PRMT5 inhibitors, compositions comprising them and their uses.

Abstract

PRMT5 INHIBITORS. The present invention provides a compound selected from compounds A, B, C, D and their pharmaceutically acceptable salts, esters and prodrugs, which are PRMT5 inhibitors. Methods for producing the compounds disclosed herein, pharmaceutical compositions comprising the compounds disclosed herein, and methods for using these compounds to treat cancer, sickle cell disease, and hereditary persistence of fetal hemoglobin mutations (HPFH) are also provided.

Description

PRMT5 inhibitors, compositions comprising them and their uses. FUNDAMENTALS OF THE INVENTION

[0001] PRMT5 (also known as JBP1, SKB1, IBP72, PRMT5 (SKBIhis and HRMTIL5) is a Type II arginine methyltransferase and was first identified in a two-hybrid search for proteins that interact with Janus tyrosine kinase (Jak2) (Pollack et al., 1999). PRMT5 plays a significant role in the control and modulation of gene transcription. Among other things, PRMT5 is known to symmetrically methylate histone H3 at Arg-8 (a site distinct from that methylated by PRMT4) and histone H4 at Arg-3 (the same site methylated by PRMT1). PRMT5 has been reported to play several roles, including but not limited to impacting cell viability, stemness, DNA damage repair, and RNA splicing (Clarke et al., Mol Cell (2017), Chiang et al., Cell Rep (2017), Gerhart et al., Sci Rep (2018)).Specifically, PRMT5 inhibition induces alternative splicing of the p53 negative regulator, MDM4, resulting in increased expression of the short isoform of MDM4 (MDM4-S), decreased expression of the full-length isoform (MDM4-FL), and increased p53 activity (Gerhart et al. Sci Rep (2018)). Most of p53's physiological functions are attributable to its role as a transcriptional activator, responding to DNA-damaging agents. The p53 state is wild-type in approximately half of human cancer cases. These include 94% in cervical cancer, 87% in blood malignancies, 85% in bone and endocrine gland cancers, and 75% in primary breast cancer. Restoring p53 in cancer cells harboring wild-type p53, through inhibitory mechanisms that suppress its function, leads to growth arrest and apoptosis and is considered a potentially effective means of tumor suppression. Petition 870260011249, dated 05 / 02 / 2026, page 6 / 233 2 / 73

[0002] In response to DNA damage caused by a variety of agents, including doxorubicin, camptothecin, and UV light, and also in response to treatment with Nutlin-3, PRMT5 knockdown results in an increase in the sub-G1 population and a concomitant reduction in G1 cells and, in the presence of p53, a significant increase in apoptosis. PRMT5 knockdown also resulted in an increased level of p21, a key p53 target gene that regulates cell cycle arrest during the p53 response, and MDM2, a p53 E3 ubiquitin ligase, but not the p53 target genes PUMA, NOXA, AlP1 & APAF1, which are linked to apoptosis.

[0003] The knockdown of PRMT5 (but not PRMT1 or CARM1 / PRMT4) results in decreased p53 stabilization, decreased basal p53 levels, decreased p53 oligomerization, and also decreased expression of elF4E, an important component of the translational machinery involved in ribosome-mRNA binding. In fact, elF4E is a potent oncogene that has been shown to promote malignant transformation in vitro and the formation of human cancer.

[0004] The role of PRMT5 in the response to DNA damage has been explored with groups reporting a role for PRMT5 in the regulation of DNA repair mediated by high-fidelity homologous recombination in both solid tumor models (Clarke et al., Mol Cell (2017)) and hematologic tumor models (Hamard et al., Cell Rep (2018)).

[0005] PRMT5 is aberrantly expressed in about half of human cancer cases, further linking this mechanism to cancers. PRMT5 overexpression has been observed in patient tissue samples and cell lines of prostate cancer (Gu et al., 2012), lung cancer (Zhongping et al., 2012), melanoma cancer (Nicholas et al., 2012), breast cancer (Powers et al., 2011), cancer Petition 870260011249, dated 05 / 02 / 2026, page 7 / 233 3 / 73 colorectal cancer (Cho et al., 2012), gastric cancer (Kim et al., 2005), esophageal and lung carcinoma (Aggarwal et al., 2010), and B-cell lymphomas and leukemia (Wang, 2008). Furthermore, elevated PRMT5 expression in melanoma, breast, and colorectal cancers has been shown to correlate with a poor prognosis.

[0006] Lymphoid malignancies, including chronic lymphocytic leukemia (CLL), are associated with PRMT5 overexpression. PRMT5 is overexpressed (at the protein level) in the nucleus and cytosol in a number of patient-derived Burkitt lymphomas; mantle cell lymphoma (MCL); EBV-transformed lymphoma in vitro; leukemia cell lines; and B-CLL cell lines, relative to normal CD19+ B lymphocytes (Pal et al., 2007; Wang et al., 2008). Interestingly, despite elevated PRMT5 protein levels in these tumor cells, PRMT5 mRNA levels are reduced (by a factor of 2–5). PRMT5 mRNA translation is, however, increased in lymphoma cells, resulting in increased PRMT5 levels (Pal et al., 2007; Wang et al., 2008).

[0007] In addition to genomic alterations, CLL, like almost all cancers, has aberrant epigenetic abnormalities characterized by global hypomethylation and hotspots of repressive hypermethylation of promoters, including tumor suppressor genes. Although the role of epigenetics in the origin and progression of CLL remains uncertain, epigenetic alterations appear to occur early in the disease, and specific DNA methylation patterns are associated with a worse prognosis (Chen et al., 2009; Kanduri et al., 2010). Global symmetric methylation of histones H3R8 and H4R3 is increased in transformed lymphoid cell lines and clinical samples of CLL (Pal et al., 2007), correlating with PRMT5 overexpression observed in a wide variety of lymphoid cancer cell lines and clinical samples of CLL. Petition 870260011249, dated 05 / 02 / 2026, page 8 / 233 4 / 73

[0008] PRMT5 is therefore a target for the identification of new cancer therapies.

[0009] Hemoglobin is an important protein in red blood cells and is essential for transporting oxygen from the lungs to the tissues. In adult humans, the most common type of hemoglobin is a tetramer called hemoglobin A, which consists of two α and two β subunits. In human infants, the hemoglobin molecule is composed of two α and γ chains. The gamma chains are gradually replaced by β subunits as the baby grows. The developmental change in the human β-like globin gene subtype, from fetal (γ) to adult (β), which begins at birth, heralds the onset of the hemoglobinopathies β-thalassemia or sickle cell disease (SCD). In β-thalassemia, the adult chains are not produced. In SCD, a point mutation in the coding sequence of the β-globin gene leads to the production of a protein with altered polymerization properties.The observation that increased expression of the γ-globin gene in adults (in the context of hereditary persistence of fetal hemoglobin mutations (HPFH)) significantly improves the clinical severity of β-thalassemia and sickle cell disease (SCD) has led to the search for therapeutic strategies to reverse γ-globin gene silencing. To date, this has been achieved through pharmacological induction, using compounds that broadly influence epigenetic modifications, including DNA methylation and histone deacetylation. The development of more targeted therapies depends on identifying the molecular mechanisms underlying fetal globin gene silencing. These mechanisms have remained undefined, despite exhaustive study of HPFH mutations and considerable progress in many other aspects of globin gene regulation.

[0010] PRMT5 plays a critical role in Petition 870260011249, dated 05 / 02 / 2026, page 9 / 233 5 / 73 triggering of coordinated repressive epigenetic events that begin with the dimethylation of histone H4 Arginine 3 (H4R3me2s) and culminate in DNA methylation and transcriptional silencing of γ genes (Rank et al., 2010). Integral to the synchronous establishment of repressive markers is the assembly of a PRMT5-dependent complex containing the DNA methyltransferase DNMT3A and other repressor proteins (Rank et al., 2010). DNMT3A is directly recruited to bind to the PRMT5-induced H4R3me2s marker, and the loss of this marker through shRNA-mediated PRMT5 knockdown, or forced expression of a mutant form of PRMT5 without methyltransferase activity, leads to a marked upregulation of γ gene expression and complete revocation of DNA methylation at the γ promoter. Treatment of human erythroid progenitors with non-specific methyltransferase inhibitors (Adox and MTA) also resulted in upregulation of γ gene expression (He Y, 2013).PRMT5 inhibitors, therefore, have potential as a therapy for hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD).

[0011] The present inventors have developed compounds that inhibit PRMT5 activity and, therefore, may be useful in the treatment of conditions improved by the inhibition of PRMT5 activity. SUMMARY OF THE INVENTION.

[0012] The present invention provides a compound selected from: Petition 870260011249, dated 05 / 02 / 2026, page 10 / 233 6 / 73 and pharmaceutically acceptable salts, esters and prodrugs thereof, which are PRMT5 inhibitors. Methods for producing compounds disclosed in this document, pharmaceutical compositions comprising the compounds disclosed in this document and methods for using these compounds to treat cancer, sickle cell disease and hereditary persistence of fetal hemoglobin mutations (HPFH) are also provided. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides a compound selected from: or a pharmaceutically acceptable salt thereof.

[0014] In one embodiment, the present invention provides a compound selected from: or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment of the invention, the compound is Petition 870260011249, dated 05 / 02 / 2026, page 11 / 233 7 / 73 1-{4-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1-yl}ethanone, (6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, (6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, (6-bromo-7-ethylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment of the invention, the compound is acceptable of the same. a pharmaceutical salt of or acceptable from the same. Invention, the compound is a pharmaceutically produced salt. acceptable of the same. Invention, the compound is a pharmaceutically produced salt.

[0019] In one embodiment of the invention, the compound is o , o ou um sal pharmaceuticalmente Petition 870260011249, dated 05 / 02 / 2026, page 12 / 233 8 / 73 acceptable of the same.

[0020] In one embodiment of the invention, the compound is 1-{4-[(4{[(3S ,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1-yl}ethanone, or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment of the invention, the compound is (6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment of the invention, the compound is (6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

[0023] In one embodiment of the invention, the compound is (6-bromo-7ethylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

[0024] In one embodiment, the present invention is a composition for the treatment of cancer comprising an effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0025] The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent) and a pharmaceutically acceptable carrier.

[0026] In one embodiment, the present invention is a composition for the treatment of hemoglobinopathies, such as Petition 870260011249, dated 05 / 02 / 2026, page 13 / 233 9 / 73 β-thalassemia or Sickle Cell Disease (SCD), comprising a compound disclosed in this document, or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment, the present invention is a composition for the treatment of hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD), comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0028] In one embodiment, the present invention is a method of inhibiting PRMT5 in a patient in need thereof, comprising administering to said patient an effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0029] In another embodiment, the present invention is a method of treating cancer comprising administering to a patient in need thereof an effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0030] In another embodiment, the present invention provides a method for treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of at least one chemotherapeutic agent.

[0031] The methods of the invention include administering a pharmaceutical composition comprising at least one compound disclosed in this document and a pharmaceutically acceptable carrier.

[0032] In another embodiment, the present invention includes a method of treating hemoglobinopathies, such as β-thalassemia or Disease Petition 870260011249, dated 05 / 02 / 2026, page 14 / 233 10 / 73 Sickle cell disease (SCD), comprising administering to a patient in need thereof a compound disclosed in this document, or a pharmaceutically acceptable salt thereof.

[0033] In another embodiment, the present invention is a method of treating cancer comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0034] In another embodiment, the present invention is a method of treating cancer comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0035] In another embodiment, the present invention is a method of treating hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD), comprising administering to a patient in need thereof a compound disclosed in this document, or a pharmaceutically acceptable salt thereof.

