the wild-type residue.

[0098] As used herein, "ESR1 mutation" or "ESR1 variant" or "variant ERa protein" refers to a non-wild-type ERa protein containing at least one amino acid mutation compared to the wild-type (the variant protein may also be referred to as a variant "Era"). As used herein, "ESR1 variant" 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 appreciate that various ESR1 mutations can result in various 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.

[0099] As used herein, a "constitutively active mutant" is a non-wild-type protein that is active without the need for a bound ligand, for example, an ERa protein that is active even in the absence of estrogen.

[0100] The cancer is preferably a cancer 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. More preferably, the cancer is breast cancer, in particular metastatic and / or advanced breast cancer.

[0101] In certain embodiments, the cancer, typically an HR+, preferably an ER+ cancer, is a human epidermal growth factor receptor 2 positive (HER2+) cancer.

[0102] In another particular embodiment, the cancer, typically an HR+, preferably an ER+ cancer, is a human epidermal growth factor receptor 2-negative (HER2- or HER2neg) cancer.

[0103] In another particular embodiment, the cancer, typically an HR+, preferably an ER+ cancer, is a human epidermal growth factor receptor 2 low (HER2 low) cancer.

[0104] In a particular embodiment, the tumor is HR+, in particular ER+, and is a "mutated ESR1" or "mutated ERa" tumor.

[0105] The tumor may also be an HR+, particularly an ER+, mutated ESR1 (or mutated ERa), and HER2- / HER2neg tumor. In some such embodiments, the HR+ / HER2- cancer, particularly breast cancer, is refractory to conventional treatments for cancer treatment, preferably with an endocrine therapy, as defined herein below, preferably selected from an anti-neoplastic agent, for example, a selective ER modulator (SERM), a selective ER downregulator degrader (SERD), an aromatase inhibitor (AI) inhibitor, CERAN, a hormone, particularly a luteinizing hormone-releasing hormone (LHRH) agonist, a gonadotropin-releasing hormone (GnRH) agonist, a cyclin-dependent kinase (CDK) inhibitor, for example, a CDK4 / 6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and a pharmaceutically acceptable salt thereof. In some such embodiments, the 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, particularly a luteinizing hormone-releasing hormone (LHRH) agonist, a gonadotropin-releasing hormone (GnRH) agonist, a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and pharmaceutically acceptable salts thereof. In some embodiments, the HR+ / HER2- breast cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

[0106] In some other aspects, the HR+ / HER2- cancer, particularly breast cancer, is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some aspects of each of the foregoing, the HR+ / HER2- cancer is advanced or metastatic HR+ / HER2- breast cancer.

[0107] In some other aspects, the cancer is HR- / HER2+, particularly HR- / HER2+ breast cancer. In some embodiments where the cancer is HER2+, the methods, combinations, and uses described herein further comprise an additional anti-cancer agent, wherein the additional anti-cancer agent is a HER2-targeting agent (e.g., trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib, or tucatinib), or an agent that targets the PI3K / AKT molecular pathway (e.g., ipatasertib).

[0108] In another particular embodiment, the tumor is an HR+, in particular an ER+, mutated ESR1 (or mutated ERa), and HER2+ / HER2pos tumor.

[0109] In another particular embodiment, the tumor is an HR+, in particular an ER+, mutated ESR1 (or mutated ERa), and HER2-low tumor.

[0110] In some aspects, the breast cancer is associated with the BRCA1 or BRCA2 gene.

[0111] In another embodiment, the breast cancer is triple-negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR-, and HER2-. In some embodiments, the TNBC is refractory 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, particularly a luteinizing hormone-releasing hormone (LHRH) agonist, a gonadotropin-releasing hormone (GnRH) agonist, a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and a pharmaceutically acceptable salt thereof. In some embodiments, the TNBC 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, particularly a luteinizing hormone-releasing hormone (LHRH) agonist, a gonadotropin-releasing hormone (GnRH) agonist, a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and a pharmaceutically acceptable salt thereof. In some embodiments, the TNBC is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some such embodiments, the TNBC is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some embodiments, the TNBC is locally recurrent / progressive or metastatic TNBC. In some aspects, the TNBC is advanced or metastatic TNBC.

[0112] 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 the mutated ERa is characterized by an altered conformation of its ligand-binding domain.

[0113] In a preferred embodiment, the mutation occurs at at least one residue selected from residues 380, 392, 404, 422, 463, 536, 537, and 538, more preferably an amino acid substitution selected from E380Q, V392I, F404fs, V422del, S463P, L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, D538G, more preferably Y537S and / or D538G.

[0114] In some aspects of each of the foregoing, the cancer, particularly breast cancer, is refractory or resistant to treatment with one or more standard therapeutic agents.

[0115] In some such embodiments, the breast cancer is refractory or resistant to treatment with an anti-neoplastic agent, preferably an endocrine / hormonal therapy agent, such as an AI, CERAN, SERD, or SERM. In some embodiments, the cancer, particularly breast cancer, is refractory or resistant to treatment with a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor. For example, in some embodiments, the 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, the breast cancer is refractory or resistant to or has progressed on treatment with an anti-neoplastic chemotherapeutic agent, such as a platinum agent, taxane, anthracycline, or an antimetabolite.

[0116] In the context of the present invention, a "conventional treatment for cancer" (also identified herein as a "standard of care treatment" or a "major cancer treatment modality") may be, for example, an anti-cancer agent selected from endocrine ( / hormonal) therapeutic agents, anti-angiogenic agents, signal transduction inhibitors, anti-neoplastic agents, small molecules, antibodies or fragments thereof (including single chain antibodies), antibody-drug conjugates (ADCs), and antisense molecules, preferably from anti-angiogenic agents, signal transduction inhibitors, anti-neoplastic agents, small molecules, growth factor receptor agents, antibodies or fragments thereof (including single chain antibodies), antibody-drug conjugates (ADCs), and antisense molecules.

[0117] Conventional treatments for cancer are, for example, selected from hormone therapy, immunotherapy, specific kinase inhibitor-based therapy, anti-angiogenic agent-based therapy, antibody-based therapy, particularly monoclonal antibody-based therapy, especially antibody-drug conjugate-based therapy, chemotherapy, radiotherapy, and surgery.

[0118] The term "conventional" means that the treatment is administered, or if not routinely administered, is appropriate and at least recommended by health authorities. "Conventional" treatments are selected by oncologists depending on the specific cancer being prevented or treated. The term "adjuvant therapy" refers to additional treatment given after the main therapeutic modality.

[0119] In the context of cancer, a conventional treatment for cancer is chemotherapy. Chemotherapeutic agents may be selected from, for example, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, taxanes, topoisomerase inhibitors, and vinca alkaloids.

[0120] In the context of cancer, particularly hormone receptor positive (HR+) cancers such as breast cancer, conventional treatments for cancer are hormonal treatments that include the administration of drugs selected from selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and complete estrogen receptor antagonists (CERANs). In certain embodiments, conventional treatments for such HR+ cancers include the use of anti-neoplastic agents and / or signal transduction inhibitors.

[0121] Conventional treatments for cancer preferably include cyclin-dependent kinase (CDK) inhibitors, such as selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitor (AI) inhibitors, CERANs, hormones, particularly endocrine therapeutic agents selected from luteinizing hormone-releasing hormone (LHRH) agonists, gonadotropin-releasing hormone (GnRH) agonists, progestins or antiandrogens, CYP17 inhibitors, antiadrenergic agents, PI3K / AKT / mTOR ("PAM") pathway inhibitors, and any combination thereof, particularly a combination of a CDK inhibitor and a hormone therapeutic agent, a CDK inhibitor and a SERD and / or a SERM, or a CDK inhibitor and a SERD and a PI3K / AKT / mTOR ("PAM") pathway inhibitor.

[0122] Certain conventional treatments for cancer involve the administration of a drug selected from an inhibitor of the ER pathway, the PI3K / Akt / mTOR ("PAM") pathway, a growth factor receptor pathway (including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin growth factor receptor (IGFR), and / or vascular endothelial growth factor receptor (VEGFR)), the cell cycle, the ubiquitin-proteasome pathway, or a protein bromodomain and / or exodomain compound. 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.

[0123] Other conventional treatments for cancer, particularly adjuvant treatments, include surgery, radiation therapy (also identified herein as "radiotherapy"), chemotherapy, immunotherapy, endocrine therapy, and targeted therapy (particularly targeted therapy that focuses on specific genes or proteins of the tumor).

[0124] In certain embodiments, 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 embodiments, the treatment is not cetuximab.

[0125] The term "anti-angiogenic agent" designates, inter alia, a VEGF inhibitor, a VEGFR inhibitor, a TIE-2 inhibitor, a PDGFR inhibitor, an angiopoietin inhibitor, a PKCf3 inhibitor, a cyclooxygenase II (COX-2) inhibitor, an integrin (alpha-v / beta-3), a matrix metalloproteinase 2 (MMP-2) inhibitor, or a matrix metalloproteinase 9 (MMP-9) inhibitor. The anti-angiogenic agent may be selected from, for example, gefitinib, cilengitide, Ziv-aflibercept (Zaltrap®), and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomeric forms of any of the foregoing. It is preferably selected from cilengitide, Ziv-aflibercept (Zaltrap®), and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomeric forms of any of the foregoing.

[0126] The term "signal transduction inhibitors" refers to, inter alia, 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 lymphoma 2 (BCL2) inhibitors, EZH2 inhibitors, FGFR pathway inhibitors, rearranged during transfection, and the like. 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 are specified.

[0127] Kinase inhibitors include, for example, abivertinib, acalabrutinib, afatinib, alectinib, almonertinib, azenosertib (ZN-c5), axitinib, binimetinib (Mektovi or ARRY-162), bosutinib, brigatinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, epertinib, erlotinib, gefitinib, gilteritinib, ibrutinib, icotinib, imatinib, lapatinib, lalotinib, larotrectinib, lazertinib, and lifilafenib. Phenib, lorlatinib, midostaurin, mobocertinib, nacotinib, nazartinib, neratinib, nilotinib, olmutinib, osimertinib, pazopanib, pimasertib, ponatinib, poziotinib, pyrotinib, refametinib, regorafenib, ruxolitinib, sapitinib, selatinib, sirotinib, tepotinib, tesevatinib, trametinib, tucatinib, barlitinib, vemurafenib, inlitinib, zanubrutinib, zolifertinib, 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, B H-2922, BI-4020, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711, C-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-1 2128, 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, MP0274, mRX-7, MTX-211, MVC-101, NRC-2694, NT-004, NT-113, OBX-1012, ORIC-114, PB-357, PF-0779954, QL-1 105, 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.

[0128] The p21-activated kinase 1 (PAK1) inhibitor can be, for example, IPA3, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0129] In certain embodiments, the signal transduction inhibitor is not a kinase inhibitor.

[0130] The proteasome inhibitor may be selected from, for example, bortezomib, carfilzomib, ixazomib, marizomib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0131] The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitor can be, for example, enasidenib, ivosidenib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.

[0132] The neurotrophin receptor kinase (NTRK) inhibitor can 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.

[0133] The hedgehog pathway inhibitor can be selected from, for example, glasdegib, sonidegib, vismodegib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0134] The PARP inhibitor may be selected from, for example, niraparib, olaparib, rucaparib, talazoparib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0135] The B-cell lymphoma 2 (BCL2) inhibitor can be, for example, venetoclax, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0136] 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.

[0137] The FGFR pathway inhibitor may be selected from, for example, lucitanib, dovitinib, AZD4547, erdafitinib, infigratinib (BGJ398), BAY-1163877, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0138] The rearranged during transfection (RET) inhibitor may be selected from, for example, vandetanib, cabozantinib, lenvatinib, sorafenib, selpercatinib, pralsetinib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0139] 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]diazepin-3-yl)-propionamide, or 11-endo-N-(5,6,7,8,9,10-hexahydro-6,9-methanobenzo[9][8]annulen-11-yl)-thiophene-2-sulfonamide, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.

[0140] 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.

[0141] The SRC3 inhibitor can be, for example, SI-2, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0142] The MYC inhibitor can be, for example, omomyc, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0143] The BET bromodomain inhibitor may be selected from, for example, JQ1, I-BET762, OTX015, I-BET151, RVX-208, MS417, ABBV-075, ABBV-744, SJ432, AZD5153, INCB054329, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0144] The farnesyl transferase inhibitor can be, for example, lonafarnib or tipifarnib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.

[0145] The HMG-CoA reductase inhibitor can be, for example, atorvastatin (Caduet, Lipitor, Lypqozet), or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0146] PI3K / AKT / mTOR ("PAM") pathway inhibitors designate compounds that are designed to inhibit phosphoinositide 3-kinase (PI3K) and / or protein kinase B (Akt) and / or mammalian target of rapamycin (mTOR). This includes, for example, phosphoinositide 3-kinase (PI3K) pathway inhibitors, ATP-competitors, dual inhibitors of class I PI3K and mTORC1 / 2; "pan-PI3K" inhibitors that inhibit all four isoforms of class I PI3K (α, β, δ, γ); isoform-specific inhibitors of the various PI3K isoforms of class II PI3K (PI3K-C2α, PI3K-C2β, and PI3K-C2γ) or any one of class III PI3K; allosteric and catalytic inhibitors of AKT; ATP-competitive inhibitors of mTOR only (and thus both mTORC1 and mTORC2), or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.PAM pathway inhibitors include, for example, mTOR inhibitors, such as bimiralisib, dactolisibu tosylate, detorsertib, everolimus, monepantel, omipalisib, onatasertib, ridaforolimus, sapanisertib, sirolimus, Streptomyces species 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; AKT / PDK1 inhibitors, such as , afuresertib, borussertib, capivasertib (AZD5363), celecoxib or celecoxib derivatives, doldabiprone (ONC-201), enzastaurin, ipatasertib, milansertib, uprosertib (GSK2141795), ALM-301, ARQ-751, AT-13148, AZD805 5, BAY-1125976, BX795, BX912, COTI-2, DC-120, FXY-1, GSK470, JRP-890, JX06, KS-99, LY-25030 29, MK-2206, NISC-6, OSU-03012, PHT-427, PTX-200, RX-0201, RX-0301, SBF1, or TAS-117; PI3K inhibitor and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.The PAM inhibitor may also be selected from AZD8055, GDC0941, selumetinib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing. The inhibitor of the PAM pathway is preferably selected from buparlisib, piralalisib, pictilisib, sonolisib, dactolisib, sapanisertib, voxtalisib, selavelsib, alpelisib, perifosine, MK2206, ipatasertib, GSK690693, temsirolimus, ridaforolimus, sirolimus, everolimus, AZD8055, OSI-027, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing, or any mixtures thereof in any ratio.

[0147] RAS / RAF / MEK / ERK ("MAPK") pathway inhibitors include, for example, VS-6766, TNO-155, SHP099, RMC-4550, RMC-4630, RMC-5845, IACS-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, C C-90003, ERAS-007, HMPL-295, IPN-ERK, KO-947, LTT462, SCH772984, TK216, ASTX-029, HH-2710, LY-3214996, selumetinib, trametinib, ulixertinib, ASN-007, ATG-017, BPI-27336, JSI-1187, MK-8353, JRP-890, JRF-108, the dual RAF / MEK inhibitors identified in WO2022 / 170060, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0148] In certain embodiments, the MAPK pathway inhibitor is not a MEK inhibitor.

[0149] In certain embodiments, the MEK inhibitor is not trametinib, cobimetinib, selumetinib, refametinib, or pimasertib. Preferably, the MEK inhibitor is not pimasertib.

