Cancer treatment using CDK inhibitors

Abstract

This specification provides compositions and methods for the treatment of cancer. The compositions are as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1, 1-Trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, (2S The formulation includes a CDK2 / 4 / 6 inhibitor selected from the group consisting of (3S,4R)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl. Some embodiments include combination therapies featuring CDK2 / 4 / 6 inhibitors in combination with at least one additional cancer drug. In some embodiments, the at least one additional cancer drug includes an endocrine therapy agent.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Patent Application No. 63 / 515,752, filed on 26 July 2023, and U.S. Patent Application No. 63 / 554,735, filed on 16 February 2024, each of which is incorporated herein by reference in whole. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are a conserved family of proline-directed serine / threonine kinases that play a crucial role in regulating cell division and proliferation. Dysregulation of CDK2, CDK4, and CDK6 (CDK2 / 4 / 6) has been demonstrated to be a major driving factor in many cancers, and inhibition of CDK2 / 4 / 6 has been a proven therapeutic approach in several diseases, including breast cancer. Therefore, there is a demand for the use of therapies that target CDK2 / 4 / 6 kinase activity to treat cancers and other diseases characterized by abnormalities in CDK2 / 4 / 6 pathway signaling. [Overview of the project] [Means for solving the problem]

[0003] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

[0004] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

[0005] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

[0006] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

[0007] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

[0008] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

[0009] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

[0010] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

[0011] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

[0012] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

[0013] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

[0014] One embodiment provides a method for treating cancer in a patient in need, the method comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

[0015] In another embodiment, the cancer is: breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), suprasquamous cancer. Skin cancer, adenocarcinoma, mesothelioma, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), renal cancer, renal cell carcinoma (RCC), liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer, gastric cancer cancer), gastric cancer The present invention provides a method selected from the group consisting of cancer, endometrial cancer, sarcoma, liposarcoma, osteosarcoma, primary brain tumor, high-grade and low-grade glioma, glioblastoma, thyroid cancer, hematological malignancies, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphoma, myeloma, neuroblastoma, Ewing's sarcoma, osteosarcoma, and Wilms' tumor. [Brief explanation of the drawing]

[0016] [Figure 1A] The results of xenografts derived from the WM3629 (class III BRAF mutant / CDK4 sensitive melanoma) cell line after treatment with compound 1 are shown. [Figure 1B] The results of xenografts derived from the WM3629 (class III BRAF mutant / CDK4 sensitive melanoma) cell line after treatment with compound 1 are shown. [Figure 2] This study demonstrates the regulation of the pharmacodynamic biomarker pRB in xenograft tumors derived from the WM3629 (class III BRAF mutant / CDK4 sensitive melanoma) cell line after 3 days of TID treatment with compound 1. [Modes for carrying out the invention]

[0017] Embedding by reference All publications, patents, and patent applications described herein are incorporated herein by reference for the specific purposes identified herein.

[0018] Specific terms In this specification and the appended claims, the singular terms “a,” “an,” and “the” shall include plural references unless the context clearly indicates otherwise. For example, “one drug” includes multiple such drugs, and “the cell” refers to one or more cells (or more cells) and their equivalents known to those skilled in the art. Where a range is used in this specification for physical properties such as molecular weight, or for chemical properties such as chemical formula, it is intended to include all combinations and subcombinations within that range, as well as specific embodiments. The term “approximately” when referring to a numerical value or range of values ​​means that the numerical value or range is an approximation of experimental variability (or within statistical experimental error), and therefore, the numerical value or range may vary by 1% to 15% in some cases. The terms “contains” (and related terms such as “contains,” “contains,” “has,” or “contains”) are not intended to preclude in other specific embodiments any embodiment of which, for example, a composition, composition, method, or process of a substance described herein, “consists of” or “essentially constitutes” the described features.

[0019] In this specification and the appended claims, unless otherwise indicated, the following terms have the meanings set forth below.

[0020] "Pharmacologically acceptable salts" include both acid-addition salts and base-addition salts. The pharmaceutically acceptable salts of heterocyclic CDK2 / 4 / 6 inhibitors described herein are intended to encompass all pharmaceutically appropriate salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base-addition salts.

[0021] "Pharmacologically acceptable acid addition salts" refer to salts that retain the biological efficacy and properties of the free base, are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. It also includes salts formed with organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of such organic acids include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Examples of salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chloridebenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Salts of amino acids such as alginates, gluconic acid, and galacturonic acid are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared by skilled technicians, according to well-known methods and techniques, by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0022] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali metals and alkaline earth metals, or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al., cited above.

[0023] A "pharmaceutically acceptable solvate" refers to a composition of a substance in a solvent-added form. In some embodiments, the solvate is formed during a manufacturing process using a pharmaceutically acceptable solvent such as water or ethanol, comprising a stoichiometric or non-stoichiometric amount of solvent. When the solvent is water, a hydrate is formed; when the solvent is alcohol, an alcoholate is formed. The solvates of the compounds described herein are conveniently prepared or formed during the manufacturing processes described herein. The compounds provided herein may exist in either a non-solvated or solvated form, as may be required.

[0024] The terms “subject” or “patient” include mammals. Examples of mammals include, but are not limited to, all members of the class Mammalia: humans, non-human primates such as chimpanzees, and other apes and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, a mammal is a human.

[0025] In this specification, “treatment,” “to treat,” “to alleviate,” and “to improve” are used interchangeably. These terms refer to, but are not limited to, approaches to obtaining beneficial outcomes or desired outcomes, such as therapeutic benefits and / or preventive benefits. “Therapeutic benefits” means the eradication or improvement of the underlying disease being treated. Therapeutic benefits may also be achieved by the eradication or improvement of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient still has the underlying disease. For preventive effects, in some embodiments, the composition is administered to patients at risk of developing a particular disease, or to patients who have not been diagnosed with the disease but report one or more physiological symptoms of that disease. As used herein, the term “to treat” means, unless otherwise indicated, reversing, alleviating, slowing the progression of, or preventing the disease or condition to which the term applies, or one or more symptoms of the disease or condition. In some embodiments, the term “to treat” includes slowing or delaying the progression of a disease or disorder to which the term applies. Furthermore, in some embodiments, the term “to treat” applies to one or more complications resulting from a disease or disorder to which the term applies. As used herein, the term “treatment” refers to an action taken as “treatment” as defined immediately prior to it, unless otherwise specified.

[0026] As used herein, the terms “tumor” or “cancer” refer to neoplastic cell proliferation, including precancerous and cancerous cells and tissues, unless otherwise specified. Tumors typically present as lesions or lumps. As used herein, “treating” a tumor means that one or more symptoms of the disease, including the tumor itself, tumor angiogenesis, or other parameters characterizing the disease, are reduced, improved, suppressed, enter into remission, or maintained in remission. “Treatment” a tumor also means that treatment eliminates, reduces, or prevents one or more characteristics of the tumor. Non-limiting examples of such characteristics include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of new functional capillaries, and persistence of such functional capillaries.

[0027] The terms "refractory" or "treatment-resistant" indicate that a patient has not responded to treatment at all.

[0028] The terms "relapse" or "post-treatment relapse" indicate that a patient has a progressive disease due to acquired resistance and / or intolerance after initially responding to treatment.

[0029] The terms "treatment resistance" or "acquired treatment resistance" refer to disease progression in patients after an initial response to prior treatment, due to clinical or molecular resistance to the treatment. Acquired resistance can result from the emergence of resistance mutations in the molecular targets of the treatment, or from the development of physiological functions such as efflux pumps.

[0030] As used herein, the term “therapeutic dose” refers to the amount of drug or pharmaceutical product that a researcher, veterinarian, physician, etc., seeks to elicit a biological or medical response in a tissue, system, animal, or human.

[0031] Other aspects, advantages, and features of the present invention will become apparent from the following detailed description.

[0032] CDK2 / 4 / 6 kinases Cyclin-dependent kinases (CDKs) are a conserved family of proline-directed serine / threonine kinases that play a crucial role in regulating cell division and proliferation. CDKs belong to the CMGC kinase family, which includes 63 members such as mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs). CDK activity is regulated through phosphorylation via interactions with cyclin proteins and other upstream kinases, such as CDK-activated kinases (CAKs). At least 21 CDKs have been identified to date, including CDK1, 2, 4, and 6 (which regulate cell cycle phase transitions), CDK7, 8, 9, 12, and 13 (which regulate gene transcription via phosphorylation of heptad repeats, including the C-terminal tail of RNA polymerase II), and CDK3 (which controls the transition from G0 (resting phase) to G1 phase of cell division). CDKs regulate the transition between the four distinct phases of the eukaryotic cell cycle: G1, S (DNA synthesis), G2, and M phases. Furthermore, CDKs are involved in the progression of many different types of cancer. In particular, dysregulation of CDK4 and CDK6 (CDK4 / 6) has been demonstrated to be a major driving factor in many cancers, and inhibition of CDK4 / 6 has been a proven therapeutic approach in several diseases, including breast cancer.

[0033] Structurally, CDK4 and CDK6 possess a bilobal structure, typical of other kinases, containing a five-stranded β-sheet at the N-terminus of the protein and a predominantly helical C-terminal domain. The ATP binding site is located in the gap between these two domains. While the structures of CDK6 and its major cyclin partner (cyclin D) have not yet been determined, the crystal structure of CDK6 bound to a viral cyclin has been elucidated, providing some structural insights into CDK6 function. Furthermore, the structures of unphosphorylated and phosphorylated CDK4 bound to cyclin D3 or cyclin D1 have also been elucidated. The kinase binding sites of CDK4 and CDK6 are highly conserved, and this structural similarity between these kinases is likely the reason why selective ATP-competitive inhibitors (CDK4 / 6 inhibitors) of both CDK4 and CDK6 have been developed.

[0034] CDK4 and CDK6 bind to D-type cyclins, activating CDK4 / 6 to phosphorylate and inactivate the retinoblastoma (Rb) protein family. Cyclin D has a tertiary structure common to other cyclins, also known as the cyclin fold. The cyclin fold contains a core consisting of two compact domains, each with five α-helices. The first five-helix bundle is the conserved cyclin box, a region of approximately 100 amino acid residues common to all cyclins. The cyclin box functions by binding to and activating CDK. The second five-helix bundle consists of the same helix arrangement but has some differences in its primary sequence. The three D-type cyclins (D1, D2, and D3) share a common α1-helix hydrophobic patch, and each of these D-type cyclins binds to and activates CDK4 and CDK6, thereby advancing the cell cycle.

[0035] cell cycle The cell cycle of eukaryotic cells is divided into two basic parts: mitosis and interphase. Mitosis (nuclear division) corresponds to the separation of daughter chromosomes and usually ends with cell division (cytoplasmic division). The period between mitosis is interphase, which generally accounts for about 95% of the cell cycle time (for example, 23 hours out of a 24-hour cycle). During interphase, chromosomes decondense and disperse throughout the nucleus, and the cell prepares for mitosis by regulating both cell growth and DNA replication. The cell grows at a constant rate throughout interphase, and most dividing cells double their volume during the mitotic cycle. In contrast, DNA is synthesized only during the relatively short portion of interphase.

[0036] The timing of the four distinct phases in the eukaryotic cell cycle is based on DNA synthesis and cell division. The M phase of the cell cycle corresponds to mitosis, which is usually followed by cytokinesis (cell division). This phase is followed by the G1 phase (gap 1), which corresponds to the interval between mitosis and the start of DNA synthesis. During the G1 phase, the cell is metabolically active and continues to grow, but its DNA does not replicate. After the G1 phase, the cell enters the S phase (synthesis phase), during which DNA replication takes place. Once DNA synthesis is complete, the cell contains two identical sets of chromosomes and enters the G2 phase (gap 2) of cell division. During the G2 phase, the cell continues to grow and proteins are synthesized in preparation for the next round of mitosis (i.e., the next M cycle).

[0037] In some cell types, including many embryonic cells, cell division is continuous, with cells continuously cycling between the M, G1, S, and G2 phases. In contrast, many cells in adult animals either completely cease division (e.g., nerve cells) or divide only when necessary to replenish cells lost due to injury. Examples of such intermittently dividing cells include skin fibroblasts and cells of many internal organs, including the liver, kidneys, and lungs. These cells complete the G1 phase and enter a quiescent phase called the G0 phase, where metabolic activity is maintained, but proliferation does not occur unless required by appropriate extracellular signals, such as those caused by local tissue damage. However, in cancer, a relatively large subpopulation of cells continues to cycle through the four phases of cell division, promoting tumor growth and disease progression.

[0038] To enter the cell cycle, cells must pass a limiting point and transition from the G1 phase to the S phase, which most cells do only if the appropriate growth factors are present. Once a cell has passed the limiting point, it will work to progress through the S phase and the remaining stages of the cell cycle, even without further growth factor stimulation. However, if growth factors are not available in the G1 phase, the progression of the cell cycle generally stops at the limiting point, and the cell enters the G0 phase (resting phase) until it receives a signal to resume cell division. The transition from the G1 phase to the S phase is partially mediated by retinoblastoma protein (RB), which is usually regulated by a delicate balance of pro-mitotic and anti-mitotic signals. In healthy cells, the balance of pro-mitotic and anti-mitotic signals is tightly controlled, and specific pro-mitotic signals (e.g., growth factors) are required for normal cells to enter the cell division cycle.

[0039] Cellular signaling network CDK4 and CDK6 are directly involved in mediating the transition from G1 to S phase. Activated CDK4 / 6 enters downstream pathways, which advance the cell into the S phase of cell division. According to the "classical" cell cycle model, the G1 / S transition is initiated in early G1, at which point the balance between pro-mitotic stimulation (via growth factor receptor activation) and repression shifts in favor of the former, leading to an increase in D-cyclin levels (D1, D2, and D3). The expression levels of D-cyclins are regulated by growth factor signaling, and the transcription, turnover, and nuclear transport of D-cyclins all depend on this signaling. D-cyclins bind to CDK4 or CDK6, and the cyclin-CDK complex then moves into the nucleus, where it is phosphorylated by the CDK-activated kinase (CAK) complex.

[0040] Once activated, the CDK4 / 6 complex phosphorylates the retinoblastoma (RB) tumor suppressor protein, as well as the associated p107 and p130 proteins. Phosphorylation of RB by CDK4 / 6 partially inhibits the activity of the E2F transcription factor family, which in turn increases the expression of E2F target genes such as type E cyclins (cyclins E1 and E2). Cyclin E then binds to and activates CDK2, which leads to hyperphosphorylation of RB. Hyperphosphorylation of RB further increases the expression of E2F target genes, which are crucial for the initiation of DNA synthesis and transition to the S phase. This creates a positive feedback loop, as E2F promotes the transcription of type E cyclins, activating CDK2 and other proteins important for S phase initiation and DNA synthesis.

[0041] Regulation of CDK4 / 6 is primarily achieved by two families of endogenous inhibitory proteins. The first is the INK4 family, including p16INK4A, p15INK4B, p18INK4C, and p19INK4D proteins, which bind to CDK4 and CDK6 to form a binary complex lacking kinase activity. The second is the CIP / KIP family, including p27KIP1, p21CIP1, and p57KIP2. These proteins bind to a variety of CDKs with more diverse functions and potently inhibit several CDKs (such as CDK4 / 6, CDK2, and CDK1). However, under certain circumstances, these proteins bind to the cyclin D-CDK4 / 6 holoenzyme, stabilizing it. These differing functions can be regulated by the degree of phosphorylation of the CIP / KIP proteins.

[0042] Prior art CDK4 / 6 kinase inhibitors Multiple CDK inhibitors have been developed and tested in various types of cancer. First-generation CDK inhibitors, including flavopyridol (an inhibitor of at least CDK1, 2, 4, and 9) and roscovitine (an inhibitor of at least CDK1, 2, 5, 7, and 9), were pan-inhibitors acting on multiple kinases. These first-generation CDK inhibitors had limited clinical success due to an insufficient balance of efficacy and toxicity. Second-generation inhibitors, such as dinaciclib (an inhibitor of CDK1, 2, 5, and 9), were developed to enhance the potency and selectivity of CDKs compared to other kinases. However, these compounds showed limited efficacy and considerable toxicity in clinical trials. The toxicity of these compounds stems from their broad activity against numerous CDK isoforms (such as CDK1 and CDK9) necessary for the proliferation (CDK1) and survival (CDK9) of normal cells. In recent years, selective CDK4 / 6 inhibitors have been developed that exhibit more targeted action against tumor cells and reduced toxicity. This third-generation CDK inhibitor selectively binds to the ATP binding pocket of CDK4 / 6, selectively inhibiting CDK4 and CDK6 with potent efficacy and low toxicity.

[0043] To date, three CDK4 / 6 inhibitors—palbociclib, ribociclib, and abemaciclib—have received FDA approval for use in oncology. Additionally, trilaciclib is approved for the treatment of chemotherapy-induced myelosuppression. Palbociclib received FDA accelerated approval in 2015 in combination with letrozole for the treatment of estrogen receptor-positive (ER+) advanced breast cancer. In 2017, palbociclib received FDA full approval in combination with an aromatase inhibitor for use in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Ribociclib was approved in 2017 in combination with an aromatase inhibitor (such as letrozole) for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer. In 2017, abemaciclib received FDA approval as monotherapy or in combination with fulvestrant for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer whose disease has progressed after endocrine therapy. In 2018, abemaciclib received a second approval for use in combination with an aromatase inhibitor as first-line endocrine therapy for postmenopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. More recently, in 2021, abemaciclib was approved in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for adjuvant therapy in adult patients with early-stage breast cancer that is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and lymph node-positive, in combination with endocrine therapy (tamoxifen or an aromatase inhibitor).

