Substituted pyridopyrimidinone compounds and compositions comprising the same and uses thereof

Abstract

The present application provides a kind of substituted pyridopyrimidinone compound and the composition comprising the compound and its purposes, the compound such as shown in formula (I) or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate compound.The compound of formula (I) can be used as SMN2 (Survival of motor neuron 2) gene splicing regulator, for treating Spinal Muscular Atrophy (SMA), with high selectivity and good pharmacokinetic characteristics.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and particularly relates to a substituted pyridopyrimidinone compound and compositions comprising the compound, as well as their uses. More specifically, this invention relates to certain deuterium-substituted 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one compounds and their pharmaceutically acceptable salts, tautomers, stereoisomers, prodrugs, crystal forms, hydrates, or solvent compounds. These deuterium-substituted compounds and their compositions can be used as SMN2 (Survival of motor neuron 2) gene splicing regulators for the treatment of spinal muscular atrophy (SMA), exhibiting high selectivity and favorable pharmacokinetic properties. Background Technology

[0002] Spinal muscular atrophy (SMA) is a variety of inherited and acquired central nervous system (CNS) disorders characterized by progressive damage to motor neurons in the spinal cord and brainstem, resulting in muscle weakness and atrophy. The most common form of SMA is caused by mutations in the survival motor neuron (SMN) gene and can severely affect individuals from infancy to adulthood.

[0003] The clinical spectrum of SMA has been divided into the following five groups:

[0004] (1) Type O SMA (intrauterine SMA) is the most severe form of the disease and begins before birth. Typically, the first symptom of type O SMA is reduced fetal movement, which can be observed between 30 and 36 weeks of gestation. After birth, these newborns move very little and have difficulty swallowing and breathing.

[0005] (2) Type I SMA (infantile SMA or Werdning-Hoffman disease) presents with symptoms between 0 and 6 months of age. This type of SMA is also very severe. Patients are never able to sit up, and death usually occurs within the first 2 years due to lack of respiratory support.

[0006] (3) Type 2 SMA (transitional SMA) has an age of onset between 7 and 18 months. Patients are able to sit up without support, but cannot stand or walk independently. The prognosis in this group depends largely on the degree of respiratory involvement.

[0007] (4) Type 3 SMA (juvenile or Kugelberg-Welander disease) is usually diagnosed after 18 months. Individuals with type 3 SMA may be able to walk independently at times during the course of the disease, but usually rely on a wheelchair during adolescence or adulthood.

[0008] (5) Type 4 SMA (adult-onset SMA). Weakness symptoms usually begin in the tongue, hands, or feet in late adolescence and then spread to other areas of the body. Adult SMA progresses more slowly and has little or no impact on life expectancy.

[0009] The SMN gene map has been obtained through linkage analysis of a complex region in chromosome 5q. In humans, this region contains approximately 500,000 base pairs (kb) of inverted replication, resulting in two nearly identical copies of the SMN gene. SMA is caused by inactivating mutations or deletions of telomere copies of the gene (SMN1) on two chromosomes, leading to loss of function of the SMN1 gene. However, all patients retain a centromere copy of the gene (SMN2), and the copy number of the SMN2 gene in SMA patients is generally negatively correlated with disease severity; that is, patients with less severe SMA have more copies of SMN2. Nevertheless, SMN2 cannot fully compensate for the loss of SMN1 function due to alternative splicing of exon 7 caused by translationally silent C-to-T mutations in exon 7. Therefore, most of the transcript produced by SMN2 lacks exon 7 (Δ7SMN2) and encodes a truncated SMN protein with impaired function and rapid degradation.

[0010] SMN proteins are thought to play a role in RNA processing and metabolism, functioning as well-identified mediators of the assembly of a specific type of RNA-protein complex known as snRNP. In motor neurons, SMNs may have other functions; however, their role in preventing selective degeneration of motor neurons is not well-established.

[0011] In most cases, SMA is diagnosed based on clinical symptoms and the presence of at least one SMN1 gene copy. However, in approximately 5% of cases, SMA is caused by mutations in genes other than SMN1 inactivation, some of which are known while others are not. In some cases, when SMN1 gene testing is not feasible or shows no abnormalities, other tests such as electromyography (EMG) or muscle tissue examination may be indicated.

[0012] Risdiplam (chemical name 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one, with the following structural formula) is the world's first oral small molecule SMN2 gene splicing regulator for the treatment of SMA, which can systemically increase functional SMN protein.

[0013] Risdiplam

[0014] Poor absorption, distribution, metabolism, and / or excretion (ADME) properties are known to be a major cause of clinical trial failures for many drug candidates. Many currently marketed drugs also have limited applicability due to their poor ADME properties. Rapid drug metabolism can render many potentially highly effective treatments ineffective due to their rapid elimination from the body. While frequent or high-dose administration may address the issue of rapid drug clearance, this approach can lead to problems such as poor patient compliance, side effects from high doses, and increased treatment costs. Furthermore, rapidly metabolized drugs may expose patients to adverse toxicities or reactive metabolites.

[0015] Discovering novel and effective SMN2 gene splicing regulators with good oral bioavailability and drug-like properties remains a challenging task. Therefore, there is still a need in the art to develop compounds with higher selective inhibitory activity and / or better pharmacodynamics / pharmacokinetics suitable for use as SMN2 gene splicing regulators, and this invention provides such compounds. Summary of the Invention

[0016] To address the above-mentioned technical problems, this invention discloses a novel deuterium-substituted pyridopyrimidine ketone compound as a novel and effective SMN2 gene splicing regulator, which can increase functional SMN protein for the treatment of SMA. Furthermore, the compound of this invention also exhibits better metabolic stability and / or pharmacokinetic properties.

