Classifications

• • 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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