Substituted pyrrolotriazine compounds, pharmaceutical compositions thereof, and uses thereof

Abstract

The present invention provides substituted pyrrolotriazine compounds and pharmaceutical compositions, as well as uses thereof. The pyrrolotriazine compounds are compounds of formula (Φ) or pharmaceutically acceptable salts, prodrugs, hydrates or solvates, crystalline forms, stereoisomers, or isotopic variants thereof. The compounds and compositions of the present invention can be used to treat diseases associated with KIT and / or PDGFRα. [Formula 1]

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to substituted pyrrolotriazine compounds and pharmaceutical compositions containing the same, and their uses. More specifically, the present invention relates to 1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethylamine substituted with specific deuterium or its stereoisomers. These deuterium-substituted compounds and their compositions can be used for treating diseases related to KIT and / or PDGFRα, and these deuterium-substituted compounds have better pharmacokinetic properties.

Background Art

[0002] The receptor tyrosine kinase KIT (also known as CD117) is a type of transmembrane receptor protein with tyrosine kinase activity encoded by the retroviral oncogene KIT. The KIT kinase is composed of an extracellular domain, a transmembrane domain, and an intracellular domain. The KIT ligand is stem cell factor (SCF), which binds to the extracellular domain of KIT, induces receptor dimerization, and activates downstream signaling pathways. Usually, KIT mutations occur in the DNA encoding the juxtamembrane domain (exon 11). They also occur, although less frequently, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations lead to high cell division rates and potential genomic instability by making KIT function independent of activation by SCF. Mutant KIT is involved in the pathogenesis of several diseases and conditions, including systemic mastocytosis (SM), gastrointestinal stromal tumors (GIST), acute myeloid (myelocytic) leukemia (AML), melanoma, and seminoma. Therefore, there is a need to develop therapeutic agents that inhibit KIT, particularly drugs that inhibit mutant KIT.

[0003] The platelet-derived growth factor receptor (Platelet Derived Growth Factor Receptor) is a cell surface tyrosine kinase receptor as a member of the platelet-derived growth factor (PDGF) family. The PDGF subunits PDGFα and PDGFβ are important factors that regulate many diseases, including cell proliferation, cell differentiation, cell growth, development, and cancer. The PDGFRα D842V mutation has been found in a distinct subset of gastrointestinal stromal tumors (GIST) that usually arise from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance.

[0004] Gastrointestinal stromal tumor (GIST) is a rare cancer that occurs in interstitial cells of Cajal or common progenitor cells, caused by mutations in the tyrosine kinase receptor KIT (CD117) or platelet-derived growth factor receptor alpha polypeptide (PDGFRα). 80% - 85% of GISTs are mutations in the KIT gene, including rare mutation sites such as exon 11, exon 9, exon 13, and exon 17. Mutations in the PDGFRα gene account for 5% - 10%, and are commonly seen in mutations of exon 18 and exon 12.

[0005] Avapritinib (also known as BLU-285, chemical name (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethylamine, with the following structural formula) is an oral small molecule drug developed by Blueprint Medicines Corporation in the United States. It is a highly selective PDGFRα and KIT inhibitor, showing activity against mutations in KIT and PDGFRα (including KIT D816V, PDGFRα D842V, and mutations in KIT exon 17, etc.). Currently, it is in Phase I clinical trials. In June 2017, avapritinib received FDA breakthrough therapy designation for the treatment of patients with unresectable or metastatic GIST with PDGFRα D842V mutation. So far, the FDA has granted orphan drug status to avapritinib for use in the treatment of gastrointestinal stromal tumor (GIST) and systemic mastocytosis (SM).

[0006] [Chemical formula]

[0007] Inadequate absorption, distribution, metabolism, and / or excretion (ADME) properties are known to be a major cause of failure in clinical trials of many drug candidates. Many currently marketed drugs also have limited applications due to poor ADME properties. The rapid metabolism of drugs can result in many drugs that could originally treat diseases efficiently being difficult to develop into drugs because they are removed from the body metabolism too quickly. Although the problem of rapid drug clearance can be solved by frequent or high-dose administration, this method can cause problems such as poor patient compliance, side effects due to high-dose administration, and increased treatment costs. Furthermore, drugs that are rapidly metabolized can also expose patients to harmful toxic or reactive metabolites.

[0008] Avatrombopag can effectively treat GIST and SM as a highly selective PDGFRα and KIT inhibitor. However, in this field, serious clinical needs have not yet been met, and it remains a challenging task to find new compounds that can treat KIT- and / or PDGFRα-mediated diseases, have good oral bioavailability, and have pharmaceutical properties. Therefore, in this field, there is still a need to develop compounds with selective inhibitory activity against mutant KIT and / or PDGFRα-mediated diseases suitable as therapeutic agents, and / or better pharmacodynamics / pharmacokinetics. The present invention provides such compounds.

Summary of the Invention

[0009] To address the above technical problems, the present invention discloses novel deuterium-substituted pyrrolotriazine compounds having better KIT and / or PDGFRα kinase inhibitory activity, high selectivity against drug-resistant mutant KIT exon 17 mutations, KIT D816V, PDGFRα D842V, and combinations thereof, while having lower side effects and better pharmacokinetic performance, which are useful for the treatment of systemic mastocytosis (SM), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML), as well as compositions and uses thereof.

[0010] As used herein, the term "compound of the present invention" means a compound represented by formula (I). This term also includes pharmaceutically acceptable salts, prodrugs, hydrates or solvates, crystal polymorphs, stereoisomers or isotopic variants of the compound of formula (I).

[0011] In contrast, the present invention adopts the following technical solutions.

[0012] In a first aspect of the present invention, there is provided a compound of formula (Φ), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystal polymorph, stereoisomer or isotopic variant thereof.

[0013]

Chemical formula

[0014] Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH3, CD3, CHD2 or CH2D, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11 are each independently selected from hydrogen, deuterium, halogen, or trifluoromethyl, The additional condition is that the compound of the above formula contains at least one deuterium atom.

[0015] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount. In certain embodiments, the pharmaceutical composition further comprises another therapeutic agent that is active against a mutant KIT having a mutation in exon 9 or exon 11.

[0016] In another aspect, the present invention provides a method for manufacturing a pharmaceutical composition as described above, comprising the step of mixing a pharmaceutically acceptable excipient with a compound of the present invention to form the pharmaceutical composition.

[0017] The present invention also relates to, in another aspect, providing a method for treating a KIT-mediated disease in a subject. The method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. In certain embodiments, the KIT has a mutation in exon 9. In certain embodiments, the KIT has a mutation in exon 11. In certain embodiments, the KIT has a mutation in exon 17. In certain embodiments, the KIT is mutated at residue 816. In certain embodiments, the compound is administered orally, subcutaneously, intravenously or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the KIT-mediated disease is mastocytosis, gastrointestinal stromal tumor, or acute myeloid leukemia.

[0018] The present invention also relates, in another aspect, to a method for treating a disease mediated by PDFGRα in a subject. This method includes administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present invention. In certain embodiments, PDFGRα has a mutation in exon 18. In certain embodiments, PDFGRα is mutated at residue 842. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the mutant PDFGRα-mediated disease is mastocytosis, gastrointestinal stromal tumor, or acute myeloid leukemia.

[0019] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description of the invention, examples, and claims.

[0020] Definitions As used herein, "deuterated," unless otherwise indicated, means that one or more hydrogens in a compound or group are replaced by deuterium, and the deuteration can be mono-substitution, di-substitution, multi-substitution, or full substitution. The term "one or more deuterations" is used interchangeably with "one or more times deuterated."

[0021] As used herein, "non-deuterated compound" means, unless otherwise indicated, a compound in which the proportion of deuterium atoms is 0.015% or less of the natural deuterium isotope content.

[0022] The term "pharmaceutically acceptable salt" means those salts that are suitable for contact with the tissues of humans and lower animals within the scope of reliable medical judgment, without undue toxicity, irritation, allergy, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases.

[0023] The compounds of the present invention can be in amorphous or crystalline form. Further, the compounds of the present invention can exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "crystalline form" generally refers to different array patterns of chemical drug molecules, which are expressed as the existence forms of pharmaceutical raw materials in the solid state. A drug may exist in the state of multiple crystalline substances, and different crystalline forms of the same drug may have different dissolution and absorption in the body and may affect the elution and release of the formulation.

[0024] The term "crystalline form" generally refers to different array patterns of chemical drug molecules, which are expressed as the existence forms of pharmaceutical raw materials in the solid state. A drug may exist in the state of multiple crystalline substances, and different crystalline forms of the same drug may have different dissolution and absorption in the body and may affect the elution and release of the formulation.

[0025] As used herein, the term "subject" includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or the elderly)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and / or dogs. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human animal.

[0026] The terms "disease", "disorder" and "illness" are used interchangeably herein.

[0027] Unless otherwise indicated, as used herein, the term "treatment" includes an action that reduces the severity of a disease, disorder, or illness that occurs when a subject has a particular disease, disorder, or illness, or delays the progression of the disease, disorder, or illness ("therapeutic treatment"), and an action that occurs before the subject begins to have a particular disease, disorder, or illness ("preventive treatment").

[0028] Generally, the "effective amount" of a compound means an amount sufficient to cause a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health status and symptoms of the subject. The effective amount includes a therapeutically and prophylactically effective amount.

[0029] Unless otherwise indicated, as used herein, the "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder or illness, or to delay or minimize one or more symptoms associated with the disease, disorder, or illness. The therapeutically effective amount of a compound means the amount of a therapeutic agent used alone or in combination with other treatments that provides a therapeutic benefit during the treatment of a disease, disorder, or illness. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or illness, or enhances the therapeutic effect of other therapeutic agents.

[0030] Unless otherwise indicated, as used herein, the "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or illness, or an amount sufficient to prevent one or more symptoms associated with the disease, disorder or illness, or an amount sufficient to prevent recurrence of the disease, disorder or illness. The prophylactically effective amount of a compound means the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit during the prevention of a disease, disorder, or illness. The term "prophylactically effective amount" can include an amount that improves the overall prevention, or enhances the prophylactic effect of other prophylactic agents.

[0031] "Combination" and related terms mean that the therapeutic agents of the present invention are administered simultaneously or sequentially. For example, the compounds of the present invention can be administered simultaneously or sequentially in separate unit dosage forms from other therapeutic agents, or simultaneously in a single unit dosage form together with other therapeutic agents.

Mode for Carrying Out the Invention

[0032] Compound As used herein, "the compounds of the present invention" means compounds of formula (Φ), compounds of formula (I) and compounds of formula (II) below, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, crystal polymorphs, prodrugs, or active metabolites thereof.

