WO2022105852A1 - 三嗪二酮类衍生物、其制备方法及其在医药上的应用 - Google Patents

三嗪二酮类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2022105852A1
WO2022105852A1 PCT/CN2021/131642 CN2021131642W WO2022105852A1 WO 2022105852 A1 WO2022105852 A1 WO 2022105852A1 CN 2021131642 W CN2021131642 W CN 2021131642W WO 2022105852 A1 WO2022105852 A1 WO 2022105852A1
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general formula
alkyl
group
pharmaceutically acceptable
cycloalkyl
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PCT/CN2021/131642
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English (en)
French (fr)
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张晓敏
胡伟民
费洪博
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202180065655.5A priority Critical patent/CN116323598A/zh
Priority to AU2021381664A priority patent/AU2021381664A1/en
Priority to MX2023005533A priority patent/MX2023005533A/es
Priority to KR1020237019549A priority patent/KR20230110538A/ko
Priority to EP21893999.9A priority patent/EP4249474A4/en
Priority to CA3198934A priority patent/CA3198934A1/en
Priority to JP2023530323A priority patent/JP2023550444A/ja
Priority to US18/253,704 priority patent/US20240010639A1/en
Publication of WO2022105852A1 publication Critical patent/WO2022105852A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/42—One nitrogen atom
    • C07D251/46—One nitrogen atom with oxygen or sulfur atoms attached to the two other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a triazine dione derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to triazinedione derivatives represented by general formula (I), preparation methods thereof, pharmaceutical compositions containing the derivatives, and uses thereof in the preparation of myosin inhibitors and use in the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM) or heart disease with pathophysiological features associated with HCM.
  • HCM hypertrophic cardiomyopathy
  • Hypertrophic cardiomyopathy is a dominantly inherited myocardial disease associated with genetic mutations. The global incidence is about 0.2%, and it is the most important cause of sudden death in young people under the age of 35 (C. Vaughan Tuohy, et al., European Journal of Heart Failure, 22, 2020, 228-240).
  • the clinical features are asymmetric hypertrophy of the left ventricular wall, often invading the ventricular septum, smaller ventricular chamber, obstruction of left ventricular blood filling, and decreased ventricular diastolic compliance. According to the presence or absence of left ventricular outflow tract obstruction, it is divided into obstructive and non-obstructive hypertrophic cardiomyopathy.
  • ⁇ -blockers and calcium channel blockers are used in clinical treatment of hypertrophic cardiomyopathy to reduce cardiac contraction and relieve symptoms. But these treatments are palliative. Heart transplantation can only be performed when HCM progresses to an advanced stage (Radhakrishnan Ramaraj, Cardiology in Review, 16(4), 2008, 172-180). Therefore, it is very urgent to find a treatment method for the root cause of HCM.
  • MYH7 causes earlier disease onset and more severe cardiac hypertrophy than other sarcomeric protein genes.
  • Myosin is the constituent unit of myofibrillar thick filaments and plays an important role in muscle movement. Its molecular shape is like a bean sprout and consists of two heavy chains and multiple light chains. The head of myosin combines with actin to form a cross bridge, which greatly increases the ATPase activity of myosin, catalyzes the hydrolysis of ATP, and generates energy to promote the sliding of the cross bridge and perform muscle contraction.
  • MYH7 gene mutation leads to increased myosin ATPase activity, decreased myosin super-relaxed state (SRX) ratio, increased cross bridge between myosin and actin, leading to cardiac contraction Dysfunction (Eric M.Green, et al., Science, 351(6273), 2016, 617-621; Ruth F. Sommese, et al., Proceedings of the National Academy Sciences, 110(31), 2013, 12607- 12612). Therefore, myosin is an important target for the treatment of hypertrophic cardiomyopathy.
  • Patent applications that have disclosed myosin inhibitors include WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1, and CN110698415A, among others.
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 1 is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, C(O)R 6 , C(O )OR 7 , S(O) t R 8 , S(O) t NR 9 R 10 , C(O)NR 9 R 10 , NR 9 R 10 and
  • Each R 2 is the same or different, and is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkane base, C(O)R 6 , C(O)OR 7 , S(O) t R 8 , S(O) t NR 9 R 10 , C(O)NR 9 R 10 and NR 9 R 10 ;
  • R 1 and one adjacent R 2 , or two adjacent R 2 are condensed with ring A to form a cycloalkyl or heterocyclyl; wherein, the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl;
  • L 2 is selected from covalent bonds, (CH 2 ) r , C(O), NR a , oxygen atoms and sulfur atoms;
  • Ra is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 5 is the same or different, and is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkane radicals, cycloalkyls, heterocyclyls, aryls and heteroaryls;
  • R 3a is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkoxy, haloalkoxy, cyano, amino , substituted with one or more substituents in nitro and hydroxyl;
  • R 3b is a hydrogen atom
  • R 0 is alkyl or Wherein, the alkyl group is optionally substituted by one or more substituents selected from halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl;
  • L 1 is a covalent bond or (CH 2 ) r ;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 4 is the same or different, and is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxy, hydroxy Alkyl, C(O)R 6 , C(O)OR 7 , S(O) t R 8 , S(O) t NR 9 R 10 , C(O)NR 9 R 10 , cycloalkyl, -( CH2 ) r -cycloalkyl, heterocyclyl, -( CH2 ) r -heterocyclyl, aryl, -( CH2 ) r -aryl, heteroaryl and -( CH2 ) r -heteroaryl base;
  • R 6 is the same or different at each occurrence, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • Alkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro substituted with one or more substituents in hydroxy, hydroxy and hydroxyalkyl;
  • R 7 is the same or different at each occurrence, and is each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group ;
  • R 8 is the same or different at each occurrence and is each independently selected from a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heterocyclyl Aryl;
  • R 9 and R 10 are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, -(CH 2 ) r - Cycloalkyl, heterocyclyl, -( CH2 ) r -heterocyclyl, aryl, -( CH2 ) r -aryl, heteroaryl, and -( CH2 ) r -heteroaryl; or R9 and R 10 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy , cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl,
  • p 0, 1, 2, 3, 4, 5, or 6;
  • r is 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3, 4, 5, or 6;
  • t 0, 1 or 2.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:
  • Rings A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein ring A is selected from 3- to 8-membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; preferably, Ring A is phenyl.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
  • R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1), general formula (II) or a pharmaceutically acceptable salt thereof is general formula (II-1) ) or a pharmaceutically acceptable salt thereof:
  • R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is C 1-6 alkyl or Wherein, the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, amino and hydroxyl Substituted; L 1 is a covalent bond or (CH 2 ) r ; Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; Each R 4 is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1- 6 haloalkyl, C 1-6 hal
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is selected from C 1-6 alkyl, 3- to 8-membered cycloalkyl and 3- to 12-membered heterocyclic groups; preferably, R 0 is selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3 to 6-membered heterocyclyl; further preferably, R 0 is selected from isopropyl, tetrahydropyranyl and cyclohexyl; more preferably, R 0 is isopropyl or tetrahydropyranyl; most preferably, R 0 is tetrahydropyranyl.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is C 1-6 alkyl; preferably, R 0 is isopropyl.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and Preferably, R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and wherein rings C, L2, R5 and p are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl ; p is 0, 1, 2, 3, 4, 5, or 6.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and Preferably, R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p is 0, 1 or 2.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and Preferably, R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1, or 2.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1, or 2.
  • each R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 -6 haloalkyl and C 1-6 haloalkoxy; preferably, each R 2 is the same or different, and each is independently a hydrogen atom or halogen; more preferably, each R 2 is the same or different, and each independently is a halogen ; most preferably, R 2 is a fluorine atom.
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 and an adjacent R 2 , or two Adjacent R 2 , fused with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group; preferably, R 1 and one adjacent R 2 , or two adjacent R 2 , fused with ring A to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; more preferably, R 1 and the adjacent one R 2 are fused with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl base and cyclohexyl.
  • the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 and an adjacent R 2 , or two The adjacent R 2 is fused with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group; preferably, R 1 and an adjacent one of R 2 are fused with ring A to form a cyclopentyl group.
  • the compound represented by general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 and an adjacent R 2 , or two Adjacent R 2 , fused with phenyl to form 3- to 8-membered cycloalkyl or 3- to 12-membered heterocyclic group; preferably, R 1 and one adjacent R 2 , or two adjacent R 2 , Condensed with phenyl to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; more preferably, R 1 and the adjacent one R 2 are condensed with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl base and cyclohexyl.
  • the compound represented by general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 and an adjacent R 2 , or two The adjacent R 2 is fused with a phenyl group to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group; preferably, R 1 and an adjacent one of R 2 are fused with a phenyl group to form a cyclopentyl group.
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl ; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 is the same or different, and each is independently selected from a
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from C 1-6 alkyl, C 1 -6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from C 1-6 alkyl, C 1 -6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are fused with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are fused with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are fused with ring A to form a cyclopentyl group.
  • R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom
  • ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl
  • each R 5 is the same or different, and is independently selected from hydrogen atom, halogen
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl ; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 is the same or different, and each is independently selected from
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from C 1-6 alkyl, C 1 -6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are condensed with phenyl to form a 3- to 6-membered cycloalkyl group or a 3- to 6-member
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and the adjacent one R 2 are condensed with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are condensed with a phenyl group to form a cyclopentyl group.
  • R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom
  • ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl
  • each R 5 is the same or different, and is independently selected from
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 3a is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably, R 3a is C 1-6 alkyl; more preferably, R 3a is methyl.
  • the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein m is 0, 1 or 2; preferably, m is 0 or 1.
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, R f is selected from hydrogen atom, halogen and C 1-6 alkyl group, n is 0 or 1, R 1 and R 2 are as shown in as defined in formula (I) or general formula (I-1); preferably, for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, and R 1 and R 2 are as defined in general formula (I) or general formula (I-1); more preferably, selected from Most preferably, for
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, R f is selected from hydrogen atom, halogen and C 1-6 alkyl group, n is 0 or 1, R 1 and R 2 are as shown in as defined in formula (II) or general formula (II-1); preferably, for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, and R 1 and R 2 are as defined in general formula (II) or general formula (II-1); more preferably, selected from Most preferably, for
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein ring A is phenyl; R 0 is selected from C 1- 6 -alkyl, 3- to 8-membered cycloalkyl and 3- to 12-membered heterocyclyl; R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1 -6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl,
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein ring A is phenyl; R 0 is C 1-6 alkyl; R 1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl ; p is 0, 1, 2, 3, 4, 5
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is selected from C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is C 1-6 alkyl; R 1 is selected from from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are condensed with phenyl to form a 3- to 6-membered cyclo
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is C 1-6 alkyl; R 1 is C 1-6 haloalkoxy or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and the adjacent one R 2 are condensed with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl; R 3a is a methyl group; R 3b is a hydrogen atom; m is 0 or 1.
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 is selected from C 1-6 alkyl, 3- to 8-membered cycloalkyl and 3- to 12-membered heterocyclic group; R 1 Selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 halo
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 is a C 1-6 alkyl group; R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl
  • the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 is a C 1-6 alkyl group; R 1 is a C 1-6 haloalkoxy group or L 2 is a covalent bond or an oxygen atom; Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 hydroxyalkyl ; p is 0, 1,
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 is selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic group; R 1 Selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 is a C 1-6 alkyl group; R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and L 2 is a covalent bond or an oxygen atom; ring C is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; each R 5 is the same or different, and each is independently selected From hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 is a C 1-6 alkyl group; R 1 is a C 1-6 haloalkoxy group or L 2 is a covalent bond or an oxygen atom; ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 is the same or different, and is independently selected from hydrogen atom, halogen and C 1-6 alkyl; p is 0, 1 or 2; each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; R 3a is a methyl group; R 3b is a hydrogen atom; m is 0 or 1.
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is selected from isopropyl, tetrahydropyranyl and cyclohexyl; for wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 1 is selected from C 1-6 alkyl, C 1-6 haloalkoxy and Each R 2 is the same or different, and each is independently a hydrogen atom or a halogen; or R 1 and an adjacent one R 2 are condensed with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl; R 3a is Methyl; R 3b is a hydrogen atom; L 2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofur
  • the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R 0 is tetrahydropyranyl; for R 1 is a C 1-6 alkyl group; R 2 is a hydrogen atom or halogen; R 3a is a methyl group; R 3b is a hydrogen atom.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable of salt;
  • R w is a leaving group, preferably pyrazolyl
  • Rings A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA-1) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I-1) or pharmaceutically acceptable salts thereof;
  • R w is a leaving group, preferably pyrazolyl
  • Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable of salt;
  • R w is a leaving group, preferably pyrazolyl
  • R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA-1) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof;
  • R w is a leaving group, preferably pyrazolyl
  • R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (II-1).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the general formula (I), the general formula (I-1), the general formula (II), the general formula (II-1) and the table of the present disclosure.
  • the present disclosure further relates to compounds of general formula (I), general formula (I-1), general formula (II), general formula (II-1), and Table A, or pharmaceutically acceptable salts thereof, or compounds including the same Use of a pharmaceutical composition in the preparation of a myosin (Myosin) inhibitor.
  • Myosin myosin
  • the present disclosure further relates to compounds of general formula (I), general formula (I-1), general formula (II), general formula (II-1), and Table A, or pharmaceutically acceptable salts thereof, or medicaments comprising the same Use of a composition in the manufacture of a medicament for the treatment of a disease or condition selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, Hypertrophic cardiomyopathy (HCM) (eg, non-obstructive hypertrophic cardiomyopathy (nHCM) and obstructive hypertrophic cardiomyopathy (oHCM)), heart failure with normal ejection fraction (HFpEF), heart failure with median ejection fraction (HFmREF) ), valve disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease
  • the present disclosure further relates to compounds of general formula (I), general formula (I-1), general formula (II), general formula (II-1), and Table A, or pharmaceutically acceptable salts thereof, or medicaments comprising the same Use of a composition in the manufacture of a medicament for the treatment of a disease or condition mediated by Myosin selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy , diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with median ejection fraction (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler Endocarditis, myocardial endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory An
  • the present disclosure further relates to a method for inhibiting Myosin, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (I-1), Formula (II), Formula (II) -1) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method of treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (I-1), Formula (II), Formula (II-1) And the compound shown in Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising it, the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restricted type Cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with median ejection fraction (HFmREF), valve disease, aortic stenosis, inflammatory cardiomyopathy, leukemia Fowler's endocarditis, myocardial endomyocardial fibrosis, invasive cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hyper
  • the present disclosure further relates to a method of treating a disease or disorder mediated by Myosin, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (I-1), formula (II), formula (II-1) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease , angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with median ejection fraction (HFmREF), valvular disease, aortic stenosis, inflammation Cardiomyopathy, Loeffler's endocarditis, myocardial endomyocardial fibrosis, invasive cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, te
  • the present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a compound comprising A pharmaceutical composition thereof for use as a medicament.
  • the present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a compound comprising A pharmaceutical composition thereof, which is used as a Myosin inhibitor.
  • the present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a compound comprising A pharmaceutical composition thereof for the treatment of a disease or condition selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with median ejection fraction (HFmREF), valvular disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler endocarditis, myocardial heart disease Intimal fibrosis, invasive cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina, and Chagas disease ; preferably selected from ischemic
  • the present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a compound comprising A pharmaceutical composition thereof for the treatment of a disease or condition mediated by Myosin selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic Dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with median ejection fraction (HFmREF), valvular disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler intracardiac Meningitis, endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease;
  • the composition can alter the natural history of HCM and other diseases, not just relieve symptoms.
