WO2023078333A1 - 一种取代的苯丙酸衍生物及其用途一种取代的苯丙酸衍生物及其用途 - Google Patents

一种取代的苯丙酸衍生物及其用途一种取代的苯丙酸衍生物及其用途 Download PDF

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WO2023078333A1
WO2023078333A1 PCT/CN2022/129479 CN2022129479W WO2023078333A1 WO 2023078333 A1 WO2023078333 A1 WO 2023078333A1 CN 2022129479 W CN2022129479 W CN 2022129479W WO 2023078333 A1 WO2023078333 A1 WO 2023078333A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
independently selected
alkyl
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PCT/CN2022/129479
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English (en)
French (fr)
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WO2023078333A8 (zh
Inventor
谭亮
董玉琼
刘敏
李姣
李健
张瑱
林晓燕
李云飞
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上海拓界生物医药科技有限公司
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Priority to CA3235992A priority Critical patent/CA3235992A1/en
Priority to KR1020247017510A priority patent/KR20240091010A/ko
Priority to AU2022381258A priority patent/AU2022381258A1/en
Priority to CN202280066584.5A priority patent/CN118055927A/zh
Publication of WO2023078333A1 publication Critical patent/WO2023078333A1/zh
Publication of WO2023078333A8 publication Critical patent/WO2023078333A8/zh

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the disclosure belongs to the field of medicine, and relates to a substituted phenylpropionic acid derivative and its application.
  • Lipoprotein(a) is a kind of blood lipid particle similar to low-density lipoprotein, which is mainly composed of inner core rich in cholesteryl ester and unique apolipoprotein(a) [Apo(a)].
  • the characteristics of long-term stability and long-term stability show a skewed distribution in the population. Studies have found that elevated Lp(a) is associated with an increased risk of cardiovascular events and associated revascularization.
  • WO2020247429 reports a class of pyrrolidone lipoprotein inhibitors that bind to human Apo(a) protein. By binding to Apo(a) protein to inhibit the combination of LDL particles and apo(a), to reduce the level of Lp(a) in plasma,
  • the compound disclosed in the present disclosure is not disclosed in any literature, and this type of compound exhibits specific binding to human Apo(a) protein, thereby reducing the level of Lp(a) in plasma.
  • the disclosure provides a compound shown in formula I or a pharmaceutically acceptable salt thereof,
  • R 1 , R 5 are independently selected from hydrogen or C 1-6 alkyl, said alkyl is optionally substituted by one or more R 1A , each R 1A is independently selected from halogen, hydroxyl, cyano or amino ;
  • R 2 and R 6 are independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl, the alkyl is optionally substituted by one or more R 2A , each R 2A is independently selected from halogen, hydroxyl, cyano base or amino;
  • R 3 and R 7 are independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by one or more R 3A Substituted, each R 3A is independently selected from halogen, hydroxyl, cyano or amino;
  • R 2 , R 3 , R 6 , and R 7 are not hydrogen or methyl at the same time;
  • R 4 and R 8 are independently selected from hydrogen or C 1-6 alkyl
  • L 1 is selected from -CH 2 NHCH 2 -, -CH 2 NH-, -NH-, -S-, -S(O)-, -S(O) 2 -, -O-, -OCH 2 -, - OCH 2 CH 2 O-, -NHSO 2 NH-,
  • R is selected from hydrogen or C 1-6 alkyl, the alkyl is optionally substituted by one or more R 4A , each R 4A is independently selected from halogen, hydroxyl, cyano or amino;
  • R b is selected from hydrogen, deuterium, halogen or C 1-6 alkyl, the alkyl is optionally substituted by one or more R 5A , each R 5A is independently selected from halogen, hydroxyl, cyano or amino;
  • R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy is optionally substituted by one or more R 6A ,
  • Each R 6A is independently selected from halogen, hydroxy, cyano or amino;
  • R d is selected from hydrogen or C 1-6 alkyl
  • n, m, and o are each independently selected from integers between 0 and 4.
  • R 2 and R 6 are independently selected from deuterium.
  • R 2 and R 6 in the compound of formula I or a pharmaceutically acceptable salt thereof are independently selected from halogen, such as fluorine or chlorine.
  • R 2 and R 6 are independently selected from C 1-6 alkyl, and the alkyl is optionally substituted by one or more R 2A , R 2A as defined above. In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 and R 6 are independently selected from methyl, ethyl or propyl.
  • R 1 and R 5 are independently selected from hydrogen.
  • R 3 and R 7 are independently selected from deuterium or C 1-6 alkoxy, and the alkoxy is optionally replaced by one or more R 3A Substitution, R 3A is as defined above.
  • R 3 and R 7 are independently selected from halogen, such as fluorine or chlorine.
  • R 3 and R 7 in the compound of formula I or a pharmaceutically acceptable salt thereof are independently selected from C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally Substituted by one or more R 3A , R 3A is as defined above.
  • L 1 is selected from -CH 2 NHCH 2 -, -CH 2 NH-, -NH-, -O-, -OCH 2 -, -OCH 2 CH 2 O-, -NHSO 2 NH-, preferably -CH 2 NHCH 2 -, -CH 2 NH-, -NH-, -OCH 2 CH 2 O-.
  • L is selected from
  • R a , R b , and R c are as defined above.
  • R b is selected from deuterium.
  • R b is selected from halogen, such as fluorine or chlorine.
  • R b in the compound of formula I or a pharmaceutically acceptable salt thereof, is selected from C 1-6 alkyl, and the alkyl is optionally substituted by one or more R 5A , and R 5A is as defined above .
  • R b in the compound of formula I or a pharmaceutically acceptable salt thereof is independently selected from methyl, ethyl or propyl.
  • R a is selected from hydrogen
  • R in the compound of formula I or a pharmaceutically acceptable salt thereof is independently selected from hydrogen or C 1-6 alkoxy, and the alkoxy is optionally substituted by one or more R 6A , R 6A is as defined above.
  • R c is independently selected from halogen, such as fluorine or chlorine.
  • R in the compound of formula I or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by one or Substituted by multiple R 6A , R 6A is as defined above.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from:
  • Another aspect of the present disclosure also provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,
  • R 11 is independently selected from hydrogen or C 1-6 alkyl, said alkyl is optionally substituted by one or more R 11A , each R 11A is independently selected from halogen, hydroxyl, cyano or amino;
  • R 12 is independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl, said alkyl is optionally substituted by one or more R 12A , each R 12A is independently selected from halogen, hydroxyl, cyano or amino ;
  • R 13 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy is optionally substituted by one or more R 13A , Each R 13A is independently selected from halogen, hydroxy, cyano or amino;
  • R 14 is independently selected from hydrogen or C 1-6 alkyl
  • W is selected from 3 or 4;
  • n1 is selected from an integer between 0-4.
  • R 12 is independently selected from hydrogen or deuterium.
  • R 12 in the compound of formula II or a pharmaceutically acceptable salt thereof is independently selected from halogen, such as fluorine or chlorine.
  • R 12 is independently selected from C 1-6 alkyl, and the alkyl is optionally substituted by one or more R 12A , R 12A is as defined above .
  • R 2 and R 6 are independently selected from methyl, ethyl or propyl.
  • R 11 in the compound of formula II or a pharmaceutically acceptable salt thereof is independently selected from hydrogen.
  • R 13 is independently selected from deuterium or C 1-6 alkoxy, and the alkoxy is optionally substituted by one or more R 13A , R 13A is as defined above.
  • R 13 in the compound of formula II or a pharmaceutically acceptable salt thereof is independently selected from halogen, such as fluorine or chlorine.
  • L is selected from In other embodiments, in the compound of formula II or its pharmaceutically acceptable salt, L is selected from
  • L is selected from
  • L 2 is
  • the compound represented by formula II or a pharmaceutically acceptable salt thereof is selected from:
  • Another aspect of the present disclosure also provides a compound represented by formula III or a pharmaceutically acceptable salt thereof,
  • R 21 and R 22 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, four-membered heterocycloalkyl, six-membered heterocycloalkyl, said alkyl , alkoxy, four-membered heterocycloalkyl or six-membered heterocycloalkyl are optionally substituted by one or more R 21A , each R 21A is independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl,
  • R 21 , R 22 and adjacent carbon atoms form a 3-6 membered heterocycloalkyl group, the heterocycloalkyl group is optionally substituted by one or more R 22A , each R 22A is independently selected from deuterium, halogen , C 1-6 alkyl;
  • R 23 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy is optionally substituted by one or more R 23A , Each R 23A is independently selected from halogen, hydroxyl, cyano or amino;
  • R 24 is independently selected from hydrogen or C 1-6 alkyl
  • S is selected from an integer between 2-4;
  • L 3 is selected from -CH 2 NHCH 2 -, -CH 2 NH-, -NH-, -S-, -S(O)-, -S(O) 2 -, -O-, -OCH 2 -, - OCH 2 CH 2 O-, -NHSO 2 NH-, nitrogen atom,
  • n1 is selected from an integer between 0-4.
  • R 21 is independently selected from four-membered heterocycloalkyl or six-membered heterocycloalkyl
  • R 22 is independently selected from hydrogen, deuterium, halogen, C 1 -6 alkyl or C 1-6 alkoxy, the alkyl, alkoxy, four-membered heterocycloalkyl or six-membered heterocycloalkyl is optionally substituted by one or more R 21A , each of R 21A independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl.
  • R 23 is independently selected from deuterium or C 1-6 alkoxy, and the alkoxy is optionally substituted by one or more R 23A , R 23A is as defined above.
  • R 23 in the compound of formula III or a pharmaceutically acceptable salt thereof is independently selected from halogen, such as fluorine or chlorine.
  • the compound of formula III or a pharmaceutically acceptable salt thereof is
  • L 3 , R 22 , R 23 , R 24 , R 21A , n2, and m2 are as defined above.
  • L 3 is selected from -CH 2 NHCH 2 -, -CH 2 NH-, -NH-, -S-, -S(O)-, - S(O) 2 -, -O-, -OCH 2 -, -OCH 2 CH 2 O-, -NHSO 2 NH- and
  • the compound of formula III or a pharmaceutically acceptable salt thereof is
  • L 3 , R 22 , R 23 , R 24 , R 21A and n2 are as defined above.
  • R 21 and R 22 in the compound of formula III or a pharmaceutically acceptable salt thereof form a 5- or 6-membered heterocycloalkyl group with adjacent carbon atoms, and the heterocycloalkyl group is optionally replaced by one or more R 22A , R 22A are each independently selected from deuterium, halogen, C 1-6 alkyl.
  • the compound of formula III or a pharmaceutically acceptable salt thereof is
  • L 3 , R 22 , R 23 , R 24 , R 22A and n2 are as defined above; p is independently selected from an integer between 0-2.