[0150] The S6K inhibitor may be selected from, for example, LY2584702, piperazinyl-pyrimidine derivatives (such as PF-4708671 or PF-4708671), A77 1726 (the active metabolite of leflunomide), FS-115, FL772, LY2780301, LYS6K2, AD80 / AD81, gingerenone, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0151] The eIF4A / E inhibitor may be selected from, for example, a rapamycin analog, ribavirin, zotatifine, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0152] Cyclin-dependent kinase (CDK) inhibitors are, for example, selected from CDK1, 2, 4, 5, 6, and / or 7 inhibitors, in particular, for example, abemaciclib (also known as LY2835219), AG024322, aloisine A, aloisine B, alsterpaullone, aminopurvalanol, AT7519, AZD-5438, AZD5597, BLU-222, BMS-387032, birocilib (XZP3287), bohemin, butyrolactone, CYC065, dalpicic rib (SHR-6390), dinaciclib, ETH-155008, flavopiridol, FCN-437c, GLR2007, indirubin, indirubin-3'-monoxime, JNJ-7706621, Kenpaullone, relociclib (also known as G1T38), meriolin 3, milciclib, narazaciclib (ON123300), NVP-LCQ19, olomoucine, olomoucine II, palbociclib (Ibrance, PD-0332991, or PF-0 0080665), PF-07220060, PF-07104091, PF-06873600, PHA-793887, purvalanol A, purvanol B, R-CR8, RGB-286638, RGB286147, ribociclib (also known as LEE-011), ribiciclib hydrochloride (P276-00), roniciclib, R-roscovitine, Ro4584820, SRX-3177, TG02, TQB3303, trilaciclib (also known as GTI128), The inhibitor may be voruciclib, xylocydin, ZK304709, 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 samuracilib (also known as CT7001 or ICE0942).

[0153] 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 pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0154] The term "antineoplastic agents" designates in particular chemotherapeutic agents and hormonal ( / endocrine) therapeutic agents.

[0155] The term "chemotherapeutic agent" designates, among others, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, biological response modifiers, histone deacetylase (HDAC) inhibitors, growth factor inhibitors, taxanes, topoisomerase inhibitors, or vinca alkaloids. The term also encompasses other compounds, such as, for example, asparaginase (pegaspargase), bexarotene, eribulin, eribulin mesylate, fosbretabulin, hydroxyurea, ixabepilone, lenamidomide, mitotane, omacetaxine, pomalidomide, tagraxosp, telotristat, thalidomide, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, and tautomers of any of the foregoing.

[0156] In preferred embodiments, the chemotherapeutic agent is selected from capecitabine, cyclophosphamide, docetaxel, doxorubicin, epirubicin, eribulin mesylate, fluorouracil, 5-fluorouracil, gemcitabine, liposomal doxorubicin, paclitaxel, vinorelbine, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0157] The alkylating agent may be selected from, for example, apaziquone, altretamine, bendamustine, busulfan, carboquone, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, fotemustine, glufosfamide, ifosfamide, improsulfan tosylate, lomustine, mechlorethamine, melphalan, mitobronitol, mitolactol, nimustine, palifosfamide, pipobroman, procarbazine, ranimustine, streptozocin, temozomide, N,N'N'-triethylenethiophosphoramide (thiotepa), trabectedin, treosulfan, trofosfamide, uramustine, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0158] The platinum coordination complex can be selected from, for example, carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0159] The cytotoxic antibiotic may be selected from, for example, aclarubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, levamisole, idarubicin, miltefosine, mitomycin, mitoxantrone, plicamycin, valrubicin, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0160] The antimetabolite may be selected from, for example, an antifolate (such as methotrexate, pemetrexed, pralatrexate, or trimetrexate), a purine analog (such as azathioprine, cladribine, fludarabine, mercaptopurine, or thioguanine), a pyrimidine analog (such as azacitidine, capecitabine, cytarabine, decitabine, floxuridine, fluorouracil, 5-fluorouracil, gemcitabine, or trifluridine / tipiracil), and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0161] The biological response modifier may be selected from, for example, aldesleukin (IL-2), denileukin diftitox, and interferon gamma.

[0162] 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.

[0163] The taxane may be selected from, for example, cabazitaxel, docetaxel, paclitaxel (e.g., paclitaxel albumin-stabilized nanoparticle formulations), tesetaxel, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0164] The topoisomerase inhibitor may be selected from, for example, etoposide, irinotecan, teniposide, topotecan, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0165] The vinca alkaloid may be selected from, for example, vinblastine, vindesine, vincristine, vinflunine, vinorelbine, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0166] The term "hormonal ( / endocrine) therapy" includes, inter alia, 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, somatostatin; progestins 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.

[0167] The anti-estrogen may be selected from, for example, selective ER down-regulators or selective ER degraders ("SERDs"), selective ER modulators ("SERMs"), aromatase inhibitors ("AIs"), and full estrogen receptor antagonists ("CERANs").

[0168] The term "selective ER modulator ("SERM")" designates an anti-estrogenic compound designed to compete with estrogen for ER binding and exhibits mixed agonist / antagonist capabilities in a tissue-specific manner. SERMs are typically selected from triphenylethylenes, benzothiophenes, phenylindoles, tetrahydronaphthalenes, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0169] The triphenylethylene is preferably tamoxifen or a "tamoxifen-like" compound such as 4-hydroxytamoxifen, afimoxifene, endoxifene, toremifene, droloxifene, or idoxifene; the benzothiophene is preferably raloxifene or arzoxifene; the phenylindole is preferably bazedoxifene or pipindoxifene; and the tetrahydronaphthalene is preferably lasofoxifene.

[0170] The term "selective ER downregulator or selective ER degrader ("SERD")" designates an anti-estrogen compound designed to create an unstable protein complex and induce proteasome-mediated ER proteolysis. SERDs are preferably selected from the group consisting of fulvestrant, elacestrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also identified as RAD-1901], amsenestrant [(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzyl], fulvest ... benzo[7]annulene-3-carboxylic acid, also identified as SAR439859], brilantrant [(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, also identified as ARN-810 or GDC-0810], camizestrant [N-[1-(3-fluoropropyl)acetidin-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 identified as AZD9833], giledestrant [3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)acetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropane- 1-ol, also identified as RG6171 or GDC9545], Lintdestrant, [(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, also identified as G1T48], AZD9496 [(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-dimethylbenzoyl[3,[4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also identified as LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing. In another preferred embodiment, the SERD compound is elacestrant, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0171] In particularly preferred embodiments, the SERD is amsenestrant [(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 identified as SAR439859], azenosertib (ZN-c5) [1-[(7R)-7-ethyl-7-hydroxy-5,6-dimethylbenzoyl[b]pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino] -2-propa-2-dimethylbenzoyl[3,4-d]pyrimidin-3-one], borestrant [(7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol-3boronic acid], brilantrant [(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, ARN-810 or GDC-08 10], camizestrant [N-[1-(3-fluoropropyl)acetidin-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 identified as AZD9833], elacestrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene also identified as RAD-1901], fulvestrant [(7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol], giledestrant [3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)acetidin-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 identified as RG6171 or GDC9545], imrunestrant [(5R)-5-[4-[2-[3-(fluoromethyl)acetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol], lintodestrant, [(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, also identified as G1T48], AZD9496 [(E)-3-[3,5-difluoro-4-[(1R,3R)- 2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-dimethylbenzoyl[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also identified as LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing. In preferred embodiments, the SERD compound is selected from amsenestrant, azenosertib (ZN-c5), borestrant, brilantrant, camizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lintodestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927, or SHR9549, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0172] The term "aromatase inhibitor ("AI")" designates a compound that reduces systemic levels of estrogen. Aromatase inhibitors can be steroidal or non-steroidal aromatase inhibitors. For example, the one or more aromatase inhibitors may 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 polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing). The AI is preferably selected from aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, vorozole, AZD9496, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0173] The term "full estrogen receptor antagonist ("CERAN")" designates a compound that potently and completely inactivates the estrogen receptor (ER). CERANs are preferably selected from the group consisting of 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-trimethyl-4-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl ... Fluoro-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. Further examples of similar CERAN compounds are described in WO 19 / 241231.

[0174] The term cell cycle inhibitor designates compounds that are designed to slow or arrest cell cycle progression through a variety of mechanisms. Cell cycle arrest can be induced at various stages, reducing the rate of cell division and the number of actively cycling cells.

[0175] The cell cycle inhibitor is preferably selected from palbociclib, ribociclib, abemaciclib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0176] The term "growth factor receptor agent" designates compounds that are 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).

[0177] The term "targeting agent" designates inhibitors of the cell cycle, the PI3K / Akt / mTOR pathway, or growth factor receptors, and / or compounds that target alterations in the ubiquitin-proteasome pathway, and / or compounds that increase the activity of bromodomains and / or extraterminal domains of proteins.

[0178] The targeting agent is preferably selected from palbociclib, ribociclib, abemaciclib, buparlisib, pilalalisib, pictilisib, sonolisib, dactolisib, sapanisertib, voxtalisib, selavelsib, alpelisib, perifosine, MK2206, ipatasertib, GSK690693, temsirolimus, ridaforolimus, sirolimus, everolimus, AZD-8055, OSI-027, lapatinib, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing. The targeting agent is more preferably palbociclib, ribociclib, abemaciclib, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer of any of the foregoing.

[0179] The term "small molecule" specifically designates small molecule compounds such as, for example, tipiracil, vistonuridine (uridine triacetate), zoledronic acid, or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0180] In the context of the present invention, the term "antibody" (or "immunoglobulin") designates 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 covers any (functional) fragments thereof.

[0181] A typical antibody consists of a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region (or domain) (abbreviated herein as VH) and a heavy chain constant region (hereafter referred to as CH). Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody's isotype as IgG, IgM, IgA, IgD, and IgE, respectively. The heavy chain constant regions of immunoglobulins IgG, IgD, and IgA (γ, δ, and α chains, respectively) contain three domains (CH1, CH2, and CH3) and a hinge region for added flexibility, while the heavy chain constant regions of immunoglobulins IgM and IgE contain four domains (CH1, CH2, CH3, and CH4). Depending on the structure of their heavy chains, antibodies of the present invention can be of the IgG, IgM, IgA, IgD, or IgE isotype. However, in a preferred embodiment, the antibodies of the invention are of the IgG isotype, ie, their heavy chains are of the gamma (γ) type.

[0182] IgG antibodies are classified into four distinct subtypes, IgG1, IgG2, IgG3, and IgG4, in order of their abundance in serum (IgG1 being the most abundant). The structure of the hinge region in the gamma chain gives each of these subtypes its unique biological profile (although there is approximately 95% similarity between their Fc regions, the structures of the hinge regions are relatively different).

[0183] Antibodies of the invention can be of the IgG1, IgG2, IgG3, or IgG4 subtype, however, in a preferred embodiment, antibodies of the invention are of the IgG1 subtype.

[0184] Each light chain contains a light chain variable region (abbreviated herein as VL) and a light chain constant region containing only one domain, CL. Two types of light chains exist in mammals: kappa (κ) chains, encoded by the immunoglobulin kappa locus on chromosome 2, and lambda (λ) chains, encoded by the immunoglobulin lambda locus on chromosome 22. In a preferred embodiment, the antibody of the present invention has a kappa light chain. The VH and VL regions are primarily responsible for binding to antigen epitopes and can be further subdivided into regions of hypervariability called "complementarity-determining regions" (CDRs), interspersed with more conserved regions called "framework regions" (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: 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 / heavy chain pair and is primarily determined by the CDRs.

[0185] The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone (or hybridome).

[0186] In contrast, the constant regions of the antibodies mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0187] As used herein, the term "antibody fragment" is intended to designate Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, single-chain antibodies, dimers, minibodies, nanobodies, diabodies, and multimers thereof, as well as bispecific antibody fragments. Antibodies can be fragmented using conventional techniques. Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies. For example, F(ab')2 fragments can be generated by treating an antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to generate 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 techniques.

[0188] Typically, antibody fragments of the present invention are functional fragments, i.e., antibody fragments capable of binding to a molecule of interest and preferably inhibiting or neutralizing its activity, just as the antibody from which it is derived does.

[0189] In another specific embodiment, the antibodies of the invention are monoclonal antibodies.

[0190] As used herein, the term "monoclonal antibody" refers to an antibody arising from a substantially homogeneous population of antibodies. More specifically, antibodies of a given interest are identical except for a few possible naturally occurring mutations that may be found in minimal proportions. In other words, a monoclonal antibody consists of a homogeneous antibody resulting from the growth of a single cell clone (e.g., a hybridoma, a eukaryotic host cell transfected with a DNA molecule encoding the homogeneous antibody, a prokaryotic host cell transfected with a DNA molecule encoding the homogeneous antibody, etc.), and is generally characterized by a heavy chain of only one isotype and subtype, and a light chain of only one kind. Furthermore, in contrast to polyclonal antibody preparations, each monoclonal antibody is directed against a single epitope of the antigen.

[0191] To produce monoclonal antibodies, antibody-producing cells (lymphocytes) can be harvested from animals immunized as described above and fused with myeloma cells by standard somatic cell fusion procedures, thereby immortalizing these cells and resulting in hybridoma cells. Such techniques (e.g., the hybridoma technique first developed by Kohler and Milstein (1975)), as well as other techniques, such as the human B-cell hybridoma technique, the EBV-hybridoma technique for producing human monoclonal antibodies, and the screening of combinatorial antibody libraries, are well known in the art. Hybridoma cells can be screened immunochemically for the production of antibodies specifically reactive with the target polypeptide, such that only monoclonal antibodies that bind to the polypeptide are isolated.

[0192] The antibodies or fragments thereof of the present invention may be human, chimeric, humanized, murine, CDR-grafted, phage-displayed, bacterial-displayed, yeast-displayed, transgenic mouse-generated, mutagenized, or randomized antibodies or fragments.

[0193] A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody (mAb) and a human immunoglobulin constant region.

[0194] Humanized forms of the antibodies of the present invention are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibodies) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin (recipient antibody) are replaced by corresponding non-human residues from the donor antibody. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. In general, humanized antibodies may comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin (donor antibody having the desired specificity, affinity, and capacity) and all or substantially all of the FRs are those of a human immunoglobulin sequence. Methods for humanizing non-human antibodies have been described in the art. Preferably, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. These non-human amino acid residues are often referred to as "import" residues, and they are typically taken from an "import" variable domain. Humanization can be essentially performed by substituting hypervariable region sequences for corresponding sequences of a human antibody. Such humanized antibodies are thus chimeric, in that substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypervariable region residues and possibly some FR residues have been substituted by residues from analogous sites in rodent antibodies. Other approaches generally involve conferring donor CDR binding affinity onto an antibody acceptor variable region framework. One approach involves simultaneously grafting and optimizing variable region binding fragment binding affinity. Another approach involves optimizing the binding affinity of antibody variable regions.

[0195] The antibodies of the present invention or fragments thereof may be administered in their "naked" or unconjugated form, or may have other agents conjugated thereto, such as drugs, toxins, or radioactive atoms.

[0196] "Antibody" refers to, for example, alemtuzumab, amelimumab, amivantamab, atezolizumab, avelumab, besilesomab, bevacizumab, blinatumomab, brentuximab, catumaxomab, cemiplimab, cetuximab, dalotuzumab, daratumumab, denosumab, dinutuximab, durvalumab, elotuzumab, erlanatamab, epratuzumab, farletuzumab, gemtuzumab, inotuzumab ozogamicin, ipilimumab, matuzumab, mogamulizumab, moxetumumab pasudotox, nimotuzumab, PF-07260437, PF-07257876, PF-07062119, necitumumab, nivolumab, obinutuzumab, ocaratuzumab, onartuzumab, ofatumumab, olaratumumab, oregovomab, panitumumab, pembrolizumab, pertuzumab, racotumomab, ramucirumab, rilotumumab, rituximab, siltuximab, tabalumab, tocilizumab, tomzotuximab, tositumomab, trastuzumab, zalutumumab, zanolimumab, or zenoctuzumab.