[0017] To address this, the present invention adopts the following technical solution:

[0018] In a first aspect, the present invention provides a compound of formula (I):

[0019]

[0020] Formula (I)

[0021] in,

[0022] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen, deuterium, halogen, or trifluoromethyl;

[0023] X1 and X2 are each independently selected from CH3, CD3, CHD2 or CH2D;

[0024] An additional condition is that the above compounds contain at least one deuterium atom;

[0025] Or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof.

[0026] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate or solvent compound thereof, and a pharmaceutically acceptable excipient. In a specific embodiment, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a preventatively effective amount.

[0027] In another aspect, the present invention provides a method for preparing a pharmaceutical composition as described above, comprising the following steps: mixing a pharmaceutically acceptable excipient with a compound of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate or solvent compound thereof, thereby forming a pharmaceutical composition.

[0028] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, tautomers, stereoisomers, prodrugs, crystal forms, hydrates or solvent compounds thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the treatment and / or prevention of spinal muscular atrophy (SMA).

[0029] In another aspect, the present invention further provides a method for treating and / or preventing spinal muscular atrophy (SMA), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate or solvent compound, or a pharmaceutical composition of the present invention.

[0030] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed description, embodiments, and claims.

[0031] definition

[0032] In this document, unless otherwise specified, "deuterated" means that one or more hydrogen atoms in a compound or group are replaced by deuterium; deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

[0033] Unless otherwise specified, "non-deuterated compounds" in this article refer to compounds containing a deuterium atom ratio not higher than the natural deuterium isotope content (0.015%).

[0034] As used herein, the term "subject" includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0035] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0036] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0037] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a response in the target organism. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include both therapeutic and prophylactic effective amounts.

[0038] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is a quantity sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the quantity of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include quantities that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of other therapeutic agents.

[0039] Unless otherwise stated, the term "preventively effective amount" of a compound as used herein is a quantity sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or a quantity sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the quantity of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term "preventively effective amount" may include quantities that improve overall prevention or enhance the preventive efficacy of other preventive agents.

[0040] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. Detailed Implementation

[0041] compound

[0042] In this document, “compound of the present invention” refers to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate or solvent compound thereof.

[0043] In one embodiment, the present invention relates to compounds of formula (I):

[0044]

[0045] Formula (I)

[0046] in,

[0047] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen, deuterium, halogen, or trifluoromethyl;

[0048] X1 and X2 are each independently selected from CH3, CD3, CHD2 or CH2D;

[0049] An additional condition is that the above compounds contain at least one deuterium atom;

[0050] Or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof.

[0051] In one specific implementation, the deuterium isotope content at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, and more preferably greater than 99%.

[0052] Specifically, in this invention, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 The deuterium isotope content at each deuteration position of X1 and X2 is at least greater than 0.015% of the natural isotope content, more preferably greater than 1%, more preferably greater than 5%, more preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, and more preferably greater than 99%.

[0053] In another specific embodiment, the compound of the present invention contains at least one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, more preferably five deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably eight deuterium atoms, more preferably nine deuterium atoms, more preferably ten deuterium atoms, more preferably eleven deuterium atoms, more preferably twelve deuterium atoms, more preferably thirteen deuterium atoms, more preferably fourteen deuterium atoms, more preferably fifteen deuterium atoms, more preferably sixteen deuterium atoms, more preferably seventeen deuterium atoms, more preferably eighteen deuterium atoms, more preferably nineteen deuterium atoms, more preferably twenty deuterium atoms, more preferably twenty-one deuterium atoms, and more preferably twenty-two deuterium atoms.

[0054] In another specific implementation plan, “R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R16 Each element is independently selected from hydrogen, deuterium, halogen, or trifluoromethyl, including R1 selected from hydrogen, deuterium, halogen, or trifluoromethyl; R2 selected from hydrogen, deuterium, halogen, or trifluoromethyl; R3 selected from hydrogen, deuterium, halogen, or trifluoromethyl, and so on, up to R... 16 Technical solutions selected from hydrogen, deuterium, halogen, or trifluoromethyl. More specifically, this includes R1 being hydrogen, R1 being deuterium, R1 being a halogen (F, Cl, Br, or I), or R1 being trifluoromethyl; R2 being hydrogen, R2 being deuterium, R2 being a halogen (F, Cl, Br, or I), or R2 being trifluoromethyl; R3 being hydrogen, R3 being deuterium, R3 being a halogen (F, Cl, Br, or I), or R3 being trifluoromethyl, and so on, up to R... 16 It is hydrogen, R 16 It is deuterium, R 16 It is a halogen (F, Cl, Br or I) or R 16 It is a trifluoromethyl technical solution.

[0055] In another specific implementation, "X1 and X2 are each independently selected from CH3, CD3, CHD2, or CH2D" includes technical solutions where X1 is selected from CH3, CD3, CHD2, or CH2D, and X2 is selected from CH3, CD3, CHD2, or CH2D. More specifically, it includes technical solutions where X1 is CH3, X1 is CD3, X1 is CHD2, or X1 is CH2D, and X2 is CH3, X2 is CD3, X2 is CHD2, or X2 is CH2D.

[0056] In another specific implementation scheme, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen or deuterium.

[0057] In another specific implementation, R1, R2, R3, R4, R5, and R6 are hydrogen.

[0058] In another specific implementation scheme, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 It is hydrogen.

[0059] In another specific implementation, X1 is CD3 or CH3.

[0060] In another specific implementation, X1 is CD3.

[0061] In another specific implementation, X2 is CD3 or CH3.

[0062] In another specific implementation, X2 is CD3.