  • the mechanisms that confer clinical benefit in HCM patients can be extended to patients with other forms of cardiac disease that share similar pathophysiology, with or without the influence of significant genetic factors.
  • effective treatment of HCM by improving ventricular relaxation during diastole may also be effective in a broader population characterized by diastolic dysfunction.
  • the composition may specifically target the source of the disorder or act on other downstream pathways. Therefore, the compounds of the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A of the present disclosure or pharmaceutically acceptable salts thereof, or compounds thereof
  • the pharmaceutical composition of ® may benefit patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy.
  • compositions may also promote beneficial ventricular remodeling from left ventricular hypertrophy due to volume or pressure overload; eg, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension; the compounds or pharmaceutically acceptable thereof
  • the salt is combined with therapies aimed at correcting or reducing the primary cause of volume or pressure overload (valve repair/replacement, effective antihypertensive therapy). By reducing left ventricular filling pressure, the compound reduces the risk of pulmonary edema and respiratory failure.
  • Reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressure reduces the risk of sudden or persistent atrial fibrillation, and it reduces arterial thromboembolic complications including, but not limited to, cerebral arterial embolic stroke associated risks.
  • Reduction or elimination of dynamic and/or static LV outflow tract obstruction reduces the likelihood of needing septal ablation therapy (surgical or percutaneous) and its attendant risks of short- and long-term complications.
  • the composition can reduce the severity of chronic ischemic states associated with HCM, and thereby reduce sudden cardiac death in patients with implantable cardioverter-defibrillators (frequent and/or repetitive ICD discharges) (SCD) or its equivalent and/or reduce the need for potentially toxic antiarrhythmic drugs.
  • implantable cardioverter-defibrillators frequent and/or repetitive ICD discharges (SCD) or its equivalent and/or reduce the need for potentially toxic antiarrhythmic drugs.
  • the composition reduces interstitial myocardial fibrosis and/or slows the progression of left ventricular hypertrophy, preventing or reversing left ventricular hypertrophy.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl yl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n- Heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhex
  • non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-Dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples of alkylene groups include, but are not limited to: methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene base (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cyclic Alkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , one or more of heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms alkenyl (ie C2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like.
  • the alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered ring alkyl), preferably having 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), more preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl).
  • Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl and cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups .
  • spirocycloalkyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan, 6-membered/4-membered or 6-membered/5-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group of rings sharing an adjacent pair of carbon atoms, wherein one or more of the rings may contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic polycyclic fused cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered RMB/4, 4/5, 4/6, 5/4, 5/5, 5/6, 5/7, 6/3, 6/ 4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • connection point can be anywhere.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • ring atoms Preferably there are 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, of which 1-4 (eg 1, 2, 3 and 4) are heterocyclic atoms (ie 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), where 1-3 are heteroatoms (eg 1, 2 and 3) (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (ie 3 to 6 membered heterocyclyl); most preferably 5 or 6 Ring atoms, of which 1-3 are heteroatoms (ie, 5 or 6 membered heterocyclyl).
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base and homopiperazinyl, etc.
  • Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused ring heterocyclic groups and bridged ring heterocyclic groups.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyl groups are classified into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiro-heterocyclyl groups .
  • spiroheterocyclyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan unit Spiroheterocyclyl.
  • spiroheterocyclyl include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which an adjacent pair of atoms is shared between rings, one or more rings may contain one or more double bonds, and one or more rings may contain one or more double bonds.
  • the atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan , 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups preferably 3-membered/4-membered, 3-
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, For example phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered heteroaryl, eg furyl, thienyl, pyridyl, pyrrolyl, N -Alkylpyrrolyl, pyridone, N-alkylpyridone (such as etc.), pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", “heterocyclylene”, “arylene”, “heteroarylene”.
  • amino protecting group refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • hydroxyl protecting group refers to an easily removed group introduced on a hydroxy group, which is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl base, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • the bond The configuration is not specified, i.e. it can be either the Z configuration or the E configuration, or both.
  • the bond can be either the Z configuration or the E configuration, or both.
  • both Z and E forms are included.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • the compound represented by the general formula (IA) or its salt (preferably hydrochloride) and the compound represented by the general formula (V) undergo a direct nucleophilic substitution reaction or a nucleophilic substitution reaction in the presence of a base to obtain the general formula ( I) the compound shown or a pharmaceutically acceptable salt thereof;
  • R w is a leaving group, preferably pyrazolyl
  • Rings A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I).
  • the preparation method of the compound represented by the general formula (I-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IA-1) or its salt directly undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) or undergoes a nucleophilic substitution reaction in the presence of a base to obtain the general formula (V).
  • R w is a leaving group, preferably pyrazolyl
  • Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (I-1).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IIA) or its salt (preferably hydrochloride) directly undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) or undergoes a nucleophilic substitution reaction in the presence of a base to obtain the general formula ( The compound shown in II) or a pharmaceutically acceptable salt thereof;
  • R w is a leaving group, preferably pyrazolyl
  • R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in general formula (II).
  • the preparation method of the compound represented by the general formula (II-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:
  • the compound represented by the general formula (IIA-1) or its salt directly undergoes a nucleophilic substitution reaction with a compound represented by the general formula (V) or undergoes a nucleophilic substitution reaction in the presence of a base to obtain the general formula (V).
  • R w is a leaving group, preferably pyrazolyl
  • R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (II-1).
  • the alkalis include organic bases and inorganic bases
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyl Lithium amide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, preferably triethylamine and N,N-diisopropylethylamine
  • the inorganic bases include but are not limited to sodium hydride , potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide.
  • the above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum Ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2- Dibromoethane and mixtures thereof.
  • the solvent used includes but is not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum Ether, ethyl
  • the above-mentioned nucleophilic substitution reaction is a conventional reaction, and the reaction temperature is 100-160°C, preferably 120°C.
  • the above-mentioned nucleophilic substitution reaction is a conventional reaction, and the reaction time is 10-20 hours; preferably 16 hours.
  • the above-mentioned nucleophilic substitution reaction can also be carried out in a microwave, and the reaction temperature of the microwave reaction is 100-160°C, preferably 140°C.
  • the above-mentioned nucleophilic substitution reaction can also be carried out in a microwave, and the reaction time of the microwave reaction is 0.5-4 hours; preferably 2 hours.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Shanghai) Co., Ltd. (Accela ChemBio Inc), Darui Chemicals and other companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: n-hexane/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • Tetrahydrofuran-3-ol 3a (2.0 g, 22.7 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and triethylamine (3.4 g, 33.7 mmol) were dissolved in dichloromethane (20 mL), and methanesulfonic acid was added at 0°C Acyl chloride (2.84 g, 24.9 mmol, Shanghai Sinopharm Chemical Reagent Co., Ltd.) was reacted at room temperature for 24 hours.
  • Bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde 7a (2.9 g, 22.0 mmol) was prepared by the method disclosed in step 1 on pages 512-513 of the patent application "WO2019023147A1" prepared) and (R)-2-methylpropane-2-sulfinamide (2.8 g, 23.0 mmol) were dissolved in dichloromethane (40 mL). Cesium carbonate (8.6 g, 26.4 mmol) was added and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 7b as a crude product (5.7 g). The crude product was used in the next step without purification.
  • 2,3-Dihydrobenzofuran-6-carbaldehyde 8a (1.0 g, 6.8 mmol, Jiangsu Aikang Biomedical Research and Development Co., Ltd.) and (R)-2-methylpropane-2-sulfinamide (860.0 mg , 7.1 mmol, Shanghai Titan Technology Co., Ltd.) was dissolved in dichloromethane (40 mL). Cesium carbonate (2.6 g, 8.1 mmol) was added and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 8b crude product (1.8 g), which was used in the next step without purification.
  • 6-Bromo-5-fluorobenzofuran 11a (3.20 g, 14.88 mmol, prepared by the patent application "Synthesis method of intermediate A1.2b on page 36 in the specification of WO2017219948A1" was dissolved in methanol (50 mL), and added [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.26 g, 1.49 mmol) and N,N-diisopropylethylamine (3.01 g, 29.75 g) mmol), replaced with carbon monoxide gas three times, and the reaction was stirred at 70 °C for 40 hours. Filtration, concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A afforded the title product 11b (1.50 g, yield: 51.9%).
  • aqueous phase was extracted with ethyl acetate (80 mL ⁇ 2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Boston Phlex C18 150*30mm, 5 ⁇ m, elution system: water (10mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, gradient elution over 20 minutes, flow rate: 30 mL/min) to give the title product 12c (2.10 g, yield : 24.4%).
  • aqueous phase was extracted with ethyl acetate (80 mL ⁇ 2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Boston Phlex C18 150*30mm, 5 ⁇ m, elution system: water (10mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, gradient elution over 20 minutes, flow rate: 30 mL/min) to give the title product 13b (5.60 g, yield : 76.1%).
  • Cyclohexyl isocyanate 17a (8.97 g, 71.66 mmol, Shanghai Titan Technology Co., Ltd.) and compound 1b (10.00 g, 68.22 mmol) were dissolved in N,N-dimethylacetamide (50 mL), and the reaction was cooled to -10 °C , 1,8-diazabicycloundec-7-ene (17.18 g, 68.22 mmol) was added dropwise, and the dropping was completed after 5 minutes, and the reaction was continued to stir for 30 minutes in an ice bath.
  • Test Example 1 Inhibitory effect of the compounds of the present disclosure on the activity of myosin ATPase.
  • Cardiac actin (Cytoskeleton, AD99)
  • Constant temperature incubator (Shanghai Boxun, SPX-100B-Z)
  • Cardiac actin 1.61 ⁇ M, myosin motor protein S1 fragment 0.07 ⁇ M were mixed with different concentrations of small molecule compounds (the initial concentration of 100 ⁇ M, 9 concentrations of 3-fold serial dilution), and incubated at 37°C for 1 hour. Then ATP 120 ⁇ M was added and incubated at 37°C for 2 hours. Finally, the detection solution (70 ⁇ L/well) in the CytoPhos TM Phosphate Detection Biological Kit was added to each well, and incubated at room temperature for 10 min.
  • Example number IC50 ( ⁇ M) 1 2.41 2 2.55 3 5.11 4 1.66 5 1.98 6 0.45 7 1.33 8 3.75 9 0.68 10 0.62 11 1.39 12 0.81 13 1.00 14 0.35 15 1.13 16 1.06
  • Test Example 2 Pharmacokinetic evaluation of the disclosed compounds in Beagle dogs
  • Beagle dogs Beagle dogs
  • the LC/MS/MS method was used to determine the drug concentrations in plasma at different times after the Beagle dogs were given the test compounds by gavage and intravenous injection.
  • the pharmacokinetic behavior of the disclosed compounds in Beagle dogs was studied, and their pharmacokinetic characteristics were evaluated.
  • Embodiment 16 compound, compound MYK-461 ( Example 1) of WO2014205223A1.
  • Example 16 Pharmacokinetics of the compound in Beagle dogs 8 Beagle dogs, half male and half male, were equally divided into 2 groups with 4 dogs in each group, provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.
  • Example 16 A certain amount of the compound of Example 16 was weighed, and 5% DMSO, 30% PG, 30% PEG400 and 35% normal saline were added to prepare a clear solution.
  • Beagle dogs were fasted overnight and were administered by intragastric administration and intravenous injection, respectively.
  • 1.0 mL of blood was collected from the jugular vein or forelimb vein in the intragastric administration group. Put it in an EDTA-K2 anticoagulation test tube, centrifuge at 10,000 rpm for 5 min (4 °C), separate the plasma within 1 h, and store it at -80 °C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. Food was taken 3 hours after administration.
  • Blood was collected from the intravenous injection group before administration and at 5min, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12.0h, and 24.0h after administration, and the treatment was the same as the intragastric administration group.
  • Determination of the content of the test compound in the plasma of Beagle dogs after oral administration and intravenous injection of drugs with different concentrations take 30 ⁇ L of Beagle dog plasma at each time after administration, add the internal standard solution (internal standard of the compound of Example 16: warfarin Lin 100ng/mL; the internal standard of compound MYK-461: tolbutamide 100ng/mL), methanol 300 ⁇ L, vortex for 1 minute, centrifuge for 7 minutes (centrifugal force 18000g), transfer 200 ⁇ L of supernatant to a 96-well plate, Plasma samples were taken from the supernatant 1 ⁇ L for LC/MS/MS analysis.
  • the compound of Example 16 of the present disclosure has good pharmacokinetic absorption in Beagle dogs.
  • the T 1/2 of the compound of Example 16 of the present disclosure is significantly shortened.
  • the compound MYK-461 has a relatively long T 1/2 , and the clinical accumulation is relatively serious.
  • the clinical administration needs to be adjusted continuously, which increases the risk of drug use.
  • Shortening T 1/2 can reduce or avoid clinical drug accumulation in the body, which is beneficial to the determination of the patient's drug dosage and avoids the risk caused by accumulation.
  • the compound of Example 16 of the present disclosure has obvious pharmacokinetic advantages over the compound MYK-461.
  • Test Example 3 Pharmacokinetic evaluation of the disclosed compounds in cynomolgus monkeys
  • the LC/MS/MS method was used to determine the drug concentrations in the plasma of cynomolgus monkeys at different times after intragastric administration and intravenous injection of the test compounds.
  • the pharmacokinetic behavior of the disclosed compounds in cynomolgus monkeys was studied, and their pharmacokinetic characteristics were evaluated.
  • Example 16 compound, compound MYK-461.
  • Example 16 Pharmacokinetics of the compound in cynomolgus monkeys: 8 cynomolgus monkeys, half male and half male, were equally divided into 2 groups with 4 animals in each group, provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.
  • Example 16 A certain amount of the compound of Example 16 was weighed, and 5% DMSO, 30% PG, 30% PEG400 and 35% normal saline were added to prepare a clear solution.
  • the cynomolgus monkeys were fasted overnight and were administered by intragastric administration and intravenous injection, respectively, at a dose of 2 mg/kg, 0.5 mg/kg, and an administration volume of 5 mL/kg and 2 mL/kg, respectively.
  • 1.0 mL of blood was collected from the forelimb vein before administration and placed in an EDTA-K2 anticoagulation test tube at 10000 rpm. Centrifuge for 5 min (4°C), separate plasma within 1 h, and store at -80°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. 3h after administration, food was taken and water was free to drink.
  • Blood was collected from the intravenous injection group before administration and at 5min, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12.0h, and 24.0h after administration, and the treatment was the same as the intragastric administration group.
  • Determination of the content of the tested compound in the plasma of cynomolgus monkeys after oral administration and intravenous injection of drugs of different concentrations take 20 ⁇ L of cynomolgus monkey plasma at each time after administration, add the internal standard solution (the internal standard of the compound of Example 16: Verapamil 10ng/mL; compound MYK-461 internal standard: camptothecin 100ng/mL), methanol 400 ⁇ L, vortex for 1 minute, centrifuge for 7 minutes (centrifugal force 18000g), transfer 200 ⁇ L of supernatant to a 96-well plate , 2 ⁇ L of the supernatant from the plasma samples were taken for LC/MS/MS analysis.
  • the internal standard solution the internal standard of the compound of Example 16: Verapamil 10ng/mL; compound MYK-461 internal standard: camptothecin 100ng/mL
  • methanol 400 ⁇ L vortex for 1 minute
  • centrifuge for 7 minutes centrifugal force 18000
  • the compound of Example 16 of the present disclosure has good pharmacokinetic absorption in cynomolgus monkeys.
  • the T 1/2 of the compound of Example 16 of the present disclosure is significantly shortened.
  • the compound MYK-461 has a relatively long T 1/2 , and the clinical accumulation is relatively serious.
  • the clinical administration needs to be adjusted continuously, which increases the risk of drug use.