  • L 3 is selected from -CH 2 NHCH 2 -, -CH 2 NH-, -NH-, -S-, -S(O)-, -S (O) 2 -, -O-, -OCH 2 -, -OCH 2 CH 2 O-, -NHSO 2 NH-
  • the compound of formula III or a pharmaceutically acceptable salt thereof is
  • L 3 , R 22 , R 23 , R 24 , R 21A and n2 are as defined above.
  • p is independently selected from 1 or 2 in the compound of formula III-c or formula III-c1 or a pharmaceutically acceptable salt thereof.
  • L in the compound of formula III-c or formula III-c1 or a pharmaceutically acceptable salt thereof is selected from nitrogen atom,
  • L in the compound of formula III-c or formula III-c1 or a pharmaceutically acceptable salt thereof is selected from nitrogen atom,
  • R 24 is selected from hydrogen.
  • R 23 is selected from hydrogen or C 1-6 alkoxy, and the alkoxy is optionally substituted by one or more R 23A , R 23A is such as the foregoing definition.
  • R 23 is selected from halogen, such as fluorine or chlorine.
  • R 23 is selected from C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by one or more Replaced by R 23A , R 23A is as defined above.
  • R 21A is selected from hydrogen.
  • the compound of Formula III or a pharmaceutically acceptable salt thereof is selected from:
  • the present disclosure also provides isotopic substitutions of the foregoing compounds or pharmaceutically acceptable salts thereof.
  • the isotopic substitution is deuterated.
  • compounds of the present disclosure In competition binding assays, compounds are tested for their in vitro binding affinity to the intended target human apolipoprotein(a).
  • the compound of the present disclosure has a good binding ability in combination with apolipoprotein (a).
  • compounds of the present disclosure bind to apolipoprotein (a) with an IC50 value in the range of 0.01 to 500 nM.
  • compounds of the present disclosure bind to apolipoprotein (a) with an IC50 value in the range of 0.01 to 100 nM.
  • compounds of the present disclosure bind to apolipoprotein (a) with an IC50 value in the range of 0.01 to 20 nM.
  • compounds of the present disclosure bind to apolipoprotein (a) with an IC50 value in the range of 0.01 to 20 nM. at 0.1 to 30 nM. In some embodiments, compounds of the disclosure bind to apolipoprotein (a) with an IC50 value of ⁇ 50 nM.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the compound represented by the aforementioned formula I or II or III or its pharmaceutically acceptable salt, or its isotope substitution and a pharmaceutically acceptable excipient agent.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotope substitutions. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preventing and/or treating diseases or conditions associated with elevated plasma levels of LP(a), by administering to the patient a therapeutically effective amount of the compound shown in the aforementioned formula I or II or III Or its pharmaceutically acceptable salt or its isotope substitution, or the aforementioned pharmaceutical composition.
  • the disease or condition associated with elevated plasma levels of LP(a) is selected from cardiovascular diseases, including but not limited to stroke, hypertensive heart disease, coronary disease.
  • the present disclosure also provides a method for preventing and/or treating patients with cardiovascular disease, which comprises administering to the patient a therapeutically effective amount of a compound represented by the aforementioned formula I or formula II or formula III or a pharmaceutically acceptable salt thereof or Its isotope substitution, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides a compound or a pharmaceutically acceptable salt thereof as shown in the aforementioned formula I or formula II or formula III or the aforementioned pharmaceutical composition used for the prevention and/or treatment of diseases associated with elevated plasma levels of LP(a) or use in medicine for a disease.
  • the disease or condition associated with elevated plasma levels of LP(a) is selected from cardiovascular diseases, including but not limited to stroke, hypertensive heart disease, coronary disease.
  • the present disclosure also provides the use of the compound represented by the aforementioned formula I or formula II or formula III, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cardiovascular diseases.
  • compositions described in the present disclosure may be selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. 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 reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or or both and Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can 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 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, agent, dye/colorant, fragrance enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
  • an “effective amount” or “therapeutically effective amount” as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to permit or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. 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 and various branched isomers, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano, or Amino.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms
  • heterocycloalkyl include: etc.
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano or amino.
  • heterocyclic ring refers to atoms other than carbon atoms that make up the ring, and includes heterocycloalkyl and heteroaryl rings.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC HP pressure liquid chromatography
  • ACQUITY UPLC BEH C18 1.7UM 2.1X50MM chromatographic column, Ultimate XB-C18 3. 0*150mm Column or Xtimate C18 2.1*30mm column.
  • MS uses a Waters SQD2 mass spectrometer to scan in positive/negative ion mode, and the mass scanning range is 100-1200.
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column;
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the flash column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or Changzhou Santai pre-packed pre-packed ultra-pure normal-phase silica gel column (40-63 ⁇ m, 60, 12g ,, 25g, 40g, 80g or other specifications).
  • Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 ⁇ m, 40g, 80g, 120g, 220g or other specifications).
  • the high-pressure column purification system uses Waters AutoP, together with Waters XBridge BEH C18 OBD Prep Column, 5 ⁇ m, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5 ⁇ m, 19mm X 150mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the known starting materials in this disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • 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 agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Step 3 Preparation of (S)-3-(3-bromo-5-fluorophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (1d)
  • compound 1c (2 g, 3.5 mol) was dissolved in tetrahydrofuran (20 mL), and after adding 1M hydrogen peroxide (5 mL), 0.5 M lithium hydroxide aqueous solution (10 mL) was slowly added dropwise, and the reaction was monitored by LCMS. After the reaction was completed, saturated sodium sulfite (10 mL) was added dropwise to quench the reaction, and stirred for 5-10 minutes.
  • reaction solution was cooled to room temperature, centrifuged and filtered, and the filtrate was purified by reverse-phase flash column chromatography (acetonitrile/water) to obtain compound 1f (173 mg, yield 50%) as a yellow oil.
  • Step 6 (R)-3-((S)-3-(3-(aminomethyl)-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl ) Preparation of pyrrolidine-1-carboxylic acid tert-butyl ester (1g)
  • Step 7 (3R)-3-[(2S)-3-(3- ⁇ [bis( ⁇ 3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[ (tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-propionyl]-5-fluorophenyl ⁇ methyl)amino]methyl ⁇ -5-fluorophenyl)-1-(tert-butoxy
  • Step 8 (2S)-3-(3- ⁇ [bis( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]-5-fluorobenzene Preparation of base ⁇ methyl)amino]methyl ⁇ -5-fluorophenyl)-2-[(3R)-pyrrolidin-3-yl]propionic acid (1)
  • Step 1 (S)-tert-butyl 4-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)piperidine-1-carboxylate (2b ) preparation
  • reaction solution was warmed to room temperature and stirred for 24 hours.
  • 2M aqueous hydrochloric acid 250 mL was added, the organic phase was separated and concentrated, and the residue was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate) to obtain oily liquid compound 2b (8 g, yield 96.7%).
  • Step 2 4-((S)-1-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-3-(3-bromophenyl)-1-oxopropane Preparation of -2-yl)piperidine-1-carboxylate tert-butyl ester (2c)
  • Step 3 Preparation of (S)-3-(3-bromophenyl)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (2d)
  • compound 2c (1.5 g, 2.6 mol) was dissolved in tetrahydrofuran (15 mL), and after adding 1M hydrogen peroxide (3.5 mL), 0.5 M lithium hydroxide aqueous solution (7 mL) was slowly added dropwise, and the reaction was monitored by LCMS. After the reaction was completed, saturated sodium sulfite (8 mL) was added dropwise to quench the reaction, and stirred for 5-10 minutes.
  • Step 4 (S)-tert-butyl 4-(3-(3-bromobenzene)-1-(tert-butoxy)-1-oxopropan-2-yl)piperidine-1-carboxylate (2e ) preparation
  • reaction solution was cooled to room temperature, centrifuged and filtered, and the filtrate was purified by reverse-phase flash column chromatography (acetonitrile/water) to obtain yellow oily compound 2f (180 mg, yield 33.7%).
  • Step 7 4-[(2S)-3-(3- ⁇ [Bis( ⁇ 3-[(2S)-3-(tert-butoxy)-2- ⁇ 1-[(tert-butoxy)carbonyl] Piperidin-4-yl ⁇ -3-propionyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]piperidine- Preparation of tert-butyl 1-carboxylate (2h)
  • Step 8 (2S)-3-(3- ⁇ [Bis( ⁇ 3-[(2S)-2-carboxylic acid-2-(piperidin-4-yl)ethyl]phenyl ⁇ methyl)amino] Preparation of methyl ⁇ phenyl)-2-(piperidin-4-yl)propionic acid (2)
  • Dissolve compound 3a (2.4g, 5.28mmol) prepared according to the method in patent WO2020247429 in anhydrous tetrahydrofuran (50mL), cool to -78°C, add 2M lithium diisopropylamide tetrahydrofuran solution (5.28mL), and react at low temperature After 30 minutes, N-fluorobisbenzenesulfonamide (5.0 g, 15.85 mmol) was added. The reaction was gradually warmed to room temperature and reacted for 16 hours. After the completion of the reaction was detected by LCMS, saturated ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate (20 mL ⁇ 2).
  • Step 5 3-[3-( ⁇ bis[(3- ⁇ 2-carboxy-2-fluoro-2-[(3S)-pyrrolidin-3-yl]ethyl ⁇ phenyl)methyl]amino ⁇ methanol yl)phenyl]-2-fluoro-2-[(3S)-pyrrolidin-3-yl]propionic acid (3)
  • reaction liquid was cooled to room temperature and centrifuged, and the filtrate was purified by reverse-phase flash column chromatography (acetonitrile/water) to obtain compound 4a (270 mg, yield 76%) as a yellow oil.
  • Step 2 (3R)-3-[(2S)-3- ⁇ 3-[( ⁇ 2-[bis( ⁇ 3-[(2S)-3-(tert-butoxy)-2-[(3R) -1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-propionyl]phenyl ⁇ methyl)amino]ethyl ⁇ ( ⁇ 3-[(2S)-3-(tert-butyl Oxygen)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-propionyl]phenyl ⁇ methyl)amino)methyl]phenyl ⁇ - 1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (4b) and (3R)-3-[(2S)-1-(tert-butoxy Base)-3-(3- ⁇ [( ⁇ 3-[(2S)-3-(tert
  • compound 1b (10.0g, 25.74mmol) was dissolved in tetrahydrofuran (10mL), cooled to -30°C, 1M bis(trimethylsilyl)amide lithium tetrahydrofuran solution (31mL, 31mmol) was added dropwise, and the addition was completed Reaction lasted for 30 minutes; a solution of 3-benzyloxybenzyl bromide (8.56g, 30.89mmol) in tetrahydrofuran (15mL) was added dropwise, reacted for 1 hour, and heated to 0°C-5°C overnight.