[0063] In another specific implementation, X1 and X2 are CD3.

[0064] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 is CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 X2 is as defined above.

[0065] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 is CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen or deuterium, and X2 is selected from CH3, CD3, CHD2 or CH2D.

[0066] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 is CD3, R1, R2, R3, R4, R5, and R6 are hydrogen, and R7, R8, R9, R6 are hydrogen. 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen or deuterium, and X2 is selected from CH3, CD3, CHD2 or CH2D.

[0067] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 is CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 It is hydrogen, and X2 is selected from CH3, CD3, CHD2 or CH2D.

[0068] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X2 is CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 X1 is as defined above.

[0069] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X2 is CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen or deuterium, and X1 is selected from CH3, CD3, CHD2 or CH2D.

[0070] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X2 is CD3, R1, R2, R3, R4, R5, and R6 are hydrogen, and R7, R8, R9, R6 are hydrogen. 10 R 11 R 12 R 13 R 14 R 15 and R 16Each is independently selected from hydrogen or deuterium, and X1 is selected from CH3, CD3, CHD2 or CH2D.

[0071] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X2 is CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 It is hydrogen, and X1 is selected from CH3, CD3, CHD2 or CH2D.

[0072] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 and X2 are CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 As defined above.

[0073] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 and X2 are CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each is independently selected from hydrogen or deuterium.

[0074] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 and X2 are CD3, R1, R2, R3, R4, R5, and R6 are hydrogen, and R7, R8, R9, R6 are hydrogen. 10 R 11 R 12 R 13 R14 R 15 and R 16 Each is independently selected from hydrogen or deuterium.

[0075] In some embodiments of the compound of formula (I), preferably, the present invention relates to the above-described compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, wherein X1 and X2 are CD3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 and R 16 It is hydrogen.

[0076] In a preferred embodiment of the present invention, the compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, prodrug, crystal form, hydrate, or solvent compound thereof, is selected from any of the following compounds:

[0077] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0078] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0079] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0080] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0081] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0082] The compounds of this invention can be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0083] This invention also includes isotopically labeled compounds that are equivalent to those of the compounds of this invention, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0084] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and 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 of which is incorporated herein by reference.

[0085] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0086] Method for preparing the compounds of the present invention

[0087] The compounds of this invention (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes (such as those described below). The reactions used to prepare the compounds of this invention can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive with the starting materials (reactants), intermediates, or products at temperatures in which the reaction is carried out (e.g., temperatures in the range of solvent freezing temperature to solvent boiling point). The intended reaction can be carried out in one solvent or a mixture of more than one solvent. Those skilled in the art can select the solvent for a specific reaction step according to the specific reaction procedure.

[0088] The preparation of the compounds of this invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine whether protection and deprotection are necessary and the appropriate selection of protecting groups. The chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0089] The compounds of this invention can be prepared into a single stereoisomer by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomers, separating the diastereomers and recovering the optically pure enantiomer. Enantiomer resolution can be performed using diastereomer derivatives of the compounds of this invention, preferably dissociable complexes (e.g., crystalline diastereomer salts). The diastereomers have significantly different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and can be readily separated by the advantage of these dissimilarity. The diastereomers can be separated by chromatography, preferably by a separation / resolution technique based on differences in solubility. The optically pure enantiomer, along with the resolving agent, is then recovered by any practical means that does not racemate. A more detailed description of techniques applicable to the resolution of compounds from racemic mixtures to obtain stereoisomers can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981.

[0090] The reaction can be monitored using any suitable method known in the art. For example, it can be monitored using spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13C) Infrared (IR) spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry (MS) or chromatographic methods (such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC)) can be used to monitor product formation.

[0091] Pharmaceutical compositions, formulations and kits

[0092] In another aspect, the present invention provides pharmaceutical compositions comprising the compound of the present invention (also referred to as the "active ingredient") and pharmaceutically acceptable excipients. 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 preventatively effective amount of the active ingredient.

[0093] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as 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.

[0094] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0095] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes 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, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0096] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0097] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0098] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0099] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, 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 results in a slow release of the active ingredient, while a bolus dose delivered directly to a vein (e.g., via IV infusion) allows for a more rapid delivery, causing the concentration of the active ingredient in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0100] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, for the purpose of precise dosing, the compositions are provided in unit dose form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0101] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0102] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically chosen in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0103] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0104] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0105] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0106] 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 a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0107] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0108] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0109] The compounds of this 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 at Remington's Pharmaceutical Sciences.

[0110] This invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether-substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0111] Indications

[0112] On the other hand, it is provided that compounds of formula (I) disclosed herein (including all individual embodiments and subsets thereof) or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvents have valuable pharmacological properties and have been found to enhance the inclusion of exon 7 of SMN1 and / or SMN2 into the mRNA transcribed from the SMN1 and / or SMN2 genes, thereby increasing the expression of SMN proteins in human subjects in need of such expression.

[0113] The compounds of this invention can be used alone or in combination with other drugs to treat or prevent diseases caused by inactivating mutations or deletions of the SMN1 gene and / or associated with loss or defective function of the SMN1 gene. These diseases include, but are not limited to, spinal muscular atrophy (SMA).

[0114] The compounds of the present invention can be used alone or in combination with other drugs for the treatment or prevention of spinal muscular atrophy (SMA). Treatment of SMA includes one or more of the following effects: (1) reducing or improving the severity of SMA; (2) delaying the onset of SMA; (3) inhibiting the progression of SMA; (4) reducing hospitalization of subjects; (5) reducing the length of hospital stay of subjects; (6) increasing the survival of subjects; (7) improving the quality of life of subjects; (8) reducing the number of SMA-related symptoms; (9) reducing or improving the severity of one or more SMA-related symptoms; (10) inhibiting the development or onset of SMA symptoms; and / or (11) inhibiting the progression of SMA-related symptoms.