[0033] In one embodiment, the present invention relates to a compound of formula (Φ), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystal form, stereoisomer or isotopic variant thereof.

[0034]

Chemical formula

[0035] Wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH3, CD3, CHD2 or CH2D, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10and Y 11 is independently selected from hydrogen, deuterium, halogen, or trifluoromethyl, and the additional condition is that the compound of the above formula contains at least one deuterium atom.

[0036] In another embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof, which is a compound of formula (I) or formula (II).

[0037]

Chemical formula

[0038] wherein, R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH3, CD3, CHD2 or CH2D, Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 and Y 11 are each independently selected from hydrogen, deuterium, halogen, or trifluoromethyl, and the additional condition is that the compound of the above formula contains at least one deuterium atom.

[0039] In one embodiment, the content of the deuterium isotope of deuterium at the deuterated position exceeds at least 0.015% more than the content of the natural deuterium isotope, preferably exceeds 30%, more preferably exceeds 50%, more preferably exceeds 75%, more preferably exceeds 95%, and more preferably exceeds 99%.

[0040] Specifically, in the present invention, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、X 1 and X 2 each have a content of the deuterium isotope at the deuterated position of at least 5%, preferably exceeding 10%, more preferably exceeding 15%, more preferably exceeding 20%, more preferably exceeding 25%, more preferably exceeding 30%, more preferably exceeding 35%, more preferably exceeding 40%, more preferably exceeding 45%, more preferably exceeding 50%, more preferably exceeding 55%, more preferably exceeding 60%, more preferably exceeding 65%, more preferably exceeding 70%, more preferably exceeding 75%, more preferably exceeding 80%, more preferably exceeding 85%, more preferably exceeding 90%, more preferably exceeding 95%, and more preferably exceeding 99%.

[0041] In one embodiment, "R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8"Each independently selected from hydrogen or deuterium" means that R 1 is selected from hydrogen or deuterium, R 2 is selected from hydrogen or deuterium, R 3 is selected from hydrogen or deuterium, and similarly, R 8 is selected from hydrogen or deuterium, including the technical solutions until R 1 is hydrogen or R 1 is deuterium, R 2 is hydrogen or R 2 is deuterium, R 3 is hydrogen or R 3 is deuterium, and similarly, R 8 is hydrogen or R 8 is deuterium, including the technical solutions until

[0042] In another embodiment, "X 1 and X 2 are each independently selected from CH3, CD3, CHD2 or CH2D" means that X 1 is selected from CH3, CD3, CHD2 or CH2D, and X 2 is selected from CH3, CD3, CHD2 or CH2D, including the technical solutions. More specifically, X 1 is CH3, X 1 is CD3, X 1 is CHD2 or X 1 is CH2D, and X 2 is CH3, X 2 is CD3, X 2 is CHD2 or X 2 is CH2D, including the technical solutions.

[0043] In another embodiment, "Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 and Y 11"Each independently selected from hydrogen, deuterium, halogen, or trifluoromethyl" means that Y 1 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, and Y 2 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, and Y 3 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, and similarly, Y 11 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, including the technical solutions until Y 1 is hydrogen, Y 1 is deuterium, Y 1 is halogen (F, Cl, Br or I) or Y 1 is trifluoromethyl, and Y 2 is hydrogen, Y 2 is deuterium, Y 2 is halogen (F, Cl, Br or I) or Y 2 is trifluoromethyl, and Y 3 is hydrogen, Y 3 is deuterium, Y 3 is halogen (F, Cl, Br or I) or Y 3 is trifluoromethyl, and similarly, Y 11 is hydrogen, Y 11 is deuterium, Y 11 is halogen (F, Cl, Br or I) or Y 11 is trifluoromethyl, including the technical solutions until.

[0044] In another embodiment, the present invention relates to Y 1 ~Y 11 each independently selected from hydrogen or deuterium, and R 1 ~R 8 , X 1 and X 2 are as defined above, and the additional condition is that the compound contains at least one deuterium atom, for a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof.

[0045] In another embodiment, the present invention provides that Y 1 ~Y 11 are each independently selected from hydrogen or deuterium, and R 1 ~R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, and relates to a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof.

[0046] In another embodiment, the present invention provides that Y 1 ~Y 11 are both hydrogen, and R 1 ~R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH3, CD3, CHD2 or CH2D, with the additional condition that the compound contains at least one deuterium atom, and relates to a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof.

[0047] In another embodiment, the present invention provides that Y 1 ~Y 11 are both hydrogen, and R 1 ~R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, and relates to a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof.

[0048] In another embodiment, the present invention relates to Y 1 ~Y 11 both being hydrogen, and R 1 ~R 4 both being hydrogen or deuterium, R 5 ~R 8 both being hydrogen or deuterium, X 1 and X 2 each independently being selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof.

[0049] In another embodiment, the present invention relates to Y 1 ~Y 11 both being hydrogen, and R 1 ~R 4 both being hydrogen, R 5 ~R 8 both being hydrogen or deuterium, X 1 and X 2 each independently being selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically, "Y 1 ~Y 11 both being hydrogen, and R 1 ~R 4 both being hydrogen, R 5 ~R 8 both being hydrogen, and X 1 is CH3, X 2 is CD3", "Y 1 ~Y 11 both being hydrogen, and R 1 ~R 4 both being hydrogen, R 5 ~R 8 both being hydrogen, and X 1is CD3, and X 2 is CH3, and Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both hydrogen, and R 5 ~R 8 are both hydrogen, and X 1 is CD3, and X 2 is CD3, and Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both hydrogen, and R 5 ~R 8 are both deuterium, and X 1 is CH3, and X 2 is CH3, and Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both hydrogen, and R 5 ~R 8 are both deuterium, and X 1 is CH3, and X 2 is CD3, and Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both hydrogen, and R 5 ~R 8 are both deuterium, and X 1 is CD3, and X 2 is CH3, or Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both hydrogen, and R 5 ~R 8 are both deuterium, and X 1 is CD3, and X 2 is CD3, including the technical solution.

[0050] In another embodiment, the present invention provides that Y 1 ~Y 11 are both hydrogen, and R 1~R 4 are both deuterium, and R 5 ~R 8 are both hydrogen or deuterium, and X 1 and X 2 are each independently selected from CH3 or CD3, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically, "Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, R 5 ~R 8 are both hydrogen, and X 1 is CH3, and X 2 is CH3", "Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, R 5 ~R 8 are both hydrogen, and X 1 is CH3, and X 2 is CD3", "Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, R 5 ~R 8 are both hydrogen, and X 1 is CD3, and X 2 is CH3", "Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, R 5 ~R 8 are both hydrogen, and X 1 is CD3, and X 2 is CD3", "Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, R 5 ~R8 are both deuterium, and X 1 is CH3, and X 2 is CD3」, 「Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, and R 5 ~R 8 are both deuterium, and X 1 is CH3, and X 2 is CD3」, 「Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, and R 5 ~R 8 are both deuterium, and X 1 is CD3, and X 2 is CH3」, or 「Y 1 ~Y 11 are both hydrogen, and R 1 ~R 4 are both deuterium, and R 5 ~R 8 are both deuterium, and X 1 is CD3, and X 2 is CD3」, including technical solutions. In another embodiment, the present invention relates to Y 1 ~Y 11 are both hydrogen, and R 1 ~R 8 are both hydrogen or deuterium, and X 1 and X 2 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof.

[0051] In another embodiment, the present invention relates to Y 1 ~Y 11 are both hydrogen, and R 1 ~R 8are both hydrogen, X 1 and X 2 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, for a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically, "Y 1 ~Y 11 are both hydrogen, R 1 ~R 8 are both hydrogen, and X 1 is CH3 and X 2 is CD3", "Y 1 ~Y 11 are both hydrogen, R 1 ~R 8 are both hydrogen, and X 1 is CD3 and X 2 is CH3", "Y 1 ~Y 11 are both hydrogen, R 1 ~R 8 are both hydrogen, and X 1 is CD3 and X 2 is CD3" including technical solutions.

[0052] In another embodiment, the present invention relates to a compound of formula (Φ), formula (I) or formula (II) in which Y 1 ~Y 11 are both hydrogen and R 1 ~R 8 are both deuterium, and X 1 and X 2 are each independently selected from CH3 or CD3, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically, "Y 1 ~Y 11 are both hydrogen, R 1 ~R 8 are both deuterium, and X 1 is CH3 and X 2 is CD3", "Y1 ~Y 11 are both hydrogen, and R 1 ~R 8 are both deuterium, and X 1 is CD3, and X 2 is CH3」or「Y 1 ~Y 11 are both hydrogen, and R 1 ~R 8 are both deuterium, and X 1 is CD3, and X 2 is CD3」, including the technical solution.

[0053] In another embodiment, the present invention relates to Y 1 ~Y 11 are both hydrogen, X 1 is CH3, and R 1 ~R 4 are both hydrogen or deuterium, and R 5 ~R 8 are both hydrogen or deuterium, X 2 is independently selected from CH3 or CD3 respectively, and the additional condition is that the compound contains at least one deuterium atom, regarding the compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically,「Y 1 ~Y 11 are both hydrogen, X 1 is CH3, and R 1 ~R 4 is hydrogen, and R 5 ~R 8 is deuterium, and X 2 is CH3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CH3, and R 1 ~R 4 is hydrogen, and R 5 ~R 8 is deuterium, and X 2 is CD3」,「Y 1 ~Y 11 are both hydrogen, X1 is CH3, and R 1 ~R 4 is deuterium, and R 5 ~R 8 is hydrogen, and X 2 is CH3」, 「Y 1 ~Y 11 are both hydrogen, and X 1 is CH3, and R 1 ~R 4 is deuterium, and R 5 ~R 8 is hydrogen, and X 2 is CD3」, 「Y 1 ~Y 11 are both hydrogen, and X 1 is CH3, and R 1 ~R 8 is hydrogen, and X 2 is CD3」, 「Y 1 ~Y 11 are both hydrogen, and X 1 is CH3, and R 1 ~R 8 is deuterium, and X 2 is CH3」, 「Y 1 ~Y 11 are both hydrogen, and X 1 is CH3, and R 1 ~R 8 is deuterium, and X 2 is CD3」, including.

[0054] In another embodiment, the present invention provides that Y 1 ~Y 11 are both hydrogen, and X 1 is CD3, and R 1 ~R 8 are each independently selected from hydrogen or deuterium, and X 2 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically, "Y1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 4 is hydrogen, R 5 ~R 8 is deuterium, X 2 is CH3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 4 is hydrogen, R 5 ~R 8 is deuterium, X 2 is CD3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 4 is deuterium, R 5 ~R 8 is hydrogen, X 2 is CH3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 4 is deuterium, R 5 ~R 8 is hydrogen, X 2 is CD3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 8 is hydrogen, X 2 is CH3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 8 is hydrogen, X 2 is CD3」,「Y 1 ~Y 11 are both hydrogen, X 1 is CD3, and R 1 ~R 8 is deuterium, X2 is CH3」,「Y 1 ~Y 11 are both deuterium, and X 1 is CD3, and R 1 ~R 8 are hydrogen, and X 2 is CD3」.