  • Step 2 Preparation of (S)-3-(3-(benzyloxy)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (6b)
  • Step 7 (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-3-(tert-butoxy)- 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-3 -(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl ⁇ methyl)amino]methyl
  • phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (6g)
  • Step 8 (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-Carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ Ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2- Preparation of [(3R)-pyrrolidin-3-yl]propionic acid tetrahydrochloride (6)
  • Step 1 (R)-3-((S)-3-(3-((2-(((Benzyloxy)carbonyl)amino)ethyl)amino)phenyl)-1-(tert-butoxy
  • Step 2 (R)-3-((S)-3-(3-((2-aminoethyl)amino)phenyl)-1-(tert-butoxy)-1-oxopropane-2- Base) the preparation of pyrrolidine-1-carboxylate tert-butyl ester (7b)
  • Step 4 (2S)-3-[3-( ⁇ [2-( ⁇ 3-[(2S)-2-Carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ Amino)ethyl]( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino ⁇ methyl)phenyl]- Preparation of 2-[(3R)-pyrrolidin-3-yl]propionic acid pentahydrochloride (7)
  • Test Example 1 Compound inhibits Lp(a) assembly activity test
  • This disclosure uses double antibody ELISA method to detect the assembly efficiency of Apo(a) and ApoB protein, the antibodies are ApoB-Capture antibody (Mabtech) and Apo(a)-Detector antibody (Abcam); the detection samples are human transgenic hApo(a ) and hApoB mouse plasma were diluted 500 times for use.
  • reaction solution to the ELISA detection plate pre-coated with ApoB-Capture antibody, incubate at room temperature for 2 hours, and then wash the plate 4 times with washing solution; add biotin-labeled Apo(a)-Detector antibody, and incubate at room temperature for 1 hour , wash the plate and add the chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB, purchased from Abcam) solution; after incubating at room temperature for 15 minutes, add the reaction stop solution, mix well and immediately use the enzyme The standard instrument detects the absorbance at 450nm. Finally, GraphPad Prism 9 software was used for data analysis and IC50 calculation.
  • TMB 3,3',5,5'-tetramethylbenzidine
  • the 0% inhibition rate of Apo (a) and ApoB protein assembly corresponds to the OD value when the compound concentration is 0 (1%DMSO); the 100% inhibition rate of Apo (a) and ApoB protein assembly corresponds to adding only ApoB protein solution ( hApoB mouse plasma dilutions) when the OD value.
  • the LC/MS/MS method was used to determine the drug concentration in blood plasma of Beagle dogs at different times after intragastric administration of the compound of the present disclosure. To study the pharmacokinetic behavior of the disclosed compound in Beagle dogs, and evaluate its pharmacokinetic characteristics.
  • Drug preparation Weigh a certain amount of drug, add normal saline to make a 2 mg/mL colorless and clear solution.
  • Beagle dogs are given the compound of the disclosure by intragastric administration, and about 0.6 mL of blood is collected by peripheral venipuncture at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 , 4°C, centrifuge at 2000 rpm for 10 minutes to separate the plasma, and store it at -75°C.
  • Determination of the content of the compound to be tested in Beagle dog plasma at different blood collection time points Take 33 ⁇ L of Beagle dog plasma (30 ⁇ L plasma and 3 ⁇ L blank) taken at various times after administration and add it to 18 ⁇ L of 6% perchloric acid solution, vortex Mix for 30 seconds, centrifuge at 3900 rpm for 15 minutes at 4°C, then add 200 ⁇ L of acetonitrile solution containing internal standard dexamethasone after alkalinization (adjust the pH to 10-11 with ammonia water) to precipitate protein, and vortex for 30 seconds. Centrifuge at 3900 rpm for 15 minutes at 4°C, take the supernatant from the plasma sample, dilute it 3 times with water, and take 8 ⁇ L for LC/MS/MS analysis.
  • WinNonlin 6.1 software was used to calculate pharmacokinetic parameters by non-compartmental model method.
  • the beagle pharmacokinetic parameters of the disclosed compounds are shown in Table 2 below.
  • Compound 6 has better oral absorption in Beagle dogs, better blood exposure, long half-life, excellent pharmacokinetic characteristics, and oral administration has obvious advantages.
  • Test Example 3 In vivo pharmacokinetic experiment in cynomolgus monkeys
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after intragastric administration of the compound of the present disclosure to cynomolgus monkeys.
  • the pharmacokinetic behavior of the disclosed compound in cynomolgus monkeys was studied, and its pharmacokinetic characteristics were evaluated.
  • mice 2 cynomolgus monkeys (one male and one female) healthy for 24-36 months in each group
  • Drug preparation Weigh a certain amount of drug and add physiological saline to make 10 mg/mL (reference substance 1) and 3 mg/mL (compound 6) colorless and clear solutions.
  • cynomolgus monkeys administered the compound of the present disclosure by intragastric administration 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours after administration, about 0.5 mL of blood was collected by peripheral venipuncture, and placed in a test tube containing EDTA-K2 , 4°C, centrifuge at 2000 rpm for 10 minutes to separate the plasma, and store it at -75°C.
  • Determination of the content of the compound to be tested in cynomolgus monkey plasma at different blood collection time points Take 33 ⁇ L of cynomolgus monkey plasma (30 ⁇ L plasma and 3 ⁇ L blank) taken at various times after administration and add it to 18 ⁇ L of 6% perchloric acid solution, vortex Mix for 30 seconds, centrifuge at 3900 rpm for 15 minutes at 4°C, then add 200 ⁇ L of acetonitrile solution containing internal standard dexamethasone after alkalinization (adjust the pH to 10-11 with ammonia water) to precipitate protein, and vortex for 30 seconds. Centrifuge at 3900 rpm for 15 minutes at 4°C, take the supernatant from the plasma sample, dilute it 3 times with water, and take 8 ⁇ L for LC/MS/MS analysis.