[0197] The term "antibody-drug conjugate" ("ADC") specifically designates ADC compounds such as, for example, trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki (Enhertu®), trastuzumab duocarmazine, dicitamab vedotin, ladiratumab vedotin (also known as SGN-LIV1A), depatuxizumab mafodotin, SN-38, or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0198] The term "antisense molecule" refers to a class of oligonucleotide molecules that contain sequence complementarity to target RNA molecules, such as mRNA, viral RNA, or other RNA species, and inhibit the function of the target RNA after sequence-specific binding. Antisense molecules can be selected from antisense oligodeoxyribonucleotides (ODNs), i.e., single-stranded DNA molecules, small interfering RNA (siRNA) molecules, ribozymes, DNAzymes, and pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of any of the foregoing.

[0199] Within the context of the present invention, "non-responder" or "resistant" refers to the phenotype of a subject who does not respond to conventional treatments for cancer, particularly the cancers identified herein, i.e., the tumor volume does not decrease substantially or the symptoms of the cancer in the subject do not alleviate, or the cancer progresses, e.g., the tumor volume increases and / or the tumor develops local or distant metastases. The terms "non-responder" or "resistant" also refer to the phenotype of a subject who dies from cancer.

[0200] Within the context of the present invention, "responder" or "susceptible" refers to the phenotype of a subject that responds to a treatment for cancer, particularly a conventional treatment for cancer as defined herein, i.e., the tumor volume is reduced, at least one of its symptoms is alleviated, or the progression of the cancer is arrested or slowed.

[0201] A subject who responds to cancer treatment, within the meaning of the present invention, is typically a subject who has a much longer probability of disease-free survival ("DFS") or metastasis-free survival ("MFS") than a patient who is not identified as susceptible to cancer treatment using the methods described herein. In preferred embodiments, a subject who responds to cancer treatment is one who is completely treated (cured), i.e., one who survives the cancer (wherein the detected or measured parameter (e.g., expression product of a gene disclosed herein) has a beneficial impact on "overall survival" (OS)).

[0202] Within the context of the present invention, the term pathological complete response ("pCR") means that the tumor size is dramatically reduced under anticancer treatment, typically after neoadjuvant hormonal therapy, and then becomes operable (potentially treatable by surgery) or undetectable.

[0203] Within the context of the present invention, the term "progressive disease" refers to a growth in tumor size or tumor expansion of at least 20 percent since the start of treatment. In other words, if the tumor size in a scan is 20 percent larger than originally measured, it is called progressive disease.

[0204] The terms "primary endocrine resistance" or "primary hormone resistance" used to characterize patients refers to a patient's relapse within the first 2 years of adjuvant hormone therapy or progressive disease within the first 6 months of primary hormone therapy in the metastatic setting.

[0205] The terms "secondary endocrine resistance" or "secondary hormone resistance" used to characterize patients refer to a patient's relapse after 2 years on adjuvant hormone therapy, a patient's relapse within the first 12 months after completing adjuvant therapy, or progressive disease 6 months after initiating endocrine therapy in the metastatic setting.

[0206] The term "early relapse" refers to a relapse occurring less than 12 months after adjuvant endocrine therapy.

[0207] The term "late relapse" refers to a relapse occurring after 12 months of adjuvant therapy.

[0208] The term "sample" refers to a material or mixture of materials containing one or more components of interest. A sample from a subject refers to a sample obtained from a subject, including samples of biological tissue or fluid origin obtained, arrived at, or collected in vivo or in situ. A sample can be obtained from an area of a subject containing precancerous or cancerous cells or tissue, or from another tissue or fluid in a subject. Such samples can be, but are not limited to, organs, tissues, fractions, and cells isolated from a mammal. Exemplary samples include lymph nodes, whole blood, partially purified blood, serum, plasma, bone marrow, and peripheral blood mononuclear cells ("PBMCs"). A sample can also be a tissue biopsy. Exemplary samples also include cell lysates, cell cultures, cell lines, tissues, organs, biological fluids, blood samples, urine samples, and the like.

[0209] The sample preferably contains 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, for example, found in a subject's blood sample. ctDNA can be, for example, found in a subject's plasma sample.

[0210] A sample from a subject can have multiple copies of the ESR1 gene. These copies can encode wild-type and / or mutant ERa proteins. As used herein, a sample from a subject with an ESR1 mutation can also have one or more copies of the wild-type ESR1 gene and / or wild-type ERa protein.

[0211] The term "about" when used to modify a numerically defined parameter means that the parameter may vary upward or downward by an amount of 10% of the numerical value stated for that parameter. For example, a dose of "about 5 mg" means 5 mg ± 10%, i.e., the dose may vary from 4.5 mg to 5.5 mg.

[0212] As used herein, an "effective dosage" or "effective amount" of a compound, combination, or composition is an amount sufficient to affect any one or more beneficial or desired results, including the biochemical, histological, and / or behavioral symptoms of a disease, its complications, and intermediate pathological phenotypes exhibited during the development of a disease.

[0213] As used herein, an "effective dosage" or "effective amount" of a compound or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired results, including the biochemical, histological, and / or behavioral symptoms of a disease, its complications, and intermediate pathological phenotypes exhibited during the development of a disease.

[0214] For therapeutic use, a "therapeutically effective amount" refers to that amount of a compound or combination being administered that will relieve to some extent one or more of the symptoms of the disorder being treated. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasiveness to some extent, (4) alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer, (5) reducing the dose of other pharmaceutical agents needed to treat the disease, and / or (6) enhancing the effect of another pharmaceutical agent, and / or (7) slowing the progression of the disease in a patient.

[0215] An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of a drug, compound, combination, or pharmaceutical composition is an amount sufficient to achieve prophylactic or therapeutic treatment either directly or indirectly. As will be understood in a clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, combination, or pharmaceutical composition.

[0216] As used herein, "pharmaceutically acceptable carrier" refers to a carrier, excipient, or diluent that does not cause significant irritation to an organism or abrogate the biological activity and properties of an active compound or therapeutic agent. Pharmaceutically acceptable carriers can include any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient will largely depend on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents (such as hydrates and solvates). Pharmaceutical compositions can contain additional ingredients, such as flavorings, binders, and excipients, if desired. Thus, for oral administration, tablets containing various excipients such as citric acid can be used, along with various disintegrants such as starch, alginic acid, and certain complex silicates, and binders such as sucrose, gelatin, and acacia. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid compositions can also be used in soft and hard-filled gelatin capsules. Thus, non-limiting examples of materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein can be combined with a diluent such as water, ethanol, propylene glycol, glycerin, or a combination thereof, as well as various sweeteners or flavorings, colorings or pigments, and, if desired, emulsifying or suspending agents.

[0217] As used herein, the term "combination" or "combination therapy" refers to the administration of each therapeutic agent of the combination therapy of the invention, either alone or in the form of a pharmaceutical composition or medicament, either sequentially, concurrently, or simultaneously.

[0218] As used herein, the term "sequential" or "sequentially" refers to the administration of each therapeutic agent of a combination therapy of the invention, either alone or in a pharmaceutical formulation, one after the other, and each therapeutic agent can be administered in any order. Sequential administration can be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, e.g., one agent is a tablet and another is a sterile liquid, and / or when the agents are administered according to different dosing schedules, e.g., one agent is administered once daily and the second agent is administered less frequently, such as once weekly.

[0219] As used herein, the term "concurrently" refers to the administration of each therapeutic agent in a combination therapy of the invention, either alone or in separate medicaments, with the second therapeutic agent being administered immediately after the first, and the therapeutic agents being administered in any order. In a preferred embodiment, the therapeutic agents are administered concurrently.

[0220] As used herein, the term "concurrently" refers to the administration of each therapeutic agent of the combination therapy of the present invention in the same pharmaceutical composition. As will be appreciated by those skilled in the art, the combination therapy may be usefully administered to a subject during various stages of their treatment.

[0221] In some embodiments of each of the methods, combinations, and uses herein, the combination therapy is administered to a subject that has not been previously treated, i.e., is treatment naive.

[0222] 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 durable response after at least one prior treatment with an anti-cancer agent identified herein, i.e., the subject is treatment-emergent.

[0223] Quinazoline carboxamide azetidine compounds Quinazolinecarboxamide doazetidine compounds useful in the context of the present invention, in particular in the treatment of hormone-dependent diseases, particularly cancers as described herein, preferably breast cancer, are compounds defined by formula (I): [ka] and / or any pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers thereof (including any mixtures thereof in any ratio), wherein: R 1 is H or LA, R 2 is Hal, O(LA), N(LA)(LA)′, CONH(LA), Ar, CONH, or A; R 3' , R 3'' are independently H, LA, or Hal; Ar is a monocyclic or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3, or 4 N, O, and / or S atoms and 5, 6, 7, 8, 9, or 10 skeletal atoms, which is unsubstituted or, independently of one another, is selected from the group consisting of 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, NHSOA, NHSO2(Ar1), COA, CO(Ar1), SO2NH2, SO2A, SO2(Ar1) and / or SO2Hal, the N atoms of the rings may be replaced by O atoms to form N-oxide groups, and in the case of bicyclic aromatic rings, one of the two rings may be partially saturated, Ar1 is a monocyclic aromatic homo- or heterocycle having 0, 1, 2, or 3 N, O, and / or S atoms and 5 or 6 skeletal atoms, which may be unsubstituted or mono-, di-, or tri-substituted, independently of one another, by Hal, LA, OH, SH, O(LA), NH, NH(LA), N(LA), NO, CN, OCN, SCN, COOH, COO(LA), CONH, CONH(LA), CON(LA), NHCO(LA), CHO, CO(LA), SON, NH, SO(LA), and / or SOHal; A is unbranched or branched, straight-chain or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH groups may be replaced by O or S atoms and / or by -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO- or -CH=CH- groups, in which one to three H atoms may be replaced by Hal, in which one or two CH groups may be replaced by OH, SH, NH, NH(LA), N(LA)2, NHCOOH, NHCONH2 or CN, L A is unbranched or branched straight-chain alkyl having 1, 2, 3 or 4 C atoms, in which 1, 2 or 3 H atoms may be replaced by Hal, such as methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, Hal is F, Cl, or Br, preferably F or Cl, most preferably F].

[0224] A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, or 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.

[0225] A more preferably represents alkyl as defined above, in which one or two CH groups may be replaced by O or S atoms and / or by NH, N(LA), CONH, NHCO, or -CH=CH- groups, and / or in which one to three H atoms may be replaced by F and / or Cl, such as trifluoromethyl, pentafluoroethyl, 1,1-difluoromethyl, 1,1,1-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0226] In a preferred embodiment, the novel quinazoline carboxamide azetidine compounds have the formula (II): [ka] and / or any pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers thereof, including any mixtures thereof in any ratio, wherein: 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>NHSO2(LA)(CO(LA), SO2NH2, SO2(LA), or SO2Hal, R 5 , R 6 may be taken together with the phenyl group to which they are attached to form a 9- or 10-membered bicyclic ring system, in which one or two of the non-phenyl carbon atoms may be independently replaced by NH, O, or S; R 5 and R 6 The ring formed by may be unsubstituted or mono- or di-substituted by Hal or LA, R 5 , R6 , R 7 may be AM, O(Ar1), NH(A), CONH(Ar1), NHCO(Ar1), NHCONH(Ar1), NHSO2(Ar1), CO(Ar1), or SO2(Ar1), while one of R 5 , R 6 , R 7 the other two of which 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 given for formula (I).

[0227] In more preferred embodiments of formulas (I) and (II), the stereochemistry at the central chiral carbon atom is as shown in formulas (I') and (II'). [ka]

[0228] In general, all residues occurring multiple times may be the same or different, i.e., independent of each other. Above and below, residues and parameters have the meanings given for Formula (I), Formula (II), Formula (I'), and Formula (II''), unless expressly indicated otherwise.

[0229] Compounds of sub-formulae 1 to 12 of formulae (II) and (II') are more preferred, in which in sub-formula 1: 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; In sub-formula 2, R 1 , R 2 is H, In sub-formula 3, R 3' , R 3'' are independently H, OH, or F; In sub-formula 4, R 4 , R 8 are independently H, F, or Cl; In lower formula 5, R 5 , R 7 are independently H, F, Cl, Br, CN, methoxy, or CF; In sub-formula 6, R 5 , R 6 together with the phenyl groups to which they are attached form benzo-1,2-dioxolyl, in which the carbon atoms bridging the two oxygen atoms may be unsubstituted or mono- or disubstituted by F or methyl; Among the seven lower expressions, R 6 is H, F, Cl, or CF3, Among the eight lower expressions, R 5 , R 6 are independently H, F, Cl, Br, methyl, CHF2, or CF3; Among the 9 lower expressions, R 1 , R 2 , R 3' , R 3'' , R 4 , R 7 , R 8 is H, Among the 10 lower-level expressions, R 1 , R 2 , R 3' , R 3'' , R 4 , R 7 , R 8 is H, R 5 , R 6 are independently H, F, Cl, Br, methyl, CHF2, or CF3; Among the 11 lower expressions, R 1 , R 2、 R 3' , R 3'' , R 4 , R 8 is H, R5 is Br, methyl, CHF2, or CF3, R 6 is F, Cl, or CF3, R 7 is H or F, Among the 12 lower expressions, R 1 , R 2 , R 4 , R 8 is H, R 3' is F or methyl, R 3'' is H, R 5 is Br, methyl, CHF2, or CF3, R 6 is F, Cl, or CF3, R 7 is H or F, The remaining residues have the meanings given for formula (I).

[0230] The compounds of formula (I), formula (II), formula (I'), and formula (II') may have one or more chiral centers. Therefore, they exist in various enantiomeric forms and may be racemic or optically active. Therefore, the present invention also relates to the 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 differ, it may be desirable to use enantiomers. In these cases, the final products or even intermediates can be separated into enantiomeric compounds by chemical or physical means known to those skilled in the art, or even used as such in synthesis.

[0231] In the case of racemic amines, diastereomers can be formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriately N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or the R- and S-configurations of various optically active camphorsulfonic acids. Also advantageous is the chromatographic resolution of enantiomers with the aid of an optically active resolving agent (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other derivatives of carbohydrates or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile in a ratio of, for example, 82:15:3. An elegant method for resolving racemates containing ester groups (e.g., acetyl esters) is the use of enzymes, particularly esterases.

[0232] The compounds of the present invention may be in the form of prodrug compounds. The term "prodrug compound" refers to a derivative that is converted into a biologically active compound according to the present invention under physiological conditions in vivo, for example, by enzymatic or non-enzymatic oxidation, reduction, hydrolysis, etc. Examples of prodrugs include compounds in which the amino group of the compounds of the present invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamino, or pivaloyloxymethylamino, or compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or converted to borate, such as acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, or alanyloxy, or compounds in which the carboxyl group is esterified or amidated, or compounds in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to a target and / or the cytosol of a cell. These compounds can be produced from the compounds of the present invention according to well-known methods. Other examples of prodrugs are compounds in which the carboxylate in the compounds of the invention is converted to, for example, an alkyl-, aryl-, choline-, amino-, acyloxymethyl ester, or linolenoyl-ester.

[0233] Metabolites of the compounds of the present invention are also within the scope of the present invention.

[0234] Where tautomers of the compounds of the invention, such as keto-enol tautomers or prodrugs thereof, may exist, the individual forms, such as the keto or enol forms, are claimed separately and together in any ratio of mixtures. The same applies to stereoisomers, such as enantiomers, cis / trans isomers, conformers, etc.

[0235] If desired, isomers can be separated by methods well known in the art, for example, liquid chromatography. The same applies to enantiomers, for example, by using a chiral stationary phase. Furthermore, enantiomers can be isolated by converting them 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 a compound of the present invention can be obtained from stereoselective synthesis using optically pure starting materials.