[0055] In another embodiment, the present invention relates to Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 8 are each independently selected from hydrogen or deuterium, X 1 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically,「Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 4 is hydrogen, and R 5 ~R 8 is deuterium, and X 1 is CH3」,「Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 4 is hydrogen, and R 5 ~R 8 is deuterium, and X 2 is CD3」,「Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 4 is deuterium, and R 5 ~R 8 is hydrogen, and X 1 is CH3」,「Y 1 ~Y 11are both hydrogen, and X 2 is CH3, and R 1 ~R 4 are deuterium, and R 5 ~R 8 are hydrogen, and X 1 is CD3」,「Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 8 are hydrogen, and X 1 is CD3」,「Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 8 are deuterium, and X 1 is CH3」,「Y 1 ~Y 11 are both hydrogen, and X 2 is CH3, and R 1 ~R 8 are deuterium, and X 1 is CD3」 includes.

[0056] In another embodiment, the present invention provides Y 1 ~Y 11 are both hydrogen, and X 2 is CD3, and R 1 ~R 8 are each independently selected from hydrogen or deuterium, and X 1 are each independently selected from CH3 or CD3, with the additional condition that the compound contains at least one deuterium atom, a compound of formula (Φ), formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystalline form, stereoisomer or isotopic variant thereof. More specifically,「Y 1 ~Y 11 are both hydrogen, and X 2 is CD3, and R 1 ~R 4 are hydrogen, and R 5 ~R 8 are deuterium, and X 1is CH3」, 「Y 1 ~Y 11 are both hydrogen, X 2 is CD3, and R 1 ~R 4 is hydrogen, R 5 ~R 8 is deuterium, X 1 is CD3」, 「Y 1 ~Y 11 are both hydrogen, X 2 is CD3, and R 1 ~R 4 is deuterium, R 5 ~R 8 is hydrogen, X 1 is CH3」, 「Y 1 ~Y 11 are both hydrogen, X 2 is CD3, and R 1 ~R 4 is deuterium, R 5 ~R 8 is hydrogen, X 1 is CD3」, 「Y 1 ~Y 11 are both hydrogen, X 2 is CD3, and R 1 ~R 8 is hydrogen, X 1 is CH3」, 「Y 1 ~Y 11 are both hydrogen, X 2 is CD3, and R 1 ~R 8 is hydrogen, X 1 is CD3」, 「Y 1 ~Y 11 are both hydrogen, X 2 is CD3, and R 1 ~R 8 is deuterium, X 1 is CH3」, 「Y 1 ~Y 11 are both deuterium, X 2 is CD3, and R 1 ~R 8 is hydrogen, X 1 includes the case where is CD3」.

[0057] As a preferred embodiment of the present invention, the compound is any of the following structures, or a pharmaceutically acceptable salt thereof, but is not limited to the following structures.

[0058]

Chemical formula

[0059]

Chemical formula

[0060]

Chemical formula

[0061]

Chemical formula

[0062] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention encompasses all such compounds, including their cis and trans isomers, R- and S-enantiomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures thereof that fall within the scope of the present invention. Substituents such as alkyl groups may further contain additional asymmetric carbon atoms. All such isomers and their mixtures are intended to be included in the present invention.

[0063] For example, if a specific enantiomer of a compound of the present invention is desired, it can be produced by asymmetric synthesis or the mixture of diastereomers obtained can be separated and the auxiliary group dissociated to provide the pure desired enantiomer by derivatization using a chiral auxiliary. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers thus formed are resolved by fractional crystallization or chromatographic means well known in the art, and then the pure enantiomer is recovered.

[0064] Unless otherwise specified, if the disclosed compounds are named without specifying stereochemistry or are shown by structure and have one or more chiral centers, it should be understood that all stereoisomers of the corresponding compounds and mixtures of their enantiomers are represented.

[0065] The "enantiomeric excess" or "percent enantiomeric excess" of a composition can be calculated using the general formula shown below. In the examples shown below, the composition contains 90% of one enantiomer (e.g., the S enantiomer) and 10% of the other enantiomer (e.g., the R enantiomer).

[0066]

Equation

[0067] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is described as having an enantiomeric excess of 80%.

[0068] The compounds or compositions described herein may contain one form of a compound having an enantiomeric excess of at least 50%, 75%, 90%, 95% or 99%, for example, the S-enantiomer. In other words, such a compound or composition contains the S-enantiomer with an enantiomeric excess over the R-enantiomer.

[0069] One of ordinary skill in the art will understand that an organic compound can form a complex with a solvent and that it can react in the solvent in question or precipitate or crystallize from the solvent in question. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

[0070] The term "solvate" generally means a form of a compound or its salt that is combined with a solvent and is formed by a solvolysis reaction. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein can be produced, for example, in crystalline form and may also be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes solvates in solution state and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0071] The term "hydrate" means a compound combined with water. Generally, it is determined by the ratio of the number of water molecules contained in the hydrate of the compound to the number of molecules of the corresponding compound in the corresponding hydrate. Therefore, the hydrate of a compound can be represented, for example, by the general formula R·xH2O (wherein R is the corresponding compound and x is a number greater than 0). A given compound may form one or more hydrate types, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0072] The compounds of the present invention can be in an amorphous or crystalline form (crystal polymorph). Furthermore, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all of the amorphous or crystalline forms of the compounds of the present invention within its scope. The term "crystal polymorph" means a crystalline form of a compound (or its salt, hydrate, or solvate) with a specific crystal packing arrangement. All crystal polymorphs have the same elemental composition. Usually, different crystalline forms have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optoelectronic properties, stabilities, and solubilities. The crystalline form may be dominant depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors. The various crystal polymorphs of a compound can be produced by crystallization under different conditions.

[0073] The present invention also includes isotope-labeled compounds that are equivalent to those represented by formula (I) but in which one or more atoms are substituted by atoms having an atomic mass or mass number different from the normal atomic mass or mass number in nature. Examples of isotopes that can be introduced into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P,32 P, 35 S, 18 F, and 36 Cl are included. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, and pharmaceutically acceptable salts of the compounds or the prodrugs are all within the scope of the present invention. Compounds of the present invention labeled with an isotope, such as those introducing a radioactive isotope (e.g., 3H and 14 C), can be used in assays of the tissue distribution of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because their production and detection are easy. Furthermore, substitution with a heavier isotope, such as deuterium (i.e., 2 H), may be preferred in some cases because it provides higher metabolic stability and therapeutic benefits, such as an extended in vivo half-life or a reduced required dose. Compounds of formula (I) of the present invention labeled with an isotope and their prodrugs can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents when carrying out the processes disclosed in the following schemes and / or examples and preparation examples.

[0074] Furthermore, prodrugs are also included within the context of the present invention. As used herein, the term "prodrug" means, for example, a compound that is converted in vivo to its active form having a medical effect by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrug as as Novel Delivery Systems, ACS Symposium Series Vol. 14, Edward B. Roche ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association, Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each document being incorporated herein by reference.

[0075] A prodrug is any of the compounds of the present invention that are covalently bound, and when such a prodrug is administered to a patient, it releases the parent compound in the body. Prodrugs are typically produced by modifying functional groups, and the modifications are made such that the relevant modification can generate the parent compound through customary operations or cleavage in the body. Prodrugs include, for example, compounds of the present invention in which a hydroxyl group, an amino group, or a thiol group is bound to any group, and when administered to a patient, can cleave to form a hydroxyl group, an amino group, or a thiol group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl group, thiol group, and amino group functional groups of the compounds of formula (I). Also, in the case of a carboxylic acid (-COOH), for example, esters such as methyl ester, ethyl ester, etc. can be used. The ester may itself be active and / or may be hydrolyzed under human biological conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that are readily decomposed in the human body to release the parent acid or its salt.

[0076] Synthesis The compounds of the present invention (including their salts and N-oxides) can be produced using known organic synthesis techniques and can be synthesized according to any of various possible synthetic routes such as those of the following schemes. The reactions for producing the compounds of the present invention can be carried out in a suitable solvent, and those skilled in the art of organic synthesis can easily select the solvent. A suitable solvent may not substantially react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (for example, a temperature within the temperature range from the freezing temperature to the boiling point of the solvent). A given reaction can be carried out in one solvent or a mixture of one or more solvents. The solvent for a specific reaction step can be selected by those skilled in the art depending on the specific reaction step.

[0077] The production of the compounds of the present invention may relate to the protection and deprotection of different chemical groups. The necessity for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups can be referred to, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is hereby incorporated by reference in its entirety.

[0078] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry (MS), or chromatography (high performance liquid chromatography (HPLC) or thin layer chromatography (TLC)).

[0079] Pharmaceutical Compositions, Formulations and Kits In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0080] As used herein, a pharmaceutically acceptable excipient means a non-toxic carrier, adjuvant or vehicle that does not impair the pharmacological activity of the compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0081] The present invention also includes kits (e.g., pharmaceutical packages). The kits provided can include a compound of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the compound of the present invention and other therapeutic agents. In some embodiments, the kits provided can optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the present invention and / or other therapeutic agents. In some embodiments, there are provided those in which the compound of the present invention and other therapeutic agents in the first and second containers are combined to form one unit dosage form.

[0082] The pharmaceutical compositions provided by the present invention can be administered by a number of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration by implant, or other methods of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion techniques.

[0083] Generally, an effective amount of the compounds provided herein is administered. The amount of the compound actually administered can be determined by the physician according to the circumstances, including the disease being treated, the selected route of administration, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0084] When the compounds provided herein are used to prevent the diseases described in the present invention, they are typically administered under the supervision of a physician based on the physician's recommendation, and the dosage level is as described above. Subjects at risk of developing a particular disease generally include subjects with a family history of that disease, or subjects determined to be particularly susceptible to the development of that disease by genetic testing or screening.

[0085] The pharmaceutical compositions provided herein can also be administered for a long period of time (“long-term administration”). Long-term administration means administering the compound or its pharmaceutical composition over a long period, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or, for example, continuously for an indefinite period during the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over a long period, for example, within a treatment window.