  • Shortening T 1/2 can reduce or avoid clinical drug accumulation in the body, which is beneficial to the determination of the patient's drug dosage and avoids the risk caused by accumulation.
  • the compound of Example 16 of the present disclosure has obvious pharmacokinetic advantages over the compound MYK-461.
  • Test Example 4 Toxicokinetic evaluation of the compounds of the present disclosure to SD rats after repeated administration for 14 days
  • LC/MS/MS method was used to determine the concentration of drug prototype in plasma and administration solution at different times after SD rats were given the test compound by gavage. To study the toxicokinetic behavior of the disclosed compounds in SD rats, and evaluate their toxicokinetic characteristics.
  • Example 16 compound, compound MYK-461.
  • Example 16 A certain amount of the compound of Example 16 was weighed, and 15% PEG400 and 85% (10% TPGS+1% HPMC K100LV) were added to prepare a light yellow homogeneous suspension solution.
  • the doses of the compound of Example 16 were 5 mg/kg, 15 mg/kg, and 30 mg/kg, respectively, and the administration volume was 10 mL/kg, respectively.
  • the doses of compound MYK-461 were 0.5 mg/kg, 1.5 mg/kg, and 3 mg/kg, respectively, and the doses were all 10 mL/kg.
  • 0.2mL of blood was collected from the orbit at 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, and 24.0h after administration, and on the 7th and 14th days before administration and 0.5h, 1.0h after administration , 2.0h, 4.0h, 8.0h, and 24.0h, 0.2mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000rpm for 1min (4°C), and the plasma was separated within 1h, and stored at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.
  • Determination of the content of the test compound in the plasma of SD rats after oral administration of drugs of different concentrations take 20 ⁇ L of SD rat plasma at each time after administration, add 50 ⁇ L of internal standard solution (internal standard of the compound in Example 16: Vera Pamir 100ng/mL; internal standard of compound MYK-461: camptothecin 100ng/mL), acetonitrile 200 ⁇ L, vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 1 ⁇ L of the supernatant of the plasma sample was taken for LC /MS/MS analysis.
  • internal standard solution internal standard of the compound in Example 16: Vera Pamir 100ng/mL
  • internal standard of compound MYK-461 camptothecin 100ng/mL
  • acetonitrile 200 ⁇ L Vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm)
  • 1 ⁇ L of the supernatant of the plasma sample was taken for LC /MS/MS analysis.
  • Example 16 of the present disclosure does not accumulate significantly in SD rats after repeated administration of the compound of Example 16 to SD rats for 14 days, while the compound MYK-461 accumulates seriously in SD rats, increasing the risk of drug use. Obviously, the compound of Example 16 of the present disclosure has obvious toxicokinetic advantages over the compound MYK-461.
  • Test Example 5 Identification of Reactive Metabolites of Compounds of the Disclosure in Human Liver Microsomes
  • Example 16 compound, compound MYK-461.
  • test compound solution Take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve, and mix well to obtain a stock solution with a concentration of 30 mM.
  • the stock solution at a concentration of 10 mM was diluted 10-fold with 50% acetonitrile/water (v/v) to give working solution 1 at a concentration of 3.0 mM.
  • Working solution 1 with a concentration of 3.0 mM was diluted 10-fold with PBS to obtain working solution 2 at 300 ⁇ M, which was stored at 4°C before use.
  • phosphate buffer solution Preparation of phosphate buffer solution: Weigh appropriate amounts of K 2 HPO 4 and KH 2 PO 4 respectively, dissolve them in 4L of pure water to prepare a buffer solution with a concentration of 100mM, and then adjust the pH to 7.4 with phosphoric acid or sodium hydroxide .
  • liver microsome solution Take an appropriate amount of liver microsome stock solution (concentration of 20 mg/mL) of each species, and dilute it to 1.43 mg/mL microsomal solution with phosphate buffer solution (pH 7.4) of concentration 100 mM.
  • NADPH cofactor solution Weigh an appropriate amount of NADPH and magnesium chloride and dissolve in an appropriate amount of phosphate buffer (pH value is 7.4) with a concentration of 100 mM, so that the concentrations of NADPH and magnesium chloride are 10 mM and 30 mM, respectively, for use.
  • GSH glutathione
  • the incubation system is as follows:
  • Liver microsomal protein concentration 1mg/mL species people
  • Test compound concentration 30 ⁇ M NADPH concentration 1.0mM MgCl concentration 3.0mM GSH concentration 5mM Incubation medium 100mM PBS System pH 7.4 Incubation temperature 37°C Incubation time 60min Incubation volume 200 ⁇ L positive control Diclofenac (10 ⁇ M)

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Abstract

提供一种三嗪二酮类衍生物、其制备方法及其在医药上的应用。具体而言，提供一种通式(I)所示的三嗪二酮类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是在制备肌球蛋白(Myosin)抑制剂中的用途和在制备用于治疗肥厚型心肌病(HCM)或具有与HCM相关的病理生理学特征的心脏病的药物中的用途。

Description

三嗪二酮类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种三嗪二酮类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的三嗪二酮类衍生物、其制备方法及含有该衍生物的药物组合物，以及其在制备肌球蛋白(Myosin)抑制剂中的用途和在制备用于治疗肥厚型心肌病(HCM)或具有与HCM相关的病理生理学特征的心脏病的药物中的用途。
背景技术
肥厚型心肌病(HCM)是一种与基因突变相关的显性遗传性心肌疾病。全球发病率约为0.2％，是导致35岁以下年轻人猝死的最重要原因(C.Vaughan Tuohy,et al.,European Journal of Heart Failure,22,2020,228-240)。临床上表现出来的特征为左室壁呈不对称性肥厚，常侵及室间隔，心室内腔变小，左心室血液充盈受阻，心室舒张期顺应性下降。根据左心室流出道有无梗阻分为梗阻性及非梗阻性肥厚型心肌病。现临床上对于肥厚型心肌病的治疗多采用β-阻断剂和钙离子通道阻断剂来降低心脏收缩，缓解症状。但这些治疗都是治标不治本。HCM进展到晚期只能进行心脏移植(R adhakrishnan Ramaraj,Cardiology in Review,16(4),2008,172-180)。因而找到一种针对HCM发病根源的治疗方法非常迫切。
现有研究发现70％的HCM病人都是由于肌节蛋白基因突变导致的。其中5-7％的病人中发现多个位点突变。现已确定约70多个致病突变，但这些突变大多都具有家族特异性，仅有少数几个热点被确定，例如MYH7 R403Q和R453C突变(Norbert Frey,et al.,Nature Reviews Cardiology,9,2011,91-100；M.Sabater-Molina,et al.,Clinical Genetics,93,2018,3-14)。针对基因突变致病机率的研究发现MYH7基因突变病人约占30％。相比较于其他肌节蛋白基因，MYH7会导致疾病早发以及更严重的心肌肥大。肌球蛋白是肌原纤维粗肌丝的组成单位，在肌肉运动中起重要作用。其分子形状如豆芽状，由两条重链和多条轻链构成。肌球蛋白头部与肌动蛋白结合形成横桥，使肌球蛋白的ATP酶活性大大提高，催化ATP水解反应，产生能量促使横桥滑动，进行肌肉收缩。研究结果表明MYH7基因突变会导致肌球蛋白ATP酶活性升高，肌球蛋白超松弛态(super-relaxed state，SRX)比例降低，肌球蛋白和肌动蛋白间的横桥增加，导致心脏收缩功能异常(Eric M.Green,et al.,Science,351(6273),2016,617-621；Ruth F.Sommese,et al.,Proceedings of the National Academy Sciences,110(31),2013,12607-12612)。因此肌球蛋白是治疗肥厚型心肌病的重要靶点。
现已公开肌球蛋白抑制剂的专利申请包括WO2014205223A1、 WO2014205234A1、WO2019028360A1、WO2020092208A1和CN110698415A等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2021131642-appb-000001
其中：
环A选自环烷基、杂环基、芳基和杂芳基；
R 1选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、C(O)R 6、C(O)OR 7、S(O) tR 8、S(O) tNR 9R 10、C(O)NR 9R 10、NR 9R 10和
Figure PCTCN2021131642-appb-000002
各个R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、C(O)R 6、C(O)OR 7、S(O) tR 8、S(O) tNR 9R 10、C(O)NR 9R 10和NR 9R 10；
或者R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成环烷基或杂环基；其中，所述的环烷基或杂环基任选地被选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；
L 2选自共价键、(CH 2) r、C(O)、NR a、氧原子和硫原子；
R a选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
环C选自环烷基、杂环基、芳基和杂芳基；
各个R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 3a选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷氧基、卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；
R 3b为氢原子；
R 0为烷基或
Figure PCTCN2021131642-appb-000003
其中，所述的烷基任选被选自卤素、烷氧基、卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；
L 1为共价键或(CH 2) r；
环B选自环烷基、杂环基、芳基和杂芳基；
各个R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氧代、氰基、硝基、羟基、羟烷基、C(O)R 6、C(O)OR 7、S(O) tR 8、S(O) tNR 9R 10、C(O)NR 9R 10、环烷基、-(CH 2) r-环烷基、杂环基、-(CH 2) r-杂环基、芳基、-(CH 2) r-芳基、杂芳基和-(CH 2) r-杂芳基；
R 6在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基中的一个或多个取代基所取代；
R 7在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 8在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、羟基、环烷基、杂环基、芳基和杂芳基；
R 9和R 10在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、-(CH 2) r-环烷基、杂环基、-(CH 2) r-杂环基、芳基、-(CH 2) r-芳基、杂芳基和-(CH 2) r-杂芳基；或者R 9和R 10与相连的氮原子一起形成杂环基，所述的杂环基任选地被选自卤素、烷基、氧代、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
p为0、1、2、3、4、5或6；
r为0、1、2、3、4、5或6；
m为0、1、2、3或4；
s为0、1、2、3、4、5或6；并且
t为0、1或2。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(I-1)所示的化合物或其可药用的盐：
Figure PCTCN2021131642-appb-000004
其中：
环A、R 0、R 1、R 2、R 3a、R 3b和m如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中环A选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；优选地，环A为苯基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
Figure PCTCN2021131642-appb-000005
其中：
R 0、R 1、R 2、R 3a、R 3b和m如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)所示的化合物或其可药用的盐，其为通式(II-1)所示的化合物或其可药用的盐：
Figure PCTCN2021131642-appb-000006
其中：
R 0、R 1、R 2、R 3a、R 3b和m如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所 示的化合物或其可药用的盐，其中R 0为C 1-6烷基或
Figure PCTCN2021131642-appb-000007
其中，所述的C 1-6烷基任选地被选自卤素、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、氨基和羟基中的一个或多个取代基所取代；L 1为共价键或(CH 2) r；环B选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 4相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氧代、氰基、羟基和C 1-6羟烷基；r为0、1、2、3、4、5或6；s为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0选自C 1-6烷基、3至8元环烷基和3至12元杂环基；优选地，R 0选自C 1-6烷基、3至6元环烷基和3至6元杂环基；进一步优选地，R 0选自异丙基、四氢吡喃基和环己基；更优选地，R 0为异丙基或四氢吡喃基；最优选地，R 0为四氢吡喃基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0为C 1-6烷基；优选地，R 0为异丙基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000008
优选地，R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000009
其中环C、L 2、R 5和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000010
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000011
优选地，R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000012
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自 氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000013
优选地，R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000014
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000015
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；优选地，各个R 2相同或不同，且各自独立地为氢原子或卤素；更优选地，各个R 2相同或不同，且各自独立地为卤素；最优选地，R 2为氟原子。
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐，其中R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至8元环烷基或3至12元杂环基；优选地，R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至6元环烷基或3至6元杂环基；更优选地，R 1和相邻的一个R 2与环A稠合形成环丁基、四氢呋喃基、环戊基和环己基。
在本公开一些实施方案中，所述的通式(I)或通式(I-1)所示的化合物或其可药用的盐，其中R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至8元环烷基或3至12元杂环基；优选地，R 1和相邻的一个R 2与环A稠合形成环戊基。