[0236] The compounds of the present invention can be in the form of a pharmaceutically acceptable salt or solvate.

[0237] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. When a compound of the present invention contains one or more acidic or basic groups, the present invention also includes its corresponding pharmaceutically or toxicologically acceptable salts, particularly its pharmaceutically acceptable salts. Thus, compounds of the present invention containing acidic groups can exist in salt form and can be used in accordance with the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of the present invention containing one or more basic groups, i.e., groups that can be protonated, can exist in salt form and can be used in accordance with the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic 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, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. When the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also encompasses inner salts or betaines (zwitterions) in addition to the salt forms mentioned above. 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 a solvent or dispersion medium, or by anion or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, due to their low physiological compatibility, are not directly suitable for pharmaceutical use but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0238] The term "pharmaceutically acceptable solvate" refers to an addition form with a pharmaceutically acceptable solvent containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, for example, a mono- or dihydrate. When the solvent is alcohol, the solvate formed is an alcoholate, for example, a methanolate or an ethanolate. When the solvent is ether, the solvate formed is an etherate, for example, diethyl etherate.

[0239] Thus, the following are also in accordance with the invention: a) all stereoisomers or tautomers of the compound, including mixtures thereof in any ratio; b) prodrugs of the compounds, or stereoisomers or tautomers of these prodrugs; c) pharmaceutically acceptable salts of the compounds and items referred to under (a) and (b); d) Pharmaceutically acceptable solvates of the compounds and items referred to under (a), (b), and (c).

[0240] It will be understood that all references to the compounds above and below are intended to include pharmaceutically acceptable solvates of those items, particularly the compounds, or pharmaceutically acceptable salts thereof.

[0241] In the context of the present invention, a preferred quinazolinecarboxamide azetidine compound is 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide (also identified herein as "M2698").

[0242] The quinazoline carboxamide azetidine compounds used in the present invention, such as the compounds of formula (I), (II), (I'), and (II') defined above, preferably M2698, are further described in International Patent Application WO2012 / 69146, "Quinazoline carboxamide azetidines." Those skilled in the art can refer to this patent application for the synthesis of these quinazoline carboxamide azetidine compounds.

[0243] The present invention also provides compositions comprising a quinazolinecarboxamide azetidine compound, preferably M2698. In certain embodiments, a composition comprises a quinazolinecarboxamide azetidine compound, preferably M2698, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0244] an additional therapeutic agent, preferably an anti-cancer agent As taught hereinabove, in preferred embodiments, the combination or composition comprises, in addition to the quinazolinecarboxamide azetidine compound, particularly 4-[(S)-2-acetidin-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 separate therapeutic agent, preferably an anticancer agent.

[0245] In a preferred embodiment, the at least one separate therapeutic agent, preferably an anti-cancer agent, is an anti-neoplastic agent, a signal transduction inhibitor, or a mixture thereof, as described in the "Definitions" section herein.

[0246] The combinations or compositions of the invention may comprise one or more additional separate therapeutic agents, preferably anti-cancer agents (also identified herein as agent (c)), particularly endocrine / hormonal therapy agents, anti-angiogenic agents, signal transduction inhibitors, anti-neoplastic 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-neoplastic agents, small molecules, growth factor receptor agents, antibodies or fragments thereof, antibody-drug conjugates (ADCs), or antisense molecules, in amounts that together are effective for the treatment of cancer.

[0247] In some embodiments, the additional anticancer agent is abemaciclib (LY2835219), abiraterone, abiraterone acetate, abivertinib, acalabrutinib, aclarubicin, aldesleukin (IL-2), ado-trastuzumab emtansine, afatinib dimaleate, afimoxifen, afresertib, alectinib, alemtuzumab, altretamine, almonertinib, aloisine A, aloisine B, alpelisib, alsterpaullone, amifostine, Amsenestrant (SAR439859), amelimumab, aminoglutethimide, aminopurvalanol, anastrozole, amivantamab, apalutamide, apaziquone, aprepitant, arsenic trioxide, arzoxifene, asparaginase (peguaspargase), atezolizumab, atorvastatin (Caduet, Lipitor, Lypqozet), avapritinib, avelumab, axitinib, azacitidine, azathioprine, azetidin, azetidin Nosertib (ZN-c5), bazedoxifene, belinstat, bendamustine hydrochloride, bevacizumab, bexarotene, bicalutamide, bimiralisib, binimetinib (Mektovi or ARRY-162), vilociclib (XZP3287), bleomycin sulfate, blinatumomab, bohemin, borestrant, bortezomib, borsutem, bosutinib, brantuximab vedotin, brigatinib, brilantrant (GDC-0810), buparlisib (BKM120), bucuraminib Lufan, butyrolactone, cabazitaxel, cabozantinib-s-malate, calaspargase pegol-mknl, camizestrant (AZD9833), capecitabine, capivasertib (AZD5363), caplacizumab-yhdp, capmatinib hydrochloride, carboquone, carboplatin, carfilzomib, carmustine, cemiplimab-rwlc, celecoxib, celecoxib derivatives, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormethine, cilengitide Cisplatin, cladribine, clofarabine, cobimetinib, copanlisib hydrochloride, crizotinib, cyclophosphamide, cyproterone, cytarabine, dabrafenib mesylate, dacarbazine, dacomitinib, dactinomycin, dactolisib tosylate,Darpiciclib (SHR-6390), daratumumab, daratumumab and hyaluronidase-fihj, darbepoetin alfa, darolutamide, dasatinib, daunorubicin hydrochloride, decitabine, defibrotide sodium, degarelix, denileukin, depatuxizumab mafodotin, detrusertib, diftitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dichloroacetate, dinaciclib, dinutuximab, dicitamab vedotin (RC48-ADC), docetaxel, dordabiprone (ONC-201), dovitinib, hydrochloride Doxorubicin, droloxifene, durvalumab, duvelisib, elacestrant, elotuzumab, ertanexor, eltrombopag olamine, erlanatamab, emapalumab-Izsg, ertanexor (KPT-8602), enasidenib mesylate, encorafenib, enfortumab vedotin-ejfv, endoxifen, entrectinib, enzalutamide, enzastaurin, epertinib, epirubicin hydrochloride, epoetin alfa, eptaplatin, erdafitinib, eribulin mesylate, erlotinib hydrochloride, etoposide , etoposide phosphate, everolimus, exemestane, fadrozole, fedratinib hydrochloride (filgrastim®), flavopiridol, floxuridine, fludarabine phosphate, fluorouracil, 5-fluorouracil, flutamide, formestane, fosbretabine, fostamatinib disodium, fotemustine, fulvestrant, gefitinib, gemcitabine hydrochloride, gemtuzumab ozogamicin, zingerenone, gilteritinib fumarate, gildestrant (GDC9545), glasdegib maleate, glucan Lupidase, glufosfamide, goserelin acetate, granisetron, granisetron hydrochloride, histrelin, hydroxyurea, ibntumomab, tiuxetan, ibrutinib, icotinib, idarubicin hydrochloride, idelalisib, idoxifene, ifosfamide, imatinib mesylate, imiquimod, improsulfan tosylate, indirubin, indirubin-3'-monoxime, infigratinib (BGJ398), inotuzumab ozogamicin, interferon alpha-2b recombinant, interferon gamma,Iobenguane I-131, ipatasertib, ipilimumab, irinotecan hydrochloride, isatuximab-irfc, ivosidenib, ixabepilone, ixazomib citrate, kenpaullone, ketoconazole, laditratumab vedotin (also known as SGN-LIV1A), lanreotide acetate, lapatinib ditosylate, laditratumab vedotin (SGN-LIV1A), larotrectinib sulfate, larotinib, larotrectinib, lasofoxifene, lazertinib, lenamidomide, lenalidomide Vatinib mesylate, letrozole, lerociclib (G1T38), leucovorin calcium, leuprolide acetate, levamisole, lifirafenib, lobaplatin, lomustine, lonafarnib, lorlatinib, lucitanib, lurbinectedin, luteinizing hormone-releasing hormone (LHRH) agonists, marizomib, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, melphalan hydrochloride, mercaptopurine, meliorin 3, methotrexate, midostaurin, milciclib, miltefosine, mitobronitol, mitomycin Traktol, miriplatin hydrate, milansertib, mitomycin, mitotane, mitoxantrone hydrochloride, mobocertinib, mogamulizumab, mogamulizumab-kpkc, monepantel, moxetumumab-pasudotox-tdfk, nacotinib, narazaciclib (ON123300), nazartinib, necitumumab, nedaplatin, nelarabine, neratinib maleate, nilotinib, nilutamide, nimotuzumab, nimustine, niraparib tosylate monohydrate, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaparib , olmutinib, olomoucine, olomoucine II, omacetaxine omepesuccinate, omipalisib, omomycete, ondansetron hydrochloride, 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, pexidartinib hydrochloride, pictilisib (GDC0941), pimasertib, piperazinyl-pyrimidine derivative (PF-4708671, PF-4708671), plerixafor, picoplatin, pipindoxifene, pipobroman, plicamycin, polatuzumab vedotin-piiq, pomalidomide, ponatinib hydrochloride, pralsetinib, poziotinib, prasugrel-lactam Trexate, prednisone, pralsetinib, procarbazine hydrochloride, propranolol hydrochloride, purvalanol A, purvalanol B, radium-223 dichloride, pyrotinib, raloxifene hydrochloride, ramucirumab, ranimustine, rapamycin analogues, rasburicase, ravulizumab-cwvz, recombinant interferon alfa-2b, refametinib, regorafenib, ribavirin, ribociclib (LEE-011), ridaforolimus, lintodextrin, ripretinib, rituximab, rolapitant, ribiciclib hydrochloride (P276-00), Nishiclib, romidepsin, romiplostim, R-roscovitine, rucaparib cansylate, ruxolitinib, sacituzumab govitecan-hziy, sapanisertib, sapitinib, satraplatin, seratinib, selinexor, selpercatinib, selumetinib sulfate, Streptomyces spp. OA293, streptozocin, siltuximab, sipuleucel-t, sonalisib, sonidegib, sirolimus, sirotinib, somatostatin (pasireotide), sorafenib tosylate, Streptomyces spp. OA293, streptozocin , sunitinib, tagraxosp-erzs, talazoparibut tosilate, talimogene laherparepvec, tamoxifen, tazemetostat hydrobromide, telotristat, temozolomide, temsirolimus, teniposide, tepotinib, tesevatinib, tesetaxel, testolactone, thalidomide, thioguanine, thiotepa (N,N'N'-triethylenethiophosphoramide), tipifarnib, tipiracil, tisagenlexucel, tocilizumab, tomzotuximab, topotecan hydrochloride, toremifene, tositumomab, trabectedin, trametinib,Trastuzumab, trastuzumab deruxtecan (Enhertu®), trastuzumab duocarmazine (SYD985), trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™), trastuzumab emtansine, treosulfan, trilaciclib (GTI128), trifluridine and tipiracil hydrochloride, trimetrexate, triptorelin, trofosfamide, tucatinib, ulixertinib, uprosertib (GSK2141795), uramustine Valrubicin, vandetanib, vallitinib, vemurafenib, venetoclax, vinblastine, vinblastine sulfate, vindesine, vincristine sulfate, vinflunine, vinorelbine tartrate, vismodegib, vistoneuridine (uridine triacetate), vitusertib, vorinostat, vorozole, voruciclib, xylocidine, inlitinib, zanubrutinib, ziv-aflibercept, xenoctuzumab, ziv-aflibercept (Zaltrap®), zotatifin, zoledronic acid, zolifertinib, 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, AZD 5438, AZD5597, AZD8055, AZD9496, BAY-1125976, BAY-1163877, BAY-2476568, BAY-293, BBP-398, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, B I-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-0316、D-0502、DBPR-112、DC-120、DFN-S29、DGD-I202、DHM-ZS、DS-2087b、DTRMWXHS-12、DZD-9008、EO-1001、ERAS-007、ERAS-601、ES-072、ETH-155008、ETS-001、FCN-411、FCN-437c、FHND-9041、FL772、FLAG-001、FLAG-003、FmAb-2、FP-208、FS-115、FT-I S18、FXY-1、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-077 9954, PF-4708671, PHA-793887, PHT-427, PQR-514, PTX-200, PTX-367, QL-1105, QL-1203, QR-213, R-CR8, R, G6171, RGB286147, RGB-286638, RLY-1971, RMC-4550, RMC-4630, RMC-5552, RMC-5845, Ro458 4820, 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 -118811, SPR-965, SRX-3177, SYN-004, TAM-03, TAS-117, TAS-6417, TAS-ASTX, TG02, TGRX-3 60, TK216, TNO-155, TQB3303, TQB-3804, UBP-1215, VRN-071918, VRN-6, VS-6766, WBP-297, W J-13404, WSD-0922, WXFL-10030390, X-37-SHP2, XP-105, XZP-5809, YZJ-0318, ZK304709, ZN The additional anticancer agent is selected from the group consisting of E-4, ZR-2002, ZSP-0391, ZW49, 10Z-hymenialdisine, 5-iodo-indirubin-3'-monoxime or free base, and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomeric form of any of the foregoing, or any combination thereof. The additional anticancer agent can also be samuracilib (also known as CT7001 or ICE0942).

[0248] In a preferred embodiment, the additional anticancer agent is selected from the group of compounds listed herein above, said list excluding afatinib dimaleate, brigatinib, cetuximab, erlotinib hydrochloride, gefitinib, icotinib, simertinib, pimasertib, and / or tepotinib.

[0249] Pharmaceutical Compositions and Combinations A "pharmaceutical composition" refers to a mixture of one or more of the therapeutic agents described herein, or pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, tautomers, hydrates, or prodrugs thereof, as the active ingredient, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, a pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0250] Thus, a "pharmaceutical composition" typically refers to one or more active ingredients, one or more inactive ingredients that constitute the carrier, and any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or the dissociation of one or more of the ingredients, or any other type of reaction or interaction of one or more of the ingredients. Thus, a pharmaceutical composition of the present invention typically encompasses any composition made by mixing a therapeutically effective amount of a compound of the present invention, preferably at least (a) a quinazolinecarboxamide azetidine 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, including any mixture thereof in any ratio), with (b) a separate therapeutic agent, preferably an anti-neoplastic agent and / or signal transduction inhibitor, and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may further comprise, as active ingredients, one or more other compounds, such as one or more additional therapeutic, preferably anti-cancer, agents of the present invention ("(c)"), or prodrug compounds or other known substances active against hormone-dependent diseases, preferably cancer.

[0251] 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 (ocular), pulmonary (nasal or buccal inhalation), or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and on the nature of the active ingredients. These may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0252] The (pharmaceutical) combination or pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension; for parenteral injection as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream; or for rectal administration as a suppository.

[0253] Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose, which may be suitably buffered, if desired.

[0254] The combination or pharmaceutical composition may be in unit dosage form suitable for single administration of a precise amount.

[0255] Suitable combination or pharmaceutical compositions for the delivery of the therapeutic agents of the combination therapies of the present invention, and methods for their preparation, will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may 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.

[0256] The therapeutic agents of the combination therapy of the invention may be administered orally, which may involve swallowing, so that the therapeutic agents enter the gastrointestinal tract, or may use buccal or sublingual administration, in which the therapeutic agents enter the bloodstream directly from the mouth.

[0257] Formulations suitable for oral administration include solid formulations such as tablets, particulate, liquid, or powder-containing capsules, lozenges (including those filled with liquid), chewable tablets, multi- and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesives), vaginal ovules, sprays, and liquid formulations.

[0258] Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations can be used as fillers in soft or hard capsules, and typically contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstituting solids, for example, from sachets.

[0259] The therapeutic agents of the combination therapy of the present invention may also be used in fast-dissolving, fast-disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), pp. 981-986, Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.