[0086] The pharmaceutical composition of the present invention can be further delivered using various administration methods. For example, in some embodiments, the pharmaceutical composition can be administered as a bolus, for example, to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient. For example, an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus delivered directly into the vein (e.g., by IV infusion) is delivered more rapidly and can rapidly increase the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition is administered, for example, as a continuous infusion by IV infusion, and can provide a steady-state concentration of the active ingredient in the body of the subject. Further, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0087] The oral composition can take the form of a bulk liquid solution or suspension or a bulk powder. However, more generally, the composition is provided in unit dosage form to facilitate accurate dosage administration. The term "unit dosage form" means a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of the active substance suitable to produce the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is generally a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder are various carriers or excipients and processing aids useful for forming the desired dosage form.

[0088] For oral doses, typical regimens are 1 to 5 oral doses per day, particularly 2 to 4 oral doses, typically 3 oral doses. Using these dosage administration modes, each dose provides from about 0.01 to about 20 mg / kg of the compound of the present invention, and preferred doses each provide from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg.

[0089] To provide blood levels similar to or lower than the injected dose used, the transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 10% by weight, more preferably about 0.5 to about 15% by weight.

[0090] The injected dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour within a range of about 1 to about 120 hours, particularly 24 to 96 hours. To obtain a sufficient steady-state level, a preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be administered. The maximum total dose cannot exceed about 2 g / day for a human patient weighing 40 - 80 kg.

[0091] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, etc. Solid forms may include, for example, binders (such as microcrystalline cellulose, tragacanth, or gelatin), excipients (such as starch, or lactose), disintegrants (such as alginic acid, Primogel, or corn starch), lubricants (such as magnesium stearate), glidants (such as colloidal silica), sweetening agents (such as sucrose, or saccharin), or flavoring agents (such as mint, methyl salicylate, or orange-flavored flavoring agents), or compounds having similar properties.

[0092] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As described above, in such compositions, the active compound is typically the minor component, often about 0.05 to 10% by weight, and the remainder is injectable excipients, etc.

[0093] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include the active ingredient or other components for enhancing the stable skin penetration of the formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0094] The compounds of the present invention can also be administered via a transdermal device. Thus, transdermal administration can be achieved using a reservoir or porous membrane type, or patches of various solid matrices.

[0095] The above components in compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, etc. are described in Part 8 of Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and this document is incorporated herein by reference.

[0096] The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0097] The present invention further relates to a pharmaceutically acceptable formulation of the compound of the present invention. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α, β, and γ-cyclodextrins, each consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally contain one or more substituents (including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the linked sugar moieties. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as calupol. See, for example, U.S. Patent No. 5,376,645. In some embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0098] Indications The compounds of the present invention can be used to treat human or non-human diseases associated with abnormal KIT activity. Activating mutations in KIT are present in various indications, including systemic mastocytosis, gastrointestinal stromal tumors, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumors, and mediastinal B-cell lymphoma.

[0099] Mastocytosis refers to a group of diseases characterized by excessive mast cell accumulation in one or more tissues. Mastocytosis is classified into two groups of diseases: (1) cutaneous mastocytosis (CM), which presents in a form limited to the skin, and (2) systemic mastocytosis (SM), which presents in a form where mast cells infiltrate organs outside the dermis, with or without skin lesions. SM is further classified into five forms: indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM associated with hematologic mast cell lineage disorders (SM-AHNMD), and mast cell leukemia (MCL).

[0100] The diagnosis of systemic mastocytosis is based in part on histological and cytological studies of the bone marrow, which show that mast cells often have an atypical appearance upon infiltration and abnormally express non-mast cell markers (CD25 and / or CD2). A diagnosis of SM is made when bone marrow mast cell infiltration is noted in any of the following: (1) abnormal mast cell morphology (spindle cells), (2) plasma levels elevated to 20 ng / mL or greater, or (3) the presence of an activating KIT T D816V mutation.

[0101] Activating mutations at the position of D816 are found in a wide variety of mastocytosis cases (90 - 98%), and the most common mutations among them are D816V and D86H, as well as D816Y. The D816V mutation is present in the activation loop within the kinase domain, resulting in constitutive activation of the KIT kinase.

[0102] The compounds of the present invention are also useful for the treatment of gastrointestinal stromal tumors (GIST). Total surgical resection remains the primary treatment option selected for patients with primary GIST. Surgery is effective in approximately 50% of GIST patients, and in the remaining patients, tumor recurrence often occurs. Also, initial treatment with a KIT inhibitor such as imatinib has been demonstrated to be sufficient for initial treatment. However, resistance to imatinib occurs within several months due to somatic mutations. These second-generation imatinib-resistant mutations are most frequently located in exons 11, 13, 14, 17, or 18. Sunitinib is the standard for most second-line treatments of imatinib-resistant tumors and is effective against those containing mutations in exons 11, 13, and 14. However, second-generation KIT mutations in exons 17 and 18 are resistant to sunitinib treatment, and furthermore, tumors containing third-generation resistant mutations in exons 17 and 18 appear several months after sunitinib treatment. Regorafenib showed desirable results in a phase 3 clinical trial of imatinib- and sunitinib-resistant GIST against some, but not all, mutations in exons 17 and 18 (D816 is one of them). Therefore, there is a need for a therapeutic agent to treat patients with specific exon 17 mutant GIST that cannot be resolved with regorafenib.

[0103] In a refractory GIST setting, by using a composition of imatinib, sunitinib, and / or regorafenib together with the compounds disclosed herein, in addition to using the compounds described herein as a single agent, the occurrence of resistance to exon 17 mutations can be prevented.

[0104] There is a subset of GIST patients who have the D842V mutation in PDGFRα, and GIST patients in this subgroup can be stratified by identifying the corresponding mutation. All currently available tyrosine kinase inhibitors are difficult to treat patients in this subset. The compounds described herein are useful for treating these patients because they have activity against PDGFRα D842V.

[0105] The compounds described herein are also useful for the treatment of acute myeloid leukemia (AML). AML patients also potentially have mutations in KIT, and most of these mutations are at the position of D816.

[0106] In addition, mutations in KIT are associated with Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), non-small cell carcinoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0107] The compounds of the present invention are active against one or more KIT mutations in exon 17 (e.g., D816V, D816Y, D816F, D816K, D816A, D816G, D820A, D820E, D820G, N822K, N822H, Y823D and A829P), but are much less active against wild-type KIT and can be used for the treatment of diseases. These compounds can be administered in combination with agents that a) are active against other activating mutations of KIT, such as mutations in exons 9 and 11, but b) are inactive against mutations in exon 17. Such agents include imatinib, sunitinib and regatinib. Thus, the combination of the said compound and the said agent will inhibit the mutant KIT in exon 17 and inhibit the mutant KIT in exon 19 / 11. The said compound and agent can be administered simultaneously or according to an alternating protocol. That is, the inhibitor of mutant KIT in exon 17 can be administered alone for a period, and then the inhibitor of mutant KIT in exon 9 / 11 can be administered alone for a period. Then this cycle can be repeated. Such a protocol is thought to be able to delay the development of resistance to the inhibitor of mutant KIT in exon 17 and / or the inhibitor of mutant KIT in exon 9 / 11.

[0108] Also, the compounds of the present invention that can be selected against mutations in exon 17 can be administered in combination with an agent that is active against mutations in exons 9 / 11 and a third agent that covers the mutations that are deleted in the case of a two-way combination. The combination of the three agents can inhibit a series of KIT mutations and, in some cases, can inhibit wild-type KIT. The said agents can be administered simultaneously or according to an alternating protocol. They may be administered alone each time, or two of the agents may be administered together for a period and then the third agent may be administered alone for a period. Such a protocol is thought to be able to delay the development of resistance to the mutant KIT inhibitor.

Example

[0109] The present invention will be further described below with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not described usually follow conventional conditions or conditions proposed by the manufacturer. Parts and percentages are by weight parts and weight percentages unless otherwise specified.

[0110] Generally, in the manufacturing process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (for example, 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.

[0111] The abbreviations used in this specification have the following meanings.

[0112]

Table A

[0113] Example 1: Preparation of (4-fluorophenyl)(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (Intermediate A-1)

[0114]

Chemical formula

[0115] Synthesis is carried out according to the following route.

[0116]

Chemical formula

[0117] Step 1: Synthesis of Compound 3 Into a 250 mL single-necked flask equipped with magnetic stirring, add 1,4-dioxane (100 mL) and Compound 1 (10.0 g, 53.59 mmol), stir to dissolve, cool in an ice-water bath, then add Compound 2 (9.98 g, 53.59 mmol) and DIPEA (20.8 mL, 134 mmol), remove the ice bath, and react with stirring at room temperature for 3 hours under a nitrogen atmosphere. Distill off the solvent under reduced pressure and pass through a silica gel column to obtain 18.0 g (yield: 99.85%) of a white solid. LC-MS (APCI): m / z = 337.2 (M+1) + 。

[0118] Step 2: Synthesis of Compound 4 Into a 500 mL single-necked flask equipped with magnetic stirring and a condenser tube, add THF (100 mL), methanol (100 mL) and Compound 3 (17.0 g, 50.54 mmol), stir to dissolve, add an aqueous NaOH solution (4.04 g, 0.11 mol, 100 mL) with stirring, heat to 70 °C under a nitrogen atmosphere, maintain this temperature, react with stirring for 2 hours, cool to room temperature, adjust the pH to 5 with 1M HCl(aq.), precipitate a large amount of white solid, filter, wash with water (10 mL), and dry under vacuum to obtain 15.0 g (yield: 96.26%) of a white solid. LC-MS (APCI): m / z = 309.2 (M+1) + 。

[0119] Step 3: Synthesis of Compound 5 To a 250 mL single-necked flask equipped with magnetic stirring, compound 4 (6.90 g, 22.38 mmol) and dry dichloromethane (100 mL) were added, and the mixture was stirred until dissolved. HOBT (3.63 g, 26.85 mmol), EDCI (6.43 g, 33.57 mmol) and triethylamine (9.06 g, 89.51 mmol) were added, and the mixture was reacted with stirring at room temperature for 1 hour under a nitrogen atmosphere. After adding N,O-dimethylhydroxylamine hydrochloride (2.62 g, 26.85 mmol), the reaction was continued with stirring for 3 hours under a nitrogen atmosphere. Water (50 mL) was added to stop the reaction, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 3.0 g (yield: 38.15%) of a white solid. LC-MS (APCI): m / z = 352.2 (M+1) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 2H), 3.90 (t, J = 5.2 Hz, 4H), 3.62 (s, 3H), 3.51 (t, J = 5.2 Hz, 4H), 3.36 (s, 3H), 1.49 (s, 9H).