在本公开一些实施方案中，所述的通式(II)或通式(II-1)所示的化合物或其可药用的盐，其中R 1和相邻的一个R 2，或者两个相邻的R 2，与苯基稠合形成3至8元环烷基或3至12元杂环基；优选地，R 1和相邻的一个R 2，或者两个相邻的R 2，与苯基稠合形成3至6元环烷基或3至6元杂环基；更优选地，R 1和相邻的一个R 2与苯基稠合形成环丁基、四氢呋喃基、环戊基和环己基。
在本公开一些实施方案中，所述的通式(II)或通式(II-1)所示的化合物或其可药用的盐，其中R 1和相邻的一个R 2，或者两个相邻的R 2，与苯基稠合形成3至8 元环烷基或3至12元杂环基；优选地，R 1和相邻的一个R 2与苯基稠合形成环戊基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000016
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；或者R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至8元环烷基或3至12元杂环基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000017
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1或2；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；或者R 1和相邻的一个R 2与环A稠合形成3至6元环烷基或3至6元杂环基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000018
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与环A稠合形成环丁基、四氢呋喃基、环戊基和环己基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000019
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与环A稠合形成环丁基、四氢呋喃基、环戊基和环己基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000020
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与环A稠合形成环戊基。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000021
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；或者R 1和相邻的一个R 2，或者两个相邻的R 2，与苯基稠合形成3至8元环烷基或3至12元杂环基。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000022
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与苯基稠合形成3至6元环烷基或3至6元杂环基。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000023
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与苯基稠合形成环丁基、四氢呋喃基、环戊基和环己基。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000024
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自 氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与苯基稠合形成环戊基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；优选地，R 3a为C 1-6烷基；更优选地，R 3a为甲基。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)、通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中m为0、1或2；优选地，m为0或1。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000025
为
Figure PCTCN2021131642-appb-000026
其中，环M为3至8元环烷基或3至12元杂环基，R f选自氢原子、卤素和C 1-6烷基，n为0或1，R 1和R 2如通式(I)或通式(I-1)中所定义；优选地，
Figure PCTCN2021131642-appb-000027
为
Figure PCTCN2021131642-appb-000028
Figure PCTCN2021131642-appb-000029
其中，环M为3至6元环烷基或3至6元杂环基，R 1和R 2如通式(I)或通式(I-1)中所定义；更优选地，
Figure PCTCN2021131642-appb-000030
选自
Figure PCTCN2021131642-appb-000031
Figure PCTCN2021131642-appb-000032
最优选地，
Figure PCTCN2021131642-appb-000033
为
Figure PCTCN2021131642-appb-000034
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用 的盐，其中
Figure PCTCN2021131642-appb-000035
选自
Figure PCTCN2021131642-appb-000036
Figure PCTCN2021131642-appb-000037
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000038
为
Figure PCTCN2021131642-appb-000039
其中，环M为3至8元环烷基或3至12元杂环基，R f选自氢原子、卤素和C 1-6烷基，n为0或1，R 1和R 2如通式(II)或通式(II-1)中所定义；优选地，
Figure PCTCN2021131642-appb-000040
为
Figure PCTCN2021131642-appb-000041
Figure PCTCN2021131642-appb-000042
其中，环M为3至6元环烷基或3至6元杂环基，R 1和R 2如通式(II)或通式(II-1)中所定义；更优选地，
Figure PCTCN2021131642-appb-000043
选自
Figure PCTCN2021131642-appb-000044
Figure PCTCN2021131642-appb-000045
Figure PCTCN2021131642-appb-000046
最优选地，
Figure PCTCN2021131642-appb-000047
为
Figure PCTCN2021131642-appb-000048
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000049
选自
Figure PCTCN2021131642-appb-000050
Figure PCTCN2021131642-appb-000051
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中环A为苯基；R 0选自C 1-6烷基、3至8元环烷基和3至12元杂环基；R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000052
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；或者R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至8元环烷基或3至12元杂环基；R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；R 3b为氢原子；m为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中环A为苯基；R 0为C 1-6烷基；R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000053
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；或者R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至8元环烷基或3至12元杂环基；R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；R 3b为氢原子；m为0、1或2。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0选自C 1-6烷基、3至6元环烷基和3至6元杂环基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000054
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤 素；或者R 1和相邻的一个R 2与苯基稠合形成3至6元环烷基或3至6元杂环基；R 3a为甲基；R 3b为氢原子；m为0或1。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0为C 1-6烷基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000055
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与苯基稠合形成3至6元环烷基或3至6元杂环基；R 3a为甲基；R 3b为氢原子；m为0或1。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0为C 1-6烷基；R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000056
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与苯基稠合形成环丁基、四氢呋喃基、环戊基和环己基；R 3a为甲基；R 3b为氢原子；m为0或1。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000057
为
Figure PCTCN2021131642-appb-000058
其中，环M为3至6元环烷基或3至6元杂环基；R 0选自C 1-6烷基、3至8元环烷基和3至12元杂环基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000059
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；R 3b为氢原子；m为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用 的盐，其中
Figure PCTCN2021131642-appb-000060
为
Figure PCTCN2021131642-appb-000061
其中，环M为3至6元环烷基或3至6元杂环基；R 0为C 1-6烷基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000062
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；R 3b为氢原子；m为0、1或2。
在本公开一些实施方案中，所述的通式(I)、通式(I-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000063
为
Figure PCTCN2021131642-appb-000064
其中，环M为3至6元环烷基或3至6元杂环基；R 0为C 1-6烷基；R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000065
L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；各个R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；R 3b为氢原子；m为0、1或2。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000066
为
Figure PCTCN2021131642-appb-000067
其中，环M为3至6元环烷基或3至6元杂环基；R 0选自C 1-6烷基、3至6元环烷基和3至6元杂环基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000068
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6 卤代烷氧基和C 1-6羟烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；R 3a为甲基；R 3b为氢原子；m为0或1。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000069
为
Figure PCTCN2021131642-appb-000070
其中，环M为3至6元环烷基或3至6元杂环基；R 0为C 1-6烷基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000071
L 2为共价键或氧原子；环C选自3至6元环烷基、3至6元杂环基和5或6元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；R 3a为甲基；R 3b为氢原子；m为0或1。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2021131642-appb-000072
为
Figure PCTCN2021131642-appb-000073
其中，环M为3至6元环烷基或3至6元杂环基；R 0为C 1-6烷基；R 1为C 1-6卤代烷氧基或
Figure PCTCN2021131642-appb-000074
L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；R 3a为甲基；R 3b为氢原子；m为0或1。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0选自异丙基、四氢吡喃基和环己基；
Figure PCTCN2021131642-appb-000075
为
Figure PCTCN2021131642-appb-000076
Figure PCTCN2021131642-appb-000077
其中，环M为3至6元环烷基或3至6元杂环基；R 1选自C 1-6烷基、C 1-6卤代烷氧基和
Figure PCTCN2021131642-appb-000078
各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与苯基稠合形成环丁基、四氢呋喃基、环戊基和环己基；R 3a为甲基；R 3b为氢原子；L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤 素和C 1-6烷基；p为0、1或2。
在本公开一些实施方案中，所述的通式(II)、通式(II-1)所示的化合物或其可药用的盐，其中R 0为四氢吡喃基；
Figure PCTCN2021131642-appb-000079
为
Figure PCTCN2021131642-appb-000080
R 1为C 1-6烷基；R 2为氢原子或卤素；R 3a为甲基；R 3b为氢原子。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2021131642-appb-000081
Figure PCTCN2021131642-appb-000082
Figure PCTCN2021131642-appb-000083
Figure PCTCN2021131642-appb-000084
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021131642-appb-000085
通式(IA)所示的化合物或其盐(优选为盐酸盐)与通式(V)所示的化合物发生亲核取代反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选为吡唑基；
环A、R 0、R 1、R 2、R 3a、R 3b和m如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(I-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021131642-appb-000086
通式(IA-1)所示的化合物或其盐(优选为盐酸盐)与通式(V)所示的化合物发生亲核取代反应，得到通式(I-1)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选吡唑基；
环A、R 0、R 1、R 2、R 3a、R 3b和m如通式(I-1)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021131642-appb-000087
通式(IIA)所示的化合物或其盐(优选为盐酸盐)与通式(V)所示的化合物发生亲核取代反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选为吡唑基；
R 0、R 1、R 2、R 3a、R 3b和m如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(II-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021131642-appb-000088
通式(IIA-1)所示的化合物或其可盐(优选为盐酸盐)与通式(V)所示的化合物发生亲核取代反应，得到通式(II-1)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选为吡唑基；
R 0、R 1、R 2、R 3a、R 3b和m如通式(II-1)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物在制备肌球蛋白(Myosin)抑制剂中的用途。
本公开进一步涉及通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐或包括其的药物组合物在制备用于治疗疾病或病症的药物中的用途，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)(如非梗阻性肥厚型心肌病(nHCM)和梗阻性肥厚型心肌病(oHCM))、正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
本公开进一步涉及通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐或包括其的药物组合物在制备用于治疗由Myosin介导的疾病或病症的药物中的用途，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)、 正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
本公开进一步涉及一种抑制肌球蛋白(Myosin)的方法，其包括给予所需患者治疗有效量的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)、正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
本公开进一步涉及一种治疗由Myosin介导的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)、正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作肌球蛋白(Myosin) 抑制剂。
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗疾病或病症，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)、正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
本公开进一步涉及一种通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗由Myosin介导的疾病或病症，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)、正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物可改变HCM和其它疾病的自然病史，而不仅仅是缓解症状。对HCM患者给予临床益处的机制可延用于具有其它形式的心脏疾病的患者，所述其它形式的心脏疾病共同具有相似的病理生理学，且具有或不具有显著的遗传因素的影响。例如，通过改善在舒张期内的心室舒张而进行的HCM的有效治疗，也可有效用于特征在于舒张期功能障碍的更宽范围的群体。
本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物可特定地靶标病症的根源或作用于其它下游途径。因此，本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物可对患有射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛或限制型心肌病的患者给予益处。
本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物也可促进由于容量或压力过度负荷造成的左 心室肥大的有益心室重构；例如慢性二尖瓣返流、慢性主动脉瓣狭窄或慢性系统性高血压；所述化合物或其可药用的盐联合旨在纠正或减轻容量或压力过度负荷的主要原因的疗法(瓣修复/替换、有效的抗高血压疗法)。通过降低左心室充盈压，化合物可降低肺水肿和呼吸衰竭的风险。降低或消除功能性二尖瓣返流和/或降低左心房压力可降低突发性或持久性心房纤颤的风险，且其降低了动脉血栓栓塞性并发症包括但不限于脑动脉栓塞性中风的伴随性风险。降低或消除动态和/或静态左心室流出道阻塞可减少需要间隔消融治疗(手术或经皮)的可能性及其短期和长期并发症的伴随性风险。
本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物可降低与HCM相关的慢性局部缺血状态的严重性，且由此降低具有可植入的复律器-除颤器(频繁和/或重复的ICD放电)的患者中的心脏性猝死(SCD)或其等同疾病的风险和/或降低对于可能有毒的抗心律不齐药物的需求。
本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物在降低或消除对于并行药物(具有其伴随的潜在毒性、药物-药物相互作用和/或副作用)的需求方面是有价值的。
