WO2024240249A1 - 一种苯并噻二氮卓化合物及其用途 - Google Patents

一种苯并噻二氮卓化合物及其用途 Download PDF

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Publication number
WO2024240249A1
WO2024240249A1 PCT/CN2024/095190 CN2024095190W WO2024240249A1 WO 2024240249 A1 WO2024240249 A1 WO 2024240249A1 CN 2024095190 W CN2024095190 W CN 2024095190W WO 2024240249 A1 WO2024240249 A1 WO 2024240249A1
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membered
alkyl
cycloalkyl
further substituted
compound
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English (en)
French (fr)
Inventor
高勇
赵大敏
嵇彦鹏
葛兴枫
倪涛
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN202480031405.3A priority Critical patent/CN121175293A/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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings

Definitions

  • the present invention belongs to the field of medical technology, and relates to a benzothiadiazepine compound and a use thereof.
  • the present invention also relates to a preparation method of the benzothiadiazepine compound and a pharmaceutical composition containing the compound.
  • NTCP sodium taurocholate cotransporting polypeptide refers to the sodium ion-taurocholate cotransporter, which is encoded by the SLC10A1 gene.
  • NTCP is the main protein that transports Na ions and bile acids on the liver cell membrane. It plays an important role in the enterohepatic circulation of bile acids and is a potential target for antiviral and cholestatic indications.
  • NTCP is located in the basolateral domain (blood side) of hepatocytes in humans, rats and other species, and NTCP is not detected in any other tissues.
  • HBV envelope protein is composed of 3 proteins, namely large envelope protein (LHBs), middle envelope protein (MHBs) and small envelope protein (SHBs), including preS1, preS2 and S regions.
  • LHBs large envelope protein
  • HHBs middle envelope protein
  • SHBs small envelope protein
  • inhibiting NTCP can reduce the entry of bile acid into the liver, thereby increasing the circulating bile acid pool.
  • the increased bile acid pool can play a role in FXR excitation.
  • NTCP inhibition significantly improved liver fat accumulation and steatosis, and alleviated liver damage.
  • the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
  • X is selected from C(RaRb ) or NRc or
  • L is selected from a bond, O, S, (C( RaRb ) ) p , ( NRc ) q or (C( RaRb ) ) i- ( NRc ) j ;
  • R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -( CH2 ) nRal , -( CH2 ) nORal , -(CH2) nC (O) Ral , - ( CH2 ) nC (O) ORal , -( CH2 ) nS (O) mRal , -(CH2) nNRa2Ral , - ( CH2 ) nNRa2C (O) ORa3 , - ( CH2 ) nNRa2C (O)( CH2 ) nlRal , - ( CH2 ) n
  • R1 and R2 together with the carbon atom to which they are attached form a C3-14 cycloalkyl or a 3-14 membered heterocyclic group, wherein The C 3-14 cycloalkyl or 3-14 membered heterocyclyl may be further substituted with one or more substituents;
  • R 2 and R c together with the carbon atom and the nitrogen atom to which they are attached form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents;
  • Ra and Rb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl or 3-14 membered heterocyclyl, wherein the amino, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl or 3-14 membered heterocyclyl may be further substituted with one or more substituents;
  • R c is selected from hydrogen, hydroxyl, amino, mercapto, C 1-12 alkyl or C 1-12 alkoxy, wherein the amino, C 1-12 alkyl or C 1-12 alkoxy may be further substituted with one or more substituents;
  • L is selected from (NR c ) q or (C( RaRb ) ) i- (NR c ) j , R c on different nitrogen atoms and the nitrogen atom to which they are attached together form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents;
  • L is selected from (C( RaRb )) i- ( NRc ) j , Ra on the carbon atom and the carbon atom to which it is attached, Rc on the nitrogen atom and the nitrogen atom to which it is attached together form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents;
  • R3 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano , C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl , -( CH2 ) nRal , -( CH2 ) nORal , -( CH2 )nC(O) Ral, -(CH2)nC(O)ORal , - ( CH2 ) nS (O ) mRal , -( CH2 )nNRa2Ra3, - ( CH2 ) nNRa2C ( O) ORa3 , - ( CH2 ) nNRa2C (O) ( CH2 ) nlRa3 , - ( CH2 ) nNRa
  • A is selected from
  • Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, wherein the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted by one or more substituents;
  • R4 is selected from C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, wherein the C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more substituents;
  • R 5 and R 5' are each independently selected from hydrogen, deuterium, halogen, amino, C 1-12 alkyl or C 1-12 alkoxy; the amino, C 1-12 alkyl or C 1-12 alkoxy may be further substituted with one or more substituents;
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, and the amino, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-104 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more substituents;
  • p, q, i or j are independently selected from 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • n and n1 are each independently selected from 0, 1, 2, 3 or 4;
  • the conditions are:
  • R1 and R2 are each independently selected from hydrogen or unsubstituted C1-12 alkyl, R4 is not substituted or unsubstituted phenyl.
  • the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is a compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof.
  • X is selected from C(RaRb ) or NRc ;
  • L is selected from a bond, O, S, (C( RaRb ) ) p , ( NRc ) q or (C( RaRb ) ) i- ( NRc ) j ;
  • R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -( CH2 ) nRal , -( CH2 ) nORal , -(CH2) nC (O) Ral , - ( CH2 ) nC (O) ORal , -( CH2 ) nS (O) mRal , -(CH2) nNRa2Ral , - ( CH2 ) nNRa2C (O) ORa3 , - ( CH2 ) nNRa2C (O)( CH2 ) nlRal , - ( CH2 ) n
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-14 cycloalkyl or a 3-14 membered heterocyclyl, which may be further optionally substituted by one or more R bb ;
  • R 2 and R c together with the carbon atom and nitrogen atom to which they are attached form a 3-14 membered heterocyclic group, which may be further optionally substituted with one or more R bb ;
  • Ra and Rb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl or 3-14 membered heterocyclyl, wherein the amino, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl or 3-14 membered heterocyclyl may be further substituted with one or more Rcc ;
  • R c is selected from hydrogen, hydroxyl, amino, mercapto, C 1-12 alkyl or C 1-12 alkoxy, and the amino, C 1-12 alkyl or C 1-12 alkoxy may be further substituted with one or more R c ;
  • L is selected from (C( RaRb )) i- ( NRc ) j , Ra on the carbon atom and the carbon atom to which it is attached, Rc on the nitrogen atom and the nitrogen atom to which it is attached together form a 3-14 membered heterocyclic group, which may be further optionally substituted with one or more Rd3 ;
  • R3 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano , C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl , -( CH2 ) nRal , -( CH2 ) nORal , -( CH2 )nC(O) Ral, -(CH2)nC(O)ORal , - ( CH2 ) nS (O ) mRal , -( CH2 )nNRa2Ra3, - ( CH2 ) nNRa2C ( O) ORa3 , - ( CH2 ) nNRa2C (O) ( CH2 ) nlRa3 , - ( CH2 ) nNRa
  • A is selected from
  • Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more R g ;
  • R 4 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, wherein the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more R h ;
  • R 5 and R 5' are each independently selected from hydrogen, deuterium, halogen, amino, C 1-12 alkyl or C 1-12 alkoxy; the amino, C 1-12 alkyl or C 1-12 alkoxy may be further substituted with one or more R i ;
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, and the amino, C1-12 alkyl, C1-12 alkoxy, C2-12 alkenyl, C2-12 alkynyl, C3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-104 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more Rj ;
  • p, q, i or j are independently selected from 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • n and n1 are each independently selected from 0, 1, 2, 3 or 4;
  • the conditions are:
  • R1 and R2 are each independently selected from hydrogen or unsubstituted C1-12 alkyl, R4 is not substituted or unsubstituted phenyl.
  • the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is a compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof.
  • X is selected from C(RaRb ) or NRc ;
  • L is selected from a bond, O, S, (C( RaRb ) ) p , ( NRc ) q or (C( RaRb ) ) i- ( NRc ) j ;
  • R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) nRal , -( CH2 ) nORal , -(CH2) nC (O ) Ral , -( CH2 ) nC (O ) ORal , -( CH2 ) nS ( O ) mRal , -(CH2)nNRa2Ral, - (CH2) nNRa2C ( O ) ORa3 , - ( CH2 ) nNRa2C (O)( CH2 ) nlRal , - ( CH2 ) nNRa2 a
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-12 cycloalkyl or a 3-12 membered heterocyclic group, and the C 3-12 cycloalkyl or 3-12 membered heterocyclic group may be further substituted with one or more R bb ;
  • R 2 and R c together with the carbon atom and nitrogen atom to which they are attached form a 3-12 membered Heterocyclyl, wherein the 3-14 membered heterocyclyl may be further substituted with one or more R bb ;
  • Ra and Rb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein the amino, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl or 3-12 membered heterocyclyl may be further substituted with one or more Rcc ;
  • R c is selected from hydrogen, hydroxyl, amino, mercapto, C 1-6 alkyl or C 1-6 alkoxy, and the amino, C 1-6 alkyl or C 1-6 alkoxy may be further substituted with one or more R c ;
  • Ra and Rb on the same or different carbon atoms and the carbon atom to which they are attached together form a C3-12 cycloalkyl or 3-12 membered heterocyclyl, which may be further substituted with one or more Rd ;
  • L is selected from (C( RaRb )) i- ( NRc ) j , Ra on the carbon atom and the carbon atom to which it is attached, Rc on the nitrogen atom and the nitrogen atom to which it is attached together form a 3-12 membered heterocyclic group, which may be further optionally substituted by one or more Rd ;
  • R3 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) nRal , -( CH2 ) nORal , -( CH2 ) nC (O)Ral, -( CH2 ) nC (O ) ORal , -( CH2 ) nS (O ) mRal , - ( CH2 ) nNRa2Ra3 , - ( CH2 ) nNRa2C ( O ) ORa3 , - ( CH2 ) nNRa2C ( O)(CH2) nlRa3 , - ( CH2 ) n
  • A is selected from
  • Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, and the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl may be further substituted with one or more R g ;
  • R 4 is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl may be further substituted with one or more R h ;
  • R 5 and R 5' are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl or C 1-6 alkoxy; the amino, C 1-6 alkyl or C 1-6 alkoxy may be further substituted with one or more R i ;
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, and the amino, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl may be further substituted with one or more Rj ;
  • p, q, i or j are independently selected from 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • n and n1 are each independently selected from 0, 1, 2, 3 or 4;
  • the conditions are:
  • R1 and R2 are each independently selected from hydrogen or unsubstituted C1-12 alkyl, R4 is not substituted or unsubstituted phenyl.
  • R d described in the present disclosure is selected from R d1 , R d2 or R d3 .
  • Rd1 , Rd2 , or Rd3 described in the present disclosure may be Rd .
  • the "one or more” is each independently selected from 1, 2, 3, 4, 5 or 6.
  • the "one or more” is each independently selected from 1, 2, 3, 4 or 5.
  • the "one or more” is each independently selected from 1, 2, 3 or 4.
  • the "one or more” is each independently selected from 1, 2 or 3.
  • the "hetero" is each independently selected from oxygen, sulfur, nitrogen and phosphorus heteroatoms, wherein nitrogen atoms are optionally quaternized or oxidized to N(O), sulfur atoms are optionally oxidized to S(O) or S(O) 2 , phosphorus atoms are optionally oxidized to P(O) or P(O) 2 , and other variables are as defined in the present disclosure.
  • the "hetero" is each independently selected from oxygen, sulfur, and nitrogen heteroatoms, wherein nitrogen atoms are optionally quaternized or oxidized to N(O), sulfur atoms are optionally oxidized to S(O) or S(O) 2 , and other variables are as defined in the present disclosure.
  • Ra and Rb are each independently selected from hydrogen, deuterium, C1-6 alkyl or C1-6 alkoxy, which may be further optionally substituted with one or more Rcc .
  • Ra and Rb are each independently selected from hydrogen, deuterium, C1-3 alkyl or C1-3 alkoxy, which may be further optionally substituted with one or more Rcc .
  • Ra and Rb are each independently selected from hydrogen or C1-3 alkyl, which may optionally be further substituted with one or more Rcc .
  • Ra and Rb are each independently selected from hydrogen or methyl.
  • Ra is selected from hydrogen and Rb is selected from methyl; or Ra is selected from methyl and Rb is selected from hydrogen.
  • Ra and Rb are both selected from hydrogen.
  • Ra and Rb are both selected from methyl.
  • R c is selected from hydrogen or C 1-6 alkyl, which may optionally be further substituted with one or more Re .
  • R c is selected from hydrogen or C 1-3 alkyl, which may optionally be further substituted with one or more Re .
  • R c is selected from hydrogen or methyl optionally substituted with deuterium.
  • R c is selected from hydrogen, methyl, or -CD 3 .
  • R c is selected from methyl
  • R c is selected from hydrogen.
  • Ra and Rb on the same or different carbon atoms and the carbon atom to which they are attached together form a C3-6 cycloalkyl or 3-6 membered heterocyclyl, which may be further substituted with one or more Rd or Rd1 .
  • Ra and Rb on the same or different carbon atoms and the carbon atom to which they are attached together form a C3-6 cycloalkyl group, which may be further substituted with one or more Rd or Rd1 .
  • Ra and R on the same or different carbon atoms are R d or R d 1 are optionally substituted with one or more R d or R d 1.
  • Ra and Rb on the same or different carbon atoms and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which may be further optionally substituted with one or more Rd or Rd1 .
  • Ra and Rb on the same or different carbon atoms and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl or azetidinyl group, which may be further optionally substituted with one or more Rd or Rd1 .
  • Ra and Rb on the same or different carbon atoms and the carbon atom to which they are attached together form a cyclopropyl or cyclobutyl group, which may be further optionally substituted with one or more Rd or Rd1 .
  • Ra and Rb on the same carbon atom and the carbon atom to which they are attached together form a cyclopropyl group, which may be optionally further substituted with one or more Rd or Rd1 .
  • Ra and Rb on different carbon atoms and the carbon atom to which they are attached together form a cyclobutyl group, which may be optionally further substituted with one or more Rd or Rd1 .
  • the “ same or different carbon atoms” are “two same or two different carbon atoms”; alternatively, the “same carbon atom” is “two same carbon atoms”; alternatively, the “different carbon atoms” are “two different carbon atoms”.
  • the “ same or different carbon atoms” are “two same or two different carbon atoms at both ends”; alternatively, the “same carbon atom” is “two same carbon atoms at both ends”; alternatively, the “different carbon atoms” are “two different carbon atoms at both ends”.
  • Rc on different nitrogen atoms and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclic group, which may be optionally further substituted with one or more Rd or Rd2 .
  • R c on different nitrogen atoms and the nitrogen atom to which they are attached together form a 1,3-diazetidinyl, imidazolidinyl or piperazinyl group, which may be further substituted with one or more R d or R d2 .
  • R c on different nitrogen atoms and the nitrogen atom to which they are attached together form a 1,3-diazetidinyl group, which may be further optionally substituted with one or more R d or R d2 .
  • the “different nitrogen atoms” are “two different nitrogen atoms”.
  • the “different nitrogen atoms” are “two different nitrogen atoms at both ends”.
  • Rc on the nitrogen atom and the nitrogen atom to which it is attached together form a 3-6 membered heterocyclic group, which may be optionally further substituted with one or more Rd or Rd3 .
  • L when L is selected from (C(RaRb))i-(NRc ) j , Ra on the carbon atom and the carbon atom to which it is attached, Rc on the nitrogen atom and the nitrogen atom to which it is attached together form an azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl or piperazinyl group, and the azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl or piperazinyl group may be further substituted with one or more Rd or Rd3 .
  • the “ Ra on a carbon atom and the carbon atom attached to it, Rc on a nitrogen atom and the nitrogen atom attached to it” means “ Ra on a carbon atom and the carbon atom attached to it, Rc on a nitrogen atom and the nitrogen atom attached to it”.
  • the “ Ra on the carbon atom and the carbon atom connected to it, Rc on the nitrogen atom and the nitrogen atom connected to it” means “ Ra on a carbon atom at one end and the carbon atom connected to it, Rc on a nitrogen atom at the other end and the nitrogen atom connected to it”.
  • X is selected from NR c .
  • X is selected from CH 2 , CH(CH 3 ), C(CH 3 ) 2 , or N(CH 3 ), said X being optionally substituted with one or more deuteriums.
  • X is selected from CH 2 , CH(CH 3 ), C(CH 3 ) 2 , or N(CH 3 ).
  • X is selected from
  • X is selected from NH, N(CH 2 D), N(CHD 2 ), or N(CD 3 ).
  • X is selected from NH or N(CD 3 ).
  • X is selected from CH 2 , N(CH 3 ), NH, N(CD 3 ) or
  • X is selected from CH 2 or N(CH 3 ).
  • X is selected from N(CD 3 ) or N(CH 3 ).
  • X is selected from N(CH 3 ).
  • L is selected from a bond, (C( RaRb ) ) p , or (C( RaRb ) ) i- ( NRc ) j .
  • p, q, i or j are each independently selected from 1 or 2.
  • i and j are each selected from 1.
  • q is 2.
  • L is selected from a bond, -C( RaRb )-, -C( RaRb ) -C( RaRb )-, -C (RaRb ) -NRc- , -C ( RaRb ) -C ( RaRb )-C ( RaRb )-, or C ( RaRb ) -C ( RaRb ) -NRc .
  • L is selected from C( RaRb ), -C ( RaRb ) -C ( RaRb )-, or -C( RaRb ) -NRc- .
  • L is selected from a bond.
  • L is selected from a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 , wherein each r is independently selected from 1, 2, 3 or 4. In some embodiments, wherein each r is independently selected from 1 or 2.
  • L is selected from a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 ,
  • L is selected from a bond, CH 2 , C(CH 3 ) 2 ,
  • structural fragment LR 4 is selected from -R 4 , -OR 4 , -SR 4 , -(C(R a R b )) p -R 4 , -(NR c ) q -R 4 , -(C(R a R b )) i -(NR c ) j -R 4 , or -(NR c ) j -(C(R a R b )) i -R 4 .
  • structural fragment LR 4 is selected from -R 4 , -(C( RaRb ) ) p -R 4 or -(C( RaRb ) ) i- ( NRc ) j -R 4 .
  • the structural fragment LR 4 is selected from -R 4 , -CH 2 R 4 , -C(CH 3 ) 2 R 4 ,
  • Rcc , Rd1 , Rd2 , Rd3 and Re are each independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-3 alkyl or C1-3 alkoxy, and the C1-3 alkyl or C1-3 alkoxy may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • Rcc , Rd1 , Rd2 , Rd3 , and Re are each independently selected from deuterium, halogen, or hydroxyl.
  • Rcc , Rd1 , Rd2 , Rd3 and Re are each independently selected from F.
  • Rcc , Rd and Re are each independently selected from deuterium, halogen, hydroxyl, amino, cyano , C1-3 alkyl or C1-3 alkoxy, which may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • Rcc , Rd, and Re are each independently selected from deuterium, halogen, or hydroxyl.
  • Rcc , Rd, and Re are each independently selected from F.
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, NH 2 , thiol, cyano, C 1-6 alkyl, C 1-6 alkoxy, or -(CH 2 ) n OR a1 , wherein the C 1-6 alkyl or C 1-6 alkoxy may be further substituted with one or more Raa .
  • R 1 and R 2 are each independently selected from -(CH 2 ) n R a1 .
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, or —(CH 2 ) n OR a1 , wherein the C 1-6 alkyl or C 1-6 alkoxy may be further substituted with one or more R aa .
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, -(CH 2 ) n R a1 or -(CH 2 ) n OR a1 , which may be further substituted with one or more R aa .
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, or -(CH 2 ) n OR a1 , which may be further substituted with one or more R aa .
  • n and n1 are each independently selected from 0, 1 or 2.
  • n is selected from 1 or 2.
  • n is selected from 0.
  • R 1 and R 2 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 OR a1 , -CH 2 CH 2 OR a1 , wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl may be further substituted with one or more Raa .
  • R 1 and R 2 are each independently selected from -CH 2 Ra1 .
  • R 1 and R 2 are each independently selected from hydrogen, n-butyl, -CH 2 R a1 , -CH 2 OR a1 , -CH 2 CH 2 OR a1 , wherein the n-butyl may be further optionally substituted with one or more R aa .
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, which may be further optionally substituted with one or more R bb .
  • R 1 and R 2 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothioph
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclopentyl group, which may be optionally further substituted with one or more R bb .
  • R 2 and R c together with the carbon atom and nitrogen atom to which they are attached form a 3-6 membered heterocyclic group, which may be further optionally substituted with one or more R bb .
  • X when X is selected from ( NRc ) q , R2 and Rc, together with the carbon atom and the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl or piperazinyl group, which may be further optionally substituted with one or more Rbb .
  • R 2 and R c together with the carbon atom and nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, which may be further optionally substituted with one or more R bb groups.
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, NH2 , C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclyl, and the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl or 3-6 membered heterocyclyl may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, C1-6 alkyl or C3-6 cycloalkyl, which may be further substituted with one or more Rj . In some embodiments, Ra1 , Ra2 or Ra3 are each independently selected from phenyl, which may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from C1-6 alkyl, C3-6 cycloalkyl or phenyl, and the C1-6 alkyl, C3-6 cycloalkyl or phenyl may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or phenyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or phenyl may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from methyl, ethyl, cyclopropyl or phenyl, which may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl may be further substituted with one or more Rj .
  • Ra1 , Ra2 or Ra3 are each independently selected from hydrogen, methyl, ethyl, tert-butyl or cyclopentyl, which may be further optionally substituted with one or more Rj .
  • Raa , Rbb and Rj are each independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-3 alkyl or C1-3 alkoxy, and the C1-3 alkyl or C1-3 alkoxy may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • Raa , Rbb and Rj are each independently selected from deuterium, halogen or hydroxyl.
  • Rbb is selected from C1-3 alkyl, which may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • Rbb is selected from methyl or ethyl. In other embodiments, Rbb is selected from ethyl.
  • Raa , Rbb , and Rj are each independently selected from F.
  • Ra1 is selected from C1-6 alkyl, which may be further substituted with one or more Rj .
  • Ra1 is selected from C1-3 alkyl.
  • Ra1 is selected from methyl, ethyl, cyclopropyl or phenyl, which may be further substituted with one or more F.
  • Ra1 is selected from methyl, ethyl, cyclopropyl, or 2-fluorophenyl.
  • Ra1 is selected from methyl or ethyl.
  • Rj is selected from F or -( CH2 ) nS (O) mRa1 .
  • Rj is selected from F or -SRal .
  • Rj is selected from F or -SCH3 .
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclopentyl group.
  • R 2 and R c together with the carbon atom and nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, which may be further optionally substituted with one or more methyl or ethyl groups; R 1 is selected from H.
  • R 1 is selected from H.
  • R 1 is selected from H.
  • R 1 is selected from H.
  • R 1 is selected from H.
  • R 1 is selected from H.
  • R 1 is selected from H.
  • R1 is selected from H.
  • R 1 and R 2 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 OR a1 , -CH 2 CH 2 OR a1 , the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl optionally may be further substituted with one or more F, and R a1 is selected from methyl or ethyl.
  • R1 and R2 are each independently selected from hydrogen, n- butyl , -CH2Ra1 , -CH2ORal , -CH2CH2ORal , wherein the n-butyl may be further substituted with one or more F, and Ra1 is selected from methyl, ethyl or cyclopropyl .
  • R 1 and R 2 are each independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3 , the n - butyl group may be further substituted with one or more F.
  • R 1 and R 2 are each independently selected from hydrogen, n-butyl, -CH 2 OCH 2 CH 3 , or -CH 2 CH 2 OCH 3 , wherein the n-butyl group may be further optionally substituted with one or more Fs.
  • R 1 and R 2 are each independently selected from hydrogen or n-butyl, which n-butyl may be further substituted with one or more F. In some embodiments, R 1 and R 2 are each independently selected from hydrogen, n-butyl, -CH 2 OCH 2 CH 3 or -CH 2 CH 2 OCH 3 .
  • R 1 and R 2 are each independently selected from hydrogen, n-butyl, -CH 2 OCH 2 CH 3 or -CH 2 CH 2 OCH 3 .
  • R 1 is selected from H.
  • R 1 is selected from H
  • R 2 is selected from n-butyl, -CH 2 OCH 2 CH 3 or -CH 2 CH 2 OCH 3 .
  • R 1 is selected from H
  • R 2 is selected from n-butyl, -CH 2 OCH 2 CH 3 or -CH 2 CH 2 OCH 3 .
  • R 1 is selected from H and R 2 is selected from n-butyl.
  • R 1 is selected from H
  • R 2 is selected from
  • R 3 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy or -(CH 2 ) n S(O) m R a1 , wherein the amino, C 1-6 alkyl or C 1-6 alkoxy may be further substituted with one or more R f .
  • R 3 is selected from C 3-6 cycloalkyl or -(CH 2 ) n NR a2 R a3 , wherein the C 3-6 cycloalkyl may be further substituted with one or more R f .
  • R 3 is selected from -(CH 2 ) n OR a1 .
  • R 3 is selected from halogen, hydroxy, NH 2 , cyano, C 1-3 alkyl, C 1-3 alkoxy, or -(CH 2 ) n S(O) m R a1 , wherein the C 1-3 alkyl or C 1-3 alkoxy may be further substituted with one or more R f .
  • R 3 is selected from methyl, ethyl, methoxy, ethoxy or -(CH 2 ) n S(O) m R a1 , wherein the methyl, ethyl, methoxy, ethoxy may be further substituted with one or more R f .
  • R 3 is selected from cyclopropyl, cyclobutyl or -(CH 2 ) n NR a2 R a3 , wherein the cyclopropyl or cyclobutyl may be further substituted with one or more R f .
  • R 3 is selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -(CH 2 ) n OR a1 , -(CH 2 ) n NR a2 R a3 -(CH 2 ) n S(O) m R a1 , wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group may be further substituted with one or more R f .
  • R 3 is selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -OR a1 , -NR a2 R a3 , -S(O) m R a1 , and the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group may be optionally further substituted with one or more R f .
  • R 3 is selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -OR a1 , -NR a2 R a3 , -SR a1 , and the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group may be optionally further substituted with one or more R f .
  • R 3 is selected from methyl, ethoxy, cyclopropyl, -OR a1 , -NR a2 R a3 , -SR a1 , and the methyl, ethoxy or cyclopropyl group may be optionally further substituted with one or more R f .
  • Rf is selected from deuterium, halogen, hydroxyl, amino, cyano, C1-3 alkyl or C1-3 alkoxy, and the C1-3 alkyl or C1-3 alkoxy may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • Rf is selected from deuterium, halogen, or hydroxyl.
  • Rf is selected from F.
  • R 3 is selected from -(CH 2 ) n S(O) m R a1 . In other embodiments, R 3 is selected from cyclopropyl or -(CH 2 ) n NR a2 R a3 .
  • m is selected from 0.
  • Ra1 is selected from methyl.
  • Ra2 or Ra3 are each independently selected from H or methyl.
  • Ra2 or Ra3 are both selected from methyl.
  • R 3 is selected from -SCH 3 . In other embodiments, R 3 is selected from cyclopropyl or -N(CH 3 ) 2 .
  • R 3 is selected from methyl, CF 3 CH 2 O- or
  • A is selected from
  • A is selected from
  • R 5 and R 5' are each independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl or C 1-3 alkoxy; the amino, C 1-3 alkyl or C 1-3 alkoxy may be further substituted with one or more R i .
  • R 5 and R 5′ are each independently selected from hydrogen, deuterium, halogen, or C 1-3 alkyl; the C 1-3 alkyl may optionally be further substituted with one or more R i .
  • R 5 and R 5' are each independently selected from hydrogen, deuterium, halogen, NH 2 , methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy may be further substituted with one or more R i .
  • R 5 and R 5' are each independently selected from hydrogen, deuterium, halogen or methyl, and the methyl may be further substituted with one or more R i .