[0044] The development of selective CDK4 / 6 inhibitors has fundamentally altered the approach to managing this disease (hormone receptor-positive, HER2-negative advanced breast cancer), nearly doubling progression-free survival (PFS) in most patients. However, resistance to CDK4 / 6 inhibitors is considered almost inevitable in most patients. The mechanisms of resistance to these drugs are multifactorial, and research in this area is ongoing, but several mechanisms of resistance to CDK4 / 6 inhibitors have been elucidated to date.

[0045] Firstly, overexpression of CDK6 (and possibly CDK4) is a major resistance mechanism to CDK4 / 6 inhibitors. Studies using human cell lines have shown that increased CDK6 expression reduces the response to CDK4 / 6 inhibitors, and subsequent CDK6 knockdown restores treatment sensitivity, suggesting that CDK6-mediated drug resistance may be independent of CDK4 expression. However, both increased and decreased CDK4 expression have been detected in CDK4 / 6 inhibitor-resistant breast cancer cells, indicating that the role of CDK4 expression in CDK4 / 6 inhibitor resistance needs further investigation. Secondly, several preclinical studies have suggested that Rb loss is involved as a driving factor in resistance to CDK4 / 6 inhibitors. Without the inhibitory effect of Rb, E2F family transcription factors remain unregulated, which promotes uncontrolled cell progression to the S phase, independently of CDK4 / 6 activity. Acquired CDK4 / 6 inhibitor resistance due to RB1 mutations has been confirmed in several patients treated with CDK4 / 6 inhibitors. Thirdly, decreased cyclin D1 expression can lead to resistance to CDK4 / 6 inhibitors. Since cyclin D1 expression is regulated by the estrogen receptor (ER), decreased ER expression leads to decreased cyclin D1 expression. In preclinical studies, resistance to abemaciclib was associated with the disappearance of cyclin D1 and the resulting disappearance of ER / PR expression. Resistance in these patients may be related to the decrease in cyclin D1 associated with the disappearance of ER. Another resistance mechanism to CDK4 / 6 inhibitors arises from increased CDK2 activity via amplification of cyclin E. Therefore, CDK2 / 4 / 6 inhibitors may offer the potential to reverse the acquired treatment resistance observed with clinical CDK4 / 6 inhibitors. Additional mechanisms of action include overexpression of Brk (breast cancer-related kinase), overexpression of the E2F2 transcription factor, and overexpression of cyclin E1 or E2. Thus, there is a need for a new generation of CDK inhibitors that are less susceptible to one or more of these resistance mechanisms and offer longer progression-free survival.

[0046] Heterocyclic CDK2 / 4 / 6 inhibitors and their prodrugs Heterocyclic CDK2 / 4 / 6 inhibitors and their prodrugs, as disclosed in Table 1, are described herein.

[0047] Compound 1, disclosed in PCT / US2023 / 061287, is a reversible small molecule CDK2 / 4 / 6 inhibitor. Compound 2, a valine ester prodrug of Compound 1, is also disclosed herein.

[0048] Compound 3 is disclosed in PCT / US2023 / 061287 and is a reversible small molecule CDK2 / 4 / 6 inhibitor. Compound 4, a valine ester prodrug of Compound 3, is also disclosed herein.

[0049] Compound 5 is disclosed in PCT / US2023 / 061287 and is a reversible small molecule CDK2 / 4 / 6 inhibitor. Compounds 6-10, 15, and 20, which are prodrugs of compound 5, are also disclosed herein.

[0050] Compound 11 is provided herein together with prodrug compound 12.

[0051] Compound 13 is provided herein together with prodrug compound 14. Compounds 16 and 17 are provided herein and are stereoisomers of compound 13.

[0052] Compound 18 is provided herein together with prodrug compound 19.

[0053] [Table 1]

[0054] [Table 2]

[0055] [Table 3]

[0056] [Table 4]

[0057] [Table 5]

[0058] One embodiment is as follows:

[0059] [ka] The present invention provides compounds selected from the group consisting of the above, or pharmaceutically acceptable salts or solvates thereof.

[0060] Another embodiment is as follows:

[0061] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0062] Another embodiment is as follows:

[0063] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0064] Another embodiment is as follows:

[0065] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0066] Another embodiment is as follows:

[0067] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0068] Another embodiment is as follows:

[0069] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0070] Another embodiment is as follows:

[0071] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0072] Another embodiment is as follows:

[0073] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0074] Another embodiment is as follows:

[0075] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0076] Another embodiment is as follows:

[0077] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0078] Another embodiment is as follows:

[0079] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0080] Another embodiment is as follows:

[0081] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0082] Another embodiment is as follows:

[0083] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0084] Another embodiment is as follows:

[0085] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0086] Another embodiment is as follows:

[0087] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0088] Another embodiment is as follows:

[0089] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0090] Another embodiment is as follows:

[0091] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0092] Another embodiment is as follows:

[0093] [ka] The present invention provides compounds having the structure, or pharmaceutically acceptable salts or solvates thereof.

[0094] Cancer and its treatment methods In one embodiment, a method for inhibiting the CDK2 / 4 / 6 enzyme is provided, which comprises contacting the CDK2 / 4 / 6 enzyme with compound 1, 3, or 5 disclosed herein. In another embodiment, a method for inhibiting the CDK2 / 4 / 6 enzyme is provided, which comprises contacting the CDK2 / 4 / 6 enzyme with compound 11, 13, 16, 17, or 18 disclosed herein. In yet another embodiment, the contact is performed in vitro. In yet another embodiment, the contact is performed in vivo.

[0095] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (compound 1), or a pharmaceutically acceptable salt or solvate thereof.

[0096] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (compound 1), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0097] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 2), or a pharmaceutically acceptable salt or solvate thereof.

[0098] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 2), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0099] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 3), or a pharmaceutically acceptable salt or solvate thereof.

[0100] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 3), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0101] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (compound 4), or a pharmaceutically acceptable salt or solvate thereof.

[0102] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (compound 4), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0103] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (compound 5), or a pharmaceutically acceptable salt or solvate thereof.

[0104] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (compound 5), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0105] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 6), or a pharmaceutically acceptable salt or solvate thereof.

[0106] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 6), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0107] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt or solvate thereof: (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 7); Sulfamic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 8); [(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxyphosphonic acid (compound 9); ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonic acid (compound 10); 2-methylpropanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 15); and Diammonium phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl (compound 20).

[0108] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof: (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 7); Sulfamic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 8); [(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxyphosphonic acid (compound 9); ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonic acid (compound 10); 2-methylpropanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (compound 15); and Diammonium phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl (compound 20).

[0109] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt or solvate thereof: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 11); (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (compound 12); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 13); (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (compound 14); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 16); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 17); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-trifluoromethanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 18); and (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrili]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (compound 19).

[0110] One embodiment provides a method for treating cancer in a patient in need, which involves administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 11); (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl(2S)-2-amino-3-methylbutanoic acid (compound 12); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 13); (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (compound 14); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 16); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 17); 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-trifluoromethanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (compound 18); and (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrili]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (compound 19).

[0111] In another embodiment, the cancer is: breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), suprasquamous cancer. Skin cancer, adenocarcinoma, mesothelioma, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), kidney cancer, renal cell carcinoma (RCC), liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer, stomach cancer, gastric cancer, intrauterine cancer The present invention provides a method selected from the group consisting of membrane carcinoma, sarcoma, liposarcoma, osteosarcoma, primary brain tumor, high-grade and low-grade glioma, glioblastoma, thyroid cancer, hematological malignancy, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphoma, myeloma, neuroblastoma, Ewing's sarcoma, osteosarcoma, and Wilms' tumor.

[0112] In some embodiments, the cancer is locally advanced or regionally advanced cancer. In some embodiments, the cancer is a metastatic solid tumor. In some embodiments, the cancer is a metastatic brain tumor.

[0113] In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is adenocarcinoma of NSCLC. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is liposarcoma.

[0114] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is locally advanced. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor positive (HR+), i.e., the breast cancer is estrogen receptor positive (ER+) and / or progesterone receptor positive (PR+). In some embodiments, the breast cancer is hormone receptor negative (HR-), i.e., the breast cancer is estrogen receptor negative (ER-) and / or progesterone receptor negative (PR-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (HER2+). In some embodiments, the breast cancer is HR+ / HER2- breast cancer. In some embodiments, the breast cancer is HR- / HER2+ breast cancer. In some embodiments, the breast cancer is ER+ / HR+. In some embodiments, the breast cancer is ER+ / HER2-. In some embodiments, the breast cancer is triple-negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR-, and HER2-.

[0115] In some embodiments, the breast cancer is endocrine therapy-resistant, trastuzumab or pertuzumab-resistant, or exhibits primary or acquired resistance to CDK4 / CDK6 inhibitors. In some embodiments, the breast cancer is resistant to treatment with standard therapeutic agents; for example, the breast cancer may exhibit primary or acquired resistance to endocrine therapy, HER2-targeted agents (e.g., tamoxifen, trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib, or tucatinib), or CDK4 / 6 inhibitors. In some embodiments, the subject is refractory to endocrine therapy.

[0116] In some embodiments, breast cancer is refractory to or resistant to antitumor chemotherapy drugs such as platinum-based drugs, taxanes, anthracyclines, or antimetabolites, or progresses during such treatment.

[0117] In some embodiments, breast cancer progresses during or within 12 months of completing adjuvant therapy with aromatase inhibitors. In some embodiments, breast cancer progresses during or within 12 months of completing adjuvant therapy with tamoxifen.

[0118] In some embodiments, compound 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is administered as first-line therapy. In other embodiments, compound 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy. In some embodiments, compound 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors. In some embodiments, compound 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents such as aromatase inhibitors, selective estrogen receptor modulators (SERMs) (e.g., tamoxifen); or selective estrogen degraders / downregulators (SERDs). In some embodiments, compound 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with one or more chemotherapy regimens. In some embodiments, compound 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, is administered as a second-line (or subsequent) therapy after treatment with a HER2-targeted agent.

[0119] In some embodiments, compound 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, is administered as first-line therapy. In other embodiments, compound 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy. In some embodiments, compound 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors. In some embodiments, compound 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents such as aromatase inhibitors, selective estrogen receptor modulators (SERMs) (e.g., tamoxifen), or selective estrogen degradation accelerators / downregulators (SERDs). In some embodiments, compound 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with one or more chemotherapy regimens. In some embodiments, compound 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, is administered as a second-line (or subsequent) therapy after treatment with a HER2-targeted agent.

[0120] In some embodiments, compound 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, is administered as first-line therapy. In other embodiments, compound 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy. In some embodiments, compound 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors. In some embodiments, compound 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents such as aromatase inhibitors, selective estrogen receptor modulators (SERMs) (e.g., tamoxifen); or selective estrogen degradation accelerators / down regulators (SERDs). In some embodiments, compound 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, is administered as second-line (or subsequent) therapy after treatment with one or more chemotherapy regimens. In some embodiments, compound 5 or 6, or a pharmaceutically acceptable salt or solvate thereof, is administered as a second-line (or subsequent) therapy after treatment with a HER2-targeted agent.

[0121] In some embodiments, the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as first-line therapy. In other embodiments, the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as second-line (or subsequent) therapy. In some embodiments, the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors. In some embodiments, the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents such as aromatase inhibitors, selective estrogen receptor modulators (SERMs) (e.g., tamoxifen); or selective estrogen degradation accelerators / downregulators (SERDs). In some embodiments, the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as second-line (or subsequent) therapy after treatment with one or more chemotherapy regimens. In some embodiments, the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as second-line (or subsequent) therapy after treatment with HER2-targeted agents.

[0122] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, and an endocrine therapy agent.

[0123] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, and an endocrine therapy agent.

[0124] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof, and an endocrine therapy agent.

[0125] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, and an endocrine therapy agent.

[0126] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, and an endocrine therapy agent.

[0127] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl]-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, and an endocrine therapy agent.

[0128] One embodiment provides a method for treating cancer in patients in need, which comprises administering the compounds listed in Table 1, or pharmaceutically acceptable salts or solvates thereof, and endocrine therapeutic agents.

[0129] "Endocrine therapy drugs" are biological (high molecular weight) or chemical (low molecular weight) compounds that are useful in treating cancer, regardless of their mechanism of action.

[0130] In some embodiments, the endocrine therapy agent is an aromatase inhibitor, an androgen receptor inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In some embodiments, the endocrine therapy agent is an androgen receptor inhibitor. In some embodiments, the endocrine therapy agent is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane. In one embodiment, the aromatase inhibitor is letrozole. In some embodiments, the endocrine therapy agent is a SERD. In some such embodiments, SERD is selected from the group consisting of: fulvestrant, eracetrant (RAO-1901, Radius Health / Menarini), amsenetrant (SAR439859, Sanofi), giredetrant (GOC9545, Roche), RG6171 (Roche), camizestrant (AZO9833, AstraZeneca), AZO9496 (AstraZeneca), lintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), 0-0502 (Inventisbio), LY3484356 (Eli Lilly), and SHR9549 (Jiansu Hengrui Medicine). In some embodiments, SERD is fulvestrant. In some embodiments, the endocrine therapy agent is SERM. In some of these embodiments, the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, rasofoxifene, bazedoxefene, and afimoxifene. In some of these embodiments, the SERM is tamoxifen or raloxifene. In preferred embodiments, the endocrine therapy agent is letrozole or fulvestrant.

[0131] In some embodiments, endocrine therapy drugs are administered in accordance with the package insert or standard treatment provided by a healthcare professional. The term “package insert” refers to the instructions typically included with the market packaging of a therapeutic product, including information regarding instructions, usage, dosage, administration, contraindications, and / or precautions for use of the therapeutic product.

[0132] In certain embodiments, the endocrine therapy agent is administered to the subject in the course of treatment with one of the compounds 1-6 or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the initial dose of the endocrine therapy agent is administered before the initial dose of one of the compounds 1-6 or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the initial dose of the endocrine therapy agent is administered on the same day as the initial dose of one of the compounds 1-6 or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the initial dose of the endocrine therapy agent is administered after the initiation of treatment with one of the compounds 1-6 or a pharmaceutically acceptable salt or solvate thereof.

[0133] In certain embodiments, the subject has previously received treatment with one or more lines of endocrine therapy before being administered any one of compounds 1-6, or a pharmaceutically acceptable salt or solvate thereof.

[0134] In certain embodiments, prior to administration of any one of compounds 1-6, or any pharmaceutically acceptable salt or solvate thereof, the subject has previously received treatment by chemotherapy, radiotherapy, and / or surgical resection.

[0135] In certain embodiments, the subject has previously received treatment with a CDK4 / 6 inhibitor before being administered any one of compounds 1-6, or any pharmaceutically acceptable salt or solvate thereof.

[0136] In certain embodiments, the endocrine therapy agent is administered to the subject in the course of treatment with the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates. In certain embodiments, the initial dose of the endocrine therapy agent is administered before the initial dose of the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates. In certain embodiments, the initial dose of the endocrine therapy agent is administered on the same day as the initial dose of the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates. In certain embodiments, the initial dose of the endocrine therapy agent is administered after the initiation of treatment with the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates.

[0137] In certain embodiments, prior to administering the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates, the subject has previously received treatment with one or more lines of endocrine therapy.

[0138] In certain embodiments, prior to administration of the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates, the subject has previously received treatment by chemotherapy, radiotherapy, and / or surgical resection.

[0139] In certain embodiments, prior to administering the compounds listed in Table 1, or their pharmaceutically acceptable salts or solvates, the subjects have previously received treatment with CDK4 / 6 inhibitors.

[0140] In some embodiments, the treatments described herein result in a complete response (CR), a partial response (PR), or stable condition (SD) in the subject.

[0141] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0142] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0143] One embodiment provides a method for treating cancer in a patient in need, comprising administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0144] One embodiment provides a method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0145] One embodiment provides a method for treating cancer in a patient in need, which comprises administering to the patient (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, wherein cancer is defined as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0146] One embodiment provides a method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein cancer is defined as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0147] One embodiment provides a method for treating cancer in a patient in need, comprising administering to the patient one of the compounds in Table 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor, where cancer is defined as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B It is a solid tumor characterized by the following:

[0148] Another embodiment provides a method in which a solid tumor is characterized by CDK4 amplification or mutation. Another embodiment provides a method in which a solid tumor is characterized by cyclin D1 amplification. Another embodiment provides a method in which a solid tumor is characterized by cyclin E amplification. Another embodiment provides a method in which a solid tumor is characterized by loss of the negative regulatory gene CDKN2A or CDKN2B.

[0149] Another embodiment provides a method for a patient who has not previously received CDK4 inhibitor therapy. Another embodiment provides a method for a patient who is resistant to CDK4 inhibitor or CDK6 inhibitor therapy.

[0150] Pharmaceutical composition In certain embodiments, the heterocyclic CDK2 / 4 / 6 inhibitors described herein by compounds 1-6, or their pharmaceutically acceptable salts or solvates, are administered as pure chemicals. In other embodiments, the heterocyclic CDK2 / 4 / 6 inhibitors described herein by compounds 1-6, or their pharmaceutically acceptable salts or solvates, are combined with a pharmaceutically appropriate or acceptable carrier (also referred to herein as a pharmaceutically appropriate or acceptable excipient, a physiologically appropriate or acceptable excipient, or a physiologically appropriate or acceptable carrier) selected based on a preferred route of administration and standard medical practice.