[0115] Symptoms of SMA include muscle weakness, hypotonia, difficulty crying, difficulty coughing, limping or falling tendency, difficulty sucking or swallowing, difficulty breathing, accumulation of secretions in the lungs or throat, clenched fists with sweaty hands, tongue tremors / vibrations, head often tilted to one side (even when lying down), legs tending to be weaker than the arms, legs often in a "frog leg" position, difficulty feeding, increased susceptibility to respiratory infections, weak intestines / bladder, below-normal weight, inability to sit without support, inability to walk, inability to crawl, hypotonia, loss of reflexes, and multiple congenital contractures (joint contractures) associated with loss of anterior horn cells.

[0116] The compounds of the present invention can be used alone or in combination with other drugs to treat SMA and can achieve one or more of the following beneficial effects: (1) reducing muscle weakness; (2) increasing muscle strength; (3) reducing muscle atrophy; (4) reducing loss of motor function; (5) increasing motor neurons; (6) reducing motor neuron loss; (7) preventing the degeneration of insufficient motor neurons in SMA; (8) improving motor function; (9) improving lung function; and / or (10) reducing loss of lung function.

[0117] Example

[0118] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0119] Abbreviations:

[0120] Pd(dppf)Cl2: [1,1'-bis(triphenylphosphine)ferrocene]palladium dichloride

[0121] Pd(OAc)2: Palladium acetate

[0122] PCy3: Tricyclohexylphosphide

[0123] TsCl: p-Toluenesulfonyl chloride

[0124] KOAc: Potassium Acetate

[0125] Isopropyl acetate: Isopropyl acetate

[0126] TFA: Trifluoroacetic acid

[0127] DMSO: Dimethyl sulfoxide

[0128] DMF: N,N-dimethylformamide

[0129] EA: Ethyl acetate

[0130] Xylene: xylene

[0131] MeOH: Methanol

[0132] Dioxide: 1,4-dioxane

[0133] DCM: Dichloromethane

[0134] Intermediate compound A-1 7-(4-oxo-2-(p-toluenesulfonyloxy)-4H-pyrido[1,2-a]pyrimidine-7- Preparation of tert-butyl 4,7-diazaspiro[2.5]oct-4-carboxylate

[0135] A-1

[0136] The following synthetic route was adopted.

[0137]

[0138] Step 1: Synthesis of tert-butyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylate

[0139] 5-Bromo-2-nitropyridine (2.0 g, 10 mmol) and tert-butyl 4,7-diazaspiro[2.5]octyl-4-carboxylate (2.23 g, 10.5 mmol) were dissolved in 10 mL of dimethyl sulfoxide. Lithium chloride (1.47 g, 35 mmol) and tetramethylguanidine (4.4 mL, 35 mmol) were added sequentially. The reaction mixture was heated to 80 °C and stirred overnight under nitrogen protection. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction mixture was slowly added dropwise to ice water, precipitating a pale yellow solid. The solid was filtered, and the filter cake was dried under vacuum to obtain 2.76 g of a yellow solid, with a yield of 82.6%. LC-MS (APCI): m / z = 335.1 (M+1) + .

[0140] Step 2: Synthesis of tert-butyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro[2.5]oct-4-carboxylate

[0141] The tert-butyl 7-(6-nitropyridin-3-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylate obtained in the previous step (2.76 g, 8.26 mmol) was placed in a 100 ml flask, dissolved in 10 ml of ethyl acetate and 10 ml of methanol. Under nitrogen protection, 10% wt Pd / C (300 mg) was added, and the mixture was purged three times with hydrogen. The mixture was stirred at room temperature for 2–4 hours. The reaction was monitored by TLC until completion. The mixture was filtered with diatomaceous earth as an aid, and the filtrate was concentrated to dryness. 2.55 g of crude product was obtained and directly added to the next reaction step without further purification. LC-MS (APCI): m / z = 305.4 (M+1) + .

[0142] Step 3: Synthesis of tert-butyl 7-(2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2,5]octyl-4-carboxylate

[0143] 2.0 g (6.58 mmol) of tert-butyl 7-(6-aminopyridin-3-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylate and 3.66 g (7.89 mmol) of bis(2,4,6-trichlorophenyl)malonate were added to a reaction flask, followed by 25 mL of xylene. The reaction mixture was heated to 150 °C and stirred for 1–2 hours under nitrogen protection. The reaction was monitored by TLC until completion. After cooling to room temperature, a pale yellow solid precipitated. The solid was filtered, washed with a small amount of ethyl acetate, and dried under vacuum to give 1.92 g of solid, with a yield of 78.4%. LC-MS (APCI): m / z = 373.4 (M+1) + .

[0144] Step 4: Synthesis of intermediate compound A-1

[0145] 1.12 g (3.0 mmol) of tert-butyl 7-(2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylic acid was dissolved in 40 mL of anhydrous dichloromethane. Triethylamine (0.54 mL, 3.9 mmol) was added, and TsCl (0.63 g, 3.3 mmol) was added in portions under nitrogen protection. After the addition was complete, the mixture was stirred at room temperature for 2–4 hours, and the reaction was monitored by TLC until completion. The reaction was quenched with 30 mL of water, and the mixture was extracted 3–4 times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 1.4 g of product (yield: 88.7%). LC-MS (APCI): m / z = 527.8 (M+1) + .