[0036] In another embodiment, the present invention is a method of treating hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD), comprising administering to a patient in need thereof a compound disclosed in this document, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] In another embodiment, the present invention is a method of treating cancer comprising administering to a patient in need thereof a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0038] In another embodiment, the present invention is a method of treating hemoglobinopathies, such as β-thalassemia or Disease Petition 870260011249, dated 05 / 02 / 2026, page 15 / 233 11 / 73 Sickle cell (SC), comprising administering to a patient in need thereof a composition containing a compound disclosed in this document, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0039] In another embodiment, the present invention is the use of a compound disclosed in this document, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0040] Another embodiment of the present invention is the use of a compound disclosed in this document, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD).

[0041] In another embodiment, the present invention includes the use of the compound disclosed in this document, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD).

[0042] Another embodiment is the use of the compound disclosed in this document, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer. In a subemphasis, the cancer is i) cardiac cancer, ii) lung cancer, iii) gastrointestinal cancer, iv) genitourinary tract cancer, v) liver cancer, vi) bone cancer, vii) nervous system cancer, viii) gynecological cancer, ix) hematological cancer, x) skin cancer or xi) adrenal cancer.

[0043] Another embodiment is the use of a compound described in this document, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD). Petition 870260011249, dated 05 / 02 / 2026, page 16 / 233 12 / 73

[0044] In another embodiment, the present invention includes compounds disclosed herein, for use in the treatment of cancer or hemoglobinopathies, such as β-thalassemia or Sickle Cell Disease (SCD). In another embodiment, the present invention includes compounds disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of heart cancer, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, hematological cancer, skin cancer, or adrenal cancer.

[0045] In one example of the invention, the cancer treated is colorectal cancer (such as, for example, colon adenocarcinoma and colon adenoma). Thus, another example of the invention is directed to a method of treating colorectal cancer in a patient in need of such treatment, said method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to said patient. Another example of the invention is directed to a method of treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one chemotherapeutic agent.

[0046] The invention also provides any of the above methods of treating cancer, wherein the cancer is melanoma. Thus, another example of the invention is directed to a method of treating melanoma in a patient in need of such treatment, said method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to said patient. Another example of the invention is directed to a method of treating melanoma in a patient Petition 870260011249, dated 05 / 02 / 2026, page 17 / 233 13 / 73 in need of such treatment, the said method comprising administering to the said patient an effective amount of a compound disclosed in this document, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one chemotherapeutic agent.

[0047] The cancer treatment methods described in this document may optionally include the administration of an effective amount of radiation (i.e., the cancer treatment methods described in this document may optionally include the administration of radiotherapy).

[0048] The cancer treatment methods described in this document include cancer treatment methods comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with radiotherapy and / or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxicostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitor of inherent multidrug resistance, an antiemetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immune response-enhancing drug,an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, a therapeutic siRNA, γsecretase and / or NOTCH inhibitors, receptor tyrosine kinase (RTK) interfering agents, a cellular checkpoint interfering agent, and any of the listed therapeutic agents. Petition 870260011249, dated 05 / 02 / 2026, page 18 / 233 14 / 73 in this document or a pharmaceutically acceptable salt thereof.

[0049] In any of the cancer treatment methods described in this document, unless otherwise indicated, the methods may optionally include the administration of an effective amount of radiotherapy. For radiation therapy, gamma radiation is preferred.

[0050] In one embodiment, the compound disclosed in this document is selected from the group consisting of the compounds exemplified in this document, for example, in Examples 1 - 4, or a pharmaceutically acceptable salt thereof.

[0051] The term composition is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified quantities. The term anticancer agent means a drug (medicine or pharmaceutically active ingredient) or antibody for the treatment of cancer. The term at least one means one or more than one. The meaning of at least one with reference to the number of compounds of the invention is independent of the meaning with reference to the number of chemotherapeutic agents. The term chemotherapeutic agent means a drug (medicine or pharmaceutically active ingredient) for the treatment of cancer (i.e., an antineoplastic agent). The term effective amount means a therapeutically effective amount.The term therapeutically effective amount means the quantity of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human being investigated by a researcher, veterinarian, physician, or other clinician. Thus, for example, in the cancer treatment methods described in this document, the effective amount (or therapeutically effective amount) is the amount of the active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human being being investigated by a researcher, veterinarian, physician, or other clinician. Petition 870260011249, dated 05 / 02 / 2026, page 19 / 233 15 / 73 effective) means the amount of the compound (or drug) or radiation that results in: (a) the reduction, relief or disappearance of one or more symptoms caused by cancer, (b) the reduction in tumor size, (c) the elimination of the tumor and / or (d) long-term disease stabilization (growth arrest) of the tumor. Furthermore, for example, an effective amount, or a therapeutically effective amount of the PRMT5 inhibitor (i.e., a compound of the invention) is that amount that results in the reduction of PRMT5 activity. The term cancer treatment refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing cancer cells and also refers to an effect that results in the inhibition of cancer growth and / or metastasis.

[0052] The methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the Physicians' Desk Reference (PDR), e.g., the Physicians' Desk Reference, 64th Edition, 2010 (published by PDR Network, LLC in Montvale, NJ 07645-1725), currently accessible through www.pdr.net; disclosures thereof are incorporated herein by reference thereto.

[0053] If the patient is responding, or is stable, after the therapy cycle has been completed, the therapy cycle may be repeated according to the judgment of the skilled clinician. After the therapy cycles have been completed, the patient may be allowed to continue with the compounds of the invention at the same dose that was administered in the treatment protocol. This maintenance dose may be continued until the patient progresses or ceases to tolerate the dose (in which case the dose may be reduced and the patient may be continued with the dose). Petition 870260011249, dated 05 / 02 / 2026, p. 20 / 233 16 / 73 reduced).

[0054] Those skilled in the art will recognize that the actual dosages and administration protocols employed in the methods of the invention may be varied according to the judgment of the skilled clinician. The actual dosage employed may vary depending on the patient's requirements and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the domain of the art. A determination to vary the dosages and administration protocols may be made after the skilled clinician takes into consideration factors such as the patient's age, condition, and size, as well as the severity of the cancer being treated and the patient's response to treatment.

[0055] The amount and frequency of administration of the compound disclosed in this document and of chemotherapeutic agents will be regulated according to the judgment of the attending clinician (physician), considering factors such as the patient's age, condition and size, as well as the severity of the cancer to be treated.

[0056] The compounds of the invention are also useful in the preparation of a medicament that is useful in the treatment of cancer.

[0057] Instant compounds are also useful in combination with therapeutic, chemotherapeutic, and anticancer agents. Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic, and anticancer agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 9th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. A person skilled in the common art would be able to discern which combinations of agents would be useful based on the specific characteristics of the drugs and cancer involved. Such agents include the following: estrogen receptor modulators, Petition 870260011249, dated 05 / 02 / 2026, page 21 / 233 17 / 73 Programmed cell death protein 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenylprotein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapy, γ-secretase inhibitors, receptor tyrosine kinase (RTK) interfering agents, and cell cycle checkpoint interfering agents. Instant compounds are particularly useful when co-administered with radiotherapy.

[0058] The chemotherapeutic agent may be administered according to therapeutic protocols well known in the art. It will be evident to those skilled in the art that the administration of the chemotherapeutic agent may be varied depending on the cancer to be treated and the known effects of the chemotherapeutic agent on that disease. Furthermore, according to the knowledge of the clinician skilled in the art, the therapeutic protocols (e.g., dosage amounts and administration intervals) may be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents.

[0059] Initial administration may be performed according to established protocols known in the art, and then, based on the observed effects, the dosage, modes of administration, and administration times may be modified by the skilled clinician.

[0060] The particular choice of chemotherapeutic agent will depend on the attending physicians' diagnosis and their judgment of the patient's condition and the appropriate treatment protocol. Petition 870260011249, dated 05 / 02 / 2026, page 22 / 233 18 / 73

[0061] Determining the order of administration and the number of repetitions of administration of the chemotherapeutic agent during a treatment protocol is within the knowledge of the versed physician after evaluating the cancer to be treated and the patient's condition.

[0062] Thus, based on experience and knowledge, the practicing physician can modify each protocol for the administration of a chemotherapeutic agent according to the individual needs of the patient as treatment progresses. All such modifications are within the scope of the present invention.

[0063] The anticancer agent may be administered according to therapeutic protocols well known in the art. It will be evident to those skilled in the art that the administration of the anticancer agent may be varied depending on the cancer to be treated and the known effects of the anticancer agent on that disease. Furthermore, according to the knowledge of the clinician skilled in the art, the therapeutic protocols (e.g., dosage amounts and administration intervals) may be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents.

[0064] Initial administration may be performed according to established protocols known in the art, and then, based on the observed effects, the dosage, modes of administration, and administration times may be modified by the skilled clinician.

[0065] The particular choice of anticancer agent will depend on the attending physicians' diagnosis and their judgment of the patient's condition and the appropriate treatment protocol.

[0066] Determining the order of administration and the number of repetitions of administration of the anticancer agent during a protocol Petition 870260011249, dated 05 / 02 / 2026, page 23 / 233 Treatment 19 / 73 is within the knowledge of a skilled physician after evaluating the cancer to be treated and the patient's condition.

[0067] Thus, based on experience and knowledge, the practicing physician can modify each protocol for the administration of an anticancer agent according to the individual needs of the patient as treatment progresses. All such modifications are within the scope of the present invention.

[0068] The attending clinician, in judging whether treatment is effective at the administered dosage, will consider the patient's overall well-being as well as more definitive signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual tumor shrinkage, or inhibition of metastasis. Tumor size can be measured by standard methods such as radiological studies, for example, computed tomography or magnetic resonance imaging, and successive measurements can be used to judge whether tumor growth has been slowed or even reversed. Relief of disease-related symptoms, such as pain and improvement in overall condition, can also be used to help judge the effectiveness of the treatment.

[0069] The compounds, compositions and methods provided in this document are useful for the treatment of cancer. Cancers that can be treated by the compounds, compositions and methods disclosed in this document include, but are not limited to: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell; (3) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, Petition 870260011249, dated 05 / 02 / 2026, page 24 / 233 20 / 73 lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectal; (4) Genitourinary tract: kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); (5) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;(6) Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma tumor, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyofibroma, osteoid osteoma and giant cell tumors; (7) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, meningioma, glioma, sarcoma); (8) Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumoral cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma,; Petition 870260011249, dated 05 / 02 / 2026, p. 25 / 233 21 / 73 unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; (9) Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic wart, lipoma, angioma, dermatofibroma, keloids, psoriasis; and (11) Adrenal glands: neuroblastoma.Examples of cancers that can be treated by the compounds, compositions, and methods of the invention include thyroid cancer, anaplastic thyroid carcinoma, epidermal cancer, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), sarcoma, tetracarcinoma, hepatoma, and multiple myeloma. Thus, the term cancer cell, as used in this document, includes a cell affected by any of the conditions identified above.