[0260] In tablet dosage forms, the therapeutic agent may comprise 1 wt% to 80 wt% of the dosage form, more typically 5 wt% to 60 wt% of the dosage form. In addition to the active agent, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant may comprise 1 wt% to 25 wt%, preferably 5 wt% to 20 wt%, of the dosage form.

[0261] Binders are generally used to provide binding properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, 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.

[0262] Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants are typically present in amounts of 0.2 wt% to 5 wt% of the tablet, and glidants are typically present in amounts of 0.2 wt% to 1 wt% of the tablet.

[0263] Tablets also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are generally present in an amount of 0.25 wt% to 10 wt%, preferably 0.5 wt% to 3 wt%, of the tablet.

[0264] Other conventional ingredients include antioxidants, colorants, flavorings, preservatives, and taste-masking agents. An exemplary tablet may contain up to about 80 wt% of an active agent, about 10 wt% to about 90 wt% of a binder, about 0 wt% to about 85 wt% of a diluent, about 2 wt% to about 10 wt% of a disintegrant, and about 0.25 wt% to about 10 wt% of a lubricant.

[0265] Tablet blends may be compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends may be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated or encapsulated.

[0266] Tablet formulations are detailed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, H. Lieberman and L. Lachman, Marcel Dekker, New York, NY, 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[0267] Solid formulations for oral administration may be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.

[0268] Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersions and osmotic and coated particles, can be found in Verma et al., Pharmaceutical Technology Online, 25(2), pp. 1-14 (2001). The use of chewing gum to achieve sustained release is described in WO 2000 / 035298. The disclosures of these references are incorporated herein by reference in their entirety.

[0269] The kits described herein may be particularly suitable for administering different dosage forms, e.g., oral and parenteral, for administering different active (especially therapeutic) agents of a combination or composition at different dosing intervals, or for titrating the active (especially therapeutic) agents of a combination or composition relative to one another. To aid compliance, the kits typically include instructions for administration and may be provided with a memory aid. The kits may further include other materials that may be useful for administering the medications, such as diluents, filters, IV bags and lines, needles, and syringes. The kits may further include any other materials, such as PCR tests, that may be useful for stratifying the prognosis of metastatic breast cancer by identifying tumors with evolving resistance to endocrine therapy.

[0270] Certain kits include: i) (a) a quinazolinecarboxamide azetidine compound (M2698), which is preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, including any mixture thereof in any ratio, and (b) in separate containers, a separate therapeutic agent as described herein, e.g., an anti-neoplastic agent and / or a signal transduction inhibitor, 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).

[0271] A more specific kit includes: i) (a) a quinazolinecarboxamide azetidine compound (M2698), preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, including any mixture thereof in any ratio; and (b) a quinazolinecarboxamide azetidine compound (M2698), preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, including any mixture thereof in any ratio; and (i) a composition comprising a separate therapeutic agent described herein, e.g., an anti-neoplastic agent, such as a selective ER modulator ("SERM"), a selective ER downregulator / degrader ("SERD"), an aromatase inhibitor ("AI"), a complete estrogen receptor antagonist (CERAN), or a combination of (a) and (b), and a pharmaceutically acceptable carrier, in a container comprising: (i) a composition comprising a separate therapeutic agent described herein, e.g., an anti-neoplastic agent, such as a selective ER modulator ("SERM"), a selective ER downregulator / degrader ("SERD"), an aromatase inhibitor ("AI"), a complete estrogen receptor antagonist (CERAN), or a combination of (a) and (b), and a pharmaceutically acceptable carrier; and (ii) materials for administering compounds (a) and / or (b).

[0272] An even more specific kit includes: i) (a) a quinazolinecarboxamide azetidine compound (M2698), preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof (including any mixture thereof in any ratio); and (b) in separate containers, a separate therapeutic agent as described herein, such as, for example, amsenestrant, azenosetran, or the like. and ii) a composition comprising a selective ER downregulator / degrader ("SERD"), more preferably elacestrant, selected from luteb (ZN-c5), bolestrant, brilantrant, camizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lintodestrant, AZD9496, D-0502, LY3484356, GDC-0927, and SHR9549, or a combination of (a) and (b), and a pharmaceutically acceptable carrier; and ii) materials for administering compounds (a) and / or (b).

[0273] Another particular kit comprises: i) (a) a quinazolinecarboxamide azetidine compound (M2698), preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof (including any mixture thereof in any ratio), and (b) in separate containers, a separate therapeutic agent described herein, e.g., 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; and ii) materials for administering compounds (a) and / or (b).

[0274] Another particular kit comprises: i) (a) a quinazolinecarboxamide azetidine compound (M2698), preferably 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof (including any mixture thereof in any ratio), and (b) in separate containers, a separate therapeutic agent as described herein, such as a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK4 / 6 inhibitor, such as abemaciclib, palbocilcib, ribociclib, more preferably abemaciclib, or the like, 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).

[0275] When treating or preventing the cancers mentioned herein with quinazolinecarboxamide azetidine compounds, particularly M2698, satisfactory results are generally obtained when the compound is administered in 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, optionally given as a single daily dose. The daily dose of M2698 administered to a subject is, for example, about 60 mg to about 300 mg, preferably about 80 mg to about 280 or 300 mg, and more preferably about 160 mg to about 240 mg.

[0276] In certain embodiments, the quinazolinecarboxamide azetidine compound of Formula (I) is 4-[(S)-2-acetidin-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 in a dose of about 50 mg to about 800 mg, preferably about 80 mg to about 300 mg, and more preferably about 240 mg.

[0277] In a particular embodiment, the anti-neoplastic agent is elacestrant, and elacestrant is present in the combination or composition at a dose of about 200 mg to about 500 mg, preferably about 300 mg to about 400 mg, and more preferably about 350 mg. Elacestrant is optionally present as the particular active ingredient in the combination or composition, and another, different active ingredient also present in the combination or composition is 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide ("M2698") (used as the quinazolinecarboxamide azetidine compound).

[0278] Other examples of therapeutically effective amounts of elacestrant or a solvate (e.g., hydrate) or salt thereof for use in the methods disclosed herein include, but are not limited to, qd doses of 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 for subjects with resistant ER-driven tumors or cancers; and qd doses of about 150 to about 1500 mg, about 200 to about 100 mg for subjects with both wild-type ER-driven tumors and / or cancers and resistant tumors and / or cancers. For subjects with (predominantly) wild-type ER-driven tumors and / or cancers, qd doses include 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. In certain embodiments, the dosage of an anti-neoplastic agent (e.g., elacestrant), or a polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, for use in the invention disclosed herein can be approximately 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, e.g., 172 mg, 258 mg, or 345 mg, po, qd, for an adult subject. This daily dosage can be achieved via a single administration or multiple administrations.

[0279] Effective dosages of anticancer agents, particularly small molecule inhibitors, typically range from about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human subject, this amounts 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. While in some cases dosage levels at the lower end of the aforementioned ranges may be more than sufficient, in other cases even larger doses may be used without causing any adverse side effects, provided that such larger doses are first divided into several smaller doses administered throughout the day. Doses may be administered as a single dose (QD) or, optionally, subdivided into smaller doses suitable for BID (twice daily), TID (three times daily), or QID (four times daily) administration.

[0280] The therapeutically effective amount of a compound will depend on several factors, including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the method of administration, and is ultimately determined by the treating physician or veterinarian. However, an effective amount of a compound according to the invention will generally be in the range of 0.1 to 100 mg / kg of recipient (mammalian subject) body weight / day, with a more typical range of 1 to 10 mg / kg of body weight / day. Thus, the actual daily amount for an adult mammal weighing 70 kg will usually be 70 to 700 mg, which can be administered as a single dose or as a series of partial doses, usually administered daily (e.g., 2, 3, 4, 5, or 6 times, etc.), so that the total daily dose remains the same. The effective amount of a salt, solvate, polymorph, tautomer, enantiomer, or stereoisomer thereof can be determined as a fraction of the effective amount of the compound according to the invention itself.

[0281] In some embodiments, the CDK inhibitor, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, is administered in a daily dosage of about 1 mg to about 1000 mg per day. In some embodiments, the compound, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, is administered in a daily dosage of about 10 mg to about 500 mg per day. In some embodiments, it is administered in a dosage of about 25 mg to about 300 mg per day. In some embodiments, this is 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, 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 administered on a QD, BID, TID, or QID schedule.

[0282] In certain embodiments, the signal transduction inhibitor is a cyclin-dependent kinase (CDK) inhibitor, e.g., selected from CDK1, 2, 4, 5, 6, and / or 7 inhibitors and any mixtures thereof, more preferably a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, administered orally at a daily dose of about 25 mg to about 600 mg per day, optionally 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 another embodiment, the CDK4 / 6 inhibitor is abemaciclib, or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof, administered orally in 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, administered orally in 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, administered orally in a daily dose of about 200 mg to about 600 mg per day.

[0283] This dosing regimen can be adjusted by the oncologist to provide the patient with the optimal therapeutic response.

[0284] In a particular example, quinazolinecarboxamide azetidine compounds, particularly M2698, can be formulated as the active compound in a combination or pharmaceutical composition administered orally, for example, at a dose of 80 mg / dose, once or several times daily, preferably several times daily, to achieve the desired therapeutic effect. In a preferred embodiment of the invention, patients receive a dose of 240 mg / day of M2698.

[0285] Alternatively, the acceptable (pharmaceutical) combinations or compositions described herein may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the active compounds of the present application with a suitable non-irritating excipient or carrier that is solid at room temperature but liquid at body temperature (e.g., rectal or vaginal) and therefore melts in the rectal or vaginal cavity to release the active compound. Such materials include, for example, cocoa butter, suppository wax (e.g., beeswax), and / or polyethylene glycol.

[0286] In practical use, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. As noted hereinabove, the carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).

[0287] The pharmaceutically acceptable combinations and compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms can also contain, as is common practice, additional substances other than inert diluents, such as lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavors, or colorants can also be added.

[0288] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is incorporated into at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and / or acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, dipotassium phosphate, sorbitol ... Potato or tapioca starch, alginic acid, certain silicates, and / or sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and / or glycerol monostearate, h) absorbents such as kaolin and / or bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and any mixture thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. The active compound can also be in microencapsulated form with one or more of the above-mentioned excipients.

[0289] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols. The 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 pharmaceutical formulating art. These may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) 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.

[0290] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent (%) of the active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be from about 2 percent to about 80 percent of the weight of the unit, for example, 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) dosage will be obtained. The active compound can also be administered intranasally, for example, via drops or spray.

[0291] 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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and any mixture thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and perfumes.

[0292] The compounds of the present invention can also be administered parenterally.These active compounds can be prepared in water in suitable mixture with a surfactant such as hydroxypropyl cellulose to form a solution or suspension.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0293] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and vegetable oils, or any suitable mixture thereof.

[0294] Any suitable route of administration may be used to provide a mammal, particularly a human, with an effective dose of a compound of the present invention, including oral, rectal, topical, parenteral, ocular, pulmonary, and / or nasal routes. Dosage forms include tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compounds of the present invention are administered orally.

[0295] The effective dosage of any active ingredient described herein may vary depending on the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by one skilled in the art, typically an oncologist.

[0296] subject As explained above, in the context of the present invention, the term "patient" or "subject" refers to any single subject for whom treatment is desired or who is participating in a clinical trial, epidemiological study, or used as a control, and includes human and mammalian animal subjects.

[0297] A "subject" or "patient" is typically a mammal. The subject can be a human or a non-human mammal, such as a rodent, e.g., a mouse or rat, a rabbit, a primate such as a monkey, a dog, a cat, a bovine animal, an equine animal, e.g., a horse, or a transgenic species thereof.

[0298] In a particular embodiment, the mammal is a human being, regardless of age or sex.

[0299] In some embodiments, the subject is an adult human subject. The subject is preferably female.

[0300] In some such embodiments, the subject is a postmenopausal woman or man.

[0301] In some such embodiments, the subject is a pre-menopausal or peri-menopausal woman.

[0302] In some such embodiments, the subject is a pre- or peri-menopausal woman treated with a luteinizing hormone-releasing hormone (LHRH) and / or gonadotropin-releasing hormone (GnRH) agonist, such as buserelin, cetrorelix, gonadorelin, goserelin, leuprolide, triptorelin, or triptrelix.

[0303] 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, such as goserelin, leuprolide, triptorelin, and degarelix.

[0304] In some embodiments, the subject is a human child aged between birth and 18 years.

[0305] The subject is typically one who has a hormone-dependent disease, preferably cancer, and unless otherwise specified in this disclosure, the cancer is characterized by malignant tumors and / or metastases, preferably located in the brain, bone, lung, or liver.

[0306] In certain embodiments, the subject is a child between the ages of birth and 15 years with childhood cancer.

[0307] The subject is preferably a subject or patient with a hormone receptor-positive benign, pre-malignant, or malignant tumor ["HR+", e.g., estrogen receptor+ ("ER+") and / or progesterone receptor+ ("PgR+")], preferably an estrogen receptor-positive (ER+) pre-malignant or malignant tumor.

[0308] In certain embodiments, the subject has a malignant tumor that is ER+, regardless of her / his epidermal growth factor receptor-2 status (the tumor or subject may be "HER2 positive," "HER2 negative," or "HER2 low").

[0309] In a preferred embodiment, the subject is suffering from breast cancer, preferably advanced breast cancer, particularly advanced metastatic breast cancer.

[0310] In typical embodiments, the patient has a histologically and / or cytologically confirmed diagnosis of breast cancer with hormone receptor-positive status (ER and / or PgR positive). The patient may further 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.

[0311] In particular and preferred embodiments of the present invention, the subject is undergoing or has undergone treatment for cancer, in particular conventional treatment for cancer, preferably hormonal treatment for cancer.

[0312] This typically means that before assessing the sensitivity of a 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 protocol or a portion of a complete conventional treatment protocol, for example, at least one cycle of the entire planned treatment protocol.In a preferred embodiment, the subject has been treated with or exposed to a drug used in hormone therapy as defined herein, for example, a drug selected from a selective ER modulator (SERM), a selective ER downregulator degrader (SERD), an aromatase inhibitor (AI), and a complete estrogen receptor antagonist ("CERAN").

[0313] In certain embodiments, the subject is a subject being 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, particularly 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.

[0314] Subjects may be those who have exhausted all standard accepted treatment options and have disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria (EA Eisenhauer, Eur J Cancer. 2009 Jan;45(2):228-47) and a tumor with available biopsy.

[0315] The subject as described herein above is preferably a subject or patient with a breast cancer tumor, more preferably a breast cancer tumor that expresses the estrogen receptor alpha (ERα) protein (encoded by the ESR1 gene).

[0316] In a preferred embodiment, to monitor the subject's disease progression or response to treatment, the subject's ESR1 mutation status is determined on circulating tumor deoxyribonucleic acid (ctDNA) before or during any treatment with the combination or composition of the present invention using methods known to those skilled in the art, such as the Guardant360 CDx assay. Preferably, the ESR1 mutation status is limited to ESR1 missense mutations in the ligand-binding domain (between codons 310 and 547).

[0317] Patients are preferably treated with a combination or composition of the invention when disease progression and / or unacceptable treatment-induced toxicity is observed (or detected, for example, by analyzing ESR1 mutation status) following a separate, previously administered treatment.

[0318] The subject may be one suffering from emerging resistance to hormone therapy.

[0319] The subject is preferably one suffering from acquired resistance to hormone therapy.

[0320] In a preferred embodiment of the invention, the subject is one who has developed (acquired) endocrine resistance during or after hormonal / endocrine treatment and whose tumor is characterized by mutated estrogen receptor alpha (ERa). ERa mutations are typically responsible for ER-independent growth of cancer cells or tumors.