[0146] Intermediate B-1 2-methyl-8-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane) Preparation of alkyl-2-yl)imidazo[1,2-b]pyridazine

[0147] B-1

[0148] The following synthetic route was adopted.

[0149]

[0150] Step 1: Synthesis of compound 4-bromo-6-chloropyridazine-3-amine

[0151] 6-Chlorpyridazine-3-amino (4.0 g, 31 mmol), sodium acetate (2.03 g, 24.8 mmol), and acetic acid (0.5 g, 8.27 mmol) were placed in a 100 mL flask, and 40 mL of methanol was added. Then, 1,3-dibromo-5,5-dimethylhydantoin (5.3 g, 18.5 mmol) was added in portions. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the temperature was lowered to 0 °C, and the reaction was quenched by slowly adding 10 mL of saturated sodium sulfite solution. The methanol was removed by concentration, and the mixture was diluted with a small amount of water. The pH was adjusted to 7-8 with 1N sodium hydroxide, resulting in the precipitation of a pale yellow solid. The solid was filtered, washed with water, and dried under vacuum to give 4.5 g of the target product (yield: 70.1%). No further purification was required, and the product was directly added to the next reaction. LC-MS (APCI): m / z = 208.1 (M+1) + .

[0152] Step 2: Synthesis of compound 6-chloro-4-(methyl-d3)pyridazine-3-amine

[0153] The 4-bromo-6-chloropyridazine-3-amine (2.07 g, 10 mmol) obtained in the previous step was dissolved in 100 mL of anhydrous THF. Under nitrogen protection, deuterated methyl magnesium iodide (27 mL, 27 mmol) was slowly added dropwise. After the addition was complete, a solution of zinc chloride in 2-methyltetrahydrofuran (2.5 mL, 5 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) were added sequentially. The mixture was heated to 50 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and the reaction was quenched by adding 50 mL of saturated ammonium chloride. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain 1.34 g of product, yield: 44.3%. LC-MS (APCI): m / z = 147.5 (M+1) + .

[0154] Step 3: Synthesis of compound 6-chloro-2-methyl-8-(methyl-d3)imidazo[1,2-b]pyridazine

[0155] 6-Chloro-4-(methyl-d3)pyridazin-3-amino (194 mg, 1.33 mmol) was dissolved in 10 mL of anhydrous DMF. The mixture was heated to 100 °C, and 3 mL of bromoacetone (200 mg, 1.46 mmol) in DMF was slowly added dropwise. Under nitrogen protection, the mixture was heated to 110 °C and stirred for 2–3 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain 140 mg of solid, with a yield of 57.1%. LC-MS (APCI): m / z = 185.5 (M+1) + .

[0156] Step 4: Synthesis of intermediate compound B-1

[0157] 6-Chloro-2-methyl-8-(methyl-d3)imidazo[1,2-b]pyridazine (90 mg, 0.5 mmol), pinacol diboronate (380 mg, 1.5 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), PCy3 (14 mg, 0.05 mmol), and potassium acetate (100 mg, 1.0 mmol) were added to a 20 mL microwave-safe tube. Under nitrogen protection, 8 mL of isopropyl acetate was added. The tube was sealed and microwaved to 80 °C for 1 hour. The reaction was monitored by TLC until completion. After cooling to room temperature, the solution was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 108 mg of solid. Yield: 79.1%. LC-MS (APCI): m / z = 277.2 (M+1) + .

[0158] Intermediate B-2 8-methyl-2-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane) Preparation of alkyl-2-yl)imidazo[1,2-b]pyridazine

[0159] B-2

[0160] The following synthetic route was adopted.

[0161]

[0162] Step 1: Synthesis of compound 1-bromopropane-2-one-1,1,3,3,3-d5

[0163] Deuterated acetone (5 g, 78.1 mmol) was added to 100 ml of methanol, and the mixture was cooled to 0°C. The dioxane complex of bromine (19.4 g, 78.1 mmol) was added in portions. The mixture was stirred in an ice bath for 3-4 hours. After the reaction was completed by GC monitoring, 80 ml of water was added to quench the reaction. The mixture was extracted 3-4 times with 80 ml of diethyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at low temperature to remove the solvent and obtain the crude product. This crude product was directly added to the next reaction without further purification.

[0164] Step 2: Synthesis of compound 6-chloro-4-methylpyridazine-3-amine

[0165] 1-Bromopropane-2-one-1,1,3,3,3-d5 (2.07 g, 10 mmol) was dissolved in 100 mL of anhydrous THF. Under nitrogen protection, methylmagnesium iodide (27 mL, 27 mmol) was slowly added dropwise. After the addition was complete, a solution of zinc chloride in 2-methyltetrahydrofuran (2.5 mL, 5 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) were added sequentially. The mixture was heated to 50 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and the reaction was quenched by adding 50 mL of saturated ammonium chloride. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, concentrated, and purified by silica gel column chromatography to give 1.18 g of product (yield: 39.0%). LC-MS (APCI): m / z = 144.2 (M+1) + .

[0166] Step 3: Synthesis of compound 6-chloro-8-methyl-2-(methyl-d3)imidazo[1,2-b]pyridazine

[0167] 6-Chloro-4-methylpyridazine-3-amino (194 mg, 1.34 mmol) was dissolved in 10 mL of anhydrous DMF. The solution was heated to 100 °C, and 3 mL of a solution of 1-bromopropane-2-one-1,1,3,3,3-d5 (200 mg, 1.40 mmol) in DMF was slowly added dropwise. Under nitrogen protection, the temperature was raised to 110 °C and the mixture was stirred for 2–3 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction was quenched with 10 mL of saturated sodium bicarbonate aqueous solution. The mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain 152 mg of solid, with a yield of 61.9%. LC-MS (APCI): m / z = 185.5 (M+1) + .