[0070] In the treatment of breast cancer (e.g., postmenopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer), the compounds disclosed in this document may be used with an effective amount of at least one anti-hormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH analogs; and optionally an effective amount of at least one chemotherapeutic agent. Examples of aromatase inhibitors include, but are not limited to: Anastrozole (e.g., Arimidex), Letrozole (e.g., Petition 870260011249, dated 05 / 02 / 2026, page 26 / 233 Examples of antiestrogens include, but are not limited to: 22 / 73 (e.g., Femara), Exemestane (Aromasin), Fadrozole, and Formestane (e.g., Lentaron). Examples of antiestrogens include, but are not limited to: Tamoxifen (e.g., Nolvadex), Fulvestrant (e.g., Faslodex), Raloxifene (e.g., Evista), and Acolbifen. Examples of LHRH analogs include, but are not limited to: Goserelin (e.g., Zoladex) and Leuprolide (e.g., Leuprolide Acetate, such as Lupron or Lupron Depot). Examples of chemotherapeutic agents include, but are not limited to: Trastuzumab (e.g., Herceptin), Gefitinib (e.g., Iressa), Erlotinib (e.g., Erlotinib HCl, such as Tarceva), Bevacizumab (e.g., Avastin), Cetuximab (e.g., Erbitux), and Bortezomib (e.g., Velcade).

[0071] Estrogen receptor modulators refers to compounds that interfere with or inhibit estrogen binding to the receptor, regardless of the mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone, and SH646.

[0072] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0073] Androgen receptor modulators refer to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of the mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate. Petition 870260011249, dated 05 / 02 / 2026, p. 27 / 233 23 / 73

[0074] Retinoid receptor modulators refer to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of the mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.

[0075] Cytotoxic / cytostatic agents refers to compounds that cause cell death or inhibit cell proliferation primarily by directly interfering with cell function or inhibit or interfere with cell miosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia-activated compounds, microtubule inhibitors / microtubule-stabilizing agents, mitotic kinesinase inhibitors, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal / anti-hormonal therapeutic agents, hematopoietic growth factors, therapeutic agents targeting monoclonal antibodies, topoisomerase inhibitors, proteasome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.

[0076] Examples of cytotoxic / cytostatic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, dibrospidemioxide chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminodichloro(2-methylpyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum] Petition 870260011249, dated 05 / 02 / 2026, page 28 / 233 24 / 73 (II)]bis[diamine(chloro)platinum (II)]tetrachloride, di-aryzidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarrubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarrubicin, elinafide, MEN10755, 4-desmethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00 / 50032), Raf kinase inhibitors (such as Bay43-9006) and inhibitors mTOR (such as Wyeth's CCI-779).

[0077] An example of a compound that can be activated by hypoxia is tirapazamine.

[0078] Examples of proteasome inhibitors include, but are not limited to, lactacystin and MLN-341 (Velcade).

[0079] Examples of microtubule inhibitors / microtubule stabilizing agents include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleucoblastine, docetaxol, rhizoxine, dolastatin, mivobulin isethionate, auristatin, cemadotine, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoroN-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine, TDX258, the epothilones (see, for example, US Patent 6,284,781 and 6,288,237) and BMS188797. In one example, epothilones are not included among microtubule inhibitors / microtubule stabilizing agents.

[0080] Some examples of topoisomerase inhibitors are topotecan, hypaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'O-exo-benzylidene-chartreusine, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':b,7]indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(Nisopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, Petition 870260011249, dated 05 / 02 / 2026, page 29 / 233 25 / 73 BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4hydroxy-3,5-dimethoxyphenyl]-5,5a,6 ,8,8a,9hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3(methylenedioxy)-5-methyl-7-hydro xi-8-methoxybenzo[c]-phenanthridinium,6,9bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3aminopropylamine)-7,10-di-hydroxy-2-(2-hydroxyethylaminomethyl)-6Hpyrazole-4,15,1-acrydione, N-[1-[2(diethylamino)ethylamino]-7-methoxy9-oxo-9H-thioxanthene-4-ylmethyl]formamide,N-(2(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2(dimethylamino)ethyl]amino]-3-hydroxy-7-H quinoline-7-one, and dimesna.

[0081] Examples of inhibitors of mitotic kinesins and, in particular, the human cytotic kinesin KSP, are described in Publications WO03 / 049527, WO03 / 079973, WO04 / 037171, WO05 / 018638, WO05 / 017190, WO03 / 039460, WO03 / 049679, WO03 / 099211, WO04 / 058148, WO05 / 019206, US2005 / 0176776. WO03 / 050064, WO03 / 049678, WO03 / 105855, WO04 / 058700, WO05 / 019205, WO03 / 050122, WO04 / 039774, WO03 / 106417, WO04 / 126699, WO05 / 018547, For example, mitotic kinesin inhibitors include, but are not limited to, KSP inhibitors, MKLP1 inhibitors, CENP-E inhibitors, MCAK inhibitors, and Rab6-KIFL inhibitors.

[0082] Examples of histone deacetylase inhibitors include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98, and scriptaid. Further reference to other histone deacetylase inhibitors can be found in the following manuscript; Miller, TA et al. J. Med. Chem. 46(24):5097-5116 (2003). Petition 870260011249, dated 05 / 02 / 2026, page 30 / 233 26 / 73

[0083] Inhibitors of kinases involved in mitotic progression include, but are not limited to, aurora kinase inhibitors, Polo-like kinase (PLK) inhibitors; in particular PLK-1 inhibitors, bub-1 inhibitors, and bub-R1 inhibitors. An example of an aurora kinase inhibitor is VX-680 (tozasertib).

[0084] Antiproliferative agents include oligonucleotides of Antisense RNA and DNA, such as G3139, ODN698, GEM231 and INX3001, and antimetabolites, such as enocitabine, carmofur, tegafur, pentostatin, doxyfluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocphosphate, fosteabine sodium hydrate, raltitrexed, paltitrexed, emitefur, thiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecitidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N'(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)tetradecadienoyl]glycylamino]-L-glycero-BL-mannoheptopyranosyl]adenine, aplidin, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidin[5,4-b][1,4]thiazin-6-yl(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, acetic acid ester 11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxyN4-palmitoyl-1-BD-arabino furanosyl cytosine, 3-aminopyridine-2carboxaldehyde thiosemicarbazone and trastuzumab.

[0085] Examples of therapeutic agents targeting monoclonal antibodies include those therapeutic agents that have cytotoxic agents or radioisotopes linked to a cancer cell-specific or target cell-specific monoclonal antibody. Examples include Bexxar.

[0086] HMG-CoA reductase inhibitor refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of inhibitors of Petition 870260011249, dated 05 / 02 / 2026, page 31 / 233 27 / 73 HMG-CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (MEVACOR®; see U.S. Patents 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Patents 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Patents 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Patents 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see US Patents 5,273,995, 4,681,893, 5,489,691 and 5,342,952), rosuvastatin (CRESTOR® US Patent RE37,314) and cerivastatin (also known as rivastatin and BAYCHOL®; see US Patent 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the present methods are described on page 87 of M. Yalpani, Cholesterol Lowering Drugs, Chemistry & Industry, pp. 85-89 (February 5, 1996) and US Patents 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor, as used in this document, includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid), as well as salt and ester forms of compounds that have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of the invention.

[0087] Prenyl-protein transferase inhibitor refers to a compound that inhibits any one or any combination of prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl transferase type I (GGPTase-I), and geranylgeranyl transferase type II (GGPTase-II, also called Rab GGPTase). For an example of the role of a prenyl-protein transferase inhibitor in angiogenesis, see European J. of Cancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

[0088] Angiogenesis inhibitor refers to compounds that inhibit Petition 870260011249, dated 05 / 02 / 2026, page 32 / 233 28 / 73 the formation of new blood vessels, regardless of the mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2) tyrosine kinase receptor inhibitors, epidermal-derived, fibroblast-derived, or platelet-derived growth factor inhibitors, MMP (matrix metalloproteinase) inhibitors, integrin blockers, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, as well as selective cyclooxygenase-2 inhibitors such as celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Ophthalmol., Vol. 108, p. 573). (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p.105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatory drugs (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylprednisolone, betamethasone), carboxiamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagilol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00 / 44777; and WO 00 / 61186).

[0089] Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the present invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Petition 870260011249, dated 05 / 02 / 2026, page 33 / 233 29 / 73 Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins, and carboxypeptidase U inhibitors (also known as thrombin-activated fibrinolysis inhibitor [TAFIa] inhibitors) (see Thrombosis Res. 101:329-354 (2001)). TAFIa inhibitors were described in US No. Ser. 60 / 310,927 (filed August 8, 2001) and 60 / 349,925 (filed January 18, 2002).

[0090] Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA-damaging agents. Such agents include ATR inhibitors, ATM inhibitors, CHK1 and CHK2 kinases, and cdk and cdc kinase inhibitors, and are specifically exemplified by 7-hydroxystaurosporine, flavopiridol, CYC202 (Cyclacel), and BMS-387032.

[0091] Agents that interfere with receptor tyrosine kinases (RTKs) refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3, and c-Met. Other agents include RTK inhibitors as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

[0092] Inhibitors of cell proliferation and survival signaling pathways refers to compounds that inhibit signal transduction cascades downstream of cell surface receptors. Such agents include serine / threonine kinase inhibitors (including, but not limited to, Akt inhibitors, as described in WO 02 / 083064, WO 02 / 083139, WO 02 / 083140, US 2004-0116432, WO 02 / 083138, US 2004 / 0102360, WO 03 / 086404, WO 03 / 086279, WO 03 / 086394, WO 03 / 084473, WO 03 / 086403, WO 2004 / 041162, WO 2004 / 096131, WO Petition 870260011249, dated 05 / 02 / 2026, page 34 / 233 30 / 73 2004 / 096129, WO 2004 / 096135, WO 2004 / 096130, WO 2005 / 100356, WO 2005 / 100344, US 7,454,431, US 7,589,068), Raf kinase inhibitors (e.g., BAY-43-9006), MEK inhibitors (e.g., CI-1040 and PD-098059), mTOR inhibitors (e.g., Wyeth CCI779), and PI3K inhibitors (e.g., LY294002).

[0093] As described above, combinations with NSAIDs are directed toward the use of NSAIDs that are potent COX-2 inhibitors. For the purposes of this specification, an NSAID is potent if it has an IC50 for COX-2 inhibition of 1μM or less, as measured by cellular or microsomal assays.

[0094] The invention also encompasses combinations with NSAIDs that are selective COX-2 inhibitors. For the purposes of this descriptive report, NSAIDs that are selective COX-2 inhibitors are defined as those that have a specificity for inhibiting COX-2 over COX-1 of at least 100 times, as measured by the ratio of COX-2 IC50 to COX-1 IC50 assessed by cellular or microsomal assays. Such compounds include, but are not limited to, those disclosed in U.S. Patent 5,474,995, U.S. Patent 5,861,419, U.S. Patent 6,001,843, U.S. Patent 6,020,343, U.S. Patent 5,409,944, U.S. Patent 5,436,265, U.S. Patent 5,536,752, U.S. Patent 5,550,142, U.S. Patent 5,604,260, U.S. Patent 5,698,584, U.S. Patent 5,710,140, ​​WO 94 / 15932, U.S. Patent 5,344,991, U.S. Patent 5,134,142, U.S. Patent 5,380,738, U.S. Patent 5,393,790, U.S. Patent 5,466,823, U.S. Patent 5,633,272 and U.S. Patent 5,932,598, all of which are incorporated herein by reference.

[0095] COX-2 inhibitors that are particularly useful in the present treatment method are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof. Petition 870260011249, dated 05 / 02 / 2026, page 35 / 233 31 / 73

[0096] Compounds that have been described as specific COX-2 inhibitors and are therefore useful in the present invention include, but are not limited to, the following: rofecoxib, etoricoxib, parecoxib, BEXTRA® and CELEBREX® or a pharmaceutically acceptable salt thereof.

[0097] Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, manopentaose sulfate phosphate, 7,7-(carbonyl-bis [imino-N-methyl-4,2-pyrrolocarbonilymino[N-methyl-4,2-pyrrole]-carbonilymino]-bis-(1,3-naphthalene disulfonate) and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416) or a pharmaceutically acceptable salt thereof.