  • R 5 and R 5' are both selected from methyl.
  • R 5 is selected from hydrogen, deuterium, or halogen.
  • R 5 is selected from hydrogen or F. In other embodiments, R 5 is selected from methyl, which may be further optionally substituted with one or more R 1 .
  • R 5 is selected from F. In other embodiments, R 5 is selected from CF 3 .
  • R i is selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • R i is selected from deuterium, halogen, or hydroxyl.
  • R i is selected from F.
  • A is selected from In some embodiments, A is selected from R 4 is not
  • A is selected from
  • A is selected from Or in other embodiments, A is selected from Ring B is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-
  • the 10-membered heteroaryl group, the C 3-10 cycloalkyl group, the 3-10-membered heterocyclyl group, the C 6-10 aryl group or the 5-10-membered heteroaryl group may be further substituted by one or more R g .
  • A is selected from Or in other embodiments, A is selected from Ring B is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl may be further substituted with one or more R g .
  • A is selected from Or in other embodiments, A is selected from Ring B is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl may be further substituted with one or more Rg .
  • A is selected from Or in other embodiments, A is selected from Ring B is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl may be further substituted with one or more Rg .
  • ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and the ring B may be further substituted with one or more Rg .
  • A is selected from Or in other embodiments, A is selected from Ring B is selected from phenyl, pyrrolyl, furanyl, thienyl or pyridinyl, and the phenyl, pyrrolyl, furanyl, thienyl or pyridinyl may be further substituted with one or more R g .
  • ring B is selected from cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, piperidinyl or thiazolyl, and the ring B may be further substituted with one or more R g .
  • A is selected from When , the two bonds to ring B are bonded to different ring atoms. Alternatively, the two bonds to ring B are bonded to the same ring atom.
  • A is selected from Or in other embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g . In other embodiments, the ring B is selected from The ring B may optionally be further substituted with one or more R g .
  • a is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g . In other embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g .
  • A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g .
  • A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g .
  • A is selected from
  • A is selected from
  • Rg is selected from deuterium, halogen, hydroxyl, amino, cyano, C1-3 alkyl or C1-3 alkoxy, and the C1-3 alkyl or C1-3 alkoxy may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.
  • Rg is selected from halogen, hydroxy, NH2 , methyl, ethyl, methoxy or ethoxy, which may optionally be further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.
  • Rg is selected from halogen, hydroxy, NH2 , methyl, ethyl, methoxy, or ethoxy, which may be further substituted with one or more substituents selected from halogen.
  • Rg is selected from halogen, hydroxy, NH2 , methyl, ethyl, methoxy, or ethoxy, which may be further substituted with one or more F.
  • Rg is selected from F, methyl, or trifluoromethyl.
  • Rg is selected from F.
  • A is selected from Ring B is selected from
  • A is selected from Ring B is selected from
  • A is selected from Ring B is selected from
  • A is selected from Ring B is selected from
  • A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g . In other embodiments, A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g .
  • A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g .
  • A is selected from Structural unit Selected from
  • A is selected from Structural unit Selected from
  • A is selected from Structural unit Selected from
  • A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g .
  • A is selected from Structural unit Selected from
  • A is selected from Structural unit Selected from
  • R 4 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, and the C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl may be further substituted with one or more R h .
  • R 4 is selected from C 5-8 cycloalkyl, 5-8 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, and the C 5-8 cycloalkyl, 5-8 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl may be further substituted with one or more R h .
  • R 4 is selected from C 8-10 cycloalkyl, and the C 8-10 cycloalkyl may be further substituted with one or more R h .
  • R 4 is selected from C 8-10 polycyclic cycloalkyl, and the C 8-10 polycyclic cycloalkyl may be further substituted with one or more R h.
  • R 4 is selected from C 8-10 polycyclic cycloalkyl , and the polycyclic is bicyclic, tricyclic or tetracyclic, and the C 8-10 polycyclic cycloalkyl may be further substituted with one or more R h .
  • R 4 is selected from C 5-8 cycloalkyl, C 6-11 aryl , or 5-10 membered heteroaryl, which may be further optionally substituted with one or more R h .
  • R 4 is selected from C 5-8 cycloalkyl, phenyl, C 9-11 aryl , or 5-10 membered heteroaryl, which may be further optionally substituted with one or more R h .
  • R 4 is selected from C 5-8 cycloalkyl, C 9-11 aryl , or 5-10 membered heteroaryl, which may be further optionally substituted with one or more R h .
  • R4 is selected from phenyl, indolinyl, isoindolinyl, benzodioxolanyl, benzopyrazolidine ring group, benzimidazolidine ring group, benzotetrahydrothiophene ring group, benzotetrahydrofuran ring group, 3H-spiro [benzofuran-2,1'-cyclopropane], benzotetrahydropyran ring group, benzothiazolidine ring group, benzisothiazolidine ring group, benzoxazolidine ring group, benzisoxazolidine ring group, benzopiperidine ring group, benzopiperazine ring group, benzomorpholine ring group, benzothiazinane ring group, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazoly
  • R 4 is selected from cyclobutyl, cyclopentyl, cyclohexyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, benzocyclopentyl or benzocyclohexyl, which R 4 may be further substituted with one or more R h .
  • R is selected from phenyl, indolinyl, isoindolinyl, benzopyrazolidine, benzotetrahydrofuran, 3H-spiro[benzofuran-2,1′-cyclopropane], benzotetrahydropyran, benzopiperidine, furanyl, thienyl, pyridyl, benzothiophene, benzothiazole, benzooxazole, indolyl, benzimidazole, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, quinolyl, isoquinolyl, 2,3-dihydrofuro[2,3-b]pyridine, 2,3-dihydrofuro[3,2-b]pyridine, 2,3-dihydrofuro[3,2-c]pyridine or bicyclo[1.1.1]pentanyl, and R may be further substituted with one or more R.
  • R 4 is selected from cyclobutyl, 1,2-dihydropyridinyl, adamantyl or benzocyclobutyl, which R 4 may be further substituted with one or more R h .
  • R is selected from indolinyl, isoindolinyl, benzopyrazolidine, benzotetrahydrofuran, 3H-spiro[benzofuran-2,1′-cyclopropane], benzotetrahydropyran, benzopiperidine, furanyl, thienyl, pyridyl, benzothiophene, benzothiazole, benzooxazole, indolyl, benzimidazole, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, quinolyl, isoquinolyl, 2,3-dihydrofuro[2,3-b]pyridine, 2,3-dihydrofuro[3,2-b]pyridine, 2,3-dihydrofuro[3,2-c]pyridine or bicyclo[1.1.1]pentanyl, and R may be further substituted with one or more R.
  • R4 is selected from cyclobutyl, 1,2-dihydropyridinyl, adamantyl, benzocyclobutyl, phenyl, indolyl, isoindolyl, benzopyrazolidine ring group, benzotetrahydrofuran ring group, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyran ring group, benzodioxolanyl, benzotetrahydropyran ring group, benzopiperidine ring group, furanyl, thienyl, pyridyl, benzothiophene ring group, benzothiazole ring group, benzoxazole ring group, indolyl, benzimidazole ring group, thieno[3 ,2-b]pyridine ring group, thieno[2,3-b]pyridine ring group, quinolyl, iso
  • R 4 contains an aromatic ring structure (eg, a phenyl ring structure) or a heteroaromatic ring (eg, a thiophene ring structure), in the structural fragment LR 4 , L is connected to the aromatic ring or heteroaromatic ring of R 4 .
  • aromatic ring structure eg, a phenyl ring structure
  • heteroaromatic ring eg, a thiophene ring structure
  • R4 is selected from The R 4 may optionally be further substituted with one or more R h . In some embodiments, R 4 is selected from The R 4 may optionally be further substituted by one or more R h . In other embodiments, R 4 is selected from The R 4 may be further optionally substituted by one or more R h .
  • R4 is selected from The R 4 may be further optionally substituted by one or more R h .
  • R4 is selected from The R 4 may be further optionally substituted by one or more R h .
  • R4 is selected from The R 4 may be further substituted with one or more R h , and L is selected from C( RaRb ) or -C( RaRb )-C( RaRb )-.
  • R h is selected from -(CH 2 ) n P(O)R a2 R a3 . In other embodiments, R h is selected from -(CH 2 ) n O(CH 2 ) n S(O) m R al .
  • n1 is selected from 0.
  • Ra2 is selected from hydrogen.
  • Ra3 is selected from C1-6 alkyl or C3-6 cycloalkyl , which may be further substituted with one or more Rj .
  • Ra3 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, which may be further substituted with one or more Rj .
  • Ra3 is selected from tert-butyl or cyclopentyl.
  • R h is selected from or methoxy, which may optionally be further substituted with one or more halogens.
  • R h is selected from hydroxy or -OCH 2 SCH 3 .
  • R h is selected from or methoxy, which may optionally be further substituted with one or more F or Cl.
  • R is selected from or methoxy, which may optionally be further substituted with one or more F.
  • R4 is selected from
  • R4 is selected from
  • R4 is selected from
  • R4 is selected from
  • R4 is selected from
  • R4 is selected from and L is selected from C( RaRb ) or -C( RaRb ) -C ( RaRb )-.
  • R4 is selected from and L is selected from a bond.
  • R4 is selected from The R 4 may be further optionally substituted by one or more R h .
  • R4 is selected from Said R 4 may optionally be further substituted by one or more R h , and L is selected from a bond.
  • R4 is selected from
  • the compound of formula (I) of the present disclosure its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (I-1), the compound of formula (I-2), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and Ring B are as defined in the present disclosure.
  • the compound of formula (I) of the present disclosure its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (II-1), the compound of formula (II-2), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 2 , R 3 , R 4 , R 5 , X and ring B are as defined in the present disclosure.
  • the compound of formula (I) of the present disclosure its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (III-1), the compound of formula (III-2), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 and Ring B are as defined in the present disclosure.
  • the compound of formula (I) of the present disclosure its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compound of formula (IV-1), the compound of formula (IV-2), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 4 , R 5 and Ring B are as defined in the present disclosure.
  • the compound of formula (I) of the present disclosure, its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (Ia), the compound of formula (I-1a), the compound of formula (I-2a), the compound of formula (II-1a), the compound of formula (II-2a), the compound of formula (III-1a), the compound of formula (III-2a), the compound of formula (IV-1a), the compound of formula (IV-2a), its stereoisomer or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and Ring B are as defined in the present disclosure.
  • the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.
  • the compounds of the present disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:
  • the compounds of the present disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds: Compound, its stereoisomer or pharmaceutically acceptable salt thereof:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating or preventing a disease, comprising administering a therapeutically effective amount of the above compound, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating or preventing a disease.
  • the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating or preventing a disease.
  • the present disclosure provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof for treating or preventing a disease.
  • the disease is selected from a disease associated with inhibition of sodium taurocholate co-transporting peptide (NTCP) and/or inhibition of sodium-dependent bile acid transporter (ASBT).
  • NTCP sodium taurocholate co-transporting peptide
  • ASBT sodium-dependent bile acid transporter
  • the disease associated with inhibition of sodium taurocholate co-transporting peptide (NTCP) and/or inhibition of sodium-dependent bile acid transporter (ASBT) is selected from conditions, disorders and diseases requiring inhibition of bile acid circulation, such as cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases.
  • inhibiting sodium taurocholate cotransporter peptide (NTCP) and/or inhibiting sodium-dependent bile acid transporter (ASBT) is selected from selectively inhibiting sodium taurocholate cotransporter peptide (NTCP), or simultaneously inhibiting sodium taurocholate cotransporter peptide (NTCP) and sodium-dependent bile acid transporter (ASBT).
  • the compounds disclosed herein have good inhibitory activity on NTCP and/or ASBT and can selectively inhibit NTCP and/or ASBT.
  • the compounds disclosed herein also have good in vitro and in vivo efficacy and in vitro and in vivo pharmacokinetic properties.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the present disclosure, prepared from compounds with specific substituents discovered in the present disclosure with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Certain specific compounds of the present disclosure contain basic and acidic functional groups and can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases.
  • the preparation method of such salts is: in water or an organic solvent or a mixture of the two, via the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid to prepare.
  • the compounds of the present disclosure may exist in specific stereoisomeric forms.
  • the present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.
  • 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
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some bonding electrons.
  • the compounds of the present disclosure may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compounds.
  • compounds may be labeled with radioactive isotopes, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present disclosure, whether radioactive or not, are included in the scope of the present disclosure.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.
  • substitutions means that any one or more hydrogen atoms on a particular atom are replaced by substituents, which may include deuterium and hydrogen variants, and the number of substituents includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, based on what is chemically feasible.
  • substituted heterocyclyl include, but are not limited to, the terms “alkyl”, “alkenyl”, “alkynyl”, “spirocycloalkyl”, “fused cycloalkyl”, “bridged cycloalkyl”, “heterocyclyl”, “spiroheterocyclyl”, “fused heterocyclyl”, “bridged heterocyclyl”, “alkoxy”, “cycloalkyl”, “heterocycloalkyl”, “heteroaryl”, “alkyl ring”, “heteroalkyl ring”, “heteroaryl ring”, etc.
  • the “substituent” include deuterium, tritium, —OH, —SH, halogen, —NH 2 , nitro, nitroso, —CN, an azido group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a halo-cycloalkynyl group,
  • the “substituent” is selected from deuterium, tritium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo- 3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, halo-
  • Cmn means that the moiety has an integer number of carbon atoms in a given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C1-3 means that the group may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.
  • m-n member herein refers to the integer number of the moiety in a given range.
  • 3-12 member means that the group may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 members.
  • 5-10 member means that the group may have 5, 6, 7, 8, 9 or 10 members.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or their variants may be independently selected. Combinations of molecules are permitted only if such combinations result in stable compounds.
  • linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to an -OH group.
  • amino refers to a -NH2 group.
  • mercapto refers to a -SH group.
  • cyano refers to a -CN group.
  • nitro refers to the -NO2 group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be straight chain or branched.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion i.e., alkyl
  • alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
  • alkoxy refers to an -O-alkyl group.
  • alkylamino refers to an -NH-alkyl group.
  • dialkylamino refers to -N(alkyl) 2 .
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH), and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls; preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl.
  • spirocycloalkyl includes:
  • Non-limiting examples include:
  • fused cycloalkyl refers to a 5-20 membered all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • it is 6-14 members, more preferably 7-10 members.
  • the cycloalkyl group is preferably a cycloalkyl group, a tricycloalkyl group, a tetracycloalkyl group or a polycycloalkyl group, preferably a bicycloalkyl group or a tricycloalkyl group, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.
  • the cycloalkyl may be optionally substituted or unsubstituted.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; wherein the ring atom may further be boron or P(O) p (wherein p is an integer from 0 to 2).
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.
  • heterocyclic groups include:
  • spiro heterocyclic group refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/5-yuan or 5-yuan/6-yuan single spiral heterocyclic group.
  • spiral heterocyclic groups include:
  • fused heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group of 5 to 14 members, in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, and more preferably 7 to 10 members.
  • bridged heterocyclic groups include:
  • heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl ring. It should be understood that the fused system formed after fusion belongs to the category of "heterocyclyl" defined in the present disclosure. Non-limiting examples of “heterocyclyl” also include: wait.
  • aryl refers to a group of 6 to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) aromatic rings with a conjugated ⁇ electron system, preferably 6 to 10 members, the aromatic rings may be phenyl rings and naphthyl rings, more preferably phenyl rings, the aromatic rings may be fused to heteroaryl, heterocyclic or cycloalkyl rings, wherein the ring connected to the parent structure is an aromatic ring, it should be understood that the fused system formed after fusion belongs to the category of "aryl” defined in the present disclosure, non-limiting examples of "aryl” include: phenyl, naphthyl,
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaromatic ring in the heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, and the heteroaromatic ring can be, for example, an imidazolyl ring, a furyl ring, a thienyl ring, a thiazolyl ring, a pyrazolyl ring, an oxazolyl ring, a pyrrolyl ring, a triazolyl ring, a tetrazolyl ring, a pyridyl ring, a pyrimidyl ring, a thiadiazole ring, a pyrazinyl ring, etc., preferably a triazolyl ring, a thienyl ring, an imidazolyl ring,
  • heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaromatic ring. It should be understood that the fused system formed after the fusion belongs to the category of "heteroaryl” defined in the present disclosure.
  • heteroaryl include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl,
  • treatment means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, or (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the disclosure that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • prophylactically effective amount means an amount of a compound of the present disclosure that prevents or delays a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present disclosure that constitutes a “prophylactically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.
  • the therapeutic or preventive dose of the disclosed compounds may be determined, for example, based on the specific use of the treatment or prevention, the mode of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
  • the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration. Some typical doses range from about 0.001 mg/kg to about 1000 mg/kg body weight/day.
  • the dose is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration.
  • the effective dose may be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.
  • “Pharmaceutical composition” means a composition containing one or more compounds, isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.
  • the raw materials or intermediates used in the embodiments of the present disclosure can be obtained from commercial sources or prepared by methods of the prior art.
  • some of the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis with reference to the following routes:
  • R 2 , R 4 and Ring B are as defined in the present disclosure.
  • the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis with reference to the routes or methods of the following examples, and the obtained compounds can be characterized by known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, etc.
  • Boc represents tert-butyloxycarbonyl
  • intermediate 1B (10.00 g) and tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 60.5 mL) were added to tetrahydrofuran (100 mL) and stirred at 75°C for reaction. After the reaction was complete, methanol (50 mL) was added to the reaction solution for quenching, and the reaction was stirred at 60°C for 1 hour.
  • intermediate 1C (1.00 g), intermediate K (2.27 g), and triethylamine (1.21 g) were added to tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 1D (2.51 g). MS (ESI): m/z 518.94 [M+H] + .
  • Boc-D-norleucine (3.0 g), 3-aminothiophene hydrochloride (1.8 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.9 g), and triethylamine (7.2 mL) were added to N,N-dimethylformamide (80 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water and dried to obtain intermediate 3A (4.0 g).
  • intermediate 3A (4.0 g) and trifluoroacetic acid (10 mL) were added to dichloromethane (30 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH value was about 9) with saturated sodium bicarbonate aqueous solution under ice-water bath, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 3B (3.3 g). MS (ESI): m/z 213.11 [M+H] + .
  • intermediate 3B (3.3 g) and tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 22 mL) were added to tetrahydrofuran (60 mL) and stirred at 75°C for reaction. After the reaction was complete, methanol (20 mL) was added to the reaction solution for quenching, and the reaction was stirred at 60°C for 1 hour.
  • intermediate 3C (1.20 g), intermediate K (2.45 g), and N,N-diisopropylethylamine (2.1 mL) were added to tetrahydrofuran (60 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 3D (2.10 g). MS (ESI): m/z 524.91 [M+H] + .
  • intermediate 10A 5.60 g
  • trifluoroacetic acid 20 mL
  • dichloromethane 80 mL
  • the solvent was evaporated under reduced pressure to obtain intermediate 10B (5.91 g).
  • intermediate 10B (3.94 g), intermediate K (5.00 g), and triethylamine (6.94 g) were added to tetrahydrofuran (150 mL), and the mixture was stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 10C (3.11 g). MS (ESI): m/z 472.00 [M+H] - .
  • intermediate 10E (1.08 g) and tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 2.5 mL) were added to tetrahydrofuran (40 mL) and stirred at 75°C for reaction. After the reaction was complete, methanol (20 mL) was added to the reaction solution for quenching, and the reaction was stirred at 60°C for 1 hour.
  • triphenylphosphine (3.76 g) and carbon tetrabromide (2.38 g) were dissolved in dichloromethane (40 ml), and then ethyl 3,3,3-trifluoropyruvate (1.00 g) was slowly added dropwise. After the addition was completed, the mixture was stirred in an ice bath to react. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 38A (1.20 g).
  • Boc-norleucine (8.80 g), intermediate 45B (6.33 g), triethylamine (15.40 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (21.70 g) were added to N,N-dimethylformamide (100 mL), and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 45C (12.11 g). MS (ESI): m/z 365.31 [M+H] + .
  • intermediate 45D (3.99 g), intermediate K (5.50 g), and triethylamine (6.11 g) were added to tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 45E (7.40 g). MS (ESI): m/z 591.06 [M+H] + .
  • intermediate 45E 7.40 g
  • tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 18.9 mL) were added to tetrahydrofuran (50 mL) and stirred at 75°C.
  • methanol 50 mL was added to the reaction solution to quench, and the reaction was stirred at 60°C for 1 hour.
  • the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH value was about 9) with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 45F (5.30 g).
  • reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 45J (100 mg).
  • BOC-D-proline (7.00 g), aniline (13.48 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.55 g), and triethylamine (18.2 mL) were added to N,N-dimethylformamide (80 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water and dried to obtain intermediate 53A (7.60 g). MS (ESI): m/z 291.13 [M+H] + .
  • intermediate 53A (7.60 g) and trifluoroacetic acid (30 mL) were added to dichloromethane (100 mL) and stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH value was about 9) with saturated sodium bicarbonate aqueous solution under ice-water bath, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 53B (5.0 g). MS (ESI): m/z 191.12 [M+H] + .
  • intermediate 53B (5.0 g) and tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 38 mL) were added to tetrahydrofuran (100 mL) and stirred at 75°C. After the reaction was complete, methanol (30 mL) was added to the reaction solution to quench, and the reaction was stirred at 60°C for 2 hours.
  • intermediate 53C (3.0 g), intermediate K (1.6 g), and N,N-diisopropylethylamine (3.44 mL) were added to tetrahydrofuran (100 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 53D (3.0 g). MS (ESI): m/z 502.96 [M+H] + .
  • BOC-D-homoproline (3.07 g)
  • 2-methyl-5-amino-2,3-dihydrobenzofuran (2.00 g)
  • O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.63 g)
  • triethylamine (4.07 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate.
  • intermediate 57A (4.10 g) and trifluoroacetic acid (10 mL) were added to dichloromethane (50 mL) and stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH about 9) with saturated sodium bicarbonate aqueous solution under ice-water bath, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 57B (3.00 g). MS (ESI): m/z 261.17 [M+H] + .
  • intermediate 57B (3.00 g), intermediate K (5.00 g), and triethylamine (4.66 g) were added to tetrahydrofuran (80 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 57C (6.25 g). MS (ESI): m/z 587.00 [M+H] + .
  • intermediate 57D 250 mg
  • tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 4.6 mL) were added to tetrahydrofuran (3 mL) and stirred at 75°C.
  • methanol 5 mL was added to the reaction solution to quench, and the reaction was stirred at 65°C for 1 hour.
  • the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH value was about 9) with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 57E (230 mg).
  • intermediate 58B (2.00 g), intermediate K (5.07 g), and triethylamine (5.91 g) were added to tetrahydrofuran (60 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether/ethyl acetate) to obtain intermediate 58C (4.61 g). MS (ESI): m/z 497.89 [M+H] + .
  • intermediate 58D (4.40 g), aniline (0.85 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.48 g), and triethylamine (2.75 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate.
  • 71A (6.00 g), aniline (2.30 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.50 g), and triethylamine (13.40 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate.
  • intermediate 71C (3.50 g) and trifluoroacetic acid (15 mL) were added to dichloromethane (80 mL) and stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the pH was adjusted to alkaline (about 9) with saturated sodium bicarbonate aqueous solution under ice-water bath, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 71D (2.40 g). MS (ESI): m/z 233.23 [M+H] + .
  • intermediate 71D (2.40 g), intermediate K (4.00 g), and triethylamine (3.00 g) were added to tetrahydrofuran (70 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 71E (5.30 g). MS (ESI): m/z 559.03 [M+H] + .
  • intermediate 71F 750 mg
  • tetrahydrofuran solution of borane dimethyl sulfide complex 1 mL, 10 mol/L
  • borane dimethyl sulfide complex 1 mL, 10 mol/L
  • methanol 5 mL
  • the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH value 1.0) with saturated sodium bicarbonate aqueous solution.
  • About 9 extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 71G (700 mg).
  • Compound 71 was prepared by substituting (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid for (S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid to obtain Compound 72 (240 mg). MS (ESI): m/z 507.1422 [M+H] + .
  • intermediate 82A (6.13 g), aniline (3.00 g), N,N-diisopropylethylamine (6.92 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15.26 g) were added to N,N-dimethylformamide (50 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate.
  • intermediate 82C (2.68 g), intermediate K (4.76 g), and triethylamine (5.32 g) were added to tetrahydrofuran (50 mL) and stirred at room temperature for reaction. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 82D (5.50 g). MS (ESI): m/z 530.95 [M+H] + .
  • intermediate 82F (1.27 g) and tetrahydrofuran solution of borane dimethyl sulfide complex (10 mol/L, 4 mL) were added to tetrahydrofuran (25 mL) and stirred at 75°C.
  • methanol 14 mL was added to the reaction solution to quench, and the reaction was stirred at 60°C for 2 hours.
  • the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH about 9) with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 82G (0.43 g).
  • Compound 72 was prepared by replacing (R)-1-(tert-butyloxycarbonyl)-4-oxopiperidine-2-carboxylic acid with N-Boc-4-oxo-D-proline to prepare Compound 87 (150 mg) from Intermediate 87C'.
  • Huh-7D-NTCP cells were cultured in DMEM medium (VivaCell, C3113-0500) supplemented with 10% FBS (Gibco, 2409126CP) at 37°C under 5% CO 2 conditions.
  • Huh-7D-NTCP cells were inoculated in a 96-well plate (Eppendorf, 30730119) and incubated at 37°C for 24 hours under 5% CO2 .
  • DMSO Sigma, D2650
  • DMEM medium VivaCell, C3113-0500
  • a total of 8 concentration points were set, with the highest concentration point being 20 ⁇ M and 3-fold dilution.
  • the culture supernatant was discarded, and then 90 ⁇ L of DMEM medium containing the compound was added to the well, and 90 ⁇ L of DMEM medium was added to the well as a negative control, and incubated at 37°C for 1 hour.
  • DMEM medium (VivaCell, C3113-0500) was used to dilute Myrcludex B-FITC (HBV/2-48 myr (C)-FITC with lysine (K) at the C-terminus) to a concentration of 100 nM after adding to the well plate. Then, 10 ⁇ L of DMEM medium containing Myrcludex B-FITC was added to all wells and incubated at 37°C for 1 hour.
  • Test Example 2 In vitro CYP450 enzyme inhibition activity
  • the human liver microsome incubation system was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.2 mg/ml), mixed CYP450 specific substrates, test compounds and NADPH+ MgCl2 solution, and incubated at 37°C and 300 rpm for 0.5 hours.
  • a positive control group and a negative control group were also set up.
  • the positive control group was a system in which the test compound was replaced by a specific inhibitor
  • the negative control group was a system in which the test compound was replaced by a solvent.
  • the incubated samples were added with an acetonitrile solution containing an internal standard to prepare a supernatant by protein precipitation, which was diluted and used for LC/MS/MS to determine the metabolites of specific substrates.
  • the inhibition rate was calculated using the formula (1-(test group/negative control group)) ⁇ 100%.
  • the disclosed compounds have good stability in human liver microsomes, with a residual amount of >80% after 60 minutes.
  • ICR mice weighing 18-22 g, were randomly divided into groups after acclimation for 3-5 days, with 9 mice in each group, and were intragastrically gavaged with a solution of the test compound at a dose of 10 mg/kg.
  • Blood was collected from the eye sockets at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare plasma samples for testing.
  • the disclosed compound has good pharmacokinetic properties, high bioavailability, and a relative bioavailability of more than 75%.
  • Test Example 4 In vitro test of hNTCP transporter and in vitro test of hASBT transporter
  • HEK293-hNTCP cells human NTCP overexpressing cells
  • DMEM Viva Cell, C3113-0500
  • 10% fetal bovine serum Gibco, 10099-141
  • 200 ⁇ g/ml G418 Gbico, 10131-027
  • Cells in the logarithmic growth phase were digested with trypsin (Gbico, 12604-021) and plated, and the cell density was adjusted to 4 ⁇ 10 5 cells/ml, and the cell suspension was 500 ⁇ L/well.