  • WinNonlin 6.1 software was used to calculate pharmacokinetic parameters by non-compartmental model method.
  • the pharmacokinetic parameters of the compounds of the present disclosure in cynomolgus monkeys are shown in Table 3 below.
  • mice were used as test animals, and a high dose of the disclosed compound was orally gavaged, and the mice were clinically observed to evaluate the safety of the disclosed compound.
  • mice Take 8 male C57/6J mice, numbered 1-8 respectively, and weigh them. Fasted for 4 hours before the start of the experiment, and weighed after the fast (0h). 6 rats with average body weight were selected into the group, 3 rats in each group, divided into 2 groups.
  • the first group (G1) was given the reference substance 1, and the second group (G2) was given the compound Example 6 of the present disclosure.
  • the compounds in the G1 and G2 groups were all administered orally by gavage, the dose was 1000mg/kg, and the solvents were all normal saline.
  • the mice in the experimental group were clinically observed at 15min, 30min, 1h, 2h, 4h, 6h, and 24h after administration. Both groups were given food 2 hours after the medicine. The body weight of the mice was monitored for 7 consecutive days, and the results are shown in Table 4 below.

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Abstract

提供一种取代的苯丙酸衍生物及其用途，具体提供一种如式II所示化合物或其可药用盐，可用于制备预防和/或治疗心血管疾病的药物。

Description

一种取代的苯丙酸衍生物及其用途 技术领域
本公开属于医药领域，涉及一种取代的苯丙酸衍生物及其用途。
背景技术
脂蛋白(a)[Lp(a)]是一种类低密度脂蛋白的血脂颗粒，主要由富含胆固醇酯的内核和特有的载脂蛋白(a)[Apo(a)]组成，具有基因多态性和长期稳定的特点，在人群中呈偏态分布。有研究发现Lp(a)升高与罹患心血管事件风险增加及相关血运重建有关。
现已有多种针对LDL-c升高、HDL-c降低和甘油三酸酯升高的治疗方案，而对于Lp(a)浓度升高的患者还没有批准的治疗药物。
WO2020247429报道了一类吡咯烷酮类脂蛋白抑制剂，该类化合物与人Apo(a)蛋白结合。通过与Apo(a)蛋白质结合来抑制LDL颗粒与apo(a)的结合，达到降低血浆中Lp(a)水平，
Figure PCTCN2022129479-appb-000001
本公开的化合物并没有在任何文献中公开，且该类化合物展现特异性与人Apo(a)蛋白结合，进而达到降低血浆中Lp(a)水平。
发明内容
本公开(The disclosure)提供了式I所示化合物或其可药用盐，
Figure PCTCN2022129479-appb-000002
其中R 1、R 5独立地选自氢或C 1-6烷基，所述烷基任选被一个或多个R 1A所取代，R 1A各自独立地选自卤素、羟基、氰基或氨基；
R 2、R 6独立地选自氢、氘、卤素或C 1-6烷基，所述烷基任选被一个或多个R 2A所取代，R 2A各自独立地选自卤素、羟基、氰基或氨基；
R 3、R 7独立地选自氢、氘、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述烷基或 烷氧基任选被一个或多个R 3A所取代，R 3A各自独立地选自卤素、羟基、氰基或氨基；
且，R 2、R 3、R 6、R 7不同时为氢或甲基；
R 4、R 8独立地选自氢或C 1-6烷基；
L 1选自-CH 2NHCH 2-、-CH 2NH-、-NH-、-S-、-S(O)-、-S(O) 2-、-O-、-OCH 2-、-OCH 2CH 2O-、-NHSO 2NH-、
Figure PCTCN2022129479-appb-000003
R a选自氢或C 1-6烷基，所述烷基任选被一个或多个R 4A所取代，R 4A各自独立地选自卤素、羟基、氰基或氨基；
R b选自氢、氘、卤素或C 1-6烷基，所述烷基任选被一个或多个R 5A所取代，R 5A各自独立地选自卤素、羟基、氰基或氨基；
R c独立地选自氢、氘、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R 6A所取代，R 6A各自独立地选自卤素、羟基、氰基或氨基；
R d选自氢或C 1-6烷基；
n、m、o各自独立选自0～4之间整数。
在一些实施方案中，式I化合物或其可药用盐中R 2、R 6独立地选自氘。
在一些实施方案中，式I化合物或其可药用盐中R 2、R 6独立地选自卤素，例如氟或氯。
在一些实施方案中，式I化合物或其可药用盐中R 2、R 6独立地选自C 1-6烷基，所述烷基任选被一个或多个R 2A所取代，R 2A如前述所定义。在一些实施方案中，式I化合物或其可药用盐中R 2、R 6独立地选自甲基、乙基或丙基。
在一些实施方案中，式I化合物或其可药用盐中R 1、R 5独立地选自氢。
在一些实施方案中，式I化合物或其可药用盐中R 3、R 7独立地选自氘或C 1-6烷氧基，所述烷氧基任选被一个或多个R 3A所取代，R 3A如前述所定义。
在一些实施方案中，式I化合物或其可药用盐中R 3、R 7独立地选自卤素，例如氟或氯。
在一些实施方案中，式I化合物或其可药用盐中R 3、R 7独立地选自C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R 3A所取代，R 3A如前述所定义。
进一步地，在某一些实施方案中，式I化合物或其可药用盐中L 1选自-CH 2NHCH 2-、-CH 2NH-、-NH-、-O-、-OCH 2-、-OCH 2CH 2O-、-NHSO 2NH-，优选-CH 2NHCH 2-、-CH 2NH-、-NH-、-OCH 2CH 2O-。
在另一些实施方案中，式I化合物或其可药用盐中L 1选自
Figure PCTCN2022129479-appb-000004
其中o、R a、R b、R c如前述所定义。
在另一些实施方案中，式I化合物或其可药用盐中R b选自氘。
在另一些实施方案中，式I化合物或其可药用盐中R b选自卤素，例如氟或氯。
在另一些实施方案中，式I化合物或其可药用盐中R b选自C 1-6烷基，所述烷基任选被一个或多个R 5A所取代，R 5A如前述所定义。在一些实施方案中，式I化合物或其可药用盐中R b独立地选自甲基、乙基或丙基。
在一些实施方案中，式I化合物或其可药用盐中R a选自氢。
在一些实施方案中，式I化合物或其可药用盐中R c独立地选自氢或C 1-6烷氧基，所述烷氧基任选被一个或多个R 6A所取代，R 6A如前述所定义。
在一些实施方案中，式I化合物或其可药用盐中R c独立地选自卤素，例如氟或氯。
在一些实施方案中，式I化合物或其可药用盐中R c独立地选自C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R 6A所取代，R 6A如前述所定义。
本公开中式I化合物或其可药用盐包括但不限于：
Figure PCTCN2022129479-appb-000005
Figure PCTCN2022129479-appb-000006
Figure PCTCN2022129479-appb-000007
在一些实施方案中，式I化合物或其可药用盐选自：
Figure PCTCN2022129479-appb-000008
Figure PCTCN2022129479-appb-000009
本公开另一方面还提供了式II所示化合物或其可药用盐，
Figure PCTCN2022129479-appb-000010
其中R 11独立地选自氢或C 1-6烷基，所述烷基任选被一个或多个R 11A所取代，R 11A各自独立地选自卤素、羟基、氰基或氨基；
R 12独立地选自氢、氘、卤素或C 1-6烷基，所述烷基任选被一个或多个R 12A所取代，R 12A各自独立地选自卤素、羟基、氰基或氨基；
R 13独立地选自氢、氘、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R 13A所取代，R 13A各自独立地选自卤素、羟基、氰基或氨基；
R 14独立地选自氢或C 1-6烷基；
W选自3或4；
L 2选自
Figure PCTCN2022129479-appb-000011
Figure PCTCN2022129479-appb-000012
n1选自0-4之间整数。
在一些实施方案中，式II化合物或其可药用盐中R 12独立地选自氢或氘。
在一些实施方案中，式II化合物或其可药用盐中R 12独立地选自卤素，例如氟或氯。
在一些实施方案中，式II化合物或其可药用盐中R 12独立地选自C 1-6烷基，所述烷基任选被一个或多个R 12A所取代，R 12A如前述定义。在另一些实施方案中，式II化合物或其可药用盐中R 2、R 6独立地选自甲基、乙基或丙基。
在一些实施方案中，式II化合物或其可药用盐中R 11独立地选自氢。
在一些实施方案中，式II化合物或其可药用盐中R 13独立地选自氘或C 1-6烷氧基，所述烷氧基任选被一个或多个R 13A所取代，R 13A如前述定义。
在一些实施方案中，式II化合物或其可药用盐中R 13独立地选自卤素，例如氟或氯。
在另一些实施方案中，式II化合物或其可药用盐中L 2选自
Figure PCTCN2022129479-appb-000013
Figure PCTCN2022129479-appb-000014
Figure PCTCN2022129479-appb-000015
在另一些实施方案中，式II化合物或其可药用盐中L 2选自
Figure PCTCN2022129479-appb-000016
Figure PCTCN2022129479-appb-000017
在另一些实施方案中，式II化合物或其可药用盐中L 2选自
Figure PCTCN2022129479-appb-000018
Figure PCTCN2022129479-appb-000019
在另一些实施方案中，式II化合物或其可药用盐中L 2为
Figure PCTCN2022129479-appb-000020
本公开中式II化合物或其可药用盐包括但不限于：
Figure PCTCN2022129479-appb-000021
Figure PCTCN2022129479-appb-000022
在一些实施方案中，式II所示化合物或其可药用盐选自：
Figure PCTCN2022129479-appb-000023
Figure PCTCN2022129479-appb-000024
本公开另一方面还提供了式III所示化合物或其可药用盐，
Figure PCTCN2022129479-appb-000025
其中，R 21、R 22独立地选自氢、氘、卤素、C 1-6烷基、C 1-6烷氧基、四元杂环烷基、六元杂环烷基，所述烷基、烷氧基、四元杂环烷基或六元杂环烷基任选被一个或多个R 21A所取代，R 21A各自独立地选自氢、氘、卤素或C 1-6烷基，
或者，R 21、R 22与相邻碳原子形成3-6元杂环烷基，所述杂环烷基任选被一个 或多个R 22A所取代，R 22A各自独立地选自氘、卤素、C 1-6烷基；
R 23独立地选自氢、氘、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R 23A所取代，R 23A各自独立地选自卤素、羟基、氰基或氨基；
R 24独立地选自氢或C 1-6烷基；
S选自2-4之间整数；
L 3选自-CH 2NHCH 2-、-CH 2NH-、-NH-、-S-、-S(O)-、-S(O) 2-、-O-、-OCH 2-、-OCH 2CH 2O-、-NHSO 2NH-、氮原子、
Figure PCTCN2022129479-appb-000026
Figure PCTCN2022129479-appb-000027
n1选自0-4之间整数。