[0098] As used above, integrin blockers refers to compounds that selectively antagonize, inhibit, or neutralize the binding of a physiological ligand to αvβ3 integrin, to compounds that selectively antagonize, inhibit, or neutralize the binding of a physiological ligand to αγβ5 integrin, to compounds that antagonize, inhibit, or neutralize the binding of a physiological ligand to αvβ3 integrin and to αvβ5 integrin, and to compounds that antagonize, inhibit, or neutralize the activity of particular integrins expressed in capillary endothelial cells. The term also refers to antagonists of αvβ6, α7β8, α1β1, α2β1, α5β1, α6β1, and α6β4 integrins. The term also refers to antagonists of any combination of αγβ3, αvβ5, αγβ6, αvβ8, α1β1, α2β1, α5β1, α6β1 and α6β4 integrins.

[0099] Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allylamino)-17 Petition 870260011249, dated 05 / 02 / 2026, page 36 / 233 32 / 73 desmethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6] benzodiazocin-1-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrole [2,3d]pyrimidinomethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7dimethoxy-quinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974 or a pharmaceutically acceptable salt thereof.

[00100] Combinations with compounds other than anticancer compounds are also covered in current methods. For example, combinations of the presently claimed compounds with PPAR-γ (i.e., PPAR-gamma) and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPARγ and PPAR-δ are peroxisome proliferator-activated receptors γ and δ. The expression of PPAR-γ in endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999; 274:9116-9121; Invest. Oftalmol Vis. Sci. 2000; 41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. Oftamol. 2001; 119:709-717). Examples of PPAR-γ agonists and PPAR-γ / α agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2 Petition 870260011249, dated 05 / 02 / 2026, p. 37 / 233 33 / 73 benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09 / 782,856) and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)2-ethylchromano-2-carboxylic acid (disclosed in USSN 60 / 235,708 and 60 / 244,697), or a pharmaceutically acceptable salt thereof.

[00101] Another example of the present invention is the use of the compounds now disclosed in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies for cancer treatment, see Hall et al., (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et al., (Cancer Medicine, 5th Ed., pp. 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to, p53, which can be distributed via recombinant virus-mediated gene transfer (see U.S. Patent No. 6,069,134, for example), a uPA / uPAR antagonist (Adenovirus-Mediated Delivery of a uPA / uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice, Gene Therapy, August 1998;5(8): 1105-13), and interferon gamma (J. Immunol. 2000;164:217-222).

[00102] The compounds of the present invention can also be administered in combination with an inherent multidrug resistance (MDR) inhibitor, in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include p-glycoprotein (P-gp) inhibitors, such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar), or a pharmaceutically acceptable salt thereof.

[00103] A compound of the present invention can be used in conjunction with antiemetic agents to treat nausea or vomiting, including acute, delayed, late-phase and anticipatory vomiting, which may result from the use of a compound of the present invention, alone or with radiotherapy. For the prevention or treatment of vomiting, a Petition 870260011249, dated 05 / 02 / 2026, p. 38 / 233 The compound of the present invention can be used in conjunction with other antiemetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten, or others as disclosed in US Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, and antidopaminergics, such as phenothiazines (e.g., prochlorperazine, fluphenazine, thioridazine, and mesoridazine), metoclopramide, and dronabinol. In another example, combination therapy with an antiemetic agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist, and a corticosteroid is disclosed for the treatment or prevention of emesis that may result from the administration of these compounds.

[00104] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous activator of the erythropoiesis receptor (such as epoetin alfa).

[00105] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor that regulates the production and function of neutrophils, such as a human granulocyte colony-stimulating factor (G-CSF). Examples of a G-CSF include filgrastim.

[00106] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be administered with an immune-boosting drug, such as levamisole, isoprinosine. Petition 870260011249, dated 05 / 02 / 2026, page 39 / 233 35 / 73 and Zadaxin, or a pharmaceutically acceptable salt thereof.

[00107] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, metyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafilline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfinavir, or a pharmaceutically acceptable salt thereof.

[00108] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for treating or preventing cancer in combination with Pgp and / or BCRP inhibitors including: cyclosporine A, PSC833, GF120918, cremoforEL, fumitremorgine C, Ko132, Ko134, Iressa, imatnib mesylate, EKI-785, Cl1033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, triprostatin A, flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifedipine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinol, or a pharmaceutically acceptable salt thereof.

[00109] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood as including bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include, but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, nedronate, pyridronate and Petition 870260011249, dated 05 / 02 / 2026, page 40 / 233 36 / 73 tiludronate, including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.

[00110] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include, but are not limited to: anastrozole, letrozole and exemestane, or a pharmaceutically acceptable salt thereof.

[00111] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for treating or preventing cancer in combination with siRNA therapy.

[00112] The compounds of the present invention may also be administered in combination with γ-secretase inhibitors and / or NOTCH signaling inhibitors. Such inhibitors include compounds described in WO 01 / 90084, WO 02 / 30912, WO 01 / 70677, WO 03 / 013506, WO 02 / 36555, WO 03 / 093252, WO 03 / 093264, WO 03 / 093251, WO 03 / 093253, WO 2004 / 039800, WO 2004 / 039370, WO 2005 / 030731, WO 2005 / 014553, USSN 10 / 957,251, WO 2004 / 089911, WO 02 / 081435, WO 02 / 081433, WO 03 / 018543, WO 2004 / 031137, WO 2004 / 031139, WO 2004 / 031138, WO 2004 / 101538, WO 2004 / 101539 and WO 02 / 47671 (including LY-450139), or a pharmaceutically acceptable salt thereof.

[00113] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for treating or preventing cancer in combination with PARP inhibitors.

[00114] A compound of the present invention, or a pharmaceutically acceptable salt thereof, may also be useful for the treatment of cancer in combination with the following therapeutic agents: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumab Petition 870260011249, dated 05 / 02 / 2026, page 41 / 233 37 / 73 (Campath®); alitretinoin (Panretin®); halopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzumab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomibe (Velcade®); intravenous busulfan (Busulfex®); oral busulfan (Myleran®); calusteron (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 implant (Gliadel Wafer®); celecoxibe (Celebrex®); cetuximabe (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); lipoxomic cytarabine (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); liposomal daunorubicin (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileucine diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); liposomal doxorubicin (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution®; epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intra-arterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); Petition 870260011249, dated 05 / 02 / 2026, page 42 / 23338 / 73 gosserelin acetate (Zoladex Implant®); gosserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); ibritumomabe tiuxetan (Zevalin®); idarrubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alpha 2a (Roferon A®); Interferon alpha-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); leuprolide acetate (Eligard®); levamisol (Ergamisol®); lomustine, CCNU (CeeBU®); mechlorethamine, nitrogênio mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxysalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrona (Novantrone®); nandrolona fenpropionate (Durabolin50®); nelarabine (Arranon®); Nofetumomabe (Verluma®); Oprelvecin (Neumega®); oxaliplatin (Eloxatin®);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobromane (Vercyte®); plicamycin, mithramycin (Mithracin®); sodium porfimer (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab / I-131 tositumomab (Bexxar®); Petition 870260011249, dated 05 / 02 / 2026, page 43 / 233 39 / 73 Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); uracil mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®), or a pharmaceutically acceptable salt thereof.

[00115] In one example, the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an epidermal-derived growth factor inhibitor, a fibroblast-derived growth factor inhibitor, a platelet-derived growth factor inhibitor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxiamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetylcarbonyl)-fumagilol, thalidomide, angiostatin, troponin-1, or an antibody to VEGF. In one example, the estrogen receptor modulator is tamoxifen or raloxifene, or a pharmaceutically acceptable salt thereof.

[00116] Thus, the scope of the present invention encompasses the use of the compounds presently claimed in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPARγ agonists, PPAR-δ agonists, an inhibitor of inherent multidrug resistance, an antiemetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immune-boosting drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an agent Petition 870260011249, dated 05 / 02 / 2026, page 44 / 233 40 / 73 siRNA therapeutic agents, γ-secretase and / or NOTCH inhibitors, receptor tyrosine kinase (RTK) interfering agents, a cell cycle checkpoint interfering agent, and any of the therapeutic agents listed above.

[00117] Also included in the scope of the claims is a method of treating cancer comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with radiotherapy and / or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxicostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitor of inherent multidrug resistance, an antiemetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immune response-enhancing drug,A cell proliferation and survival signaling inhibitor, a bisphosphonate, an aromatase inhibitor, a therapeutic siRNA, γsecretase and / or NOTCH inhibitors, receptor tyrosine kinase (RTK) interfering agents, a cell checkpoint interfering agent, and any of the therapeutic agents listed in this document.

[00118] Yet another example of the invention is a method of treating cancer comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with paclitaxel or trastuzumab.

[00119] The invention also covers a method of treatment or Petition 870260011249, dated 05 / 02 / 2026, page 45 / 233 41 / 73 cancer prevention comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof.

[00120] The therapeutic combination disclosed in this document may be used in combination with one or more other active agents, including, but not limited to, other anticancer agents that are used in the prevention, treatment, control, improvement, or risk reduction of a specific disease or condition (e.g., cell proliferation disorders). In one embodiment, a compound disclosed in this document is combined with one or more other anticancer agents for use in the prevention, treatment, improvement, control, or risk reduction of a specific disease or condition for which the compounds disclosed in this document are useful. Such other active agents may be administered, by a route and in an amount commonly used for the same, before, contemporaneously, or sequentially with a compound of this disclosure.

[00121] The present invention also includes a pharmaceutical composition useful for treating or preventing cancer comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, a cell proliferation and survival signaling inhibitor, a bisphosphonate, an aromatase inhibitor, Petition 870260011249, dated 05 / 02 / 2026, page 46 / 233 42 / 73 a siRNA therapeutic, γ-secretase and / or NOTCH inhibitors, receptor tyrosine kinase (RTK) interfering agents, a cell cycle checkpoint interfering agent, and any of the therapeutic agents listed above.

[00122] The present invention includes compounds disclosed in this document, as well as pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors of the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

[00123] The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt. The term pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds covered by the term pharmaceutically acceptable salt refer to non-toxic salts of the compounds of the invention that are generally prepared by reacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, 4-bromobenzenesulfonate, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclohexylamidosulfonate, cyclopentane propionate, diethylacetic acid, digluconate, dihydrochloride, dodecylsulfonate, edetate, edisylate, estolate, esilate, ethanesulfonate, formic acid, fumarate, gluceptate, glucoheptanoate, gluconate, glucuonate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylrescinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic acid, isothionate, lactate, lactobionate. Petition 870260011249, dated 05 / 02 / 2026, page 47 / 233 43 / 73 laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, ammonium salt, N-methylglucamine, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoaclate, thiocyanate, tosylate, trietiodide, trifluoroacetate, trifluoromethylsulfonate, ptoluenesulfonate, undeconate, valerate and the like.

[00124] Furthermore, where the compounds of the invention have an acidic fraction, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamic, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.

[00125] With basic reagents, such as hydroxides, carbonates, hydrogen carbonates, alkoxides and ammonia, organic bases or, alternatively, basic amino acids, the compounds disclosed in this document form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. Pharmaceutically acceptable salts derived from non-toxic organic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, ornithine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, Petition 870260011249, dated 05 / 02 / 2026, page 48 / 233 44 / 73 trimethylamine, tripropilamine, trometamol, tromethamine and the like. In addition, basic nitrogen-containing groups are included that can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides, such as benzyl and phenethyl bromides and others.