  • the cells were cultured in a 37°C, 5% CO 2 saturated humidity incubator for adherent growth for 24 hours. The experiment can be carried out when the confluence is ⁇ 90%.
  • the cell supernatant was discarded, and 250 ⁇ L of pre-incubation solution was added to each well (the negative group was the blank solvent group, and the test group was the compound group.
  • the final concentrations were as follows: 100 nM, 30 nM, 10 nM, 5 nM, 3 nM, 1 nM, 0.3 nM), mixed, pre-incubated at 37 ° C for 30 min, and the pre-incubation solution was removed.
  • HEK293-hASBT cells human ASBT overexpressing cells
  • DMEM Viva Cell, C3113-0500
  • 10% fetal bovine serum Gibco, 10099-141
  • 200 ⁇ g/ml G418 Gbico, 10131-027
  • Cells in the logarithmic growth phase were digested with trypsin (Gbico, 12604-021) and plated, and the cell density was adjusted to 4 ⁇ 10 5 cells/ml.
  • the cell suspension was 500 ⁇ L/well and cultured in a 37°C, 5% CO 2 saturated humidity incubator. The cells adhered to the wall for 24 hours, and the experiment could be carried out when the confluence was ⁇ 90%.
  • the cell supernatant was discarded, and 250 ⁇ L of pre-incubation solution was added to each well (the negative group was the blank solvent group, and the test group was the compound group.
  • the final concentrations were as follows: 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 2 ⁇ M, 1 ⁇ M, 300 nM, and 100 nM.) Mix well, pre-incubate at 37°C for 30 min, and remove the pre-incubation solution.

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Abstract

本公开属于医药技术领域，涉及一种苯并噻二氮卓化合物及其用途，本公开还涉及苯并噻二氮卓化合物的制备方法以及含有该化合物的药物组合物。本公开具体涉及式(I)化合物、其立体异构体或其药学上可接受的盐及其用途。

Description

一种苯并噻二氮卓化合物及其用途
相关申请的交叉引用
本公开要求向中国知识产权局提交的第202310608988.9号中国专利申请、第202410160508.1号中国专利申请和第202410622891.8号中国专利申请的优先权和权益，上述中国专利申请的全部内容通过援引并入本文。
技术领域
本公开属于医药技术领域，涉及一种苯并噻二氮卓化合物及其用途，本公开还涉及苯并噻二氮卓化合物的制备方法以及含有该化合物的药物组合物。
背景技术
NTCP(sodium taurocholate cotransportingpolypeptide)指钠离子-牛磺胆酸共转运蛋白，由SLC10A1基因编码。NTCP是肝细胞膜上转运Na离子和胆汁酸的主要蛋白，在胆汁酸的肠肝循环过程中发挥重要作用，是抗病毒和胆汁淤积适应症的潜在靶标。NTCP位于人、大鼠和其他物种的肝细胞的基底外侧结构域(血液侧)，在其他任何组织中均为检测到NTCP。
HBV包膜蛋白由3中蛋白质组成，分别为包膜大蛋白(LHBs)、包膜中蛋白(MHBs)和包膜小蛋白(SHBs)，包括preS1、preS2和S区域。科学家发现HBV和HDV通过与具有HBV preS1表面蛋白结构域的NTCP结合而进入肝细胞。同时在体外，敲除NTCP蛋白能够很好地抑制HBV/HDV感染肝细胞。因此，目前在研的NTCP抑制剂抗病毒作用机理是依赖于肝细胞表面蛋白NTCP的特异性结合与阻断，介导的NTCP抑制作用能够阻止HBV和HDV进入细胞，进而防止肝细胞受到感染。此外，在胆汁酸代谢方面，抑制NTCP能够减少胆汁酸进入肝脏，从而使循环胆酸池升高。升高的胆酸池能够起到FXR激动的作用。同时NTCP抑制显著改善了肝脏脂肪聚集和脂肪变，缓解了肝损伤。
发明详述
一方面，本公开涉及式(I)化合物、其立体异构体或其药学上可接受的盐，
其中，
X选自C(RaRb)或NRc或
L选自键、O、S、(C(RaRb))p、(NRc)q或(C(RaRb))i-(NRc)j；
R1和R2各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
或者，R1和R2以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述 C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个取代基取代；
或者，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个取代基取代；
Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个取代基取代；
Rc选自氢、羟基、氨基、巯基、C1-12烷基或C1-12烷氧基，所述氨基、C1-12烷基或C1-12烷氧基任选地可进一步被一个或多个取代基取代；
或者，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个取代基取代；
或者，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个取代基取代；
或者，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个取代基取代；
R3选自氢、氘、卤素、硝基、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2- 12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-10元杂芳基任选地可进一步被一个或多个取代基取代；
A选自
环B选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
R4选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-12烷基或C1-12烷氧基；所述氨基、C1- 12烷基或C1-12烷氧基任选地可进一步被一个或多个取代基取代；
Ra1、Ra2或Ra3各自独立地选自氢、氘、卤素、硝基、羟基、疏基、氰基、氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-104元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
p、q、i或j分别独立地选自1、2或3；
m选自0、1或2；
n和n1各自独立地选自0、1、2、3或4；
条件是：
当A选自L为键，且R1和R2各自独立地选自氢或未取代C1-12烷基时，R4不为取代或未取代的苯基。
在一些实施方案中，式(I)化合物、其立体异构体或其药学上可接受的盐，
其中，
X选自C(RaRb)或NRc；
L选自键、O、S、(C(RaRb))p、(NRc)q或(C(RaRb))i-(NRc)j；
R1和R2各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个Raa取代；
或者，R1和R2以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环环烷基或3-14元杂环基任选地可进一步被一个或多个Rbb取代；
或者，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rbb取代；
Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个Rcc取代；
Rc选自氢、羟基、氨基、巯基、C1-12烷基或C1-12烷氧基，所述氨基、C1-12烷基或C1-12烷氧基任选地可进一步被一个或多个Re取代；
或者，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个Rd1取代；
或者，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rd2取代；
或者，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rd3取代；
R3选自氢、氘、卤素、硝基、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2- 12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-10元杂芳基任选地可进一步被一个或多个Rf取代；
A选自
环B选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个Rg取代；
R4选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个Rh取代；
R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-12烷基或C1-12烷氧基；所述氨基、C1- 12烷基或C1-12烷氧基任选地可进一步被一个或多个Ri取代；
Ra1、Ra2或Ra3各自独立地选自氢、氘、卤素、硝基、羟基、疏基、氰基、氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-104元芳基或5-14元杂芳基任选地可进一步被一个或多个Rj取代；
Raa、Rbb、Rcc、Rd1、Rd2、Rd3、Re、Rf、Rg、Rh、Ri和Rj各自独立地选自氘、卤素、羟基、氨基、硝基、氰基、巯基、＝O、C1-12烷基、C1-12烷氧基、C3-14环烷基、3-14元杂环基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nO(CH2)nS(O)mRal、-(CH2)nP(O)Ra2Ra3、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述C1-12烷基、C1-12烷氧基、C3-14环烷基或3-14元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代；
p、q、i或j分别独立地选自1、2或3；
m选自0、1或2；
n和n1各自独立地选自0、1、2、3或4；
条件是：
当A选自L为键，且R1和R2各自独立地选自氢或未取代C1-12烷基时，R4不为取代或未取代的苯基。
在一些实施方案中，式(I)化合物、其立体异构体或其药学上可接受的盐，
其中，
X选自C(RaRb)或NRc；
L选自键、O、S、(C(RaRb))p、(NRc)q或(C(RaRb))i-(NRc)j；
R1和R2各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地可进一步被一个或多个Raa取代；
或者，R1和R2以及与它们相连的碳原子一起形成C3-12环烷基或3-12元杂环基，所述C3-12环烷基或3-12元杂环基任选地可进一步被一个或多个Rbb取代；
或者，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-12元 杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rbb取代；
Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基或3-12元杂环基，所述氨基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基或3-12元杂环基任选地可进一步被一个或多个Rcc取代；
Rc选自氢、羟基、氨基、巯基、C1-6烷基或C1-6烷氧基，所述氨基、C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Re取代；
或者，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-12环烷基或3-12元杂环基，所述C3-12环烷基或3-12元杂环基任选地可进一步被一个或多个Rd取代；
或者，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-12元杂环基，所述3-12元杂环基任选地可进一步被一个或多个Rd取代；
或者，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-12元杂环基，所述3-12元杂环基任选地可进一步被一个或多个Rd取代；
R3选自氢、氘、卤素、硝基、羟基、氨基、巯基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地可进一步被一个或多个Rf取代；
A选自
环B选自C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地可进一步被一个或多个Rg取代；
R4选自C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地可进一步被一个或多个Rh取代；
R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-6烷基或C1-6烷氧基；所述氨基、C1- 6烷基或C1-6烷氧基任选地可进一步被一个或多个Ri取代；
Ra1、Ra2或Ra3各自独立地选自氢、氘、卤素、硝基、羟基、疏基、氰基、氨基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述氨基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地可进一步被一个或多个Rj取代；
Raa、Rbb、Rcc、Rd、Re、Rf、Rg、Rh、Ri和Rj各自独立地选自氘、卤素、羟基、氨基、硝基、氰基、巯基、＝O、C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nO(CH2)nS(O)mRal、-(CH2)nP(O)Ra2Ra3、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基任选地可进一 步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代；
p、q、i或j分别独立地选自1、2或3；
m选自0、1或2；
n和n1各自独立地选自0、1、2、3或4；
条件是：
当A选自L为键，且R1和R2各自独立地选自氢或未取代C1-12烷基时，R4不为取代或未取代的苯基。
在一些实施方案中，本公开所述的Rd选自Rd1、Rd2或Rd3。
在一些实施方案中，本公开所述的Rd1、Rd2或Rd3可以是Rd。
在一些实施方案中，Raa、Rbb、Rcc、Rd1、Rd2、Rd3、Re、Rf、Rg、Rh、Ri和Rj各自独立地选自氘、卤素、羟基、氨基、硝基、氰基、巯基、＝O、C1-12烷基、C1-12烷氧基、C3-14环烷基、3-14元杂环基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nP(O)Ra2Ra3、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述C1-12烷基、C1-12烷氧基、C3-14环烷基或3-14元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Raa、Rbb、Rcc、Rd、Re、Rf、Rg、Rh、Ri和Rj各自独立地选自氘、卤素、羟基、氨基、硝基、氰基、巯基、＝O、C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nP(O)Ra2Ra3、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Raa、Rbb、Rcc、Rd、Re、Rf、Rg、Rh、Ri和Rj各自独立地选自氘、卤素、羟基、氨基、硝基、氰基、巯基、＝O、C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，所述“被一个或多个”各自独立地选自被1、2、3、4、5或6个。
在一些实施方案中，所述“被一个或多个”各自独立地选自被1、2、3、4或5个。
在一些实施方案中，所述“被一个或多个”各自独立地选自被1、2、3或4个。
在一些实施方案中，所述“被一个或多个”各自独立地选自被1、2或3个。
在一些实施方案中，所述“杂”各自独立地选自氧、硫、氮和磷的杂原子，其中氮原子任选地被季铵化或被氧化为N(O)，硫原子任选被氧化为S(O)或S(O)2，磷原子任选被氧化为P(O)或P(O)2，其他变量如本公开所定义。
在一些实施方案中，所述“杂”各自独立地选自氧、硫和氮的杂原子，其中氮原子任选地被季铵化或被氧化为N(O)，硫原子任选被氧化为S(O)或S(O)2，其他变量如本公开所定义。
在一些实施方案中，Ra和Rb各自独立地选自氢、氘、C1-6烷基或C1-6烷氧基，所述C1- 6烷基或C1-6烷氧基任选地可进一步被一个或多个Rcc取代。
在一些实施方案中，Ra和Rb各自独立地选自氢、氘、C1-3烷基或C1-3烷氧基，所述C1- 3烷基或C1-3烷氧基任选地可进一步被一个或多个Rcc取代。
在一些实施方案中，Ra和Rb各自独立地选自氢或C1-3烷基，所述C1-3烷基任选地可进一步被一个或多个Rcc取代。
在一些实施方案中，Ra和Rb各自独立地选自氢或甲基。
在一些实施方案中，Ra选自氢，Rb选自甲基；或者Ra选自甲基，Rb选自氢。
在一些实施方案中，Ra和Rb均选自氢。
在一些实施方案中，Ra和Rb均选自甲基。
在一些实施方案中，Rc选自氢或C1-6烷基，所述C1-6烷基任选地可进一步被一个或多个Re取代。
在一些实施方案中，Rc选自氢或C1-3烷基，所述C1-3烷基任选地可进一步被一个或多个Re取代。
在一些实施方案中，Rc选自氢或任选被氘取代的甲基。
在一些实施方案中，Rc选自氢、甲基或-CD3。
在一些实施方案中，Rc选自甲基。
在一些实施方案中，Rc选自氢。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-6环烷基或3-6元杂环基，所述C3-6环烷基或3-6元杂环基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-6环烷基，所述C3-6环烷基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丙基、环丁基、环戊基、环己基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基或吗啉基，所述环丙基、环丁基、环戊基、环己基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基或吗啉基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丙基、环丁基、环戊基或环己基，所述环丙基、环丁基、环戊基或环己基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丙基、环丁基或氮杂环丁基，所述环丙基、环丁基或氮杂环丁基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丙基，所述环丙基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丁基，所述环丁基任选地可进一步被一个或多个Rd或Rd1取代。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，所述“相同或不同碳原子”为“两个相同或两个不同碳原子”；或者，所述“相同碳原子”为“两个相同碳原子”；或者，所述“不同碳原子”为“两个不同碳原子”。
在一些实施方案中，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，所述“相同或不同碳原子”为“两端的两个相同或两端的两个不同碳原子”；或者，所述“相同碳原子”为“两端的两个相同碳原子”；或者，所述“不同碳原子”为“两端的两个不同碳原子”。
在一些实施方案中，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-6元杂环基，所述3-6元杂环基任选地可进一步被一个或多个Rd或Rd2取代。
在一些实施方案中，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成1,3-二氮杂环丁烷基、咪唑烷基或哌嗪基，所述1,3-二氮杂环丁烷基、咪唑烷基或哌嗪基任选地可进一步被一个或多个Rd或Rd2取代。
在一些实施方案中，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成1,3-二氮杂环丁烷基，所述1,3-二氮杂环丁烷基任选地可进一步被一个或多个Rd或Rd2取代。
在一些实施方案中，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，所述“不同氮原子”为“两个不同氮原子”。
在一些实施方案中，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，所述“不同氮原子”为“两端的两个不同氮原子”。
在一些实施方案中，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-6元杂环基，所述3-6元杂环基任选地可进一步被一个或多个Rd或Rd3取代。
在一些实施方案中，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、哌啶基或哌嗪基，所述氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、哌啶基或哌嗪基任选地可进一步被一个或多个Rd或Rd3取代。
在一些实施方案中，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成氮杂环丁基，所述氮杂环丁基任选地可进一步被一个或多个Rd或Rd3取代。
在一些实施方案中，当L选自(C(RaRb))i-(NRc)j时，所述“碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子”为“一个碳原子上的Ra以及与它相连的碳原子、一个氮原子上的Rc以及与它相连的氮原子”。
在一些实施方案中，当L选自(C(RaRb))i-(NRc)j时，所述“碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子”为“一端的一个碳原子上的Ra以及与它相连的碳原子、另一端的一个氮原子上的Rc以及与它相连的氮原子”。
在一些实施方案中，X选自NRc。
在一些实施方案中，X选自CH2、CH(CH3)、C(CH3)2或N(CH3)，所述X任选被一个或多个氘取代。
在一些实施方案中，X选自CH2、CH(CH3)、C(CH3)2或N(CH3)。
在一些实施方案中，X选自
在一些实施方案中，X选自NH、N(CH2D)、N(CHD2)或N(CD3)。
在一些实施方案中，X选自NH或N(CD3)。
在一些实施方案中，X选自CH2、N(CH3)、NH、N(CD3)或
在一些实施方案中，X选自CH2或N(CH3)。
在一些实施方案中，X选自N(CD3)或N(CH3)。
在一些实施方案中，X选自N(CH3)。
在一些实施方案中，L选自键、(C(RaRb))p或(C(RaRb))i-(NRc)j。
在一些实施方案中，p、q、i或j分别独立地选自1或2。
在一些实施方案中，i和j分别选自1。
在一些实施方案中，q为2。
在一些实施方案中，L选自键、-C(RaRb)-、-C(RaRb)-C(RaRb)-、-C(RaRb)-NRc-、-C(RaRb)-C(RaRb)-C(RaRb)-或C(RaRb)-C(RaRb)-NRc。
在一些实施方案中，L选自C(RaRb)、-C(RaRb)-C(RaRb)-或-C(RaRb)-NRc-。
在一些实施方案中，L选自键。
在一些实施方案中，L选自键、CH2、CH(CH3)、C(CH3)2、 其中每一个r各自独立的选自1、2、3或4。在一些实施方案中，其中每一个r各自独立的选自1或2。
在一些实施方案中，L选自键、CH2、CH(CH3)、C(CH3)2、
在一些实施方案中，L选自键、CH2、C(CH3)2、
在一些实施方案中，结构片段L-R4选自-R4、-O-R4、-S-R4、-(C(RaRb))p-R4、-(NRc)q-R4、-(C(RaRb))i-(NRc)j-R4或-(NRc)j-(C(RaRb))i-R4。
在一些实施方案中，结构片段L-R4选自-R4、-(C(RaRb))p-R4或-(C(RaRb))i-(NRc)j-R4。
在一些实施方案中，结构片段L-R4选自-R4、-CH2R4、-C(CH3)2R4、
在一些实施方案中，Rcc、Rd1、Rd2、Rd3和Re各自独立地选自氘、卤素、羟基、氨基、氰基、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rcc、Rd1、Rd2、Rd3和Re各自独立地选自氘、卤素或羟基。
在一些实施方案中，Rcc、Rd1、Rd2、Rd3和Re各自独立地选自F。
在一些实施方案中，Rcc、Rd和Re各自独立地选自氘、卤素、羟基、氨基、氰基、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rcc、Rd和Re各自独立地选自氘、卤素或羟基。
在一些实施方案中，Rcc、Rd和Re各自独立地选自F。
在一些实施方案中，R1和R2各自独立地选自氢、氘、卤素、羟基、NH2、巯基、氰基、C1-6烷基、C1-6烷氧基或-(CH2)nORal，所述C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Raa取代。在一些实施方案中，R1和R2各自独立地选自-(CH2)nRal。
在一些实施方案中，R1和R2各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基或-(CH2)nORal，所述C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Raa取代。
在一些实施方案中，R1和R2各自独立地选自氢、C1-6烷基、-(CH2)nRal或-(CH2)nORal，所述C1-6烷基可进一步被一个或多个Raa取代。
在一些实施方案中，R1和R2各自独立地选自氢、C1-6烷基或-(CH2)nORal，所述C1-6烷基可进一步被一个或多个Raa取代。
在一些实施方案中，n和n1各自独立地选自0、1或2。
在一些实施方案中，n选自1或2。
在一些实施方案中，n选自0。
在一些实施方案中，R1和R2各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、-CH2ORal、-CH2CH2ORal，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基任选地可进一步被一个或多个Raa取代。在一些实施方案中，R1和R2各自独立地选自-CH2Ral。
在一些实施方案中，R1和R2各自独立地选自氢、正丁基、-CH2Ral、-CH2ORal、-CH2CH2ORal，所述正丁基任选地可进一步被一个或多个Raa取代。
在一些实施方案中，R1和R2以及与它们相连的碳原子一起形成C3-6环烷基或3-6元杂环基，所述C3-6环烷基或3-6元杂环基任选地可进一步被一个或多个Rbb取代。
在一些实施方案中，R1和R2以及与它们相连的碳原子一起形成环丙基、环丁基、环戊基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基或吗啉基，所述环丙基、环丁基、环戊基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基或吗啉基任选地可进一步被一个或多个Rbb取代。
在一些实施方案中，R1和R2以及与它们相连的碳原子一起形成环戊基，所述环戊基任选地可进一步被一个或多个Rbb取代。
在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-6元杂环基，所述3-6元杂环基任选地可进一步被一个或多个Rbb取代。
在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、哌啶基或哌嗪基，所述氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、哌啶基或哌嗪基任选地可进一步被一个或多个Rbb取代。
在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成吡咯烷基或哌啶基，所述吡咯烷基或哌啶基任选地可进一步被一个或多个Rbb取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自氢、氘、卤素、硝基、羟基、疏基、氰基、NH2、C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环基，所述C1-6烷基、C1-6烷氧基、C3-6环烷基或3-6元杂环基任选地可进一步被一个或多个Rj取代。在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自氢、C1-6烷基或C3-6环烷基，所述C1-6烷基或C3-6环烷基任选地可进一步被一个或多个Rj取代。在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自苯基，所述苯基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自C1-6烷基、C3-6环烷基或苯基，所述C1-6烷基、C3-6环烷基或苯基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或苯基，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或苯基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自甲基、乙基、环丙基或苯基，所述甲基、乙基、环丙基或苯基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基或环戊基，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基或环戊基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1、Ra2或Ra3各自独立地选自氢、甲基、乙基、叔丁基或环戊基，所述甲基、乙基、叔丁基或环戊基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Raa、Rbb和Rj各自独立地选自氘、卤素、羟基、氨基、氰基、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Raa、Rbb和Rj各自独立地选自氘、卤素或羟基。在另一些实施方案中，Rbb选自C1-3烷基，所述C1-3烷基可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。在另一些实施方案中，Rbb选自甲基或乙基。在另一些实施方案中，Rbb选自乙基。
在一些实施方案中，Raa、Rbb和Rj各自独立地选自F。
在一些实施方案中，Ra1选自C1-6烷基，所述C1-6烷基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra1选自C1-3烷基。
在一些实施方案中，Ra1选自甲基、乙基、环丙基或苯基，所述甲基、乙基、环丙基或苯基任选地可进一步被一个或多个F取代。
在一些实施方案中，Ra1选自甲基、乙基、环丙基或2-氟苯基。
在一些实施方案中，Ra1选自甲基或乙基。
在一些实施方案中，Rj选自F或-(CH2)nS(O)mRal。
在一些实施方案中，Rj选自F或-SRal。
在一些实施方案中，Rj选自F或-SCH3。
在一些实施方案中，R1和R2以及与它们相连的碳原子一起形成环戊基。
在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成吡咯烷基或哌啶基，所述吡咯烷基或哌啶基任选地可进一步被一个或多个甲基或乙基取代；R1选自H。
在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成吡咯烷基或哌啶基，所述吡咯烷基或哌啶基任选地可进一步被一个乙基取代；R1选自H。在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成R1选自H。在另一些实施方案中，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成 R1选自H。
在一些实施方案中，R1和R2各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、-CH2ORal、-CH2CH2ORal，所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基任选地可进一步被一个或多个F取代，Ra1选自甲基或乙基。
在一些实施方案中，R1和R2各自独立地选自氢、正丁基、-CH2Ral、-CH2ORal、-CH2CH2ORal，所述正丁基任选地可进一步被一个或多个F取代，Ra1选自甲基、乙基或环丙基。
在一些实施方案中，R1和R2各自独立地选自氢、正丁基、-CH2OCH2CH3或-CH2CH2OCH3，所述正丁基任选地可进一步被一个或多个F取代。
在一些实施方案中，R1和R2各自独立地选自氢、正丁基、-CH2OCH2CH3或-CH2CH2OCH3，所述正丁基任选地可进一步被一个或多个F取代。
在一些实施方案中，R1和R2各自独立地选自氢或正丁基，所述正丁基可进一步被一个或多个F取代。在一些实施方案中，R1和R2各自独立地选自氢、正丁基、 -CH2OCH2CH3或-CH2CH2OCH3。
在一些实施方案中，R1和R2各自独立地选自氢、正丁基、 -CH2OCH2CH3或-CH2CH2OCH3。
在一些实施方案中，R1选自H。
在一些实施方案中，R1选自H，R2选自正丁基、 -CH2OCH2CH3或-CH2CH2OCH3。
在一些实施方案中，R1选自H，R2选自正丁基、 -CH2OCH2CH3或-CH2CH2OCH3。
在一些实施方案中，R1选自H，R2选自正丁基。
在一些实施方案中，R1选自H，R2选自
在一些实施方案中，R3选自氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基或-(CH2)nS(O)mRal，所述氨基、C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Rf取代。在另一些实施方案中，R3选自C3-6环烷基或-(CH2)nNRa2Ra3，所述C3-6环烷基任选地可进一步被一个或多个Rf取代。在一些实施方案中，R3选自-(CH2)nORal。
在一些实施方案中，R3选自卤素、羟基、NH2、氰基、C1-3烷基、C1-3烷氧基或-(CH2)nS(O)mRal，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个Rf取代。
在一些实施方案中，R3选自甲基、乙基、甲氧基、乙氧基或-(CH2)nS(O)mRal，所述甲基、乙基、甲氧基、乙氧基任选地可进一步被一个或多个Rf取代。在另一些实施方案中，R3选自环丙基、环丁基或-(CH2)nNRa2Ra3，所述环丙基或环丁基任选地可进一步被一个或多个Rf取代。
在一些实施方案中，R3选自甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、-(CH2)nORal、-(CH2)nNRa2Ra3-(CH2)nS(O)mRal，所述甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选地可进一步被一个或多个Rf取代。
在一些实施方案中，R3选自甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、-ORal、-NRa2Ra3、-S(O)mRal，所述甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选地可进一步被一个或多个Rf取代。
在一些实施方案中，R3选自甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、-ORal、-NRa2Ra3、-SRal，所述甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选地可进一步被一个或多个Rf取代。
在一些实施方案中，R3选自甲基、乙氧基、环丙基、-ORal、-NRa2Ra3、-SRal，所述甲基、乙氧基或环丙基任选地可进一步被一个或多个Rf取代。
在一些实施方案中，Rf选自氘、卤素、羟基、氨基、氰基、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rf选自氘、卤素或羟基。
在一些实施方案中，Rf选自F。
在一些实施方案中，R3选自-(CH2)nS(O)mRal。在另一些实施方案中，R3选自环丙基或-(CH2)nNRa2Ra3。
在一些实施方案中，m选自0。
在一些实施方案中，Ra1选自甲基。
在另一些实施方案中，Ra2或Ra3各自独立地选自H或甲基。
在另一些实施方案中，Ra2或Ra3均选自甲基。
在一些实施方案中，R3选自-SCH3。在另一些实施方案中，R3选自环丙基或-N(CH3)2。
在另一些实施方案中，R3选自甲基、CF3CH2O-或