在一些实施方案中，式III化合物或其可药用盐中R 21独立地选自四元杂环烷基或六元杂环烷基，R 22独立地选自氢、氘、卤素、C 1-6烷基或C 1-6烷氧基，所述烷基、烷氧基、四元杂环烷基或六元杂环烷基任选被一个或多个R 21A所取代，R 21A各自独立地选自氢、氘、卤素、C 1-6烷基。
在一些实施方案中，式III化合物或其可药用盐中R 23独立地选自氘或C 1-6烷氧基，所述烷氧基任选被一个或多个R 23A所取代，R 23A如前述所定义。
在一些实施方案中，式III化合物或其可药用盐中R 23独立地选自卤素，例如氟或氯。
在一些实施方案中，式III化合物或其可药用盐为
Figure PCTCN2022129479-appb-000028
其中L 3、R 22、R 23、R 24、 R 21A、n2、m2如前述定义。
在另一些实施方案中，式III化合物或其可药用盐中L 3选自-CH 2NHCH 2-、-CH 2NH-、-NH-、-S-、-S(O)-、-S(O) 2-、-O-、-OCH 2-、-OCH 2CH 2O-、-NHSO 2NH-和
Figure PCTCN2022129479-appb-000029
在另一些实施方案中，式III化合物或其可药用盐为
Figure PCTCN2022129479-appb-000030
Figure PCTCN2022129479-appb-000031
其中L 3、R 22、R 23、R 24、R 21A、n2如前述定义。
在一些实施方案中，式III化合物或其可药用盐中R 21、R 22与相邻碳原子形成5或6元杂环烷基，所述杂环烷基任选被一个或多个R 22A所取代，R 22A各自独立地选自氘、卤素、C 1-6烷基。
在另一些实施方案中，式III化合物或其可药用盐为
Figure PCTCN2022129479-appb-000032
其中L 3、R 22、R 23、R 24、R 22A、n2如前述定义；p独立地选自0-2之间整数。
在一些实施方案中，式III化合物或其可药用盐中L 3选自-CH 2NHCH 2-、-CH 2NH-、-NH-、-S-、-S(O)-、-S(O) 2-、-O-、-OCH 2-、-OCH 2CH 2O-、-NHSO 2NH-
Figure PCTCN2022129479-appb-000033
在一些实施方案中，式III化合物或其可药用盐为
Figure PCTCN2022129479-appb-000034
其中L 3、R 22、R 23、R 24、R 21A、n2如前述定义。
在一些实施方案中，式III-c或式III-c1化合物或其可药用盐中p独立地选自1或2。
在一些实施方案中，式III-c或式III-c1化合物或其可药用盐中L 3选自氮原子、
Figure PCTCN2022129479-appb-000035
在一些实施方案中，式III-c或式III-c1化合物或其可药用盐中L 3选自氮原子、
Figure PCTCN2022129479-appb-000036
在一些实施方案中，式III或式III-c或式III-c1化合物或其可药用盐中R 24选自氢。
在一些实施方案中，式III化合物或其可药用盐中R 23选自氢或C 1-6烷氧基，所述烷氧基任选被一个或多个R 23A所取代，R 23A如前述定义。
在一些实施方案中，式III化合物或其可药用盐中R 23选自卤素，例如氟或氯。
在一些实施方案中，式III化合物或其可药用盐中R 23选自C 1-6烷基或C 1-6烷 氧基，所述烷基或烷氧基任选被一个或多个R 23A所取代，R 23A如前述定义。
在一些实施方案中，式III化合物或其可药用盐中R 21A选自氢。
本公开中式III所示化合物或其可药用盐包括但不限于：
Figure PCTCN2022129479-appb-000037
在一些实施方案中，式III化合物或其可药用盐选自：
Figure PCTCN2022129479-appb-000038
本公开还提供前述化合物或其可药用盐的同位素取代物。在一些实施方案中，所述同位素取代物为氘代物。
在竞争结合试验中，测试化合物与预期目标人类载脂蛋白(a)的体外结合亲和力。本公开化合物与载脂蛋白(a)结合具有较好的结合力。在一些实施方案中，本公开化合物与载脂蛋白(a)结合的IC50值在0.01至500nM。在一些实施方案中，本公开化合物与载脂蛋白(a)结合的IC50值在0.01至100nM。在一些实施方案中，本公开化合物与载脂蛋白(a)结合的IC50值在0.01至20nM。在一些实施方案中，本公开化合物与载脂蛋白(a)结合的IC50值在0.01至20nM。在0.1至30nM。在一些实施方案中，本公开化合物与载脂蛋白(a)结合的IC 50值<50nM。
本公开中还提供了一种药物组合物，包括至少一种治疗有效量的前述式I或II或III所示化合物或其可药用盐、或其同位素取代物以及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开还提供一种预防和/或治疗与LP(a)血浆水平升高相关的疾病或病症的方法，其通过向所述患者施用治疗有效量的如前述式I或II或III所示化合物或其可药用盐或其同位素取代物，或前述药物组合物。
在一些实施方案中，与LP(a)血浆水平升高相关的疾病或病症选自心血管疾病，包括但不限于中风、高血压性心脏病、冠性病。
本公开还提供一种预防和/或治疗患有心血管疾病患者的方法，其包括向所述患者施用治疗有效量的如前述式I或式II或式III所示化合物或其可药用盐或其同位素取代物、或前述药物组合物。
本公开还提供了如前述式I或式II或式III所示化合物或其可药用盐或前述药物组合物在制备用于预防和/或治疗与LP(a)血浆水平升高相关的疾病或病症的药物中的用途。在一些实施方案中，与LP(a)血浆水平升高相关的疾病或病症选自心 血管疾病，包括但不限于中风、高血压性心脏病、冠性病。
本公开还提供了如前述式I或式II或式III所示化合物或其可药用盐或前述药物组合物在制备用于预防和/或治疗心血管疾病的药物中的用途。
本公开中所述化合物可药用盐可选自无机盐或有机盐。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开所述化合物的化学结构中，键
Figure PCTCN2022129479-appb-000039
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022129479-appb-000040
可以为
Figure PCTCN2022129479-appb-000041
或
Figure PCTCN2022129479-appb-000042
或者同时包含
Figure PCTCN2022129479-appb-000043
和
Figure PCTCN2022129479-appb-000044
两种构型。
本公开所述化合物的化学结构中，键
Figure PCTCN2022129479-appb-000045
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022129479-appb-000046
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“治疗有效量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
“烷基”指饱和的脂族烃基团，包括1至6个碳原子的直链和支链基团。非 限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氰基或氨基。
术语“杂环烷基(Heterocycloalkyl)”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至6个环原子，“杂环烷基”非限制性实例包括：
Figure PCTCN2022129479-appb-000047
Figure PCTCN2022129479-appb-000048
等等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢、氘、卤素或C 1-6烷基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氰基或氨基。
术语“杂环”指构成环的原子除碳原子外还有其他原子，其包括杂环烷基和杂芳环。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“氨基”指-NH 2。
术语“氧代”指＝O取代基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶 剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100～1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60，12g,，25g，40g，80g或其他规格)。
反相柱层析一般使用常州三泰预填超纯C18硅胶柱(20-45μm，
Figure PCTCN2022129479-appb-000049
40g，80g，120g，220g或其他规格)。
高压柱纯化系统使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，
Figure PCTCN2022129479-appb-000050
5μm，19mm X 150mm或者Atlantis T3 OBD Prep Column，
Figure PCTCN2022129479-appb-000051
5μm，19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或 HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
Figure PCTCN2022129479-appb-000052
(2S)-3-(3-{[双({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]-5-氟苯基}甲基)氨基]甲基}-5-氟苯基)-2-[(3R)-吡咯烷-3-基]丙酸(化合物1)
Figure PCTCN2022129479-appb-000053
步骤1:(R)-3-(2-((S)-4-苄基-2-氧代噁唑烷-3-基)-2-氧代乙基)吡咯烷-1-羧酸叔丁酯(1b)的制备
将原料(R)-N-叔丁氧羰基-3-四氢吡咯乙酸(化合物1a，9g,39mmol)溶于无水四氢呋喃(100mL)，冷却至0℃，加入三乙胺(13.6mL,98mmol)，0℃下搅拌反应5分钟。加入新戊酰氯(5.8g，47.1mmol)，加入过程中温度不超过10℃，搅拌反应15分钟后，加入氯化锂(1.9g，47.1mmol)和溶有(S)-4-苄基-2-噁唑烷酮(6.9g，39mmol)的四氢呋喃溶液(100mL)。反应液升至室温，搅拌24小时。加入2M盐酸水溶液(500mL)，分离得到有机相，浓缩，剩余物经硅胶快速柱层析(石油醚/乙酸乙酯)纯化得到油状液体化合物1b(12.5g,收率82％)。
MS(ESI):m/z＝411.1[M+Na] +。
步骤2：(R)-3-((S)-1-((S)-4-苄基-2-氧代噁唑烷-3-基)-3-(3-溴-5-氟苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(1c)的制备
将化合物1b(3.5g,9mmol)溶于无水四氢呋喃(50mL)，氮气保护，冷却至0℃，滴加1M双(三甲基硅基)酰胺锂四氢呋喃溶液(10mL,10mmol)，反应15分钟后，缓慢滴加溶有3-氟-5-溴溴苄(2.8g,10.8mmol)的四氢呋喃溶液(25mL)，反应过夜。LCMS监测反应完成后，加入饱和NH 4Cl溶液(10mL)淬灭反应，乙酸乙酯萃取，有机相浓缩得到粗品，粗品经反相快速柱层析(乙腈/水)纯化得化合物1c(1.8g,收率34.6％)。
MS(ESI):m/z＝597.4[M+Na] +
步骤3：(S)-3-(3-溴-5-氟苯基)-2-((R)-1-(叔丁氧羰基)吡咯烷-3-基)丙酸(1d)的制备
冰浴下，将化合物1c(2g,3.5mol)溶于四氢呋喃(20mL)，加入1M双氧水(5mL)后，缓慢滴加0.5M氢氧化锂水溶液(10mL)，LCMS监测反应。反应结束后，滴加饱和亚硫酸钠(10mL)淬灭反应，搅拌5-10分钟。滴加5M氢氧化钠水溶液，调节pH>12，加入水，乙酸乙酯(100mL)萃取，收集水相，用2M盐酸水溶液调pH至3左右，乙酸乙酯萃取(100mL×2)，分离得到有机相，浓缩得到黄色油状液体化合物1d，无需纯化，直接用于下一步。
MS(ESI):m/z＝361.7[M-C(CH 3) 3+H] +。
步骤4：(R)-3-((S)-3-(3-溴-5-氟苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(1e)的制备
将化合物1d(1.8g,4.3mmol)溶于2-甲基四氢呋喃(25mL)，加入O-叔丁基-N,N'-二异丙基异脲(2.17g,10.8mmol)，升温至65℃反应3小时后，加入O-叔丁基-N,N'-二异丙基异脲(862mg,4.3mmol)，搅拌反应过夜。LCMS监测反应结束后，过滤，滤液浓缩，剩余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到化合物1e(1.3g,收率64％)。
MS(ESI)m/z＝361.7[M-2C(CH 3) 3+H] +。
步骤5：(R)-3-((S)-1-(叔丁氧基)-3-(3-氟-5-甲酰基苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(1f)的制备