[00126] The preparation of pharmacologically acceptable salts of salt-forming compounds disclosed in this document, including their stereoisomeric forms, is carried out by known methods, for example, by mixing a compound of the present invention with an equivalent amount of a solution containing a desired acid, base or the like, and then collecting the desired salt by filtering the salt or distilling the solvent. The compounds of the present invention and their salts can form solvates with a solvent such as water, ethanol or glycerol. The compounds of the present invention can form an acid addition salt and a base addition salt simultaneously according to the type of side chain substituent.

[00127] The present invention encompasses all stereoisomeric forms of the compounds disclosed in this document. When linkages to the chiral carbon are represented as straight lines in the structural formulas of the invention, it is understood that both (R) and (S) configurations of the chiral carbon, and consequently both enantiomers and mixtures thereof, are encompassed by the compounds. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both (R) and (S) configurations of the chiral carbon, and therefore individual enantiomers and mixtures thereof, are encompassed by the name. The production of specific stereoisomers or mixtures of Petition 870260011249, dated 05 / 02 / 2026, p. 49 / 233 45 / 73 themselves can be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of the invention.

[00128] Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. When the compounds of the invention are capable of tautomerization, all individual tautomers, as well as their mixtures, are included within the scope of the invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such isomers and tautomers and mixtures thereof.

[00129] In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variations of the compounds specifically and generically described. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enrichment to deuterium may provide certain therapeutic advantages, such as increasing the in vivo half-life or reducing dosage requirements, or it may provide a useful compound as a standard for characterization of biological samples.Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes of. Petition 870260011249, dated 05 / 02 / 2026, page 50 / 233 46 / 73 general process and examples in this document using appropriate isotopically enriched reagents and / or intermediates.

[00130] Furthermore, the compounds of the present invention may exist in amorphous form and / or one or more crystalline forms and, as such, all amorphous and crystalline forms and mixtures thereof of the compounds disclosed in this document are intended to be included within the scope of the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly pharmaceutically acceptable solvates and hydrates, of the present compounds are also encompassed within the scope of the invention, along with non-solvated and anhydrous forms.

[00131] The present invention includes compounds disclosed herein, as well as salts thereof, particularly pharmaceutically acceptable salts, solvates of such compounds and solvated salt forms thereof, where such forms are possible, unless otherwise specified.

[00132] Commonly used abbreviations for alkyl groups are used throughout the descriptive report, for example, methyl may be represented by conventional abbreviations including Me or CH3 or a symbol that is an extended bond as the terminal group, for example, ethyl may be represented by Et or CH2CH3, propyl may be represented by “Pr” or CH2CH2CH3, butyl may be represented by Bu or CH2CH2CH2CH3, etc. C1-4 alkyl (or C1-C4 alkyl), for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. For example, the structures hn^CH3 and hn the. have equivalent meanings. C1-4 alkyl includes n-, iso-, sec-, and t-butyl, ne-isopropyl, ethyl, and methyl. If no number is specified, 1-4 atoms Petition 870260011249, dated 05 / 02 / 2026, p. 51 / 233 47 / 73 of the carbon atoms are destined for linear or branched alkyl groups.

[00133] Furthermore, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl or pivaloyloxymethyl derivatives or acyl alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, may be used. These esters and acyl groups known in the art are included for modifying solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[00134] If the compounds disclosed in this document contain both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The salts can be obtained from the compounds disclosed in this document by conventional methods known to those skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anionic exchange or cationic exchange of other salts. The present invention also includes all salts of the compounds disclosed in this document which, due to low physiological compatibility, are not directly suitable for use in pharmaceutical products, but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts.

[00135] The invention also includes derivatives of the compounds disclosed in this document, acting as prodrugs and solvates. Any pharmaceutically acceptable prodrug modification of a compound of the invention that results in in vivo conversion into a compound within the scope of the invention is also within the scope of the invention. Prodrugs, after administration to the patient, are converted in the body by normal metabolic or chemical processes, such as through hydrolysis in the blood, into the disclosed compounds. Petition 870260011249, dated 05 / 02 / 2026, page 52 / 233 48 / 73 in this document. Such prodrugs include those that demonstrate enhanced bioavailability, tissue specificity, and / or cellular distribution, to improve the drug uptake of the compounds disclosed in this document. The effect of such prodrugs may result from the modification of physicochemical properties, such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the drug's permeation properties. For example, esters may optionally be made by esterification of an available carboxylic acid group or by forming an ester at an available hydroxyl group in a compound. Similarly, labile amides may be made.Pharmaceutically acceptable esters or amides of the compounds of the invention can be prepared to act as prodrugs that can be hydrolyzed back to an acid (or -COO- depending on the pH of the fluid or tissue where the conversion occurs) or hydroxyl form, particularly in vivo, and as such are encompassed within the scope of the invention. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C1-6 alkyl esters and -C1-6 alkyl substituted by phenyl esters.

[00136] When any variable occurs more than once in any constituent or in the schemes disclosed in this document, its definition in each occurrence is independent of its definition in all other occurrences. Furthermore, combinations of substituents and / or variables are permitted only if these combinations result in stable compounds.

[00137] Except where indicated, the term halogen means fluorine, chlorine, bromine or iodine.

[00138] Where the ring atoms are represented by variables such as X, for example, Petition 870260011249, dated 05 / 02 / 2026, page 53 / 233 49 / 73 The variables are defined by indicating the atom located at the variable position in the ring without representing the ring bonds associated with the atom. For example, when X in the ring above is nitrogen, the definition will show N and will not represent the bonds associated with it, for example, it will not show =N-. Similarly, when X is a carbon atom that is replaced by bromide, the definition will show C-Br and will not represent the bonds associated with it, for example, it will not show "tf — C-Br". II.

[00139] The invention also relates to medicaments containing at least one compound of those disclosed in this document and / or a pharmaceutically acceptable salt of the compound and an optionally stereoisomeric form of the compound or a pharmaceutically acceptable salt of the stereoisomeric form of the compound, together with a pharmaceutically acceptable vehicle, carrier, additive and / or other active and auxiliary substances.

[00140] The medicines according to the invention can be administered by oral, inhalation, rectal or transdermal administration or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating endoprostheses (stents) with compounds disclosed in this document and other surfaces that come into contact with blood in the body is possible.

[00141] The invention also relates to a process for the production of a medicament, comprising bringing at least one compound disclosed in this document into a suitable administration form using a pharmaceutically acceptable carrier and, Petition 870260011249, dated 05 / 02 / 2026, page 54 / 233 50 / 73 optionally, other suitable active substances, additives or excipients.

[00142] Suitable solid or galenic preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, injectable drops or solutions and preparations with prolonged release of active substance, in whose preparation usual excipients, such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. The commonly used auxiliaries that can be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents, such as, for example, sterile water and mono- or polyhydric alcohols, such as glycerol.

[00143] The dosage regimen using the compounds is selected according to a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or its salt that will be used. A physician or veterinarian skilled in the art can readily determine and prescribe the effective amount of drug needed to prevent, contain or halt the progression of the condition.

[00144] Oral dosages of the compounds, when used for the indicated effects, will vary from about 0.01 mg per kg of body weight per day (mg / kg / day) to about 30 mg / kg / day, preferably 0.025-7.5 mg / kg / day, more preferably 0.1-2.5 mg / kg / day and most preferably 0.1-0.5 mg / kg / day (unless otherwise specified). Petition 870260011249, dated 05 / 02 / 2026, page 55 / 233 51 / 73 Alternatively, the quantities of active ingredients are on a free basis. For example, an 80 kg patient would receive between approximately 0.8 mg / day and 2.4 g / day, preferably 2-600 mg / day, more preferably 8200 mg / day, and most preferably 8-40 mg / kg / day. A properly prepared once-daily medication would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, for example, 8 mg, 10 mg, 20 mg, and 40 mg. Advantageously, the compounds can be administered in divided doses two, three, or four times a day. For twice-daily administration, a properly prepared medication would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably between 4 mg and 20 mg, for example, 4 mg, 5 mg, 10 mg and 20 mg.

[00145] Intravenously, the patient would receive the active ingredient in quantities sufficient to distribute from approximately 0.01 mg per kg of body weight per day (mg / kg / day) to approximately 30 mg / kg / day, preferably 0.025-7.5 mg / kg / day, more preferably 0.1-2.5 mg / kg / day and even more preferably 0.1-0.5 mg / kg / day. Such quantities may be administered in several suitable ways, for example, large volumes of low concentrations of active ingredient over a prolonged period or several times a day, small volumes of high concentrations of active ingredient over a short period, for example, once a day. Typically, a conventional intravenous formulation can be prepared containing an active ingredient concentration between approximately 0.01–1.0 mg / ml, for example, 0.1 mg / ml, 0.3 mg / ml, and 0.6 mg / ml, and administered in daily amounts between 0.01 ml / kg of patient weight and 10.0 ml / kg of patient weight, for example, 0.1 ml / kg, 0.2 ml / kg, 0.5 ml / kg. Petition 870260011249, dated 05 / 02 / 2026, page 56 / 233 52 / 73 For example, an 80 kg patient receiving 8 ml twice daily of an intravenous formulation with an active ingredient concentration of 0.5 mg / ml receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid, or any pharmaceutically acceptable acid / base conjugate with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. The choice of the appropriate buffer and pH of a formulation, depending on the solubility of the drug to be administered, is readily made by a person skilled in the art.

[00146] The compounds of the invention can be prepared using reactions as shown in the following Reaction Schemes, in addition to other standard manipulations known from the literature or exemplified in experimental procedures. The illustrative Reaction Schemes below are therefore not limited by the listed compounds or any particular substituents employed for illustrative purposes. Methods for preparing the compounds of the invention General Methods

[00147] The compounds of the present invention can be readily produced from known compounds or commercially available compounds by, for example, known processes described in published documents and produced by production processes described below. The present invention is not limited to the production processes described below. The invention also includes processes for the preparation of compounds of the invention.

[00148] It should be noted that when a compound disclosed in this document has a reactive group, such as a hydroxyl group, amino group, carboxyl group, or thiol group as its substituent, such group may be suitably protected with a protecting group at each step of Petition 870260011249, dated 05 / 02 / 2026, page 57 / 233 53 / 73 reaction and the protecting group can be removed at a subsequent stage. The process of such introduction and removal of the protecting group can be appropriately determined depending on the group to be protected and the type of protecting group, and such introduction and removal are conducted, for example, by the process described in the review section of Greene, TW, et al., “Protective Groups in Organic Synthesis”, 2007, 4th Ed., Wiley, New York, or Kocienski, P., “Protecting Groups” 1994, Thieme.

[00149] It should be noted that if there is a discrepancy between the chemical name and the structure, the structure is understood to prevail.

[00150] The present invention is not limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrations of a few aspects of the invention, and any embodiments that are functionally equivalent are within the scope of this invention. In fact, various modifications of the invention beyond those shown and described herein will become apparent to those skilled in the relevant art and will be within the scope of the appended claims.

[00151] All solvents used were commercially available and were used without further purification. The reactions were typically carried out using anhydrous solvents under an inert nitrogen atmosphere.

[00152] The raw materials used were available from commercial sources or prepared according to procedures in the literature and had experimental data consistent with those reported.