在另一些实施方案中，A选自
在一些实施方案中，A选自
在一些实施方案中，R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-3烷基或C1-3烷氧基；所述氨基、C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个Ri取代。
在一些实施方案中，R5和R5’各自独立地选自氢、氘、卤素或C1-3烷基；所述C1-3烷基任选地可进一步被一个或多个Ri取代。
在一些实施方案中，R5和R5’各自独立地选自氢、氘、卤素、NH2、甲基、乙基、甲氧基或乙氧基，所述甲基、乙基、甲氧基或乙氧基任选地可进一步被一个或多个Ri取代。在另一些实施方案中，R5和R5’各自独立地选自氢、氘、卤素或甲基，所述甲基任选地可进一步被一个或多个Ri取代。在另一些实施方案中，R5和R5’均选自甲基。
在一些实施方案中，R5选自氢、氘或卤素。
在一些实施方案中，R5选自氢或F。在另一些实施方案中，R5选自甲基，所述甲基任选地可进一步被一个或多个Ri取代。
在一些实施方案中，R5选自F。在另一些实施方案中，R5选自CF3。
在一些实施方案中，Ri选自氘、卤素、羟基、氨基、氰基、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Ri选自氘、卤素或羟基。
在一些实施方案中，Ri选自F。
在一些实施方案中，A选自在一些实施方案中，A选自R4不为
在一些实施方案中，A选自
在一些实施方案中，A选自或在另一些实施方案中，A选自 环B选自C3-10环烷基、3-10元杂环基、C6-10芳基或5- 10元杂芳基，所述C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自或在另一些实施方案中，A选自 环B选自C3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基，所述C3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自或在另一些实施方案中，A选自 环B选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自或在另一些实施方案中，A选自 环B选自苯基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑环、异噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基或哒嗪基，所述苯基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑环、异噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基或哒嗪基任选地可进一步被一个或多个Rg取代。在另一些实施方案中，环B选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基或吗啉基，所述环B任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自或在另一些实施方案中，A选自 环B选自苯基、吡咯基、呋喃基、噻吩基或吡啶基，所述苯基、吡咯基、呋喃基、噻吩基或吡啶基任选地可进一步被一个或多个Rg取代。在另一些实施方案中，环B选自环丙基、环丁基、环己基、氮杂环丁基、哌啶基或噻唑基，所述环B任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自时，与环B相连的两个键键合在不同的环原子上。或者，与环B相连的两个键键合在同一个环原子上。
在一些实施方案中，A选自或在另一些实施方案中，A选自 环B选自 所述环B任选地可进一步被一个或多个Rg取代。在另一些实施方案中，环B选自所述环B任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自环B选自 所述环B任选地可进一步被一个或多个Rg取代。在另一些实施方案中，A选自环B选自 所述环B任选地可进一步被一个或多个Rg取代。
在另一些实施方案中，A选自环B选自所述环B任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自环B选自所述环B任选地可进一步被一个或多个Rg取代。
在另一些实施方案中，A选自
在另一些实施方案中，A选自
在一些实施方案中，Rg选自氘、卤素、羟基、氨基、氰基、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rg选自卤素、羟基、NH2、甲基、乙基、甲氧基或乙氧基，所述甲基、乙基、甲氧基或乙氧基任选地可进一步被一个或多个选自氘、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rg选自卤素、羟基、NH2、甲基、乙基、甲氧基或乙氧基，所述甲基、乙基、甲氧基或乙氧基任选地可进一步被一个或多个选自卤素的取代基取代。
在一些实施方案中，Rg选自卤素、羟基、NH2、甲基、乙基、甲氧基或乙氧基，所述甲基、乙基、甲氧基或乙氧基任选地可进一步被一个或多个F取代。
在一些实施方案中，Rg选自F、甲基或三氟甲基。
在一些实施方案中，Rg选自F。
在一些实施方案中，A选自环B选自
在另一些实施方案中，A选自环B选自
在另一些实施方案中，A选自环B选自
在一些实施方案中，A选自环B选自
在一些实施方案中，A选自结构单元选自 所述环B任选地可进一步被一个或多个Rg取代。在另一些实施方案中，A选自结构单元选自所述环B任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自结构单元选自 所述环B任选地可进一步被一个或多个Rg取代。
在一些实施方案中，A选自结构单元选自
在另一些实施方案中，A选自结构单元选自
在一些实施方案中，A选自结构单元选自
在另一些实施方案中，A选自结构单元分别选自 所述环B任选地可进一步被一个或多个Rg取代。
在另一些实施方案中，A选自结构单元分别选自
在另一些实施方案中，A选自结构单元 分别选自
在一些实施方案中，R4选自C3-10环烷基、3-10元杂环基、C6-12芳基或5-10元杂芳基，所述C3-10环烷基、3-10元杂环基、C6-12芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自C5-8环烷基、5-8元杂环基、C6-12芳基或5-10元杂芳基，所述C5-8环烷基、5-8元杂环基、C6-12芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代。在一些实施方案中，R4选自C8-10环烷基，所述C8-10环烷基任选地可进一步被一个或多个Rh取代。在一些实施方案中，R4选自C8-10多环环烷基，所述C8-10多环环烷基任选地可进一步被一个或多个Rh取代。在一些实施方案中，R4选自C8-10多环环烷基，所述多环为二环、三环或四环，所述C8-10多环环烷基任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自C5-8环烷基、C6-11芳基或5-10元杂芳基，所述C5-8环烷基、C6-11芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自C5-8环烷基、苯基、C9-11芳基或5-10元杂芳基，所述C5-8环烷基、苯基、C9-11芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自C5-8环烷基、C9-11芳基或5-10元杂芳基，所述C5-8环烷基、C9-11芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自苯基、吲哚啉基、异吲哚啉基、苯并二氧戊环基、苯并吡唑烷环基、苯并咪唑烷环基、苯并四氢噻吩环基、苯并四氢呋喃环基、3H-螺[苯并呋喃-2,1'-环丙烷]、苯并四氢吡喃环基、苯并噻唑烷环基、苯并异噻唑烷环基、苯并噁唑烷环基、苯并异噁唑烷环基、苯并哌啶环基、苯并哌嗪环基、苯并吗啉环基、苯并噻嗪烷环基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑环、异噻唑基、三唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、哒嗪基、苯并呋喃环基、苯并噻吩环基、苯并噻唑环基、苯并噁唑环基、吲哚基、异吲哚基、苯并咪唑环基、吲唑基、吡咯并[2,3-b]吡啶环基、吡咯并[2,3-c]吡啶环基、吡咯并[3,2-c]吡啶环基、吡咯并[3,2-b]吡啶环基、咪唑并[4,5-b]吡啶环基、咪唑并[4,5-c]吡啶环基、咪唑并[1,2-a]吡啶环基、咪唑并[1,5-a]吡啶环基、吡唑并[4,3-d]吡啶环基、吡唑并 [4,3-c]吡啶环基、吡唑并[3,4-c]吡啶环基、吡唑并[1,5-a]吡啶环基、噻吩并[3,2-b]吡啶环基、噻吩并[2,3-b]吡啶环基、嘌呤基、吲嗪基、喹啉基、异喹啉基、吡咯并[1,2-a]哒嗪环基、咪唑并[1,2-c]嘧啶环基、吡唑并[1,5-a]吡嗪环基、吡咯并[1,2-a]吡嗪环基、2,3-二氢呋喃并[2,3-b]吡啶环基、2,3-二氢呋喃并[3,2-b]吡啶环基、2,3-二氢呋喃并[3,2-c]吡啶环基、2,3-二氢呋喃并[2,3-c]吡啶环基、双环[1.1.1]戊烷基或双环[2.2.2]辛烷基，所述R4任选地可进一步被一个或多个Rh取代。在一些实施方案中，R4选自2,3-二氢苯并[b][1,4]二噁英基、6,7-二氢-4H-吡唑[5,1-c][1,4]噁嗪基，所述R4任选地可进一步被一个或多个Rh取代。
在另一些实施方案中，R4选自环丁基、环戊基、环己基、1,2-二氢吡啶基、金刚烷基、苯并环丁基、苯并环戊基或苯并环己基，所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自苯基、吲哚啉基、异吲哚啉基、苯并吡唑烷环基、苯并四氢呋喃环基、3H-螺[苯并呋喃-2,1'-环丙烷]、苯并四氢吡喃环基、苯并哌啶环基、呋喃基、噻吩基、吡啶基、苯并噻吩环基、苯并噻唑环基、苯并噁唑环基、吲哚基、苯并咪唑环基、噻吩并[3,2-b]吡啶环基、噻吩并[2,3-b]吡啶环基、喹啉基、异喹啉基、2,3-二氢呋喃并[2,3-b]吡啶环基、2,3-二氢呋喃并[3,2-b]吡啶环基、2,3-二氢呋喃并[3,2-c]吡啶环基或双环[1.1.1]戊烷基，所述R4任选地可进一步被一个或多个Rh取代。
在另一些实施方案中，R4选自环丁基、1,2-二氢吡啶基、金刚烷基或苯并环丁基，所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自吲哚啉基、异吲哚啉基、苯并吡唑烷环基、苯并四氢呋喃环基、3H-螺[苯并呋喃-2,1'-环丙烷]、苯并四氢吡喃环基、苯并哌啶环基、呋喃基、噻吩基、吡啶基、苯并噻吩环基、苯并噻唑环基、苯并噁唑环基、吲哚基、苯并咪唑环基、噻吩并[3,2-b]吡啶环基、噻吩并[2,3-b]吡啶环基、喹啉基、异喹啉基、2,3-二氢呋喃并[2,3-b]吡啶环基、2,3-二氢呋喃并[3,2-b]吡啶环基、2,3-二氢呋喃并[3,2-c]吡啶环基或双环[1.1.1]戊烷基，所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自环丁基、1,2-二氢吡啶基、金刚烷基、苯并环丁基、苯基、吲哚啉基、异吲哚啉基、苯并吡唑烷环基、苯并四氢呋喃环基、3H-螺[苯并呋喃-2,1'-环丙烷]、苯并四氢吡喃环基、苯并二氧戊环基、苯并四氢吡喃环基、苯并哌啶环基、呋喃基、噻吩基、吡啶基、苯并噻吩环基、苯并噻唑环基、苯并噁唑环基、吲哚基、苯并咪唑环基、噻吩并[3,2-b]吡啶环基、噻吩并[2,3-b]吡啶环基、喹啉基、异喹啉基、2,3-二氢呋喃并[2,3-b]吡啶环基、2,3-二氢呋喃并[3,2-b]吡啶环基、2,3-二氢苯并[b][1,4]二噁英基、6,7-二氢-4H-吡唑[5,1-c][1,4]噁嗪基、2,3-二氢呋喃并[3,2-c]吡啶环基或双环[1.1.1]戊烷基，所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，当R4含有芳香环结构(例如苯基环结构)或杂芳香环(例如噻吩环结构)时，所述结构片段L-R4中，L与R4的芳香环或杂芳香环连接。
在一些实施方案中，R4选自 所述R4任选地可进一步被一个或多个Rh取代。在一些实施方案中，R4选自 所述R4任选地可进一步被一个或多个Rh取代。在另一些实施方案中，R4选自所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自 所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自 所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自所述R4任选地可进一步被一个或多个Rh取代，且L选自C(RaRb)或-C(RaRb)-C(RaRb)-。
在一些实施方案中，Rh选自氘、卤素、羟基、NH2、＝O、C1-6烷基、C1-6烷氧基、C3-6环烷基、3-6元杂环烷基、-(CH2)nC(O)Ral、-(CH2)nNRa2C(O)(CH2)nlRa3或-(CH2)nC(O)NRa2(CH2)nlRa3，所述C1-6烷基、C1-6烷氧基、C3-6环烷基或3-6元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。在另一些实施方案中，Rh选自-(CH2)nP(O)Ra2Ra3。在另一些实施方案中，Rh选自-(CH2)nO(CH2)nS(O)mRal。
在一些实施方案中，Rh选自卤素、羟基、＝O、C1-6烷基、C1-6烷氧基、3-6元杂环烷基、-(CH2)nC(O)Ral、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nC(O)NRa2(CH2)nlRa3、-(CH2)nO(CH2)nS(O)mRal或-(CH2)nP(O)Ra2Ra3，所述C1-6烷基、C1-6烷氧基或3-6元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rh选自卤素、羟基、＝O、C1-6烷基、C1-6烷氧基、3-6元杂环烷基、-C(O)Ral、-NRa2C(O)Ra3、-OCH2SRal或-P(O)Ra2Ra3，所述C1-6烷基、C1-6烷氧基或3-6元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rh选自卤素、＝O、C1-6烷基、C1-6烷氧基、3-6元杂环烷基、-(CH2)nC(O)Ral、-(CH2)nNRa2C(O)(CH2)nlRa3或-(CH2)nC(O)NRa2(CH2)nlRa3，所述C1-6烷基或3-6元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，n1选自0。
在一些实施方案中，Rh选自卤素、＝O、甲基、乙基、异丙基、甲氧基、乙氧基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基、吗啉基、-C(O)Ral、-NRa2C(O)Ra3或-C(O)NRa2Ra3，所述甲基、乙基、异丙基、甲氧基、乙氧基、氧杂环丁基、硫杂环丁基、氮杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基、吗啉基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Rh选自卤素、羟基、＝O、甲基、甲氧基、吡咯烷基、-C(O)Ral、-NRa2C(O)Ra3、-OCH2SRal或-P(O)Ra2Ra3，所述甲基、甲氧基或吡咯烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代。
在一些实施方案中，Ra2选自氢。
在一些实施方案中，Ra3选自C1-6烷基或C3-6环烷基，所述C1-6烷基或C3-6环烷基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra3选自甲基、乙基、异丙基、叔丁基、环丙基、环丁基或环戊基，所述甲基、乙基、异丙基、叔丁基、环丙基、环丁基或环戊基任选地可进一步被一个或多个Rj取代。
在一些实施方案中，Ra3选自叔丁基或环戊基。
在一些实施方案中，Rh选自F、＝O、甲基、吡咯烷基、-C(O)CH3、或-C(O)NHC(CH3)3，所述甲基或吡咯烷基任选地可进一步被一个或多个选自＝O或卤素的取代基取代。在另一些实施方案中，Rh选自或甲氧基，所述甲氧基任选地可进一步被一个或多个卤素取代。在另一些实施方案中，Rh选自羟基或-OCH2SCH3。
在一些实施方案中，Rh选自F、＝O、甲基、吡咯烷基、-C(O)CH3、或-C(O)NHC(CH3)3，所述甲基或吡咯烷基任选地可进一步被一个或多个选自＝O或F的取代基取代。在另一些实施方案中，Rh选自或甲氧基，所述甲氧基任选地可进一步被一个或多个F或Cl取代。在另一些实施方案中，Rh选自或甲氧基，所述甲氧基任选地可进一步被一个或多个F取代。
在一些实施方案中，Rh选自F、羟基、＝O、甲基、甲氧基、吡咯烷基、-C(O)CH3、-OCH2SCH3、-C(O)NHC(CH3)3、所述甲基、甲氧基或吡咯烷基任选地可进一步被一个或多个选自＝O、F或Cl的取代基取代。
在一些实施方案中，Rh选自F、＝O、甲基、三氟甲基、-C(O)CH3、或-C(O)NHC(CH3)3。在另一些实施方案中，Rh选自或甲氧基。在另一些实施方案中，Rh选自羟基、CH3SCH2O-或
在一些实施方案中，R4选自
在另一些实施方案中，R4选自
在一些实施方案中，R4选自
在一些实施方案中，R4选自
在一些实施方案中，R4选自
在一些实施方案中，R4选自且L选自C(RaRb)或-C(RaRb)-C(RaRb)-。
在一些实施方案中，R4选自且L选自键。
在一些实施方案中，R4选自所述R4任选地可进一步被一个或多个Rh取代。
在一些实施方案中，R4选自所述R4任选地可进一步被一个或多个Rh取代，且L选自键。
在另一些实施方案中，R4选自
在上文中，虚线，例如“---”，表示与结构式(例如式(I))的其余部分的连接键。
在一些实施方案中，本公开的式(I)化合物、其立体异构体或其药学上可接受的盐选自式(I-1)化合物、式(I-2)化合物、其立体异构体或其药学上可接受的盐：
其中，R1、R2、R3、R4、R5、X和环B的定义如本公开所述。
在一些实施方案中，本公开的式(I)化合物、其立体异构体或其药学上可接受的盐选自式(II-1)化合物、式(II-2)化合物、其立体异构体或其药学上可接受的盐：
其中，R2、R3、R4、R5、X和环B的定义如本公开所述。
在一些实施方案中，本公开的式(I)化合物、其立体异构体或其药学上可接受的盐选自式(III-1)化合物、式(III-2)化合物、其立体异构体或其药学上可接受的盐：
其中，R1、R2、R3、R4、R5和环B的定义如本公开所述。
在一些实施方案中，本公开的式(I)化合物、其立体异构体或其药学上可接受的盐选自式(IV-1)化合物、式(IV-2)化合物、其立体异构体或其药学上可接受的盐：
其中，R1、R2、R4、R5和环B的定义如本公开所述。
在一些实施方案中，本公开的式(I)化合物、其立体异构体或其药学上可接受的盐选自式(Ia)化合物、式(I-1a)化合物、式(I-2a)化合物、式(II-1a)化合物、式(II-2a)化合物、式(III-1a)化合物、式(III-2a)化合物、式(IV-1a)化合物、式(IV-2a)化合物、其立体异构体或其药学上可接受的盐：

其中，R1、R2、R3、R4、R5、X和环B的定义如本公开所述。
在一些实施方案中，本公开包含上述定义的变量及其实施方案，以及它们的任意组合。
在一些实施方案中，本公开的化合物、其立体异构体或其药学上可接受的盐选自以下化合物、其立体异构体或其药学上可接收的盐：














在一些实施方案中，本公开的化合物、其立体异构体或其药学上可接受的盐选自以下化 合物、其立体异构体或其药学上可接收的盐：





























另一方面，本公开提供了药物组合物，其包含本公开的上述化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本公开的药物组合物还包括药学上可接受的辅料。
另一方面，本公开提供了治疗或预防疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
另一方面，本公开提供了上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备治疗或预防疾病的药物中的用途。
另一方面，本公开提供了上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在治疗或预防疾病中的用途。
另一方面，本公开提供了治疗或预防疾病的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
在一些实施方案中，所述疾病选自与抑制牛磺胆酸钠共转运肽(NTCP)和/或抑制钠依赖性胆汁酸转运蛋白(ASBT)相关疾病。
在一些实施方案中，与抑制牛磺胆酸钠共转运肽(NTCP)和/或抑制钠依赖性胆汁酸转运蛋白(ASBT)相关疾病选自需要抑制胆汁酸循环的病症、障碍及疾病，诸如心血管疾病、脂肪酸代谢及葡萄糖利用病症、胃肠道疾病及肝病。
在一些实施方案中，抑制牛磺胆酸钠共转运肽(NTCP)和/或抑制钠依赖性胆汁酸转运蛋白(ASBT)选自选择性抑制牛磺胆酸钠共转运肽(NTCP)、或同时抑制牛磺胆酸钠共转运肽(NTCP)和钠依赖性胆汁酸转运蛋白(ASBT)。
本公开化合物对NTCP和/或ASBT抑制活性较好，并且可选择性抑制NTCP和/或ASBT，本公开化合物还具有良好的体内外药效和体内外药代动力学性质。
定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理 解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本公开化合物的盐，由本公开发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本公开的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本公开的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本公开的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本公开的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本公开的化合物可以存在特定的立体异构体形式。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。
除非另有规定，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型。
本公开的化合物和中间体还可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-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本公开的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
术语“一个或多个取代”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，取代基的数目包括1、2、3、4、5、6、7、8、9或10，以化学上可以实现为基础。
本文所述的“取代基”包括但不限于上下文提及的术语“烷基”、“烯基”、“炔基”、“螺环烷基”、“稠环烷基”、“桥环烷基”、“杂环基”、“螺杂环基”、“稠杂环基”、“桥杂环基”、“烷氧基”、“环烷基”、“杂环烷基”、“杂芳基”、“烷环”、“杂烷环”、“杂芳环”等， 及相应的非限制性或示例性基团，其中所述“取代基”一些非限制性实例包括氘、氚、-OH、-SH、卤素、-NH2、硝基、亚硝基、-CN、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、羧醛基团、亚胺基团、烷基、卤代-烷基、环烷基、卤代-环烷基、烯基、卤代-烯基、环烯基、卤代-环烯基、炔基、卤代-炔基、环炔基、卤代-环炔基、杂烷基、卤代-杂烷基、烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳烷基、芳基烷氧基、芳基烷硫基、杂芳基、杂芳基氧基、杂芳基硫基、杂芳烷基、杂芳基烷氧基、杂芳基烷硫基、杂环基、杂环基氧基、杂环基硫基、杂环基烷基、杂环基烷氧基、杂环基烷硫基、酰基、酰氧基、氨基甲酸酯基团、酰胺基团、脲基、环氧基团和酯基团等，所述基团任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、杂环烷基、杂环烷基烷基、杂环烷基氧基、杂芳基、杂芳基烷基、杂芳基氧基、芳基、芳基烷基或芳基氧基。
在本文的部分实施方案中，所述“取代基”选自氘、氚、羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、醛基、亚胺基团、C1-12烷基、卤代-C1-12烷基、3-12元环烷基、卤代-3-12元环烷基、C2-12烯基、卤代-C2-12烯基、3-12元环烯基、卤代-3-12元环烯基、C2-12炔基、卤代-C2-12炔基、8-12元环炔基、卤代-8-12元环炔基、C1-12杂烷基、卤代-C1-12杂烷基、C1-12烷氧基、C1-12烷硫基、6-10元芳基、6-10元芳基氧基、6-10元芳基硫基、6-10元芳基C1-12亚烷基、6-10元芳基C1- 12烷氧基、6-10元芳基C1-12烷硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、5-10元杂芳基亚烷基、5-10元杂芳基烷氧基、5-10元杂芳基烷硫基、3-12元杂环基、3-12元杂环基氧基、3-12元杂环基硫基、3-12元杂环基C1-12亚烷基、3-12元杂环基C1-12烷氧基、3-12元杂环基C1-12烷硫基、C1-12酰基、C1-12酰氧基、氨基甲酸酯基团、C1-12酰胺基、脲基、环氧基团、C2-12酯基团和氧代，所述取代基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、C1-12烷基、C2-12烯基、C2-12炔基、C1-12烷氧基、卤代C1-12烷氧基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、羧基、-C(O)O-C1-12烷基、-OC(O)-C1-12烷基、-C(O)NH2、-C(O)NH-C1-12烷基、-C(O)N(C1-12烷基)2、-NHC(O)-C1-12烷基、-C(O)-C1-12烷基、-S(O)-C1- 12烷基、-S(O)2-C1-12烷基、-S(O)2NH2、-S(O)2NH-C1-12烷基、-S(O)2N(C1-12烷基)2、3-12元环烷基、3-12元环烷基C1-12亚烷基、3-12元环烷基氧基、3-12元杂环基、3-12元杂环基C1-12亚烷基、3-12元杂环基氧基、3-12元杂环烷基、3-12元杂环烷基C1-12亚烷基、3-12元杂环烷基氧基、5-10元杂芳基、5-10元杂芳基C1-12亚烷基、5-10元杂芳基氧基、6-10元芳基、6-10元芳基C1-12亚烷基或6-10元芳基氧基。
本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C1- 3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。
本文中的m-n元，是该部分具有给定范围中的整数元。例如“3-12元”是指该基团可具有3元、4元、5元、6元、7元、8元、9元、10元、11元或12元。例如“5-10元”是指该基团可具有5元、6元、7元、8元、9元或10元。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变 体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”是指-OH基团。
术语“氨基”是指-NH2基团。
术语“巯基”是指-SH基团。
术语“氰基”是指-CN基团。
术语“硝基”是指-NO2基团。
术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、 仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。
术语“烷氧基”是指-O-烷基。
术语“烷基氨基”是指-NH-烷基。
术语“二烷基氨基”是指-N(烷基)2。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基；优选环丙基、环丁基、环己基、环戊基和环庚基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双 环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的。
术语“杂环基”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20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；其中所述的环原子可以进一步为硼或P(O)p(其中p是整数0至2)。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选四氢呋喃基、吡唑烷基、吗啉基、哌嗪基和吡喃基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。杂环基的非限制性实例包括：
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基环，应当理解，稠合之后形成的稠合体系属于本公开定义的“杂环基”的范畴，“杂环基”的其非限制性实例还包括：等。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)的芳香环的基团，优选为6至10元，芳香环可以是苯基环和萘基环，更优选苯基环，所述芳香环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳香环，应当理解，稠合之后形成的稠合体系属于本公开定义的“芳基”的范畴，“芳基”的非限制性实例包括：苯基、萘基、
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基中的杂芳香环优选为5至10元，更优选为5元或6元，杂芳香环可以是例如咪唑基环、呋喃基环、噻吩基环、噻唑基环、吡唑基环、噁唑基环、吡咯基环、三唑基环、四唑基环、吡啶基环、嘧啶基环、噻二唑环、吡嗪基环等，优选为三唑基环、噻吩基环、咪唑基环、吡唑基环、嘧啶基环或噻唑基环；更有选三唑基环、吡咯基环、噻吩基环、噻唑基环或嘧啶基环。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳香环，应当理解，稠合之后形成的稠合体系属于本公开定义的“杂芳基”的范畴，“杂芳基”的其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、
术语“治疗”意为将本公开所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本公开所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，或(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“预防有效量”意指预防或延迟本文中所述的特定疾病、病况或障碍的本公开化合物的用量。构成“预防有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
本公开化合物的治疗或预防剂量可根据例如以下而定：治疗或预防的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本公开化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本公开化合物，用于肠胃外给药。某些典型剂量范围为约0.001mg/kg～约1000mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
词语"包括(comprise)"或"包含(comprise)"及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
“药物组合物”表示含有一种或多种本公开所述化合物、其异构体或其药学上可接受的盐，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。
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。
本公开具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本公开实施方式中所用原料或中间体可以通过市售获得或通过现有技术的方法制备得到。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本公开中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc。
在一些实施方案中，本公开的部分化合物可以由有机合成领域技术人员参考以下路线来制备：
路线1：
路线2：
路线3：
其中，R2、R4和环B的定义如本公开所述。
具体实施方式
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本公开的范围。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下，针对本发明具体实施方式进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
本公开的化合物可以由有机合成领域技术人员参考以下实施例的路线或方法制备得到，所得化合物可以用已知的仪器或方法进行表征，包括但不限于质谱，核磁等。
本公开采用下述缩略词：
Boc代表叔丁氧羰基；
实施例1：化合物1的制备
0℃下，Boc-正亮氨酸(25.00g)、苯胺(10.07g)、三乙胺(21.88g)、1-丙基磷酸酐(41.30g)于N,N-二甲基甲酰胺(90mL)中，加毕，室温搅拌反应。反应完全，反应液倒入冰水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体1A(26.12g)。MS(ESI):m/z 329.41[M+Na]+。
中间体1A(26.12g)于1,4-二氧六环(250mL)和氯化氢的1,4-二氧六环溶液(4M,106mL)中，室温搅拌反应。反应完全，反应液减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体1B(16.43g)。MS(ESI):m/z 207.37[M+H]+。
0℃下，中间体1B(10.00g)、硼烷二甲硫醚络合物的四氢呋喃溶液(2M,60.5mL)于四氢呋喃(100mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(50mL)淬灭，60℃搅拌反应1小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得中间体1C(5.67g)。MS(ESI):m/z 193.39[M+H]+。
0℃下，中间体1C(1.00g)、中间体K(2.27g)、三乙胺(1.21g)于四氢呋喃(50mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体1D(2.51g)。MS(ESI):m/z 518.94[M+H]+。
中间体1D(2.50g)、碳酸钾(1.24g)、铜粉(0.31g)于N,N-二甲基甲酰胺(25mL)中，115℃搅拌反应。反应完全，过滤，滤液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体1E(1.88g)。MS(ESI):m/z 439.10[M+H]+。
中间体1E(1.88g)、碳酸铯(1.24g)、碘甲烷(3.04g)于N-甲基吡咯烷酮(10mL)中，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得中间体1F(2.07g)。MS(ESI):m/z 452.98[M+H]+。
中间体1F(2.07g)、甲硫醇钠(1.60g)于N,N-二甲基甲酰胺(25mL)，加毕，80℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体1G(1.71g)。MS(ESI):m/z 407.21[M+H]+。
中间体1G(1.71g)经用手性制备(CHIRALART Cellulose-SC柱(30*250mm，5μm)，洗脱体系：乙醇/正己烷(15％/85％))，得中间体1H(RT＝1.787min，1.42g)，MS(ESI):m/z407.28[M+H]+。和中间体1I(RT＝1.073min，0.31g)，MS(ESI):m/z 407.42[M+H]+。
0℃下，中间体1H(0.50g)、三乙胺(0.19g)、三氟甲磺酸酐(0.42g)于二氯甲烷(15mL)中，0℃搅拌反应。反应完全，反应液倒入水中，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体1J(0.61g)。MS(ESI):m/z 539.08[M+H]+。
中间体1J(0.61g)、(5-(甲氧羰基)噻吩-3-基)硼酸(0.25g)、磷酸三钾(0.48g)、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(0.09g)于1,4-二氧六环(15mL)和水(1.5mL)中，氮气保护下，100℃搅拌反应。反应完全，反应液减压蒸除溶剂并通过柱层析(洗脱体系：二氯甲烷/甲醇)分离得中间体1K(0.52g)。MS(ESI):m/z 531.25[M+H]+。
中间体1K(200mg)，氢氧化锂一水合物(32mg)于1,4-二氧六环(6mL)和水(2mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为3)，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得化合物1(160mg)。MS(ESI):m/z 517.1289[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.82(s,1H),7.66(s,1H),7.23-7.20(m,2H),7.15(s,1H),6.81-6.77(m,3H),4.10(d,J＝16.1Hz,1H),3.82(d,J＝8.3Hz,1H),3.28-3.10(m,1H),2.54(s,3H),2.35(s,3H),1.68-1.49(m,2H),1.43-1.27(m,4H),0.91(t,J＝6.7Hz,3H).