[0168] Step 4: Synthesis of intermediate compound B-2

[0169] 6-Chloro-8-methyl-2-(methyl-d3)imidazo[1,2-b]pyridazine (90 mg, 0.5 mmol), pinacol diboronate (380 mg, 1.5 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), PCy3 (14 mg, 0.05 mmol), and potassium acetate (100 mg, 1.0 mmol) were added to a 20 mL microwave-safe tube. Under nitrogen protection, 8 mL of isopropyl acetate was added. The tube was sealed and microwaved to 80 °C for 1 hour. The reaction was monitored by TLC until completion. After cooling to room temperature, the solution was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 111 mg of solid. Yield: 81.3%. LC-MS (APCI): m / z = 277.2 (M+1) + .

[0170] Intermediate compound B-2 2,8-bis(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane heterocycle) Preparation of pentane-2-yl)imidazo[1,2-b]pyridazine

[0171] B-3

[0172] The following synthetic route was adopted.

[0173]

[0174] Step 1: Synthesis of compound 6-chloro-4-(methyl-d3)pyridazine-3-amine

[0175] 4-Bromo-6-chloropyridazine-3-amine (2.07 g, 10 mmol) was dissolved in 100 mL of anhydrous THF. Under nitrogen protection, deuterated methyl magnesium iodide (27 mL, 27 mmol) was slowly added dropwise. After the addition was complete, a solution of zinc chloride in 2-methyltetrahydrofuran (2.5 mL, 5 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) were added sequentially. The mixture was heated to 50 °C and stirred for 4–6 hours. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and the reaction was quenched by adding 50 mL of saturated ammonium chloride. The mixture was extracted 3–4 times with ethyl acetate. The organic phases were combined, concentrated, and purified by silica gel column chromatography to give 1.32 g of product (yield: 43.6%). LC-MS (APCI): m / z = 144.2 (M+1) + .

[0176] Step 2: Synthesis of compound 6-chloro-2,8-bis(methyl-d3)imidazo[1,2-b]pyridazine

[0177] 6-Chloro-4-(methyl-d3)pyridazine-3-amino (194 mg, 1.32 mmol) was dissolved in 10 mL of anhydrous DMF. The solution was heated to 100 °C, and 3 mL of a solution of 1-bromopropane-2-one-1,1,3,3,3-d5 (200 mg, 1.40 mmol) in DMF was slowly added dropwise. Under nitrogen protection, the temperature was raised to 110 °C and the mixture was stirred for 2–3 hours. The reaction was monitored by TLC until completion. After cooling to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted 3–4 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain 163 mg of solid, with a yield of 66.4%. LC-MS (APCI): m / z = 188.5 (M+1) + .

[0178] Step 3: Synthesis of intermediate compound B-3

[0179] 6-Chloro-2,8-bis(methyl-d3)imidazo[1,2-b]pyridazine (90 mg, 0.5 mmol), pinacol diboronate (380 mg, 1.5 mmol), Pd(OAc)2 (6 mg, 0.025 mmol), PCy3 (14 mg, 0.05 mmol), and potassium acetate (100 mg, 1.0 mmol) were added to a 20 mL microwave-safe tube. Under nitrogen protection, 8 mL of isopropyl acetate was added. The tube was sealed and microwaved to 80 °C for 1 hour. The reaction was monitored by TLC until completion. After cooling to room temperature, the solution was concentrated to remove the solvent, and purified by silica gel column chromatography to obtain 95 mg of solid. Yield: 69.6%. LC-MS (APCI): m / z = 280.2 (M+1) + .

[0180] Example 1 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2-methyl-8-(methyl-d3)imidazo[1,2- Preparation of [b]pyridazine-6-yl]pyrido[1,2-a]pyrimidin-4-one (compound T-1)

[0181] T-1

[0182] The following synthetic route was adopted.

[0183]

[0184] Step 1: Synthesis of tert-butyl 7-(2-(2-methyl-8-(methyl-d3)imidazo[1,2-b]pyridazin-6-yl)-4-oxopyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2,5]octyl-4-carboxylate

[0185] Intermediate compounds A-1 (90 mg, 0.17 mmol) and B-1 (52 mg, 0.19 mmol) were added to 10 mL of acetonitrile and 2 mL of water. Under nitrogen protection, Pd(dppf)Cl2 (12 mg, 0.017 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added. The mixture was heated to 80 °C and stirred overnight. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature and concentrated to remove the solvent. The solution was purified by silica gel column chromatography to give 69 mg of solid, yield: 81.1%. LC-MS (APCI): m / z = 505.2 (M+1) + .

[0186] Step 2: Synthesis of compound T-1

[0187] The tert-butyl 7-(2-(2-methyl-8-(methyl-d3)imidazo[1,2-b]pyridazin-6-yl)-4-oxopyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylic acid obtained in the previous step (69 mg, 0.14 mmol) was added to 5 mL of dichloromethane, followed by the addition of TFA (0.2 mL, 2.8 mmol). The mixture was stirred at room temperature for 0.5–1 hour. After the reaction was complete as monitored by TLC, 10 mL of dichloromethane was added for dilution. The mixture was washed 2–3 times successively with 20 mL of saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain 48 mg of off-white solid, yield: 87.2%. LC-MS (APCI): m / z = 405.5 (M+1) + . 1 H NMR (400 MHz, CDCl3)δ8.45 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 1.0Hz, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.80 (s, 1H), 7.70 (dd, J = 9.7, 2.5 Hz,1H), 7.38 (s, 1H), 3.31-3.22 (m, 2H), 3.20-3.16 (m, 2H), 3.08 (s, 2H), 2.55(s, 3H), 1.68 (br s,1H), 0.77-0.75 (m, 2H), 0.67-0.64 (m,2 H).