[0120] Step 4: Synthesis of compound 7 To a 100 mL two-necked flask equipped with magnetic stirring, compound 5 (3.0 g, 8.54 mmol) and anhydrous THF (30 mL) were added, and the mixture was stirred until dissolved. The flask was evacuated and protected with nitrogen, cooled in an ice-water bath, and a THF solution of compound 6 (2 M, 8.54 mL, 17.07 mmol) was added dropwise. After the addition was complete, the ice-water bath was removed, and the reaction was carried out with stirring at room temperature for 3 hours. Dilute hydrochloric acid (1 M, 15 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to distill off the solvent, and the residue was passed through a silica gel column to obtain 2.37 g (yield: 71.8%) of an off-white solid. LC-MS (APCI): m / z = 387.1 (M+1) + 。 11H NMR (300 MHz, CDCl3) δ 8.77 (s, 2H), 7.82 - 7.77 (m, 2H), 7.21 - 7.16 (m, 2H), 3.98 - 3.95 (m, 4H), 3.56 - 3.52 (m, 4H), 1.50 (s, 9H).

[0121] Step 5: Synthesis of Intermediate A-1 To a 100 mL single-necked flask equipped with magnetic stirring, compound 7 (2.37 g, 6.13 mmol) and dichloromethane (25 mL) were added, stirred and dissolved, TFA (5 mL) was added, and the reaction was carried out with stirring at room temperature for 2 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, saturated aqueous sodium bicarbonate solution (10 mL) was added, and extraction was performed with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 1.50 g (yield: 85.42%) of a yellow solid. LC-MS (APCI): m / z = 287.1 (M+1) + .

[0122] Example 2: Preparation of (4-Fluorophenyl)(2-(piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)methanone (Intermediate A-2)

[0123] [Chemical formula]

[0124] Synthesis is carried out according to the following route.

[0125] [Chemical formula]

[0126] Step 1: Synthesis of Compound 9 To a 100 mL single-necked flask equipped with magnetic stirring, 1,4-dioxane (60 mL) and Compound 1 (4.0 g, 21.4 mmol) were added, stirred to dissolve, cooled in an ice-water bath, and then Compound 8 (2.48 g, 25.6 mmol) and DIPEA (7.5 g, 53.6 mmol) were added. The ice bath was removed, and the reaction was carried out with stirring at room temperature for 3 hours under a nitrogen atmosphere. Boc2O (9.3 g, 40.3 mmol) was added, and the reaction was continued with stirring for 1 hour. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column to obtain 3.5 g (yield: 47.4%) of a white solid. LC-MS (APCI): m / z = 345.2 (M+1) + 。

[0127] Step 2: Synthesis of Compound 10 To a 100 mL single-necked flask equipped with magnetic stirring and a condenser tube, THF (30 mL), methanol (30 mL) and Compound 9 (3.5 g, 10.17 mmol) were added, stirred to dissolve, and an aqueous NaOH solution (0.83 g, 20.34 mmol, dissolved in 30 mL of water) was added with stirring. The temperature was raised to 70 °C under a nitrogen atmosphere, maintained at this temperature, and the reaction was carried out with stirring for 2 hours. It was cooled to room temperature, the pH was adjusted to 5 with 1M HCl(aq.), a large amount of white solid was precipitated, filtered, washed with water (10 mL), and dried in vacuo to obtain 3.0 g (yield: 93.05%) of a white solid. LC-MS (APCI): m / z = 317.2 (M+1) + 。

[0128] Step 3: Synthesis of Compound 11 To a 100 mL single-necked flask equipped with magnetic stirring, compound 10 (3.0 g, 9.48 mmol) and dry dichloromethane (30 mL) were added, and the mixture was stirred until dissolved. HOBT (1.54 g, 11.38 mmol), EDCI (2.73 g, 14.22 mmol) and triethylamine (3.84 g, 37.93 mmol) were added, and the mixture was reacted with stirring at room temperature for 1 hour under a nitrogen atmosphere. After adding N,O-dimethylhydroxylamine hydrochloride (1.11 g, 11.38 mmol), the reaction was continued with stirring for 3 hours under a nitrogen atmosphere. Water (30 mL) was added to stop the reaction, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 3.0 g (yield: 88.02%) of a white solid. LC-MS (APCI): m / z = 360.2 (M+1) + . 1 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 2H), 3.62 (s, 3H), 3.36 (s, 3H), 1.49 (s, 9H).

[0129] Step 4: Synthesis of compound 12 To a 100 mL two-necked flask equipped with magnetic stirring, compound 11 (3.0 g, 8.35 mmol) and anhydrous THF (30 mL) were added, and the mixture was stirred until dissolved. The flask was evacuated and protected with nitrogen, cooled in an ice-water bath, and a THF solution of compound 6 (2 M, 8.35 mL, 16.69 mmol) was added dropwise. After the addition was complete, the ice-water bath was removed, and the reaction was carried out with stirring at room temperature for 3 hours. Dilute hydrochloric acid (1 M, 15 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the residue was passed through a silica gel column to obtain 2.37 g (yield: 72.0%) of an off-white solid. LC-MS (APCI): m / z = 395.1 (M+1) + . 1 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 2H), 7.82 - 7.77 (m, 2H), 7.21 - 7.16 (m, 2H), 1.50 (s, 9H).

[0130] Step 5: Synthesis of Intermediate A-2 To a 50 mL single-necked flask equipped with magnetic stirring, compound 12 (2.37 g, 6.01 mmol) and dichloromethane (25 mL) were added, stirred and dissolved, trifluoroacetic acid (5 mL) was added, and the reaction was carried out with stirring at room temperature for 2 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, saturated aqueous sodium bicarbonate solution (10 mL) was added, extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 1.50 g (yield: 84.82%) of a yellow solid. LC-MS (APCI): m / z = 295.1 (M+1) + 。

[0131] Example 3: Preparation of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (Intermediate B-1)

[0132]

Chem.

[0133] Synthesis is carried out according to the following route.

Chem.

[0134] Step 1: Synthesis of Compound 15 To a 100 mL single-necked flask equipped with magnetic stirring, compound 13 (4.18 g, 20.09 mmol), compound 14 (2.15 g, 10.05 mmol), cesium carbonate (9.82 g, 30.14 mmol), Pd(dppf)Cl2 (1.63 g, 2.22 mmol), 1,4-dioxane (100 mL) and water (20 mL) were added, evacuated and replaced with nitrogen gas three times, heated to 110 °C under a nitrogen atmosphere and left overnight, cooled to room temperature, silica gel of 80 - 100 mesh (50 g, 120 mL) was added, concentrated to dryness under reduced pressure, and passed through a silica gel column to obtain 1.2 g (yield: 55.5%) of a yellow solid. LC-MS (APCI): m / z = 216.1 (M+1)+ .

[0135] Step 2: Synthesis of Intermediate B-1 To a 50 mL single-necked flask equipped with magnetic stirring, compound 15 (1.0 g, 4.58 mmol) and phosphorus oxychloride (10 mL) were added. The temperature was raised to 95 °C under a nitrogen atmosphere and maintained at this temperature for 5 hours while stirring and reacting. After cooling to room temperature, the residual phosphorus oxychloride was distilled off under reduced pressure. Dichloromethane (30 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added. The organic layer was separated, the aqueous layer was extracted with dichloromethane (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 480 mg (yield: 36.84%) of a white solid. LC-MS (APCI): m / z = 234.1 (M+1) + . 1 1H NMR (400 MHz, CDCl3) δ 19 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.00 (d, J = 1.6 Hz, 1H), 3.98 (s, 3H).

[0136] Example 4: Preparation of 4-chloro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (Intermediate B-2)

[0137]

Chemical formula

[0138] Synthesis is carried out according to the following route.

[0139]

Chemical formula

[0140] Step 1: Synthesis of Compound 17 In a 100 mL two-necked flask equipped with magnetic stirring, compound 16 (5.0 g, 25.77 mmol) and anhydrous THF (40 mL) were added, stirred until dissolved, and while cooling in an ice-water bath, NaH (2.25 g, 51.54 mmol, 55% w / w) was slowly added. After stirring for 10 minutes (min) under a nitrogen atmosphere, CD3I (7.47 g, 51.54 mmol) was added dropwise. After the addition was complete, the ice bath was removed, and the reaction was carried out with stirring at room temperature overnight under a nitrogen atmosphere. Methanol (5 mL) was added to stop the reaction, and further ethyl acetate (30 mL) was added to dilute the reaction solution. The insoluble solid was filtered off, and the filtrate was concentrated and passed through a silica gel column to obtain 3.5 g (yield: 64.35%) of a colorless oil. LC-MS (APCI): m / z = 212.1 (M + 1) + .

[0141] Step 2: Synthesis of compound 18 In a 100 mL single-necked flask equipped with magnetic stirring, compound 17 (3.49 g, 16.54 mmol), compound 14 (1.77 g, 8.27 mmol), cesium carbonate (8.08 g, 24.81 mmol), Pd(dppf)Cl2 (678 mg, 0.83 mmol), 1,4-dioxane (70 mL), ethanol (15 mL) and water (10 mL) were added. The flask was evacuated and replaced with nitrogen gas three times. Then, the temperature was raised to 110 °C under a nitrogen atmosphere and left overnight, cooled to room temperature, silica gel (50 g, 120 mL) with a mesh size of 80 - 100 was added, concentrated to dryness under reduced pressure, and passed through a silica gel column to obtain 1.1 g (yield: 60.95%) of a yellow solid. LC-MS (APCI): m / z = 219.1 (M + 1) + .

[0142] Step 3: Synthesis of intermediate B-2 To a 50 mL single-necked flask equipped with magnetic stirring, compound 18 (1.0 g, 4.58 mmol) and phosphorus oxychloride (10 mL) were added. The temperature was raised to 95 °C under a nitrogen atmosphere and maintained at this temperature for 5 hours with stirring for the reaction. After cooling to room temperature, the residual phosphorus oxychloride was distilled off under reduced pressure. Dichloromethane (30 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added. The organic layer was separated, the aqueous layer was extracted with dichloromethane (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 330 mg (yield: 30.43%) of a white solid. LC-MS (APCI): m / z = 237.1 (M+1) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.00 (d, J = 1.6 Hz, 1H).

[0143] Example 5: Preparation of 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethylamine (Compound 22), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethylamine (Compound T-1-S), and (R)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethylamine (Compound T-1-R)

[0144]

Chemical Structure

[0145] Perform the synthesis through the following route.

[0146]

Chemical formula

[0147] Step 1: Synthesis of Compound 19 Add Compound A-1 (261.3 mg, 0.91 mmol) and 1,4-dioxane (10 mL) to a 50 mL single-necked flask equipped with magnetic stirring, stir to dissolve, add DIPEA (200 mg, 1.52 mmol) and Compound B-2 (180 mg, 0.76 mmol), and react with stirring overnight at room temperature under a nitrogen atmosphere. Distill off the solvent under reduced pressure, and pass the residue through a silica gel column to obtain 340 mg (yield: 91.89%) of a yellow solid. LC-MS (APCI): m / z = 487.1 (M+1) + 。 1 1H NMR (400 MHz, DMSO-D6) δ 8.82 (s, 2H), 7.83 - 7.79 (m, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.20 (t, J = 8.4 Hz, 2H), 6.80 (s, 1H), 4.09 - 4.07 (m, 4H), 3.90 - 3.88 (m, 4H).