实施例2：化合物2的制备
参照实施例1化合物1的制备方法，用中间体1I替换中间体1H得化合物2(80mg)。MS(ESI):m/z 517.1289[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.76(s,1H),7.66(s,1H),7.23-7.20(m,2H),7.14(s,1H),6.81–6.77(m,3H),4.09(d,J＝16.1Hz,1H),3.83(s,1H),3.26-3.08(m,1H),2.53(s,3H),2.35(s,3H),1.69-1.49(m,2H),1.44-1.28(m,4H),0.91(t,J＝6.8Hz,3H).
实施例3：化合物3的制备
0℃下，Boc-D-正亮氨酸(3.0g)、3-氨基噻吩盐酸盐(1.8g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(5.9g)、三乙胺(7.2mL)于N,N-二甲基甲酰胺(80mL)中，加毕，室温搅拌反应。反应完全，将反应液中倒入冰水中，搅拌，过滤，滤饼用水洗涤后干燥得中间体3A(4.0g)。MS(ESI):m/z 313.09[M+H]+。
0℃下，中间体3A(4.0g)、三氟乙酸(10mL)于二氯甲烷(30mL)中，加毕，室温搅拌反应。反应完全，减压蒸除溶剂，冰水浴下，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体3B(3.3g)。MS(ESI):m/z213.11[M+H]+。
0℃下，中间体3B(3.3g)、硼烷二甲硫醚络合物的四氢呋喃溶液(2M,22mL)于四氢呋喃(60mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(20mL)淬灭，60℃搅拌反应1小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体3C(1.2g)。MS(ESI):m/z 199.15[M+H]+。
0℃下，中间体3C(1.20g)、中间体K(2.45g)、N,N-二异丙基乙胺(2.1mL)于四氢呋喃(60mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体3D(2.10g)。MS(ESI):m/z 524.91[M+H]+。
中间体3D(2.10g)、碳酸钾(0.99g)、铜粉(0.25g)于N,N-二甲基甲酰胺(50mL)中，115℃搅拌反应。反应完全，过滤，滤液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体3E(1.30g)。MS(ESI):m/z 445.02[M+H]+。
中间体3E(1.30g)、碳酸铯(1.90g)、碘甲烷(2.00g)于N-甲基吡咯烷酮(40mL)中，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体3F(1.30g)。MS(ESI):m/z 459.01[M+H]+。
中间体3F(1.30g)、甲硫醇钠(0.98g)于N,N-二甲基甲酰胺(30mL)，加毕，80℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体3G(0.80g)。MS(ESI):m/z 413.13[M+H]+。
0℃下，中间体3G(200mg)于N,N-二甲基甲酰胺(10mL)中，缓慢加入氢化钠(97mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(263mg)的N,N-二甲基甲酰胺(1mL)溶液，加毕，70℃搅拌反应。反应完全，向反应液中依次加入饱和氯化铵水溶液，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体3H(160mg)。MS(ESI):m/z 529.17[M+H]+。
中间体3H(160.0mg)、氢氧化锂一水合物(32mg)于1,4-二氧六环(8mL)和水(2mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物3(70mg)。MS(ESI):m/z 501.0980[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.55(d,J＝18.5Hz,1H),7.46(s,1H),7.36(dd,J＝3.1,5.1Hz,1H),7.18(s,1H),6.57(d,J＝4.5Hz,1H),6.39(s,1H),3.86(d,J＝15.0Hz,2H),3.33-3.31(m,1H),2.51(s,3H),2.41(s,3H),1.66-1.45(m,2H),1.43-1.27(m,4H),0.93-0.89(m,3H).
实施例4：化合物4的制备
参照实施例3化合物3的制备方法，用Boc-L-正亮氨酸替换Boc-D-正亮氨酸得化合物4(60mg)。MS(ESI):m/z 501.0987[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.36-7.35(m,2H),7.21(d,J＝18.3Hz,1H),7.17(s,1H),6.55(d,J＝4.8Hz,1H),6.35(s,1H),3.86-3.83(m,2H),3.33-3.31(m,1H),2.50(s,3H),2.40(s,3H),1.62-1.47(m,2H),1.41-1.29(m,4H),0.92-0.90(m,3H).
实施例5：化合物5的制备
参照实施例3化合物3的制备方法，用4-甲氧基苄胺替换3-氨基噻吩盐酸盐得化合物5(100mg)。MS(ESI):m/z 539.1686[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.48(d,J＝18.7Hz,1H),7.39(s,1H),7.32(d,J＝8.3Hz,2H),6.92(d,J＝8.5Hz,2H),6.84(s,1H),4.66(d,J＝14.4Hz,1H),4.43(d,J＝14.4Hz,1H),3.73(s,3H),3.63-3.55(m,1H),3.24(m,1H),3.09-3.06(m,1H),2.56(s,3H),2.39(s,3H),1.52-1.41(m,1H),1.20(m,3H),1.11(m,2H),0.80(t,J＝7.1Hz,3H).
实施例6：化合物6的制备
参照实施例3化合物3的制备方法，用2,3-二氢苯并呋喃-5-胺替换3-氨基噻吩盐酸盐得化合物6(30mg)。MS(ESI):m/z 537.1530[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.33(s,1H),7.20(d,J＝18.2Hz,1H),6.86(s,1H),6.78(s,1H),6.64(d,J＝8.5Hz,1H),6.58(d,J＝9.1Hz,1H),4.46(t,J＝8.6Hz,2H),3.93(d,J＝15.8Hz,1H),3.72(d,J＝9.0Hz,1H),3.21(m,1H),3.11(t,J＝8.6Hz,2H),2.56(s,3H),2.29(s,3H),1.55-1.49(m,2H),1.39-1.27(m,4H),0.89(t,J＝6.6Hz,3H).
实施例7：化合物7的制备
参照实施例3化合物3的制备方法，用双环[1.1.1]戊烷-1-胺盐酸盐替换3-氨基噻吩盐酸盐得化合物7(60mg)。MS(ESI):m/z 485.1579[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.49(d,J＝18.6Hz,1H),7.36(s,1H),6.99(s,1H),3.66(s,1H),3.39(m,2H),2.54(s,3H),2.51(s,3H),2.45(s,1H),2.11(d,J＝8.6Hz,3H),1.94(d,J＝8.5Hz,3H),1.57-1.43(m,2H),1.40-1.31(m,4H),0.92(t,J＝6.0Hz,3H).
实施例8：化合物8的制备
参照实施例3化合物3的制备方法，用双环[1.1.1]戊烷-1-胺盐酸盐替换3-氨基噻吩盐酸盐，用Boc-L-正亮氨酸替换Boc-D-正亮氨酸得化合物8(10mg)。MS(ESI):m/z 485.1579[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.26(s,1H),7.21-7.17(m,1H),6.98(s,1H),3.66(s,1H),3.39(m,2H),2.50(s,3H),2.49(s,3H),2.44(s,1H),2.09(d,J＝8.6Hz,3H),1.93(d,J＝8.3Hz,3H),1.57-1.43(m,2H),1.40-1.30(m,4H),0.92(t,J＝6.9Hz,3H).
实施例9：化合物9的制备
参照实施例3化合物3的制备方法，用2,3-二氢苯并呋喃-6-胺替换3-氨基噻吩盐酸盐得化合物9(40mg)。MS(ESI):m/z 537.1533[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.58(brs,1H),7.74(d,J＝18.6Hz,1H),7.53(s,1H),7.12(s,1H),6.99(d,J＝8.7Hz,1H),6.11(s,2H),4.49-4.45(m,2H),3.99(d,J＝16.0Hz,1H),3.83-3.82(m,1H),3.21(m,1H),3.05(t,J＝8.6Hz,2H),2.49(s,3H),2.41(s,3H),1.62-1.56(m,1H),1.53-1.47(m,1H),1.39-1.29(m,4H),0.91(t,J＝6.8Hz,3H).
实施例10：化合物10的制备
0℃下，氢化钠(2.28g，60％w/w)缓慢加入Boc-D-高丝氨酸(5.00g)的N,N-二甲基甲酰胺(50mL)溶液中，0℃搅拌反应0.5小时。加入碘甲烷(9.71g)，加毕，室温搅拌反应。反应完全，反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体10A(5.60g)。MS(ESI):m/z 248.10[M+H]+。
0℃下，中间体10A(5.60g)、三氟乙酸(20mL)于二氯甲烷(80mL)中，加毕，室温搅拌反应。反应完全，反应液减压蒸除溶剂后得中间体10B(5.91g)。MS(ESI):m/z 148.15[M+H]+。
0℃下，中间体10B(3.94g)、中间体K(5.00g)、三乙胺(6.94g)于四氢呋喃(150mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体10C(3.11g)。MS(ESI):m/z 472.00[M+H]-。
中间体10C(2.50g)、氢氧化钠(0.53g)于四氢呋喃(40mL)和水(10mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为3),乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体10D(2.30g)。MS(ESI):m/z 457.97[M+H]-。
中间体10D(2.30g)、苯胺(0.47g)、N,N-二异丙基乙胺(1.93g)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.28g)于N,N-二甲基甲酰胺(45mL)中，室温搅拌反应。反应完全，反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体10E(1.08g)。MS(ESI):m/z 534.87[M+H]+。
0℃下，中间体10E(1.08g)、硼烷二甲硫醚络合物的四氢呋喃溶液(2M,2.5mL)于四氢呋喃(40mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(20mL)淬灭，60℃搅拌反应1小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体10F(1.04g)。MS(ESI):m/z 520.94[M+H]+。
参照实施例3化合物3的制备方法，用中间体10F替换中间体3D得化合物10(25mg)。MS(ESI):m/z 497.1213[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.43(s,1H),7.37(d,J＝18.3Hz,1H),7.19-7.15(m,3H),6.74(t,J＝7.3Hz,1H),6.67(d,J＝8.1Hz,2H),4.12(d,J＝16.2Hz,1H),4.01(s,1H),3.50-3.43(m,3H),3.29(s,3H),2.52(s,3H),2.40(s,3H),1.88-1.82(m,1H),1.80-1.73(m,1H)。
实施例11：化合物11的制备
常温下，1-苄基-2-甲基-(R)-氮杂环丙烷-1,2-二羧酸酯(4.50g)于氯仿(40ml)中，搅拌下依次加入乙醇(67ml)和三氟化硼乙醚(2.4ml)，加毕，室温搅拌反应。反应完全，将反应液倒入冰水中，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得中间体11A(5.10g)。
中间体11A(5.10g)，钯碳(2.00g，钯含量10％，含水量50％)于甲醇(40mL)中，氢气置换3次后，室温搅拌反应。反应完全，过滤，浓缩得中间体11B(2.89g)。
参照实施例10化合物10的制备方法，用中间体11B替换中间体10B得化合物11(100mg)。MS(ESI):m/z 497.1219[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.74(d,J＝18.6Hz,1H),7.56(s,1H),7.23-7.15(m,3H),6.76(t,J＝7.2Hz,1H),6.70(d,J＝8.00Hz,2H),4.04(s,2H),3.66-3.58(m,2H),3.51-3.47(m,3H),2.59(s,3H),2.41(s,3H),1.16(t,J＝6.9Hz,3H).
实施例12：化合物12的制备
中间体3E(1.00g)、碳酸铯(1.10g)、对甲氧基溴苄(0.80g)于N-甲基吡咯烷酮(20mL)中，室温搅拌反应。反应完全，将反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体12A(1.00g)。MS(ESI):m/z 565.12[M+H]+。
中间体12A(1.00g)、甲硫醇钠(0.62g)于N,N-二甲基甲酰胺(35mL)，加毕，80℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得中间体12B(0.90g)。MS(ESI):m/z 519.20[M+H]+。
0℃下，中间体12B(900mg)于N,N-二甲基乙酰胺(20mL)中，缓慢加入氢化钠(347mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(941mg)的N,N-二甲基甲酰胺(2mL)溶液，加毕，70℃搅拌反应。反应完全，将反应液倒入饱和氯化铵水溶液中，乙 酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体12C(560mg)。MS(ESI):m/z 635.27[M+H]+。
中间体12C(560mg)、氢氧化锂一水合物(93mg)于1,4-二氧六环(20mL)和水(5mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯中，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得中间体12D(460mg)。MS(ESI):m/z 607.20[M+H]+。
中间体12D(460mg)于三氟乙酸(40mL)中，55℃搅拌反应。反应完全，将反应液倒入乙酸乙酯，用碳酸氢钠溶液调节至弱酸性(pH值约为5),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物12(140mg)。MS(ESI):m/z 487.0831[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.61(brs,1H),7.54-7.51(m,2H),7.40(d,J＝9.3Hz,1H),7.37-7.35(m,1H),7.19(s,1H),6.59-6.56(m,1H),6.37(s,1H),4.14(d,J＝15.2Hz,1H),3.49–3.39(m,1H),3.00-2.92(m,1H),2.41(s,3H),1.62-1.51(m,1H),1.51-1.25(m,5H),0.90(t,J＝7.2Hz,3H).
实施例13：化合物13的制备
参照实施例1化合物1的制备方法，用4-(甲氧基羰基)噻吩-2-硼酸频哪醇酯替换(5-(甲氧羰基)噻吩-3-基)硼酸得化合物13(80mg)。MS(ESI):m/z 517.1304[M+H]+。
1H NMR(500MHz,DMSO-d6)δ12.89(s,1H),8.39(d,J＝1.5Hz,1H),7.73(s,1H),7.62(d,J＝1.5Hz,1H),7.24(t,J＝7.9Hz,2H),7.13(s,1H),6.84(dd,J＝8.2,4.9Hz,3H),4.11(d,J＝16.0Hz,1H),3.79(d,J＝11.6Hz,1H),3.44(s,1H),2.57(s,3H),2.36(s,3H),1.63-1.54(m,2H),1.41-1.28(m,4H),0.91(t,J＝6.9Hz,3H).
实施例14：化合物14的制备
参照实施例1化合物1的制备方法，用(4-氟-5-(甲氧基羰基)噻吩-3-基)硼酸替换(5-(甲氧羰基)噻吩-3-基)硼酸得化合物14(80mg)。MS(ESI):m/z 535.1201[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝4.2Hz,1H),7.62(s,1H),7.24(dd,J＝8.5,7.1Hz,2H),7.15(s,1H),6.86-6.78(m,3H),4.11(d,J＝16.1Hz,1H),3.81(d,J＝11.4Hz,1H),3.41(s,1H),2.55(s,3H),2.34(s,3H),1.65-1.52(m,2H),1.41-1.30(m,4H),0.91(t,J＝6.8Hz,3H).
实施例15：化合物15的制备
参照实施例1化合物1的制备方法，用2-甲氧羰基吡啶-4-硼酸频哪醇酯替换(5-(甲氧羰基)噻吩-3-基)硼酸得化合物15(100mg)。MS(ESI):m/z 510.1530[M+H]-。
1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.11(s,1H),7.72-7.68(m,1H),7.65(s,1H),7.24(t,J＝7.8Hz,2H),7.18(s,1H),6.86-6.83(m,3H),4.13(d,J＝16.2Hz,1H),3.81(s,1H),3.45(s,1H),2.58(s,3H),2.34(s,3H),1.68-1.48(m,2H),1.47-1.28(m,4H),0.91(t,J＝6.8Hz,3H).
实施例16：化合物16的制备
参照实施例10化合物10的制备方法，用D-正亮氨酸甲酯盐酸盐替换中间体10B，用1-甲基-5-氨基吲哚替换苯胺得化合物16(40mg)。MS(ESI):m/z 548.1699[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.45(s,1H),7.37-7.31(m,3H),7.18-7.14(m,1H),6.97(dd,J＝8.7,2.2Hz,1H),6.60(s,1H),6.38(d,J＝3.0Hz,1H),4.03-3.93(m,2H),3.79(s,3H),3.72(s,1H),2.84(s,3H),2.06(s,3H),1.50-1.43(m,2H),1.36-1.29(m,4H),0.90(t,J＝7.0Hz,3H).
实施例17：化合物17的制备
参照实施例16化合物16的制备方法，用6-氨基-1-甲基苯并咪唑替换1-甲基-5-氨基吲哚，得化合物17(18mg)。MS(ESI):m/z 549.1651[M+H]+。
1H NMR(500MHz,Methanol-d4)δ8.49(s,1H),7.59(s,1H),7.56(d,J＝9.0Hz,1H),7.38(d,J＝17.5Hz,1H),7.10(s,1H),7.02-6.98(m,1H),6.91(dd,J＝9.0,2.3Hz,1H),4.20(d,J＝16.0Hz,1H),4.02-3.99(m,1H),3.89(s,3H),3.49(s,1H),2.62(s,3H),2.33(s,3H),1.67-1.61(m,2H),1.51-1.36(m,4H),0.95(t,J＝7.0Hz,3H).
实施例18：化合物18的制备
中间体1H(100mg)、反式-3-羟基环丁烷羧酸甲酯(35mg)、偶氮二甲酸二乙酯(129mg)、三苯基膦(194mg)于四氢呋喃(5mL)中，微波60℃反应。反应完全，反应液浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体18A(140mg)。MS(ESI):m/z 519.19[M+H]+。
参照实施例3化合物3的制备方法，用中间体18A替换中间体3H得化合物18(78mg)。MS(ESI):m/z 505.1832[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.24(s,1H),7.17-7.14(m,2H),7.02(s,1H),6.75-6.72(m,1H),6.65-6.63(m,2H),4.80-4.74(m,1H),4.06-3.97(m,2H),3.27(m,1H),2.93-2.86(m,1H),2.83-2.75(m,2H),2.53(s,3H),2.42-2.37(m,2H),2.31(s,3H),1.61-1.54(m,2H),1.48-1.33(m,4H),0.96(t,J＝7.10Hz,3H).
实施例19：化合物19的制备
参照实施例18化合物18的制备方法，用顺式-3-羟基环丁烷羧酸甲酯替换反式-3-羟基环丁烷羧酸甲酯得化合物19(56mg)。MS(ESI):m/z 505.1836[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.17-7.14(m,3H),7.03(s,1H),6.75-6.72(m,1H),6.65-6.63(m,2H),5.03-4.98(m,1H),4.06-3.97(m,2H),3.27(m,1H),3.22-3.16(m,1H),2.82-2.74(m,2H),2.53(s,3H),2.53-2.46(m,2H),2.32(s,3H),1.61-1.53(m,2H),1.49-1.34(m,4H),0.96(t,J＝7.10Hz,3H).
实施例20：化合物20的制备
参照实施例3化合物3的制备方法，用2-甲基-6-氨基苯并噁唑替换3-氨基噻吩盐酸盐，用氢化铝锂的四氢呋喃溶液(2.5mol/L)替换硼烷二甲硫醚络合物的四氢呋喃溶液(2.0mol/L)得化合物20(15mg)。MS(ESI):m/z 550.1487[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.60(s,1H),7.51(d,J＝17.4Hz,1H),7.41(d,J＝8.8Hz,1H),7.14(s,1H),6.95(s,1H),6.77(dd,J＝1.8,8.8Hz,1H),4.14-4.11(m,1H),3.98-3.97(m,1H),3.49-3.37(m,1H),2.61(s,3H),2.57(s,3H),2.36(s,3H),1.65-1.56(m,2H),1.49-1.38(m,4H),0.96(t,J＝7.15Hz,3H).
实施例21：化合物21的制备
参照实施例19化合物19的制备方法，用中间体3G替换中间体1H得化合物21(18mg)。MS(ESI):m/z 511.1390[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.24-7.22(m,1H),7.10(s,1H),7.07(s,1H),6.52(d,J＝5.15Hz,1H),6.21(s,1H),5.00-4.95(m,1H),3.98(m,1H),3.86(d,J＝15.75Hz,1H),3.35(m,1H),3.21-3.15(m,1H),2.79-2.73(m,2H),2.56(s,3H),2.52-2.49(m,2H),2.33(s,3H),1.62-1.51(m,2H),1.50-1.35(m,4H),0.96(t,J＝7.00Hz,3H).
实施例22：化合物22的制备
参照实施例3化合物3的制备方法，用4-氨基-1-甲基吡啶-乙酮替换3-氨基噻吩盐酸盐得化合物22(15mg)。MS(ESI):m/z 526.1489[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.61(s,1H),7.79(d,J＝18.5Hz,1H),7.55(s,1H),7.37(d,J＝7.7Hz,1H),7.26(s,1H),5.45(d,J＝61.2Hz,2H),4.18-3.75(m,2H),3.27(s,3H),3.22-3.13(m,1H),2.48(s,3H),2.44(s,3H),1.74-1.59(m,1H),1.50-1.44(s,1H),1.39-1.30(s,4H),0.93-0.90(m,3H).
实施例23：化合物23的制备
参照实施例3化合物3的制备方法，用顺式-3-甲氧基环丁胺盐酸盐替换3-氨基噻吩盐酸盐得化合物23(45mg)。MS(ESI):m/z 503.1688[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.26(s,1H),7.04(d,J＝19.3Hz,1H),6.74(s,1H),4.45-4.39(m,1H),3.86(s,3H),3.82-3.75(m,1H),3.23-3.16(m,1H),3.07(s,1H),2.86-2.81(m,2H),2.53(s,2H),2.44(s,3H),2.30-2.15(m,1H),1.95(s,1H),1.65-1.35(m,8H),0.97(t,J＝6.7Hz,3H).
实施例24：化合物24的制备
中间体1H(200mg)、三苯基膦(380mg)、偶氮二甲酸二乙酯(257mg)、1-(羟甲基)环丙烷甲酸甲酯(147mg)于四氢呋喃(2mL)中，微波80℃反应。反应完全，反应液减压蒸除溶剂并通过柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体24A(250mg)。MS(ESI):m/z519.47[M+H]+。
中间体24A(250mg)，氢氧化锂一水合物(60mg)于1,4-二氧六环(20mL)和水(5mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为4)，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得化合物24(243mg)。MS(ESI):m/z 505.1840[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.37(s,1H),7.20-7.09(m,2H),7.02(s,1H),6.73(t,J＝7.3Hz,1H),6.63(d,J＝8.2Hz,2H),4.33-4.25(m,2H),4.08-3.94(m,2H),3.28-3.25(m,1H),2.54(s,3H),2.31(s,3H),1.70-1.54(m,2H),1.49-1.37(m,4H),1.35-1.33(m,2H),1.17-1.14(m,2H),0.96(t,J＝6.9Hz,3H).
实施例25：化合物25的制备
参照实施例3化合物3的制备方法，用2-甲基-5-氨基-2,3-二氢苯并呋喃替换3-氨基噻吩盐酸盐得化合物25(170mg)。MS(ESI):m/z 551.1690[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.46(s,1H),7.37(d,J＝17.6Hz,1H),6.92(dd,J＝6.3,2.4Hz,1H),6.81(dt,J＝8.6,2.5Hz,1H),6.72(s,1H),6.65(dd,J＝8.5,1.0Hz,1H),4.93-4.88(m,1H),3.90(d,J＝13.6Hz,1H),3.74(s,2H),3.30-3.23(m,1H),2.82-2.77(m,1H),2.75(s,3H),2.23(d,J＝1.2Hz,3H),1.71-1.63(m,1H),1.48-1.34(m,8H),0.93(t,J＝7.0Hz,3H).
实施例26：化合物26的制备
中间体1J(550mg)、(S)-哌啶-3-羧酸甲酯(219mg)、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(160mg)、2-二环己基磷-2,4,6-三异丙基联苯(146mg)、碳酸铯(998mg)于1,4-二氧六环(20mL)中，氮气置换后，微波110℃反应。反应完全，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体26A(67mg)。MS(ESI):m/z 532.49[M+H]+。
中间体26A(67mg)，氢氧化锂一水合物(53mg)于1,4-二氧六环(20mL)和水(5mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为4)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得化合物26(18mg)。MS(ESI):m/z 518.2147[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.53(s,1H),7.21-7.15(m,2H),7.00(s,1H),6.78(t,J＝7.3Hz,1H),6.71(d,J＝8.1Hz,2H),4.07(d,J＝16.0Hz,1H),3.94(s,1H),3.45(d,J＝11.2Hz,1H),3.35-3.32(m,1H),3.10(d,J＝11.4Hz,1H),2.81(t,J＝10.5Hz,1H),2.76-2.69(m,2H),2.56(s,3H),2.28(s,3H),2.09-2.06(m,1H),1.90-1.85(m,1H),1.80-1.71(m,1H),1.66-1.55(m,3H),1.48-1.33(m,4H),0.96(t,J＝6.9Hz,3H).
实施例27：化合物27的制备
中间体1J(2.00g)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.61g)、三乙胺(0.75g)于1,4-二氧六环(50mL)中，通入一氧化碳至15个大气压，100℃反应。反应完全，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体27A(1.20g)。MS(ESI):m/z 449.45[M+H]+。
中间体27A(0.80g)、氢氧化锂一水合物(0.75g)于1,4-二氧六环(40mL)和水(10mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为4)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体27B(0.73g)。MS(ESI):m/z 435.46[M+H]+。
中间体27B(200mg)、1-氨基环丙基甲酸甲酯(64mg)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(262mg)、三乙胺(233mg)于N,N-二甲基甲酰胺(20mL)中，加毕，室温搅拌反应。反应完全，将反应液中倒入冰水中，搅拌，过滤，滤饼用水洗涤后干燥得中间体27C(240mg)。MS(ESI):m/z 532.45[M+H]+。
中间体27C(240mg)，氢氧化锂一水合物(189mg)于1,4-二氧六环(20mL)和水(5mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为4)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得化合物27(120mg)。MS(ESI):m/z 518.1789[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.99(s,1H),7.30(t,J＝7.9Hz,2H),7.00-6.97(m,3H),6.91(s,1H),4.09(d,J＝14.9Hz,1H),3.80-1.71(m,2H),2.73(s,3H),2.19(s,3H),1.73-1.66(m,1H),1.58-1.34(m,7H),1.25-1.23(m,2H),0.94(t,J＝7.0Hz,3H).
实施例28：化合物28的制备
参照实施例27化合物27的制备方法，用2-氨基-2-甲基丙酸甲酯替换1-氨基环丙基甲酸甲酯得化合物28(80mg)。MS(ESI):m/z 520.1943[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.91(s,1H),7.28(t,J＝7.9Hz,2H),6.98-6.96(m,3H),6.93(s,1H),4.10(d,J＝15.5Hz,1H),3.82-3.63(m,2H),2.71(s,3H),2.22(s,3H),1.72-1.65(m,1H),1.58(d,J＝4.9Hz,6H),1.55-1.34(m,5H),0.94(t,J＝7.0Hz,3H).