将化合物1e(430mg,0.9mmol)，醋酸钯(40mg，0.2mmol)，1,4-双(二苯基膦)丁烷(83mg，0.2mmol)、N-甲酰糖精(442mg，2.1mmol)，碳酸钠(270mg，2.5mmol)和三乙基硅烷(174mg，1.5mmol)加入到20mL微波反应管中，氮气保护，加入无水N,N-二甲基甲酰胺(6ml)，立即用塑料螺帽密封。室温下搅拌混合物10分钟，随后将反应液加热至75℃，反应16小时。LCMS监测反应结束后，将反应液冷却至室温，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到黄色油状化合物1f(173mg,收率50％)。
MS(ESI):m/z＝444.4[M+Na] +。
步骤6：(R)-3-((S)-3-(3-(氨基甲基)-5-氟苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(1g)的制备
将化合物1f(100mg,0.23mmol)溶于7M氨甲醇溶液(2mL)，滴加1滴乙酸并加入分子筛，室温搅拌15分钟，加入氰基硼氢化钠(150mg,2.3mmol)，封管微波80℃反应1小时。反应结束后，冷却至室温，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到黄色油状化合物1g(60mg，收率60％)。
MS(ESI):m/z＝423.8[M+H] +。
步骤7：(3R)-3-[(2S)-3-(3-{[双({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰 基]吡咯烷-3-基]-3-丙酰基]-5-氟苯基}甲基)氨基]甲基}-5-氟苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(1h)的制备
将化合物1g(60mg,0.14mmol)溶于无水甲醇(8mL)，加入化合物1f(180mg,0.412mmol)，室温下滴加1滴乙酸并加入分子筛，搅拌反应15分钟，加入氰基硼氢化钠(100mg,1.4mmol)，升温至75℃反应4小时后，室温反应过夜。LCMS监测反应结束后，加入少量DMF溶解，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到白色固体化合物1h(130mg，收率74.2％)。
MS(ESI):m/z＝1233.9[M+H] +
步骤8：(2S)-3-(3-{[双({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]-5-氟苯基}甲基)氨基]甲基}-5-氟苯基)-2-[(3R)-吡咯烷-3-基]丙酸(1)的制备
将化合物1h(130mg,0.105mmol)溶于无水二氧六环(1mL)，加入4M氯化氢二氧六环溶液(3mL)，室温反应。LCMS监测反应完成后，将反应液浓缩，粗品经反相制备(乙腈/水+1％甲酸)得到标题化合物1(45mg,收率55.8％)。
MS(ESI):m/z＝765.3[M+H] +。
1H NMR(400MHz,D 2O)δ8.45(s,1H),7.10(d,J＝9.7Hz,3H),7.06–7.00(m,6H),4.27(s,6H),3.64–3.54(m,3H),3.49–3.38(m,3H),3.32–3.22(m,3H),3.08–2.99(m,3H),2.88–2.73(m,6H),2.56–2.42(m,6H),2.20–2.08(m,3H),1.78(d,J＝9.6Hz,3H)。
实施例2
Figure PCTCN2022129479-appb-000054
(2S)-3-(3-{[双({3-[(2S)-2-羧酸-2-(哌啶-4-基)乙基]苯基}甲基)氨基]甲基}苯基)-2-(哌啶-4-基)丙酸(2)
Figure PCTCN2022129479-appb-000055
步骤1：(S)-4-(2-(4-苄基-2-氧代噁唑烷-3-基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(2b)的制备
将原料1-叔丁氧羰基-4-哌啶乙酸(化合物2a，5g,21mmol)溶于无水四氢呋喃(50mL)，冷却至0℃，加入三乙胺(7.5mL,51mmol)，0℃下搅拌反应5分钟,加入新戊酰氯(3.0g，24mmol)。加入过程中温度不超过10℃，搅拌15分钟后，加入氯化锂(1.0g，24mmol)和溶有(S)-4-苄基-2-噁唑烷酮(3.6g，22mmol)的四氢呋喃溶液(50mL)。反应液升至室温，搅拌24小时。加入2M盐酸水溶液(250mL)，分离得到有机相，浓缩，剩余物经硅胶快速柱层析(石油醚/乙酸乙酯)纯化得到油状液体化合物2b(8g,收率96.7％)。
MS(ESI):m/z＝425.6[M+Na] +。
步骤2：4-((S)-1-((S)-4-苄基-2-氧代噁唑烷-3-基)-3-(3-溴苯基)-1-氧代丙烷-2-基)哌啶-1-羧酸叔丁酯(2c)的制备
将化合物2b(5g,12mmol)溶于无水四氢呋喃(80mL)，氮气保护，冷却至0℃，
滴加1M双(三甲基硅基)酰胺锂四氢呋喃溶液(15mL,15mmol)，反应15分钟后，缓慢滴加溶有3-溴苄溴(3g,12mmol)的四氢呋喃溶液(15mL)，反应过夜。LCMS监测反应完成后，加入饱和NH 4Cl溶液(15mL)淬灭反应，乙酸乙酯萃取，有机相浓缩得到粗品，粗品经反相快速柱层析(乙腈/水)纯化得化合物2c(1.8g,收率25.3％)。
MS(ESI):m/z＝593.5[M+Na] +。
步骤3：(S)-3-(3-溴苯基)-2-(1-(叔丁氧羰基)哌啶-4-基)丙酸(2d)的制备
冰浴下，将化合物2c(1.5g,2.6mol)溶于四氢呋喃(15mL)，加入1M双氧水(3.5mL)后，缓慢滴加0.5M氢氧化锂水溶液(7mL)，LCMS监测反应。反应结束后，滴加饱和亚硫酸钠(8mL)淬灭反应，搅拌5-10分钟。滴加5M氢氧化钠水溶液，调节pH>12，加入水，乙酸乙酯(80mL)萃取，收集水相，用2M盐酸水溶液调pH至3左右，乙酸乙酯萃取(80mL×2)，分离得到有机相，浓缩得到黄色油状液体化合物2d，无需纯化，直接用于下一步。
MS(ESI):m/z＝358.7[M-C(CH 3) 3+H] +。
步骤4：(S)-4-(3-(3-溴苯)-1-(叔丁氧基)-1-氧代丙烷-2-基)哌啶-1-羧酸叔丁酯(2e)的制备
将化合物2d(1.0g,2.4mmol)溶于2-甲基四氢呋喃(20mL)，加入O-叔丁基-N,N'-二异丙基异脲(1.21g,6mmol)，升温至65℃反应3小时后，加入O-叔丁基-N,N'-二异丙基异脲(481mg,2.4mmol)，搅拌反应过夜。LCMS监测反应结束后，过滤，滤液浓缩，剩余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到化合物2e(600mg,收率52.8％)。
MS(ESI)m/z＝358.7[M-2C(CH 3) 3+H] +。
步骤5：(S)-4-(1-(叔丁氧基)-3-(3-甲酰基苯基)-1-氧代丙烷-2-基)哌啶-1-羧酸叔丁酯(2f)的制备
将化合物2e(600mg,1.2mmol)，醋酸钯(58mg，0.3mmol)，1,4-双(二苯基膦)丁烷(102mg，0.3mmol)、N-甲酰糖精(622mg，3.0mmol)，碳酸钠(380mg，3.6mmol)和三乙基硅烷(256mg，2.2mmol)加入到20mL微波反应管中，氮气保护，加入无水N,N-二甲基甲酰胺(10ml)，立即用塑料螺帽密封。室温下搅拌混合物10分钟，随后将反应液加热至75℃，反应16小时。LCMS监测反应结束后，将反应液冷却至室温，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到黄色油状化合物2f(180mg,收率33.7％)。
MS(ESI):m/z＝440.3[M+Na] +。
步骤6：(S)-4-(3-(3-(氨基甲基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)哌啶-1-羧酸叔丁酯(2g)的制备
将化合物2f(80mg,0.19mmol)溶于7M氨甲醇溶液(2mL)，滴加1滴乙酸，室温搅拌15分钟,加入氰基硼氢化钠(150mg,2.3mmol)，封管微波80℃反应1小时。反应结束后，冷却至室温，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到黄色油状化合物2g(40mg,收率50％)。
MS(ESI):m/z＝419.4[M+H] +。
步骤7：4-[(2S)-3-(3-{[双({3-[(2S)-3-(叔丁氧基)-2-{1-[(叔丁氧基)羰基]哌啶-4-基}-3-丙酰基]苯基}甲基)氨基]甲基}苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基]哌啶-1-羧酸叔丁酯(2h)的制备
将化合物2g(50mg,0.14mmol)溶于无水甲醇(8mL)，加入2f(120mg,0.412mmol)，室温下滴加1滴乙酸并加入分子筛，搅拌反应15分钟，加入氰基硼氢化钠(100mg,1.4mmol)，升温至75℃反应4小时后，室温反应过夜。LCMS监测反应结束后，加入少量DMF溶解，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到白色固体化合物2h(100mg,收率68.5％)。
MS(ESI):m/z＝1221.9[M+H] +。
步骤8：(2S)-3-(3-{[双({3-[(2S)-2-羧酸-2-(哌啶-4-基)乙基]苯基}甲基)氨基]甲基}苯基)-2-(哌啶-4-基)丙酸(2)的制备
将化合物2h(100mg,0.08mmol)溶于无水二氧六环(0.8mL)，加入4M氯化氢二氧六环溶液(2.5mL)，室温反应。LCMS监测反应完成后，将反应液浓缩，粗品经反相制备得到(乙腈/水+1％甲酸)标题化合物2(30mg,收率48.7％)。
MS(ESI):m/z＝753.9[M+H] +。
1H NMR(400MHz,D 2O)δ8.46(s,1H),7.45–7.32(m,6H),7.27–7.18(m,6H),4.30(s,6H),3.55–3.38(m,6H),3.06–2.91(m,9H),2.77–2.67(m,3H),2.43–2.32(m,3H),2.23–2.13(m,3H),1.96–1.76(m,6H),1.63–1.45(m,6H)。
实施例3
Figure PCTCN2022129479-appb-000056
3-[3-({双[(3-{2-羧基-2-氟-2-[(3S)-吡咯烷-3-基]乙基}苯基)甲基]氨基}甲基)苯基]-2-氟-2-[(3S)-吡咯烷-3-基]丙酸(3)
Figure PCTCN2022129479-appb-000057
步骤1：(3S)-3-(3-(3-溴苯基)-1-(叔丁氧基)-2-氟-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(3b)的制备
将按照专利WO2020247429中方法制备的化合物3a(2.4g,5.28mmol)溶于无水四氢呋喃(50mL)，冷却至-78℃，加入2M二异丙基氨基锂四氢呋喃溶液(5.28mL),低温下反应30分钟，接着加入N-氟代双苯磺酰胺(5.0g,15.85mmol)。反应逐渐升温至室温，反应16小时。LCMS检测反应完成后，向反应液加入饱和氯化铵溶液，乙酸乙酯萃取(20mL×2)。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经反相快速柱层析(乙腈/水)纯化得到化合物3b(2g，收率80％)。
MS(ESI)m/z＝372.2[M+H-100] +。
步骤2：(3S)-3-(1-(叔丁氧基)-2-氟-3-(3-甲酰基苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(3c)的制备
将化合物3b(1000mg,2.12mmol)，N-甲酰基糖精(894mg,4.23mmol)，醋酸钯(48mg,0.21mmol)，1,4-双(二苯基膦)丁烷(181mg,0.42mmol)，三乙基硅烷(902mg,4.23mmol)加入微波反应管中，然后加入N,N-二甲基甲酰胺(15mL)。置换氮气后，80℃反应过夜。LCMS检测反应完成后，向反应液中加入饱和氯化铵溶液，乙酸乙酯萃取(20mL×2)。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经反相快速柱层析(乙腈/水)纯化得到化合物3c(350mg，收率39％)。
MS(ESI)m/z＝444.3[M+Na] +。
步骤3：(3S)-3-(3-(3-(氨基甲基)苯基)-1-(叔丁氧基)-2-氟-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(3d)的制备
将化合物3c(130mg,0.31mmol)加入微波管中，用甲醇(2mL)溶解，后加入7M氨甲醇溶液(2mL)和1滴乙酸，室温搅拌30分钟后，再加入氰基硼 氢化钠(92mg,1.54mmol)，80℃微波反应1小时。LCMS监测反应完成后，减压浓缩得到粗产品，粗品经反相快速柱层析(乙腈/水)纯化得到淡黄色油状物化合物3d(50mg，收率38％)。
MS(ESI)m/z＝423.6[M+H] +。
步骤4：(3S)-3-[3-(3-{[双({3-[3-(叔丁氧基)-2-[(3S)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-2-氟-3-丙酰基]苯基}甲基)氨基]甲基}苯基)-1-(叔丁氧基)-2-氟-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(3e)的制备