[0151] This specification provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers, a heterocyclic CDK2 / 4 / 6 inhibitor as described herein by compound 1 to 6, or a stereoisomer thereof, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. The carrier (or excipient) is acceptable or appropriate if it is compatible with the other components of the composition and is not harmful to the recipient (i.e., subject or patient) of the composition.

[0152] In certain embodiments, the heterocyclic CDK2 / 4 / 6 inhibitors described herein by the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are administered as pure chemical substances. In other embodiments, the heterocyclic CDK2 / 4 / 6 inhibitors described herein by the compounds in Table 1, or their pharmaceutically acceptable salts or solvates, are combined with a pharmaceutically appropriate or acceptable carrier (also referred to herein as a pharmaceutically appropriate or acceptable excipient, a physiologically appropriate or acceptable excipient, or a physiologically appropriate or acceptable carrier) selected based on a preferred route of administration and standard medical practice.

[0153] This specification provides a pharmaceutical composition comprising a heterocyclic CDK2 / 4 / 6 inhibitor described herein by the compounds of Table 1, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or appropriate when it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject or patient) of the composition.

[0154] One embodiment provides:

[0155] [Chemical formula] a pharmaceutical composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof; and at least one pharmaceutically acceptable excipient.

[0156] Another embodiment provides a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridin-2-yl}pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0157] Another embodiment provides a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0158] Another embodiment provides a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0159] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0160] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0161] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0162] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0163] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0164] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0165] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0166] [ka] To provide a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0167] Another embodiment is at least one pharmaceutically acceptable excipient and the following:

[0168] [Chemical Formula] To provide a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0169] Another embodiment is at least one pharmaceutically acceptable excipient and the following:

[0170] [Chemical Formula] To provide a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0171] Another embodiment is at least one pharmaceutically acceptable excipient and the following:

[0172] [Chemical Formula] To provide a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0173] Another embodiment is at least one pharmaceutically acceptable excipient and the following:

[0174] [Chemical Formula] [[ID=​​​​​​​ [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0177] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0178] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0179] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0180] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0181] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0182] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0183] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0184] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0185] Another embodiment includes at least one pharmaceutically acceptable excipient, and the following:

[0186] [ka] The present invention provides a pharmaceutical composition comprising a compound having the structure, or a pharmaceutically acceptable salt or solvate thereof.

[0187] One embodiment provides a method for preparing a pharmaceutical composition, which comprises mixing a heterocyclic CDK2 / 4 / 6 inhibitor, or its stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate, as described herein, with a pharmaceutically acceptable carrier.

[0188] This specification provides a method for orally administering a pharmaceutical composition. Suitable oral dosage forms include, for example, tablets, pills, pouches, or capsules made of hard or soft gelatin, methylcellulose, or other suitable materials that readily dissolve in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used, for example, those containing pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0189] This specification provides a method for administering pharmaceutical compositions by injection. In some embodiments, the heterocyclic CDK2 / 4 / 6 inhibitors described herein, or pharmaceutically acceptable salts or solvates thereof, are formulated for administration by injection. In some cases, the injectable formulation is an aqueous formulation. In some cases, the injectable formulation is a non-aqueous formulation. In some cases, the injectable formulation is an oily formulation, such as sesame oil.

[0190] The dose of compositions comprising heterocyclic CDK2 / 4 / 6 inhibitors, or their stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates, as described herein varies depending on the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors. The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose, as well as the duration and frequency of administration, is determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dose and treatment regimen provides a sufficient amount of the composition to produce a therapeutic and / or preventive benefit (e.g., improved clinical outcomes such as a higher frequency of complete or partial remission, extended disease-free survival and / or overall survival, or reduced symptom severity). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose varies depending on the patient's body mass, weight, or blood volume.

[0191] Numbered Embodiments Embodiment 1. A method for treating cancer in a patient who requires it, the following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A method comprising administering to a patient a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 2. A method for treating cancer in a patient who requires it, the following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A method comprising administering to a patient a pharmaceutical composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 3. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 4. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 5. A method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 6. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 7. A method for treating cancer in a patient in need, comprising administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 8. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 9. A method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 10. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 11. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 12. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 13. A method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 14. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 15. The cancer is: breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell carcinoma, adenocarcinoma , mesothelioma, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), renal cancer, renal cell carcinoma (RCC), liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer, stomach cancer, gastric cancer, endometrial cancer, sarcoma, fat The method according to any one of Embodiments 1 to 14, selected from the group consisting of sarcomas, osteosarcomas, primary brain tumors, high-grade and low-grade gliomas, glioblastomas, thyroid cancers, hematological malignancies, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphomas, myelomas, neuroblastomas, Ewing's sarcoma, osteosarcoma, and Wilms' tumor. Embodiment 16. The method according to Embodiment 15, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, or a combination thereof. Embodiment 17. The method according to any one of Embodiments 1 to 16, wherein the cancer is locally advanced, regionally advanced, or a metastatic solid tumor. Embodiment 18. The method according to any one of Embodiments 1 to 14, wherein the cancer is a metastatic disease of the CNS. Embodiment 19. The method according to Embodiment 15, wherein the cancer is NSCLC. Embodiment 20. The method according to Embodiment 19, wherein the cancer is an adenocarcinoma of NSCLC. Embodiment 21. The method according to Embodiment 15, wherein the cancer is prostate cancer. Embodiment 22. The method according to Embodiment 15, wherein the cancer is colorectal cancer. Embodiment 23. The method according to Embodiment 15, wherein the cancer is a liposarcoma. Embodiment 24. The method according to Embodiment 15, wherein the cancer is breast cancer. Embodiment 25. The method according to Embodiment 24, wherein the breast cancer is advanced or metastatic breast cancer. Embodiment 26. The method according to Embodiment 24, wherein the breast cancer is locally advanced cancer. Embodiment 27. The method according to Embodiment 24, wherein the breast cancer is metastatic breast cancer. Embodiment 28. The method according to Embodiment 24, wherein the breast cancer is hormone receptor positive (HR+). Embodiment 29. The method according to Embodiment 24, wherein the breast cancer is estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or a combination thereof. Embodiment 30. The method according to Embodiment 24, wherein the breast cancer is hormone receptor-negative (HR-). Embodiment 31. The method according to Embodiment 24, wherein the breast cancer is estrogen receptor-negative (ER-), progesterone receptor-negative (PR-), or a combination thereof. Embodiment 32. The method according to Embodiment 24, wherein the breast cancer is human epidermal growth factor receptor 2 negative (HER2-). Embodiment 33. The method according to Embodiment 24, wherein the breast cancer is human epidermal growth factor receptor 2 positive (HER2+). Embodiment 34. The method according to Embodiment 24, wherein the breast cancer is HR+ / HER2- breast cancer. Embodiment 35. The method according to Embodiment 24, wherein the breast cancer is HR- / HER2+ breast cancer. Embodiment 36. The method according to Embodiment 24, wherein the breast cancer is ER+ / HR+. Embodiment 37. The method according to Embodiment 24, wherein the breast cancer is ER+ / HER2-. Embodiment 38. The method according to Embodiment 24, wherein the breast cancer is triple-negative breast cancer (TNBC). Embodiment 39. The method according to Embodiment 24, wherein the breast cancer is ER-, PR-, and HER2-. Embodiment 40. The method according to Embodiment 24, wherein the breast cancer is endocrine therapy-resistant breast cancer, trastuzumab or pertuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibitors. Embodiment 41. The method according to any one of Embodiments 24 to 40, wherein the breast cancer is resistant to treatment with standard therapeutic agents. Embodiment 42. The method according to any one of Embodiments 24 to 40, wherein the subject is refractory to endocrine therapy. Embodiment 43. The method according to any one of Embodiments 24 to 40, wherein the breast cancer is refractory or resistant to treatment with antitumor chemotherapy drugs, or progresses during such treatment. Embodiment 44. The method according to any one of Embodiments 24 to 40, wherein the breast cancer is progressing during or within 12 months after treatment with adjuvant therapy with an aromatase inhibitor. Embodiment 45. The method according to any one of Embodiments 24 to 40, wherein the breast cancer is progressing during or within 12 months after treatment with adjuvant therapy with tamoxifen. Embodiment 46. The method according to any one of Embodiments 1 to 45, wherein the above method is a primary treatment. Embodiment 47. The method according to any one of Embodiments 1 to 45, wherein the above method is a second-line treatment or a subsequent treatment. Embodiment 48. The method according to Embodiment 47, wherein the method is performed following treatment with an endocrine therapy drug, a CDK4 / CDK6 inhibitor, or a combination thereof. Embodiment 49. The method according to Embodiment 47, wherein the above method is performed following treatment with an endocrine therapy drug. Embodiment 50. The method according to Embodiment 47, wherein the above method is performed following treatment with one or more chemotherapy regimens. Embodiment 51. The method according to Embodiment 47, wherein the above method is performed following treatment with a HER2-targeted drug. Embodiment 52. A method for treating breast cancer in patients who require it, the following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A method comprising administering to a patient an endocrine therapy agent a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 53. The method according to Embodiment 52, wherein the compound is (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 54. The method according to Embodiment 52, wherein the compound is (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 55. The method according to Embodiment 52, wherein the compound is 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 56. The method according to Embodiment 52, wherein the compound is (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 57. The method according to Embodiment 52, wherein the compound is (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 58. The method according to Embodiment 52, wherein the compound is (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 59. The method according to any one of Embodiments 52 to 58, wherein the endocrine therapy agent is selected from the group consisting of biological polymer agents or chemically low molecular weight compounds useful for the treatment of cancer. Embodiment 60. The method according to any one of Embodiments 52 to 58, wherein the endocrine therapy agent is selected from the group consisting of aromatase inhibitors, androgen receptor inhibitors, selective estrogen receptor degraders (SERDs), or selective estrogen receptor modulators (SERMs). Embodiment 61. The method according to Embodiment 60, wherein the endocrine therapy drug is an androgen receptor inhibitor. Embodiment 62. The method according to Embodiment 60, wherein the endocrine therapy drug is an aromatase inhibitor. Embodiment 63. The method according to Embodiment 62, wherein the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane. Embodiment 64. The method according to Embodiment 62, wherein the aromatase inhibitor is letrozole. Embodiment 65. The method according to Embodiment 60, wherein the endocrine therapy drug is SERD. Embodiment 66. The method according to Embodiment 60, wherein SERD is selected from the group consisting of: fulvestrant, elastrant (RAO-1901), amsenetrant (SAR439859), gillederant (GOC9545), RG6171, camizestrant (AZO9833), AZO9496, lintdestrant, ZN-c5, LSZ102, 0-0502, LY3484356, and SHR9549. Embodiment 67. The method according to Embodiment 60, wherein SERD is full vestrant. Embodiment 68. The method according to Embodiment 60, wherein the endocrine therapy drug is a SERM. Embodiment 69. The method according to Embodiment 68, wherein the SERM is selected from the group consisting of tamoxifen, raloxifen, toremifene, lasofoxifen, bazedoxefene, and afimoxifen. Embodiment 70. The method according to Embodiment 68, wherein the SERM is tamoxifen or raloxifen. Embodiment 71. The method according to Embodiment 60, wherein the endocrine therapy agent is letrozole or fulvestrant. Embodiment 72. The method according to any one of Embodiments 52 to 71, wherein the endocrine therapy agent is administered to a subject in the course of treatment with (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 73. The method according to any one of Embodiments 52 to 71, wherein the endocrine therapy agent is administered before the first dose of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 74. The method according to any one of Embodiments 52 to 71, wherein the initial dose of the endocrine therapy agent is administered on the same day as the initial dose of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 75. The method according to any one of Embodiments 52 to 71, wherein the initial dose of the endocrine therapy agent is administered after the initiation of treatment with (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 76. The method according to any one of Embodiments 52 to 71, wherein the subject has previously received treatment with one or more lines of endocrine therapy prior to administration of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol or a pharmaceutically acceptable salt or solvate thereof to the subject. Embodiment 77. The method according to any one of Embodiments 51 to 62, wherein the subject has previously received treatment by chemotherapy, radiotherapy, and / or surgical resection prior to administration of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol or a pharmaceutically acceptable salt or solvate thereof to the subject. Embodiment 78. The method according to any one of Embodiments 51 to 62, wherein the subject has previously received treatment with a CDK4 / 6 inhibitor prior to administration of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol or a pharmaceutically acceptable salt or solvate thereof to the subject. Embodiment 79. The endocrine therapy drug is as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 52, administered to a patient during the course of treatment with a compound selected from the group consisting of the following. Embodiment 80. The endocrine therapy drug is as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 52, which is administered to the patient before administering an initial dose of a compound selected from the group consisting of the above. Embodiment 81. The initial dose of the endocrine therapy drug is as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 52, wherein the compound selected from the group consisting of is administered to the patient on the same day as the first dose of the compound. Embodiment 82. The initial dose of the endocrine therapy drug is as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 52, administered to the patient after the initiation of treatment with a compound selected from the group consisting of the following. Embodiment 83. The following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 52, wherein, prior to administration to the patient of a compound selected from the group consisting of, the patient has previously received treatment with one or more lines of endocrine therapy. Embodiment 84. The following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 1, wherein the patient has previously received treatment by chemotherapy, radiotherapy, and / or surgical resection prior to administration to the patient of a compound selected from the group consisting of the above. Embodiment 85. The following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to Embodiment 1, wherein the patient has previously received treatment with a CDK4 / 6 inhibitor before administration to the patient of a compound selected from the group consisting of the following. Embodiment 86. The method according to any one of Embodiments 1 to 85, wherein the method results in a complete response (CR), partial response (PR), or stable disease (SD) in a subject having a regional progressive disease or metastatic disease. Embodiment 87. The method according to any one of Embodiments 1 to 86, wherein the treatment results in complete response, partial response, or stabilization of intracranial metastatic disease or primary brain tumor. Embodiment 88. The method according to any one of Embodiments 1 to 87, wherein the treatment results in a reduction of disease recurrence in local, distal, or intracellular areas of the CNS, or a combination thereof. Embodiment 89. The method according to Embodiment 18, wherein the diseased site is the brain. Embodiment 90. The method according to Embodiment 15, wherein the patient has localized or regionally advanced cancer. Embodiment 91. A method for treating cancer in a patient who requires it, the following: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitriel; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl The procedure involves administering to a patient a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt or solvate thereof, wherein cancer is: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method. Embodiment 92. A method for treating cancer in a patient in need, comprising administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof, or (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method. Embodiment 93. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, or (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method. Embodiment 94. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, or (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of Cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method. Embodiment 95. The method according to Embodiment 91, wherein the solid tumor is characterized by CDK4 amplification or mutation. Embodiment 96. The method according to Embodiment 91, wherein the solid tumor is characterized by cyclin D1 amplification. Embodiment 97. The method according to Embodiment 91, wherein the solid tumor is characterized by cyclin E amplification. Embodiment 98. The method according to Embodiment 91, wherein the solid tumor is characterized by the absence of the negative regulatory gene CDKN2A or CDKN2B. Embodiment 99. The method according to any one of Embodiments 1 to 98, wherein the patient has not previously received CDK4 inhibitor therapy. Embodiment 100. The method according to any one of Embodiments 1 to 99, wherein the patient is resistant to CDK4 inhibitor or CDK6 inhibitor therapy. Embodiment 101. The following:

[0192] [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 102. The following:

[0193] [ka] A compound according to Embodiment 101 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 103. The following:

[0194] [ka] A compound according to Embodiment 101 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 104. Below

[0195] [ka] A compound according to Embodiment 101 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 105. At least one pharmaceutically acceptable excipient, and the following:

[0196] [ka] A pharmaceutical composition comprising a compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof. [Examples]

[0197] These examples are provided for illustrative purposes only and do not limit the scope of the claims set forth herein.

[0198] I. Chemical synthesis Example 1: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol

[0199] [ka] Step 1: 5-(3,3,3-trifluoroprop-1-en-2-yl)pyridine-2-amine To a solution of 5-bromopyridine-2-amine (50 g, 288.996 mmol) and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (64.2 g, 288.996 mmol) in dioxane (500 mL) and water (100 mL), Cs2CO3 (188.3 g, 577.992 mmol) and Pd(dppf)Cl2.CH2Cl2 (23.54 g, 28.900 mmol) were added. The reaction mixture was stirred under a nitrogen atmosphere at 85°C for 5 hours. After the resulting mixture was cooled to room temperature, it was filtered. The filtrate was washed with Â(3 × 500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1) to obtain 5-(3,3,3-trifluoroprop-1-en-2-yl)-2-pyridine-2-amine (48 g, 88%) as a yellow oil. C8H7F3N2[M+H] + MS ESI calculated value: 189.06, measured value: 189.10. 1 ¹H NMR (400MHz, chloroform-d): δ 8.17 (d, J=2.4Hz, 1H), 7.56 (dd, J=8.8, 2.4Hz, 1H), 6.53 (d, J=8.8Hz, 1H), 5.88 (q, J=1.6Hz, 1H), 5.70 (q, J=1.6Hz, 1H), 4.68 (br, 2H). 19 1F NMR (377 MHz, chloroform-d) δ-65.20 (3F).