实施例29：化合物29的制备
参照实施例26化合物26的制备方法，用(R)-哌啶-3-羧酸甲酯替换(S)-哌啶-3-羧酸甲酯得化合物29(18mg)。MS(ESI):m/z 518.2154[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.54(s,1H),7.19-7.16(m,2H),7.00(s,1H),6.78(t,J＝7.3Hz,1H),6.71(d,J＝8.1Hz,2H),4.07(d,J＝16.0Hz,1H),3.94(s,1H),3.40-3.37(m,1H),3.35-3.32(m,1H),3.16(d,J＝10.8Hz,1H),2.80-2.68(m,3H),2.56(s,3H),2.28(s,3H),2.10-2.07(m,1H),1.91-1.87(m,1H),1.80-1.71(m,1H),1.64-1.54(m,3H),1.49-1.38(m,4H),0.96(t,J＝6.9Hz,3H).
实施例30：化合物30的制备
参照实施例24化合物24的制备方法，用(1S,2S)-2-(羟甲基)环丙烷甲酸乙酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物30(200mg)。MS(ESI):m/z 505.1831[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.34(s,1H),7.17-7.14(m,2H),7.03(s,1H),6.74(t,J＝7.25Hz,1H),6.64(t,J＝8.15Hz,2H),4.22-4.19(m,1H),4.06-3.98(m,3H),3.28-3.22(m,1H),2.53(s,3H),2.32(s,3H),1.91-1.84(m,1H),1.76-1.72(m,1H),1.60-1.53(m,2H),1.50-1.34(m,4H),1.25-1.21(m,1H),1.13-1.09(m,1H),0.96(t,J＝7.10Hz,3H).
实施例31：化合物31的制备
参照实施例26化合物26的制备方法，用甲基3-氟吖丁啶-3-甲酸基酯盐酸替换(S)-哌啶-3-羧酸甲酯得化合物31(235mg)。MS(ESI):m/z 508.1748[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.22-7.07(m,4H),6.72(t,J＝7.30Hz,1H),6.62(d,J＝8.15Hz,2H),4.57-4.48(m,2H),4.33-4.24(m,2H),4.05-3.97(m,2H),3.28-3.22(m,1H),2.54(s,3H),2.36(s,3H),1.61-1.55(m,2H),1.48-1.33(m,4H),0.96(t,J＝7.10Hz,3H).
实施例32：化合物32的制备
参照实施例24化合物24的制备方法，用(1S,2R)-2-(羟甲基)环丙烷甲酸甲酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物32(150mg)。MS(ESI):m/z 505.1833[M+H]+。
1H NMR(500MHz,DMSO-d6)δ12.23(s,1H),7.24(s,1H),7.14(t,J＝7.6Hz,2H),7.03(s,1H),6.69(t,J＝7.2Hz,1H),6.56(d,J＝7.6Hz,2H),4.42-4.39(m,1H),4.20(t,J＝8.7Hz,1H),4.01(d,J＝15.9Hz,1H),3.94-3.82(m,1H),3.19(s,1H),2.45(s,3H),2.34(s,3H),1.83-1.75(m,2H),1.62-1.59(m,1H),1.53-1.46(m,1H),1.39-1.30(m,4H),1.20-1.16(m,1H),1.02-0.99(m,1H),0.91(t,J＝6.50Hz,3H).
实施例33：化合物33的制备
参照实施例24化合物24的制备方法，用(1R,2R)-2-(羟甲基)环丙烷甲酸乙酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物33(250mg)。MS(ESI):m/z 505.1836[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.35(s,1H),7.18-7.14(m,2H),7.03(s,1H),6.74(t,J＝7.3Hz,1H),6.64(d,J＝6.6Hz,2H),4.24-4.21(m,1H),4.07-3.98(m,3H),3.28-3.22(m,1H),2.54(s,3H),2.33(s,3H),1.91-1.85(m,1H),1.76-1.73(m,1H),1.61-1.54(m,2H),1.49-1.35(m,4H),1.25-1.21(m,1H),1.13-1.09(m,1H),0.96(t,J＝7.1Hz,3H).
实施例34：化合物34的制备
参照实施例1化合物1的制备方法，用D-Boc-正亮氨酸替换Boc-正亮氨酸得化合物34F(1.00g)。MS(ESI):m/z 453.39[M+H]+。
中间体34F(1.00g)、环丙基三氟硼酸钾(0.55g)、碳酸钾(0.76g)、四三苯基膦钯(0.51g)于1,4-二氧六环(50mL)和水(10mL)中，氮气保护下，100℃搅拌反应。反应完全，反应液先减压蒸除大部分后，再用二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体34G(0.91g)。MS(ESI):m/z 415.32[M+H]+。
中间体34G(914mg)于二氯甲烷中(50mL)中，-5℃冷却下，向反应液中缓慢滴加三溴化硼乙醚溶液(3.0mL，2mol/L)。加毕，室温搅拌。反应完全，用20mL甲醇淬灭，减压浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体34H(200mg)。MS(ESI):m/z 401.51[M+H]+。
0℃下，中间体34H(200mg)于N,N-二甲基甲酰胺(10mL)中，缓慢加入氢化钠(140mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(650mg)的N,N-二甲基甲酰胺(1mL)溶液，加毕，85℃搅拌反应。反应完全，向反应液中依次加入饱和氯化铵水溶液，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体34I(178mg)。MS(ESI):m/z 517.49[M+H]+。
中间体34I(178.0mg)、氢氧化锂一水合物(58mg)于1,4-二氧六环(10mL)和水(2.5mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物34(60mg)。MS(ESI):m/z 489.1868[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.59(s,1H),7.53(d,J＝17.6Hz,1H),7.20-7.17(m,2H),6.83(s,1H),6.80(t,J＝7.3Hz,1H),6.69(d,J＝8.2Hz,2H),4.07(d,J＝16.0Hz,1H),3.92(s,1H),2.59(s,3H),2.22-2.16(m,1H),1.63-1.53(m,2H),1.48-1.34(m,4H),1.06-1.04(m,1H),0.95(t,J＝6.9Hz,3H),0.91-0.86(m,2H),0.70-0.64(m,2H).
实施例35：化合物35的制备
参照实施例24化合物24的制备方法，用顺式-4-羟基环己烷羧酸甲酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物35(140mg)。MS(ESI):m/z 533.2151[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.37(s,1H),7.17-7.14(m,2H),7.02(s,1H),6.74(t,J＝7.30Hz,1H),6.64(d,J＝8.15Hz,2H),4.45-4.39(m,1H),4.05-3.98(m,2H),3.27(m,1H),2.54(s,3H),2.44-2.37(m,1H),2.30(s,3H),2.21-2.15(m,2H),2.11-2.08(m,2H),1.69-1.56(m,6H),1.51-1.33(m,4H),0.96(t,J＝7.10Hz,3H).
实施例36：化合物36的制备
参照实施例24化合物24的制备方法，用反式-4-羟基环己烷羧酸甲酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物36(180mg)。MS(ESI):m/z 533.2150[M+H]+。
1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),7.28(s,1H),7.18-7.11(m,2H),7.04(s,1H),6.69(t,J＝7.2Hz,1H),6.57(d,J＝8.1Hz,2H),4.76(s,1H),3.89(s,1H),3.21(s,1H),2.44(s,3H),2.39-2.35(m,1H),2.34(s,3H),1.93-1.59(m,9H),1.52-1.45(m,1H),1.36-1.30(m,3H),0.93-0.90(m,3H).
实施例37：化合物37的制备
中间体1J(1.00g)、联硼酸频哪醇酯(0.94g)、1,1-双(二苯基膦)二荗铁二氯化钯(0.27g)、乙酸钾(0.36g)于1,4-二氧六环(50Ml)中，氮气置换后，100℃反应。反应完全，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体37A(0.69g)。MS(ESI):m/z 517.28[M+H]+。
参照实施例1化合物1的制备方法，用2-溴噻唑-5-甲酸甲酯替换(5-(甲氧羰基)噻吩-3-基)硼酸与中间体37A反应后，继续转化得化合物37(33mg)。MS(ESI):m/z 518.1247[M+H]+。
1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),8.39(s,1H),7.35(t,J＝7.6Hz,2H),7.11(d,J＝8.1Hz,2H),7.06(t,J＝7.4Hz,1H),6.93(s,1H),4.10(d,J＝15.4Hz,1H),3.93-3.88(m,1H),3.75(m,1H),2.80(s,3H),2.27(s,3H),1.75-1.70(m,1H),1.56-1.33(m,5H),0.94(t,J＝7.0Hz,3H).
实施例38：化合物38的制备
冰浴氮气保护下，三苯基膦(3.76g)、四溴化碳(2.38g)于二氯甲烷(40ml)中，然后缓慢滴加3,3,3-三氟丙酮酸乙酯(1.00g)，加毕，冰浴下搅拌反应。反应完全，反应液浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体38A(1.20g)。
-50℃氮气保护下，异丙基氯化镁(2M,1.8mL)缓慢加入到中间体38A(1.20g)的乙醚(40ml)溶液中，搅拌15min，然后加入甲醇(6ml)。缓慢升至室温搅拌。反应完全，加水淬灭反应，乙醚萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体38B(0.28g)。
碳酸钾(67mg)，四三苯基膦钯(56mg)，中间体38B(100mg)，中间体37A(460mg)于二氧六环(15ml)和水(3ml)中，氮气保护，油浴100℃反应。反应完全，反应液浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体38C(117mg)。MS(ESI):m/z 557.30[M+H]+。
中间体38C(115mg)、氢氧化锂一水合物(20mg)于1,4-二氧六环(10mL)和水(2.5mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物38(30mg)。MS(ESI):m/z 529.1430[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.96(d,J＝84.0Hz,1H),7.72-7.42(m,1H),7.27-7.21(m,2H),7.12(d,J＝4.2Hz,1H),6.88-6.80(m,3H),4.08(d,J＝16.1Hz,1H),3.86-3.73(m,1H),2.53(s,3H),2.42(d,J＝3.9Hz,3H),1.61-1.53(m,2H),1.34(d,J＝8.8Hz,2H),1.24(d,J＝6.7Hz,3H),0.90(t,J＝6.5Hz,3H).
实施例39：化合物39的制备
参照实施例37化合物37的制备方法，用5-溴噻吩-2-甲酸甲酯替换2-溴噻唑-5-甲酸甲酯,得到化合物39(130mg)。MS(ESI):m/z 517.1292[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.80(s,1H),7.75(d,J＝3.8Hz,1H),7.30-7.27(m,3H),6.98-6.94(m,4H),4.12(d,J＝15.3Hz,1H),3.80(s,1H),3.66-3.65(m,1H),2.71(s,3H),2.24(s,3H),1.72-1.65(m,1H),1.59-1.48(m,1H),1.48-1.33(m,4H),0.94(t,J＝7.0Hz,3H).
实施例40：化合物40的制备
参照实施例3化合物3的制备方法，用2-(二甲基氧磷基)苯胺替换3-氨基噻吩盐酸盐得化合物40(300mg)。MS(ESI):m/z 571.1525[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.52(s,1H),8.04(dd,J＝12.4,7.7Hz,1H),7.81(t,J＝7.8Hz,1H),7.59-7.53(m,4H),5.88(s,1H),4.24-4.22(m,1H),3.99(d,J＝13.5Hz,1H),3.42(d,J＝14.4Hz,1H),2.64(s,3H),1.94(s,3H),1.73(t,J＝13.1Hz,4H),1.43-1.14(m,7H),0.97-0.73(m,3H).
实施例41：化合物41的制备
参照实施例3化合物3的制备方法，用4-(二甲基氧磷基)苯胺替换3-氨基噻吩盐酸盐得化合物41(80mg)。MS(ESI):m/z 571.1501[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.63(s,1H),7.77(d,J＝18.5Hz,1H),7.58(s,1H),7.52(dd,J＝10.9,8.5Hz,2H),7.28(s,1H),6.69(d,J＝8.2Hz,2H),4.10(d,J＝16.1Hz,1H),3.94-3.88(m,1H),3.25(s,1H),2.47(d,J＝11.1Hz,6H),1.72-1.62(m,1H),1.58-1.48(M,7H),1.40-1.31(m,4H),0.93(d,J＝6.9Hz,3H).
实施例42：化合物42的制备
中间体3E(800mg)、环丙基硼酸(617mg)、无水醋酸铜(391mg)、2,2’-联吡啶(1400mg)、碳酸钠(381mg)于1,2-二氯乙烷中，在敞口环境中，80℃反应。反应完全，过滤反应液，滤液浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体42A(250mg)。MS(ESI):m/z 485.21[M+H]+。
参照实施例3化合物3的制备方法，用中间体42A替换中间体3F得化合物42(12mg)。MS(ESI):m/z 527.1141[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.37(s,1H),7.31-7.26(m,2H),6.86(s,1H),6.82(d,J＝5.15Hz,1H),4.18-4.13(m,1H),3.98-3.95(m,1H),3.68(s,1H),2.38(s,1H),2.20(s,3H),1.79-1.71(m,1H),1.47-1.40(m,1H),1.35-1.62(m,5H),0.84-0.78(m,4H),0.69-0.63(m,1H),0.57-0.45(m,2H).
实施例43：化合物43的制备
中间体27B(100mg)，牛磺酸(57.6mg)，三乙胺(70mg)，O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(131mg)溶于DMF中，加毕，室温搅拌反应。反应完全，反应液倒入水中，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物43(75mg)。MS(ESI):m/z 542.1463[M+H]+。
1H NMR(500MHz,MeOD)δ7.84(s,1H),7.20(t,J＝7.8Hz,2H),6.89-6.87(m,3H),6.83(s,1H),3.99(d,J＝14.2Hz,1H),3.69-3.54(m,4H),3.03(s,2H),2.62(s,3H),2.12(s,3H),1.22–1.15(m,6H),0.84(t,3H).
实施例44：化合物44的制备
参照实施例3化合物3的制备方法，用1-金刚烷胺替换3-氨基噻吩盐酸盐得化合物44(65mg)。MS(ESI):m/z 553.2203[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.44(s,1H),7.38(d,J＝17.6Hz,1H),7.21(s,1H),3.91-3.87(m,1H),3.43(d,J＝15.9Hz,1H),2.54-2.48(m,4H),2.37(s,3H),2.13-2.07(m,6H),1.79-1.77(m,3H),1.72-1.65(m,6H),1.52-1.36(m,6H),0.97(t,J＝6.4Hz,3H).
实施例45：化合物45的制备
2-金刚烷酮(10.00g)、盐酸羟胺(9.30g)、醋酸钠(10.90g)于甲醇(200mL)中，加毕，65℃搅拌反应。反应完全，减压蒸除溶剂，残留物用乙酸乙酯溶解，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体45A(11.10g)。
0℃下，45A(11.00g)于四氢呋喃(250mL)中，缓慢加入四氢铝锂的四氢呋喃溶液(2.5M，80mL),加毕，65℃搅拌反应。反应完全，冰浴下，向反应液中依次缓慢加入冰水(8mL)、氢氧化钠水溶液(8mL，15％)和冰水(24mL)，搅拌10分钟后，加入无水硫酸钠(30g)，然后经硅藻土过滤，滤液浓缩得得中间体45B(8.80g)。MS(ESI):m/z 152.31[M+H]+。
0℃下，Boc-正亮氨酸(8.80g)、中间体45B(6.33g)、三乙胺(15.40g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(21.70g)于N,N-二甲基甲酰胺(100mL)中，加毕，室温搅拌反应。反应完全，反应液倒入冰水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体45C(12.11g)。MS(ESI):m/z 365.31[M+H]+。
中间体45C(7.00g)，三氟乙酸(20mL)于二氯甲烷(100mL)中，室温搅拌反应。反应完全，反应液减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体45D(4.60g)。MS(ESI):m/z 265.25[M+H]+。
0℃下，中间体45D(3.99g)、中间体K(5.50g)、三乙胺(6.11g)于四氢呋喃(100mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体45E(7.40g)。MS(ESI):m/z 591.06[M+H]+。
0℃下，中间体45E(7.40g)、硼烷二甲硫醚络合物的四氢呋喃溶液(2M,18.9mL)于四氢呋喃(50mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(50mL)淬灭，60℃搅拌反应1小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体45F(5.30g)。MS(ESI):m/z 579.05[M+H]+。
中间体45F(2.00g)、叔丁醇钾(0.97g)、铜粉(1.32g)于N,N-二甲基乙酰胺(100mL)中，95℃搅拌反应。反应完全，过滤，滤液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食 盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体45G(0.81g)。MS(ESI):m/z 497.08[M+H]+。
中间体45G(0.40g)、碳酸铯(0.31g)、碘甲烷(0.33g)于N-甲基吡咯烷酮(10mL)中，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得中间体45H(0.22g)。MS(ESI):m/z 511.02[M+H]+。
中间体45H(0.18g)、甲硫醇钠(0.74g)于N,N-二甲基甲酰胺(25mL)，加毕，80℃搅拌反应。反应完全，反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体45I(0.15g)。MS(ESI):m/z 465.21[M+H]+。
0℃下，中间体45I(120mg)于N,N-二甲基乙酰胺(6mL)中，缓慢加入氢化钠(62mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(280mg)的N,N-二甲基乙酰胺(6mL)溶液，加毕，80℃搅拌反应。反应完全，将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体45J(100mg)。MS(ESI):m/z 581.23[M+H]+。
中间体45J(100mg)、氢氧化锂一水合物(108.4mg)于1,4-二氧六环(8mL)和水(4mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物45(70mg)。MS(ESI):m/z 553.2208[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.40(s,1H),7.29(d,J＝17.6Hz,1H),7.01(s,1H),4.06-4.00(m,1H),3.60(s,1H),3.20-3.18(m,1H),2.46-2.41(m,1H),2.38(s,3H),2.29(s,3H),2.23-2.18(m,2H),2.04-2.01(m,2H),1.91-1.88(m,1H),1.79-1.71(m,4H),1.68-1.60(m,3H),1.48-1.45(m,1H),1.40-1.27(m,6H),1.11-1.08(m,1H),0.86(t,J＝6.8Hz,3H).
实施例46：化合物46的制备
中间体45G(0.40g)、碳酸铯(0.30g)、4-甲氧基氯苄(0.11g)于DMF(10mL)中，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体46A(0.21g)。MS(ESI):m/z 617.14[M+H]+。
参照实施例12化合物12的制备方法，用中间体46A替换中间体12A得化合物46(80mg)。MS(ESI):m/z 539.2056[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.46(s,1H),7.26(d,J＝17.6Hz,1H),6.99(s,1H),3.57-3.49(m,3H),2.37(s,3H),2.32(d,J＝12.3Hz,1H),2.20-2.15(m,2H),2.09-2.06(m,1H),2.02(d,J＝12.5Hz,1H),1.91-1.88(m,1H),1.80-1.70(m,4H),1.68-1.61(m,3H),1.46-1.44(m,1H),1.40-1.21(m,7H),1.11-1.08(m,1H),0.84(t,J＝7.2Hz,3H).
实施例47：化合物47的制备
参照实施例45化合物45的制备方法，用3,4-(亚甲二氧基)苯胺替换中间体45B得化合物47(100mg)。MS(ESI):m/z 539.1331[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.42(s,1H),7.30(d,J＝17.6Hz,1H),6.82(s,1H),6.64(d,J＝8.4Hz,1H),6.40(d,J＝2.2Hz,1H),6.30(dd,J＝2.2,8.4Hz,1H),5.80(dd,J＝1.0,7.3Hz,2H),3.86-3.83(m,1H),3,76-3.71(m,1H),3.45-3.39(m,1H),2.58(s,3H),2.22(s,3H),1.59-1.52(m,1H),1.46-1.25(m,5H),0.85(t,J＝7.0Hz,3H).
实施例48：化合物48的制备
参照实施例45化合物45的制备方法，用4-氨基苯并环丁烯替换中间体45B得化合物48(190mg)。MS(ESI):m/z 521.1568[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.41(s,1H),7.32(d,J＝17.6Hz,1H),6.80(d,J＝7.4Hz,1H),6.81(s,1H),6.63(dd,J＝1.6,8.0Hz,1H),6.57(s,1H),3.92(d,J＝15.6Hz,2H),3.71(m,1H),3.45-3.39(m,1H),3.00(s,3H),2.57(s,3H),2.18(s,3H),1.58-1.51(m,1H),1.44-1.21(m,5H),0.84(t,J＝7.0Hz,3H).
实施例49：化合物49的制备
参照实施例24化合物24的制备方法，用羟基三甲基乙酸甲酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物49(200mg)。MS(ESI):m/z 507.1981[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.38(s,1H),7.22-7.15(m,2H),7.04(s,1H),6.77-6.74(m,1H),6.66(d,J＝8.2Hz,2H),4.15(s,2H),4.13-3.96(m,2H),3.32-3.17(m,1H),2.57(s,3H),2.33(s,3H),1.64-1.57(m,2H),1.52-1.40(m,4H),1.39(d,J＝2.7Hz,6H),0.99(t,J＝7.2Hz,3H).
实施例50：化合物50的制备
参照实施例3化合物3的制备方法，用4-氟苯胺替换3-氨基噻吩盐酸盐得中间体50G(1.04g)。MS(ESI):m/z 425.16[M+H]+。
再参照实施例24化合物24的制备方法，用羟基三甲基乙酸甲酯替换1-(羟甲基)环丙烷甲酸甲酯得化合物50(230mg)。MS(ESI):m/z 525.1878[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.24(s,1H),6.88(s,1H),6.84-6.78(m,2H),6.55-6.53(m,2H),4.02(s,2H),3.91-3.85(m,2H),3.20-3.11(m,1H),2.45(s,3H),2.20(s,3H),1.51-1.42(m,2H),1.38-1.28(m,4H),1.26(d,J＝2.2Hz,6H),0.86(t,J＝7.0Hz,3H).
实施例51：化合物51的制备
参照实施例45化合物45的制备方法，用1-金刚烷甲胺替换中间体45B得化合物51(29mg)。MS(ESI):m/z 567.2375[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.53(s,1H),7.49(d,J＝18.7Hz,1H),7.38(s,1H),7.24(s,1H),3.98(s,1H),3.77(d,J＝14.7Hz,1H),3.09-3.01(m,2H),2.72(d,J＝14.8Hz,1H),2.53(s,3H),2.40(s,3H),1.90-1.86(m,3H),1.62-1.54(m,6H),1.48-1.28(m,12H),0.92-0.90(m,3H).
实施例52：化合物52的制备
参照实施例46化合物46的制备方法，用中间体51E替换中间体45G得化合物52(30mg)。MS(ESI):m/z 553.2209[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.50(s,1H),7.43(s,1H),7.36(d,J＝18.7Hz,1H),7.25(s,1H),6.98(d,J＝9.4Hz,1H),3.81(d,J＝14.8Hz,1H),3.51-3.44(m,1H),3.38-3.35(m,1H),2.70-2.64(m,2H),2.52(s,3H),1.87(s,3H),1.62-1.53(m,6H),1.51-1.27(m,12H),0.89(t,J＝7.2Hz,3H).
实施例53：化合物53的制备
0℃下，BOC-D-脯氨酸(7.00g)、苯胺(13.48g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(18.55g)、三乙胺(18.2mL)于N,N-二甲基甲酰胺(80mL)中，加毕，室温搅拌反应。反应完全，将反应液中倒入冰水中，搅拌，过滤，滤饼用水洗涤后干燥得中间体53A(7.60g)。MS(ESI):m/z 291.13[M+H]+。
0℃下，中间体53A(7.60g)、三氟乙酸(30mL)于二氯甲烷(100mL)中，加毕，室温搅拌反应。反应完全，减压蒸除溶剂，冰水浴下，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体53B(5.0g)。MS(ESI):m/z191.12[M+H]+。
0℃下，中间体53B(5.0g)、硼烷二甲硫醚络合物的四氢呋喃溶液(2M,38mL)于四氢呋喃(100mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(30mL)淬灭，60℃搅拌反应2小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体53C(4.5g)。MS(ESI):m/z 177.14[M+H]+。
0℃下，中间体53C(3.0g)、中间体K(1.6g)、N,N-二异丙基乙胺(3.44mL)于四氢呋喃(100mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体53D(3.0g)。MS(ESI):m/z 502.96[M+H]+。
中间体53D(3.0g)、叔丁醇钾(1.67g)、铜粉(2.27g)于N,N-二甲基甲酰胺(25mL)中，115℃微波加热搅拌反应。反应完全，过滤，滤液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体53E(0.25g)，MS(ESI):m/z 388.25[M+H]+；53F(2.0g)，MS(ESI):m/z 423.10[M+H]+。
中间体53F(2.0g)、甲硫醇钠(3.32g)于N,N-二甲基甲酰胺(30mL)，加毕，100℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体53G(1.50g)。MS(ESI):m/z 377.18[M+H]+。
0℃下，中间体53G(400mg)于N,N-二甲基甲酰胺(25mL)中，缓慢加入氢化钠(255mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(1.2g)的N,N-二甲基甲酰胺(1mL)溶液，加毕，90℃搅拌反应。反应完全，向反应液中依次加入饱和氯化铵水溶液，乙 酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体53H(250mg)。MS(ESI):m/z 493.16[M+H]+。
中间体53H(250mg)、氢氧化锂一水合物(64mg)于1,4-二氧六环(20mL)和水(5mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物53(55mg)。MS(ESI):m/z 465.0953[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.49(s,1H),7.38(d,J＝17.4Hz,1H),7.11(t,J＝7.6Hz,2H),7.02(s,1H),6.74-6.68(m,3H),4.18(dd,J＝15.8,2.4Hz,1H),4.06-4.03(m,1H),3.45-3.40(m,1H),3.06-2.99(m,2H),2.26(s,3H),2.18-2.10(m,1H),1.96-1.79(m,2H),1.71-1.65(m,1H).
实施例54：化合物54的制备
参照实施例53化合物53的制备方法，用中间体53E替换中间体53F得化合物54(100mg)。MS(ESI):m/z 462.1497[M+H]+。
1H NMR(500MHz,DMSO)δ7.59(d,J＝18.5Hz,1H),7.11(t,J＝7.7Hz,2H),7.03(d,J＝2.8Hz,1H),6.93(d,J＝2.9Hz,1H),6.67(t,J＝7.2Hz,1H),6.45(s,2H),4.24-3.96(m,2H),3.44-3.29(m,1H),3.15-2.95(m,2H),2.69(s,6H),2.20-2.10(m,1H),2.03-1.88(m,2H),1.84-1.67(m,1H).
实施例55：化合物55的制备
参照实施例53化合物53的制备方法，用BOC-D-高脯氨酸替换BOC-D-脯氨酸得化合物55(30mg)。MS(ESI):m/z 479.1112[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.56(s,1H),7.49(d,J＝17.4Hz,1H),7.19-7.13(m,3H),6.79-6.68(m,3H),4.18-4.06(m,2H),3.68-3.60(m,1H),3.49-3.47(m,1H),2.63-2.57(m,1H),2.39(s,3H),1.96-1.85(m,1H),1.79-1.75(m,1H),1.66-1.54(m,2H),0.91-0.87(m,2H).
实施例56：化合物56的制备
0℃下，中间体55F(100mg)、三乙胺(233mg)、三氟甲磺酸酐(520mg)于二氯甲烷(15mL)中，0℃搅拌反应。反应完全，反应液倒入水中，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，分离得中间体56A(120mg)。MS(ESI):m/z 523.08[M+H]+。
中间体56A(120mg)、4-(4,4,5,5-四甲基-2-1,3,-二噁硼烷基)噻吩2-甲酸甲酯(85mg)、磷酸三钾(89mg)、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(16mg)于1,4-二氧六环(20mL)和水(4mL)中，氮气保护下，100℃搅拌反应。反应完全，反应液减压蒸除溶剂并通过柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体56B(45mg)。MS(ESI):m/z 515.16[M+H]+。
中间体56B(45mg)，氢氧化锂一水合物(15mg)于1,4-二氧六环(20mL)和水(5mL)中，室温搅拌反应。反应完全，反应液用1M稀盐酸溶液调节至酸性(pH值约为4)，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得化合物56(27mg)。MS(ESI):m/z 501.0972[M+H]+。
1H NMR(500MHz,MeOD)δ7.76(dd,J＝47.3,1.5Hz,2H),7.63(s,1H),7.16-7.04(m,3H),6.79-6.56(m,3H),4.10-4.01(m,2H),3.59(dd,J＝16.0,10.7Hz,1H),3.39-3.34(m,1H),2.57-2.52(m,1H),2.23(s,3H),1.91-1.75(m,2H),1.73-1.63(m,1H),1.60-1.47(m,2H),1.42-1.29(m,1H).