[00153] The abbreviations used are the conventional ones in the technique of the following. ACN acetonitrile Ar Aril Aq. Aqueous Petition 870260011249, dated 05 / 02 / 2026, page 58 / 233 54 / 73 BSA bovine serum albumin Boc tert-butyloxycarbonyl protecting group BrettPhos G3 [(2-Di-cyclohexylphosphine-3,6dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'biphenyl)]palladium(II) methanesulfonate °C degree Celsius CDCl3 deuterated chloroform CD3OD deuterated methanol CHCl3 chloroform Cs2CO3 cesium carbonate DCM dichloromethane DIEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DTT dithiothreitol EtOAc ethyl acetate EtOH ethanol g gram h hour(s) H2 Hydrogen H2O Water HATU N-[(Dimethylamino)-I H-1,2,3-triazolo-[4,5-b ]pyridin-1-ylmethylene]-N-methylmethammonium hexafluorophosphate N-oxide HCl hydrochloric acid High-Performance Liquid Chromatography (HPLC) K2CO3 potassium carbonate L Liter LCMS liquid chromatography and mass spectrometry LiBr lithium bromide Petition 870260011249, dated 05 / 02 / 2026, page 59 / 233 55 / 73 M molar MHz Megahertz MeCN Acetonitrile MeOH methanol MS mass spectrometry MsCl methanesulfonyl chloride mmol millimol mg milligram min minute(s) mL milliliter(s) N2 nitrogen NaH sodium hydride NaHCO3 Sodium bicarbonate NaI sodium iodide NaOH Sodium hydroxide NBS N-bromosuccinimide nM nanomolar NMP N-methyl-2-pyrrolidone N normal NH3 H2O ammonia in water NH4OH ammonium hydroxide NMR nuclear magnetic resonance Pd / C or Pd-C palladium on carbon PdCl2(dppf) [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium(II) Pet Ether. petroleum ether psi pounds per square inch rt room temperature saturates SM starting material SFC supercritical fluid chromatography Petition 870260011249, dated 05 / 02 / 2026, page 60 / 233 56 / 73 tBuOK tert-potassium butoxide (or t-BuOK) T3P propylphosphonic anhydride TBAB tetrabutylammonium bromide TEA triethylamine TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid THF tetrahydrofuran TLC thin-layer chromatography Prep. TLC Preparative TLC TMSCBrF2 (bromodifluoromethyl)trimethylsilane μL microliter vol volume General Synthetic Schemes

[00154] Although the present invention has been described in conjunction with the specific examples presented above, many alternatives, modifications, and variations thereof will be apparent to those skilled in the art. In some cases, the order of carrying out the steps in the reaction schemes may be varied to facilitate the reaction or to avoid undesirable reaction products. All such alternatives, modifications, and variations are intended to fall within the meaning and scope of the present invention. The primary and intermediate materials are obtained from commercial sources, produced using known procedures, or are otherwise illustrated.

[00155] Various methods for preparing the compounds of this invention are described in the following Schemes and Examples. Unless otherwise indicated, all variables are as defined above. In all general schemes, Ar means an optionally substituted aryl or heteroaryl moiety. Diagram 1: Petition 870260011249, dated 05 / 02 / 2026, page 61 / 233 57 / 73 Ar-C02H amine HATU Base amine, HATU or T3P

[00156] In Scheme 1, optionally substituted hydroxypiperidines 1 can be coupled to an optionally substituted aryl or heteroaryl carboxylic acid using standard amide coupling conditions to provide amide 2. R2 is hydrogen. R3 is hydrogen. R9 is hydrogen. Scheme 2:

[00157] In Scheme 2, optionally substituted bromopyridines 3 can be crossed with substituted amines in the presence of a metal catalyst to generate compounds of form 4. W) W2é SYNTHESIS OF INTERMEDIARIES Intermediate 1: OS^SM-O^-dihydroisoquinolin^dHj-iDpiperidin-S-ol Petition 870260011249, dated 05 / 02 / 2026, page 62 / 233 58 / 73 TEA, MSCI toluene TFA, NBS, NaOH H2O, toluene Intermediate 1 Step 1: To a solution of 1-benzylpiperidin-4-ol (200 g, 1.05 mol) in toluene (1.6 L), TEA (175 mL, 1.25 mol) was added dropwise at 25 °C. MsCl (97.1 mL, 1.25 mol) was added dropwise to the mixture slowly at 0 °C. The mixture was stirred at 25 °C for 2 h. Water (750 mL) was added to the mixture. The organic layer was washed with water (2 x 400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-benzylpiperidin-4-yl methanesulfonate, which was used without further purification.

[00158] Step 2: To a solution of 1-benzylpiperidin-4-yl methanesulfonate (280 g, 1.04 mol) in DMA (800 mL) was added tBuOK (175 g, 1.56 mol) in portions at 25 °C. The mixture was stirred at 45 °C for 8 h. The reaction was stopped with water (1.0 L) and the mixture was extracted with EtOAc (600 mL x 3). The organic layer was washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-benzyl-1,2,3,6-tetrahydropyridine as a solid. This material was used without further purification.1H NMR (400 MHz, CDCh) δ 7.28-7.14 (m, 5H), 5.68-5.65 (m, 1H), 5.59-5.55 (m, 1H), 3.50 (s, 2H), 2.91-2.87 (m, 2H), 2.49-2.46 (m, 2H), 2.10-2.06 (m, 2H).

[00159] Step 3: To a solution of 1-benzyl-1,2,3,6-tetrahydropyridine (160 g, 924 mmol) in water (1.0 L), TFA (68.4 mL, 924 mmol) was added dropwise at 25 °C. NBS (197 g, 1.11 mol) was added to the mixture in portions slowly at 25 °C. The mixture was stirred at 45 Petition 870260011249, dated 05 / 02 / 2026, p. 63 / 233 59 / 73 °C for 12 h. Toluene (1.2 L) at 25 °C was added to the mixture, followed by a solution of NaOH (240 g, 6.00 mol) in H2O (260 mL). The mixture was heated to 45 °C for 1 h. The aqueous layer was extracted with EtOAc (1.2 L x 2), and the combined organic layers were washed with brine (2 x 1.0 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-15% ethyl acetate / petroleum ether gradient) to yield 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane as an oil, which was used without further purification.

[00160] Step 4: LiBr (66.1 g, 761 mmol) was added to a solution of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane (80 g, 423 mmol) in ACN (600 mL) in portions at 25 °C. The mixture was stirred at 30 °C for 0.5 h. 1,2,3,4-tetrahydroisoquinoline (53.1 mL, 423 mmol) was added to the mixture in portions slowly at 25 °C. The mixture was stirred at 30 °C for 10 h. Water (250 mL) and EtOAc (250 mL) were added to the mixture. The combined organic layers were washed with brine (2 x 250 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (60% ethyl acetate / petroleum ether gradient) to yield trans-1-benzyl-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol as an oil.1H NMR (400 MHz, CDCla) δ 7.28-7.21 (m, 5H), 7.10-7.07 (m, 3H), 7.07-6.97 (m, 1H), 3.91-3.87 (m, 1H), 3.72-3.64 (m, 2H), 3.54-3.52 (m, 2H), 3.20-3.15 (m, 1H), 3.03-2.99 (m, 1H), 2.98-2.96 (m, 1H), 2.87-2.84 (m, 2H), 2.61-2.58 (m, 1H), 2.37-2.30 (m, 1H), 1.97-1.96 (m, 1H), 1.89-1.83 (m, 1H), 1,731.69 (m, 1H), 1.61-1.55 (m, 1H).

[00161] Step 5: A solution of trans-1-benzyl-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (90 g, 279 mmol) in MeOH (800 mL) was added to a bottle containing Pd-C (10% by weight; 40 g) under a N2 atmosphere. The mixture was degassed and filled. Petition 870260011249, dated 05 / 02 / 2026, page 64 / 233 60 / 73 again with H2 (three times). The resulting mixture was stirred under H2 (50 psi) at 50 °C for 6 h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (water / ACN with ammonium hydroxide modifier at 0.05%) to give trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (Intermediate 1) as an oil, which could be used in subsequent reactions. MS: 233 (M + 1).

[00162] Trans-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol was purified by chiral SFC (Chiralpak AD-H column, isopropanol / CO2) to give two products as solids: Intermediário 1 (pico 1): (3 S ,4 S )-4-(3,4-di-hidroisoquinolin-2(1H)il)piperidin-3-ol. 1H NMR (400 MHz, DMSO-d6) δ 7,10-7,01 (m, 4H), 4,16 (br s, 1H), 3,85-3,71 (m, 2H), 3,48-3,46 (m, 1H), 3,02-2,91 (m, 1H), 2,892,88 (m, 2H), 2,79-2,73 (m, 3H), 2,39-2,35 (m, 2H), 2,22-2,19 (m, 1H), 2,0 (br s, 1H), 1,70-1,65 (m, 1H), 1,37-1,30 (m, 1H) Pico 2: (3RJ4R)-4-(3J4-di-hidroisoquinoljni-2X1H)-iJ)pipeT^^ NMR (400 MHz, DMSO-d6) δ 7,15-7,01 (m, 4H), 4,18 (br s, 1H), 3,863,72 (m, 2H), 3,49-3,47 (m, 1H), 3,01-2,90 (m, 1H), 2,90-2,89 (m, 2H), 2,80-2,72 (m, 3H), 2,39-2,35 (m, 2H), 2,21-2,20 (m, 1H), 2,0 (br s, 1H), 1,70-1,65 (m, 1H), 1,38-1,31 (m, 1H). Intermediário 2: ácido 6-(2J2-difluorociclopropil)imidazo[1J2-a]pirimidina2-carboxílico 1 ,F ,γ1 2 κ+FX Br Cs2CO3, PdCI2(dppf) 1 THF, water i> 9 Br^íO^ N NH2 Ο θ F _ í| q Dioxane, 80 °C \ * FV 2) SFC 5 FNC| 1) Bis(4-methoxybenzyl)amine yc TMSCBrF2, TBAB rf YD|EA, NMP 110 °C Toluene, 110 °C fA-Y^N 2) TFA, DCM, TfOH 3 4 V 7 (first elution) Ηα«γ V intermediate 2 8 (second elution) Petition 870260011249, dated 05 / 02 / 2026, p. 65 / 233 61 / 73 Step 1: To a solution of 5-bromo-2-chloropyrimidine (200 mg, 1.03 mmol) in THF (5 mL) and water (1 mL) was added potassium trifluoro(vinyl)borate (230 mg, 1.55 mmol), CS2CO3 (1010 mg, 3.10 mmol) and PdCl2(dppf) (151 mg, 0.207 mmol). The reaction mixture was stirred at 85 °C for 2 h under a nitrogen atmosphere. The reaction was cooled to room temperature and treated with water. The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (3% ethyl acetate / petroleum ether) to provide 2-chloro-5-vinylpyrimidine as a solid. MS: 141 (M + 1).

[00163] Step 2: A mixture of tetrabutylammonium bromide (0.193 g, 0.598 mmol), 2-chloro-5-vinylpyrimidine (1.4 g, 10 mmol) and (bromodifluoromethyl)trimethylsilane (6.07 g, 29.9 mmol) in toluene (5 mL) was stirred at 110 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (10 / 1 to 5 / 1 v / v petroleum ether / ethyl acetate) to yield 2-chloro-5-(2,2-difluorocyclopropyl)pyrimidine as a solid. MS: 191 (M + 1.1H NMR (400 MHz, CDCl3) δ 8.51 (s, 2H), 2.79 - 2.60 (m, 1H), 2.08 - 1.98 (m, 1H), 1.76 - 1.62 (m, 1H).