本公开的通式(I)、通式(I-1)、通式(II)、通式(II-1)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物可降低间质性心肌纤维化和/或减缓左心室肥大的进展，阻止或逆转左心室肥大。
化合物MYK-461(
Figure PCTCN2021131642-appb-000089
WO2014205223A1的实施例1)由于T 1/2比较长，在临床上蓄积比较严重，临床给药需要不断地调整，增加了用药风险，而本公开实施例16化合物的T 1/2有明显的缩短。此外，本公开的实施例16化合物对大鼠灌胃重复给药14天后在大鼠体内的蓄积不明显，而化合物MYK-461在大鼠体内蓄积严重。在人肝微粒体中反应性代谢产物鉴定实验中，未检测到与本公开实施例16化合物相关的谷胱甘肽(GSH)结合物，但检测到与化合物MYK-461相关的GSH结合物。可见，本公开的实施例16化合物较化合物MYK-461具有明显的药代动力学优势和毒代动力学优势，表现出更好的安全性。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成持续释放剂型，例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓 剂、锭剂或糖浆。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或支链脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C 1-12烷基)，更优选具有1至6个碳原子的烷基(即C 1-6烷基)。烷基的非限制性实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。最优选具有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、 氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C 1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C 1-6亚烷基)。亚烷基的非限制性实例包括但不限于：亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，优选具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的烯基(即C 2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基(即C 2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C 2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基，环烷基环具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即3至20元环烷基)，优选具有3至12个碳原子(即3至12元环烷基)，优选具有3至8个碳原子(即3至8元环烷基)，更优选具有3至6个碳原子(即3至6元环烷基)。单环环烷基的非限制性实例包括：环丙基、 环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基或多螺环烷基(如双螺环烷基)，优选单螺环烷基和双螺环烷基。更优选3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元、6元/4元或6元/5元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021131642-appb-000090
其连接点可在任意位置。
术语“稠环烷基”指5至20元，环之间共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环稠环烷基，优选双环或三环，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021131642-appb-000091
，其连接点可在任意位置。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环桥环烷基，优选双环、三环或四环桥环烷基，更优选双环或三环桥环烷基。桥环烷基的非限制性实例包括：
Figure PCTCN2021131642-appb-000092
其连接点可在任意位置。
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2021131642-appb-000093
等；优选
Figure PCTCN2021131642-appb-000094
Figure PCTCN2021131642-appb-000095
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其具有3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选具有3至12个(例如3、4、5、6、7、8、9、10、11或12个)环原子，其中1-4个(例如1、2、3和4个)是杂原子(即3至12元杂环基)；更优选具有3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)(即3至8元杂环基)；更优选具有3至6个环原子，其中1-3个是杂原子(即3至6元杂环基)；最优选包含5或6个环原子，其中1-3个是杂原子(即5或6元杂环基)。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。多环杂环基包括螺环杂环基、稠环杂环基和桥环杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基或多螺杂环基(如双螺杂环基)，优选单螺杂环基和双螺杂环基。更优选3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021131642-appb-000096
等。
术语“稠杂环基”指5至20元，环之间共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环稠杂环基，优选双环或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4 元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021131642-appb-000097
Figure PCTCN2021131642-appb-000098
等。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环桥杂环基，优选双环、三环或四环桥杂环基，更优选双环或三环桥杂环基。桥杂环基的非限制性实例包括：
Figure PCTCN2021131642-appb-000099
等。
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021131642-appb-000100
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021131642-appb-000101
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指包含1至4个杂原子(例如1、2、3和4个)、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选5元或6元杂芳基，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、吡啶酮基、N-烷基吡啶酮(如
Figure PCTCN2021131642-appb-000102
等)、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基和四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021131642-appb-000103
Figure PCTCN2021131642-appb-000104
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“亚环烷基”、“亚杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选 地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，通常用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅烷基(TBS)、叔丁基二苯基硅基、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本公开所述化合物的化学结构中，键
Figure PCTCN2021131642-appb-000105
表示未指定构型，即如果化学结 构中存在手性异构体，键
Figure PCTCN2021131642-appb-000106
可以为
Figure PCTCN2021131642-appb-000107
或者同时包含
Figure PCTCN2021131642-appb-000108
Figure PCTCN2021131642-appb-000109
两种构型。
本公开所述化合物的化学结构中，键
Figure PCTCN2021131642-appb-000110
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2021131642-appb-000111
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。
本公开还包括各种氘化形式的化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取 代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1至6个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021131642-appb-000112
通式(IA)所示的化合物或其盐(优选盐酸盐)与通式(V)所示的化合物直接发生亲核取代反应或在碱的存在下发生亲核取代反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选为吡唑基；
环A、R 0、R 1、R 2、R 3a、R 3b和m如通式(I)中所定义。
方案二
本公开通式(I-1)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2021131642-appb-000113
通式(IA-1)所示的化合物或其盐(优选盐酸盐)与通式(V)所示的化合物直接发生亲核取代反应或在碱的存在下发生亲核取代反应，得到通式(I-1)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选吡唑基；
环A、R 0、R 1、R 2、R 3a、R 3b和m如通式(I-1)中所定义。
方案三
本公开通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2021131642-appb-000114
通式(IIA)所示的化合物或其盐(优选盐酸盐)与通式(V)所示的化合物直接发生亲核取代反应或在碱的存在下发生亲核取代反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选为吡唑基；
R 0、R 1、R 2、R 3a、R 3b和m如通式(II)中所定义。
方案四
本公开通式(II-1)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2021131642-appb-000115
通式(IIA-1)所示的化合物或其盐(优选盐酸盐)与通式(V)所示的化合物直接发生亲核取代反应或在碱的存在下发生亲核取代反应，得到通式(II-1)所示的化合物或其可药用的盐；
其中：
R w为离去基团，优选为吡唑基；
R 0、R 1、R 2、R 3a、R 3b和m如通式(II-1)中所定义。
上述方案中，所述的碱包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、乙酸钠、乙酸钾、乙醇钠、叔丁醇钠和叔丁醇钾，优选三乙胺和N,N-二异丙基乙胺；所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾。
上述反应优选在溶剂中进行，所用的溶剂包括但不限于：N-甲基吡咯烷酮、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
上述亲核取代反应为常规反应，反应温度为100-160℃，优选为120℃。
上述亲核取代反应为常规反应，反应时间为10-20小时；优选为16小时。
上述亲核取代反应也可以在微波中进行，微波反应的反应温度为100-160℃，优选为140℃。
上述亲核取代反应也可以在微波中进行，微波反应的反应时间为0.5-4小时；优选为2小时。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(上海)有限公司(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：正己烷/乙酸乙酯体系，B：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
6-(((S)-1-(2-氟-5-(((S)-四氢呋喃-3-基)氧基)苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮1
Figure PCTCN2021131642-appb-000116
第一步
3-异丙基-6-(1H-吡唑-1-基)-1,3,5-三嗪-2,4(1H,3H)-二酮1c
将2-异氰氧基丙烷1a(4.06g，47.71mmol，上海泰坦科技股份有限公司)和1H-吡唑-1-甲脒盐酸盐1b(6.66g，45.44mmol，上海毕得医药科技有限公司)溶于N,N-二甲基乙酰胺(35mL)，冷却到-10℃，滴加1,8-二氮杂二环十一碳-7-烯(12.00g，47.65mmol)，5分钟后滴毕，反应在冰浴下继续搅拌30分钟。冰浴下，加入N,N'-羰基二咪唑(9.80g，68.08mmol)，冷却到-5℃，滴加1,8-二氮杂二环十一碳-7-烯(17.14g，68.06mmol)，10分钟后滴毕，反应在冰浴下继续搅拌1小时。室温下，加入2N盐酸(132mL)，30分钟后滴毕。过滤，收集滤饼，真空干燥，得到标题产物1c(3.30g，产率：32.9％)。
MS m/z(ESI):222.0[M+1]。
第二步
(S)-2-氟-5-((四氢呋喃-3-基)氧基)苯甲醛1e
将4-氟-3-甲酰基苯基苯硼酸1d(10.00g，59.55mmol，瀚海化工有限公司)和(S)-四氢呋喃-3-醇(15.80g，179.33mmol，韶远化学科技(上海)有限公司)溶于二氯甲烷(100mL)，加入醋酸铜(22.00g，121.13mmol)，吡啶(10.00g，126.42mmol)和三乙胺(13.00g，128.71mmol)，室温搅拌24小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1e(1.00g，产率：8.0％)。
MS m/z(ESI):211.0[M+1]。
第三步
(R)-N-(2-氟-5-(((S)-四氢呋喃-3-基)氧基)苯甲亚基)-2-甲基丙烷-2-亚磺酰胺1f
将化合物1e(1.00g，4.76mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(580mg，4.78mmol，上海毕得医药科技有限公司)溶于二氯甲烷(20mL)，加入碳酸铯(1.90g，5.83mmol)，室温搅拌16小时。过滤，减压浓缩，得到标题产物1f粗品(1.40g，产率：93.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):313.9[M+1]。
第四步
(R)-N-((S)-1-(2-氟-5-(((S)-四氢呋喃-3-基)氧基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺1g
将化合物1f粗品(100mg，0.32mmol)溶于二氯甲烷中(5mL)，氮气置换三次。反应冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(0.22mL，0.66mmol，上海泰坦科技股份有限公司)。氮气保护下，反应在室温搅拌5小时。加入饱和氯化铵溶液(10mL)，分出有机相。水相用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1g(105mg，产率：99.9％)。
MS m/z(ESI):330.0[M+1]。
第五步
(S)-1-(2-氟-5-(((S)-四氢呋喃-3-基)氧基)苯基)乙-1-胺盐酸盐1h
将化合物1g(105mg，0.32mmol)溶于乙醇中(5mL)，冷却到0℃，滴加氯化亚砜(101mg，0.85mmol，上海沪试化工有限公司)。反应在室温搅拌1小时。减压浓缩，得到标题产物1h粗品(83mg，产率：99.5％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):208.9[M-16]。
第六步
6-(((S)-1-(2-氟-5-(((S)-四氢呋喃-3-基)氧基)苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮1
将化合物1c(70mg，0.32mmol)和化合物1h(83mg，0.32mmo)溶于N-甲基吡咯烷酮(8mL)，加入三乙胺(64mg，0.63mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物1(6mg，产率：5.0％)。
MS m/z(ESI):379.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.50(brs,1H),7.66(brs,1H),7.11(m,1H),6.92(m,1H),6.84(m,1H),5.22(m,1H),4.96(m,1H),4.80(m,1H),3.89-3.71(m,4H),2.19(m,1H),2.02-1.88(m,1H),1.39(d,3H),1.29(d,6H)。
实施例2
6-(((S)-1-(2-氟-5-(((R)-四氢呋喃-3-基)氧基)苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮2
Figure PCTCN2021131642-appb-000117
第一步
(R)-2-氟-5-((四氢呋喃-3-基)氧基)苯甲醛2a
将化合物1d(10g，59.5mmol)和(R)-四氢呋喃-3-醇(10g，113mmol，上海毕得医药科技有限公司)溶于二氯甲烷(100mL)，加入吡啶(10g，126mmol，adamas)，三乙胺(13g，129mmol，adamas)，无水醋酸铜(23g，127mmol，上海毕得医药科技有限公司)，反应搅拌24小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2a(1.9g，产率：15.2％)。
MS m/z(ESI):211.0[M+1]。
第二步
(R)-N-(2-氟-5-(((R)-四氢呋喃-3-基)氧基)苯甲亚基)-2-甲基丙烷-2-亚磺酰胺2b
将化合物2a(1.9g，9.04mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(1.1g，9.08mmol，adamas)溶于二氯甲烷(30mL)，加入碳酸铯(3.6g，11.4mmol)，搅拌反应16小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物2b粗品(2.8g，产率：98.8％)。
MS m/z(ESI):313.9[M+1]。
第三步
(R)-N-((S)-1-(2-氟-5-(((R)-四氢呋喃-3-基)氧基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺2c
将化合物2b粗品(300mg，0.96mmol)溶于二氯甲烷中(10mL)，氮气置换三次。反应冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(0.67mL，2.01mmol，上海泰坦科技股份有限公司)。氮气保护下，反应在室温搅拌5小时。加入饱和氯化铵溶液(10mL)，分出有机相。水相用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2c(315mg，产率：99.9％)。
MS m/z(ESI):330.0[M+1]。
第四步
(S)-1-(2-氟-5-(((R)-四氢呋喃-3-基)氧基)苯基)乙胺盐酸盐2d
将化合物2c(315mg，0.96mmol)溶于乙醇中(6mL)，冷却到0℃，滴加氯化亚砜(303mg，2.55mmol，上海沪试化工有限公司)。反应在室温搅拌1小时。减压浓缩，得到标题产物2d粗品(250mg，产率：99.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):208.9[M-16]。
第五步
6-(((S)-1-(2-氟-5-(((R)-四氢呋喃-3-基)氧基)苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮2
将化合物1c(164mg，0.74mmol)和化合物2d(250mg，0.96mmo)溶于N-甲基吡咯烷酮(8mL)，加入三乙胺(75mg，0.74mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸 氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物2(30mg，产率：10.7％)。
MS m/z(ESI):379.0[M+1]。
1H NMR(500MHz,DMSO-d 6):δ10.52(brs,1H),7.27(brs,1H),7.13(m,1H),6.92-6.83(m,2H),5.20(m,1H),4.97(m,1H),4.79(m,1H),3.88-3.73(m,4H),2.20(m,1H),1.95(m,1H),1.39(d,3H),1.29(d,6H)。
实施例3
3-异丙基-6-(((1S)-1-(3-((四氢呋喃-3-基)氧基)苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮3
Figure PCTCN2021131642-appb-000118
第一步
四氢呋喃-3-基甲磺酸酯3b
将四氢呋喃-3-醇3a(2.0g，22.7mmol，韶远化学科技(上海)有限公司)和三乙胺(3.4g，33.7mmol)溶于二氯甲烷(20mL)，0℃加入甲基磺酰氯(2.84g，24.9mmol，上海国药集团化学试剂有限公司)，室温反应24小时。加入水(100mL)，用二氯甲烷(20mL×2)萃取，合并有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3b(3.1g，产率：82.2％)。