[0200] Step 2: 5-(1,1,1-trifluoropropan-2-yl)pyridine-2-amine 5-(3,3,3-trifluoropropan-1-en-2-yl)pyridine-2-amine (48 g, 255.112 mmol) was dissolved in MeOH (500 mL) and Pd / C (10%, 9.23 g) was added. The mixture was hydrogenated at room temperature under a hydrogen atmosphere of 2 atm for 4 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / Âi (1 / 1) to obtain 5-(1,1,1-trifluoropropan-2-yl)pyridine-2-amine (40 g, 82%) as a brown oil. C8H9F3N2[M+H] + MS ESI calculated value: 191.07, measured value: 190.95. 1 ¹H NMR (400MHz, chloroform-d): δ 8.00 (d, J=2.4Hz, 1H), 7.44 (dd, J=8.4, 2.4Hz, 1H), 6.54 (dd, J=8.4Hz, 1H), 4.48 (br, 2H), 3.36-3.28 (m, 1H), 1.49 (d, J=7.2Hz, 3H). 19 F NMR (377 MHz, chloroform-d) δ-72.12 (3F).

[0201] Step 3: 2-Bromo-5-(1,1,1-trifluoropropan-2-yl)pyridine A solution of 5-(1,1,1-trifluoropropan-2-yl)pyridin-2-amine (45 g, 236.632 mmolv) in HBr (300 mL, 40% aqueous solution) was stirred, and Br₂ (58.6 mL, 1142.933 mmol) was added dropwise at -20 °C. The resulting mixture was stirred at -20 °C for 1.5 hours. A solution of NaNO₂ (76.6 g, 1109.804 mmol) in water (450 mL) was added dropwise to this at -20 °C. The resulting mixture was stirred at 10 - 20 °C for an additional 1 hour. The mixture was cooled to -20 °C. The reaction was quenched at -20 °C using a solution of NaOH (300 g, 7503.601 mmol) in water (450 mL). The resulting mixture was extracted with EtOAc (3 × 500 L). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (8 / 1) to obtain 2-bromo-5-(1,1,1-trifluoropropan-2-yl)pyridine (42 g, 70%) as a brown oil. C₈H₇BrF₃N₂ [M+H] + MS ESI calculated values for: 253.97, 255.97, measured values: 253.90, 255.90. 1 H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 2.4 Hz, 1H), 7.57 - 7.51 (m, 2H), 3.54 - 3.41 (m, 1H), 1.55 (d, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, chloroform-d) δ -71.65 (3F).

[0202] Step 4: 2-Bromo-5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine 2-Bromo-5-(1,1,1-trifluoropropan-2-yl)pyridine (60 g) was separated by Prep-chiral-HPLC using the following conditions: column: CHIRAL ART Cellulose-SB, 7*25 cm, 10 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 200 mL / min; gradient: A:B = 90:10; wavelength: 220 nm. At RT1:6.0 minutes, 2-bromo-5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine (29.4g, 49%) was obtained as a yellow oil. At RT2:8.4 minutes, 2-bromo-5-[(2R)-1,1,1-trifluoropropan-2-yl]pyridine (27.4g, 46%) was obtained as a yellow oil.

[0203] Step 5: (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-ol Solutions of 7-bromo-2-chloro-5-fluoropyrrolo[2,1-f][1,2,4]triazine (1.6 g, 6.388 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (1.18 g, 7.666 mmol), and DIEA (3.34 mL, 19.164 mmol) in NMP (15 mL) were stirred at 80°C for 16 hours. The resulting mixture was cooled to room temperature and purified by reverse-phase chromatography under the following conditions: column, C18 column; aqueous solution of CH3CN (10 mmol / L NH4HCO3), 20%~45%; detector: UV 254 / 220 nm to obtain (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-ol (1.7 g, 80%) as a brown solid. 11 H 12 BrFN4O2[M+H] + MS ESI calculated values: 331.01, 333.01; measured values: 331.05, 333.05. 1 ¹H NMR (400MHz, chloroform-d): δ 8.58 (s, ¹H), 6.38 (s, ¹H), 5.03 (brs, ¹H), 4.13-4.08 (m, ¹H), 4.05-3.96 (m, ¹H), 3.87-3.79 (m, ¹H), 3.71-3.62 (m, ¹H), 3.54-3.47 (m, ¹H), 3.29-3.23 (m, ¹H), 2.16-2.08 (m, ¹H), 1.78-1.67 (m, ¹H). 19 F NMR (376 MHz, chloroform-d) δ-156.40 (1F).

[0204] Step 6: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol To a stirred mixture of 2-bromo-5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine (17.84 g, 70.210 mmol) and hexabutyldistanane (44.80 g, 77.232 mmol), Pd(OAc)2 (0.74 g, 3.276 mmol) and PCy3 (1.97 g, 7.021 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 110°C for 24 hours. The resulting mixture was then cooled to room temperature. (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-ol (15.5 g, 46.807 mmol), Pd(PPh3)4 (2.70 g, 2.340 mmol), and CuI (3.57 g, 18.723 mmol) were added at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 120°C for a further 16 hours. The resulting mixture was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH(10 / 1). Under the following conditions: C18 column, mobile phase: aqueous solution of CH3CN (10 mmol / L NH4HCO3), 45%~65%; detector: UV254nm, the crude product was purified by reverse-phase chromatography to obtain (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (9.52 g, 47%) as a pale yellow solid. 19 H 19 F4N5O2[M+H] + MS ESI calculated value: 426.15, measured value: 426.25. 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.84(d,J=8.4Hz,1H),8.67(d,J=1.2Hz,1H),8.01(dd, J=8.4,1.2Hz,1H),7.16(d,J=7.6Hz,1H),7.09(s,1H),4.98(d,J=5.2Hz,1H),4.03-3.91(m,1H),3.89-3.85(m,2H) ,3.78-3.70(m,1H),3.62-3.55(m,1H),3.52-3.41(m,1H),3.18-3.13(m,1H),2.17-2.14(m,1H),1.58-1.45(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-70.17(3F),-161.59(1F).

[0205] Example 2: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl

[0206] [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (1.53 g, 7.053 mmol) in DMF (25 mL), N,N'-diisopropylcarbodiimide (0.65 g, 5.172 mmol) was added at room temperature. Then, a solution of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (1 g, 2.351 mmol) and DMAP (28 mg, 0.235 mmol) in DCM (25 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (2 / 1) to obtain (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (1.4 g, 95%) as a pale yellow solid. 29 H 36 F4N6O5[M+H] + MS ESI calculated value: 625.27, measured value: 625.30. 1 H NMR(400MHz,chloroform-d)δ8.79-8.69(m,2H),8.62(d,J=2.4Hz,1H),7.77(dd,J=8.4,2.4Hz,1H),7.12(s,1H),5.44(brs,1H),5.09-5.04(m,2H),4.2 5-3.97(m,4H),3.73-3.44(m,3H),2.52-2.37(m,1H),2.15-2.12(m,1H), 1.79-7.75(m,1H),1.60(d,J=7.2Hz,3H),1.45(s,9H),0.92-0.85(m,6H). 19 F NMR (377 MHz, chloroform-d) δ -71.41 (3F), -160.41 (1F).

[0207] Step 2: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (1.5 g, 2.401 mmol) was stirred in DCM (10 mL), to which TFA (2 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basicized to pH 8 with saturated NaHCO3 and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 20%~50%; detector: reverse-phase chromatography using UV254nm to purify the residue and obtain (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl]pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (1.00 g, 79%) as a yellow solid. 24 H 28 F4N6O3[M+H] + MS ESI calculated value: 525.22, measured value: 525.25. 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.86(d,J=8.4Hz,1H),8.68(s,1H),8.03(d, J=8.4,1H),7.40(d,J=7.6Hz,1H),7.12(s,1H),4.88-4.82(m,1H),4.14-4.12(m,1 H),4.01-3.90(m,3H),3.60-3.55(m,1H),3.39-3.32(m,1H),2.97(d,J=5.2Hz,1H ),2.13-2.10(m,1H),1.81-1.69(m,2H),1.58-1.51(m,5H),0.65(d,J=6.8Hz,6H). 19 F NMR(377MHz,DMSO-d6)δ-70.19,-161.39.

[0208] Example 3: 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0209] [ka] Step 1: 2,4-Dichloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine A mixture of 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (2.00 g, 10.638 mmol), 1-ethylcyclobutane-1-carboxylic acid (4.09 g, 31.914 mmol), and AgNO3 (3.61 g, 21.276 mmol) in CH3CN (50 mL) and H2O (25 mL) was stirred, and a solution of (NH4)2S2O8 (12.14 g, 53.190 mmol) in H2O (25 mL) was added dropwise at 50°C. The resulting mixture was stirred at 50°C for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA(10 / 1) to obtain 2,4-dichloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine (2.20 g, 76%) as a yellow oil. 12 H 13 Cl2N3[M+H] + MS ESI calculated value: 270.05, measured value: 269.95. 1 ¹H NMR (400MHz, chloroform-d): δ 7.03 (d, J=4.8Hz, 1H), 6.79 (d, J=4.8Hz, 1H), 2.52-2.44 (m, 2H), 2.33-2.26 (m, 2H), 2.10-2.06 (m, 3H), 1.95-1.87 (m, 1H), 0.61 (t, J=7.2Hz, 3H).

[0210] Step 2: 2-Chloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine 2,4-Dichloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine (2.20 g, 8.143 mmol) was stirred in i-PrOH (50 mL), to which NaBH4 (0.46 g, 12.215 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL). The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. DDQ (2.77 g, 12.215 mmol) and DCM (50 mL) were added to the residue. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was quenched with saturated NaHCO3 (aq.) (50 mL). The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (10 / 1) to obtain 2-chloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine (1.30 g, 67%) as a yellow oil. 12 H 14 ClN3[M+H] + MS ESI calculated value: 236.09, measured value: 236.05. 1 H NMR (400MHz, chloroform-d) δ6.89(s,1H),6.90(d,J=4.8Hz,1H),6.77(d,J=4.8Hz,1H),2.52-2 .45(m,2H),2.32-2.25(m,2H),2.15-2.04(m,3H),1.95-1.85(m,1H),0.59(t,J=7.2Hz,3H).

[0211] Step 3: 2,5-Dichloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine A mixture of 2-chloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine (3.3 g, 14,000 mmol) and NCS (1.96 g, 14,700 mmol) in DMF (50 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / ethyl acetate (1 / 1) to obtain 2,5-dichloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine (3.0 g, 79%) as a yellow solid. 12 H 13 Cl2N3[M+H] + MS ESI calculated value: 270.05, measured value: 270.05. 1 ¹H NMR (400MHz, chloroform-d): δ 8.75 (s, 1H), 6.72 (s, 1H), 2.51-2.40 (m, 2H), 2.34-2.24 (m, 2H), 2.14-2.06 (m, 3H), 1.97-1.87 (m, 1H), 0.63 (t, J=7.2Hz, 3H).

[0212] Step 4: 2,5-Dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine A mixture of 2,5-dichloro-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine (3.0 g, 11.105 mmol) and I2 (11.27 g, 44.420 mmol) in DMF (60 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated Na2S2O3 (100 mL). The resulting mixture was extracted with ELISA (3 × 200 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / ELISA (1 / 1) to obtain 2,5-dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine (3.0 g, 68%) as a yellow solid. 12 H 12 Cl2N3[M+H] + MS ESI calculated value: 395.95; measured value: 395.95. 1 ¹H NMR (400 MHz, chloroform-d): δδ 8.71 (s, 1H), 2.79-2.62 (m, 2H), 2.56-2.40 (m, 2H), 2.20-2.04 (m, 3H), 1.93-1.79 (m, 1H), 0.88-0.74 (m, 3H).

[0213] Step 5: (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-ol DIEA (1.31 g, 10.100 mmol) was added to a stirred mixture of 2,5-dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine (1 g, 2.525 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (0.78 g, 5.050 mmol) in DMSO (10 mL). The reaction mixture was stirred at 80°C for 16 hours. The resulting mixture was purified by reverse-phase chromatography using a C18 column under the following conditions: mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 30%~80%; detector, UV254nm, to obtain (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]aminooxan-3-ol (1g, 82%) as a brown solid. 17 H 22 ClN4O2[M+H] + MS ESI calculated value: 477.05, measured value: 477.05. 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),6.86(d,J=6.8Hz,1H),4.92(d,J=5.2Hz,1H),3.84-3.80(m,2H),3.58-3.45(m,2H),3.33-3.27(m,1H) ,3.07-3.02(m,1H),2.71-2.53(m,2H),2.33-2.25(m,2H),2.14-1.95(m,4H),1.82-1.74(m,1H),1.45-1.38(m,1H),0.72(t,J=7.2Hz,3H).

[0214] Step 6: Acetate (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-ol (530 mg, 1.112 mmol) and TEA (675 mg, 6.672 mmol) were stirred in DCM (5 mL) to which Ac2O (454 mg, 4.448 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA(4 / 1) to obtain (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]aminooxan-3-yl acetate (570 mg, 98%) as a yellow solid. 19 H 24 ClN4O3[M+H] + MS ESI calculated value: 519.06, measured value: 519.10. 1 ¹H NMR (400MHz, chloroform-d): δ 8.53 (s, 1H), 5.05-4.82 (m, 2H), 4.15-3.93 (m, 2H), 3.87-3.83 (m, 1H), 3.57-3.51 (m, 1H), 3.45-3.40 (m, 1H), 2.83-2.63 (m, 2H), 2.47-2.30 (m, 3H), 2.16-2.06 (m, 6H), 1.93-1.79 (m, 1H), 1.68-1.62 (m, 1H), 0.81 (t, J=7.2Hz, 3H).

[0215] Step 7: Acetate (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl acetate (130 mg, 0.251 mmol) and Zn(CN)2 (44 mg, 0.377 mmol, 1.5 equivalents) were stirred in DMF (3 mL) and Pd(PPh3)4 (29 mg, 0.025 mmol) was added under a nitrogen atmosphere. The reaction mixture was irradiated with microwaves at 120 °C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (3 / 1) to obtain (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl) acetate (90 mg, 86%) as a yellow solid. 20 H 24 ClN5O3[M+H] + MS ESI calculated value: 418.16, measured value: 418.00. 1 ¹H NMR (400MHz, chloroform-d): δ 8.64 (s, 1H), 5.22 (d, J=7.2Hz, 1H), 4.96-4.91 (m, 1H), 4.05-3.89 (m, 2H), 3.86-3.73 (m, 1H), 3.53-3.47 (m, 1H), 3.42-3.37 (m, 1H), 2.73-2.62 (m, 2H), 2.44-2.24 (m, 3H), 2.24-2.02 (m, 6H), 1.99-1.87 (m, 1H), 1.68-1.63 (m, 1H), 0.79 (t, J=7.2Hz, 3H).

[0216] Step 8: 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile A solution of (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl acetate (80 mg, 0.191 mmol) and K2CO3 (53 mg, 0.382 mmol) in MeOH (2 mL) was stirred at 0°C for 30 minutes. The reaction mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase: aqueous solution of CH3CN (10 mM NH4HCO3), 20%~60%; detector: 254 nm to obtain 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (45.3 mg, 63%) as an off-white solid. 18 H 22 ClN5O2[M+H] + MS ESI calculated value: 376.15, measured value: 376.15. 1 H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.33(d,J=7.2Hz,1H),4.95(d,J=4.8Hz,1H),3.85-3.81(m,2H),3.61-3.55(m,1H),3.52-3.47(m,1H) ,3.34-3.27(m,1H),3.08-3.02(m,1H),2.64-2.50(m,2H),2.27-1.99(m,6H),1.90-1.85(m,1H),1.46-1.42(m,1H),0.69(t,J=7.2Hz,3H).

[0217] Example 4: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl

[0218] [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (208 mg, 0.957 mmol) and N,N'-diisopropylcarbodiimide (89 mg, 0.702 mmol) were stirred in DMF (1 mL). 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (120 mg, 0.319 mmol) and a DCM (1 mL) solution of DMAP (4 mg, 0.032 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with ELISA (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (2 / 1) to obtain (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (117 mg, 64%) as a yellow solid. 28 H 39 ClN6O5[M+H] + MS ESI calculated value: 575.27, measured value: 575.40.

[0219] Step 2: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (100 mg, 0.174 mmol) was dissolved in DCM (1 mL) to which TFA (0.2 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase: Aqueous solution of CH3CN (10 mmol / L NH4HCO3), 44%~74%; Wavelength: 254 / 220 nm to obtain (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl (51.9 mg, 63%) as an off-white solid. 23 H 31 ClN6O3[M+H] + MS ESI calculated value: 475.21, measured value: 475.35. 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.58(d,J=6.8Hz,1H),4.85-4.83(m,1H),3.92-3.85(m,3H),3.48-3.45(m,1H),3.30-3.22(m,1H), 3.03(d,J=5.2Hz,1H),2.64-2.54(m,2H),2.27-2.01(m,6H),1.89-1.86(m,1H),1.76-1.71(m,2H),1.69-1.58(m,2H),1.79-1.68(m,9H).

[0220] Example 5: (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol

[0221] [ka] Step 1: Acetate (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-yl A mixture of (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-ol (6.1 g, 18.421 mmol), Ac2O (2.82 g, 27.631 mmol), and TEA (12.8 mL, 92.105 mmol) in DCM (100 mL) was stirred at 50°C for 16 hours. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1) to obtain (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-yl acetate (6.2 g, 90%) as a yellow solid. 13 H 14 BrFN4O3[M+H] + MS ESI calculated values: 373.02, 375.02; measured values: 373.00, 375.00. 1 ¹H NMR (400MHz, chloroform-d): δ 8.57 (s, 1H), 6.35 (s, 1H), 5.13 (d, J=7.2Hz, 1H), 4.99-4.93 (m, 1H), 4.13-4.01 (m, 2H), 4.00-3.95 (m, 1H), 3.62-3.56 (m, 1H), 3.46-3.40 (m, 1H), 2.52-2.46 (m, 1H), 2.06 (s, 3H), 1.74-1.60 (m, 1H). 19 F NMR (377 MHz, chloroform-d) δ-157.88 (1F).