[0188] Example 2 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(8-methyl-2-(methyl-d3)imidazo[1,2- Preparation of [b]pyridazine-6-yl]pyrido[1,2-a]pyrimidin-4-one (compound T-2)

[0189] T-2

[0190] The following synthetic route was adopted.

[0191]

[0192] Step 1: Synthesis of compound tert-butyl 7-(2-(2-(methyl-d3)-8-methylimidazo[1,2-b]pyridazin-6-yl)-4-oxopyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2,5]octyl-4-carboxylate

[0193] Intermediate compounds A-1 (90 mg, 0.17 mmol) and B-2 (52 mg, 0.19 mmol) were added to 10 mL of acetonitrile and 2 mL of water. Under nitrogen protection, Pd(dppf)Cl2 (12 mg, 0.017 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added. The mixture was heated to 80 °C and stirred overnight. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature and concentrated to remove the solvent. The solution was purified by silica gel column chromatography to give 74 mg of solid, yield: 87.0%. LC-MS (APCI): m / z = 505.2 (M+1) + .

[0194] Step 2: Synthesis of compound T-2

[0195] The tert-butyl 7-(2-(2-(methyl-d3)-8-methylimidazo[1,2-b]pyridazin-6-yl)-4-oxopyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylic acid obtained in the previous step (74 mg, 0.15 mmol) was added to 5 mL of dichloromethane, followed by the addition of TFA (0.2 mL, 2.8 mmol). The mixture was stirred at room temperature for 0.5–1 hour. After the reaction was complete as monitored by TLC, 10 mL of dichloromethane was added for dilution. The mixture was washed 2–3 times successively with 20 mL of saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain 51 mg of off-white solid, yield: 92.6%. LC-MS (APCI): m / z = 405.5 (M+1) + . 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.4 Hz, 1H), 7.94 (d, J =1.0 Hz, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.81 (s, 1H), 7.73 (dd, J = 9.7, 2.5Hz, 1H), 7.38 (s, 1H), 3.31-3.22 (m, 2H), 3.20-3.16 (m, 2H), 3.09 (s, 2H), 2.74 (d, J = 0.9 Hz, 3H), 1.69 (br s,1H), 0.77-0.75 (m, 2H), 0.68-0.64 (m,2H).

[0196] Example 3: 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-bis(methyl-d3)imidazo[1,2-b]) Preparation of pyridazine-6-yl)pyrido[1,2-a]pyrimidin-4-one (compound T-3)

[0197] T-3

[0198] The following synthetic route was adopted.

[0199]

[0200] Step 1: Synthesis of compound tert-butyl 7-(2-(2,8-bis(methyl-d3)imidazo[1,2-b]pyridazin-6-yl)-4-oxopyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2,5]octyl-4-carboxylate

[0201] Intermediate compounds A-1 (90 mg, 0.17 mmol) and B-2 (52 mg, 0.19 mmol) were added to 10 mL of acetonitrile and 2 mL of water. Under nitrogen protection, Pd(dppf)Cl2 (12 mg, 0.017 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added. The mixture was heated to 80 °C and stirred overnight. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature and concentrated to remove the solvent. The solution was purified by silica gel column chromatography to give 58 mg of solid, yield: 68.2%. LC-MS (APCI): m / z = 508.2 (M+1) + .

[0202] Step 2: Synthesis of compound T-3

[0203] The tert-butyl 7-(2-(2,8-bis(methyl-d3)imidazo[1,2-b]pyridazin-6-yl)-4-oxopyrido[1,2-a]pyrimidin-7-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylic acid obtained in the previous step (58 mg, 0.12 mmol) was added to 5 mL of dichloromethane, followed by the addition of TFA (0.2 mL, 2.8 mmol). The mixture was stirred at room temperature for 0.5–1 hour. After the reaction was complete as monitored by TLC, 10 mL of dichloromethane was added for dilution. The mixture was washed 2–3 times successively with 20 mL of saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain 35 mg of off-white solid, yield: 63.5%. LC-MS (APCI): m / z = 408.5 (M+1) + . 1 H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 1.0 Hz,1H), 7.74 (d, J = 9.6 Hz, 1H), 7.81 (s, 1H), 7.70 (dd, J = 9.7, 2.5 Hz, 1H),7.39 (s, 1H), 3.30-3.22 (m, 2H), 3.20-3.16 (m, 2H), 3.08 (s, 2H), 1.69 (br s,1H), 0.78-0.75 (m, 2H), 0.68-0.62 (m,2 H).

[0204] Bioactivity testing.

[0205] (1) Evaluation of metabolic stability

[0206] Metabolic stability is generally used to describe the rate and extent to which a compound is metabolized, and it is one of the main factors affecting pharmacokinetic properties. Many compounds are substrates for CYP450 enzymes and other drug-metabolizing enzymes, and liver microsomes are a system rich in CYP450. The purpose of this experiment is to study the in vitro metabolic stability of the compound of this invention by incubating it separately with human and SD rat liver microsomes and using LC-MS / MS to detect the remaining proportion of the compound.

[0207] Solution preparation

[0208] Phosphate-buffered saline (PBS): Mix 150 mL of pre-prepared KH₂PO₄ (0.5 M) solution and 700 mL of K₂HPO₄ (0.5 M) solution. Adjust the pH of the mixture to 7.4 with K₂HPO₄ (0.5 M) solution to obtain a 5-fold concentration PBS. Store at 4°C for later use. Before use, dilute PBS 5 times with ultrapure water and add 3.3 mM magnesium chloride to obtain 100 mM phosphate-buffered saline PBS.