1H NMR(500MHz,CDCl 3)δ5.34(m,1H),4.06-3.89(m,4H),3.06(s,3H),2.29-2.24(m,2H)。
第二步
3-((四氢呋喃-3-基)氧基)苯甲醛3c
将化合物3b(700mg，4.21mmol)和3-羟基苯甲醛(500mg，4.09mmol，韶远化学科技(上海)有限公司)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸钾(850mg，6.16mmol)，90℃反应16小时。加水稀释(50mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标 题产物3c(710mg，产率：90.2％)。
MS m/z(ESI):193.0[M+1]。
第三步
(R)-2-甲基-N-(3-((四氢呋喃-3-基)氧基)苯甲亚基)丙烷-2-亚磺酰胺3d
将化合物3c(710mg，3.69mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(450mg，3.71mmol)溶于二氯甲烷(10mL)，加入碳酸铯(1.5g，4.60mmol)，搅拌反应16小时。过滤，浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3d(1.08g，产率：99.0％)。
MS m/z(ESI):296.0[M+1]。
第四步
(R)-2-甲基-N-((1S)-1-(3-((四氢呋喃-3-基)氧基)苯基)乙基)丙烷-2-亚磺酰胺3e
将化合物3d(500mg，1.69mmol)溶于二氯甲烷(10mL)。氮气保护下，冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(1.2mL，3.6mmol)。反应升到室温搅拌16小时。0℃下，加饱和氯化铵水溶液(20mL)，分出有机相。水相用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物3e(490mg，产率：92.9％)。
MS m/z(ESI):312.1[M+1]。
第五步
(1S)-1-(3-((四氢呋喃-3-基)氧基)苯基)乙胺盐酸盐3f
将化合物3e(490mg，1.57mmol)溶于乙醇(5.0mL)，0℃下，加入氯化亚砜(220mg，1.85mmol)。室温搅拌1小时。反应液减压浓缩，得到标题产物3f粗品(390mg，102％)，粗品无需纯化直接用于下一步。
MS m/z(ESI):208.1[M+1]。
第六步
3-异丙基-6-(((1S)-1-(3-((四氢呋喃-3-基)氧基)苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮3
将化合物1c(150mg，0.68mmol)和化合物3f(211mg，0.87mmo)溶于N-甲基吡咯烷酮(6mL)，加入三乙胺(69mg，0.68mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物3(40mg，产率：16.4％)。
MS m/z(ESI):361.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.45(brs,1H),7.28-7.25(m,2H),6.92-6.88(m,2H),6.81(m,1H),5.02-4.98(m,2H),4.81(m,1H),3.90-3.74(m,4H),2.19(m,1H),1.92(m,1H),1.40(d,3H),1.29(d,6H)。
实施例4
(S)-3-异丙基-6-((1-(3-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮4
Figure PCTCN2021131642-appb-000119
第一步
3-((6-甲基吡啶-3-基)氧基)苯甲醛4b
将(3-甲酰基苯基)硼酸4a(800mg，5.34mmol，韶远化学科技(上海)有限公司)和6-甲基吡啶-3-酚(300mg，275mmol，上海毕得医药科技有限公司)溶于二氯甲烷(6.0mL)，加入三乙胺(560mg，5.54mmol)，吡啶(440mg，5.56mmol)和无水醋酸铜(1.0g,5.51mmol，上海毕得医药科技有限公司)，反应搅拌24小时。铺硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4b(410mg，产率：69.9％)。
MS m/z(ESI):214.0[M+1]。
第二步
(R)-2-甲基-N-(3-((6-甲基吡啶-3-基)氧基)苯甲亚基)丙烷-2-亚磺酰胺4c
将化合物4b(410mg，1.92mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(235mg，1.94mmol，adamas)溶于二氯甲烷(6mL)，加入碳酸铯(760mg，2.33mmol)，搅反应拌16小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4c(560mg，产率：92.0％)。
MS m/z(ESI):317.1[M+1]。
第三步
(R)-2-甲基-N-((S)-1-(3-((6-甲基吡啶-3-基)氧基)苯基)乙基)丙烷-2-亚磺酰胺4d
将化合物4c(500mg，1.58mmol)溶于二氯甲烷(10mL)。氮气保护下，反应冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(1.1mL，3.3mmol，上海 泰坦科技股份有限公司)。反应升到室温搅拌16小时。0℃下，加饱和氯化铵水溶液(20mL)，分出有机相。水相用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4d(480mg，产率：91.3％)。
MS m/z(ESI):333.1[M+1]。
第四步
(S)-1-(3-((6-甲基吡啶-3-基)氧基)苯基)乙胺盐酸盐4e
将化合物4d(250mg，0.75mmol)溶于乙醇中(6mL)，冷却到0℃，滴加氯化亚砜(238mg，2.00mmol，上海沪试化工有限公司)。反应在室温搅拌1小时。减压浓缩，得到标题产物4e粗品(199mg，产率：99.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):229.0[M+1]。
第五步
(S)-3-异丙基-6-((1-(3-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮4
将化合物1c(129mg，0.58mmol)和化合物4e(200mg，0.76mmo)溶于N-甲基吡咯烷酮(6mL)，加入三乙胺(59mg，0.58mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物4(4mg，产率：1.8％)。
MS m/z(ESI):382.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.46(brs,1H),8.24(s,1H),7.40-7.34(m,3H),7.27(m,1H),7.13(m,1H),7.05(s,1H),6.86(m,1H),5.03(m,1H),4.80(m,1H),2.45(s,3H),1.39(d,3H),1.29(d,6H)。
实施例5
(S)-3-异丙基-6-((1-(3-(三氟甲氧基)苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮5
Figure PCTCN2021131642-appb-000120
Figure PCTCN2021131642-appb-000121
第一步
(R)-2-甲基-N-(3-(三氟甲氧基)苯甲亚基)丙烷-2-亚磺酰胺5b
将3-(三氟甲氧基)苯甲醛5a(1.0g，5.26mmol，上海毕得医药科技有限公司)和(R)-2-甲基丙烷-2-亚磺酰胺(640mg，5.28mmol)溶于二氯甲烷(20mL)，加入碳酸铯(2.1g，6.44mmol)，搅拌反应16小时。过滤，浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物5b(1.45g，产率：94.0％)。
MS m/z(ESI):294.0[M+1]。
第二步
(R)-2-甲基-N-((S)-1-(3-(三氟甲氧基)苯基)乙基)丙烷-2-亚磺酰胺5c
将化合物5b(500mg，1.70mmol)溶于二氯甲烷(10mL)。氮气保护下，冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(1.2mL，3.6mmol)。反应升到室温搅拌16小时。0℃下，加饱和氯化铵水溶液(20mL)，分出有机相。水相用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物5c(490mg，产率：92.9％)。
MS m/z(ESI):310.0[M+1]。
第三步
(S)-1-(3-(三氟甲氧基)苯基)乙胺盐酸盐5d
将化合物5c(250mg，0.81mmol)溶于乙醇中(10mL)，冷却到0℃，滴加氯化亚砜(256mg，2.15mmol，上海沪试化工有限公司)。反应在室温搅拌1小时。减压浓缩，得到标题产物5d粗品(195mg，产率：99.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):188.8[M-16]。
第四步
(S)-3-异丙基-6-((1-(3-(三氟甲氧基)苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮5
将化合物1c(119mg，0.54mmol)和化合物5d(195mg，0.81mmo)溶于N-甲基吡咯烷酮(6mL)，加入三乙胺(54mg，0.53mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸 氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物5(30mg，产率：15.6％)。
MS m/z(ESI):359.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.49(brs,1H),7.68(brs,1H),7.48(m,1H),7.40-7.35(m,2H),7.25(m,1H),5.10(m,1H),4.81(m,1H),1.42(d,3H),1.29(d,6H)。
实施例6
(S)-6-((1-(5-环丙基-2-氟苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮6
Figure PCTCN2021131642-appb-000122
第一步
5-环丙基-2-氟苯甲醛6b
将5-溴-2-氟苯甲醛6a(10.00g，49.26mmol，上海毕得医药科技有限公司)和环丙基硼酸(6.35g，73.93mmol，韶远化学科技(上海)有限公司)溶于1,4-二氧六环(100mL)和水(5mL)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(2.42g，2.96mmol)和磷酸三钾(27.15g，128.07mmol)，置换氮气三次，100℃搅拌16小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物6b(7.00g，产率：86.6％)。
1H NMR(500MHz,CDCl 3)δ10.32(s,1H),7.52(m,1H),7.31(m,1H),7.05(m,1H),1.91(m,1H),1.01-0.97(m,2H),0.70-0.66(m,2H)。
第二步
(R)-N-(5-环丙基-2-氟苯甲亚基)-2-甲基丙烷-2-亚磺酰胺6c
将化合物6b(1.00g，6.09mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(738mg，6.09mmol，上海毕得医药科技有限公司)溶于二氯甲烷(20mL)，加入碳酸铯(2.38g，7.30mmol)，搅拌反应16小时。过滤，减压浓缩，得到标题产物6c粗品(1.62g，产率：99.5％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):268.0[M+1]。
第三步
(R)-N-((S)-1-(5-环丙基-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺6d
将化合物6c粗品(1.62g，6.06mmol)溶于二氯甲烷中(10mL)，氮气置换三次。反应冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(4.25mL，12.75mmol，上海泰坦科技股份有限公司)。氮气保护下，反应在室温搅拌5小时。加入饱和氯化铵溶液(10mL)，分出有机相。水相用乙酸乙酯(40mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物6d(1.70g，产率：99.0％)。
MS m/z(ESI):284.0[M+1]。
第四步
(S)-1-(5-环丙基-2-氟苯基)乙胺盐酸盐6e
将化合物6d(300mg，1.06mmol)溶于乙醇中(10mL)，冷却到0℃，滴加氯化亚砜(335mg，2.82mmol，上海沪试化工有限公司)。反应在室温搅拌1小时。减压浓缩，得到标题产物6e粗品(228mg，产率：99.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):179.9[M+1]。
第五步
(S)-6-((1-(5-环丙基-2-氟苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮6
将化合物1c(156mg，0.71mmol)和化合物6e(190mg，0.88mmo)溶于N-甲基吡咯烷酮(8mL)，加入三乙胺(71mg，0.71mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物6(50mg，产率：21.3％)。
MS m/z(ESI):333.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.48(brs,1H),7.20(brs,1H),7.12(m,1H),7.06(m,1H),6.98(m,1H),5.22(m,1H),4.80(m,1H),1.92(m,1H),1.40(d,3H),1.29(d,6H),0.95-0.91(m,2H),0.65-0.62(m,2H)。
实施例7
(S)-6-((1-(双环[4.2.0]辛-1(6),2,4-三烯-3-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮7
Figure PCTCN2021131642-appb-000123
Figure PCTCN2021131642-appb-000124
第一步
(R)-N-(双环[4.2.0]辛-1(6),2,4-三烯-3-基甲亚基)-2-甲基丙烷-2-亚磺酰胺7b
将双环[4.2.0]辛-1(6),2,4-三烯-3-甲醛7a(2.9g，22.0mmol，采用专利申请“WO2019023147A1中说明书第512-513页步骤1公开的方法”制备而得)和(R)-2-甲基丙烷-2-亚磺酰胺(2.8g，23.0mmol)溶于二氯甲烷(40mL)。加入碳酸铯(8.6g，26.4mmol)，搅拌反应16小时。反应液过滤，滤液减压浓缩，得到标题产物7b粗品(5.7g)，粗品无需纯化直接用于下一步。
MS m/z(ESI):236.1[M+1]。
第二步
(R)-N-((S)-1-(双环[4.2.0]辛-1(6),2,4-三烯-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺7c
-50℃下，向化合物7b粗品(2.8g，12.1mmol)的无水二氯甲烷(80mL)溶液中，滴加3M甲基溴化镁的甲基四氢呋喃溶液(8.1mL，24.2mmol，上海泰坦科技股份有限公司)。氮气保护，室温反应16小时。加入饱和氯化铵水溶液(50mL)，二氯甲烷(50mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物7c(2.0g，产率：66.2％)。
MS m/z(ESI):252.1[M+1]。
第三步
(S)-1-(双环[4.2.0]辛-1(6),2,4-三烯-3-基)乙胺盐酸盐7d
将化合物7c(500.0mg，2.0mmol)溶于甲醇(3mL)，滴加4M氯化氢的1,4-二氧六环溶液(2mL)。反应搅拌1小时。减压浓缩，得到标题产物7d粗品(366.0mg)，粗品无需纯化直接用于下一步。
MS m/z(ESI):131.1[M-16]。
第四步
(S)-6-((1-(双环[4.2.0]辛-1(6),2,4-三烯-3-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮7
将化合物1c(182mg，0.82mmol)和化合物7d(182mg，0.99mmo)溶于N-甲基吡咯烷酮(6mL)，加入三乙胺(83mg，0.82mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸 氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物7(30mg，产率：12.1％)。
MS m/z(ESI):301.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.46(brs,1H),7.22(brs,1H),7.15(m,1H),7.10-7.01(m,2H),4.96(m,1H),4.80(m,1H),3.14-3.08(m,4H),1.39(d,3H),1.29(d,6H)。
实施例8
(S)-6-((1-(2,3-二氢苯并呋喃-6-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮8
Figure PCTCN2021131642-appb-000125
第一步
(R)-N-((2,3-二氢苯并呋喃-6-基)甲亚基)-2-甲基丙烷-2-亚磺酰胺8b
将2,3-二氢苯并呋喃-6-甲醛8a(1.0g，6.8mmol，江苏艾康生物医药研发有限公司)和(R)-2-甲基丙烷-2-亚磺酰胺(860.0mg，7.1mmol，上海泰坦科技股份有限公司)溶于二氯甲烷(40mL)。加入碳酸铯(2.6g，8.1mmol)，搅拌反应16小时。反应液过滤，滤液减压浓缩，得到标题产物8b粗品(1.8g)，粗品无需纯化直接用于下一步。
MS m/z(ESI):252.0[M+1]。
第二步
(R)-N-((S)-1-(2,3-二氢苯并呋喃-6-基)乙基)-2-甲基丙烷-2-亚磺酰胺8c
-50℃下，向化合物8b粗品(1.7g，6.8mmol)的无水二氯甲烷(45mL)溶液中，滴加3M甲基溴化镁的甲基四氢呋喃溶液(4.9mL，14.6mmol)。氮气保护，室温反应16小时。加入饱和氯化铵水溶液(30mL)，二氯甲烷(30mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物8c(1.6g，产率：90.6％)。
MS m/z(ESI):268.1[M+1]。
第三步
(S)-1-(2,3-二氢苯并呋喃-6-基)乙胺盐酸盐8d
将化合物8c(534.0mg，2.0mmol)溶于甲醇(3mL)，滴加4M氯化氢的1,4-二氧六环溶液(2mL)。反应搅拌1小时。减压浓缩，得到标题产物8d粗品(400.0mg)，粗品无需纯化直接用于下一步。
MS m/z(ESI):147.1[M-16]。
第四步
(S)-6-((1-(2,3-二氢苯并呋喃-6-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮8
将化合物1c(168mg，0.76mmol)和化合物8d(186mg，0.93mmo)溶于N-甲基吡咯烷酮(8mL)，加入三乙胺(77mg，0.76mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物8(15mg，产率：6.2％)。
MS m/z(ESI):317.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ10.45(brs,1H),7.21-7.16(m,2H),6.80-6.74(m,2H),4.95(m,1H),4.80(m,1H),4.52-4.49(m,2H),3.14-3.11(m,2H),1.39(d,3H),1.29(d,6H)。
实施例9
(S)-6-((1-(2,3-二氢-1H-茚-5-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮9
Figure PCTCN2021131642-appb-000126
第一步
(R)-N-(1-(2,3-二氢-1H-茚-5-基)乙亚基)-2-甲基丙烷-2-亚磺酰胺9b
向1-(2,3-二氢-1H-茚-5-基)乙-1-酮9a(1.0g，6.3mmol，梯希爱(上海)化成工业 发展有限公司)和(R)-2-甲基丙烷-2-亚磺酰胺(1.1g，8.8mmol，上海泰坦科技股份有限公司)的无水四氢呋喃(20mL)中，加入1M三异丙氧基氯化钛己烷溶液(7.5mL，7.5mmol，上海泰坦科技股份有限公司)。65℃下搅拌反应16小时。加入饱和碳酸氢钠水溶液(30mL)，乙酸乙酯(50mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物9b(570.0mg，产率：34.7％)。
MS m/z(ESI):264.0[M+1]。
第二步
(R)-N-((S)-1-(2,3-二氢-1H-茚-5-基)乙基)-2-甲基丙烷-2-亚磺酰胺9c
-78℃下，向化合物9b(570mg，2.2mmol)的无水四氢呋喃(10mL)中，滴加1M三仲丁基硼氢化锂四氢呋喃溶液(3.5mL，3.5mmol，上海泰坦科技股份有限公司)。0℃反应1小时。加入饱和氯化铵水溶液(20mL)，乙酸乙酯(30mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，得到标题产物9c粗品(570mg)，粗品无需纯化直接用于下一步。
MS m/z(ESI):266.1[M+1]。
第三步
(S)-1-(2,3-二氢-1H-茚-5-基)乙胺盐酸盐9d
将化合物9c粗品(570mg，2.2mmol)溶于甲醇(3mL)，滴加4M氯化氢的1,4-二氧六环溶液(2mL)。反应搅拌1小时。减压浓缩，得到标题产物9d粗品(430.0mg)，粗品无需纯化直接用于下一步。
MS m/z(ESI):145.1[M-16]。
第四步
(S)-6-((1-(2,3-二氢-1H-茚-5-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮9
将化合物1c(170mg，0.77mmol)和化合物9d(186mg，0.94mmo)溶于N-甲基吡咯烷酮(8mL)，加入三乙胺(78mg，0.77mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物9(30mg，产率：12.4％)。