[0148] Step 2: Synthesis of Compound 20 Add Compound 19 (340 mg, 0.70 mmol) and anhydrous THF (10 mL) to a 50 mL single-necked flask equipped with magnetic stirring, stir to dissolve, add S-tert-butylsulfinamide (321 mg, 2.66 mmol) and tetraethyl titanate (526 mg, 2.31 mmol), heat to 70 °C under a nitrogen atmosphere, maintain this temperature, and react with stirring overnight. Cool to room temperature, add water (10 mL) to stop the reaction, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with water (30 mL), wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and pass through a silica gel column to obtain 290 mg (yield: 70.37%) of a yellow solid. LC-MS (APCI): m / z = 590.3 (M+1)+ . 1 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 4.19 - 4.16 (m, 4H), 4.06 - 4.04 (m, 4H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0149] Step 3: Synthesis of Compound 21 To a 50 mL two-necked flask equipped with magnetic stirring, add Compound 20 (290 mg, 0.49 mmol) and anhydrous THF (5 mL), stir to dissolve, evacuate and protect with nitrogen gas, cool to 0 °C, and slowly add dropwise a THF solution of methylmagnesium bromide (1.0 mL, 3.0 mmol, 3 M). After the addition is complete, continue the reaction with stirring at 0 °C for 1 hour. Add saturated aqueous ammonium chloride solution (5 mL) to stop the reaction, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with water (10 mL), wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, concentrate, and pass through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 606.3 (M + 1) + . 1 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 4.19 - 4.16 (m, 4H), 4.06 - 4.04 (m, 4H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0150] Step 4: Synthesis of Compound 22 To a 50 mL two-necked flask equipped with magnetic stirring, compound 21 (160 mg, 0.26 mmol) and methanol (3 mL) were added, stirred and dissolved. After adding a dioxane solution of hydrogen chloride (3 mL, 4 M), the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg (yield: 75.48%) of a white solid (compound 22). 1 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.08 - 4.04 (m, 4H), 3.89 - 3.85 (m, 4H), 2.44 (br s, 1H), 1.70 (s, 3H).

[0151] Step 4: Synthesis of compounds T-1-S and T-1-R 100 mg of compound 22 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic compound 22 was separated by chiral HPLC using the following separation conditions. Chiral preparative chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle size of the filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0152] Compound T-1-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-1-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 502.3 (M+1) + . 1 1H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.08 - 4.04 (m, 4H), 3.89 - 3.85 (m, 4H), 2.44 (br s, 1H), 1.70 (s, 3H).

[0153] Example 6: 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound 26), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-2-S), and (R)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-2-R) Preparation

[0154]

Chemical formula

[0155] Synthesis is carried out according to the following route.

[0156]

Chemical formula

[0157] Step 1: Synthesis of Compound 23 To a 50 mL single-necked flask equipped with magnetic stirring, compound A-1 (261.3 mg, 0.91 mmol) and 1,4-dioxane (10 mL) were added, and the mixture was stirred until dissolved. DIPEA (200 mg, 1.52 mmol) and compound B-1 (180 mg, 0.76 mmol) were added, and the reaction was carried out with stirring overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column to obtain 340 mg (yield: 91.89%) of a yellow solid. LC-MS (APCI): m / z = 487.1 (M+1) + 。 1 H NMR (400 MHz, DMSO-D6) δ 8.82 (s, 2H), 7.83 - 7.79 (m, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.20 (t, J = 8.4 Hz, 2H), 6.80 (s, 1H), 4.09 - 4.07 (m, 4H), 3.96 (s, 3H), 3.90 - 3.88 (m, 4H).

[0158] Step 2: Synthesis of compound 24 To a 50 mL single-necked flask equipped with magnetic stirring and a condenser tube, compound 23 (340 mg, 0.70 mmol) and anhydrous THF (10 mL) were added, and the mixture was stirred until dissolved. S-tert-butylsulfinamide (321 mg, 2.66 mmol) and tetraethyl titanate (526 mg, 2.31 mmol) were added, and the temperature was raised to 70 °C under a nitrogen atmosphere. This temperature was maintained, and the reaction was carried out with stirring overnight. After cooling to room temperature, water (10 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 290 mg (yield: 70.37%) of a yellow solid. LC-MS (APCI): m / z = 587.3 (M+1) + 。 11H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 4.19 - 4.16 (m, 4H), 4.06 - 4.04 (m, 4H), 3.95 (s, 3H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0159] Step 3: Synthesis of Compound 25 Magnesium powder (140 mg, 5.79 mmol) was added to a 50 mL two-necked flask equipped with magnetic stirring and a condenser tube. The flask was evacuated and protected with nitrogen gas. Ether (5 mL) and deuterated iodomethane (700 mg, 4.83 mmol) were added via syringe. The temperature was raised to reflux and maintained, and the reaction was carried out with stirring for 2 hours. It was cooled to room temperature.

[0160] Compound 24 (290 mg, 0.49 mmol) and anhydrous THF (5 mL) were added to another 50 mL two-necked flask equipped with magnetic stirring. The mixture was stirred until dissolved, evacuated, and protected with nitrogen gas. It was cooled to 0 °C, and the ether solution of CD3MgI prepared above was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at 0 °C for 1 hour. A saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 606.3 (M + 1) + 。 11H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 4.19 - 4.16 (m, 4H), 4.06 - 4.04 (m, 4H), 3.97 (s, 3H), 3.78 (s, 1H), 1.22 (s, 9H).

[0161] Step 4: Synthesis of Compound 26 To a 50 mL two-necked flask equipped with magnetic stirring, compound 25 (160 mg, 0.26 mmol) and methanol (3 mL) were added, stirred and dissolved, and a dioxane solution of hydrogen chloride (3 mL, 4 M) was added. Then, the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg (yield: 75.48%) of a white solid. LC-MS (APCI): m / z = 502.3 (M+1) + . 1 1H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.08 - 4.04 (m, 4H), 3.89 - 3.85 (m, 4H), 3.84 (s, 3H), 2.44 (br s, 1H).

[0162] Step 5: Synthesis of Compounds T-2-S and T-2-R 100 mg of compound 26 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic compound 26 was separated by chiral HPLC using the following separation conditions.

[0163] Chiral separation chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle diameter of filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0164] Compound T-2-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-2-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 502.3 (M+1) + . 1 1H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.08 - 4.04 (m, 4H), 3.89 - 3.85 (m, 4H), 3.84 (s, 3H), 2.44 (br s, 1H).

[0165] Example 7: 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound 28), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-3-S), and Preparation of (R)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-3-R)

[0166]

Chemical formula

[0167] Synthesis is carried out through the following route.

[0168]

Chemical formula

[0169] Step 1: Synthesis of Compound 27 Magnesium powder (140 mg, 5.79 mmol) was added to a 50 mL two-necked flask equipped with magnetic stirring and a condenser tube. The flask was evacuated and protected with nitrogen gas. Ether (5 mL) and deuterated iodomethane (700 mg, 4.83 mmol) were added via syringe. The temperature was raised to reflux and maintained, and the reaction was carried out with stirring for 2 hours. It was cooled to room temperature.

[0170] Compound 21 (290 mg, 0.49 mmol) and anhydrous THF (5 mL) were added to another 50 mL two-necked flask equipped with magnetic stirring. The mixture was stirred until dissolved, evacuated, and protected with nitrogen gas. It was cooled to 0 °C, and the ether solution of CD3MgI prepared above was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 609.3 (M+1) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 4.19 - 4.16 (m, 4H), 4.06 - 4.04 (m, 4H), 3.78 (s, 1H), 1.22 (s, 9H).

[0171] Step 2: Synthesis of Compound 28 To a 50 mL two-necked flask equipped with magnetic stirring, Compound 27 (160 mg, 0.26 mmol) and methanol (3 mL) were added, stirred to dissolve, and after adding a dioxane solution of hydrogen chloride (3 mL, 4 M), the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg (yield: 75.48%) of a white solid. LC-MS (APCI): m / z = 502.3 (M + 1) + . 1 1H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.08 - 4.04 (m, 4H), 3.89 - 3.85 (m, 4H), 2.44 (br s, 1H).

[0172] Step 3: Synthesis of Compounds T-3-S and T-3-R 100 mg of Compound 28 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic Compound 28 was separated by chiral HPLC using the following separation conditions.

[0173] Chiral separation chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle diameter of the filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0174] Compound T-3-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-3-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 502.3 (M+1) + 。 1 1H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.08 - 4.04 (m, 4H), 3.89 - 3.85 (m, 4H), 2.44 (br s, 1H).

[0175] Example 8: 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethylamine (Compound 32), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethylamine (Compound T-4-S), and (R)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethylamine (Compound T-4-R) Preparation

[0176]

Chemical Structure

[0177] Synthesis is carried out through the following route.

[0178]

Chemical Structure

[0179] Step 1: Synthesis of Compound 29 To a 50 mL single-necked flask equipped with magnetic stirring, Compound A-2 (261.3 mg, 0.88 mmol) and 1,4-dioxane (10 mL) were added, stirred and dissolved, DIPEA (200 mg, 1.52 mmol) and Compound B-1 (200 mg, 0.88 mmol) were added, and the reaction was carried out with stirring overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column to obtain 340 mg (yield: 78.7%) of a yellow solid. LC-MS (APCI): m / z = 492.1 (M+1) + . 1 H NMR (400 MHz, DMSO-D6) δ 8.82 (s, 2H), 7.83 - 7.79 (m, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.20 (t, J = 8.4 Hz, 2H), 6.80 (s, 1H), 3.93 (s, 3H).