[0321] In a preferred embodiment, the cancer sample or cells are obtained from a subject harboring a genetic alteration, typically a mutation that affects the sequence of the translated protein and results in, for example, the loss (deletion) of one or more amino acids, the addition of one or more amino acids, and / or the substitution of at least one amino acid for another, in the estrogen receptor 1 (ESR1) gene of SEQ ID NO: 3, which is responsible for the expression of mutated ERa. In a preferred embodiment, the mutation (including, for example, an addition, deletion, substitution, or frameshift mutation) occurs in the ligand-binding domain of the wild-type ERa protein sequence of SEQ ID NO: 1. In a particular embodiment, the tumor is characterized by a conformational change in the ligand-binding domain (SEQ ID NO: 2) of the ERa protein, which is responsible for the constitutive activation of the ER receptor even in the absence of estrogen.

[0322] The subject may be one who suffers from an existing mutation in the ESR1 gene, typically a mutation that is responsible for the expression of a mutated ERa, which mutation is responsible for constitutive activation of the ER receptor even in the absence of estrogen.

[0323] A patient's estrogen receptor 1 (ESR1) or ERa protein status can be determined by detecting mutations in the ESR1 gene or ERa protein.

[0324] Those skilled in the art will understand 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 the highly sensitive next-generation sequencing platform Guardant360™ (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 part of the test performed on liquid tumor biopsy.

[0325] Another useful tool is the Sysmex® Inostics Liquid Biopsy (ONCOBEAM™) ctDNA biomarker standard test (www.sysmex-inostics.com, see https: / / cdn2.hubspot.net / hubfs / 5871980 / OncoBEAM_ctDNA_Testing_in_Clinical_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., European Society for Medical Poster presented at the Oncology 2014 Congress; September 26-30, 2014, Madrid, Spain; #1270P; 25. Murtaza M. et al., Nature. 497, 108-112 (2013). This diagnostic test can detect any ESR1 mutation with a low sensitivity limit of 0.05%.

[0326] In a preferred embodiment of the present invention, ER+ breast cancer is a cancerous tumor characterized by a mutated estrogen receptor alpha (ERa), 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 an altered conformation of the ligand binding domain of the ERa protein (SEQ ID NO: 2) and / or by expression of ERa in a constitutively active form that does not require the presence or binding of its hormonal ligand to be active.

[0327] In another preferred embodiment of the present invention, ERa mutations can be confirmed by determining a first mutant allele frequency ("MAF") value of a first ERa variant greater than or equal to 0.5% (≧) and / or a second MAF value of a second ERa variant less than or equal to 0.5% (<). The mutant allele frequency or "MAF" is the ratio, expressed as a decimal, of the number of individual gene reads carrying a particular mutation compared to the wild-type sequence at a particular position divided by the total number of individual gene reads across the same locus. For example, for a particular sequence position, if the total sequencing depth is 10,000 and an adenine (A) base accounts for 9,900 distinct occurrences, the remaining distinct sequencing occurrences may include, for example, 23 occurrences with a thymine (T) base at the same position, 42 occurrences with a cytosine (C) base at the same position, and the remaining 35 occurrences with a guanine (G) base at the same position. Because the vast majority of sequences have an adenine base at that position (thereby rendering adenine at that position the "wild-type" base), the mutant allele frequency of having a thymine (T) base is calculated as (T) / (T+C+G+A), or here 23 / 10000=0.0023. Because those skilled in the art understand that the genetic code is redundant, mutant allele frequencies can also be calculated based on the codons encoding specific amino acids in a particular protein sequence. Thus, a MAF value reflecting an amino acid mutation will group all nucleic acid sequences encoding the same mutation. Those skilled in the art also understand that a single gene may encode amino acid mutations at different positions. Thus, MAF values can be calculated for multiple amino acid mutations at different positions in a single gene.

[0328] 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 E380Q, V392I, F404fs, V422del, S463P, L536H, L536P, L536Q, L536R, Y537C, Y537D, Y537S, Y537N, D538G, more preferably a Y537S and / or D538G mutation.

[0329] Those skilled in the art will appreciate that various 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 certain embodiments, mutations at specific positions in the ERa protein sequence, particularly mutations at amino acid positions 537 and / or 538 in SEQ ID NO: 1 (as opposed to ESR1 gene mutations in codons for positions that have an altered nucleic acid sequence but still encode the wild-type amino acid residue for a given position in the ERa protein), are evaluated in the methods disclosed herein.

[0330] In a preferred embodiment, the patient has been treated with (has been exposed to) or is still being treated with drugs used to treat cancer, particularly drugs used in hormone therapy, such as selective ER receptor modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and / or full estrogen receptor antagonists ("CERANs"), luteinizing hormone-releasing hormone (LHRH), and / or gonadotropin-releasing hormone (GnRH) agonists, such as selective ER receptor modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and / or full estrogen receptor antagonists ("CERANs"), as further exemplified below. The patient is preferably a subject who does not respond to (or is, in other words, resistant to) hormone therapy.

[0331] In an even more preferred embodiment, the patient is receiving a drug used to treat cancer, particularly a drug selected from drugs used in hormonal ( / endocrine) therapy, CDK inhibitors, PI3K / AKT / mTOR ("PAM") pathway inhibitors, and any combination thereof, particularly: - i) CDK inhibitors [abemaciclib (also known as LY2835219), AG024322, aloisine A, aloisine B, alsterpaullone, aminopurvalanol, AT7519, AZD-5438, AZD5597, BLU-222, BMS-387032, vilociclib (XZP3287), bohemin, butyrolactone, CYC065, dalpiciclib (SHR-6390), de inaciclib, ETH-155008, flavopiridol, FCN-437c, GLR2007, indirubin, indirubin-3'-monoxime, JNJ-7706621, Kenpaullone, lerociclib (also known as G1T38), meriolin 3, milciclib, narazaciclib (ON123300), NVP-LCQ19, olomoucine, olomoucine II, palbociclib (Ib rance, 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), ribiciclib hydrochloride (P27 6-00), roniciclib, R-roscovitine, Ro4584820, samlaciclib (also known as CT7001 or ICE0942), SRX-3177, TG02, TQB3303, trilaciclib (also known as GTI128), voruciclib, xylocidine, ZK304709, 10Z-hymenialdisine, 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 described in WO2022 / 018596, etc.] with ii) a hormone therapy agent (such as 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 - i) a CDK inhibitor, such as any one of the CDK inhibitors described herein above, and ii) a SERD (fulvestrant, elacestrant [(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also identified as RAD-1901], amsenestrant [(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 identified as SAR439859], brilantrant [(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, also identified as ARN-810 or GDC-0810], camizestrant [N-[1-(3-fluoropropyl)acetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoromethyl)-2 ... ethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine, also identified as AZD9833], giledestrant [3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)acetidin-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 identified as RG6171 or GDC9545 ], Lintdestrant, [(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, also identified as G1T48], AZD9496 [(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-dimethylbenzoyl[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also identified as LSZ102), D-0502, LY3484356, GDC-0927, SHR9549, D0502, etc. In another embodiment, the SERD is, for example, amsenestrant [(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 identified as SAR439859], azenosertib (ZN-c5) [1-[(7R)-7-ethyl-7-hydroxy-5,6-dimethylbenzoyl[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]estra-1,3,5(10)-triene-3,17-diol-3boronic acid], brilantrant [(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazole) -5-yl)but-1-en-1-yl)phenyl)acrylic acid, also identified as ARN-810 or GDC-0810], camizestrant [N-[1-(3-fluoropropyl)acetidin-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 identified as AZD9833], elacestrant [ (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, also identified as RAD-1901], fulvestrant [(7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol], gildestrant [3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)acetidin-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 identified as RG6171 or GDC9545], imulnestrant [(5R)-5-[4-[2-[3-(fluoromethyl)acetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol], lintodestrant, [(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophene] indol-1-yl)phenyl)acrylic acid, identified also as G1T48], AZD9496 [(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-dimethylbenzoyl[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid], (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (also identified as LSZ102), D-0502, LY3484356, GDC-0927, or SHR9549]; - i) a CDK inhibitor, such as any one of the CDK inhibitors described herein above; ii) a SERD, such as any one of the SERDs described herein above; and iii) a PI3K / AKT / mTOR ("PAM") pathway inhibitor (bimiralisib, dactolisibut tosylate, detrusertib, everolimus, monepantel, omipalisib, onatasertib, ridaforolimus, sapanisertib, sirolimus, Streptomyces spp. 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, bolusertib, capivasertib (AZD5363), celecoxib or a celecoxib derivative, doldabiprone (ONC-201), enzastaurin, ipatasertib, milansertib, 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, alpelisib, buparlisib (BKM120), copanlisib, duvelisib, idelalisib, paxalisib, pictilisib (GDC0941), and sonalisib, etc. have been treated with (been exposed to) or are still being treated with

[0332] The patient is preferably a subject who does not respond (or in other words is resistant) to treatment.

[0333] In certain embodiments, the patient has been exposed to or is still exposed to standard of care treatment with anti-cancer agents, more preferably anti-neoplastic agents and / or signal transduction inhibitors.

[0334] In another specific embodiment, the patient has been exposed to or is still exposed to a SERD compound, such as volestrant, camizestrant, and / or fulvestrant, in combination with a CDK4 / 6 inhibitor, such as abemaciclib, palbociclib, and / or ribociclib.

[0335] In another specific embodiment, the patient has been exposed to or is still exposed to a SERD compound, such as camizestrant, in combination with a CDK4 / 6 inhibitor, such as palbociclib.

[0336] In another specific embodiment, the patient has been exposed to or is still exposed to a SERD compound, such as bolestrant, camizestrant, elacestrant, and / or fulvestrant, in combination with a CDK4 / 6 inhibitor, such as abemaciclib, palbociclib, and / or ribociclib, and a PI3K / AKT / mTOR ("PAM") pathway inhibitor, such as alpelisib, capivasertib, and / or everolimus.

[0337] In another particular embodiment, the patient has been exposed to or is still exposed to a SERD compound, such as fulvestrant, in combination with a CDK4 / 6 inhibitor, such as abemaciclib, palbociclib, and / or ribociclib, and a PI3K / AKT / mTOR ("PAM") pathway inhibitor, such as capivasertib.

[0338] Treatment may occur in a neoadjuvant setting (ie, before surgery) or not (ie, after surgery).

[0339] In certain embodiments, the patient is a postmenopausal patient with advanced ER+ breast cancer who has been exposed to a SERM such as tamoxifen, a SERD compound such as volestrant, camizestrant, elacestrant, and / or fulvestrant, an AI such as letrozole, or a CERAN such as OP-1250, preferably a SERD compound, particularly fulvestrant.

[0340] In another particular embodiment, the patient has been exposed to or is still exposed to a hormonal agent, preferably a SERD compound such as bolestrant, camizestrant, elacestrant, and / or fulvestrant, an AI such as letrozole, a CERAN such as OP-1250, or a PI3K / Akt / mTOR ("PAM") pathway inhibitor.

[0341] In further particular embodiments, the patient has been exposed to or is still exposed to a hormone therapy agent, preferably a SERD compound such as volestrant, camizestrant, elacestrant, and / or fulvestrant, an AI compound such as letrozole, a CERAN compound such as OP-1250, and a CDK4 / 6i such as palbociclib (PD0332991), ribociclib (LEE011), and / or abemaciclib (LY2835219).

[0342] In further particular embodiments, the patient has been exposed to or is still exposed to a hormonal therapy agent, such as fulvestrant, letrozole, or lapatinib, preferably a compound such as vorestrant, fulvestrant, camizestrant, elacestrant, letrozole, and / or lapatinib.

[0343] In another particular embodiment, the patient is a premenopausal patient with advanced ER+ breast cancer who has been exposed to hormone therapy, including removal or neutralization of the ovaries (either by oophorectomy, radiation therapy, or by administering a luteinizing hormone-releasing hormone antagonist), and administration of a SERM, such as tamoxifen.

[0344] In another particular embodiment, the patient has been exposed to or is still being exposed to an antiestrogen in combination with a targeting agent, i.e., an inhibitor of the cell cycle, the PI3K / Akt / mTOR pathway, growth factor receptors, a compound that targets alterations in the ubiquitin-proteasome pathway, or a compound that increases the activity of bromodomains and / or extraterminal domains of proteins.

[0345] In further particular embodiments, patients have been exposed to the same or different hormone therapies, preferably different (separate) independent therapies, sequentially in a sequential treatment sequence / line (from 1 to 12 lines of treatment, with a median of 6 lines of treatment). A particular hormone treatment can occur several times, i.e., be used in several sequences within a sequential treatment sequence.

[0346] cancer As explained above (see "Definitions" section), unless otherwise specified in this disclosure, a cancer or tumor may be pre-malignant or malignant.

[0347] In a preferred embodiment of the invention, the cancer is an estrogen receptor positive (ER+) pre-cancerous, cancerous, pre-malignant, or malignant tumor.

[0348] In certain embodiments, the pre-malignant or malignant tumor is an ER+ and "mutated ESR1" or "mutated ERa" tumor. The tumor can also be ER+, mutated ESR1 (or mutated ERa), regardless of HER2 tumor status, which can be positive, low, or negative.

[0349] In certain embodiments, the tumor may further have a confirmed or potential alteration (mutation) in the BRCA1 and / or BRCA2 gene or protein.

[0350] In another particular embodiment, the tumor has a confirmed or potential alteration (mutation) in any one of the following genes or proteins: IRS1, PTEN, PIK3CA, AKT1, AKT2, AKT3, mTOR, TSC1, TSC2, EGFR, or KRAS.

[0351] In a preferred embodiment of the invention, the cancer is characterized by malignant tumors and / or metastases, preferably to the brain, bone, lung, or liver, more particularly to the brain.

[0352] How to Select Patients 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 those who have shown resistance to hormone therapy and subsequently become sensitive or more responsive again to hormone treatment, and who are most likely to benefit from the administration of a compound or composition of the invention.

[0353] The method may be performed in vitro, ex vivo, or in vivo and typically 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 tumor's HER2 status), and, if confirmed, selecting the subject as likely to be re-sensitized to cancer treatment, particularly hormonal cancer treatment.

[0354] The sensitivity or susceptibility of a subject to a cancer treatment indicates, as already mentioned herein above, whether the subject is a "responder" or a "non-responder", in other words, whether the subject is at least partially treated (tumor growth delay or regression), preferably completely treated (cured), or not, by said anti-cancer treatment.

[0355] The methods for selecting subjects described herein are predictive methods, i.e., methods that can assess a subject's ability to respond in the context of anti-cancer treatment as defined herein, and not merely prognostic methods that can indicate whether a subject will survive or die from cancer.

[0356] Cancer Treatment The inventors advantageously describe herein a quinazolinecarboxamide doazetidine compound, a compound combination comprising a quinazolinecarboxamide doazetidine compound and preferably an anti-neoplastic agent and / or a signal transduction inhibitor, and a pharmaceutical composition comprising a quinazolinecarboxamide doazetidine compound, preferably an anti-neoplastic agent and / or a signal transduction inhibitor, optionally together with a pharmaceutically acceptable carrier, for use as a medicine in a subject in need thereof (as described herein above), preferably for treating a hormone-dependent disease, in particular cancer, preferably estrogen receptor positive (ER+) cancer (as described herein above). In a preferred embodiment, the cancer is breast cancer as described herein above, and the subject is preferably a subject as described herein above.

[0357] The products described herein (compounds of the invention, combinations or compositions comprising such compounds) preferably inhibit ER in subjects who do not respond to endocrine therapy. + For use in treating breast cancer.

[0358] Embodiments relate to therapeutic uses in oncology and corresponding methods of treating cancer, preferably breast cancer, in the subjects described herein, preferably in patients with breast cancer tumors that express the estrogen receptor alpha (ERα) protein (encoded by the ESR1 gene). The ERα protein can be a wild-type or mutated version of ERα.