[0209] NADPH regeneration system solution: Prepare an NADPH solution containing 6.5 mM NADP, 16.5 mM G-6-P, and 3 U / mL G-6-PD using 5 mL of PBS.

[0210] Internal standard termination solution: Prepare 50 ng / mL propranolol hydrochloride and 200 ng / mL tolbutamide as internal standard working solution using acetonitrile.

[0211] Human liver microsome solution: Take 0.31 mL of human liver microsomes (25 mg / mL) and add it to 0.961 mL of PBS (pH 7.4) and mix well to obtain a human liver microsome dilution with a protein concentration of 0.625 mg / mL.

[0212] SD rat liver microsomal solution: Take 0.31 mL of SD rat liver microsomal (25 mg / mL) and add it to 0.961 mL of PBS (pH 7.4) and mix well to obtain a diluted SD rat liver microsomal solution with a protein concentration of 0.625 mg / mL.

[0213] Sample working solution: Prepare a 10 mM solution using DMSO to obtain the powders of the compound of this invention and the non-deuterated compound, the positive control dextromethorphan powder, and the omeprazole powder. Then dilute with 70% acetonitrile-water to obtain a 0.25 mM sample working solution.

[0214] Sample incubation

[0215] Add 398 μL of human liver microsomal dilution to a 96-well incubation plate (N=2), and add 2 μL of the 0.25 mM test compound and dextromethorphan respectively, and mix well.

[0216] Add 398 μL of SD rat liver microsomal dilution to a 96-well incubation plate (N=2), and add 2 μL of the test compound (0.25 mM) and omeprazole respectively, and mix well.

[0217] Add 300 μL of pre-cooled stop solution to each well of the 96-well deep plate and place it on ice as a stop plate.

[0218] The 96-well incubation plate and NADPH regeneration system were placed in a 37°C water bath and incubated for 5 min with shaking at 100 rpm. 80 μL of incubation solution was taken from each well of the incubation plate and added to the stop plate. After mixing, 20 μL of NADPH regeneration system solution was added to each well as the 0 min sample. Then, 80 μL of NADPH regeneration system solution was added to each well of the incubation plate to start the reaction and begin timing. The concentration of the analyte was 1 μM, and the protein concentration was 0.5 mg / mL.

[0219] At 10, 30 and 90 min of reaction time, 100 μL of the reaction solution was added to the stop plate and the reaction was terminated by vortexing for 3 min.

[0220] Centrifuge the stop plate at 5000 rpm and 4℃ for 15 min. Take 200 μL of the supernatant into a 96-well plate pre-filled with 200 μL of ultrapure water, mix well, and perform sample analysis by LC-MS / MS, injecting 10 μL.

[0221] Sample analysis methods

[0222] In this experiment, the peak areas of the test compound, dextromethorphan, omeprazole and internal standard were detected using an LC-MS / MS system, and the peak area ratio of the compound to the internal standard was calculated.

[0223] Data processing

[0224] The peak areas of the sample and internal standard were obtained using mass spectrometry and Analyst software. The substrate elimination rate constant K was obtained by plotting the residual amount (R%) of the compound against time using the single exponential degradation model in Graphpad Prism 7.0 software.

[0225] Ct / C0 = exp(-K*t)

[0226] Calculate the half-life T using the following formula. 1 / 2 and intrinsic clearance rate CL int V / M is equal to 1 / C (protein).

[0227] .

[0228] Experimental Results: The metabolic stability of the compounds of this invention and their non-deuterated counterparts in human and SD rat liver microsomes was evaluated by simultaneous testing and comparison. Compared with the non-deuterated compounds, the compounds of this invention exhibit a longer half-life (T0). 1 / 2 and lower clearance rate CL int This can significantly improve metabolic stability. The results of the compounds in the representative examples are summarized in Table 1 below.

[0229] Table 1

[0230]

[0231] (2) Rat pharmacokinetics experiment

[0232] Six male Sprague-Dawley rats, 7-8 weeks old and weighing approximately 210g, were divided into two groups of three. Each group received a single dose of the compound (10mg / kg orally) via intravenous or oral administration, and the pharmacokinetic differences were compared.

[0233] Rats were fed a standard diet and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved in 10 mM ascorbic acid / 0.01 mg / mL sodium thiosulfate pentahydrate. Blood was collected from the orbital rim at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-administration.

[0234] Rats were briefly anesthetized after inhaling ether, and 300 μL of blood was collected from the orbital cavity in a test tube. The test tube contained 30 μL of 1% heparin solution. Before use, the test tube was dried overnight at 60 °C. After the last blood sample was collected, the rats were euthanized under ether anesthesia.

[0235] Immediately after blood sample collection, gently invert the test tube at least five times to ensure thorough mixing, then place it on ice. Centrifuge the blood sample at 4°C and 5000 rpm for 5 minutes to separate the plasma from the red blood cells. Pipette 100 μL of plasma into a clean plastic centrifuge tube, labeling it with the compound name and time point. Store the plasma at -80°C before analysis. Determine the concentration of the compound of the present invention in the plasma using LC-MS / MS. Pharmacokinetic parameters are calculated based on the plasma drug concentrations of each animal at different time points.

[0236] Experiments show that the compounds of this invention have better pharmacokinetic properties in animals, and therefore better pharmacodynamics and therapeutic effects. The results of the compounds in the exemplary examples are summarized in Table 2 below.

[0237] Table 2

[0238]

[0239] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from: 。 2. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for the treatment and / or prevention of spinal muscular atrophy (SMA).

Images