[0180] Step 2: Synthesis of Compound 30 To a 50 mL single-necked flask equipped with magnetic stirring, compound 29 (340 mg, 0.68 mmol) and anhydrous THF (10 mL) were added, stirred and dissolved. S-tert-butylsulfinamide (321 mg, 2.66 mmol) and tetraethyl titanate (526 mg, 2.31 mmol) were added. The temperature was raised to 70 °C under a nitrogen atmosphere and this temperature was maintained while reacting with stirring overnight. It was cooled to room temperature, water (10 mL) was added to stop the reaction, and it was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 290 mg (yield: 70.37%) of a yellow solid. LC-MS (APCI): m / z = 595.3 (M+1) + 。 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 3.94 (s, 3H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0181] Step 3: Synthesis of compound 31 To a 50 mL two-necked flask equipped with magnetic stirring, compound 30 (290 mg, 0.47 mmol) and anhydrous THF (5 mL) were added, stirred and dissolved. It was evacuated and protected with nitrogen gas, cooled to 0 °C, and a THF solution of methylmagnesium bromide (1.0 mL, 3.0 mmol, 3 M) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and it was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 611.3 (M+1) + 。 11H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 3.91 (s, 3H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0182] Step 4: Synthesis of Compound 32 To a 50 mL two-necked flask equipped with magnetic stirring, compound 31 (160 mg, 0.24 mmol) and methanol (3 mL) were added, stirred and dissolved. After adding a dioxane solution of hydrogen chloride (3 mL, 4 M), the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg (yield: 75.48%) of a white solid. LC-MS (APCI): m / z = 507.3 (M+1) + 。 1 1H NMR (500 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 3.84 (s, 3H), 2.43 (br s, 1H), 1.73 (s, 3H).

[0183] Step 5: Synthesis of Compounds T-4-S and T-4-R 100 mg of compound 32 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic compound 32 was separated by chiral HPLC using the following separation conditions.

[0184] Chiral separation chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle diameter of the filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0185] Compound T-4-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-4-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 507.3 (M+1) + 。 1 1H NMR (500 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 3.84 (s, 3H), 2.43 (br s, 1H), 1.73 (s, 3H).

[0186] Example 9: 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethylamine (Compound 36), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethylamine (Compound T-5-S), and (R)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethylamine (Compound T-5-R) Preparation

[0187] [Chemical Structure]

[0188] Synthesis is carried out through the following route.

[0189] [Chemical Structure]

[0190] Step 1: Synthesis of Compound 33 To a 50 mL single-necked flask equipped with magnetic stirring, Compound A-2 (261.3 mg, 0.88 mmol) and 1,4-dioxane (10 mL) were added, stirred and dissolved, DIPEA (200 mg, 1.52 mmol) and Compound B-2 (200 mg, 0.89 mmol) were added, and the reaction was carried out with stirring overnight at room temperature under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was passed through a silica gel column to obtain 340 mg (yield: 78.7%) of a yellow solid. LC-MS (APCI): m / z = 495.1 (M+1) + . 1 H NMR (400 MHz, DMSO-D6) δ 8.82 (s, 2H), 7.83 - 7.79 (m, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.20 (t, J = 8.4 Hz, 2H), 6.80 (s, 1H).

[0191] Step 2: Synthesis of Compound 34 To a 50 mL single-necked flask equipped with magnetic stirring, compound 33 (340 mg, 0.68 mmol) and anhydrous THF (10 mL) were added, stirred and dissolved. S-tert-butylsulfinamide (321 mg, 2.66 mmol) and tetraethyl titanate (526 mg, 2.31 mmol) were added. The temperature was raised to 70 °C under a nitrogen atmosphere and maintained at this temperature, and the reaction was carried out with stirring overnight. It was cooled to room temperature, water (10 mL) was added to stop the reaction, and it was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 290 mg (yield: 70.37%) of a yellow solid. LC-MS (APCI): m / z = 598.3 (M + 1) + 。 1 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0192] Step 3: Synthesis of compound 35 To a 50 mL two-necked flask equipped with magnetic stirring, compound 34 (290 mg, 0.47 mmol) and anhydrous THF (5 mL) were added, stirred and dissolved. It was evacuated and protected with nitrogen gas, cooled to 0 °C, and a THF solution of methylmagnesium bromide (1.0 mL, 3.0 mmol, 3 M) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and it was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 614.3 (M + 1) + 。 11H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (M, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 3.78 (s, 1H), 2.08 (d, J = 20.0 Hz, 3H), 1.22 (s, 9H).

[0193] Step 4: Synthesis of Compound 36 In a 50 mL two-necked flask equipped with magnetic stirring, compound 35 (160 mg, 0.24 mmol) and methanol (3 mL) were added, stirred to dissolve, and after adding a dioxane solution of hydrogen chloride (3 mL, 4 M), the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg (yield: 75.48%) of a white solid. LC-MS (APCI): m / z = 510.3 (M + 1) + 。 1 1H NMR (500 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 2.55 (br s, 1H), 1.73 (s, 3H).

[0194] Step 5: Synthesis of Compounds T-5-S and T-5-R 100 mg of compound 36 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic compound 36 was separated by chiral HPLC using the following separation conditions.

[0195] Chiral preparative chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle size of the filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0196] Compound T-5-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-5-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 510.3 (M+1) + . 1 H NMR (500 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 2.55 (br s, 1H), 1.73 (s, 3H).

[0197] Example 10: 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound 38), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-6-S), and (R)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-6-R) production

[0198] [Chemistry]

[0199] Synthesis is carried out through the following route.

[0200] [Chemistry]

[0201] Step 1: Synthesis of Compound 37 Magnesium powder (140 mg, 5.79 mmol) was added to a 50 mL two-necked flask equipped with magnetic stirring and a condenser tube, evacuated and protected with nitrogen gas. Ether (5 mL) and deuterated iodomethane (700 mg, 4.83 mmol) were added via syringe, the temperature was raised to reflux, and this temperature was maintained while reacting with stirring for 2 hours. It was cooled to room temperature.

[0202] Compound 31 (290 mg, 0.47 mmol) and anhydrous THF (5 mL) were added to another 50 mL two-necked flask equipped with magnetic stirring, stirred to dissolve, evacuated and protected with nitrogen gas, cooled to 0 °C, and the ether solution of CD3MgI prepared above was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 614.3 (M + 1) + . 1 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 3.94 (s, 3H), 3.78 (s, 1H), 1.22 (s, 9H).

[0203] Step 2: Synthesis of Compound 38 To a 50 mL two-necked flask equipped with magnetic stirring, Compound 37 (160 mg, 0.24 mmol) and methanol (3 mL) were added, stirred and dissolved. After adding a dioxane solution of hydrogen chloride (3 mL, 4 M), the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg (yield: 75.48%) of a white solid. LC-MS (APCI): m / z = 510.3 (M+1) + 。 1 H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 3.85 (s, 3H), 2.44 (br s, 2H).

[0204] Step 3: Synthesis of Compounds T-6-S and T-6-R 100 mg of Compound 38 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic Compound 38 was separated by chiral HPLC using the following separation conditions.

[0205] Chiral preparative chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle diameter of the filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0206] Compound T-6-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-6-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 510.3 (M+1) + 。 1 H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 3.85 (s, 3H), 2.44 (br s, 2H).

[0207] Example 11: 1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound 40), (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-7-S), and (R)-1-(4-Fluorophenyl)-1-(2-(4-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)pyrimidin-5-yl)ethyl-2,2,2-d3-1-amine (Compound T-7-R) production

[0208]

Chemical Structure

[0209] Synthesis is carried out according to the following route.

[0210]

Chem.

[0211] Step 1: Synthesis of Compound 39 Magnesium powder (140 mg, 5.79 mmol) was added to a 50 mL two-necked flask equipped with magnetic stirring and a condenser tube. The flask was evacuated and protected with nitrogen gas. Ether (5 mL) and deuterated iodomethane (700 mg, 4.83 mmol) were added by syringe. The temperature was raised to reflux and maintained, and the reaction was carried out with stirring for 2 hours. It was cooled to room temperature.

[0212] Compound 35 (290 mg, 0.49 mmol) and anhydrous THF (5 mL) were added to another 50 mL two-necked flask equipped with magnetic stirring, stirred to dissolve, evacuated and protected with nitrogen gas, cooled to 0 °C, and the ether solution of CD3MgI prepared above was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added to stop the reaction, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 180 mg (yield: 60.43%) of a white solid. LC-MS (APCI): m / z = 617.3 (M + 1) + 。 1 1H NMR (400 MHz, CDCl3) δ / ppm: 8.35 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.72 - 7.70 (m, 2H), 7.57 (s, 1H), 7.38 - 7.34 (m, 2H), 7.07 - 7.01 (m, 2H), 6.79 (s, 1H), 3.78 (s, 1H), 1.22 (s, 9H).

[0213] Step 2: Synthesis of Compound 40 To a 50 mL two-necked flask equipped with magnetic stirring, compound 39 (160 mg, 0.26 mmol) and methanol (3 mL) were added, stirred and dissolved, and after adding a dioxane solution of hydrogen chloride (3 mL, 4 M), the reaction was carried out with stirring at room temperature for 1 hour under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added, stirred for 2 minutes, the organic layer was separated, the aqueous phase was extracted with dichloromethane (15 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg (yield: 75.48%) of a white solid. LC-MS (APCI): m / z = 513.3 (M + 1) + 。 1 1H NMR (300 MHz, DMSO-D6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 2.44 (br s, 2H).

[0214] Step 3: Synthesis of compounds T-7-S and T-7-R 100 mg of compound 40 was dissolved in a mixed solvent of 30 mL of MeOH and 3 mL of DCM, and the racemic compound 40 was separated by chiral HPLC using the following separation conditions.

[0215] Chiral preparative chromatography column: CHIRALPAK IC (trade name), 4.6 mm × 250 mm (inner diameter × length), 5 μm (particle size of the filler) Column temperature: 30 °C Flow rate: 3.0 mL / min UV detection wavelength: 254 nm Mobile phase: MTBE:EtOH = 85:15

[0216] Compound T-7-S (38 mg, retention time: 12.092 minutes, yield: 76%) and T-7-R (30 mg, retention time: 10.757 minutes, yield: 60%) were obtained. LC-MS (APCI): m / z = 513.3 (M + 1) + 。 1 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.00 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 2.44 (br s, 2H).

[0217] Biological activity test (1) Kinase activity test The inhibitory activity of the test substance against PDGFRα (D842V) (Signalchem, P12 - 12BG) and KIT (D816V) (Signalchem, C06 - 12LG) was measured using the ADP - GloTM Kinase Assay kit (Promega, V9102).