实施例57：化合物57的制备
0℃下，BOC-D-高脯氨酸(3.07g)、2-甲基-5-氨基-2,3-二氢苯并呋喃(2.00g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(6.63g)、三乙胺(4.07g)于N,N-二甲基甲酰胺(100mL)中，加毕，室温搅拌反应。反应完全，将反应液中倒入冰水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得中间体得中间体57A(4.10g)。MS(ESI):m/z 361.15[M+H]+。
0℃下，中间体57A(4.10g)、三氟乙酸(10mL)于二氯甲烷(50mL)中，加毕，室温搅拌反应。反应完全，减压蒸除溶剂，冰水浴下，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体57B(3.00g)。MS(ESI):m/z 261.17[M+H]+。
0℃下，中间体57B(3.00g)、中间体K(5.00g)、三乙胺(4.66g)于四氢呋喃(80mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体57C(6.25g)。MS(ESI):m/z 587.00[M+H]+。
中间体57C(500mg)、碳酸铯(830mg)、碘化亚铜(16mg)、(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(12mg)于N,N-二甲基甲酰胺(30mL)中，100℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体57D(380mg)。MS(ESI):m/z 506.99[M+H]+。
0℃下，中间体57D(250mg)、硼烷二甲硫醚络合物的四氢呋喃溶液(2M,4.6mL)于四氢呋喃(3mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(5mL)淬灭，65℃搅拌反应1小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体57E(230mg)。MS(ESI):m/z492.88[M+H]+。
中间体57E(200mg)、甲硫醇钠(850mg)于N,N-二甲基甲酰胺(10mL)，加毕，80℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体57F(120mg)。MS(ESI):m/z 447.11[M+H]+。
0℃下，中间体57F(100mg)于N,N-二甲基乙酰胺(6mL)中，缓慢加入氢化钠(43mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(194mg)的N,N-二甲基甲酰胺(6mL)溶液，加毕，70℃搅拌反应。反应完全，向反应液中依次加入饱和氯化铵水溶液，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体57G(90mg)。MS(ESI):m/z 563.22[M+H]+。
中间体57G(90mg)、氢氧化锂一水合物(132mg)于1,4-二氧六环(8mL)和水(4mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物57(35mg)。MS(ESI):m/z 535.1390[M+H]+。
1H NMR(500MHz,MeOD)δ7.40(s,1H),7.30(d,J＝17.5Hz,1H),6.80(s,1H),6.71-6.69(m,1H),6.61-6.59(m,1H),6.50(dd,J＝8.5,2.0Hz,1H),4.77-4.74(m,1H),3.99-3.95(m,1H),3.88(d,J＝15.5Hz,1H),3.59(dd,J＝15.6,10.4Hz,1H),3.38-3.34(m,1H),3.17-3.11(m,1H),2.68-2.58(m,2H),2.19(s,3H),1.81-1.74(m,2H),1.68-1.64(m,1H),1.58-1.48(m,2H),1.30-1.25(m,4H).
实施例58：化合物58的制备
4-溴吡啶甲酸甲酯(12.00g)、乙烯三氟硼酸钾(11.16g)、磷酸钾(35.40g)、双三苯基磷二氯化钯(3.90g)、水(20mL)于1,4-二氧六环(100mL)中，加毕，100℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体58A(8.40g)。MS(ESI):m/z 164.02[M+H]+。
中间体58A(4.00g)、甲酸铵(6.18g)、冰醋酸(7.36g)、氢氧化钯碳(12.05g，钯含量10％，含水量50％，w/w)于四氢呋喃(40mL)和甲醇(40mL)中，室温在氢气氛围下反应。反应完全，过滤反应液，滤液用饱和饱和碳酸氢钠水溶液调pH～8，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体58B(2.20g)。MS(ESI):m/z 172.30[M+H]+。
0℃下，中间体中间体58B(2.00g)、中间体K(5.07g)、三乙胺(5.91g)于四氢呋喃(60mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体58C(4.61g)。MS(ESI):m/z 497.89[M+H]+。
中间体58C(4.60g)、氢氧化锂一水合物(3.87g)于1,4-二氧六环(20mL)和水(20mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用1M稀盐酸溶液调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得化合物58D(4.41g)。MS(ESI):m/z 483.90[M+H]+。
0℃下，中间体58D(4.40g)、苯胺(0.85g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(4.48g)、三乙胺(2.75g)于N,N-二甲基甲酰胺(100mL)中，加毕，室温搅拌反应。反应完全，将反应液中倒入冰水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体58E(3.05g)。MS(ESI):m/z 558.93[M+H]+。
参照实施例57化合物57的制备方法，用中间体58E替换中间体57C得化合物58(48mg)。MS(ESI):m/z 507.1416.[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.59(brs,1H),7.73(d,J＝18.6Hz,1H),7.53(s,1H),7.23(s,1H),7.19-7.13(m,2H),6.71(t,J＝7.2Hz,1H),6.67-6.61(m,2H),4.14-4.08(m,2H),3.56(dd,J＝16.2,11.0Hz,1H),3.39-3.37(m,1H),2.59-2.51(m,1H),2.43(s,3H),2.04(d,J＝13.6Hz,1H),1.73(d,J＝12.7Hz,1H),1.44-1.37(m,1H),1.33-1.25(m,1H),1.23-1.17(m,2H),1.16-1.07(m,1H),0.86(t,J＝7.4Hz,3H)。
实施例59：化合物59的制备
(2R,4R)-4-甲基-2-哌啶甲酸(1.50g)、二碳酸二叔丁酯(2.52g)、三乙胺(3.18g)于二氯甲烷(15mL)中，加毕，室温搅拌反应。反应完全，用稀盐酸(1mol/L)调节pH至3-5，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体59A(2.45g)。MS(ESI):m/z 244.14[M+H]+。
参照实施例45化合物45的制备方法，用中间体59A替换Boc-D-正亮氨酸，用苯胺替换中间体45B得化合物59(26mg)。MS(ESI):m/z 493.1260[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.47(s,1H),7.35(d,J＝17.3Hz,1H),7.11-7.01(m,3H),6.67(t,J＝7.3Hz,1H),6.59(d,J＝8.2Hz,2H),4.12(dd,J＝10.9,4.3Hz,1H),4.03(d,J＝16.0Hz,1H),3.50(dd,J＝16.0,10.8Hz,1H),3.44-3.39(m,1H),2.54-2.47(m,1H),2.30(s,3H),1.82(d,J＝10.1Hz,1H),1.69-1.62(m,1H),1.51-1.42(m,3H),0.85(d,J＝5.2Hz,3H).
实施例60：化合物60的制备
4-溴-2-(三氟甲基)噻吩(970mg)、醋酸钯(181mg)、碳酸铯(3.94g)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(466mg)、二苯甲酮亚胺(730mg)于1,4-二氧六环(40mL)中，氮气置换后，微波110℃反应。反应完全，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体60A(630mg)。
中间体60A(630mg)、盐酸的二氧六环溶液(4.5ml，4mol/L)于1,4-二氧六环(20mL)和水(4mL)中，室温搅拌反应。反应完全，减压蒸除溶剂，二氯甲烷打浆，过滤，得中间体60B(370mg)。
参照实施例45化合物45的制备方法，用中间体60B替换中间体45B，用(R)-1-N-Boc-哌啶-2-甲酸替换Boc-D-正亮氨酸得化合物60(20mg)。MS(ESI):m/z 553.0558[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.55(s,1H),7.47(d,J＝17.4Hz,1H),7.27(s,1H),6.94(s,1H),6.47(d,J＝1.8Hz,1H),4.33-4.20(m,1H),3.93-3.90(m,1H),3.76-3.71(m,1H),3.52-3.44(m,1H),2.61-2.55(m,1H),2.44(s,3H),1.99-1.89(m,2H),1.65-1.60(m,2H),1.40-1.35(m,2H).
实施例61：化合物61的制备
参照实施例45化合物45的制备方法，用苯并二氢吡喃-7-胺替换中间体45B，得化合物61(60mg)。MS(ESI):m/z 551.1680[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.44(s,1H),7.37(d,J＝17.4Hz,1H),6.99(s,1H),6.77(d,J＝8.4Hz,1H),6.17(dd,J＝2.0,8.3Hz,1H),6.07(d,J＝1.6Hz,1H),4.03-3.97(m,2H),3.90(d,J＝15.6Hz,1H),3.79(s,1H),3.28(s,1H),2.58(t,J＝6.4Hz,2H),2.51(s,3H),2.26(s,3H), 1.87-1.82(m,2H),1.57-1.49(m,1H),1.48-1.41(m,1H),1.38-1.28(m,4H),0.86(t,J＝7.0Hz,3H).
实施例62：化合物62的制备
参照实施例3化合物3的制备方法，用苯并二氢吡喃-6-胺盐酸盐替换3-氨基噻吩盐酸盐得化合物62(90mg)。MS(ESI):m/z 551.1699[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.47(s,1H),7.35(d,J＝17.6Hz,1H),6.80(s,1H),6.77-6.69(m,2H),6.67(d,J＝8.6Hz,1H),4.20-4.04(m,2H),3.93(d,J＝15.4Hz,1H),3.75(s,1H),3.64(d,J＝13.6Hz,1H),2.77-2.68(m,5H),2.25(s,3H),2.00-1.90(m,2H),1.73-1.59(m,1H),1.56-1.31(m,5H),0.93(t,J＝6.9Hz,3H).
实施例63：化合物63的制备
参照实施例12化合物12的制备方法，用中间体62E替换中间体3E得化合物63(45mg)。MS(ESI):m/z 537.1516[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.42(s,1H),7.26(d,J＝17.5Hz,1H),6.74(s,1H),6.65-6.54(m,3H),4.14(d,J＝15.3Hz,1H),4.02(dd,J＝5.9,4.4Hz,2H),3.40-3.30(m,1H),3.13(d,J＝14.1Hz,1H),2.63(dd,J＝7.6,5.7Hz,2H),2.17(s,3H),1.96-1.78(m,2H),1.51-1.34(m,2H),1.34-1.25(m,4H),0.82(t,J＝7.2Hz,3H).
实施例64：化合物64的制备
参照实施例12化合物12的制备方法，用中间体47E替换中间体3E得化合物64(32mg)。MS(ESI):m/z 525.1168[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.45(s,1H),7.30(d,J＝17.5Hz,1H),6.84(s,1H),6.62(d,J＝8.4Hz,1H),6.39(d,J＝2.3Hz,1H),6.29(dd,J＝2.3,8.4Hz,1H),5.79(dd,J＝1.0,6.6Hz,2H),4.15(d,J＝15.4Hz,1H),3.41-3.36(m,1H),3,07-3.03(m,1H),2.22(s,3H),1.45-1.38(m,3H),1.37-1.22(m,3H),0.83(t,J＝7.2Hz,3H).
实施例65：化合物65的制备
参照实施例3化合物3的制备方法，用4-氨基-1,3-苯并二恶茂替换3-氨基噻吩盐酸盐得化合物65(90mg)。MS(ESI):m/z 539.1313[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.38(s,1H),7.30(d,J＝17.5Hz,1H),6.72(s,1H),6.66(t,J＝8.1Hz,1H),6.47(d,J＝7.7Hz,1H),6.32(d,J＝8.4Hz,1H),5.83(d,J＝1.1Hz,1H),5.77(s,1H),4.12-4.06(m,1H),3.63(s,2H),2.64(s,3H),2.17(s,3H),1.61-1.53(m,1H),1.42-1.33(m,2H),1.32-1.16(m,3H),0.86-0.76(m,3H).
实施例66：化合物66的制备
参照实施例45化合物45的制备方法，用6-氟苯并[d][1,3]二羟基-5-胺替换中间体45B得化合物66(90mg)。MS(ESI):m/z 557.1222[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.35(s,1H),7.24(d,J＝17.7Hz,1H),6.77-6.71(m,2H),6.38(s,1H),5.94-5.89(m,2H),3.97-3.89(m,1H),3.58-3.54(m,2H),2.75(s,3H),2.11(s,3H),1.64-1.57(m,1H),1.40-1.21(m,5H),0.83(t,J＝7.0Hz,3H).
实施例67：化合物67的制备
参照实施例45化合物45的制备方法，用2,3-二氢苯并[b][1,4]二氧杂环己烷-6-胺替换中间体45B，得化合物67(16mg)。MS(ESI):m/z 553.1478[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.37(s,1H),7.18(d,J＝17.6Hz,1H),6.85(s,1H),6.62(d,J＝8.5Hz,1H),6.29-6.22(m,2H),4.12-4.07(m,4H),3.83(d,J＝15.7Hz,1H),3.72(s,1H),3.34(s,1H),2.53(s,3H),2.21(s,3H),1.53(d,1H),1.57-1.49(m,1H),1.43-1.23(m,5H),0.85(t,J＝6.9Hz,3H).
实施例68：化合物68的制备
参照实施例45化合物45的制备方法，用5-氨基-2,2-二氟-1,3-苯并二噁茂替换中间体45B，得化合物68(68mg)。MS(ESI):m/z 575.1135[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.46(s,1H),7.30(d,J＝17.4Hz,1H),7.02(s,1H),6.90(d,J＝8.8Hz,1H),6.51(s,1H),6.34(dd,J＝2.0,8.8Hz,1H),3.93-3.84(m,2H),3.30-3.24(m,1H),2.47(s,3H),2.29(s,3H),1.51-1.47(m,2H),1.40-1.28(m,4H),0.86(t,J＝7.0Hz,3H).
实施例69：化合物69的制备
钠氢(2.68g)、5-硝基二氢吲哚(5.00g)、碘甲烷(6.48g)于N,N-二甲基甲酰胺(40mL)中，0℃反应。反应完全，反应液倒入水中，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液制砂，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体69A(3.50g)。MS(ESI):m/z 179.02[M+H]+。
中间体69A(3.50g)、钯碳(2.00g，钯含量10％，含水量50％)于甲醇(20mL)中，氢气置换后室温搅拌反应。反应完全，过滤，浓缩，得中间体69B(3.0g)。MS(ESI):m/z148.95[M+H]+。
参照实施例45化合物45的制备方法，用中间体69B替换中间体45B得化合物69(12.5mg)。MS(ESI):m/z 550.1485[M+H]+。
实施例70：化合物70的制备
参照实施例3化合物3的制备方法，用2,3-二氢苯并[b][1,4]二氧杂环己烷-5-胺替换3-氨基噻吩盐酸盐得化合物70(240mg)。MS(ESI):m/z 553.22[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.30(s,1H),7.20(d,J＝17.7Hz,1H),6.79-6.76(m,1H),6.73-6.69(m,2H),6.23(s,1H),4.20-4.10(m,5H),3.65(dd,J＝15.7,3.7Hz,1H),3.54-3.48(m,1H),2.85(s,3H),2.03(s,3H),1.67-1.61(m,1H),1.41-1.21(m,5H),0.82(t,J＝7.0Hz,3H).
实施例71：化合物71的制备
0℃下，钠氢(3.21g，60％w/w)于二甲基亚砜(30mL)中，将乙基三苯基溴化鏻(29.8g)的二甲基亚砜(80mL)溶液缓慢滴加至上述溶液中，加毕，室温搅拌反应1.5小时。将(S)-1-(叔丁氧基羰基)-4-氧代哌啶-2-羧酸(6.50g)的二甲基亚砜(30mL)溶液加入至上述搅拌液中，加毕，油浴搅拌反应。反应完全，用碳酸氢钠水溶液(5％)淬灭，用甲苯洗涤萃取，水相用稀盐酸(1mol/L)调节至酸性(pH值约为3)，甲基叔丁基醚萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得中间体71A(9.00g)。MS(ESI):m/z256.34[M+H]+。
0℃下，71A(6.00g)、苯胺(2.30g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(9.50g)、三乙胺(13.40g)于N,N-二甲基甲酰胺(100mL)中，加毕，室温搅拌反应。反应完全，将反应液中倒入冰水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体71B(5.8g)。MS(ESI):m/z 331.20[M+H]+。
中间体71B(5.80g)、氢氧化钯碳(6.5g，钯含量10％，含水量50％，w/w)于四氢呋喃(20mL)和甲醇(20mL)中，氢气置换，室温搅拌反应。反应完全，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体71C(3.5g)。MS(ESI):m/z 333.20[M+H]+；71C’(1.9g)。MS(ESI):m/z 333.22[M+H]+。
0℃下，中间体71C(3.50g)、三氟乙酸(15mL)于二氯甲烷(80mL)中，加毕，室温搅拌反应。反应完全，减压蒸除溶剂，冰水浴下，用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体71D(2.40g)。MS(ESI):m/z 233.23[M+H]+。
0℃下，中间体71D(2.40g)、中间体K(4.00g)、三乙胺(3.00g)于四氢呋喃(70mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体71E(5.30g)。MS(ESI):m/z 559.03[M+H]+。
中间体71E(3.00g)、磷酸三钾(3.40g)、碘化亚铜(102mg)、(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(76mg)于N,N-二甲基甲酰胺(70mL)中，110℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体71F(750mg)。MS(ESI):m/z479.35[M+H]+。
0℃下，中间体71F(750mg)、硼烷二甲硫醚络合物的四氢呋喃溶液(1mL，10mol/L)于四氢呋喃(25mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(5mL)淬灭，65℃搅拌反应1小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值 约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体71G(700mg)。MS(ESI):m/z 465.12[M+H]+。
中间体71G(700mg)、甲硫醇钠(740mg)于N,N-二甲基甲酰胺(20mL)中，加毕，80℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体71H(650mg)。MS(ESI):m/z 419.25[M+H]+。
0℃下，中间体71H(650mg)于N,N-二甲基乙酰胺(40mL)中，缓慢加入氢化钠(373mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(1.7g)的N,N-二甲基甲酰胺(6mL)溶液，加毕，90℃搅拌反应。反应完全，向反应液中加入饱和氯化铵水溶液，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体71I(300mg)。MS(ESI):m/z 535.24[M+H]+。
中间体71I(300mg)、氢氧化锂一水合物(118mg)于1,4-二氧六环(25mL)和水(5mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用稀盐酸(1mol/L)调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物71(100mg)。MS(ESI):m/z 507.1421[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.66(brs,1H),7.67(dd,J＝18.6,1.9Hz,1H),7.52(d,J＝1.9Hz,1H),7.23(d,J＝1.8Hz,1H),7.17-7.13(m,2H),6.71(t,J＝7.2Hz,1H),6.64(d,J＝8.1Hz,2H),4.19-4.06(m,2H),3.59-3.53(m,1H),3.38(d,J＝12.1Hz,1H),2.58-2.52(m,1H),2.43(s,3H),2.04(d,J＝13.2Hz,1H),1.73(d,J＝12.8Hz,1H),1.47-1.38(m,1H),1.33-1.26(m,1H),1.25-1.18(m,2H),1.17-1.08(m,1H),0.86(t,J＝7.4Hz,3H).
实施例72：化合物72的制备
参照实施例71化合物71的制备方法，用(R)-1-(叔丁氧基羰基)-4-氧代哌啶-2-羧酸替换(S)-1-(叔丁氧基羰基)-4-氧代哌啶-2-羧酸得化合物72(240mg)。MS(ESI):m/z 507.1422[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.48-7.45(m,2H),7.22(s,1H),7.20-7.08(m,2H),6.71(t,J＝7.3Hz,1H),6.63(d,J＝8.3Hz,2H),4.16-4.03(m,2H),3.56(dd,J＝16.1,11.0Hz,1H),3.40-3.35(m,1H),2.61-2.52(m,1H),2.43(s,3H),2.11-1.98(m,1H),1.78-1.68(m,1H),1.43-1.35(m,1H),1.25-1.18(m,2H),1.16-1.08(m,1H),0.86(t,J＝7.4Hz,3H).
实施例73：化合物73的制备
参照实施例72化合物72的制备方法，从中间体72C’开始制备得化合物73(90mg)。MS(ESI):m/z 507.1428[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.55(brs,1H),7.67(d,J＝18.6Hz,1H),7.52(s,1H),7.26-7.16(m,2H),7.09(s,1H),6.82-6.79(m,3H),4.19(d,J＝14.2Hz,1H),3.68-3.46(m,2H),3.21(s,1H),2.97(s,1H),2.37(s,3H),1.96-1.85(m,1H),1.85-1.72(m,1H),1.52-1.44(m,1H),1.45-1.34(m,1H),1.33-1.19(m,3H),0.86(t,J＝7.4Hz,3H).
实施例74：化合物74的制备
参照实施例72化合物72的制备方法，从中间体71C’开始制备得化合物74(195mg)。MS(ESI):m/z 507.1420[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.56(brs,1H),7.67(d,J＝18.6Hz,1H),7.52(s,1H),7.21(dd,J＝8.8,7.1Hz,2H),7.09(s,1H),6.80(d,J＝7.8Hz,3H),4.19(d,J＝14.2Hz,1H),3.60-3.48(m,2H),3.21(s,1H),2.97(s,1H),2.37(s,3H),1.92(d,J＝12.3Hz,1H),1.83-1.76(m,1H),1.52-1.45(m,1H),1.42-1.36(m,1H),1.32-1.23(m,3H),0.86(t,J＝7.4Hz,3H).
实施例75：化合物75的制备
参照实施例45化合物45的制备方法，用5-氟苯并[d][1,3]二氧杂-4-胺替换中间体45B得中间体75F(600mg)。MS(ESI):m/z 515.2[M+H]+。
中间体75F(0.60g)、甲硫醇钠(0.45g)于N,N-二甲基甲酰胺(15mL)，加毕，100℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：二氯甲烷/甲醇)分离得中间体75G(0.40g)。MS(ESI):m/z 517.3[M+H]+。
参照实施例66化合物66的制备方法，用中间体75G替换中间体66G得化合物75(120mg)。MS(ESI):m/z 605.1287[M+H]+。
1H NMR(500MHz,CDCl3)δ7.86(brs,1H),7.56(s,1H),7.35(d,J＝16.8Hz,1H),6.92(dd,J＝9.1,5.3Hz,1H),6.74-6.66(m,2H),5.20(s,2H),4.14(s,1H),3.49-3.29(m,2H),2.60(s,3H),2.26-2.23(m,6H),1.53-1.29(m,7H),0.92(t,J＝6.8Hz,3H)。
实施例76：化合物76的制备
参照实施例45化合物45的制备方法，用2,2-二甲基苯并-1,3-二氧杂环戊烯-5-胺替换中间体45B，得化合物76(130mg)。MS(ESI):m/z 567.1636[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.39(s,1H),7.31(d,J＝17.6Hz,1H),6.76(s,1H),6.54(d,J＝8.4Hz,1H),6.34(d,J＝2.2Hz,1H),6.29(dd,J＝2.2,8.4Hz,1H),3.86-3.65(m,2H),3.53-3.42(m,1H),2.59(s,3H),2.19(s,3H),1.58-1.51(m,7H),1.44-1.24(m,5H),0.84(t,J＝7.0Hz,3H).
实施例77：化合物77的制备
参照实施例72化合物72的制备方法，用苯并[d][1,3]二氧杂环戊烯-5-胺替换苯胺，从中间体77B’开始制备得化合物得化合物77(180mg)。MS(ESI):m/z 551.1323[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.55(s,1H),7.48(d,J＝17.4Hz,1H),7.08(s,1H),6.70(d,J＝8.4Hz,1H),6.41(d,J＝2.4Hz,1H),6.30(dd,J＝2.4,8.5Hz,1H),5.88(dd,J＝0.8,7.3Hz,2H),4.22-4.18(m,1H),4.02-3.99(m,1H),3.63-3.51(m,2H),2.70-2.56(m,1H),2.38(s,3H),1.95-1.92(m,1H),1.86-1.83(m,1H),1.59-1.49(m,1H),1.38-1.21(m,4H),0.94(t,J＝7.4Hz,3H).
实施例78：化合物78的制备
参照实施例72化合物72的制备方法，从中间体77A开始制备得化合物78(280mg)。MS(ESI):m/z 551.1321[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.50(s,1H),7.36(d,J＝17.4Hz,1H),6.82(d,J＝8.3Hz,1H),6.70-6.67(m,2H),6.62(dd,J＝1.8,8.2Hz,1H),5.97(s,2H),4.18-4.14(m,1H),4.04-3.96(m,1H),3.88-3.80(m,1H),3.46-3.39(m,1H),2.89(t,J＝10.4Hz,1H),2.25(s,3H),1.88-1.84(m,1H),1.75-1.72(m,1H),1.52-1.44(m,1H),1.43-1.26(m,4H),0.92(t,J＝7.4Hz,3H).
实施例79：化合物79的制备
参照实施例12化合物12的制备方法，用中间体70E替换中间体3E得化合物79(88mg)。MS(ESI):m/z 539.1322[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.47(brs,1H),7.78(d,J＝7.6Hz,1H),7.49-7.24(m,2H),6.85-6.81(m,2H),6.79-6.74(m,1H),6.26(s,1H),4.32-4.24(m,4H),3.91(d,J＝15.2Hz,1H),3.56(dd,J＝15.9,8.1Hz,1H),2.13(s,3H),1.71-1.45(m,1H),1.46-1.31(m,2H),1.33-1.09(m,4H),0.83(q,J＝6.8Hz,3H).
实施例80：化合物80的制备
参照实施例70化合物70的制备方法，用氘代碘甲烷替换碘甲烷得化合物80(50mg)。MS(ESI):m/z 556.1666[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.28(s,1H),7.11(d,J＝17.8Hz,1H),6.77(t,J＝8.0Hz,1H),6.72-6.68(m,2H),6.24(s,1H),4.21-4.04(m,5H),3.65(dd,J＝15.7,3.6Hz,1H),3.54-3.47(m,1H),2.03(s,3H),1.68-1.58(m,1H),1.41-1.30(m,2H),1.29-1.21(m,3H),0.83(t,J＝6.9Hz,3H).
实施例81：化合物81的制备
参照实施例47化合物47的制备方法，用氘代碘甲烷替换碘甲烷得化合物81(250mg)。MS(ESI):m/z 542.11[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.53(s,1H),7.43(d,J＝17.6Hz,1H),6.93(s,1H),6.75(d,J＝8.4Hz,1H),6.52(d,J＝2.3Hz,1H),6.42(dd,J＝8.4,2.4Hz,1H),5.92(dd,J＝7.5,1.2Hz,2H),3.96(d,J＝15.8Hz,1H),3.84(s,1H),3.59-3.49(m,1H),2.33(s,3H),1.70-1.60(m,1H),1.57-1.34(m,5H),0.96(t,J＝6.8Hz,3H).