[0222] Step 2: 1-(6-chloropyridine-3-yl)cyclopropane-1-carboxylate methyl carboxylate To a stirred solution of methyl 2-(6-chloropyridine-3-yl)acetate (4 g, 21.551 mmol) in DMF (100 mL), NaH (2.1 g, 53.877 mmol, 60%) was added in several batches at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. Dibromoethane (6.1 g, 32.326 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was quenched with saturated NH4Cl (200 mL). The resulting mixture was diluted with water (200 mL) and extracted with siRNA (2 × 400 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / toluene (4 / 1) to obtain methyl 1-(6-chloropyridine-3-yl)cyclopropane-1-carboxylate (3.3 g, 72%) as a colorless oil. 10 H 10 ClNO2[M+H] + MS ESI calculated value: 212.04, measured value: 211.85. 1 ¹H NMR (400MHz, chloroform-d): δ 8.37 (d, J=2.4Hz, 1H), 7.65 (dd, J=8.4, 2.4Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 3.66 (s, 3H), 1.73-1.68 (m, 2H), 1.22-1.19 (m, 2H).

[0223] Step 3: [1-(6-chloropyridine-3-yl)cyclopropyl]methanol To a solution of methyl 1-(6-chloropyridine-3-yl)cyclopropane-1-carboxylate (3.3 g, 15.592 mmol) in MeOH (100 mL), NaBH4 (3.0 g, 77.960 mmol) was added in several batches at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated NH4Cl (100 mL). The resulting mixture was concentrated under reduced pressure to remove MeOH. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1) to obtain [1-(6-chloropyridine-3-yl)cyclopropyl]methanol (1.1 g, 38%) as a colorless oil. C9H 10 ClNO[M+H] + MS ESI calculated value: 184.05, measured value: 184.05. 1 ¹H NMR (400MHz, chloroform-d): δ 8.39 (d, J=2.4Hz, 1H), 7.69 (dd, J=8.4, 2.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 3.70 (s, 2H), 2.22 (s, 1H), 0.98-0.95 (m, 2H), 0.92-0.89 (m, 2H).

[0224] Step 4: 1-(6-chloropyridine-3-yl)cyclopropane-1-carbaldehyde [1-(6-chloropyridine-3-yl)cyclopropyl]methanol (1.1 g, 5.990 mmol) was stirred in DCM (30 mL), to which DMP (5.1 g, 11.980 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (4 / 1) to obtain 1-(6-chloropyridine-3-yl)cyclopropane-1-carbaldehyde (850 mg, 78%) as a colorless oil. C9H8ClNO[M+H] +MS ESI calculated value: 182.03, measured value: 181.90. 1 ¹H NMR (400MHz, chloroform-d): δ 9.01 (s, 1H), 8.33 (d, J=2.4Hz, 1H), 7.62 (dd, J=8.4, 2.4Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 1.83-1.51 (m, 2H), 1.59-1.36 (m, 2H).

[0225] Step 5: 2-Chloro-5-[1-(difluoromethyl)cyclopropyl]pyridine To a stirred solution of 1-(6-chloropyridine-3-yl)cyclopropane-1-carbaldehyde (850 mg, 4.680 mmol) in DCM (20 mL), DAST (2.3 g, 14.040 mmol) was added dropwise at -30°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / Âi(5 / 1) to obtain 2-chloro-5-[1-(difluoromethyl)cyclopropyl]pyridine (700 mg, 73%) as a pale yellow oil. C9H8ClF2N[M+H] + MS ESI calculated value: 204.03, measured value: 204.00. 1 ¹H NMR (400MHz, chloroform-d): δ 8.43 (d, J=2.4Hz, 1H), 7.71 (dd, J=2.4, 8.4Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 5.54 (t, J=56.4Hz, 1H), 1.33-1.17 (m, 2H), 1.03-0.96 (m, 2H). 19 F NMR (377 MHz, chloroform-d) δ-116.04 (2F).

[0226] Step 6: Acetate (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl}amino)oxan-3-yl acetate (6 g, 16.078 mmol) and bis(pinacolate)diboron (8.17 g, 32.156 mmol) were stirred in 100 mL of dioxane. Under a nitrogen atmosphere at room temperature, KOAc (4.73 g, 48.234 mmol), PPh3 (0.84 g, 3.216 mmol), and Pd(PPh3)2Cl2 (1.13 g, 1.608 mmol) were added. The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 16 hours. The mixture was then cooled to room temperature. To this, 2-chloro-5-[1-(difluoromethyl)cyclopropyl]pyridine (3.27 g, 16.078 mmol), Cs2CO3 (10.48 g, 32.156 mmol), H2O (20 mL), and Pd(dppf)Cl2·CH2Cl2 (1.31 g, 1.608 mmol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for a further 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with siRNA (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1). The crude product was purified by reverse-phase flash chromatography using the following conditions: C18 column; mobile phase: aqueous solution of CH3CN (10 mmol / L NH4HCO3), 20%~70%; wavelength: 254 nm, to obtain (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl acetate) (4.8 g, 64%) as a yellow solid. 22 H 22 F3N5O3[M+H] + MS ESI calculated value: 462.17, measured value: 462.20. 11H NMR (400 MHz, chloroform-d) δ 8.78 - 8.61 (m, 3H), 7.90 - 7.76 (m, 1H), 7.12 (s, 1H), 5.62 (t, J = 56.8 Hz, 1H), 5.16 - 4.97 (m, 2H), 4.20 - 3.95 (m, 3H), 3.68 - 3.59 (m, 1H), 3.53 - 3.48 (m, 1H), 2.50 - 2.45 (m, 1H), 2.07 (s, 3H), 1.79 - 1.67 (m, 1H), 1.30 - 1.23 (m, 2H), 1.10 - 1.03 (m, 2H). 19 19F NMR (377 MHz, chloroform-d) δ -116.08 (2F), -160.58 (1F).

[0227] Step 7: (3S,4R)-4-[(7-{5-[1-(Difluoromethyl)cyclopropyl]pyridin-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]oxan-3-ol ​​​​​+ MS ESI calculated value: 420.16, measured value: 420.10. 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.80(d,J=8.4Hz,1H),8.64(d,J=2.0Hz,1H),7.95 -7.91(m,1H),7.16-7.12(m,1H),7.08(s,1H),5.92(t,J=56.0Hz,1H),4.95(d,J=1.6Hz, 1H),3.90-3.84(m,2H),3.75-3.71(m,1H),3.61-3.56(m,1H),3.50-3.44(m,1H),3.19-3 .13(m,1H),2.17-2.13(m,1H),1.54-1.44(m,1H),1.22-1.18(m,2H),1.11-1.07(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-114.41(2F),-161.58(1F).

[0228] Example 6: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl

[0229] [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-methylbutanoic acid (2.07 g, 9.538 mmol) was added to a stirred solution in DMF (40 mL) of N,N'-diisopropylcarbodiimide (1.32 g, 10.492 mmol) at room temperature. Then, a solution of (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridin-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]oxan-3-ol (2 g, 4.769 mmol) and DMAP (58 mg, 0.477 mmol) in DCM (40 mL) was added. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1 / 1), to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridin-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]oxan-3-yl (2.8 g, 94%) as a yellow solid. C 30 H 37 F3N6O5[M+H] + The calculated value of MS ESI for: 619.28, the measured value: 619.30.

[0230] Step 2: (2S)-2-Amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridin-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]oxan-3-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (2.8 g, 4.526 mmol) was stirred in DCM (30 mL) and TFA (6 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was basicized to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: Column: WelFlash C18, Regular C18 20-40 μm, 330 g; Mobile phase: CH3CN aqueous solution (0.05% TFA), 22-52%; Wavelength: 254 / 220 nm; The resulting mixture was concentrated under reduced pressure to remove CH3CN. Next, the resulting mixture was basicized to pH 8 with saturated NaHCO3 (aq.) and then extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was freeze-dried to obtain (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (1.10 g, 46%) as a yellow solid. 25 H 29 F3N6O3[M+H] + MS ESI calculated value: 519.23, measured value: 519.35. 1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.80(d,J=8.4Hz,1H),8.64(d,J=2.0Hz,1H),7.95(dd,J=2.0,8 .4Hz,1H),7.38(d,J=8.0Hz,1H),7.10(s,1H),5.91(t,J=56.0Hz,1H),4.87-4.83(m,1H),4.15-4.10( m,1H),3.95-3.89(m,2H),3.60-3.56(m,1H),3.39-3.33(m,1H),2.98(d,J=5.2Hz,1H),2.13-2.07(m ,1H),1.77-1.67(m,2H),1.49-1.47(m,2H),1.23-1.20(m,2H),1.10-1.08(m,2H),0.68-0.65(m,6H). 19 F NMR(377MHz,DMSO-d6)δ-114.36(2F),-161.41(1F).

[0231] Example 7: (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl acetate

[0232] [ka] Step 1: Acetate (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (100 mg, 0.238 mmol) and TEA (120 mg, 1.190 mmol) were stirred in DCM (2 mL) and Ac2O (36 mg, 0.357 mmol) was added at room temperature. The resulting mixture was stirred at 50 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 20%~70%; detector, UV254nm. The residue was purified by reverse-phase chromatography to obtain (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl acetate (50.4 mg, 45%) as a yellow solid. 22 H 22 F3N5O3[M+H] + MS ESI calculated value: 462.17, measured value: 462.20. 1 H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.77(d,J=8.4Hz,1H),8.63(d,J=2.0Hz,1H),7.92( dd,J=2.0,8.4Hz,1H),7.33(d,J=8.0Hz,1H),7.09(s,1H),5.91(t,J=56.0Hz,1H),4.87-4 .81(m,1H),4.07-4.03(m,1H),3.97-3.87(m,2H),3.59-3.53(m,1H),3.38-3.31(m,1H), 2.18-2.14(m,1H),1.93(s,3H),1.75-1.66(m,1H),1.22-1.19(m,2H),1.12-1.05(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-114.33(2F),-161.32(1F).

[0233] Example 8: Sulfamic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl

[0234] [ka] Step 1: Sulfamic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoroimidazo[4,3-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (50 mg, 0.119 mmol) and TEA (36 mg, 0.357 mmol) were stirred in DMF (2 mL), to which sulfamoyl chloride (41 mg, 0.357 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 20%~60%; detector, reverse-phase chromatography using UV 254 nm to purify the mixture and obtain sulfamic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (57 mg, 93%) as a yellow solid. 20 H 21 F3N6O4S[M+H] + MS ESI calculated value: 499.13, measured value: 499.15. 1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.77(d,J=8.0Hz,1H),8.64(d,J=2.0Hz,1H),7 .95(dd,J=2.4,8.4Hz,1H),7.57(s,2H),7.19(d,J=8.0Hz,1H),7.10(s,1H),5.91(t, J=56.0Hz,1H),4.50-4.44(m,1H),4.17-4.09(m,2H),3.90-3.86(m,1H),3.59-3.50 (m,2H),2.19-2.15(m,1H),1.75-1.71(m,1H),1.24-1.20(m,2H),1.11-1.08(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-114.29(2F),-161.40(1F).

[0235] Example 9: [(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxyphosphonic acid

[0236] [ka] Step 1: [(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxyphosphonic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (50 mg, 0.119 mmol) and lysine (18.8 mg, 0.238 mmol) were stirred in THF (1 mL), to which POCl3 (36.5 mg, 0.238 mmol) was added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. H2O (2 mL) was added dropwise at 0°C. The resulting mixture was stirred for a further 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid, 10-40%); detector, reverse-phase chromatography using UV254nm to purify the residue and obtain [(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxyphosphonic acid (41.9 mg, 70%) as a yellow solid. 20 H 21 F3N5O5P[M+H] + MS ESI calculated value: 500.12, measured value: 500.10. 1 H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.73(d,J=8.4Hz,1H),8.60(d,J=2.0Hz,1H),7 .90(dd,J=2.0,8.4Hz,1H),7.65(br,1H),7.05(s,1H),5.89(t,J=56.0Hz,1H),4.17 -4.11(m,1H),4.09-3.99(m,1H),3.85-3.75(m,2H),3.59-3.51(m,1H),3.34-3.28( m,1H),2.40-2.36(m,1H),1.50-1.46(m,1H),1.19-1.16(m,2H),1.09-1.05(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-114.44(2F),-161.60(1F). 31 P NMR (162 MHz, DMSO-d6) δ -0.20.

[0237] Example 10: ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonic acid

[0238] [ka] Step 1: ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonate diethyl (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (100 mg, 0.238 mmol) and t-BuOLi (0.16 mL, 0.357 mmol, 2.2 M THF solution) were stirred in DMF (1 mL), to which [(4-methylbenzenesulfonyl)oxy]methanephosphonate diethyl (115 mg, 0.357 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The obtained mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 30%~60%; detector, UV254nm, to obtain ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonate diethyl (70 mg, 51%) as a pale yellow solid. 25 H 31 F3N5O5P[M+H] + MS ESI calculated value: 570.20, measured value: 570.30.

[0239] Step 2: ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonic acid ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonate diethyl (30 mg, 0.053 mmol) was stirred in DMF (1 mL), to which TMSBr (0.1 mL) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 20%~45%; detector, UV 254 nm, to obtain ((((3S,4R)-4-((7-(5-(1-(difluoromethyl)cyclopropyl)pyridine-2-yl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino)tetrahydro-2H-pyran-3-yl)oxy)methyl)phosphonic acid (1.2 mg, 4%) as a pale yellow solid. 21 H 23 F3N5O5P[M+H] + MS ESI calculated value: 514.14; measured value: 514.10. 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.76(d,J=8.4Hz,1H),8.63(s,1H),7.95(d,J=8.4Hz,1H),7.88(br,1H),7.05(s,1H),5.93(t,J=56.0H z,1H),4.08-4.06(m,1H),3.85-3.72(m,2H),3.68-3.63(m,3H),3.31- 3.18(m,2H),2.34-2.30(m,1H),1.43-1.40(m,1H),1.19-1.07(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-114.61(2F),-161.69(1F).

[0240] Example 11: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0241] [ka] Step 1: (3R,4S)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino-3-hydroxypiperidine-1-carboxylate tert-butyl 2,5-Dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine (70 mg, 0.17 mmol) and (3R,4S)-4-amino-3-hydroxypiperidine-1-carboxylate tert-butyl (191 mg, 0.88 mmol) were stirred in DMF (2 mL), to which DIEA (137 mg, 1.06 mmol) was added. The resulting mixture was stirred at 80°C for 16 hours. The resulting mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 50%~90%; detector, UV254nm, to obtain (3R,4S)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (90 mg, 88%) as a pale yellow oil. 22 H 31 ClN5O3[M+H] + MS ESI calculated value: 576.12, measured value: 576.15. 1¹H NMR (400MHz, chloroform-d): δ 8.54 (s, 1H), 5.11-5.08 (m, 1H), 4.10-4.06 (m, 2H), 3.83-3.74 (m, 1H), 3.11-3.07 (m, 1H), 2.99-2.87 (m, 1H), 2.75-2.70 (m, 2H), 2.37-2.33 (m, 3H), 2.19-2.04 (m, 2H), 1.95-1.73 (m, 3H), 1.50 (s, 9H), 0.81 (t, J=7.2Hz, 3H).

[0242] Step 2: (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino-3-hydroxypiperidine-1-carboxylate tert-butyl (3R,4S)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (75 mg, 0.13 mmol) and Pd(PPh3)4 (15 mg, 0.013 mmol) were stirred in DMF (1.5 mL) and Zn(CN)2 (9 mg, 0.07 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at 150 °C for 1 hour. The mixture was then cooled to room temperature. The mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mmol / L NH4HCO3), 10%~50%; detector, UV254nm, to obtain (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (40 mg, 65%) as a pale yellow oil. 23 H 31 ClN6O3[M+H] + MS ESI calculated value: 475.21, measured value: 475.35.

[0243] Step 3: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile hydrochloride (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (40 mg, 0.08 mmol) was stirred in DCM (2 mL), to which a solution of 1,4-dioxane (2 mL) in HCl (gas) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile hydrochloride (40 mg, unpurified) as a pale yellow solid. 18 H 24 Cl2N6O[M-Cl] + MS ESI calculated value: 375.16, measured value: 375.20.

[0244] Step 4: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrilate hydrochloride (45 mg, 0.12 mmol) was stirred in ELISA (2 mL) and saturated NaHCO3 (2 mL). Methanesulfonylmethanesulfonate (42 mg, 0.24 mmol) was added in small amounts at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mM NH4HCO3), 40%~70%; detector, UV254 nm, to obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (33.3 mg, 61%) as a pale yellow solid. 19 H 25 ClN6O3S[M+H] + MS ESI calculated value: 453.14, measured value: 453.15. 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),7.01(d,J=7.2Hz,1H),5.16(d,J=4.4Hz,1H),4.02-4.00(m,1H),3.66-3.62(m,1H),3.59-3.47(m,2H),3.06- 3.02(m,1H),2.99-2.92(m,4H),2.62-2.58(m,2H),2.28-2.12(m,3H),2. 09-2.00(m,2H),1.97-1.88(m,2H),1.74-1.70(m,1H),0.73-0.67(m,3H).