[00164] Step 3: A mixture of DIEA (9.6 mL, 55 mmol), bis(4-methoxybenzyl)amine (9.5 g, 37 mmol), and 2-chloro-5-(2,2-difluorocyclopropyl)pyrimidine (3.5 g, 18 mmol) in NMP (70 mL) was heated to 110 °C for 12 h. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (5% ethyl acetate / petroleum ether) to provide 5-(2,2-difluorocyclopropyl)-N,N Petition 870260011249, dated 05 / 02 / 2026, page 66 / 233 62 / 73 bis(4-methoxybenzyl)pyrimidin-2-amine as an oil. MS: 412 (M + 1).

[00165] Step 4: A mixture of 5-(2,2-difluorocyclopropyl)-N,Nbis(4-methoxybenzyl)pyrimidin-2-amine (6.0 g, 15 mmol) in DCM (10 mL), TFA (10 mL) and TfOH (0.1 mL) was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure and the residue was dissolved in water (50 mL) and basified with NH3H2O ​​to pH ~10. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (100 / 1 to 1 / 3, v / v petroleum ether / ethyl acetate) to provide 5-(2,2-difluorocyclopropyl)pyrimidin-2-amine as a solid. MS: 172 (M + 1).

[00166] Step 5: A mixture of 5-(2,2-difluorocyclopropyl)pyrimidin2-amine (1.5 g, 8.8 mmol) and ethyl 3-bromo-2-oxopropanoate (2.96 g, 11.4 mmol) in dioxane (20 mL) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (ACN / water with 0.1% TFA modifier) ​​to provide ethyl 6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidine-2-carboxylate. The racemic mixture was purified by chiral SFC (OD column, 20-30% EtOH / CO2) to yield ethyl 6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidine-2-carboxylate (isomer 1, first elution) as a solid. MS: 268 (M + 1) and ethyl 6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidine-2-carboxylate (isomer 2, second elution) as a solid. MS: 268 (M + 1).

[00167] Step 6: A solution of ethyl 6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidine-2-carboxylate (isomer 1, first elution) (180 mg, 0.674 mmol) in HCl (35% in water, 5 mL) was stirred at 70 °C for 12 h. The mixture was cooled to room temperature. Petition 870260011249, dated 05 / 02 / 2026, page 67 / 233 63 / 73 ambient, concentrated under reduced pressure to provide 6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidine-2-carboxylic acid as a solid, which was used in the next step without further purification. MS: 240 (M + 1). Note that both isomers can be hydrolyzed under the conditions described above. Intermediate 3: 6-cyclopropylimidazo[1,2-a]pyrimidine-2-carboxylic acid OH PdCl2(dppf), K2CO3 THF, water, 80 °C EtOH, 80°C HCl, 80°C Intermediate 3 Step 1: To a mixture of 5-bromopyrimidin-2-amine (2.0 g, 12 mmol) in THF (15 mL) and water (3 mL) was added K2CO3 (4.77 g, 34.5 mmol), cyclopropylboronic acid (4.94 g, 57.5 mmol) and PdCb(dppf) (0.841 g, 1.15 mmol). The mixture was degassed and refilled with N2 (3x), and the reaction was stirred at 80 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-45% ethyl acetate / petroleum ether) to provide 5-cyclopropylpyrimidin-2-amine as a solid. MS: 136 (M + 1).

[00168] Step 2: To a mixture of 5-cyclopropylpyrimidin-2-amine (3.5 g, 26 mmol) in EtOH (50 mL) was added ethyl 3-bromo-2-oxopropanoate (6.1 g, 31 mmol). The mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature and TEA (7.2 mL, 52 mmol) was added. The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (60% ethyl acetate / petroleum ether) to give ethyl 6-cyclopropylimidazo[1,2a]pyrimidine-2-carboxylate as a solid. MS: 232 (M + 1.1H NMR (500 MHz, CDCh) δ 8.50 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.0 Hz, Petition 870260011249, dated 05 / 02 / 2026, p. 68 / 233 64 / 73 1H), 8.04 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.03 - 1.87 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.12 - 1.04 (m, 2H), 0.80 - 0.72 (m, 2H).

[00169] Step 3: A mixture of ethyl 6-cyclopropylimidazo[1,2a]pyrimidine-2-carboxylate (100 mg, 0.432 mmol) in HCl (4 M in dioxane, 2 mL) was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and concentrated under reduced pressure to provide 6-cyclopropylimidazo[1,2a]pyrimidine-2-carboxylic acid as a solid, which was used in the next step without purification. MS: 204 (M + 1). Intermediate 4: 6-bromo-7-ethylimidazo[1,2-a]pyrimidine-2-carboxylic acid Br^N NH2 C| PMB Nal, NaH, DMF^ y-PMB PdCl2(dppf), CS2CO3 Dioxane, water, 100 °C nbs, chci3 N nh2Dioxane, 80 °C Br γ OH O o THE Intermediate 4

[00170] Step 1: To a mixture of 4-bromopyrimidin-2-amine (1 g, 5.8 mmol) and sodium iodide (0.086 g, 0.58 mmol) in DMF (20 mL) were added to NaH (0.575 g, 14.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then 1-(chloromethyl)-4-methoxybenzene (1.98 g, 12.6 mmol) was added. The reaction was stirred at room temperature for 30 min. The mixture was stopped with saturated aqueous ammonium chloride solution (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (10% ethyl acetate / petroleum ether) to provide 4-bromo-N,N-bis(4-methoxybenzyl)pyrimidin2-amine as an oil. MS: 414 and 416 (M + 1).

[00171] Step 2: A mixture of 4-bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine (2 g, 4.8 mmol), ethylboronic acid (1.07 Petition 870260011249, dated 05 / 02 / 2026, page 69 / 233 65 / 73 g, 14.5 mmol), PdCh(dppf) (0.71 g, 0.96 mmol) and CS2CO3 (3.15 g, 9.65 mmol) in 1,4-dioxane (10 mL) and water (10 mL) was stirred at 100 °C under a N2 atmosphere for 10 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography (10% ethyl acetate / petroleum ether) to give 4-ethyl-N,N-bis(4-methoxybenzyl)pyrimidin-2amine as an oil. MS: 364 (M + 1.1H NMR (500 MHz, CDCh) δ 8.29 (d, J = 5.04 Hz, 1H), 7.30 - 7.24 (m, 4H), 6.94 - 6.89 (m, 4H), 6.48 (d, J = 5.04 Hz, 1H), 4.86 (s, 4H), 3.90 - 3.84 (m, 6H), 2.77 - 2.63 (m, 2H), 1.33 (t, J = 7.63 Hz, 3H).

[00172] Step 3: A mixture of 4-ethyl-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine (900 mg, 2.48 mmol) in TFA (5 mL) was stirred at 40°C for 12 h. The mixture was cooled to room temperature and stopped with NH3^H2O at ~pH 7. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (30-60% ethyl acetate / petroleum ether) to provide 4-ethylpyrimidin-2-amine as a solid. MS: 124 (M + 1.1H NMR (400 MHz, CDCh) δ 8.17 (d, J = 4.82 Hz, 1H), 6.50 (d, J = 5.26 Hz, 1H), 5.04 (br s, 2H), 2.59 (q, J = 7.75 Hz, 2H), 1.24 (t, J = 7.67 Hz, 3H).

[00173] Step 4: To a solution of 4-ethylpyrimidin-2-amine (200 mg, 1.62 mmol) in chloroform (4 mL) was added NBS (318 mg, 1.79 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica (10-80% ethyl acetate / petroleum ether) to provide 5-bromo-4-ethylpyrimidin-2-amine as a solid. MS: 202 and 204 (M + 1.1H NMR (400 MHz, CDCh) δ 8.22 (s, 1H), 5.00 (br s, 2H), 2.74 (q, J = 7.45 Hz, 2H), 1.23 (t, J = 7.67 Hz, 3H).

[00174] Step 5: To a solution of 5-bromo-4-ethylpyrimidin-2-amine Petition 870260011249, dated 05 / 02 / 2026, page 70 / 233 66 / 73 (100 mg, 0.495 mmol) in 1,4-dioxane (3 mL) was added to 3-bromo-2-oxopropanoic acid (99 mg, 0.59 mmol). The reaction was stirred at 80 °C for 15 min. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (ACN / water with TFA modifier at 0.1%) to provide 6-bromo-7-ethylimidazo[1,2-a]pyrimidine-2-carboxylic acid as a solid. LCSM: 270 and 272 (M + 1). Intermediate 5: (2-bromo-5-fluoropindjn-4-iX(3SJ4^^ hydroisoquinolin-2(1 H )-yl)-3-hydroxypiperidin-1-yl)methanone DIEA, T3P DCM THE Intermediate 5

[00175] To a solution of 2-bromo-5-fluoroisonicotinic acid (538 mg, 2.44 mmol) and (3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (568 mg, 2.44 mmol) in DCM (11 mL) and DMF (5 mL) at 0 °C, DIEA (1.7 mL, 9.8 mmol) and T3P (1.7 mL, 2.9 mmol, 50% in DMF) were added. The mixture was stirred at room temperature for 1 h. The reaction was stopped with saturated aqueous NaHCOa (25 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% 3:1 EtOAc:EtOH in hexanes) to give (2-bromo-5-fluoropyridin-4-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone. MS: 434 and 436 (M + 1). EXAMPLES

[00176] The following experimental procedures detail the preparation of specific examples from this disclosure.

[00177] Note: Many of the claimed compounds exist Petition 870260011249, dated 05 / 02 / 2026, page 71 / 233 67 / 73 is a mixture of rotamers in solution at room temperature, which complicates its analysis by 1H-NMR spectroscopy. In these cases, peak shifts are listed as multiplet intervals encompassing the signals from both rotamers, rather than describing peaks of individual rotamers. Example 1: 1 -{4-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1yl}ethanone

[00178] A flask under an argon atmosphere was charged with (2-bromo-5-fluoropyridin-4-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)yl)-3-hydroxypiperidin-1-yl)methanone (300 mg, 0.691 mmol), 1-(4-aminopiperidin-1-yl)ethanone (98 mg, 0.69 mmol), Cs2CO3 (675 mg, 2.07 mmol), and THF (4.6 mL). The mixture was purged with argon for 10 min. Brett Phos precat G3 (63 mg, 0.069 mmol) was added, and the mixture was further purged with argon for 10 min. The reaction was stirred at 45 °C for 18 h. The mixture was filtered, diluted with water, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% 3:1 EtOAc:EtOH in hexanes) to yield 1-{4-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1-yl}ethanone as a solid. MS: 496 (M + 1).1H NMR (600 MHz, CD3OD) δ 7.97 (d, J = 10.4 Hz, 1H), 7.13 - 7.08 (m, 3H), 7.08 - 7.03 (m, 1H), 6.48 (d, J = 10.0 Hz, 1H), 4.78 - 4.73 (m, 1H), 4.67 - 4.58 (m, 1H), 4.44 - 4.38 (m, 1H), 4.01 - 3.85 (m, 4H), 3.83 - 3.76 (m, 1H), 3.75 - 3.70 (m, 1H), 3.66 - 3.61 (m, 1H), 3.22 - 3.15 (m, 1H), 3.07 - 2.99 (m, 2H), 2.96. Petition 870260011249, dated 02 / 05 / 2026, pág. 72 / 233 68 / 73 - 2.88 (m, 4H), 2.82 - 2.74 (m, 2H), 2.13 (s, 3H), 2.08 - 2.00 (m, 2H), 1.96 - 1.90 (m, 1H), 1.71 - 1.54 (m, 1H), 1.51 - 1.34 (m, 2H). Table 1: The following compounds are as deuterated versions of the top compound. 1b n η N π II AL Λ AAAD DH i 1-(4-((4-((3 s ,4 S )-4-(3,4dihidroisoquinolin-2(1H)yl-1,1-d2)-3- 498 1c u N > N Π II A kA ΛΛΛ A, d dH i 1-(4-((4-((3 R ,4 R )-4-(3,4dihidroisoquinolin-2(1H)yl-1,1-d2)-3- 498 Example 2: (6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidin-2yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1iDmethanone the