[0359] A particular therapeutic use, or treatment of cancer, involves the use, typically administration, of a quinazolinecarboxamide doazetidine compound, preferably 4-[(S)-2-acetidin-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 said quinazolinecarboxamide doazetidine compound, as well as the administration, in a subject in need thereof, of an anti-neoplastic agent, a signal transduction inhibitor, and any combination thereof, such as those described herein. The present invention includes the use, typically administration, of a drug selected from a selective ER modulator (SERM) described herein, a selective ER downregulator (SERD) described herein, an aromatase inhibitor (AI) described herein, a full estrogen receptor antagonist ("CERAN") described herein, a cell cycle inhibitor described herein, a PI3K / Akt / mTOR ("PAM") pathway inhibitor described herein, or an inhibitor of a growth factor receptor described herein, preferably a drug selected from a SERD, a cyclin-dependent kinase (CDK) inhibitor, a SERM, an AI, and a CERAN. In a preferred embodiment, the drug is selected from a selective ER modulator (SERM) described herein, a selective ER downregulator (SERD) described herein, an aromatase inhibitor (AI) described herein, a full estrogen receptor antagonist ("CERAN") described herein, a cyclin-dependent kinase (CDK) inhibitor described herein, and a PI3K / Akt / mTOR ("PAM") pathway inhibitor described herein.

[0360] In certain aspects of the invention, the compound or composition is administered to a subject after a first line (therapeutic) treatment step of hormone therapy and before any subsequent, typically second line, treatment, which involves administration to the subject of a separate therapeutic compound used in the treatment of cancer, typically HR+ cancer, preferably breast cancer.

[0361] The initial step may further include administration of a CDK4 / 6 inhibitor, such as, for example, palbociclib, ribociclib, or abemaciclib.

[0362] Subsequent steps may include administering to the subject a therapeutic compound selected from a SERD agent, e.g., elacestrant and / or fulvestrant, an AI, e.g., exemestane, a PI3K / Akt / mTOR ("PAM") inhibitor, e.g., alpelisib 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.

[0363] In another particular aspect, the inventors herein disclose a therapeutic use or method of treating a subject suffering from a hormone-dependent disease, preferably a cancer characterized by a mutation in estrogen receptor 1 (ESR1), wherein the mutation is an activating mutation (i.e., responsible for the constitutive activation of ESR1), as described herein above. This use / method involves administering to a subject a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-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, alone or in combination with one or several separate compounds, such as any of the drugs described herein, including, but not limited to, a SERM compound selected from tamoxifen, 4-hydroxytamoxifen, endoxifen, toremifene, droloxifene, idoxifene, raloxifene, arzoxifene, bazedoxifene, pippindoxifene, and lasofoxifene; amsenestrant, azenosertib (ZN-c5), boreham-1, bronchodilator, thiazolinone ... estrant, brilanstrant (ARN-810), kamizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lindestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927, or SHR9549, in particular elacestrant, e.g., amsenestrant, AZD9496, brilanstrant (ARN-810), kamizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lindestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927, or SHR9549. SERD compounds selected from zestrant, D-0502, elacestrant (RAD-1901), fulvestrant, preferably elacestrant, GDC-0927, giledestrant, LY3484356, and lintodestrant; AI inhibitors selected from aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, and vorozole; CERAN compounds such as OP-1250;Abemaciclib (also known as LY2835219), AG024322, aloisine A, aloisine B, alsterpaullone, aminopurvalanol, AT7519, AZD-5438, AZD5597, BLU-222, BMS-387032, vilociclib (XZP3287), Bohemin, butyrolactone, CYC065, dalpiciclib (SHR-6390), dinaciclib, ETH-155008, flavopiridol, FCN-437c, GLR2007, Inde Indirubin, indirubin-3'-monoxime, JNJ-7706621, Kenpaullone, lerociclib (also known as G1T38), meriolin 3, milciclib, narazaciclib (ON123300), NVP-LCQ19, olomoucine, olomoucine II, palbociclib (also known as Ibrance, PD-0332991, or PF-00080665), PF-07220060, PF-07104091, PF-06873600, PHA-793 887, purvalanol A, purvanol B, R-CR8, RGB-286638, RGB286147, ribociclib (also known as LEE-011), ribiciclib hydrochloride (P276-00), roniciclib, R-roscovitine, Ro4584820, samlaciclib (also known as CT7001 or ICE0942), SRX-3177, TG02, TQB3303, trilaciclib (also known as GTI128), voruciclib, xanthan gum CDK inhibitors selected from rocidin, ZK304709, 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, preferably CDK4 / 6 inhibitors selected from palbocociclib, ribociclib, and abemaciclib;and / or buparlisib (BKM120), pilaralisib (XL147, SAR245408), pictilisib (GDC-0941), sonolisib (PX-866), dactolisib (BEZ235), sapanisertib (INK128, MLN0128), voxtalisib (XL765, SAR245409), selavelisib (MLN1117), alpelisib (BYL719), perifosine (KRX-040 in combination with a PI3K / Akt / mTOR ("PAM") pathway inhibitor selected from: 1), MK2206, ipatasertib (GDC0068), GSK690693, temsirolimus (CCI-779), ridaforolimus (MK8669; deforolimus), sirolimus (rapamycin), everolimus (RAD001), AZD-8055, and OSI-027 (ASP7486). In certain embodiments, the SERD is selected from amsenestrant, azenosertib (ZN-c5), volestrant, brilanstrant, camizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lintodestrant, AZD9496, D-0502, LY3484356, GDC-0927, or SHR9549; the cyclin-dependent 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;

[0364] In a further specific aspect, the therapeutic use or method comprises administering to a subject a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-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.

[0365] In a further particular embodiment, a therapeutic use or method for treating a subject suffering from a hormone-dependent disease, preferably cancer, more preferably selected from breast cancer, ovarian cancer, endometrial cancer, in particular type I endometrial cancer, and / or cancer that has preferably metastasized to the brain, bone, lung, or liver.

[0366] In another particular aspect, the inventors herein disclose a therapeutic use or method of treating a subject suffering from a hormone-dependent disease, preferably a 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-acetidin-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 0. The patient has a (first) mutant allele frequency ("MAF") value of the first ERa variant (the first ERa variant is preferably Y537S or D538G), e.g., detected in cfDNA from a biological sample, e.g., a blood sample, obtained from the patient, of 0.5% or more (≧) (the first ERa variant is preferably Y537S or D538G), and / or a (second) MAF value of the ERa variant (the (second) ERa mutation is preferably D538G, L536H, L536P, L536Q, L536R, Y537C, Y537N, Y537D, Y537S, S463P, E380Q, V392I, F404fs, or V422del).

[0367] In a further particular aspect, the inventors also disclose herein a therapeutic use or method of treating a subject suffering from a hormone-dependent disease, preferably a 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-acetidin-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 PgR and / or ER positive status.

[0368] The present disclosure also encompasses advantageous therapeutic uses of a quinazolinecarboxamide azetidine compound, preferably 4-[(S)-2-acetidin-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 treating metastatic cancer, e.g., cancer that has spread to the brain, bone, lung, liver, or central nervous system.

[0369] As illustrated in Table A below (Table 1), M2698 is able to cross the blood-brain barrier ("BBB") from cancer that has metastasized to the brain when administered orally at 25 mg per kg of subject body weight, i.e., an amount similar to Compound 1 as defined in WO2021 / 007146 as the active compound, compared to active fulvestrant (which is unable to penetrate the blood-brain barrier).

[0370] [Table 1]

[0371] Accordingly, the present disclosure provides quinazolinecarboxamide azetidine compounds of formula I, as defined herein: [ka] or Formula II as defined herein: [ka] and a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof.

[0372] In some embodiments, the cancer subject in need of treatment has one or more CNS metastatic tumors, such as brain metastases, and optionally also bone, lung, or liver metastases.

[0373] All references mentioned herein are incorporated by reference into this application. Other features and advantages of the present invention will be seen in the following examples and figures, which are given for purposes of illustration and not limitation. [Brief explanation of the drawings]

[0374] [Figure 1] Combination of M2698 and elacestrant. Graph showing the evolution over time (up to 40 days) of the calculated mean volume and standard deviation (SD) of MCF7 tumors in each group: vehicle (n=8 mice), elacestrant alone (n=8 mice), M2698 alone (n=8 mice), and M2698 + elacestrant (n=6 mice). [Figure 2] Graph showing the evolution over time (up to 40 days) of the calculated mean volume and SD of MCF7 tumors in each of the M2698 and abemaciclib combination groups: vehicle (n=8 mice), abemaciblib alone (n=8 mice), M2698 alone (n=8 mice), and M2698 + abemaciclib (n=6 mice). [Figure 3] Combination of M2698 and elacestrant. Graph showing the evolution over time (up to 60 days) of the calculated mean volume and standard deviation (SD) of MCF7 tumors in each group: vehicle (n=8 mice), elacestrant alone (n=8 mice), M2698 alone (n=8 mice), and M2698 + elacestrant (n=6 mice). ****p<0.0001, Tukey's range test. [Figure 4]Graph showing the evolution over time (up to 60 days) of the calculated mean volume and SD of MCF7 tumors in each of the M2698 and abemaciclib combination groups: vehicle (n=8 mice), abemaciblib alone (n=8 mice), M2698 alone (n=8 mice), and M2698 + abemaciclib (n=6 mice). ****p<0.0001, Tukey's range test. [Example]

[0375] The following non-limiting examples are provided to further illustrate certain teachings provided by the present disclosure. Those skilled in the art will appreciate in light of this application that various changes can be made to the specific embodiments illustrated in the examples without departing from the spirit and scope of the present teachings.

[0376] Example 1 Materials and Methods Patient cohort criteria 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 (HER2neg or HER2-), whose tumors have confirmed or potential alterations in the PAM pathway (PAM+: e.g., PTEN, PIK3CA, AKT1, AKT3, mTOR, TSC1, or TSC2), who have exhausted all standard accepted treatment options, and who have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria (EA Eisenhauer, Eur J Cancer. 2009 Jan;45(2):228-47) and a tumor biopsy available.

[0377] Patients' estrogen receptor 1 (ESR1) status was defined by detecting any mutations (including any deletions and / or frameshifts) in the ESR1 gene in liquid tumor biopsies via the highly sensitive next-generation sequencing platform Guardant360™ (Guardant Health, USA) as a retrospective analysis, specifically at the time of study entry.

[0378] Patients with confounding EGFR, KRAS, and AKT2 alterations were excluded.

[0379] Patients with asymptomatic brain metastases that were stable for >4 weeks after treatment were eligible.

[0380] All patients underwent cardiac function testing for eligibility.

[0381] Twenty-six patients had a histologically and / or cytologically confirmed diagnosis of 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 be discontinued at least 1 year before the first dose.

[0382] Patients were enrolled at 10 sites across the United States and provided written informed consent before any study procedures were performed. The study was conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines, the ethical principles of the Declaration of Helsinki, and applicable local regulations.

[0383] drug substance: - 4-[(S)-2-Acetidin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-ethylamino]-quinazoline-8-carboxylic acid amide ("M2698" - CAS number 1379545-95-5), capsule dosage, 80 mg / capsule.

[0384] - 2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine (tamoxifen - CAS number 10540-29-1), tablet dosage, 20 mg / tablet.

[0385] A list of examples of prior endocrine anti-cancer therapies (ET) that may be administered to patients is provided in Table 1 below.

[0386] [Table 2]

[0387] ET: Endocrine therapy includes, among others, aromatase inhibitors (AIs) such as letrozole, exemestane, and anastrozole, and selective estrogen receptor degraders or modulators (SERD / Ms) such as tamoxifen and fulvestrant.

[0388] Everolimus is the only inhibitor of mTOR ("mTORi") approved for the treatment of recurrent metastatic ER+ breast cancer.

[0389] Palbociclib is one of three CDK4 / 6 kinase inhibitors (CDK4 / 6i) approved for treatment-naïve, advanced ER+ breast cancer. Ribociclib and abemaciclib can be used similarly. Trastuzumab deruxtecan is an anti-HER2 ADC (antibody-drug conjugate).

[0390] Estrogen receptor 1 (ESR1) status: Peripheral blood samples were collected from patients at study entry. Plasma was isolated from 20 ml of whole blood, 20 ng of DNA was extracted, and hybrid capture-based genomic profiling of circulating tumor DNA (ctDNA) was performed in a CLIA-certified / CAP-accredited laboratory (Guardant Health, USA) to identify substitutions, short insertions / deletions, rearrangements / fusions, and amplifications in the ESR1 gene as components of the Guardant360 assay multi-gene panel.

[0391] Study design and dosing schedule The two drug substances were administered orally once daily by swallowing the whole tablet with a full glass of water (approximately 200 mL / 8 fl oz). Participants took the total assigned dose (1 to 3 capsules of 80 mg 4-[(S)-2-acetidin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-ethylamino]-quinazoline-8-carboxylic acid amide and 20 mg tamoxifen) at the same time each morning. Participants were instructed to fast for at least 2 hours before and 1 hour after dosing.

[0392] statistical analysis 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 Response Evaluation Criteria in Solid Tumors (RECIST) as an increase of at least 20% in the sum of the largest tumor diameters, the development of any new lesions, or an absolute increase in non-measurable malignant disease (EA Eisenhauer, Eur J Cancer. 2009 January;45(2):228-47) and tumor biopsy availability. PFS was estimated using the Kaplan-Meier method.

[0393] result Of 26 patients with recurrent ER+ HER2- metastatic breast cancer treated with M2698 + tamoxifen: - One patient received M2698 for only 1 day and was not evaluable during treatment or PFS analysis - 6 patients had non-evaluable ESR1 status (questionable result due to suspected sample contamination or absence of data). Nineteen patients had evaluable ESR1 mutation status at study entry. *Nine patients showed one or more mutations (approximately 90% Y537D and D538G). *Ten patients had the non-mutated wild-type (WT) ESR1 gene sequence.

[0394] [Table 3]

[0395] Both ESR1-mutated and ESR1-WT patients had very advanced cancer and an unfavorable prognosis: both groups had received a median of approximately six previous unsuccessful anticancer therapies, and both were considered to have exhausted all available therapeutic options for treating their disease.

[0396] Patients with mutated ESR1 genes continued treatment with the M2698 + tamoxifen combination for approximately twice as long as patients with wild-type ESR1: the median treatment durations were 6 and 3.17 months, respectively, meaning that half of the ESR1-mutated subgroup of patients had stable disease lasting longer than 6 months, while half of the ESR1-WT subgroup only had stable disease for 3.17 months.

[0397] The median progression-free survival (PFS) in the ESR1 mutation subgroup was nearly twice that in the ESR1 WT group, meaning that M2698 plus tamoxifen delayed disease recurrence for a longer period in patients carrying ESR1 mutations compared with ESR1 WT: half of the patients in the ESR1 mutation group experienced cancer recurrence after 5.5 months of treatment, whereas in the ESR1 WT group, this occurred after only 2.65 months.

[0398] Table 2 (Table 3) illustrates that patients with ESR1-mutated ER+ breast cancer failed to respond and developed resistance to all available treatments, regardless of their drug class and mechanism of action. Nevertheless, they were able to derive significant clinical benefit (in terms of duration of disease stability and time to disease recurrence) when treated with M2698+tamoxifen.

[0399] conclusion Mutations in the ESR1 gene are markers of acquired resistance to all classes of endocrine therapy. They are associated with poorer clinical outcome and shorter survival.

[0400] The combined use of the M2698 compound and tamoxifen, or M2698 and any other endocrine therapy selected from those described herein, provides advantageous therapeutic benefits for patients with relapsed / refractory ER+ breast cancer whose tumors exhibit mutations in the ESR1 gene.