[0245] Example 12: (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl

[0246] [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (2.5 g, 5.519 mmol), (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3.60 g, 16.557 mmol), and DMAP (0.07 g, 0.552 mmol) were mixed in DMF (50 mL) and DCM (50 mL) and DIC (1.53 g, 12.142 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water / ice (100 mL). The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1) to obtain (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (3 g, 83%) as a yellow solid. 29 H 42 ClN7O6S[M+H] + MS ESI calculated value: 652.26, measured value: 652.30. 1H NMR(400MHz,chloroform-d)δ8.63(s,1H),5.65(d,J=8.0Hz,1H),5.39(s,1H),5 .00(d,J=8.0Hz,1H),4.13-4.02(m,2H),3.94-3.92(m,2H),3.05-3.01(m,1 H),2.97-2.93(m,1H),2.91-2.88(m,3H),2.79-2.65(m,2H),2.34-2.28(m, 2H),2.25-1.94(m,4H),1.47(s,9H),1.14-0.94(m,7H),0.83-0.79(m,3H).

[0247] Step 2: (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (3.5 g, 5.366 mmol) was stirred in DCM (35 mL), to which TFA (7 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated NaHCO3 (aq.) (200 mL) at 0°C. The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by grinding with acetonitrile / H2O (1 / 2, 60 mL) to obtain (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (2.18 g, 74%) as a yellow solid. 24 H 34 ClN7O4S[M+H] + MS ESI calculated value: 552.21, measured value: 552.15.1 H-NMR (400MHz,DMSO-d6)δ8.96(s,1H),7.62(d,J=6.0Hz,1H),5.25(s,1H),3.87-3.59(m,3H),3.20(d,J=4.8Hz,1H),3.12-3.09(m,1H), 2.98-2.92(m,4H),2.63-2.59(m,2H),2.31-2.22(m,2H),2.21-1.81(m,7H),1.59(s,2H),0.86-0.80(m,6H),0.72(t,J=7.2Hz,3H).

[0248] Example 13: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0249] [ka] Step 1: (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl}amino-3-hydroxypiperidine-1-carboxylate tert-butyl 2,5-Dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine (90 mg, 0.227 mmol) and (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylate tert-butyl (246 mg, 1.136 mmol) were mixed in NMP (2 mL) and DIEA (177 mg, 1.363 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC using PE / siRNA (2 / 1) to obtain (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (38 mg, 29%) as a yellow solid. 22 H 31 ClN5O3[M+H] + MS ESI calculated value: 576.12, measured value: 576.15.

[0250] Step 2: (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (3 g, 5.209 mmol) and Zn(CN) 20.2 g, 3.125 mmol) were stirred in DMF (30 mL) and Pd(PPh3)4 (0.6 g, 0.521 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at 120 °C for 2 hours. The resulting mixture was purified by reverse-phase chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 10-50% gradient over 10 minutes; detector, UV254nm, to obtain (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (2g, 81%) as a yellow solid. 23 H 31 ClN6O3[M+H] + MS ESI calculated value: 475.21, measured value: 475.25. 1 H NMR(400MHz,chloroform-d)δ8.66(s,1H),5.50-5.43(m,1H),4.25-4.20(m,1H),4.17-4.02(m,2H),3.76-3.72(m,1H),3.06-3.02(m,1H),2.95-2. 84(m,1H),2.69-2.63(m,2H),2.31-2.27(m,2H),2.11-2.02(m,3H),1. 99-1.88(m,2H),1.86-1.74(m,1H),1.49(s,9H),0.80(t,J=7.2Hz,3H).

[0251] Step 3: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile hydrochloride (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (2 g, 4.211 mmol) and a solution of HCl (gas) in 1,4-dioxane (40 mL) in DCM (20 mL) were stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile hydrochloride (2 g, unpurified) as a yellow solid. The crude product was used directly in the next step without further purification. 18 H 24 Cl2N6O[M+H] + MS ESI calculated value: 375.16, measured value: 375.15.

[0252] Step 4: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile A solution of 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (2 g, 5.335 mmol) and Ms2O (1.86 g, 10.670 mmol) in ethyl phosphate (20 mL) was basicized to pH 8 with saturated NaHCO3 solution. The resulting mixture was stirred at room temperature for 1 hour. The aqueous layer was extracted with ethyl phosphate (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 40%~60%; detector, reverse-phase chromatography using UV254nm to purify the residue and obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.5g, 62%) as a pale yellow solid. 19 H 25 Cl2N6O[M+H] + MS ESI calculated value: 453.14, measured value: 453.25. 1 H NMR(400MHz,chloroform-d)δ8.71(s,1H),5.75(d,J=7.6Hz,1H),4.15-4.10(m,1H),4.01-3.93(m,1H),3.89-2.84(m,1H),3.79-3.69(m,1H),3.08-3.0 4(m,1H),2.93-2.86(m,4H),2.76-2.62(m,2H),2.35-2.25(m,2H),2.19- 2.15(m,1H),2.06-2.02(m,3H),2.01-1.83(m,2H),0.80(t,J=7.2Hz,3H).

[0253] Example 14: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl

[0254] [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (532 mg, 2.45 mmol) and DIC (227 mg, 1.79 mmol) in DMF (4 mL), a solution of 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (370 mg, 0.81 mmol) and DMAP (10 mg, 0.08 mmol) in DCM (4 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (2 / 1) to obtain (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (400 mg, 75%) as a pale yellow solid. 29 H 42 ClN7O6S[M+H] + MS ESI calculated value: 652.26, measured value: 652.35.

[0255] Step 2: (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (400 mg, 0.61 mmol) and a solution of 1,4-dioxane (5 mL) in HCl (gas) were stirred in DCM (5 mL) at room temperature for 1 hour. The reaction was quenched with saturated NaHCO3 (50 mL) at room temperature. The resulting mixture was extracted with ELISA (30 mL x 3 times). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mM NH4HCO3), 20%~60%; detector, UV254nm. The residue was purified by reverse-phase chromatography to obtain (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl (333.5 mg, 97%) as a pale yellow solid. 24 H 34 ClN7O4S[M+H] + MS ESI calculated value: 552.21, measured value: 552.30. 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),7.60(brs,1H),5.33(s,1H),3.78-3.68(m,2H),3.65-3.61(m,1H),3.16-3.07( m,2H),3.02-2.92(m,4H),2.68-2.58(m,2H),2.34-1.82(m,9H),1.70(s,2H),0.87-0.83(m,3H),0.75-0.66(m,6H).

[0256] Example 15: 2-Methylpropanoate (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl

[0257] [ka] Step 1: 2-Methylpropanoate (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A stirred solution of isobutyric acid (63 mg, 0.715 mmol) in DMF (1 mL) was mixed with DIC (66 mg, 0.525 mmol) at room temperature. Subsequently, a solution of (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (100 mg, 0.238 mmol) and DMAP (3 mg, 0.024 mmol) in DCM (1 mL) at room temperature was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of acetonitrile (10 mM NH4HCO3), 20%~60%; detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain 2-methylpropanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl (55.5 mg, 47%) as a yellow solid. 24 H 26 F3N5O3[M+H] + MS ESI calculated value: 490.20, measured value: 490.20. 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.80(d,J=8.4Hz,1H),8.64(d,J=2.0Hz,1H),7.93(dd,J=8.0,2. 0Hz,1H),7.36(d,J=8.4Hz,1H),7.09(s,1H),5.91(t,J=56.0Hz,1H),4.85-4.79(m,1H),4.16-4.12(m ,1H),3.95-3.90(m,2H),3.59-3.53(m,1H),3.34-3.32(m,1H),2.43-2.36(m,1H),2.11-2.08(m,1H), 1.79-1.73(m,1H),1.23-1.20(m,2H),1.10-1.09(m,2H),0.95(d,J=7.2Hz,3H),0.87(d,J=6.8Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-114.30(2F),-161.35(1F).

[0258] Example 16: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0259] [ka] Step 1: (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl A mixture of 2,5-dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine (2.5 g, 6.312 mmol), (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate tert-butyl (1.64 g, 7.574 mmol), and DIEA (3.26 g, 25.248 mmol) in NMP (50 mL) was stirred at 80°C for 16 hours. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1) to obtain (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (3.3 g, 91%) as a yellow solid. 22 H 31 ClN5O3[M+H] + MS ESI calculated value: 576.12, measured value: 576.15. 1 H NMR(400MHz,chloroform-d)δ8.51(s,1H),4.96-4.92(m,1H),4.32-4.25(m,1H),4.16-4.10(m,2H),3.66-3.57(m,2H),2.90- 2.85(m,1H),2.80-2.66(m,3H),2.40(m,2H),2.25-2.05(m,3H),1.85(m,1H),1.50-1.48(m,10H),0.81(t,J=7.2Hz,3H).

[0260] Step 2: (3R,4R)-3-(acetyloxy)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl} A mixture of (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (3.3 g, 5.730 mmol), Ac2O (0.88 g, 8.595 mmol), and TEA (2.32 g, 22.920 mmol) in DCM (50 mL) was stirred at 50°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (2 / 1) to obtain (3R,4R)-3-(acetyloxy)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (3.3 g, 93%) as a yellow solid. 24 H 33 ClN5O4[M+H] + MS ESI calculated value: 618.13, measured value: 618.15.

[0261] Step 3: (3R,4R)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl A mixture of (3R,4R)-3-(acetyloxy)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (3.3 g, 5.341 mmol), Zn(CN)2 (345 mg, 2.938 mmol), and Pd(PPh3)4 (617 mg, 0.534 mmol) in DMF (40 mL) was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (2 / 1) to obtain (3R,4R)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (2.3 g, 83%) as a yellow solid. Calculated value by mass spectrometry (ESI): C 25 H 33 ClN6O4[M+H] + MS ESI calculated value: 517.23, measured value: 517.30. 1 H NMR(400MHz,chloroform-d)δ8.65(s,1H),5.25(brs,1H),4.92-4.88(m,1H),4.09-4.03(m,1H),3.94-3.87(m,1H),3.78-3.75(m ,1H),3.13-3.08(m,2H),2.74-2.68(m,2H),2.37-2.28(m,3H),2.23-1.92(m,7H),1.52-1.48(m,10H),0.81(t,J=7.2Hz,3H).

[0262] Step 4: Acetate (3R,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-3-yl hydrochloride (3R,4R)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (1 g, 1.934 mmol) and a solution of HCl (gas) in 1,4-dioxane (10 mL, 1 M) in DCM (10 mL) were stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain (3R,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-3-yl) hydrochloride (800 mg, 91%) as a yellow solid. 20 H 26 Cl2N6O2[M-Cl] + MS ESI calculated value: 417.17, measured value: 417.25.

[0263] Step 5: Acetate (3R,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl A solution of (3R,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-3-yl hydrochloride acetate (50 mg, 0.120 mmol), NaHCO3 (71 mg, 0.840 mmol), and methanesulfonic acid anhydride (42 mg, 0.240 mmol) in siRNA (2 mL) and H2O (2 mL) was stirred at room temperature for 40 minutes. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, 40%~60% in aqueous solution of CH3CN (10 mM NH4HCO3); detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain (3R,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl acetate (52 mg, 87%) as a pale yellow solid. 21 H 27 ClN6O4S[M+H] + MS ESI calculated value: 495.15, measured value: 495.20.

[0264] Step 6: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile The solutions of (3R,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-methanesulfonylpiperidine-3-yl acetate (50 mg, 0.101 mmol) and K2CO3 (42 mg, 0.303 mmol) in MeOH (1 mL) were stirred at room temperature for 30 minutes. Under the following conditions: C18 column; mobile phase, 45%~70% in aqueous solution of CH3CN (10 mM NH4HCO3); detector, reverse-phase flash chromatography using UV254nm to purify the mixture and obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4R)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (28 mg, 61%) as a pale yellow solid. 19 H 25 ClN6O3S[M+H] + MS ESI calculated value: 453.14; measured value: 453.25. 1 H NMR(400MHz,chloroform-d)δ8.69(s,1H),5.07(d,J=6.8Hz,1H),4.01-3.92(m,1H),3.85-3.75(m,2H),3.68-3.63(m,1H),3.01-2 .88(m,4H),2.81-2.65(m,3H),2.41-2.28(m,3H),2.25-2.15(m,1H),2.10-1.92(m,4H),1.77-1.66(m,1H),0.84-0.80(m,3H).

[0265] Example 17: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0266] [ka] Step 1: (3S,4S)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl 2,5-Dichloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine (250 mg, 0.631 mmol) and (3S,4S)-4-amino-3-hydroxypiperidine-1-carboxylate tert-butyl (164 mg, 0.757 mmol) were stirred in DMSO (2.5 mL), to which DIEA (245 mg, 1.893 mmol) was added. The resulting mixture was stirred at 120 °C for 4.5 hours. The resulting mixture was cooled to room temperature, and then purified by reverse-phase flash chromatography using the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 30%~40%; detector, UV254nm, to obtain (3S,4S)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (330 mg, 91%) as a pale yellow solid. 22 H 31 ClN5O3[M+H] + MS ESI calculated value: 576.12, measured value: 576.15.

[0267] Step 2: (3S,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (3S,4S)-4-{[5-chloro-7-(1-ethylcyclobutyl)-6-iodopyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (300 mg, 0.521 mmol) and Zn(CN)2 (37 mg, 0.313 mmol) were stirred in DMA (3 mL) to which Pd(PPh3)4 (60 mg, 0.052 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere at 140 °C for 2 hours. The mixture was cooled to room temperature. The reaction was quenched at room temperature by adding water / ice (10 mL). The resulting mixture was extracted with ELISA (3 × 50 L). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mM NH4HCO3), 40%~60%; detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain (3S,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (200 mg, 81%) as a pale yellow solid. 23 H 31 ClN6O3[M+H] + MS ESI calculated value: 475.21, measured value: 475.25.

[0268] Step 3: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile hydrochloride (3S,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (200 mg, 0.421 mmol) was stirred in DCM (2 mL), to which a solution of 1,4-dioxane (2 mL) in HCl (gas) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile hydrochloride (160 mg, unpurified) as a pale yellow solid. 18 H 24 Cl2N6O[M-Cl] + MS ESI calculated value: 375.16, measured value: 375.15.

[0269] Step 4: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxypiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrilate hydrochloride (160 mg, 0.389 mmol) and NaHCO3 (98 mg, 1.167 mmol) were stirred in H2O (3 mL) and siRNA (3 mL). Methanesulfonic anhydride (135 mg, 0.778 mmol) was added in small amounts at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with siRNA (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mM NH4HCO3), 45%~65%; detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3S,4S)-3-hydroxy-1-methanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (22.8 mg, 13%) as a pale yellow solid. 19 H 25 ClN6O3S[M+H] + MS ESI calculated value: 453.14, measured value: 453.30. 1 H NMR(400MHz,chloroform-d)δ8.69(s,1H),4.99-4.98(m,1H),3.97-3.92(m,1H),3.81-3.75(m,2H),3.61-3.59(m,1H),2.92-2.8 5(m,4H),2.78-2.65(m,3H),2.36-2.30(m,3H),2.27-2.19(m,1H),2.07-1.93(m,3H),1.73-1.69(m,1H),0.81-0.77(m,3H).

[0270] Example 18: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-trifluoromethanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0271] [ka] Step 1: (3R,4S)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-3-hydroxypiperidine-1-carboxylate tert-butyl (1 g, 2.105 mmol) and TEA (1.3 mL, 9.473 mmol) were stirred in DCM (10 mL) to which Ac2O (0.4 mL, 4.210 mmol) was added. The resulting mixture was stirred at 50°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with PE / siRNA (5 / 1) to obtain (3R,4S)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (1.0 g, 92%) as a yellow solid. 25 H 33 ClN6O4[M+H] + MS ESI calculated value: 517.23, measured value: 517.25.

[0272] Step 2: Acetate (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-3-yl hydrochloride A solution of (3R,4S)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-1-carboxylate tert-butyl (300 mg, 0.580 mmol) and DCM (10 mL) in a solution of 1,4-dioxane (20 mL) in HCl (gas) was stirred at room temperature for 40 minutes. The resulting mixture was concentrated under reduced pressure to obtain (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-3-yl hydrochloride acetate (200 mg, unpurified) as a yellow solid. 20 H 26 Cl2N6O2[M-Cl] + MS ESI calculated value: 417.17, measured value: 417.20.

[0273] Step 3: Acetate (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}piperidine-3-yl hydrochloride (200 mg, 0.480 mmol) and TEA (146 mg, 1.440 mmol) were stirred in DCM (2 mL), to which trifluoromethanesulfonyl chloride (162 mg, 0.960 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 10%~50%; detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl acetate (116 mg, 44%) as a yellow solid. 21 H 24ClN3O4S[M+H] + MS ESI calculated value: 549.12, measured value: 549.25.