[0218] The compounds were each diluted with DMSO in 12 doses at a three-fold concentration gradient. The initial concentrations of the compounds were 10 mM and 0.1 mM, respectively. In a 384-well plate (Perkin Elmer, 6007290), 100 nl of the compound dilution was added to each well to double-well with 5 μL of PDGFRα (D842V) or KIT (D816V). After incubation at 25 °C for 15 minutes, 5 μL of the substrate was added to initiate the reaction, and the mixture was incubated at 25 °C for 60 minutes. The final reaction concentrations in the system were 4 nM PDGFRα (D842V), 15 μM ATP, 0.03 mg / mL MBP / 1 nM KIT D816V), 10 μM ATP, 0.1 mg / mL Poly(4:1 Glu, Tyr) Peptide, 50 mM HEPES, 1 mM EGTA, 10 mM MgCl2, 0.01% Brij35. The test compound concentrations were 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137, 0.046, 0.015, 0.0051, 0.0017, 0.0006, 0 nM / 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.051, 0.017, 0.006, 0 nM. Then, 10 μL of ADP Glo reagent was added, and incubation was continued at 25 °C for 40 minutes. Again, 20 μL of the detection reagent was added, and after incubation at 25 °C for 40 minutes, detection was performed using an Envision microplate reader (Perkin Elmer 2104), the enzyme activity was measured in the presence of compounds at each concentration, and the inhibitory activity of compounds at different concentrations against the enzyme activity was calculated. Next, according to the four-parameter equation, the inhibitory activity of compounds at different concentrations against the enzyme activity was fitted using Graphpad 5.0 software, and the IC 50 value was calculated. The data of representative compounds tested in this analysis are shown in Table 1. A represents IC 50 < 1 nM, B represents 1 nM ≤ IC 50 < 50 nM, C represents 50 nM ≤ IC 50 < 200 nM, and D represents IC 50 ≥ 200 nM.

[0219] In the above kinase inhibition experiment, when the compound of the present invention and avapritinib, a non-deuterated compound, were tested, it was found that the compound of the present invention had stronger activity against PDGFRα (D824V) and equivalent strong activity against Kit (D816V) compared to avapritinib.

[0220] (2) Cytotoxicity experiment Cell line: Ba / F3 Kit D816V (3000 cells / well, cell type: suspension, medium: RPMI-1640 + 10% FBS), cultured at 37 °C, 5% CO2, and 95% humidity.

[0221] Reagents and consumables: Fetal bovine serum FBS (GIBCO, Cat# 10099-141), CellTiter-Glo (R) Luminescent Cell Viability Assay (Promega, Cat# G7572), 96-well clear flat bottom black wall plate (Corning (R) , Cat# 3603).

[0222] Control compound: Sunitinib (Selleck, Cat# S7781).

[0223] Cell culture and seeding: Cells in the logarithmic growth phase were collected, counted using a platelet counter, and the cell viability was detected by the trypan blue exclusion method. It was ensured that the cell viability was 90% or more. The cell concentration was adjusted, and 90 μL of cell suspension was added to each well of a 96-well plate. The cells in the 96-well plate were cultured overnight at 37 °C, 5% CO2, and 95% humidity.

[0224] Drug dilution and addition: A 10-fold drug solution with a maximum concentration of 3 μM and 9 concentrations with a 3.16-fold dilution was prepared. 10 μL of the drug solution was added to each well of the 96-well plate seeded with cells. Each drug concentration was set in three wells. The cells in the 96-well plate with added drugs were cultured at 37 °C, 5% CO2, and 95% humidity for 72 hours, and then CTG analysis was performed.

[0225] Endpoint reading plate: Dissolve the CTG reagent, equilibrate the cell plate at room temperature for 30 minutes, add an equal volume of CTG solution to each well, shake on an orbital shaker for 5 minutes to lyse the cells, leave the cell plate at room temperature for 20 minutes to stabilize the cold signal, and read the cold value.

[0226] Data processing: Analyze the data using GraphPad Prism 5.0 software, fit the data by non-linear S-curve regression to obtain a dose-effect curve, and calculate the IC 50 value from this. The data of representative example compounds tested in this analysis are shown in Table 1, where A represents IC 50 <1 nM, B represents 1 nM ≤ IC 50 <50 nM, C represents 50 nM ≤ IC 50 <200 nM, and D represents IC 50 ≥ 200 nM.

[0227] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0228] In the above cytotoxicity experiment, when the compound of the present invention and the non-deuterated compound avapritinib were tested, it was found that the compound of the present invention has strong activity against BaF3[Kit(D816V)].

[0229]

Table 1

[0230] (3) Evaluation of metabolic stability Microsome experiment: Human liver microsomes: 0.5 mg / mL, Xenotech; Rat liver microsomes: 0.5 mg / mL, Xenotech; Coenzyme (NADPH / NADH): 1 mM, Sigma Life Science; Magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).

[0231] Preparation of stock solution: A certain amount of the powder of the example compound and the control compound was precisely weighed and dissolved in DMSO to 5 mM respectively.

[0232] Preparation of phosphate buffer (100 mM, pH 7.4): 150 mL of a pre-prepared 0.5 M potassium dihydrogen phosphate solution and 700 mL of a 0.5 M dipotassium hydrogen phosphate solution were mixed. Then, the pH of the mixed solution was adjusted to 7.4 with the 0.5 M dipotassium hydrogen phosphate solution, diluted 5-fold with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM, pH 7.4) containing 100 mM potassium phosphate and 3.3 mM magnesium chloride.

[0233] An NADPH regeneration system solution (containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U / mL G-6-P D, and 3.3 mM magnesium chloride) was prepared and placed on wet ice before use.

[0234] Preparation of stop solution: An acetonitrile solution containing 50 ng / mL propranolol hydrochloride and 200 ng / mL tolbutamide (internal standard). 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of human liver microsomes was added to each and mixed well to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of SD rat liver microsomes was added to each and mixed well to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL.

[0235] Incubation of samples: The stock solutions of the corresponding compounds were diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile respectively to prepare working solutions. 398 μL of the human liver microsome or rat liver microsome dilution was added to a 96-well incubation plate (N = 2) respectively, and 2 μL of the 0.25 mM working solution was added to each and mixed uniformly.

[0236] Measurement of Metabolic Stability: 300 μL of pre-cooled stop solution was added to each well of a 96-well deep well plate, placed on ice, and used as a stop plate. A 96-well incubation plate and an NADPH regeneration system were placed in a 37 °C water bath, shaken at 100 revolutions per minute, and pre-incubated for 5 minutes. 80 μL of the incubation solution was taken out from each well of the incubation plate, added to the stop plate, mixed uniformly, and 20 μL of the NADPH regeneration system solution was added to make the sample at 0 minutes. Next, 80 μL of the NADPH regeneration system solution was added to each well of the incubation plate to initiate the reaction and start timing. The reaction concentration of the corresponding compound was 1 μM, and the protein concentration was 0.5 mg / mL. For reactions at 10, 30, and 90 minutes respectively, 100 μL of the reaction solution was taken out each time, added to the stop plate, vortexed for 3 minutes to stop the reaction. The stop plate was centrifuged at 5000×g at 4 °C for 10 minutes. 100 μL of the supernatant was taken into a 96-well incubation plate with 100 μL of distilled water added in advance, mixed uniformly, and the sample was analyzed by LC-MS / MS.

[0237] Data Analysis: The peak areas of the corresponding compound and the internal standard were detected by the LC-MS / MS system, and the peak area ratio of the compound to the internal standard was calculated. The slope was measured by plotting the natural logarithm of the percentage of the remaining amount of the compound against time, and t 1 / 2 and CL int were calculated according to the following formula. Here, V / M is equal to 1 / protein concentration.

[0238]

Equation

[0239] The compounds of the present invention and non-deuterated compounds were simultaneously tested and compared to evaluate their metabolic stability in human and rat liver microsomes. A non-deuterated compound, avapritinib, was used as a control. In the human and rat liver microsome experiments, avapritinib, a non-deuterated compound, and (R)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl -1 -amine (Compound A) were used as controls. The compounds of the present invention can significantly improve metabolic stability. The results of the liver microsome experiments of representative example compounds are summarized in Table 2 below.

[0240] [Table 2]

[0241] (4) Pharmacokinetic experiments in rats Six male Sprague-Dawley rats, 7-8 weeks old and weighing approximately 210 g, were divided into two groups (3 rats per group), and a single dose of the compound (10 mg / kg orally) was administered intravenously or orally to compare the differences in their pharmacokinetics.

[0242] The rats were fed a standard diet and given water. Food was withheld 16 hours before the test. The drug was dissolved in PEG400 and dimethyl sulfoxide. Blood was collected from the orbital sinus at the following time points after administration: 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours.

[0243] After the rats were anesthetized by inhaling ether for a short time, 300 μL of blood samples were collected from the orbital sinus into test tubes containing 30 μL of 1% heparin salt solution. The test tubes were dried overnight at 60 °C before use. After blood sample collection was completed at the last time point, the rats were sacrificed after being anesthetized with ether.

[0244] After collecting the blood sample, the test tube was gently inverted at least 5 times immediately, and after ensuring sufficient mixing, it was placed on ice. The blood sample was centrifuged at 4 °C and 5000 rpm for 5 minutes to separate plasma and red blood cells. 100 μL of plasma was pipetted into a clean plastic centrifuge tube indicating the name and time point of the compound. The plasma was stored at -80 °C before analysis. The concentration of the compound of the present invention in the plasma was measured by LC-MS / MS. The pharmacokinetic parameters were calculated based on the blood drug concentrations at different time points of each animal.

[0245] The experiment showed that the compound of the present invention has better pharmacokinetic properties in the animal body.

[0246] As described above, the present invention has been described in more detail in combination with specific preferred embodiments, but the specific implementation of the present invention is not limited to these descriptions. For those skilled in the technical field to which the present invention pertains, within the scope not departing from the spirit of the present invention, even if some simple deductions or substitutions are made, they should be considered to fall within the protection scope of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof. 【Chemical 1】 Wherein, R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R ６ 、R ７ and R ８ are selected from hydrogen or deuterium, R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R ６ 、R ７ and R ８ are identical, X １ and X ２ are each independently selected from CH ３ or CD ３ and Y １ 、Y ２ 、Y ３ 、Y ４ 、Y ５ 、Y ６ 、Y ７ 、Y ８ 、Y ９ 、Y １０ and Y １１ are hydrogen, The above compound contains at least one deuterium atom.

2. R １ 、 R ２ 、 R ３ 、 R ４ 、 R ５ 、 R ６ 、 R ７ and R ８ are hydrogen, the compound according to claim 1.

3. X １ is CH ３ The compound according to claim 1, wherein

4. X １ is CH ３ The compound according to claim 2, wherein

5. X ２ is CD ３ The compound according to any one of claims 1 to 4.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from any of the following structures. 【Chemical 2】

7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The pharmaceutical composition according to claim 7, further comprising another therapeutic agent having inhibitory activity against a mutant KIT having a mutation in exon 9 or exon 11.

9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for treating a disease mediated by KIT having a mutation in exon 9 or exon 11 or exon 17 or residue 816, or mediated by PDGFRα having a mutation in exon 18 or residue 842, wherein the disease is selected from mastocytosis, gastrointestinal stromal tumor or acute myeloid leukemia.

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