MS m/z(ESI):315.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.45(brs,1H),7.20-7.17(m,3H),7.08(m,1H),4.98(m,1H),4.80(m,1H),2.85-2.80(m,4H),2.03-1.97(m,2H),1.39(d,3H),1.29(d,6H)。
实施例10
(S)-3-异丙基-6-((1-(5,6,7,8-四氢萘-2-基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮10
Figure PCTCN2021131642-appb-000127
第一步
(R)-2-甲基-N-(1-(5,6,7,8-四氢萘-2-基)乙亚基)丙烷-2-亚磺酰胺10b
向1-(5,6,7,8-四氢萘-2-基)乙-1-酮10a(2.0g，11.5mmol，阿法埃莎(天津)化学有限公司)和(R)-2-甲基丙烷-2-亚磺酰胺(2.1g，17.3mmol，上海泰坦科技股份有限公司)的无水四氢呋喃(20mL)中，加入四乙氧基钛(4.0g，17.3mmol，安耐吉化学)。65℃下搅拌反应16小时。加入饱和碳酸氢钠水溶液(60mL)，乙酸乙酯(100mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物10b(2.6g，产率：81.6％)。
MS m/z(ESI):278.0[M+1]。
第二步
(R)-2-甲基-N-((S)-1-(5,6,7,8-四氢萘-2-基)乙基)丙烷-2-亚磺酰胺10c
将化合物10b(350mg，1.26mmol)溶于四氢呋喃中(10mL)，氮气置换三次。反应冷却到-78℃，滴加1M三仲丁基硼氢化锂的四氢呋喃溶液(2.02mL，2.02mmol，上海泰坦科技股份有限公司)。氮气保护下，0℃反应搅拌1小时。加入饱和氯化铵溶液(10mL)，分出有机相。水相用乙酸乙酯(40mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物10c(340mg，产率：96.4％)。
MS m/z(ESI):280.0[M+1]。
第三步
(S)-1-(5,6,7,8-四氢萘-2-基)乙胺盐酸盐10d
将化合物10c(340mg，1.22mmol)溶于乙醇中(10mL)，冷却到0℃，滴加氯化亚砜(290mg，2.43mmol，上海沪试化工有限公司)。反应在室温搅拌1小时。减压浓缩，得到标题产物10d粗品(257mg，产率：99.8％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):158.9[M-16]。
第四步
(S)-3-异丙基-6-((1-(5,6,7,8-四氢萘-2-基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮10
将化合物1c(271mg，1.23mmol)和化合物10d(257mg，1.47mmo)溶于N-甲基吡咯烷酮(8mL)，加入三乙胺(124mg，1.23mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物10(40mg，产率：9.9％)。
MS m/z(ESI):329.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.48(brs,1H),7.23(brs,1H),7.04-6.99(m,3H),4.94(m,1H),4.80(m,1H),2.71-2.63(m,4H),1.75-1.69(m,4H),1.37(d,3H),1.29(d,6H)。
实施例11
(S)-6-((1-(5-氟-2,3-二氢苯并呋喃-6-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮11
Figure PCTCN2021131642-appb-000128
第一步
5-氟苯并呋喃-6-羧酸甲酯11b
将6-溴-5-氟苯并呋喃11a(3.20g，14.88mmol，采用专利申请 “WO2017219948A1说明书中第36页中间体A1.2b的合成方法”制备而得)溶于甲醇(50mL)，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.26g，1.49mmol)和N,N-二异丙基乙胺(3.01g，29.75mmol)，用一氧化碳气体置换三次，70℃下搅拌反应40小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物11b(1.50g，产率：51.9％)。
MS m/z(ESI):194.8[M+1]。
第二步
5-氟-2,3-二氢苯并呋喃-6-羧酸甲酯11c
将化合物11b(1.50g，7.73mmol)溶于甲醇(50mL)，加入10％钯碳加氢催化剂(湿)，氢气置换三次，搅拌反应16小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物11c(1.37g，产率：90.4％)。
MS m/z(ESI):196.8[M+1]。
第三步
(5-氟-2,3-二氢苯并呋喃-6-基)甲醇11d
将化合物11c(1.37g，7.0mmol)溶于四氢呋喃(30mL)溶液中，滴加2M硼氢化锂的四氢呋喃溶液(34.9mL，69.8mmol)，室温搅拌反应16小时。冰浴下，加入甲醇(5mL)淬灭反应，用1M盐酸调节反应液pH＝6，用乙酸乙酯(30mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物11d(1.05g，产率：89.4％)。
MS m/z(ESI):190.0[M+22]。
第四步
5-氟-2,3-二氢苯并呋喃-6-甲醛11e
将化合物11d(1.05g，6.24mmol)溶于二氯甲烷(20mL)溶液中，加入Dess-Martin氧化剂(3.97g，9.36mmol)，室温反应2小时。冰浴下，加入饱和硫代硫酸钠(20mL)和饱和碳酸氢钠(20mL)淬灭反应，用二氯甲烷(30mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物11e(1.03g，产率：99.3％)。
MS m/z(ESI):167.0[M+1]。
第五步
(R)-N-((5-氟-2,3-二氢苯并呋喃-6-基)甲亚基)-2-甲基丙烷-2-亚磺酰胺11f
将化合物11e(1.30g，7.82mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(1.42g，11.72mmol，上海毕得医药科技有限公司)溶于二氯甲烷(20mL)。加入碳酸铯(1.58g，14.09mmol)，搅拌反应16小时。反应液过滤，滤液减压浓缩，得到标题产物11f粗品(2.80g)，粗品无需纯化直接用于下一步。
MS m/z(ESI):270.0[M+1]。
第六步
(R)-N-((S)-1-(5-氟-2,3-二氢苯并呋喃-6-基)乙基)-2-甲基丙烷-2-亚磺酰胺11g
-50℃下，向化合物11f粗品(2.80g，10.40mmol)的无水二氯甲烷(45mL)溶液中，滴加3M甲基溴化镁的甲基四氢呋喃溶液(6.93mL，20.79mmol)。氮气保护，室温反应2小时。加入饱和氯化铵水溶液(30mL)，用二氯甲烷(30mL×2)萃取。合并有机相，用无水硫酸钠干燥。过滤，减压浓缩，用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物11g(1.50g，产率：50.56％)。
MS m/z(ESI):286.0[M+1]。
第七步
(S)-1-(5-氟-2,3-二氢苯并呋喃-6-基)乙胺盐酸盐11h
将化合物11g(300mg，1.05mmol)溶于乙醇(10mL)，滴加氯化亚砜(250mg，2.10mmol)。反应搅拌1小时。减压浓缩，得到标题产物11h粗品(228mg)，粗品无需纯化直接用于下一步。
MS m/z(ESI):164.9[M-16]。
第八步
(S)-6-((1-(5-氟-2,3-二氢苯并呋喃-6-基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮11
将化合物1c(232mg，1.05mmol)和化合物11h(228mg，1.05mmo)溶于N-甲基吡咯烷酮(6mL)，加入三乙胺(106mg，1.05mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物11(90mg，产率：25.7％)。
MS m/z(ESI):334.9[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.52(brs,1H),7.28(brs,1H),7.08(d,1H),6.75(m,1H),5.14(m,1H),4.79(m,1H),4.53-4.50(m,2H),3.16-3.13(m,2H),1.38-1.37(d,3H),1.30-1.28(d,6H)。
实施例12
(S)-6-((1-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮12
Figure PCTCN2021131642-appb-000129
Figure PCTCN2021131642-appb-000130
第一步
2-氟-5-((6-甲基吡啶-3-基)氧基)苯甲醛12a
将化合物1d(61.55g，363.25mmol)和6-甲基吡啶-3-酚(20.00g，183.28mmol，上海毕得医药科技有限公司)溶于二氯甲烷(800mL)，加入三乙胺(37.02g，366.53mmol)，吡啶(28.99g，366.50mmol)和无水醋酸铜(66.58g，366.57mmol，上海毕得医药科技有限公司)，反应搅拌24小时。铺硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物12a(8.00g，产率：18.9％)。
MS m/z(ESI):231.9[M+1]。
第二步
(R)-N-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯甲亚基)-2-甲基丙烷-2-亚磺酰胺12b
将化合物12a(8.00g，34.60mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(6.29g，51.90mmol)溶于二氯甲烷(200mL)，加入碳酸铯(20.30g，62.27mmol)，搅拌反应16小时。过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物12b(8.20g，产率：70.9％)。
MS m/z(ESI):334.9[M+1]。
第三步
(R)-N-((S)-1-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺12c
将化合物12b(8.20g，24.52mmol)溶于二氯甲烷(100mL)。氮气保护下，反应冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(17.2mL，51.49mmol，上海泰坦科技股份有限公司)。反应升到室温搅拌5小时。0℃下，加饱和氯化铵水溶液(100mL)，分出有机相。水相用乙酸乙酯(80mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物12c(2.10g，产率：24.4％)。
MS m/z(ESI):349.0[M-1]。
第四步
(S)-1-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯基)乙胺盐酸盐12d
将化合物12c(1.10g，3.14mmol)溶于乙醇中(12mL)，冷却到0℃，滴加氯化亚砜(747mg，6.28mmol)。反应在室温搅拌1小时。减压浓缩，得到标题产物12d粗品(887mg，产率：99.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):247.0[M+1]。
第五步
(S)-6-((1-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮12
将化合物1c(694mg，3.14mmol)和化合物12d(887mg，3.14mmo)溶于N-甲基吡咯烷酮(12mL)，加入三乙胺(317mg，3.13mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物12(480mg，产率：38.3％)。
MS m/z(ESI):399.9[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.53(brs,1H),8.22(d,1H),7.34-7.21(m,4H),7.12(m,1H),6.95(m,1H),5.22(m,1H),4.79(m,1H),2.45(s,3H),1.41(d,3H),1.29(d,6H)。
实施例13
(S)-6-((1-(2-氟-5-甲基苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮13
Figure PCTCN2021131642-appb-000131
第一步
(R)-N-((S)-1-(2-氟-5-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺13b
将(R)-N-(2-氟-5-甲基苯甲亚基)-2-甲基丙烷-2-亚磺酰胺13a(6.90g，28.59mmol，采用专利申请“WO2020092208A1说明书中第56页中间体3B的合成方法”制备而得)溶于二氯甲烷中(100mL)，氮气置换三次。反应冷却到-60℃，滴加3M甲基溴化镁的2-甲基四氢呋喃溶液(19.1mL，57.18mmol)。氮气保护下，反应在室温搅拌2小时。加入饱和氯化铵溶液(100mL)，分出有机相。水相用乙酸乙酯(80mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物13b(5.60g，产率：76.1％)。
MS m/z(ESI):258.0[M+1]。
第二步
(S)-1-(2-氟-5-甲基苯基)乙胺盐酸盐13c
将化合物13b(670mg，2.60mmol)溶于乙醇中(10mL)，冷却到0℃，滴加氯化亚砜(620mg，5.21mmol)。反应在室温搅拌1小时。减压浓缩，得到标题产物13c粗品(493mg，产率：99.9％)。粗品无需纯化直接用于下一步。
MS m/z(ESI):153.9[M+1]。
第三步
(S)-6-((1-(2-氟-5-甲基苯基)乙基)氨基)-3-异丙基-1,3,5-三嗪-2,4(1H,3H)-二酮13
将化合物1c(712mg，3.22mmol)和化合物13c(493mg，2.60mmo)溶于N-甲基吡咯烷酮(10mL)，加入三乙胺(326mg，3.22mmol)，120℃搅拌16小时。用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物13(400mg，产率：40.6％)。
MS m/z(ESI):306.9[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.42(brs,1H),7.22-7.05(m,4H),5.21(m,1H),4.79(m,1H),2.28(s,3H),1.40(d,3H),1.29(d,6H)。
实施例14
(S)-6-((1-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)-1,3,5-三嗪-2,4(1H,3H)-二酮14
Figure PCTCN2021131642-appb-000132
Figure PCTCN2021131642-appb-000133
第一步
4-异氰氧基四氢-2H-吡喃14b
15℃下，向二(三氯甲基)碳酸酯(11.9g，40.0mmol，上海泰坦科技股份有限公司)的无水二氯甲烷(30mL)中，缓慢滴加四氢-2H-吡喃-4-胺14a(10.0g，100.0mmol，韶远化学科技(上海)有限公司)和N,N-二异丙基乙胺(28.4g，220.0mmol，上海泰坦科技股份有限公司)的无水二氯甲烷(120mL)溶液。室温反应2小时。反应液减压浓缩，得到标题产物14b粗品。粗品无需纯化直接用于下一步。
第二步
6-(1H-吡唑-1-基)-3-(四氢-2H-吡喃-4-基)-1,3,5-三嗪-2,4(1H,3H)-二酮14c
-10℃下，向化合物1b(10.5g，95.2mmol)和化合物14b粗品的无水N,N-二甲基乙酰胺(120mL)溶液中，缓慢滴加1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(15.2g，100.0mmol，韶远化学科技(上海)有限公司)。反应在0℃下搅拌1小时。随后，反应在0℃下，加入羰基二咪唑(23.2g，142.8mmol，上海毕得医药科技有限公司)和1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(21.7g，142.8mmol，韶远化学科技(上海)有限公司)。反应在60℃搅拌16小时。反应液减压浓缩，向所得残余物中加入二氯甲烷，搅拌，过滤，收集滤饼，减压干燥，得到标题产物14c(16.6g，两步产率：63.4％)。
MS m/z(ESI):264.1[M+1]。
第三步
(S)-6-((1-(2-氟-5-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)-1,3,5-三嗪-2,4(1H,3H)-二酮14
将化合物14c(148.3mg，0.7mmol)和化合物12d(198.0mg，0.7mmo)溶于N-甲基吡咯烷酮(2mL)，加入N,N-二异丙基乙胺(452.6mg，3.5mmol)，140℃微波反应2小时。用高效液相色谱法纯化(Sharpsil-T Prep C18 5um 30*150mm，洗脱体系：水(10mM碳酸氢铵)、乙腈，乙腈在20分钟内由16％(v/v)升至36％(v/v)，30mL/min，检测波长214&254nm)，得到标题产物14(95.0mg，产率：30.7％)。
MS m/z(ESI):442.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.20(s,1H),7.79(brs,1H),7.30(m,1H),7.23-7.19(m,2H),7.14(m,1H),6.92(m,1H),5.26(m,1H),4.66(m,1H),3.87-3.83(m,2H),3.32-3.25(m,3H),2.51-2.44(m,3H),2.41(s,3H),1.42-1.33(m,4H)。
实施例15
(S)-6-((1-(3-((6-甲基吡啶-3-基)氧基)苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)-1,3,5-三嗪-2,4(1H,3H)-二酮15
Figure PCTCN2021131642-appb-000134
将化合物14c(337.0mg，1.3mmol)和化合物4e(338.9mg，0.7mmo)溶于N-甲基吡咯烷酮(4mL)，加入N,N-二异丙基乙胺(827.3mg，6.4mmol)，140℃微波反应2小时。用高效液相色谱法纯化(Sharpsil-T Prep C18 5um 30*150mm，洗脱体系：水(10mM碳酸氢铵)、乙腈，乙腈在20分钟内由16％(v/v)升至36％(v/v)，30mL/min，检测波长214&254nm)，得到标题产物15(166.0mg，产率：30.6％)。
MS m/z(ESI):424.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.24(d,1H),7.66(brs,1H),7.36-7.33(m,2H),7.26(d,1H),7.14(d 1H),7.05(s,1H),6.85(d 1H),5.04(m,1H),4.66(m,1H),3.89-3.85(m,2H),3.31-3.27(m,3H),2.51-2.47(m,3H),2.45(s,3H),1.41-1.38(m,4H)。
实施例16
(S)-6-((1-(2-氟-5-甲基苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)-1,3,5-三嗪-2,4(1H,3H)-二酮16
Figure PCTCN2021131642-appb-000135
Figure PCTCN2021131642-appb-000136
将化合物14c(425mg，1.61mmol)和化合物13c(297mg，1.94mmo)溶于1,4-二氧六环(10mL)，120℃反应搅拌16小时。反应液减压浓缩，用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物16(310mg，产率：55.1％)。
MS m/z(ESI):349.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.50(brs,1H),7.28-7.05(m,4H),5.22(m,1H),4.64(m,1H),3.90-3.86(m,2H),3.33-3.27(m,2H),2.54-2.42(m,2H),2.28(s,3H),1.45-1.39(m,5H)。
实施例17
(S)-3-环己基-6-((1-(2-氟-5-甲基苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮17
Figure PCTCN2021131642-appb-000137
第一步
3-环己基-6-(1H-吡唑-1-基)-1,3,5-三嗪-2,4(1H,3H)-二酮17b
将环己基异氰酸酯17a(8.97g，71.66mmol，上海泰坦科技股份有限公司)和化合物1b(10.00g，68.22mmol)溶于N,N-二甲基乙酰胺(50mL)，反应冷却到-10℃，滴加1,8-二氮杂二环十一碳-7-烯(17.18g，68.22mmol)，5分钟后滴毕，反应在冰 浴下继续搅拌30分钟。随后，在冰浴下，加入N,N'-羰基二咪唑(14.73g，102.33mmol)，反应冷却到-5℃，滴加1,8-二氮杂二环十一碳-7-烯(25.77g，102.33mmol)，10分钟后滴毕，反应在冰浴下继续搅拌1小时。室温下，加入2N盐酸(197mL)，30分钟后滴毕。过滤，收集滤饼，真空干燥，得到标题产物17b(16.00g，产率：89.8％)。
MS m/z(ESI):262.0[M+1]。
第二步
(S)-3-环己基-6-((1-(2-氟-5-甲基苯基)乙基)氨基)-1,3,5-三嗪-2,4(1H,3H)-二酮17
将化合物17b(680mg，2.60mmol)和化合物13c(392mg，2.56mmo)溶于1,4-二氧六环(10mL)，120℃下反应搅拌16小时。反应液浓缩干，用高效液相色谱法纯化(Boston Phlex C18 150*30mm，5μm，洗脱体系：水(10mmol碳酸氢铵)、乙腈，20-95％乙腈，20分钟梯度洗脱，流速：30mL/min)，得到标题产物17(420mg，产率：46.6％)。
MS m/z(ESI):347.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ10.45(brs,1H),7.27-7.05(m,4H),5.21(m,1H),4.38(m,1H),2.28(s,3H),2.23-2.14(m,2H),1.75-1.72(m,2H),1.58(m,1H),1.50-1.47(m,2H),1.41-1.40(d,3H),1.28-1.18(m,2H),1.07(m,1H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1、本公开化合物对肌球蛋白ATP酶活性的抑制效应。