[0274] Step 4: 5-Chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-trifluoromethanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile A solution of (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl acetate (110 mg, 0.200 mmol) and K2CO3 (55 mg, 0.400 mmol) in MeOH (3 mL) was stirred at room temperature for 25 minutes. The resulting mixture was purified by reverse-phase flash chromatography under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 45%~75%; detector, UV254nm, to obtain 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-trifluoromethanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (68.4 mg, 67%) as a pale yellow solid. 19 H 22 ClF3N6O3S[M+H] + MS ESI calculated value: 507.11, measured value: 507.05. 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.15(d,J=6.4Hz,1H),5.27(d,J=4.4Hz,1H),4.08-4.04(m,1H),3.80-3.68(m,3H),3.48-3.42(m,1) H),3.38-3.34(m,1H),2.67-2.52(m,2H),2.27-2.23(m,2H),2.18-2.11(m1H),2.09-1.82(m,4H),1.78-1.72(m,1H),0.75-0.72(m,3H). 19 F NMR(377MHz,DMSO-d6)δ-75.43(3F).

[0275] Example 19: (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl

[0276] [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (49 mg, 2.250 mmol) and DIC (208 mg, 1.650 mmol) in DMF (0.2 mL), 5-chloro-7-(1-ethylcyclobutyl)-2-{[(3R,4S)-3-hydroxy-1-trifluoromethanesulfonylpiperidine-4-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrilate (380 mg, 0.750 mmol) and DMAP (9 mg, 0.075 mmol) in DCM (mL) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with  (15 mL), washed with brine (3 × 5 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1 / 1) to obtain (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (500 mg, 94%) as a yellow solid. 29 H 39 ClF3N7O6S[M+H] +MS ESI calculated value: 706.23, measured value: 706.30.

[0277] Step 2: (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (200 mg, 0.283 mmol) was stirred in DCM (2 mL), to which TFA (0.4 mL, 5.385 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched at 0°C with saturated NaHCO3 (20 mL). The resulting mixture was extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 30%~50%; detector, reverse-phase flash chromatography using UV 254 nm. The residue was purified to obtain (2S)-2-amino-3-methylbutanoic acid (3R,4S)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}-1-trifluoromethanesulfonylpiperidine-3-yl (68.4 mg, 39%) as a yellow solid. 24 H 31 ClF3N7O4S[M+H] + MS ESI calculated value: 606.18, measured value: 606.45. 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.64(d,J=6.0Hz,1H),5.31(s,1H),3 .93-3.85(m,3H),3.71-3.67(m,1H),3.51-3.49(m,1H),3.21-3.19(m,1H), 2.67-2.60(m,2H),2.31-2.26(m,2H),2.19-2.17(m,1H),2.15-1.87(m,6H ),1.75(brs,2H),2.04-2.03(m,3H),2.01-2.00(m,3H),1.98-1.97(m,3H). 19 F NMR(376MHz,DMSO-d6)δ-75.52(3F).

[0278] Example 20: Diammonium phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl

[0279] [ka] Step 1: Di-tert-butyl phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol (500 mg, 1.192 mmol), NaI (536 mg, 3.576 mmol), Ag2O (829 mg, 3.576 mmol), and 4Å MS (750 mg) were mixed in DMF (6 mL) to which di-tert-butylchloromethyl phosphate (3.08 g, 11.907 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding ice / salt (100 mL). The resulting mixture was extracted with ELISA (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (0.1% formic acid), 10%~80%; detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain di-tert-butyl phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl (210 mg, 24%) as a yellow solid. 29 H 39 F3N5O6P[M+H] + MS ESI calculated value: 642.26, measured value: 642.40.

[0280] Step 2: Diammonium phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl Di-tert-butyl phosphate (100 mg, 0.156 mmol) was mixed in 25 mL of DCM, to which 1 mL of TFA was added dropwise at -10°C. The resulting mixture was stirred at -10°C for 1 hour. The reaction was quenched by adding 50 mL of saturated aqueous NH4HCO3 at -10°C. The resulting mixture was concentrated under reduced pressure. Under the following conditions: C18 column; mobile phase, aqueous solution of CH3CN (10 mM NH4HCO3), 10%~80%; detector, reverse-phase flash chromatography using UV254nm to purify the residue and obtain diammonium phosphate {[(3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl]oxy}methyl (12.9 mg, 14%) as a yellow solid. 21 H 29 F3O6P[M+H-2NH4 + ] + MS ESI calculated value: 530.13, measured value: 530.20. 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.78(d,J=8.4Hz,1H),8.63(d,J=1.6Hz,1H),7 .95(dd,J=2.0,8.4Hz,1H),7.86(brs,1H),7.18(brs,2H),7.10-7.06(m,1H),5.93(t ,J=56.0Hz,1H),5.04-5.00(m,2H),4.13-4.09(m,1H),3.86-3.83(m,3H),3.51-3.40 (m,1H),3.38-3.20(m,1H),2.34-2.24(m,1H),1.49-1.46(m,1H),1.21-1.09(m,4H). 19 F NMR(376MHz,DMSO-d6)δ-114.51(2F),-161.67(1F).

[0281] II. Biological Evaluation Example 1: In vitro biochemical and cell assays AssayQuant CDK assay CDK / Cylin fluorescence assay The small molecule inhibition of CDK4 / cyclin D1, CDK6 / cyclin D3, and CDK2 / cyclin E1 kinase activity was evaluated using a fluorescence-based phosphosensor (AssayQuant Technologies). This sensing mechanism utilizes synthetic α-amino acids that transmit information about the phosphorylation state of the kinase substrate. When the substrate is phosphorylated, fluorescence is emitted. The CDK / cyclin complex catalyzes phosphate transfer to the substrate peptide (AQT0258 for CDK4 and CDK6 complexes; AQT0297 for CDK2 complex), resulting in an increase in fluorescence intensity directly proportional to the amount of phosphorylated substrate. 2.5 nM CDK4 / cyclin D1 (Thermo Fisher, PR8064A), 10 nM CDK6 / cyclin D3 (Carna Biosciences, 04-107), and 1.25 nM CDK2 / cyclin E1 (Eurofins, 14-475M) were prepared with 10 μM substrates in a buffer containing 10 mM MgCl2, 54 mM HEPES, 0.55 mM EGTA, 0.01% Brij-35, 0.02% BSA, 1 mM DTT, and 1% glycerol, and pre-incubated at room temperature for 30 minutes before reaction initiation. ATP was added to initiate the reaction (400 μM for CDK4, 250 μM for CDK6, and 120 μM for CDK2). The reaction was allowed to proceed at room temperature for 180 minutes, after which fluorescence was read using an EnSight Reader. IC 50 The values ​​were calculated using the conversion inhibition rate obtained with the Dotmatics Knowledge Solutions Studies curve fitting (Dotmatics, Bishops Stortford, UK, CM23), and these are shown in Table 2.

[0282] Phosphoserine 807 / 811 receptor HTRF assay Cells were seeded in 90 μL of culture medium at a rate of 25,000 or 20,000 cells per well and allowed to adhere to plates overnight at 37°C and 5% CO2. The following day, the compound was serially diluted in DMSO from a maximum dose of 10 mM to a 10.3-fold dilution curve. After a 100-fold dilution in culture medium, a further 10-fold dilution was performed in the cell plate to a final volume of 100 μL and 0.1% DMSO. The compound and cells were cultured together at 37°C and 5% CO2 for 18 hours. Phosphorylation at serine 807 / 811 was evaluated using an HTRF sandwich assay (Cisbio, 64RBS807PEH). The specific signal was positively regulated in proportion to phospho Rb (Ser807 / 811). After 18 hours of compound incubation, the cells were lysed with shaking for 45 minutes and then homogenized. Specific Eu3+ cryptotate (donor) and d2 (acceptor) labeled antibodies were added to cell lysates and incubated overnight at room temperature. Specific signals were used to determine ICs within the Dotmatics Knowledge Solutions Studies curve-fitting environment (Dotmatics, Bishops Stortford, UK, CM23). 50 The values ​​were calculated. These are shown in Tables 2 and 3.

[0283] Cyquant assay Cells were seeded at densities of 1000 to 2500 cells / well in 96-well plates coated with poly-D-lysine and incubated overnight in an incubator at 37°C and 5% CO2. The following day, the compound was serially diluted in DMSO from a maximum dose of 10 mM to a 9.3-fold dilution curve. After a 100-fold dilution in growth medium, a further 10-fold dilution was prepared in cell plates to a final volume of 150 μl in 0.1% DMSO. The compound and cells were cultured together at 37°C and 5% CO2 for 6 days. CyQuant (Invitrogen, C35011) detection buffer was prepared according to the manufacturer's instructions, and a 2-fold dilution was added to the cultured cells. After incubation of the detection reagent with the cells at 37°C for 60 minutes, fluorescence was measured using the standard "green" filter set of the Envision reader. Using specific signals, IC (Information Correction) is performed within the Dotmatics Knowledge Solutions Studies curve fitting environment (Dotmatics, Bishops Stortford, UK, CM23). 50 The values ​​were calculated. These are shown in Tables 2 and 3.

[0284] [Table 6]

[0285] [Table 7]

[0286] III. Evaluation of Xenografts Example 2: Antitumor activity and pathway inhibition of compound 1 in a WM3629 melanoma tumor model. Compound 1 demonstrated good tolerability and efficacy in a xenograft model of class III BRAF mutant / CDK4 sensitive melanoma in athymic nude mouse at doses up to 90 mg / kg TID (total daily dose of 270 mg / kg). Specifically, dose-dependent tumor growth and pathway inhibition were observed in a xenograft model derived from the WM3629 cell line. Oral administration of high-dose compound 1 at 90 mg / kg three times daily resulted in a significant T17% GI compared to vehicle treatment (p<0.001). Consistent with the observed antitumor activity, compound 1 at 90 mg / kg significantly suppressed the tumor pharmacodynamic biomarker pRB by 56% compared to vehicle treatment, as measured 1 hour after treatment (p<0.005). These data indicate that compound 1 possesses potent antitumor activity in class III BRAF mutant / CDK4 sensitive melanoma.

[0287] Method: 1 x 10⁶ athymoid nude mice 7 Individual WM3629 tumor cells were subcutaneously inoculated. The average tumor volume in each group was approximately 300 mm². 3 Grouping and treatment were initiated when the target group was reached. Mice were assigned to each group based on initial tumor volume and body weight to ensure that the mean values ​​for each treatment group were similar. Animals were administered three times daily, and tumor growth, body weight changes, and general health / behavior were monitored. In another experiment, the oncological pharmacodynamic (PD) biomarker pRB was examined after 3 days of treatment dose administration.

[0288] Results: Compound 1 demonstrated dose-dependent suppression of tumor growth compared to vehicle-treated tumors (Table 4 and Figure 1A). Lower doses of Compound 1 (10 and 30 mg / kg) resulted in TGI of 34% and 32%, respectively, with no statistically significant difference compared to vehicle treatment. Higher doses (90 mg / kg) of Compound 1 induced TGI of 47% compared to vehicle treatment (p<0.001). All tested doses were well-tolerated, and no weight loss was observed in any Compound 1 treatment group compared to vehicle treatment (Figure 1B).

[0289] [Table 8]

[0290] The ability of compound 1 to suppress the tumor pharmacodynamic biomarker pRB was investigated after treating patients with TID at doses of 10, 30, and 90 mg / kg of compound 1 for 3 days. Dose-dependent suppression of pRB by compound 1 was observed (Figure 2). At the highest dose of 90 mg / kg of compound 1, pRB was reduced by 56% and 63% at 1 hour and 7 hours after administration, respectively, compared to vehicle treatment (p<0.005 at both time points).

[0291] Example 3: Antitumor activity of compound 2 in an MCF7 breast cancer model Compound 2, a valine ester prodrug of Compound 1, showed good tolerability and efficacy at doses up to 62 mg / kg BID daily (total daily dose of 124 mg / kg / day) in a xenograft model of a thymic nude mouse with CDKN2A mutant HR+ breast cancer (MCF7). Specifically, oral administration of high-dose Compound 2 at 62 mg / kg (equivalent to 50 mg / kg Compound 1) twice daily resulted in an 81% TGI compared to vehicle-based treatment (p<0.001).

[0292] Method: 1.5 × 10⁶ athymoid nude mice 7 Individual MCF7 tumor cells were subcutaneously inoculated. The average tumor volume in each group was approximately 200 mm². 3 Grouping and treatment were initiated when the following conditions were reached. Mice were assigned to each treatment group based on initial tumor volume and body weight, ensuring that the average values ​​for each group were similar. Animals were administered twice daily, and tumor growth, body weight changes, and general health / behavior were monitored.

[0293] Results: Compound 2 demonstrated dose-dependent suppression of tumor growth compared to vehicle-treated tumors. As summarized in Table 5, a mean TGI of 59% was achieved with a 19 mg / kg BID dose of Compound 2. A higher dose of 62 mg / kg BID of Compound 2 induced an 81% TGI compared to vehicle-treated tumors (p<0.001). Both doses tested were well-tolerated, and neither Compound 2-treated group showed weight loss compared to the control group. These data indicate that Compound 2 has potent antitumor activity in the CDKN2A mutant HR+ breast cancer model.

[0294] [Table 9]

[0295] Example 4: Antitumor activity of Compound 4 and Compound 6 in the MCF7 breast cancer model Compound 4, a valine ester prodrug of Compound 3, and Compound 6, a valine ester prodrug of Compound 5, demonstrated efficacy in a CDKN2A mutant HR+ breast cancer model of athymoid nude mouse xenograft (MCF7) at doses up to 113.4 mg / kg BID daily (total daily dose of Compound 4: 226.8 mg / kg) and 37.2 mg / kg BID daily (total daily dose of Compound 6: 74.4 mg / kg), respectively. Specifically, oral administration of a high dose of Compound 4 at 113.4 mg / kg (equivalent to 90 mg / kg of Compound 3) twice daily resulted in a 59% TGI compared to vehicle treatment (p<0.001). Oral administration of a high dose of Compound 6 at 37.2 mg / kg twice daily resulted in a 70% TGI compared to vehicle treatment (p<0.001). After administering compound 4 at a dose of 113.4 mg / kg BID for 21 days, a mild weight loss of 6% was observed. Compound 6 was well-tolerated at doses up to 37.2 mg / kg BID daily, and no effect on weight was observed.

[0296] Method: 1.5 × 10⁶ athymoid nude mice 7Individual MCF7 tumor cells were subcutaneously inoculated. The average tumor volume in each group was approximately 200 mm². 3 Grouping and treatment were initiated when the following conditions were reached. Mice were assigned to each treatment group based on initial tumor volume and body weight, ensuring that the average values ​​for each group were similar. Animals were administered twice daily, and tumor growth, body weight changes, and general health / behavior were monitored.

[0297] Results: Compounds 4 and 6 showed dose-dependent suppression of tumor growth compared to the vehicle-treated group. As summarized in Table 6, low doses of compound 4 at 12.6 mg and 37.8 mg / kg BID yielded TGIs of 17% and 28%, respectively. A higher dose of compound 4 at 113.4 mg / kg BID induced a 59% TGI compared to the control group (p<0.001). The two low doses were well-tolerated and showed no weight loss compared to the control group. The higher dose of compound 4 at 113.4 mg / kg induced an overall mean weight loss of 6% per group. Compound 6 was well-tolerated and showed no weight loss compared to the control group in any group. Low doses of compound 6 at 3.72 mg and 12.4 mg / kg BID showed mean TGIs of 17% and 36%, respectively. Compound 6 at a high dose of 37.2 mg / kg BID induced 70% TGI compared to the control group (p<0.001). These data demonstrate that compounds 4 and 6 possess potent antitumor activity in the CDKN2A mutant HR+ breast cancer model.

[0298] [Table 10]

[0299] IV. ADME and Pharmacokinetic Evaluation Example 1: ADME evaluation of compounds 3, 4, 5, 6, 7, 8, 9, 10, 15, and 20 Dynamic solubility assay Stock solutions of the test compound and the control compound, diclofenac sodium, were prepared at a concentration of 10 mM in DMSO.

[0300] Procedure for measuring solubility: 30 μL each of stock solutions (10 mM) of the test compound and the control compound were sequentially added to their corresponding 96-well racks. 970 μL of PBS at pH 2.0 or pH 7.4 was added to each vial of the capless solubility sample plate. The assay was repeated twice. One stirring bar was placed in each vial and sealed with a molded PTFE / silicone plug. The solubility sample plate was then transferred to an Eppendorf ThermoMixer Comfort Plate Shaker and stirred at 25°C and 1100 RPM for 2 hours. After 2 hours, the plug was removed and the stirring bar was removed using a large magnet. The sample was transferred from the solubility sample plate to a filter plate. The entire sample was filtered using a vacuum manifold. A 5 μL aliquot was taken from the filtrate, and 5 μL of DMSO and 490 μL of H2O / acetonitrile (volume ratio 1:1) mixture were added. 200 μL of the dilution was transferred to a new 96-well plate and subjected to LC-MS / MS analysis. The dilution ratio was adjusted based on the solubility values ​​and LC-MS signal response.

[0301] Preparation of the standard (STD): 15 μL of DMSO was transferred from a 10 mM DMSO standard plate to an empty plate, and 485 μL of DMSO was added to the plate to achieve a standard concentration of 300 μM. 5 μL of DMSO STD was transferred from a 300 μM DMSO STD plate to the remaining empty plate, and then 5 μL of PBS pH 2.0, pH 4.5, or pH 7.4, along with 490 μL of a mixture of H2O and acetonitrile (1:1 v / v), was added to the plate to achieve a final standard concentration of 3 μM. 200 μL of the dilution was transferred to a new 96-well plate and subjected to LC-MS / MS analysis. The concentrations of the standard samples were adjusted based on the LC-MS signal response.

[0302] Sample analysis procedure: The plates were placed in a well-plate autosampler. The samples were evaluated by LC-MS / MS analysis.