将化合物3d(50mg,0.12mmol)和3c(100mg,0.24mmol)溶于甲醇(20mL)，加入1滴乙酸，室温搅拌30分钟后，加入氰基硼氢化钠(92mg,1.54mmol)。60℃反应5小时。LCMS监测反应完成后，减压浓缩得到粗产品，粗品经反相快速柱层析(乙腈/水)纯化得到淡黄色油状物化合物3e(80mg，收率55％)。
MS(ESI)m/z＝1233.9[M+H] +。
步骤5：3-[3-({双[(3-{2-羧基-2-氟-2-[(3S)-吡咯烷-3-基]乙基}苯基)甲基]氨基}甲基)苯基]-2-氟-2-[(3S)-吡咯烷-3-基]丙酸(3)的制备
将化合物3e(80mg,0.07mmol)溶于二氧六环(2mL)，加入4M氯化氢二氧六环溶液(2mL)，室温反应2小时。反应完成后，减压浓缩得到粗产品，粗品经反相制备(乙腈/水+1％甲酸)得到标题化合物3(20mg，收率40％)。
MS(ESI)m/z＝765.6[M+H] +。
1H NMR(400MHz,D 2O)δ8.45(s,1.5H),7.41(t,J＝7.5Hz,3H),7.34(d,J＝7.7Hz,3H),7.32–7.25(m,6H),4.17(s,6H),3.59–3.44(m,3H),3.43–3.25(m,6H),3.22(s,3H),3.20–3.09(m,6H),3.09–2.95(m,3H),2.40–2.27(m,2H),2.19–2.06(m,3H),2.02–1.90(m,1H)。
实施例4
Figure PCTCN2022129479-appb-000058
(2S)-3-{3-[({2-[双({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]乙基}({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基)甲基]苯基}-2-[(3R)-吡咯烷-3-基]丙酸(4)
Figure PCTCN2022129479-appb-000059
步骤1：(R)-3-((S)-1-(叔丁氧基)-3-(3-甲酰基苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(4a)的制备
将化合物3a(400mg,0.9mmol)，N-甲酰基糖精(428mg，2.0mmol)，醋酸钯(40mg，0.2mmol)，1,4-双(二苯基膦)丁烷(83mg，0.2mmol)，三乙基硅烷(0.24mL，1.5mmol)加入微波反应管中，然后加入N,N-二甲基甲酰胺(6mL)。置换氮气后，75℃反应过夜。LCMS监测反应完成后，将反应液冷却至室温，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到黄色油状化合物4a(270mg，收率76％)。
MS(ESI):m/z＝404.5[M+H] +。
步骤2：(3R)-3-[(2S)-3-{3-[({2-[双({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-丙酰基]苯基}甲基)氨基]乙基}({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-丙酰基]苯基}甲基)氨基)甲基]苯基}-1-(叔丁氧基)-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(4b)和(3R)-3-[(2S)-1-(叔丁氧基)-3-(3-{[({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-丙酰基]苯基}甲基)({2-[({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-丙酰基]苯基}甲基)氨基]乙基})氨基]甲基}苯基)-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(4c)的制备
将乙二胺(11mg,0.18mmol)，化合物4a(320mg,0.79mmol)溶于甲醇(20mL)，加入1滴乙酸，室温搅拌30分钟后，加入氰基硼氢化钠(60mg,0.99mmol)，升温至60℃反应5小时。LCMS监测反应完成后，减压浓缩得到粗产品，粗品经反相快速柱层析(水/乙腈)纯化得到淡黄色油状物化合物4b(50mg，收率16％)和化合物4c(150mg，收率62％)。
化合物4b:MS(ESI)m/z＝1610.2[M+H] +。
化合物4c：MS(ESI)m/z＝1222.6[M+H] +。
步骤3：(2S)-3-{3-[({2-[双({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]乙基}({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基)甲基]苯基}-2-[(3R)-吡咯烷-3-基]丙酸(4)的制备
将化合物4b(50mg,0.07mmol)溶于二氧六环(2mL)，加入4M氯化氢二氧六环溶液(2mL)，室温反应2小时。LCMS监测反应完成后，减压浓缩得到粗产品，粗品经反相制备(乙腈/水+1％甲酸)得到标题化合物4(10mg，收率87％)。
MS(ESI)m/z＝985.3[M+H] +。
1H NMR(400MHz,D 2O)δ8.44(s,3H),7.39–7.32(m,4H),7.31–7.26(m,4H),7.18–7.06(m,8H),3.88(s,8H),3.55–3.47(m,4H),3.44–3.36(m,4H),3.31–3.17(m,4H),3.05–2.87(m,8H),2.84–2.71(m,8H),2.55–2.37(m,8H),2.21–2.03(m,4H),1.84–1.62(m,4H)。
实施例5
Figure PCTCN2022129479-appb-000060
(2S)-3-(3-{[({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)({2-[({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]乙基})氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸(5)
Figure PCTCN2022129479-appb-000061
将化合物4c(80mg,0.06mmol)溶于二氧六环(2mL)，加入4M氯化氢二氧六环溶液(2mL)，室温反应2小时。LCMS监测反应完成后，减压浓缩得到粗产 品，粗品经反相制备(乙腈/水+1％甲酸)得到标题化合物5(20mg，收率40％)。
MS(ESI)m/z＝754.5[M+H] +。
1H NMR(400MHz,D 2O)δ8.43(s,3H),7.44–7.31(m,6H),7.30–7.24(m,4H),7.23–7.17(m,2H),4.28–4.03(m,6H),3.66–3.53(m,3H),3.48–3.39(m,3H),3.33–2.97(m,10H),2.91–2.73(m,6H),2.57–2.40(m,6H),2.24–2.05(m,3H),1.83–1.66(m,3H)。
实施例6
Figure PCTCN2022129479-appb-000062
(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸四盐酸盐(6)
Figure PCTCN2022129479-appb-000063
步骤1：(R)-3-((S)-1-((S)-4-苄基-2-氧代噁唑烷-3-基)-3-(3-(苄氧基)苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6a)的制备
氮气氛下，将化合物1b(10.0g,25.74mmol)溶于四氢呋喃(10mL)，降温至-30℃，滴加1M双(三甲基硅基)酰胺锂四氢呋喃溶液(31mL，31mmol)，加完后反应30分钟；滴加3-苄氧基溴苄(8.56g,30.89mmol)的四氢呋喃(15mL)溶液，反应1小时，升温至0℃-5℃反应过夜。加饱和氯化铵溶液(50mL)，甲基叔丁基醚萃取(50mL×2)，饱和氯化钠溶液洗涤(70mL)，无水硫酸钠干燥，过滤，减压浓缩，所得残余物柱层析纯化(石油醚：乙酸乙酯＝4:1)，得化合物6a(7.08g，产率：47.0％)。
步骤2：(S)-3-(3-(苄氧基)苯基)-2-((R)-1-(叔丁氧羰基)吡咯烷-3-基)丙酸(6b)的制备
将化合物6a(7g,11.983mmol)溶于四氢呋喃(70mL)，水(35mL)，加双氧水(30％)(4.07g,35.95mmol)，氢氧化锂一水合物(431mg,17.97mmol)，室温反应过夜。2M氢氧化钠溶液调节pH至＞13，甲基叔丁基醚萃取(50mL×2)，水相用2M盐酸溶液调节pH至＜3，甲基叔丁基醚萃取(50mL×2)，饱和氯化钠溶液洗涤(70mL)，无水硫酸钠干燥，过滤，减压浓缩至干，得化合物6b粗品3.11g，产物不经纯化直接进行下一步反应。
步骤3：(R)-3-((S)-3-(3-(苄氧基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6c)的制备
将上步粗品化合物6b(3.1g,7.29mmol)溶于2-甲基四氢呋喃(60mL)，后加2-叔丁基-1,3-二异丙基异脲(5.84g,29.14mmol)，升温至65℃反应过夜。过滤，滤液减压浓缩至干，所得残余物柱层析纯化(石油醚：乙酸乙酯＝5:1)，得化合物6c(2.5g,两步产率：43.3％)。
步骤4：(R)-3-((S)-1-(叔丁氧基)-3-(3-羟基苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6d)的制备
氢气氛下，将化合物6c(2.5g,5.19mmol)溶于MeOH(40mL)，加Pd/C(0.80g)，室温反应过夜，过滤，减压浓缩得化合物6d(1.78g,产率：87.6％)。
步骤5：(R)-3-((S)-3-(3-(2-(((苄氧基)羰基)氨基)乙氧基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6e)的制备
将化合物6d(400mg,0.99mmol)，N-(2-溴乙基)氨基甲酸苄酯(280mg,1.09mmol)，碳酸铯(803mg,2.47mmol)加入到N，N-二甲基甲酰胺(8mL)中，升温至80℃反应3小时。加水(40mL)，乙酸乙酯萃取(30mL×2)，饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，加压浓缩得残余物，柱层析纯化(石油醚：乙酸乙酯＝8:1)，得化合物6e(300mg，产率53.5％)。
步骤6：(R)-3-((S)-3-(3-(2-氨基乙氧基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6f)的制备
氢气氛下，将化合物6e(300mg,0.528mmol)溶于MeOH(5mL)，加Pd/C(100mg)，室温反应过夜。过滤，减压浓缩得到化合物6f(150mg，产率65.4％)。
步骤7：(3R)-3-[(2S)-1-(叔丁氧基)-3-(3-{[(2-{3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-氧代丙基]苯氧基}乙基)({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-氧代丙基]苯基}甲基)氨基]甲基}苯基)-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(6g)的制备
冰浴下，将化合物6f(150mg,0.35mmol)和化合物4a(278.6mg,0.69mmol)溶于异丙醇(6mL)，加1滴冰醋酸，保温反应30分钟。加入三乙酰氧基硼氢化钠(292.6mg,1.38mmol)，缓慢升至室温，反应过夜。饱和碳酸氢钠溶液调节pH至8-9，乙酸乙酯萃取(40mL×2)，饱和氯化钠溶液洗涤(60mL)，无水硫酸钠干燥，过滤，浓缩得粗品480mg,制备液相纯化得到化合物6g(250mg，产率59.9％)。
步骤8：(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸四盐酸盐(6)的制备
将化合物6g(100mg,0.083mmol)加入到4M盐酸二氧六环溶液(4mL)，室温搅拌过夜。倾出上清液，得固体，固体用乙酸乙酯洗涤，冻干，得化合物6(50mg，产率68.5％)。
MS m/z(ESI):741.3[M+H] +。
1H NMR(400MHz,D 2O):δ7.42-7.16(m,9H),6.86(d,J＝7.6Hz,1H),6.70(dd,J＝8.3,2.6Hz,1H),6.65(s,1H),4.43(s,4H),4.14-3.97(m,2H),3.62-3.45(m,5H),3.45-3.30(m,3H),3.29-3.14(m,3H),3.07-2.98(m,3H),2.93-2.63(m,9H),2.61-2.39(m,3H),2.24-2.02(m,3H),1.78-1.64(m,3H)。
实施例7
Figure PCTCN2022129479-appb-000064
(2S)-3-[3-({[2-({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}氨基)乙基]({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基}甲基)苯基]-2-[(3R)-吡咯烷-3-基]丙酸五盐酸盐(7)
Figure PCTCN2022129479-appb-000065
步骤1：(R)-3-((S)-3-(3-((2-(((苄氧基)羰基)氨基)乙基)氨基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(7a)的制备