[0401] The M2698 compound can be safely combined with endocrine therapy, where the endocrine agent is selected from selective ER modulators (SERMs), selective ER downregulator degraders (SERDs), aromatase inhibitors (AIs), and complete estrogen receptor antagonists (CERANs).

[0402] The M2698 compound can be safely combined with a selective ER downregulator degrader (SERD) selected from amsenestrant, azenosertib (ZN-c5), bolestrant, brilantrant, camizestrant, elacestrant, fulvestrant, giledestrant, imrunestrant, lintodestrant, AZD9496 (LSZ102), D-0502, LY3484356, GDC-0927, and SHR9549, and even more specifically elacestrant.

[0403] Additionally, the M2698 compound can be safely combined with endocrine therapy compounds described above in this specification, as well as compounds that act on the ER pathway, the PI3K / Akt / mTOR pathway, growth factor receptor pathways (involving epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin growth factor receptor (IGFR), or vascular endothelial growth factor receptor (VEGFR)), the cell cycle, the ubiquitin-proteasome pathway, or bromodomains and / or extraterminal domains of proteins.

[0404] The M2698 compound can restore the sensitivity of ER+ tumors to endocrine therapy, which is the mainstay of treatment for ER+ cancers, such as breast cancer, ovarian cancer, and type I endometrial cancer, preferably ER+ breast cancer. ER+ tumors also include any ER+ tumor that has metastasized to the brain, bone, lung, or liver, more specifically, the brain.

[0405] Furthermore, the M2698 compound can restore the sensitivity of ESR1-mutated ER+ tumors to endocrine therapy, which is the mainstay of treatment for ER+ cancers, such as 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, more specifically, the brain.

[0406] Example 2 Evaluation of the antitumor efficacy of anticancer compounds and substrate phosphorylation in a xenograft model of SCID-CB17 mice implanted with MCF7 cells. Materials and Methods Experimental design MCF7 cells were expanded in vitro in complete medium before implantation. Mice were implanted with estrogen pellets (Innovative Research of America, 0.18 mg / pellet) 24 hours before cell injection.

[0407] On the day of injection, cells were harvested, counted using trypan blue viability dye (acceptable cutoff ≥ 80% viability), and resuspended at the appropriate concentration in 50:50 PBS:Matrigel. Cells were then injected into the right flank at 5:10 6 120 mice were injected subcutaneously within 30 minutes of harvesting with 120 cells / mouse in 200 μL of PBS:Matrigel.

[0408] Tumor 100(+ / -25)mm 3 When the average volume of the tumor reaches 100 mm, mice (female mice, 5 weeks old, species: SCID-CB17, average weight 20 g (range 18-22 g)) are randomized into 8 groups (100 mice in total). All mice are observed after implantation to detect any toxic effects of the product. Endpoints are defined by animal ethics. These include tumor diameter >18 mm (1600 mm). 3 ), significant weight loss, or changes in animal welfare.

[0409] To assess the efficacy of compounds against tumorigenesis, tumor volumes are measured twice a week for 8 weeks and mice are weighed once a week for 8 weeks.

[0410] The size of the primary tumor is measured using calipers, and the tumor volume (TV) is extrapolated to a sphere by calculating the mean radius from the two measurements using the formula TV=4 / 3π×r3.

[0411] treatment Mice are randomized at the time of tumor ingestion and treated once daily for 5 weeks according to the treatments shown in Table 3 below.

[0412] [Table 4]

[0413] After 4 days of treatment, tumor sampling of 3 satellite mice 4 hours after the last treatment and 3 satellite mice 8 hours after the last treatment for 6 groups (Groups 1, 4, 5, 6, 7, and 8) for Western blot analysis (36 mice in total).

[0414] Western blot assays of 3 x 2 tumor samples from 6 satellite mice from 6 groups are performed for semi-quantification of the following proteins:

[0415] All operations were carried out on ice.

[0416] Proteins are extracted using FastPrep fp120® (Bio101). The tumors are placed in Lysing Matrix D tubes with 100 μL of RIPA lysis buffer and shaken for 12 seconds at 6.5 m / s. After 1 hour of incubation, they are centrifuged. The supernatant is collected for dose determination.

[0417] The lysate was titrated using the Bradford protein assay and adjusted to 50 μg in each sample. Each sample was then heated to 95°C for 5 minutes, loaded onto a pre-cast gel (Mini-PROTEAN®, BIO-RAD), and PAGE-SDS was applied. After electrophoresis, proteins were transferred using PVDF Mini Stacks using iBlot® 2 (Thermofisher).

[0418] statistical analysis Statistical analysis is performed thanks to GraphPad Prism software, which combines scientific graphing, comprehensive curve fitting, understandable statistics, and data organization.

[0419] Unless specified, Mann-Whitney t-test (two-tailed unpaired) was used to compare tumor volume values (mm 3 )

[0420] result Results are expressed via tumor growth curves.

[0421] The graphs in Figures 1 and 3 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), elacestrant alone (n = 8 mice), M2698 alone (n = 8 mice), and M2698 + elacestrant (n = 6 mice).

[0422] While elacestrant (50 mg / kg / day) weakly inhibited MCF7 tumor growth, M2698 (20 mg / kg / day) showed potent antitumor efficacy, and the combination of M2698 and elacestrant was significantly more effective than M2698 alone.

[0423] The graphs in Figures 2 and 4 show the evolution of the calculated mean volume and SD of MCF7 tumors over time (up to 40 and 60 days, respectively) in each group: vehicle (n = 8 mice), abemaciclib alone (n = 8 mice), M2698 alone (n = 8 mice), and M2698 + abemaciclib (n = 6 mice).

[0424] M2698 (20 mg / kg / day) potently inhibited tumor growth as efficiently as abemaciclib (40 mg / kg / day) alone, and the combination of M2698 and abemaciclib was significantly more effective than each individual compound.

[0425] Sequence Listing Free Text

[0426] SEQ ID NO: 1 (Seq:ESR1:P03372|ESR1_HUMAN-htpps: / / www.uniprot.org / uniprotkb / P03372 / history): [ka]

[0427] SEQ ID NO:2 (Sequence of the ERa Ligand Binding Domain, "LBD"): [ka]

[0428] SEQ ID NO: 3 (ESR1 gene sequence): [ka] [ka]

Claims

1. A composition comprising (a) a quinazoline carboxamide azetidine compound and (b) a combination of a separate therapeutic agent selected from anti-angiogenic agents, signaling inhibitors, antineoplastic agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, antisense molecules, small molecules, growth factor receptor agents, and any combination thereof, or a combination of (a) and (b) and a pharmaceutically acceptable carrier.

2. The quinazoline carboxamide azetidine compound is a compound of formula (I): 【Chemistry 1】 [In the formula, R 1 is H or LA, R 2 is Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH 2 , or A, R 3' , R 3'' These are independently H, LA, or Hal. Ar is a monocyclic or bicyclic aromatic homo- or heterocyclic ring having 0, 1, 2, 3, or 4 N, O, and / or S atoms, and 5, 6, 7, 8, 9, or 10 skeletal atoms, which is unsubstituted or, independently of one another, Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA 2 >NO 2 , CN, OCN, SCN, COOH, COOA, CONH 2 , CONHA, CONH(Art), CONA 2 , NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH 2 , NHSO 2 A, NHSO 2 (Ar1), COA, CO(Ar1), SO 2 NH 2 , SO 2 A, SO 2 (Ar1), and / or SO 2 is mono-, di-, or trisubstituted by Hal, the ring N atom is either substituted by an O atom to form an N-oxide group or is unsubstituted, and in the case of a bicyclic aromatic ring, one of the two rings is partially saturated or unsaturated, Ar1 is a monocyclic aromatic homo or heterocyclic ring having 0, 1, 2, or 3 N, O, and / or S atoms, and 5 or 6 skeletal atoms, which are unsubstituted or independently of each other, such as Hal, LA, OH, SH, O(LA), NH 2 NH(LA), N(LA) 2 NO 2 , CN, OCN, SCN, COOH, COO(LA), CONH 2 CONH(LA), CON(LA) 2 , NHCO(LA), CHO, CO(LA), SO 2 NH 2 , SO 2 (LA), and / or SO 2 It is replaced by one, two, or three substitutions by Hal. A is an unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 C atoms, and 1 or 2 CH 2 The group is replaced or not replaced by an O or S atom and / or by a -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO-, or -CH=CH- group, and 1 to 3 H atoms are replaced or not replaced by Hal, and 1 or 2 CH 3 The bases are OH, SH, and NH. 2 NH(LA), N(LA) 2 NHCOOH, NHCONH 2 , or replaced or not replaced by CN, LA is a non-branched or branched linear alkyl having 1, 2, 3, or 4 C atoms, and 1, 2, or 3 H atoms are replaced or not replaced by Hal, methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. Hal is F, Cl, or Br. and / or its pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers (including any mixture thereof in any ratio), The combination or composition according to claim 1, wherein the separate therapeutic agent (b) is an antineoplastic agent and / or a signal transduction inhibitor.

3. The combination or composition according to claim 1 or 2, wherein the quinazoline carboxamide azetidine compound of formula (I) is 4-[(S)-2-acetyldin-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 separate therapeutic agent is an antineoplastic agent, and the antineoplastic agent is a hormone therapy agent or a chemotherapy agent.

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

6. The combination or composition according to claim 5, wherein the SERD compound is selected from amsenestrant, azenocertib (ZN-c5), bolestrant, brilliantrant, camizestrant, elastrant, fulvestrant, giledestrant, imulnestrant, lintestrant, AZD9496, D-0502, LY3484356, GDC-0927, and SHR9549.

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

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

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

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 pharmaceutically acceptable polymorphs, enantiomers, stereoisomers, salts, solvates, or tautomers of abemaciclib, palbociclib, ribociclib, and any of the aforementioned.

12. A combination or composition according to claim 1 or 2 for use as a pharmaceutical.

13. The combination according to claim 12, wherein the quinazoline carboxamide azetidine compound, the antineoplastic agent, and / or the signal transduction inhibitor are formulated for simultaneous, concurrent, or sequential administration.

14. A combination or composition according to claim 1 or 2 for use in treating hormone-dependent disorders in a subject.

15. The combination or composition according to claim 14, wherein the hormone-dependent disease is hormone receptor-positive (HR+) cancer.

16. The combination or composition according to claim 15, wherein the hormone receptor-positive (HR+) 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 according to claim 16, wherein the hormone receptor-positive (HR+) cancer is human epidermal growth factor receptor 2-positive (HER2+) cancer, human epidermal growth factor receptor 2-negative (HER2-) cancer, or human epidermal growth factor receptor-2-low ("HER2-low") cancer.

18. The combination or composition according to claim 15, wherein the hormone receptor-positive (HR+) cancer is breast cancer.

19. The combination or composition according to claim 15, wherein the hormone receptor-positive (HR+) cancer is metastatic breast cancer that is resistant and / or refractory to standard treatment.

20. The combination or composition according to claim 15, wherein the treatment comprises administering an anticancer agent selected from anti-angiogenic agents, signaling inhibitors, antineoplastic agents, therapeutic antibodies or fragments thereof, antibody-drug conjugates, small molecules, growth factor receptor agents, and / or antisense molecules.

21. The combination or composition according to claim 14, wherein the subject has been treated with a drug selected from drugs used in hormone therapy, CDK inhibitors, PI3K / AKT / mTOR ("PAM") pathway inhibitors, or any combination thereof.

22. The combination or composition according to claim 14, wherein the quinazoline carboxamide azetidine compound of formula (I) is 4-[(S)-2-acetyldin-1-yl-1-(4-chloro-3-trifluoromethylphenyl)-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 dose of 50 mg to 800 mg.

23. The combination or composition according to claim 22, wherein the antineoplastic agent is elastrant, and elastrant is present in the combination or composition in a dose of 200 mg to 500 mg.

24. A pharmaceutical composition comprising a quinazoline carboxamide azetidine compound, or a quinazoline carboxamide azetidine compound and a pharmaceutically acceptable carrier, for use in treating estrogen receptor-positive (ER+) cancer in a subject that requires it.

25. The quinazoline carboxamide azetidine compound is a compound of formula (I): 【Chemistry 2】 [In the formula, R 1 is H or LA, R 2 is Hal, O(LA), N(LA)(LA)', CONH(LA), Ar, CONH 2 , or A, R 3' , R 3'' These are independently H, LA, or Hal. Ar is a monocyclic or bicyclic aromatic homo or heterocyclic ring having 0, 1, 2, 3, or 4 N, O, and / or S atoms, and 5, 6, 7, 8, 9, or 10 skeletal atoms, which are unsubstituted or independently of each other, such as Hal, A, Art, OH, SH, OA, O(Ar1), NH2, NHA, NH(Ar1), NA 2 >NO 2 ,CN,OCN,SCN,COOH,COOA,CONH 2 CONHA, CONH(Art), CONA 2 , NHCOA, NHCO(Art), NHCONHA, NHCONH(Art), NHCONH 2 NHSO 2 A, NHSO 2 (Ar1), COA, CO(Ar1), SO 2 NH 2 , SO 2 A, SO 2 (Ar1), and / or SO 2 It is monosubstituted, disubstituted, or trisubstituted by Hal, and the N atom of the ring is substituted by an O atom to form an N-oxide group or is not substituted, and in the case of a bicyclic aromatic ring, one of the two rings is partially saturated or unsaturated. Ar1 is a monocyclic aromatic homo or heterocyclic ring having 0, 1, 2, or 3 N, O, and / or S atoms, and 5 or 6 skeletal atoms, which are unsubstituted or independently of each other, such as Hal, LA, OH, SH, O(LA), NH 2 NH(LA), N(LA) 2 NO 2 , CN, OCN, SCN, COOH, COO(LA), CONH 2 CONH(LA), CON(LA) 2 , NHCO(LA), CHO, CO(LA), SO 2 NH 2 , SO 2 (LA), and / or SO 2 It is replaced by one, two, or three substitutions by Hal. A is an unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 C atoms, and 1 or 2 CH 2 The group is replaced or not replaced by an O or S atom and / or by a -NH-, -CO-, -NHCOO-, -NHCONH-, -N(LA)-, -CONH-, -NHCO-, or -CH=CH- group, and 1 to 3 H atoms are replaced or not replaced by Hal, and 1 or 2 CH 3 The bases are OH, SH, and NH. 2 NH(LA), N(LA) 2 NHCOOH, NHCONH 2 , or replaced or not replaced by CN, LA is a non-branched or branched linear alkyl having 1, 2, 3, or 4 C atoms, and the 1, 2, or 3 H atoms may be replaced by Hal, methyl, ethyl, trifluoromethyl, difluoromethyl, 1,1,1-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. Hal is F, Cl, or Br. The composition according to claim 24, and / or a pharmaceutically acceptable polymorph, enantiomer, stereoisomer, salt, solvate, or tautomer thereof (including any mixture thereof in any ratio).

26. The composition according to claim 24, wherein the quinazoline carboxamide azetidine compound of formula (I) is 4-[(S)-2-acetyldin-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 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 according to claims 24 to 26, wherein the cancer is human epidermal growth factor receptor 2 positive (HER2+) cancer, human epidermal growth factor receptor 2 negative (HER2-) cancer, or human epidermal growth factor receptor 2 low (HER2 low) cancer.

29. The composition according to claim 28, wherein the cancer is breast cancer.

30. The composition according to claim 29, wherein the cancer is metastatic breast cancer that is resistant and / or refractory to standard treatment.

31. A composition according to any one of claims 24 to 26 for treating ER+ breast cancer in patients who do not respond to hormone therapy.

32. The composition 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) carcinoma, the mutation occurring in the ligand-binding domain of the wild-type ERa sequence of SEQ ID NO: 1, and / or the mutated ERa is characterized by a modification of 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.

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