[0303] Data analysis: All calculations were performed using Microsoft Excel. The filtrate was analyzed and quantified against standards of known concentration using LC combined with mass spectrometry peak identification and quantification.

[0304] Human hepatocyte stability protocol Preparation of standard solutions Prepare 10 mM stock solutions of the test compound and positive control in a suitable solvent (DMSO). Dilute the 10 mM test compound and positive control to 100 μM by combining 495 μL of 50% acetonitrile / 50% water with 5 μL of the 10 mM stock solution in separate conical tubes.

[0305] Preparation of hepatocytes Place the culture medium (William E medium supplemented with GlutaMAX) and hepatocyte thawing medium in a 37°C water bath and warm for at least 15 minutes before use. Remove the cryopreserved hepatocyte vial from storage, ensuring the vial is kept at a cryogenic temperature until the thawing process begins. Place the vial in a 37°C water bath and shake gently for 2 minutes to thaw the cells. After thawing is complete, spray the vial with 70% ethanol and transfer the vial to a biosafety cabinet. Using a wide-bore pipette tip, transfer the hepatocytes to a 50 mL conical tube containing the thawing medium. Place the 50 mL conical tube in a centrifuge and spin at 100 g for 10 minutes. After spinning is complete, aspirate and remove the thawing medium, leaving approximately 1.5 × 10⁶ cells. 6 Resuspend the hepatocytes in sufficient culture medium to reach the cell / mL level. Count the cells using AOPI staining solution and measure the viable cell density. Cells with low viability (<75%) are unusable. Dilute the cells with incubation medium to achieve a standard cell density of 0.5 × 10⁻⁶. 6 Assume viable cells / mL. 0.5 × 10 6 A portion of hepatocytes with viable cells / mL are boiled for 5 minutes before plate addition as a typical negative control. This eliminates enzyme activity so that little or no substrate turnover is observed.

[0306] Stability measurement procedure Pipette 198 μL of hepatocytes into each well of a 96-well uncoated plate. Place the plate on an orbital shaker in the incubator and warm the hepatocytes for 10 minutes. Pipette 2 μL of 100 μM test compound or positive control into the corresponding wells of the 96-well uncoated plate to initiate the reaction. The final concentration of the test compound or control compound was 1 μM. Return the plate to the incubator and place it on the orbital shaker. At 0, 15, 30, 60, 90, and 120 minutes, take 25 μL aliquots of the well contents. Next, mix the aliquots with 6 volumes (150 μL) of acetonitrile containing internal standards (IS: 100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen) to stop the reaction. Centrifuge the plate at 3,220 g for 20 minutes. 100 μL of aliquot supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis. All incubations were repeated twice.

[0307] Data Analysis All calculations were performed using Microsoft Excel. Peak area was determined from the extracted ion chromatogram. The in vitro half-life (t1 / 2) was determined by regression analysis of the parent compound disappearance rate versus time curve.

[0308] The in vitro half-life (in vitro t1 / 2) was determined from the slope value: in vitro t1 / 2 = 0.693 / k k = velocity constant (- slope value); The conversion from in vitro t1 / 2 (in minutes) to scaled-up intrinsic clearance (Scaled-up CLint, mL / min / kg) was performed using the following formula (average of two repeated measurements): Scaled-up CLint = kV / N × scaling factor V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 × 10⁻¹⁰) 6 cell). The scaling factors for predicting in vivo intrinsic clearance using different species of hepatocytes are listed in Table 7 below:

[0309] [Table 11]

[0310] A positive control compound (verapamil) was added to the assay. All compound values ​​outside the specified range were excluded, and the experiment was repeated. A negative control was used to exclude false positives due to the instability of the chemical itself.

[0311] Human liver microsome stability protocol The master solution was prepared according to Table 8 below:

[0312] [Table 12]

[0313] Two separate experiments were conducted as follows: a) Using NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of 10 mM NADPH were added to the incubation. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively. b) Without NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of ultrapure water were added to the incubation. The final concentration of microsomes was 0.5 mg / mL. The reaction was initiated by adding 4 μL of 100 μM test compound solution or control compound solution to a final concentration of 1 μM, and carried out at 37°C. 50 μL aliquots were taken from the reaction solution at 0, 15, 30, 45, and 60 minutes. The reaction was stopped by adding four volumes of cold acetonitrile containing IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The sample was centrifuged at 3,220 g for 40 minutes. 100 μL of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis.

[0314] Data Analysis All calculations were performed using Microsoft Excel.

[0315] Peak areas were determined from the extracted ion chromatogram. The slope value was determined by linear regression of the natural logarithm of the residual percentage of the parent drug versus the incubation time curve.

[0316] The in vitro half-life (in vitro t1 / 2) was determined from the slope value: In Vitro T 1 / 2 =0.693 / k (In the equation, k is the velocity constant (k = -slope value)).

[0317] The conversion from in vitro t1 / 2 (min) to in vitro specific clearance (in vitro CLint, μL / min / mg protein) was performed using the following formula (average of two repeated measurements):

[0318]

number

[0319] The conversion from in vitro t1 / 2 (min) to scale-up unbound intrinsic clearance (Scale-up CLint, mL / min / kg) was performed using the following formula (average of two repeated measurements):

[0320]

number

[0321] [Table 13]

[0322] Table 10 summarizes the ADME parameters.

[0323] [Table 14]

[0324] Example 2: Pharmacokinetic evaluation of compounds 1, 3, 4, 5, and 6.

[0325] Table 11 summarizes the PK parameters of compound 1 after IV administration in several species.

[0326] Table 12 summarizes the PK parameters of compound 1 after oral administration in several species.

[0327] Table 13 summarizes the PK parameters of compounds 3, 4, 5, and 6 after oral administration in two species.

[0328] [Table 15]

[0329] [Table 16]

[0330] [Table 17]

Claims

1. A method for treating cancer in patients who need it, as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A method comprising administering to the patient a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

2. A method for treating cancer in patients who need it, as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A method comprising administering to the patient a pharmaceutical composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

3. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

4. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

5. A method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

6. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

7. A method for treating cancer in a patient in need, comprising administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

8. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

9. A method for treating cancer in a patient in need, comprising administering to the patient (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

10. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

11. A method for treating cancer in a patient in need, comprising administering (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

12. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

13. A method for treating cancer in a patient in need, comprising administering (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

14. A method for treating cancer in a patient in need, comprising administering to the patient a pharmaceutical composition comprising (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

15. The cancers include: breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer (PPC), bladder cancer, uterine cancer, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell carcinoma, adenocarcinoma, and mesothelial cancer. cancer, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), renal cancer, renal cell carcinoma (RCC), liver cancer, hepatocellular carcinoma (HCC), pancreatic cancer, gastric cancer, gastric cancer, endometrial cancer, sarcoma, liposarcoma The method according to any one of claims 1 to 14, selected from the group consisting of osteosarcoma, primary brain tumor, high-grade and low-grade glioma, glioblastoma, thyroid cancer, hematological cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphoma, myeloma, neuroblastoma, Ewing's sarcoma, osteosarcoma, and Wilms' tumor.

16. The method according to claim 15, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, stomach cancer, or a combination thereof.

17. The method according to any one of claims 1 to 16, wherein the cancer is locally advanced, regionally advanced, or a metastatic solid tumor.

18. The method according to any one of claims 1 to 14, wherein the cancer is a CNS metastatic disease.

19. The method according to claim 15, wherein the cancer is NSCLC.

20. The method according to claim 19, wherein the cancer is an adenocarcinoma of NSCLC.

21. The method according to claim 15, wherein the cancer is prostate cancer.

22. The method according to claim 15, wherein the cancer is colorectal cancer.

23. The method according to claim 15, wherein the cancer is a liposarcoma.

24. The method according to claim 15, wherein the cancer is breast cancer.

25. The method according to claim 24, wherein the breast cancer is advanced or metastatic breast cancer.

26. The method according to claim 24, wherein the breast cancer is locally advanced cancer.

27. The method according to claim 24, wherein the breast cancer is metastatic breast cancer.

28. The method according to claim 24, wherein the breast cancer is hormone receptor positive (HR+).

29. The method according to claim 24, wherein the breast cancer is estrogen receptor positive (ER+), progesterone receptor positive (PR+), or a combination thereof.

30. The method according to claim 24, wherein the breast cancer is hormone receptor-negative (HR-).

31. The method according to claim 24, wherein the breast cancer is estrogen receptor-negative (ER-), progesterone receptor-negative (PR-), or a combination thereof.

32. The method according to claim 24, wherein the breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

33. The method according to claim 24, wherein the breast cancer is human epidermal growth factor receptor 2 positive (HER2+).

34. The method according to claim 24, wherein the breast cancer is HR+ / HER2- breast cancer.

35. The method according to claim 24, wherein the breast cancer is HR- / HER2+ breast cancer.

36. The method according to claim 24, wherein the breast cancer is ER+ / HR+.

37. The method according to claim 24, wherein the breast cancer is ER+ / HER2-.

38. The method according to claim 24, wherein the breast cancer is triple-negative breast cancer (TNBC).

39. The method according to claim 24, wherein the breast cancer is ER-, PR-, and HER2-.

40. The method according to claim 24, wherein the breast cancer is endocrine therapy-resistant breast cancer, trastuzumab or pertuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibitors.

41. The method according to any one of claims 24 to 40, wherein the breast cancer is resistant to treatment with standard therapeutic agents.

42. The method according to any one of claims 24 to 40, wherein the subject is refractory to endocrine therapy.

43. The method according to any one of claims 24 to 40, wherein the breast cancer is refractory or resistant to treatment with antitumor chemotherapy drugs, or progresses during such treatment.

44. The method according to any one of claims 24 to 40, wherein the breast cancer is progressing during or within 12 months after treatment with adjuvant therapy with an aromatase inhibitor.

45. The method according to any one of claims 24 to 40, wherein the breast cancer is progressing during or within 12 months after treatment with adjuvant therapy with tamoxifen.

46. The method according to any one of claims 1 to 45, wherein the method is a primary treatment.

47. The method according to any one of claims 1 to 45, wherein the method is a second-line treatment or a subsequent treatment.

48. The method according to claim 47, wherein the method is carried out following treatment with an endocrine therapy agent, a CDK4 / CDK6 inhibitor, or a combination thereof.

49. The method according to claim 47, wherein the method is carried out following treatment with an endocrine therapy drug.

50. The method according to claim 47, wherein the method is carried out following treatment with one or more types of chemotherapy regimens.

51. The method according to claim 47, wherein the method is performed following treatment with a HER2-targeting drug.

52. Treatment methods for breast cancer in patients who require them, as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl A method comprising administering to the patient an endocrine therapy agent a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof.

53. The method according to claim 52, wherein the compound is (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

54. The method according to claim 52, wherein the compound is (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

55. The method according to claim 52, wherein the compound is 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

56. The method according to claim 52, wherein the compound is (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

57. The method according to claim 52, wherein the compound is (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

58. The method according to claim 52, wherein the compound is (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

59. The method according to any one of claims 52 to 58, wherein the endocrine therapy agent is selected from the group consisting of biological polymer agents or chemical low molecular weight compounds useful for the treatment of cancer.

60. The method according to any one of claims 52 to 58, wherein the endocrine therapy agent is selected from the group consisting of aromatase inhibitors, androgen receptor inhibitors, selective estrogen receptor degraders (SERDs), or selective estrogen receptor modulators (SERMs).

61. The method according to claim 60, wherein the endocrine therapy drug is an androgen receptor inhibitor.

62. The method according to claim 60, wherein the endocrine therapy drug is an aromatase inhibitor.

63. The method according to claim 62, wherein the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane.

64. The method according to claim 62, wherein the aromatase inhibitor is letrozole.

65. The method according to claim 60, wherein the endocrine therapy drug is SERD.

66. The method according to claim 60, wherein SERD is selected from the group consisting of: fulvestrant, elastrant (RAO-1901), amsenetrant (SAR439859), gilledetrand (GOC9545), RG6171, kamizestrant (AZO9833), AZO9496, lintdetrand, ZN-c5, LSZ102, 0-0502, LY3484356, and SHR9549.

67. The method according to claim 60, wherein the SERD is full vestrant.

68. The method according to claim 60, wherein the endocrine therapy drug is SERM.

69. The method according to claim 68, wherein the SERM is selected from the group consisting of tamoxifen, raloxifen, toremifene, lasofoxifen, bazedoxefene, and afimoxifen.

70. The method according to claim 68, wherein the SERM is tamoxifen or raloxifen.

71. The method according to claim 60, wherein the endocrine therapy agent is letrozole or fulvestrant.

72. The method according to any one of claims 52 to 71, wherein the endocrine therapy agent is administered to the subject in the course of treatment with (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

73. The method according to any one of claims 52 to 71, wherein the endocrine therapy agent is administered before the first dose of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

74. The method according to any one of claims 52 to 71, wherein the initial dose of the endocrine therapy agent is administered on the same day as the initial dose of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

75. The method according to any one of claims 52 to 71, wherein the initial dose of the endocrine therapy agent is administered after the commencement of treatment with (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

76. The method according to any one of claims 52 to 71, wherein the subject has previously received treatment with one or more lines of endocrine therapy prior to administration of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol or a pharmaceutically acceptable salt or solvate thereof to the subject.

77. The method according to any one of claims 51 to 62, wherein the subject has previously received treatment by chemotherapy, radiotherapy, and / or surgical resection prior to administration of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol or a pharmaceutically acceptable salt or solvate thereof.

78. The method according to any one of claims 51 to 62, wherein the subject has previously received treatment with a CDK4 / 6 inhibitor prior to administration of (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof.

79. The aforementioned endocrine therapy drugs are as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 52, wherein the patient is administered a compound selected from the group consisting of the following.

80. The aforementioned endocrine therapy drugs are as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 52, wherein the patient is administered a compound selected from the group consisting of the following, before administering an initial dose of the compound.

81. The initial dose of the aforementioned endocrine therapy drug is as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 52, wherein the compound selected from the group consisting of is administered to the patient on the same day as the first dose of the compound.

82. The initial dose of the aforementioned endocrine therapy drug is as follows: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 52, which is administered to the patient after the initiation of treatment with a compound selected from the group consisting of the above.

83. below: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 52, wherein, prior to administration to the patient of a compound selected from the group consisting of, the patient has previously received treatment with one or more lines of endocrine therapy.

84. below: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 1, wherein, prior to administration to the patient of a compound selected from the group consisting of, the patient has previously received treatment by chemotherapy, radiotherapy, and / or surgical resection.

85. below: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof The method according to claim 1, wherein, prior to administration to the patient of a compound selected from the group consisting of the above, the patient has previously received treatment with a CDK4 / 6 inhibitor.

86. The method according to any one of claims 1 to 85, wherein the method brings about a complete response (CR), a partial response (PR), or stable disease (SD) in the subject having a regional progressive disease or metastatic disease.

87. The method according to any one of claims 1 to 86, wherein the treatment results in complete response, partial response, or stabilization of intracranial metastatic disease or primary brain tumor.

88. The method according to any one of claims 1 to 87, wherein the treatment results in a reduction of disease recurrence in a localized area of ​​the CNS, a distal area of ​​the CNS, within the CNS, or a combination thereof.

89. The method according to claim 18, wherein the diseased site is the brain.

90. The method according to claim 15, wherein the patient has localized or regionally advanced cancer.

91. The following are cancer treatment methods for patients who require them: (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropane-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl; 5-Chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl; (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol; and (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl The procedure involves administering to the patient a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method.

92. A method for treating cancer in a patient in need, comprising administering to the patient 5-chloro-7-(1-ethylcyclobutyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof, or (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-{[5-chloro-6-cyano-7-(1-ethylcyclobutyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl]amino}oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method.

93. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, or (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(7-{5-[1-(difluoromethyl)cyclopropyl]pyridine-2-yl}-5-fluoropyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method.

94. A method for treating cancer in a patient in need, comprising administering to the patient (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-ol, or a pharmaceutically acceptable salt or solvate thereof, or (2S)-2-amino-3-methylbutanoic acid (3S,4R)-4-[(5-fluoro-7-{5-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-2-yl}pyrrolo[2,1-f][1,2,4]triazine-2-yl)amino]oxan-3-yl, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is as follows: (a) amplification or mutation of CDK4; (b) Amplification of cyclin D1; (c) amplification of cyclin E; or (d) Loss of the negative regulatory gene CDKN2A or CDKN2B A solid tumor characterized by the following method.

95. The method according to claim 91, wherein the solid tumor is characterized by CDK4 amplification or mutation.

96. The method according to claim 91, wherein the solid tumor is characterized by cyclin D1 amplification.

97. The method according to claim 91, wherein the solid tumor is characterized by cyclin E amplification.

98. The method according to claim 91, wherein the solid tumor is characterized by the absence of the negative regulatory gene CDKN2A or CDKN2B.

99. The method according to any one of claims 1 to 98, wherein the patient has not previously received CDK4 inhibitor therapy.

100. The method according to any one of claims 1 to 99, wherein the patient is resistant to CDK4 inhibitor or CDK6 inhibitor therapy.

101. below: 【Chemistry 1】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

102. below: 【Chemistry 2】 A compound according to claim 101 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

103. below: 【Transformation 3】 A compound according to claim 101 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

104. below: 【Chemistry 4】 A compound according to claim 101 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

105. At least one pharmaceutically acceptable excipient, and the following: 【Transformation 5】 A pharmaceutical composition comprising a compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

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