称取化合物3a(700mg,1.54mmol)，N-苄氧羰基乙二胺(448.81mg,2.31mmol)，BrettPhos Pd G3(49.9mg,0.06mmol)，碳酸钾(638.7mg,4.62mmol)和二氧六环(10mL)于反应瓶中，氮气置换三次，100℃反应过夜。LCMS检测生成产物，向反应液中加入乙酸乙酯和水，分液，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，将滤液浓缩进行柱层析，得到化合物7a(400mg,45.7％)
步骤2：(R)-3-((S)-3-(3-((2-氨乙基)氨基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(7b)的制备
称取化合物7a(400mg,0.71mmol)，10％Pd/C(100mg)于反应瓶中，加入甲醇(10mL)，氮气置换三次，氢气置换三次，氢气球下反应过夜。LCMS检测生成产物。过滤，将滤液浓缩，得粗品化合物7b(200mg,65.5％)。
步骤3：(3R)-3-[(2S)-1-(叔丁氧基)-3-[3-({[2-({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-氧代丙基]苯基}氨基)乙基]({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-氧代丙基]苯基}甲基)氨基}甲基)苯基]-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(7c)的制备
称取化合物7b(150mg,0.35mmol)，4a(349mg,0.87mmol)于反应瓶中，加入异丙醇(10mL)，加入一滴醋酸，冰浴下搅拌1小时，再加入醋酸硼氢化钠(218.9mg,1.04mmol)，反应过夜。向反应液中加入饱和碳酸氢钠溶液和乙酸乙酯，分液，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，将滤液浓缩得粗品产物，制备液相纯化得到化合物7c(100mg,23.9％)
步骤4：(2S)-3-[3-({[2-({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}氨基)乙基]({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基}甲基)苯基]-2-[(3R)-吡咯烷-3-基]丙酸五盐酸盐(7)的制备
称取化合物7c(100mg，8.3mmol),室温下加入4M盐酸二氧六环溶液(10mL)，搅拌过夜。将上清液倒掉，得固体，固体用乙酸乙酯洗涤，加入水溶解，冻干得化合物7(70mg,72.1％)。
MS m/z(ESI):740.4[M+1] +。
1H NMR(400MHz,D 2O):δ7.45-7.21(m,8H),7.12(t,J＝7.8Hz,1H),6.75(d,J＝7.5Hz,1H),6.53-6.38(m,2H),4.41(s,4H),3.68-3.51(m,2H),3.51-3.39(m,3H),3.38-3.18(m,8H),3.15-2.99(m,2H),2.98-2.67(m,9H),2.66-2.46(m,4H),2.26-2.06(m,3H),1.84-1.69(m,3H)。
生物学测试
测试例1：化合物抑制Lp(a)的组装活性测试
本公开利用双抗体ELISA方法检测Apo(a)与ApoB蛋白的组装效率，抗体分别是ApoB-Capture抗体(Mabtech)和Apo(a)-Detector抗体(Abcam)；检测样本分别是人转基因hApo(a)和hApoB小鼠的血浆，分别稀释500倍使用。
实验步骤：分别将等量的Apo(a)和ApoB血清与梯度浓度稀释(最高浓度100nM，3倍梯度稀释)的待测化合物混合，将混合液放在37℃培养箱里孵育2小时，然后加入终浓度为150mM的6-氨基己酸(EACA，购自Sigma)终止反应。将反应后溶液加入预先包被ApoB-Capture抗体的ELISA检测板中，室温孵育2小时，然后利用洗涤液洗板4次；加入生物素标记的Apo(a)-Detector抗体，室温孵育1小时后，洗板并加入显色底物3,3',5,5'-四甲基联苯胺(TMB，购自Abcam)溶液；室温孵育15分钟后，加入反应终止液，混匀后即刻用酶标仪检测450nm处的吸光值。最后，利用GraphPad Prism 9软件进行数据分析和IC 50的计算。
Apo(a)与ApoB蛋白组装的0％抑制率对应着化合物浓度为0(1％DMSO)时的OD值；Apo(a)与ApoB蛋白组装的100％抑制率对应着只加ApoB蛋白溶液(hApoB小鼠的血浆稀释液)时的OD值。
实验结果：
表1本公开化合物抑制Lp(a)组装活性
化合物 Lp(a)组装，IC 50(nM)
1 0.75
2 1.7
3 1.4
4 0.85
5 0.78
6 0.41
7 0.76
结论：本公开化合物表现出对Lp(a)组装明显的抑制作用。
Figure PCTCN2022129479-appb-000066
(参照物1，参照CN114008021中的实施例1方法制备)
测试例2：比格犬体内药代动力学实验
以比格犬为受试动物，应用LC/MS/MS法测定比格犬灌胃给予本公开化合物后不同时刻血浆中的药物浓度。研究本公开化合物在比格犬体内的药代动力学行为，评价其药动学特征。
试验动物：每组健康8～36月雄性比格犬2条
药物配制：称取一定量药物，加生理盐水配成2mg/mL的无色澄清溶液。
给药：比格犬禁食过夜后灌胃给药，参照物1和化合物6给药剂量均为10mg/kg。
操作：比格犬灌胃给药本公开化合物，给药后0.25、0.5、1、2、4、6、8、24小时由外周静脉穿刺采血约0.6mL，置于含EDTA-K2的试管中，4℃左右，2000转每分钟离心10分钟分离得到血浆，于-75℃保存。
测定不同采血时间点比格犬血浆中待测化合物含量：取给药后各时刻采取的比格犬血浆33μL(30μL血浆和3μL空白)加入到18μL浓度为6％的高氯酸溶液，涡旋混合30秒，4℃温度下，3900转每分钟离心15分钟，然后加入含内标地塞米松的碱化后(氨水调pH为10-11)乙腈溶液200μL沉淀蛋白，涡旋混合30秒，4℃、3900转每分钟离心15分钟，血浆样品取上清液，加水稀释3倍，取8μL进行LC/MS/MS分析。
药代动力学参数结果
LC/MS/MS分析检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数。本公开化合物的比格犬药代动力学参数如下表2。
表2本公开化合物的比格犬口服药代动力学参数
Figure PCTCN2022129479-appb-000067
Figure PCTCN2022129479-appb-000068
结论：化合物6在比格犬体内口服吸收更优，血药暴露量更佳，半衰期长，具有优异的药代动力学特征，口服给药具有明显优势。
测试例3：食蟹猴体内药代动力学实验
以食蟹猴为受试动物，应用LC/MS/MS法测定食蟹猴灌胃给予本公开化合物后不同时刻血浆中的药物浓度。研究本公开化合物在食蟹猴体内的药代动力学行为，评价其药动学特征。
试验动物：每组健康24～36月食蟹猴2只(一雄一雌)
药物配制：称取一定量药物，加生理盐水配成10mg/mL(参照物1)和3mg/mL(化合物6)的无色澄清溶液。
给药：食蟹猴禁食过夜后灌胃给药，参照物1给药剂量为50mg/kg，化合物6给药剂量为15mg/kg。
操作：食蟹猴灌胃给药本公开化合物，给药后0.25、0.5、1、2、4、6、8、24小时由外周静脉穿刺采血约0.5mL，置于含EDTA-K2的试管中，4℃左右，2000转每分钟离心10分钟分离得到血浆，于-75℃保存。
测定不同采血时间点食蟹猴血浆中待测化合物含量：取给药后各时刻采取的食蟹猴血浆33μL(30μL血浆和3μL空白)加入到18μL浓度为6％的高氯酸溶液，涡旋混合30秒，4℃温度下，3900转每分钟离心15分钟，然后加入含内标地塞米松的碱化后(氨水调pH为10-11)乙腈溶液200μL沉淀蛋白，涡旋混合30秒，4℃、3900转每分钟离心15分钟，血浆样品取上清液，加水稀释3倍，取8μL进行LC/MS/MS分析。
药代动力学参数结果
LC/MS/MS分析检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数。本公开化合物的食蟹猴药代动力学参数如下表3。
表3本公开化合物的食蟹猴口服药代动力学参数
Figure PCTCN2022129479-appb-000069
结论：化合物6在食蟹猴体内口服吸收更优，血药暴露量是参照物1的近5 倍，显示本发明化合物的药代动力学性质显著优于参照物1。
测试例4：小鼠高剂量单次耐受性实验
以C57/6J小鼠为受试动物，口服灌胃高剂量本公开化合物，对小鼠进行临床观察，评价本公开化合物的安全性。
实验方法：取8只雄性C57/6J小鼠，分别编号为1-8，称重。实验开始前禁食4小时，禁食结束后称重(0h)。取体重较平均的6只入组，每组3只，分2组。
第一组(G1)给予参照物1，第二组(G2)给予本公开化合物实施例6。G1、G2组化合物均口服灌胃给药，剂量为1000mg/kg，溶媒均为生理盐水，给药后15min、30min、1h、2h、4h、6h、24h对实验组小鼠进行临床观察，给药2h后两组均给予食物。连续7天对小鼠体重进行监测，结果如下表4。
表4本公开化合物小鼠高剂量单次耐受性实验
Figure PCTCN2022129479-appb-000070
注a平均值
结论：高剂量(1000mg/kg)给药7天后，参照物1组小鼠体重有明显下降趋势，相应化合物6组小鼠体重维持不变，甚至增长。预期在更长给药期间内，本公开化合物能展现出更为优异的安全性。

Claims (15)

  1. 一种式II所示化合物或其可药用盐，
    Figure PCTCN2022129479-appb-100001
    其中R 11独立地选自氢或C 1-6烷基，所述烷基任选被一个或多个R 11A所取代，R 11A各自独立地选自卤素、羟基、氰基或氨基；
    R 12独立地选自氢、氘、卤素或C 1-6烷基，所述烷基任选被一个或多个R 12A所取代，R 12A各自独立地选自卤素、羟基、氰基或氨基；
    R 13独立地选自氢、氘、卤素、氰基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R 13A所取代，R 13A各自独立地选自卤素、羟基、氰基或氨基；
    R 14独立地选自氢或C 1-6烷基；
    W选自3或4；
    L 2选自
    Figure PCTCN2022129479-appb-100002
    Figure PCTCN2022129479-appb-100003
    n1选自0-4之间整数。
  2. 根据权利要求1所述的化合物或其可药用盐，其中R 12独立地选自氢或氘。
  3. 根据权利要求1或2所述的化合物或其可药用盐，其中R 12独立地选自卤素，例如氟或氯；或者R 12独立地选自C 1-6烷基，所述烷基任选被一个或多个R 12A所取代，R 12A如权利要求1中所定义。
  4. 根据权利要求1-3任一项所述的化合物或其可药用盐，其中R 11独立地选自氢。
  5. 根据权利要求1-4任一项所述的化合物或其可药用盐，其中R 13独立地选自氢或氘。
  6. 根据权利要求1-4任一项所述的化合物或其可药用盐，其中R 13独立地选自氘或C 1-6烷氧基，所述烷氧基任选被一个或多个R 13A所取代，R 13A如权利要求1中定义；或R 13独立地选自卤素，例如氟或氯。
  7. 根据权利要求1-6任一项所述的化合物或其可药用盐，其中L 2选自
    Figure PCTCN2022129479-appb-100004
    Figure PCTCN2022129479-appb-100005
    优选
    Figure PCTCN2022129479-appb-100006
  8. 根据权利要求1所述的化合物或其可药用盐，其选自：
    Figure PCTCN2022129479-appb-100007
    Figure PCTCN2022129479-appb-100008
  9. 根据权利要求1所述的化合物或其可药用盐，其选自：
    Figure PCTCN2022129479-appb-100009
    Figure PCTCN2022129479-appb-100010
  10. 根据权利要求1-9任一项所述的化合物或其可药用盐的同位素取代物，优选的，所述同位素取代物为氘代物。
  11. 一种药物组合物，包括至少一种治疗有效量的如权利要求1-9任一项所述的化合物或其可药用盐、或权利要求10所述的同位素取代物，以及药学上可接受的赋形剂。
  12. 一种预防和/或治疗与LP(a)血浆水平升高相关的疾病或病症的方法，其通 过向所述患者施用有效量治疗的如权利要求1-9任一项所述的化合物或其可药用盐、或权利要求10所述的同位素取代物、或权利要求11所述的药物组合物。
  13. 一种预防和/或治疗心血管疾病患者的方法，其通过向所述患者施用治疗有效量的如权利要求1-9任一项所述的化合物或其可药用盐、或权利要求10所述的同位素取代物、或权利要求11所述的药物组合物。
  14. 根据权利要求1-9任一项所述的化合物或其可药用盐、或权利要求10所述的同位素取代物、或权利要求11所述的药物组合物在制备用于预防和/或治疗与LP(a)血浆水平升高相关的疾病或病症的药物中的用途。
  15. 根据权利要求1-9任一项所述的化合物或其可药用盐、或权利要求10所述的同位素取代物、或权利要求11所述的药物组合物在制备用于预防和/或治疗心血管疾病的药物中的用途。
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