以下方法用来测定本公开化合物对肌球蛋白ATP酶活性的抑制效应，实验方法简述如下：
一、实验材料及仪器
1、心肌肌动蛋白(Cytoskeleton，AD99)
2、肌球蛋白马达蛋白S1片段(Myosin Motor Protein S1 Fragment)(Cytoskeleton，CS-MYS03)
3、ATP(Sigma，A7699-1G)
4、UltraPure TM 1M Tris-HCl缓冲液,pH 7.5(Thermo，15567027)
5、CytoPhos TM磷酸盐检测生物试剂盒(Cytoskeleton，BK054)
6、氯化镁溶液(Sigma，68475-100ML-F)
7、氯化钾溶液(Sigma，60142-100ML-F)
8、EGTA(Sigma，E3889-100G)
9、96孔板(Corning，3697)
10、U型底96孔板(Corning，3795)
11、酶标仪(BMG，PHERAstar)
12、恒温培养箱(上海博迅，SPX-100B-Z)
二、实验步骤
心肌肌动蛋白1.61μM，肌球蛋白马达蛋白S1片段0.07μM与不同浓度的小分子化合物(首浓度100μM，3倍梯度稀释9个浓度)混合，37℃孵育1小时。再加入ATP 120μM，37℃孵育2小时。最后每孔加入CytoPhos TM磷酸盐检测生物试剂盒中的检测溶液(70μL/孔)，室温孵育10min。用酶标仪读取650nM波长的OD值，根据标准曲线计算Pi的量，数据使用GraphPad软件处理，根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度即IC 50值。实验结果详见表1。
表1本公开化合物对肌球蛋白ATP酶的抑制活性
实施例编号 IC 50(μM)
1 2.41
2 2.55
3 5.11
4 1.66
5 1.98
6 0.45
7 1.33
8 3.75
9 0.68
10 0.62
11 1.39
12 0.81
13 1.00
14 0.35
15 1.13
16 1.06
结论：本公开化合物对肌球蛋白ATP酶具有很好的抑制作用。
测试例2：本公开化合物在Beagle犬体内的药代动力学评价
1、摘要
以Beagle犬(比格犬)为受试动物，应用LC/MS/MS法测定了Beagle犬灌胃及静脉注射给予待测化合物后不同时刻血浆中的药物浓度。研究本公开化合物在Beagle犬体内的药代动力学行为，评价其药动学特征。
2、实验方案
2.1实验药品
实施例16化合物、化合物MYK-461(
Figure PCTCN2021131642-appb-000138
WO2014205223A1的实施例1)。
2.2实验动物
实施例16化合物的Beagle犬药代：Beagle犬8只，雌雄各半，平均分成2组，每组4只，上海美迪西生物医药有限公司提供。
化合物MYK-461的Beagle犬药代：Beagle犬6只，雄性，平均分成2组，每组3只，由上海美迪西生物医药有限公司提供。
2.3药物配制
称取一定量实施例16化合物，加入5％DMSO、30％PG、30％PEG400和35％生理盐水配置成澄明溶液。
称取一定量化合物MYK-461，加入5％DMSO、20％PG、20％PEG400和55％生理盐水配置成澄明溶液。
2.4给药
Beagle犬禁食一夜后分别灌胃及静脉注射给药，给药剂量分别为2mg/kg、0.5mg/kg，给药体积分别为5mL/kg、2mL/kg。
3、操作
灌胃给药组于给药前及给药后0.25h、0.5h、1.0h、2.0h、4.0h、6.0h、8.0h、12.0h、24.0h，由颈静脉或前肢静脉采血1.0mL，置EDTA-K2抗凝试管中，10000rpm离心5min(4℃)，1h内分离血浆，-80℃保存待测。采血至离心过程在冰浴条件下操作。给药后3h进食。
静脉注射给药组于给药前及给药后5min、0.25h、0.5h、1.0h、2.0h、4.0h、8.0h、12.0h、24.0h采血，处理同灌胃给药组。
测定不同浓度的药物灌胃及静脉注射给药后Beagle犬血浆中的待测化合物含量：取给药后各时刻的Beagle犬血浆30μL，加入内标溶液(实施例16化合物的内标：华法林100ng/mL；化合物MYK-461的内标：甲苯磺丁脲100ng/mL)，甲醇300μL，涡旋混合1分钟，离心7分钟(离心力18000g)，将200μL上清液转移到96孔盘，血浆样品取上清液1μL进行LC/MS/MS分析。
4、药代动力学参数结果
表2本公开化合物在Beagle犬体内的药代动力学参数
Figure PCTCN2021131642-appb-000139
Figure PCTCN2021131642-appb-000140
结论：本公开的实施例16化合物在Beagle犬体内的药代吸收良好。另外，本公开实施例16化合物的T 1/2有明显的缩短。化合物MYK-461由于T 1/2比较长，在临床上蓄积比较严重，临床给药需要不断地调整，增加了用药风险。缩短T 1/2，可以较少或避免临床上药物在体内蓄积，有利于病人用药剂量确定，避免因蓄积造成的风险。显然，本公开的实施例16化合物较化合物MYK-461具有明显的药代动力学优势。
测试例3：本公开化合物在食蟹猴体内的药代动力学评价
1、摘要
以食蟹猴为受试动物，应用LC/MS/MS法测定了食蟹猴灌胃及静脉注射给予待测化合物后不同时刻血浆中的药物浓度。研究本公开化合物在食蟹猴体内的药代动力学行为，评价其药动学特征。
2、实验方案
2.1实验药品
实施例16化合物、化合物MYK-461。
2.2实验动物
实施例16化合物的食蟹猴药代：食蟹猴8只，雌雄各半，平均分成2组，每组4只，由上海美迪西生物医药有限公司提供。
化合物MYK-461的食蟹猴药代：食蟹猴6只，雄性，平均分成2组，每组3只，由上海美迪西生物医药有限公司提供。
2.3药物配制
称取一定量实施例16化合物，加入5％DMSO、30％PG、30％PEG400和35％生理盐水配置成澄明溶液。
称取一定量化合物MYK-461，加入5％DMSO、20％PG、20％PEG400和55％生理盐水配置成澄明溶液。
2.4给药
食蟹猴禁食一夜后分别灌胃及静脉注射给药，给药剂量分别为2mg/kg、0.5mg/kg，给药体积分别为5mL/kg、2mL/kg。
3、操作
灌胃给药组于给药前及给药后0.25h、0.5h、1h、2h、4h、6h、8h、12h、24h由前肢静脉采血1.0mL，置于EDTA-K2抗凝试管中，10000rpm离心5min(4℃)，1h内分离血浆，-80℃保存待测。采血至离心过程在冰浴条件下操作。给药后3h进食，自由饮水。
静脉注射给药组于给药前及给药后5min、0.25h、0.5h、1.0h、2.0h、4.0h、8.0h、12.0h、24.0h采血，处理同灌胃给药组。
测定不同浓度的药物灌胃及静脉注射给药后食蟹猴血浆中的待测化合物含量：取给药后各时刻的食蟹猴血浆20μL，加入内标溶液(实施例16化合物的内标：维拉帕米10ng/mL；化合物MYK-461内标：喜树碱100ng/mL)，甲醇400μL，涡旋混合1分钟，离心7分钟(离心力18000g)，将200μL上清液转移到96孔盘，血浆样品取上清液2μL进行LC/MS/MS分析。
4、药代动力学参数结果
表3本公开化合物在食蟹猴体内的药代动力学参数
Figure PCTCN2021131642-appb-000141
结论：本公开的实施例16化合物化合物在食蟹猴体内的药代吸收良好。另外，本公开实施例16化合物化合物的T 1/2有明显的缩短。化合物MYK-461由于T 1/2比较长，在临床上蓄积比较严重，临床给药需要不断地调整，增加了用药风险。缩短T 1/2，可以较少或避免临床上药物在体内蓄积，有利于病人用药剂量确定，避免因蓄积造成的风险。显然，本公开的实施例16化合物较化合物MYK-461具有明显的药代动力学优势。
测试例4：本公开化合物对SD大鼠灌胃重复给药14天的毒代动力学评价
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠灌胃给予待测化合物后不同时刻血浆和给药溶液中的药物原形的浓度。研究本公开化合物在SD大鼠体内的毒代动力学行为，评价其毒代动力学特征。
2、实验方案
2.1试验药品
实施例16化合物、化合物MYK-461。
2.2实验动物
SD大鼠24只，雌雄各半，平均分为6组，每组4只，每组雌雄各半，由维通利华实验动物有限公司提供。
2.3药物配制
称取一定量实施例16化合物，加入15％PEG400和85％(10％TPGS+1％HPMC K100LV)配置成淡黄色均匀混悬溶液。
称取一定量化合物MYK-461，加入0.5％MC配置成无色澄明溶液。
2.4给药
灌胃给药，实施例16化合物的给药剂量分别为5mg/kg、15mg/kg、30mg/kg，给药体积分别均为10mL/kg。
化合物MYK-461的给药剂量分别为0.5mg/kg、1.5mg/kg、3mg/kg，给药体积分别均为10mL/kg。
3、操作
第1天于给药后0.5h、1.0h、2.0h、4.0h、8.0h、24.0h由眼眶采血0.2mL，第7天和第14天于给药前和给药后0.5h、1.0h、2.0h、4.0h、8.0h、24.0h由眼眶采血0.2mL，置EDTA-K2抗凝试管中，10000rpm离心1min(4℃)，1h内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。给药后2h进食。
测定不同浓度的药物灌胃给药后SD大鼠血浆中的待测化合物含量：取给药后各时刻的SD大鼠血浆20μL，加入50μL内标溶液(实施例16化合物的内标：维拉帕米100ng/mL；化合物MYK-461的内标：喜树碱100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(3700转/分钟)，血浆样品取上清液1μL进行LC/MS/MS分析。
4、毒代动力学参数结果
表4本公开化合物在SD大鼠体内的毒代动力学参数
Figure PCTCN2021131642-appb-000142
Figure PCTCN2021131642-appb-000143
结论：本公开的实施例16化合物对SD大鼠灌胃重复给药14天后在SD大鼠体内的蓄积不明显，而化合物MYK-461在SD大鼠体内蓄积严重，增加了用药风险。显然，本公开的实施例16化合物较化合物MYK-461具有明显的毒代动力学优势。
测试例5：本公开化合物在人肝微粒体中反应性代谢产物鉴定
本公开化合物在人肝微粒体中反应性代谢产物鉴定采用如下实验方法：
一、实验材料及仪器
1、磷酸缓冲液(购买自上海生工)
2、NADPH(ACROS，A2646-71-1)
3、人肝微粒体(Corning Gentest，Cat No，452161，Lot No.905002)
4、Thermo UHPLC-Q-Exactive Orbitrap质谱仪(Thermo Fisher Scientific)
5、Acquity BEH C 18柱，2.1×100mm，1.7μm(美国Waters公司)
6、阳性对照化合物(双氯芬酸，Diclofenac)。
二、实验药品
实施例16化合物、化合物MYK-461。
三、实验步骤
1、受试化合物溶液配制：取受试化合物适量，精密称定，加入适量的DMSO溶解后混合均匀，即得浓度为30mM的储备溶液。将浓度为10mM的储备液用50％乙腈/水(v/v)稀释10倍，得到浓度为3.0mM的工作溶液1。将浓度为3.0mM的工 作溶液1用PBS稀释10倍，得到300μM的工作溶液2，使用前于4℃保存。
2、磷酸缓冲液配制：分别称取K 2HPO 4和KH 2PO 4适量，溶于4L的纯水中,配成浓度为100mM的缓冲溶液，然后用磷酸或者氢氧化钠调整pH值为7.4。
3、肝微粒体溶液配制：分别取各个种属的肝微粒体储存液(浓度为20mg/mL)适量，用浓度为100mM的磷酸缓冲液(pH 7.4)稀释到1.43mg/mL微粒体溶液。
4、NADPH辅因子溶液的配制：称取NADPH和氯化镁适量，溶于适量的浓度为100mM的磷酸缓冲液(pH值为7.4)中，使得NADPH和氯化镁的浓度分别为10mM和30mM，备用。
5、谷胱甘肽(GSH)溶液的配制：称取GSH适量，溶于适量的浓度为100mM的磷酸缓冲液(pH值为7.4)中，使得GSH的浓度为50mM，备用。
6、孵育体系如下所示：
肝微粒体蛋白浓度 1mg/mL
种属 人
受试化合物浓度 30μM
NADPH浓度 1.0mM
MgCl 2浓度 3.0mM
GSH浓度 5mM
孵育介质 100mM PBS
体系pH 7.4
孵育温度 37℃
孵育时间 60min
孵育体积 200μL
阳性对照 双氯芬酸(10μM)
精密移取20μL浓度为300μM的工作液2，加入到1.5mL离心管中，再加入140μL浓度为1.43mg/mL的肝微粒体溶液，使得孵育体系中肝微粒体蛋白浓度为1mg/mL。再加入20μL浓度为10mM的NADPH溶液和20μL浓度为50mM的GSH溶液后，放入37℃恒温孵育箱中震荡孵育，并开始计时。孵育开始60min后，从孵育箱中取出孵育样品，加入1000μL冰冷乙腈溶液，终止反应并在室温下放置10min后，12000rpm离心10min。移取全部上清液于离心管中，37℃真空浓缩至干。残留物用200μL 25％乙腈/水溶液复溶，12000rpm离心10min，移取上清液至96孔板中，吸取5μL进行LC/MS分析。对于空白样品，加入20μL PBS代替工作液2。对于NCF样品，加入20μL PBS代替GSH溶液。阳性对照双氯芬酸(10μM)同受试化合物。采集数据经Xcalibur软件处理分析，根据精确分子量，二级质谱碎片分析本公开化合物是否会发生代谢活化产生反应性代谢产物。
表5本公开化合物在人肝微粒体中反应性代谢产物鉴定
化合物 结果
实施例16 阴性
MYK-461 阳性
结论：实验中未检测到与本公开实施例16化合物相关的GSH结合物，但检测到与化合物MYK-461相关的GSH结合物，由此可知，本公开的实施例16化合物较化合物MYK-461表现出更好的安全性。

Claims (14)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2021131642-appb-100001
    其中：
    环A选自环烷基、杂环基、芳基和杂芳基；
    R 1选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、C(O)R 6、C(O)OR 7、S(O) tR 8、S(O) tNR 9R 10、C(O)NR 9R 10、NR 9R 10和
    Figure PCTCN2021131642-appb-100002
    各个R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、C(O)R 6、C(O)OR 7、S(O) tR 8、S(O) tNR 9R 10、C(O)NR 9R 10和NR 9R 10；
    或者R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成环烷基或杂环基；其中，所述的环烷基或杂环基任选地被选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；
    L 2选自共价键、(CH 2) r、C(O)、NR a、氧原子和硫原子；
    R a选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    环C选自环烷基、杂环基、芳基和杂芳基；
    各个R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 3a选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷氧基、卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；
    R 3b为氢原子；
    R 0为烷基或
    Figure PCTCN2021131642-appb-100003
    其中，所述的烷基任选地被选自卤素、烷氧基、卤代烷氧基、氰基、氨基、硝基和羟基中的一个或多个取代基所取代；
    L 1为共价键或(CH 2) r；
    环B选自环烷基、杂环基、芳基和杂芳基；
    各个R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氧代、氰基、硝基、羟基、羟烷基、C(O)R 6、C(O)OR 7、S(O) tR 8、S(O) tNR 9R 10、C(O)NR 9R 10、环烷基、-(CH 2) r-环烷基、杂环基、-(CH 2) r-杂环基、芳基、-(CH 2) r-芳基、杂芳基和-(CH 2) r-杂芳基；
    R 6在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选地被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基中的一个或多个取代基所取代；
    R 7在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 8在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、羟基、环烷基、杂环基、芳基和杂芳基；
    R 9和R 10在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、-(CH 2) r-环烷基、杂环基、-(CH 2) r-杂环基、芳基、-(CH 2) r-芳基、杂芳基和-(CH 2) r-杂芳基；或者R 9和R 10与相连的氮原子一起形成杂环基，所述的杂环基任选被选自卤素、烷基、氧代、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    p为0、1、2、3、4、5或6；
    r为0、1、2、3、4、5或6；
    m为0、1、2、3或4；
    s为0、1、2、3、4、5或6；并且
    t为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其为通式(I-1)所示的化合物或其可药用的盐：
    Figure PCTCN2021131642-appb-100004
    其中：
    环A、R 0、R 1、R 2、R 3a、R 3b和m如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其中环A选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；优选地，环A为苯基。
  4. 根据权利要求1或3所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    Figure PCTCN2021131642-appb-100005
    其中：
    R 0、R 1、R 2、R 3a、R 3b和m如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(II-1)所示的化合物或其可药用的盐：
    Figure PCTCN2021131642-appb-100006
    其中：
    R 0、R 1、R 2、R 3a、R 3b和m如权利要求1中所定义。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 0选自C 1-6烷基、3至8元环烷基和3至12元杂环基；优选地，R 0选自C 1-6烷基、3至6元环烷基和3至6元杂环基；进一步优选地，R 0选自异丙基、四氢吡喃基和环己基；更优选地，R 0为异丙基或四氢吡喃基；最优选地，R 0为四氢吡喃基。
  7. 根据权利要求1至3、6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 1选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和
    Figure PCTCN2021131642-appb-100007
    L 2为共价键或氧原子；环C选自3至8元环烷基、3至12元杂环基、6至10元芳基和5至10元杂芳基；各个R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；p为0、1、2、3、4、5或6；R 2选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6卤代烷氧基；或者R 1和相邻的一个R 2，或者两个相邻的R 2，与环A稠合形成3至8元环烷基或3至12元杂环基。
  8. 根据权利要求1至3、6至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 1选自C 1-6烷基、C 1-6卤代烷氧基和
    Figure PCTCN2021131642-appb-100008
    L 2为共价键或氧原子；环C选自环丙基、四氢呋喃基和吡啶基；各个R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；p为0、1或2；各个R 2相同或不同，且各自独立地为氢原子或卤素；或者R 1和相邻的一个R 2与环A稠合形成环丁基、四氢呋喃基、环戊基和环己基。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 3a选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基和C 1-6羟烷基；优选地，R 3a为C 1-6烷基；更优选地，R 3a为甲基。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021131642-appb-100009
  11. 一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
    Figure PCTCN2021131642-appb-100010
    通式(IA)所示的化合物或其盐(优选为盐酸盐)与通式(V)＝所示的化合物发生亲核取代反应，得到通式(I)所示的化合物或其可药用的盐；
    其中：
    R w为离去基团，优选为吡唑基；
    环A、R 0、R 1、R 2、R 3a、R 3b和m如权利要求1中所定义。
  12. 一种药物组合物，所述药物组合物含有根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求12所述的药物组合物在制备肌球蛋白(Myosin)抑制剂中的用途。
  14. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求12所述的药物组合物在制备用于治疗疾病或病症的药物中的用途，所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛、限制型心肌病、舒张功能障碍、肥厚型心肌病(HCM)、正常射血分数心力衰竭(HFpEF)、射血分数中间值心衰(HFmREF)、瓣膜疾病、主动脉瓣狭窄、炎性心肌病、勒夫勒心内膜炎、心肌心内膜纤维化、浸润性心肌病、血色素沉着症、法布瑞氏症、糖原贮积病、先天性心脏病、法洛四联症、左心室肥厚、难治性心绞痛和恰加斯病；优选选自缺血性心脏病、限制型心肌病、肥厚型心肌病(HCM)、炎性心肌病、浸润性心肌病、先天性心脏病和左心室肥厚；更优选为肥厚型心肌病(HCM)；最优选为非梗阻性肥厚型心肌病(nHCM)或梗阻性肥厚型心肌病(oHCM)。
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