[00179] To a solution of DIEA (0.219 mL, 1.25 mmol), 6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidine-2-carboxylic acid (100 mg, 0.418 mmol) and (3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (117 mg, 0.502 mmol) in DMF (3 mL) was added to T3P (798 mg, 1.25 mmol). The mixture was stirred at 15 °C for 2 h and then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (ACN / water gradient) to obtain (6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone as a solid. MS: 454 (M+1.1H NMR (500 MHz, CD3OD) δ 8.88 (s, 1H), 8.65 (br s, 1H), 8.16 (s, 1H), 7.16 - 7.01 (m, 4H), 4.85 - 4.83 (m 2H), 4.03 3.79 (m, 3H), 3.26 - 2.71 (m, 8H), 2.15 - 1.89 (m, 3H), 1.80 - 1.70 (m, 1H). Example 3: (6-cyclopropylimjdazo[12-apinmjdjnr2-ylX(3SJ4S^hydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone Petition 870260011249, dated 05 / 02 / 2026, page 73 / 233 69 / 73

[00180] To a solution of 6-cyclopropylimidazo[1,2a]pyrimidine-2-carboxylic acid (80 mg, 0.394 mmol) in DMF (4 mL) was added HATU (180 mg, 0.472 mmol), DIEA (0.206 mL, 1.181 mmol) and (3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (91 mg, 0.394 mmol). The mixture was stirred at 15 °C for 30 min. The mixture was purified directly by reversed-phase HPLC (ACN / water gradient with TFA modifier at 0.1%) to generate (6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone as a solid. MS: 418 (M+1.1H NMR (500 MHz, CD3OD) δ 8.70 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 7.37 - 7.21 (m, 4H), 5.24 - 4.98 (m, 1H), 4.88 - 4.36 (m, 3H), 4.28 - 3.99 (m, 1H), 3.93 - 3.39 (m, 4H), 3.29 - 2.73 (m, 3H), 2.27 (br s, 1H), 2.14 - 2.06 (m, 1H), 2.05 - 1.90 (m, 1H), 1.19 - 1.07 (m, 2H), 0.92 - 0.79 (m, 2H). Example 4: (6-bromo-7-ethylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone

[00181] To a solution of 6-bromo-7-ethylimidazo[1,2a]pyrimidine-2-carboxylic acid (32 mg, 0.118 mmol) in DMF (4 mL) was added HATU (54 mg, 0.142 mmol), DIEA (0.062 mL, 0.355 mmol) and (3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-3-ol (28 mg, 0.118 mmol). The mixture was stirred at 20 °C for 30 min. The mixture was purified directly by reversed-phase HPLC (gradient of Petition 870260011249, dated 05 / 02 / 2026, page 74 / 233 70 / 73 ACN / water with TFA modifier at 0.1%) to generate (6-bromo-7ethylimidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)yl)-3-hydroxypiperidin-1-yl)methanone as a solid. MS: 484 and 486 (M+1). 1H NMR (400 MHz, CD3OD) δ 9.16 (br s, 1H), 8.15 (br s, 1H), 7.36-7.21 (m, 4H), 4.98-5.17 (m, 2H), 4.80-4.71 (m, 1H), 4.51-4.45 (m, 1H), 4.15-4.05 (m, 1H), 3.81-3.62 (m, 3H), 3.40-2.80 (m, 6H), 2.26-1.97 (m, 2H), 1.37 (t, J = 7.24 Hz, 3H). PRMT5-MEP50 Enzyme Methylation Assay

[00182] The PRMT5-MEP50 biochemical assay is a direct measurement of the methylation activity of the enzyme complex on a short peptide substrate derived from the N-terminus of histone H4. Methylation experiment was performed with recombinant PRMT5-MEP50 protein complex. The evaluation of the inhibitory effect of small molecules was measured by the effectiveness of the compounds to inhibit this reaction (EC50).

[00183] In this assay, the potency (EC50) of each compound was determined from a twenty-point titration curve (1:2 serial dilution; concentration of the top compound of 100000 nM) using the procedure outlined below. In each well of a blank ProxiPlus 384 well plate, 100 nL of the compound (1% DMSO in the final assay volume of 10 pL) were dispensed, followed by the addition of 8 pL of 1x assay buffer (50 mM bicine pH 8.0, 1 mM DTT, 0.004% Tween20, 0.01% BSA) containing 1.25 nM of complete PRMT5-MEP50 enzyme complex (FL) (recombinant proteins from baculovirus-transfected Sf21 cells: FL-PRMT5; MW = 73837 kDa and FL-MEP50; MW = 38614) and 1 pL of 150 pM S-(5'Adenosyl)-L-methionine chloride (SAM). The plates were sealed and placed in a humidified chamber at 37°C for a 60-minute pre-incubation with the compound. Subsequently, each reaction was initiated by the addition of 1 µL of 1x assay buffer containing 750 nM of peptide. Petition 870260011249, dated 05 / 02 / 2026, page 75 / 233 71 / 73 Biotinylated H4R3(Me1). The final reaction in each 10 μL well consisted of 1.0 nM PRMT5-MEP50, 75 nM biotinylated peptide, and 15 μM SAM. Methylation reactions were allowed to proceed for 150 minutes in a sealed plate at 37°C. Reactions were immediately quenched by the addition of 1 μL of 5% formic acid. Plates were then frozen and sent to SAMDI™ Tech Inc. to determine the percent conversion of H4R3(Me1) to H4R3(Me2). Dose-response curves were generated by plotting the percent effect (% product conversion; Y-axis) vs. Log10 compound concentrations (X-axis). EC50 values ​​were determined by nonlinear regression according to models for sigmoidal dose-response curves (4 parameters). PRMT5 Cell Target Engagement Assay (TE)

[00184] The PRMT5 TE assay is a biomarker assay to identify compounds that inhibit symmetric arginine dimethylation (SDMA) of PRMT5 substrates. The following substrates have been reported for PRMT5: histone H2A and H4 R3, histone H3 R2, histone H3 R8, spliceosome proteins Sm, ribosomal protein RPS10, p53, FEN1, nucleoplasmin, nucleolin, EGFR, and EBNA. The assay focuses on the detection of symmetrically dimethylated nuclear proteins using high-content imaging technology. The detection of symmetrically dimethylated nuclear protein expression is achieved through a mixture of primary rabbit monoclonal antibodies to SDMA (CST 13222), which in turn are recognized by a secondary anti-rabbit IgG antibody conjugated with Alexafluor 488 dye.The IN 2200 or OperaPhenix Cell Analyzer measures the intensity of the nuclear Alexafluor 488 fluorescent dye, which is directly related to the expression level of symmetrically dimethylated nuclear proteins at the single-cell level. The AF488 nuclear dye intensities are compared with... Petition 870260011249, dated 05 / 02 / 2026, page 76 / 233 72 / 73 is the average value for cells treated with DMSO (MIN) to report the percentage of inhibition for each well treated with the compound.

[00185] In this assay, the cellular potency (EC50) of each compound was determined from a ten-point titration curve (1:3 serial dilution; top compound concentration of 10000 nM) using the procedure outlined below. Each well of a BD Falcon collagen-coated black / clear-bottom 384-well plate was cultured with 4000 MCF-7 cells in 30 μl of medium and maintained in ligation for 5 h. The medium is Eagle Minimum Essential Medium formulated by ATCC, Catalog No. 30-2003. To produce the complete growth medium, the following components were added to the base medium: 0.01 mg / mL recombinant human insulin; fetal bovine serum to a final concentration of 10%. An additional 30 μl of medium containing 2x the compounds was added to each well. Cells were treated for 3 days in a CO2 incubator at 37 °C. On day 3, the cells were fixed with Cytofix, permeabilized with 0.4% TritonX-100 / Cytofix, and washed with D-PBS without Ca / Mg.Cells were blocked with Licor Odessey blocking reagent for 1 h at room temperature, followed by incubation with anti-SDMA antibody (1:1000) at 4 °C overnight. The first antibody was removed, followed by three washes with DPBS without Ca / Mg and 0.05% Tween20. Hoechst (5 μg / mL), deep cell mask stain (1:2000), and goat anti-rabbit IgG conjugated with Alexa488 (2 μg / mL) were added for 1 h at room temperature. A final washing step (three washes) was performed before sealing for imaging on the In Cell Analyzer 2200 or Opera-Phenix. Analyzer images were uploaded to Columbus (in WP or BOS) for image analysis. IC50 values ​​were determined by robust 4-parameter fitting of percent fluorescence units vs. compound concentrations (Log-10). Petition 870260011249, dated 05 / 02 / 2026, page 77 / 233 73 / 73

[00186] Representative compounds of the present invention were tested using the test protocol described in this example. The results are provided in Table 2 below. Table 2: Example No. Enzymatic Methylation Assay (EC50, nM) TE Assay (EC50, nM) 1 0.9 6.9 1b 0.9 2 1c 49; 9772 165 2 1.6 4.7 3 1.3 6.8 4 1.5 15

Claims

1. A compound characterized by the fact that it is selected from: or a pharmaceutically acceptable salt thereof.

2. Compound, according to claim 1, CHARACTERIZED in that it is selected from: Petition 870260011249, dated 05 / 02 / 2026, page 79 / 233 2 / 4 or a pharmaceutically acceptable salt thereof.

3. Compound, according to claim 1, or a pharmaceutically acceptable salt thereof. CHARACTERIZED by the fact that it is:

4. Compound according to claim 1, CHARACTERIZED in that it is: or a pharmaceutically acceptable salt thereof.

5. Compound according to claim 1, CHARACTERIZED in that it is: or a pharmaceutically acceptable salt thereof.

6. Compound, according to claim 1, Petition 870260011249, dated 05 / 02 / 2026, page 80 / 233 3 / 4 CHARACTERIZED by the fact that it is: or a pharmaceutically acceptable salt thereof.

7. Compound, according to claim 1, CHARACTERIZED in that it is: 1-{4-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1-yl}ethenone, or a pharmaceutically acceptable salt thereof.

8. Compound, according to claim 1, CHARACTERIZED in that it is: (6-(2,2-difluorocyclopropyl)imidazo[1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3-hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

9. Compound, according to claim 1, CHARACTERIZED in that it is: (6-cyclopropylimidazo[1 2a]pyrimidin-2-yl)((3S 4S)-4-(3 4-dihydroisoquinolin-2(1H)-yl)-3hydroxypiperidin-1-yl)methanone or a pharmaceutically acceptable salt thereof.

10. Compound, according to claim 1, CHARACTERIZED in that it is: (6-bromo-7-ethylimidazo[1,2a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2(1H)-yl)-3hydroxypiperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof.

11. Pharmaceutical composition CHARACTERIZED in that it comprises a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Petition 870260011249, dated 05 / 02 / 2026, page 81 / 233 4 / 4 12. Use of a compound as defined in any one of claims 1-10, or of a pharmaceutically acceptable salt thereof, CHARACTERIZED in that it is for the manufacture of a medicament for treating sickle cell disease or hereditary persistence of fetal hemoglobin mutations (HPFH).

13. Use of a compound as defined in any one of claims 1 to 11, or of the pharmaceutical composition as defined in claim 12, CHARACTERIZED by being for the manufacture of a medicament for the treatment of cancer.