实施例82：化合物82的制备
D-3-(环丙基)丙氨酸(3.25g)、二碳酸二叔丁酯(3.85g)、碳酸钾(6.37g)于THF(35mL)和H2O(35mL)中，加毕，室温搅拌反应。反应完全，用稀盐酸(1mol/L)调节反应液pH为3-5，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体82A(6.44g)。MS(ESI):m/z 230.13[M+H]+。
0℃下，中间体82A(6.13g)、苯胺(3.00g)、N,N-二异丙基乙胺(6.92g)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(15.26g)于N,N-二甲基甲酰胺(50mL)中，加毕，室温搅拌反应。反应完全，反应液倒入冰水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得中间体82B(7.39g)。MS(ESI):m/z 305.18[M+H]+。
中间体82B(4.00g)，三氟乙酸(15.00g)于二氯甲烷(50mL)中，室温搅拌反应。反应完全，反应液减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体82C(2.68g)。MS(ESI):m/z 205.16[M+H]+。
0℃下，中间体82C(2.68g)、中间体K(4.76g)、三乙胺(5.32g)于四氢呋喃(50mL)中，加毕，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，得中间体82D(5.50g)。MS(ESI):m/z 530.95[M+H]+。
中间体82D(3.00g)、磷酸三钾(3.60g)、碘化亚铜(216mg)、(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(160mg)于N,N-二甲基甲酰胺(60mL)中，110℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体82E(2.00g)。MS(ESI):m/z450.98[M+H]+。
中间体82E(2.00g)、碳酸铯(2.90g)、碘甲烷(1.26g)于N-甲基吡咯烷酮(20mL)中，室温搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得中间体82F(1.27g)。MS(ESI):m/z 464.99[M+H]+。
0℃下，中间体82F(1.27g)、硼烷二甲硫醚络合物的四氢呋喃溶液(10mol/L,4mL)于四氢呋喃(25mL)中，加毕，75℃搅拌反应。反应完全，向反应液中加入甲醇(14mL)淬灭，60℃搅拌反应2小时，减压蒸除溶剂，残留物用饱和碳酸氢钠水溶液调节至碱性(pH值约为9)，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得中间体82G(0.43g)。MS(ESI):m/z451.13[M+H]+。
中间体82G(0.43g)、甲硫醇钠(1.34g)于N,N-二甲基甲酰胺(20mL)，加毕，60℃搅拌反应。反应完全，反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体82H(0.31g)。MS(ESI):m/z 405.19[M+H]+。
0℃下，中间体82H(160mg)于N,N-二甲基乙酰胺(12mL)中，缓慢加入氢化钠(166mg，60％w/w)，加毕，0℃搅拌10分钟。滴加3-溴-2,2-二氟丙酸乙酯(550mg)的N,N-二甲基乙酰胺(4mL)溶液，加毕，80℃搅拌反应。反应完全，将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体82I(130mg)。MS(ESI):m/z 521.23[M+H]+。
中间体82I(130mg)、氢氧化锂一水合物(63mg)于1,4-二氧六环(15mL)和水(5mL)中，室温搅拌反应。反应完全，将反应液倒入乙酸乙酯，用稀盐酸(1mol/L)调节至酸性(pH值约为4),分相，水相用乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(C18色谱柱，洗脱体系：乙腈/水)分离得化合物82(60mg)。MS(ESI):m/z 493.1270[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.37(s,1H),7.28(d,J＝17.5Hz,1H),7.07-6.98(m,2H),6.89(s,1H),6.69-6.61(m,3H),4.05(d,J＝15.9Hz,1H),3.81(d,J＝9.1Hz,1H),3.33-3.21(m,1H),2.48(s,3H),2.16(s,3H),1.61-1.55(m,1H),1.14-1.07(m,1H),0.72-0.65(m,1H),0.42-0.34(m,2H),0.02--0.05(m,2H).
实施例83：化合物83的制备
参照实施例1化合物1的制备方法，用中间体47G替换中间体1H，用(4-氟-5-(甲氧基羰基)噻吩-3-基)硼酸替换(5-(甲氧羰基)噻吩-3-基)硼酸得化合物83(106mg)。MS(ESI):m/z 579.1091[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.61(d,J＝4.3Hz,1H),7.50(s,1H),6.73-6.66(m,2H),6.58(d,J＝2.3Hz,1H),6.49(dd,J＝8.3,2.3Hz,1H),5.85(dd,J＝7.0,1.2Hz,2H),3.84(d,J＝15.1Hz,1H),3.76-3.71(m,1H),3.67-3.62(m,1H),2.68(s,3H),2.11(s,3H),1.64-1.56(m,1H),1.44-1.23(m,5H),0.84(t,J＝6.9Hz,3H).
实施例84：化合物84的制备
参照实施例82化合物82的制备方法，用4-(氯二氟甲氧基)苯胺替换苯胺，用Boc-D-正亮氨酸替换中间体82A得化合物84(85mg)。MS(ESI):m/z 595.0961[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.50(s,1H),7.41(d,J＝17.4Hz,1H),7.09(s,1H),7.01(d,J＝9.0Hz,2H),6.67-6.61(m,2H),3.99-3.90(m,2H),3.30-3.23(m,1H),2.47(s,3H),2.31(s,3H),1.54-1.48(m,2H),1.41-1.26(m,4H),0.86(t,J＝7.0Hz,3H).
实施例85：化合物85的制备
参照实施例72化合物72的制备方法，用5-氨基-1,4-苯并二恶烷替换苯胺，从中间体71C’开始制备得化合物85(146mg)。MS(ESI):m/z 565.1460[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.42(brs,1H),7.48-7.40(m,2H),6.96-6.86(m,2H),6.79(dd,J＝7.1,2.3Hz,1H),6.05(s,1H),4.33-4.16(m,5H),4.01(s,1H),3.89(d,J＝12.6Hz,1H),2.84(t,J＝12.1Hz,1H),2.07(s,3H),1.78(d,J＝13.0Hz,1H),1.57(d,J＝11.5Hz,1H),1.48-1.30(m,2H),1.29-1.14(m,2H),1.13-1.04(m,1H),0.82(t,J＝7.4Hz,3H).
实施例86：化合物86的制备
参照实施例72化合物72的制备方法，从中间体85C’开始制备得化合物86(80mg)。MS(ESI):m/z 565.1461[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.36(s,1H),7.25(d,J＝17.6Hz,1H),6.68-6.61(m,3H),6.57(s,1H),4.26-4.14(m,4H),4.09-4.06(m,1H),3.68-3.63(m,1H),3.58-3.54(m,1H),3.49-3.45(m,1H),2.64-2.59(m,1H),2.12(s,3H),1.76-1.69(m,2H),1.46-1.39(m,1H),1.25-1.09(m,4H),0.79(t,J＝7.4Hz,3H).实施例87：化合物87的制备
参照实施例72化合物72的制备方法，用N-Boc-4-氧代-D-脯氨酸替换(R)-1-(叔丁氧基羰基)-4-氧代哌啶-2-羧酸，从中间体87C’开始制备得化合物87(150mg)。MS(ESI):m/z493.1274[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.64(brs,1H),7.66(d,J＝18.5Hz,1H),7.53(s,1H),7.19(td,J＝7.3,1.8Hz,2H),7.14(s,1H),6.84-6.68(m,3H),4.23(dd,J＝15.9,2.4Hz,1H),4.10-4.00(m,1H),3.63-3.49(m,1H),3.23-3.02(m,1H),2.63(t,J＝9.7Hz,1H),2.47-2.41(m,1H),2.39(s,3H),2.27-2.15(m,1H),1.38-1.27(m,2H),1.23-1.14(m,1H),0.83(t,J＝7.4Hz,3H).
实施例88：化合物88的制备
参照实施例72化合物72的制备方法，从中间体87C开始制备得化合物88(90mg)。MS(ESI):m/z 493.1257[M+H]+。
1H NMR(500MHz,DMSO-d6)δ13.58(brs,1H),7.72(d,J＝18.6Hz,1H),7.55(s,1H),7.23(s,1H),7.20-7.09(m,2H),6.74-6.65(m,3H),4.24(dd,J＝15.8,2.3Hz,1H),4.07(t,J＝9.3Hz,1H),3.26(t,J＝9.5Hz,1H),3.09-2.94(m,2H),2.42(s,3H),2.26-2.13(m,1H),1.99-1.87(m,1H), 1.84-1.73(m,1H),1.46-1.31(m,2H),0.83(t,J＝7.4Hz,3H).
实施例89：化合物89的制备
参照实施例1化合物1的制备方法，用70G代替1I，用(4-氟-5-(甲氧基羰基)噻吩-3-基)硼酸替换(5-(甲氧羰基)噻吩-3-基)硼酸得化合物89(100mg)。MS(ESI):m/z 593.1241[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.66(d,J＝4.1Hz,1H),7.54(s,1H),6.98-6.91(m,1H),6.91-6.80(m,2H),6.32(s,1H),4.47(dd,J＝15.7,11.6Hz,1H),4.35-4.16(m,4H),3.77(dd,J＝15.7,4.0Hz,1H),3.65-3.53(m,1H),3.03(s,3H),2.08(s,3H),1.88-1.74(m,1H),1.59-1.33(m,5H),0.95(t,J＝7.0Hz,3H).
实施例90：化合物90的制备
中间体47F(500mg)、碳酸钾(417mg)、环丙基硼酸(130mg)、四(三苯基膦)钯(232mg)、水(2mL)于1,4-二氧六环(10mL)中，氮气置换后，油浴100℃反应。反应完全，将反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体90A(367mg)。MS(ESI):m/z 459.22[M+H]+。
中间体90A(300mg)、甲硫醇钠(321mg)于N,N-二甲基甲酰胺(20mL)，加毕，微波90℃搅拌反应。反应完全，反应液倒入水中，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析(洗脱体系：石油醚/乙酸乙酯)分离得中间体90B(180mg)。MS(ESI):m/z 445.24[M+H]+。
参照实施例3化合物3的制备方法，用中间体90B替换中间体3G得化合物90(87mg)。MS(ESI):m/z 533.1759.[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.53(s,1H),7.49(d,J＝17.7Hz,1H),6.70(d,J＝8.4Hz,1H),6.67(s,1H),6.41(d,J＝2.4Hz,1H),6.31(dd,J＝8.4,2.4Hz,1H),5.88(dd,J＝8.0,1.2Hz,2H),3.92(d,J＝15.8Hz,1H),3.82(m,1H),3.45(m,1H),2.66(s,3H),2.18-2.12(m,1H),1.69-1.60(m,1H),1.56-1.33(m,5H),1.08-0.99(m,2H),0.94(t,J＝6.9Hz,3H),0.68-0.58(m,2H).
实施例91：化合物91的制备
参照实施例90化合物90的制备方法，用三甲基环三硼氧烷替换环丙基硼酸得化合物91(50mg)。MS(ESI):m/z 507.1591[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.44(s,1H),7.37(d,J＝17.6Hz,1H),6.91(s,1H),6.61(d,J＝8.4Hz,1H),6.34(d,J＝2.4Hz,1H),6.27(dd,J＝8.4,2.4Hz,1H),5.78(dd,J＝8.0,1.2Hz,2H),3.82(d,J＝15.8Hz,1H),3.73(m,1H),3.43-3.33(m,1H),2.56(s,3H),2.15(s,3H),1.60-1.46(m,1H),1.45-1.22(m,5H),0.84(t,J＝6.9Hz,3H).
实施例92：化合物92的制备
参照实施例45化合物45的制备方法，用6-氨基-3H-螺环[苯并呋喃-2,1'-环丙烷]-3-酮替换中间体45B得化合物92(25mg)。MS(ESI):m/z 563.1676[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.45(s,1H),7.32(d,J＝17.5Hz,1H),6.99(s,1H),6.92(d,J＝8.2Hz,1H),6.18(dd,J＝8.1,2.3Hz,1H),6.08-6.04(m,1H),3.91(d,J＝16.1Hz,1H),3.82(m,1H),3.27(m,1H),3.11(s,2H),2.51(s,3H),2.27(s,3H),1.57-1.40(m,2H),1.37-1.25(m,4H),1.02-0.94(m,2H),0.86(t,J＝6.8Hz,3H),0.64-0.58(m,2H).
实施例93：化合物93的制备
参照实施例82化合物82的制备方法，用7-甲基-5-氨基-2,3-二氢苯并[b][1,4]二氧六环替换苯胺，用Boc-D-正亮氨酸替换中间体82A得化合物93(50mg)。MS(ESI):m/z 567.1626[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.27(s,1H),7.11(d,J＝17.7Hz,1H),6.54-6.50(m,2H),6.26(s,1H),4.15-4.04(m,5H),3.63(dd,J＝15.6,3.6Hz,1H),3.51(s,1H),2.82(s,3H),2.11(s,3H),2.04(s,3H),1.45-1.19(m,6H),0.82(t,J＝6.8Hz,3H).
实施例94：化合物94的制备
参照实施例82化合物82的制备方法，用7-氟-5-氨基-2,3-二氢苯并[b][1,4]二氧六环替换苯胺，用Boc-D-正亮氨酸替换中间体82A得化合物94(80mg)。MS(ESI):m/z 571.1382[M+H]+。
1H NMR(500MHz,Methanol-d4)δ7.33(s,1H),7.24(d,J＝17.6Hz,1H),6.50-6.44(m,2H),6.37(s,1H),4.20-4.07(m,4H),3.93(t,J＝13.6Hz,1H),3.74(dd,J＝15.8,3.4Hz,1H),3.54(s,1H),2.78(s,3H),2.11(s,3H),1.67-1.56(m,1H),1.44-1.22(m,5H),0.83(t,J＝6.9Hz,3H).
试验例1 FITC-preS1多肽结合实验
Huh-7D-NTCP细胞在补充10％FBS(Gibco，2409126CP)的DMEM培养基(VivaCell，C3113-0500)中37℃下5％CO2的条件下培育。
将50,000个Huh-7D-NTCP细胞接种于96孔板(Eppendorf，30730119)中，37℃下5％CO2的条件下培育24小时。使用DMSO(Sigma，D2650)配置化合物母液，DMEM培养基(VivaCell，C3113-0500)进行化合物稀释，共设置8个浓度点，最高浓度点为20μM，3倍倍比稀释。弃去培养上清，随后将90μL含有化合物的DMEM培养基添加至孔中，同时90μLDMEM培养基添加至孔中设为阴性对照，37℃孵育1小时。DMEM培养基(VivaCell，C3113-0500)稀释Myrcludex B-FITC(合肥科生景肽生物科技有限公司，C-端具有赖氨酸(K)的HBV/2-48myr(C)-FITC)至加入孔板后浓度为100nM。随后将10μL含Myrcludex B-FITC的DMEM培养基添加至所有孔中，37℃孵育1小时。
弃去上清，使用200μL PBS(Gibco，C20012500BT)洗涤。将50μL胰酶(Gibco，12604-021)添加至孔中，并将该板在CO2培育箱中在37℃下孵育消化15min后，添加150μL含5％FBS(Gibco，2409126CP)的PBS(Gibco，C20012500BT)终止消化，吹吸混匀后将重悬细胞转移至96U底板(Nunc，249944)，离心机(Thermo，ST8R)1500rpm离心3min后，去除上清，加入40μL PBS(Gibco，C20012500BT)重悬细胞，随后使用流式细胞仪(赛多利斯，IQue3)收集细胞并检测细胞FITC几何平均荧光强度，计算化合物与Huh-7D-NTCP细胞的亲和力。计算公式：抑制率(％)＝(1-化合物(GMFI)/阴性对照(GMFI))×100％，GraphPad prism曲线拟合计算IC50值。
实验结果见表一，其中A代表：0nM＜IC50≤500nM；B代表：500nM＜IC50≤1000nM；C代表：1000nM＜IC50≤5000nM；D代表：5000nM＜IC50。
表一：化合物与Huh-7D-NTCP细胞亲和力FACS检测


试验例2：体外CYP450酶抑制活性
人肝微粒体温孵体系制备为混合PBS缓冲液(pH7.4)，肝微粒体溶液(0.2mg/ml)，混合CYP450特异性底物，受试化合物及NADPH+MgCl2溶液，于37℃及300rpm孵育0.5小时。另设阳性对照组与阴性对照组。阳性对照组为上述体系中用特异性抑制剂代替受试化合物，阴性对照组为上述体系中用溶剂代替受试化合物。孵育后的样本加入含内标的乙腈溶液经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定特异性底物的代谢产物。采用公式(1–(受试组/阴性对照组))×100％计算抑制率。本公开化合物具有较好的人肝微粒体稳定性，60min剩余量＞80％。
实验结果见表二。
表二人肝微粒体稳定性
试验例3：小鼠药代动力学
ICR小鼠，体重18～22g，适应3～5天后，随机分组，每组9只，按10mg/kg剂量灌胃受试化合物溶液。
采血时间点15min、0.5h、1h、2h、4h、6h、8h、10h、24h，于眼眶取血制备待测血浆样品。
吸取30μL待测血浆样品和标曲样品，加入含内标的乙腈溶液经蛋白沉淀得到上清液，稀释后用于LC/MS/MS测定。采用非房室模型拟合。本公开化合物具有良好的药代动力学性质，生物利用度较高，相对生物利用度达到75％以上。
试验结果见表三。
表三小鼠药代动力学
试验例4：hNTCP转运体体外试验和hASBT转运体体外试验
hNTCP转运体体外试验
用含有10％胎牛血清(Gibco，10099-141)、200μg/ml G418(Gbico，10131-027)的DMEM(Viva Cell，C3113-0500)完全培养基于37℃在含有5％CO2/95％空气的培养箱中培养HEK293-hNTCP细胞(人NTCP过表达细胞)。取对数生长期细胞进行胰酶(Gbico，12604-021)消化铺板，调整细胞密度4×105cells/ml，细胞悬液500μL/孔，37℃、5％ CO2饱和湿度培养箱中贴壁培养，细胞贴壁生长24h，融合度≧90％时便可开展实验。
次日，弃细胞上清，各孔加入250μL预孵育液(阴性组为空白溶媒组、受试组为化合物组。终浓度如下：100nM、30nM、10nM、5nM、3nM、1nM、0.3nM)混匀，37℃预孵育30min，除去预孵育液。各孔加入250μL孵育液(阴性组为空白溶媒组，受试组为化合物组，且均含5μM氘代牛磺酸钠(广州谱恩科学仪器有限公司，MD-1020-10mg))，混匀，37℃预孵育2min，除去孵育液。加入500μL冰PBS(Gbico，C20012500BT)终止反应，再洗涤2次，共洗涤3次。每孔加入150μL细胞裂解液(Thermo，89900)，冰上裂解20min。裂解完毕后将裂解液全部转入1.5mL离心管(AXYGEN，MCT-150-C-S)中，离心机(Thermo，ST8R)4℃、4000rpm、10min离心，分离获取上清液。吸取100μl上清，加入400μL含内标的冰乙腈沉淀得到上清液，稀释后用于LC-MS/MS分析。
hASBT转运体体外试验
用含有10％胎牛血清(Gibco，10099-141)、200μg/ml G418(Gbico，10131-027)的DMEM(Viva Cell，C3113-0500)完全培养基于37℃在含有5％CO2/95％空气的培养箱中培养HEK293-hASBT细胞(人ASBT过表达细胞)。取对数生长期细胞进行胰酶(Gbico，12604-021)消化铺板，调整细胞密度4×105cells/ml，细胞悬液500μL/孔，37℃、5％ CO2饱和湿度培养箱中贴壁培养，细胞贴壁生长24h，融合度≧90％时便可开展实验。
次日，弃细胞上清，各孔加入250μL预孵育液(阴性组为空白溶媒组、受试组为化合物组。终浓度如下：30μM、10μM、3μM、2μM、1μM、300nM、100nM。)混匀，37℃预孵育30min，除去预孵育液。各孔加入250μL孵育液(阴性组为空白溶媒组，受试组为化合物组，且均含5μM氘代牛磺酸钠(广州谱恩科学仪器有限公司，MD-1020-10mg))，混匀，37℃预孵育2min，除去孵育液。加入500μL冰PBS(Gbico，C20012500BT)终止反应，再洗涤2次，共洗涤3次。每孔加入150μL细胞裂解液(Thermo，89900)，冰上裂解20min。裂解完毕后将裂解液全部转入1.5mL离心管(AXYGEN，MCT-150-C-S)中，离心机(Thermo，ST8R)4℃、4000rpm、10min离心，分离获取上清液。吸取100μl上清，加入400μL含内标的冰乙腈沉淀得到上清液，稀释后用于LC-MS/MS分析。
hNTCP转运体体外试验和hASBT转运体体外试验结果见表四，其中A代表0nM＜IC50≤10nM；B代表：10nM＜IC50≤100nM；C代表：100nM＜IC50≤1000nM；D代表：1000nM＜IC50。
表四hNTCP转运体体外试验和hASBT转运体体外试验

Claims (15)

  1. 式(I)化合物、其立体异构体或其药学上可接受的盐，
    其中，
    X选自C(RaRb)或NRc；
    L选自键、O、S、(C(RaRb))p、(NRc)q或(C(RaRb))i-(NRc)j；
    R1和R2各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
    或者，R1和R2以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个取代基取代；
    或者，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个取代基取代；
    Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个取代基取代；
    Rc选自氢、羟基、氨基、巯基、C1-12烷基或C1-12烷氧基，所述氨基、C1-12烷基或C1-12烷氧基任选地可进一步被一个或多个取代基取代；
    或者，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个取代基取代；
    或者，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个取代基取代；
    或者，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个取代基取代；
    R3选自氢、氘、卤素、硝基、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2- 12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-10元杂芳基任选地可进一步被一个或多个取代基取代；
    A选自
    环B选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
    R4选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
    R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-12烷基或C1-12烷氧基；所述氨基、C1- 12烷基或C1-12烷氧基任选地可进一步被一个或多个取代基取代；
    Ra1、Ra2或Ra3各自独立地选自氢、氘、卤素、硝基、羟基、疏基、氰基、氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-104元芳基或5-14元杂芳基任选地可进一步被一个或多个取代基取代；
    p、q、i或j分别独立地选自1、2或3；
    m选自0、1或2；
    n和n1各自独立地选自0、1、2、3或4；
    条件是：
    当A选自L为键，且R1和R2各自独立地选自氢或未取代C1-12烷基时，R4不为取代或未取代的苯基。
  2. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，
    X选自C(RaRb)或NRc；
    L选自键、O、S、(C(RaRb))p、(NRc)q或(C(RaRb))i-(NRc)j；
    R1和R2各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个Raa取代；
    或者，R1和R2以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环环烷基或3-14元杂环基任选地可进一步被一个或多个Rbb取代；
    或者，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rbb取代；
    Ra和Rb各自独立地选自氢、氘、卤素、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个Rcc取代；
    Rc选自氢、羟基、氨基、巯基、C1-12烷基或C1-12烷氧基，所述氨基、C1-12烷基或C1-12 烷氧基任选地可进一步被一个或多个Re取代；
    或者，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-14环烷基或3-14元杂环基，所述C3-14环烷基或3-14元杂环基任选地可进一步被一个或多个Rd1取代；
    或者，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rd2取代；
    或者，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-14元杂环基，所述3-14元杂环基任选地可进一步被一个或多个Rd3取代；
    R3选自氢、氘、卤素、硝基、羟基、氨基、巯基、氰基、C1-12烷基、C1-12烷氧基、C2- 12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-10元杂芳基任选地可进一步被一个或多个Rf取代；
    A选自
    环B选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个Rg取代；
    R4选自C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基任选地可进一步被一个或多个Rh取代；
    R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-12烷基或C1-12烷氧基；所述氨基、C1- 12烷基或C1-12烷氧基任选地可进一步被一个或多个Ri取代；
    Ra1、Ra2或Ra3各自独立地选自氢、氘、卤素、硝基、羟基、疏基、氰基、氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，所述氨基、C1-12烷基、C1-12烷氧基、C2-12烯基、C2-12炔基、C3-14环烷基、3-14元杂环基、6-104元芳基或5-14元杂芳基任选地可进一步被一个或多个Rj取代；
    Raa、Rbb、Rcc、Rd1、Rd2、Rd3、Re、Rf、Rg、Rh、Ri和Rj各自独立地选自氘、卤素、羟基、氨基、硝基、氰基、巯基、＝O、C1-12烷基、C1-12烷氧基、C3-14环烷基、3-14元杂环基、-(CH2)nRal、-(CH2)nORal、-(CH2)nC(O)Ral、-(CH2)nC(O)ORal、-(CH2)nS(O)mRal、-(CH2)nO(CH2)nS(O)mRal、-(CH2)nP(O)Ra2Ra3、-(CH2)nNRa2Ra3、-(CH2)nNRa2C(O)ORa3、-(CH2)nNRa2C(O)(CH2)nlRa3、-(CH2)nNRa2C(O)NRa2Ra3、-(CH2)nC(O)NRa2(CH2)nlRa3、-OC(RalRa2)n(CH2)nlRa3或-(CH2)nNRa2S(O)mRa3，所述C1-12烷基、C1-12烷氧基、C3-14环烷基或3-14元杂环烷基任选地可进一步被一个或多个选自氘、＝O、卤素、羟基、氨基或氰基的取代基取代；
    p、q、i或j分别独立地选自1、2或3；
    m选自0、1或2；
    n和n1各自独立地选自0、1、2、3或4；
    条件是：
    当A选自L为键，且R1和R2各自独立地选自氢或未取代C1-12烷基时，R4不为取代或未取代的苯基。
  3. 根据权利要求1或2所述的式(I)化合物、其立体异构体或其药学上可接受的盐，Ra和Rb各自独立地选自氢、氘、C1-6烷基或C1-6烷氧基，所述C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Rcc取代；优选的，Ra和Rb各自独立地选自氢、氘、C1-3烷基或C1-3烷氧基，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个Rcc取代；优选的，Ra和Rb各自独立地选自氢或甲基。
  4. 根据权利要求1-3任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，Rc选自氢或C1-6烷基，所述C1-6烷基任选地可进一步被一个或多个Re取代；优选的，Rc选自氢或C1-3烷基，所述C1-3烷基任选地可进一步被一个或多个Re取代；优选的，Rc选自氢、甲基或-CD3。
  5. 根据权利要求1-4任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成C3-6环烷基或3-6元杂环基，所述C3-6环烷基或3-6元杂环基任选地可进一步被一个或多个Rd取代；优选的，当L选自(C(RaRb))p或(C(RaRb))i-(NRc)j时，相同或不同碳原子上的Ra和Rb以及与它们相连的碳原子一起形成环丙基或环丁基，所述环丙基或环丁基任选地可进一步被一个或多个Rd取代；
    或者，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成3-6元杂环基，所述3-6元杂环基任选地可进一步被一个或多个Rd取代；优选的，当L选自(NRc)q或(C(RaRb))i-(NRc)j时，不同氮原子上的Rc以及与它们相连的氮原子一起形成1,3-二氮杂环丁烷基，所述1,3-二氮杂环丁烷基任选地可进一步被一个或多个Rd取代；或者，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成3-6元杂环基，所述3-6元杂环基任选地可进一步被一个或多个Rd取代；优选的，当L选自(C(RaRb))i-(NRc)j时，碳原子上的Ra以及与它相连的碳原子、氮原子上的Rc以及与它相连的氮原子一起形成氮杂环丁基，所述氮杂环丁基任选地可进一步被一个或多个Rd取代；
    或者，L选自键、C(RaRb)、-C(RaRb)-C(RaRb)-、-C(RaRb)-NRc-、-C(RaRb)-C(RaRb)-C(RaRb)-或C(RaRb)-C(RaRb)-NRc；优选的，L选自C(RaRb)、-C(RaRb)-C(RaRb)-或-C(RaRb)-NRc-；优选的，L选自键；或者优选的，L选自键、CH2、C(CH3)2、
  6. 根据权利要求1-5任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，X选自CH2、N(CH3)、NH、N(CD3)或优选的，X选自N(CH3)。
  7. 根据权利要求1-6任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，R1和R2各自独立地选自氢、氘、卤素、羟基、NH2、巯基、氰基、C1-6烷基、C1-6烷氧基、-(CH2)nRal或-(CH2)nORal，所述C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Raa取代；优选的，R1和R2各自独立地选自氢、氘、C1-6烷基、C1-6烷氧基、-(CH2)nRal或-(CH2)nORal，所述C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Raa取代；优选的，R1和R2各自独立地选自氢、C1-6烷基、-(CH2)nRal或-(CH2)nORal，所述C1-6烷基可进一步被一个或多个Raa 取代；优选的，R1和R2各自独立地选自氢、正丁基、-CH2Ral、-CH2ORal、-CH2CH2ORal，所述正丁基任选地可进一步被一个或多个F取代，Ra1选自甲基、乙基或环丙基；优选的，R1和R2各自独立地选自氢、正丁基、-CH2OCH2CH3或-CH2CH2OCH3，所述正丁基任选地可进一步被一个或多个F取代；优选的，R1和R2各自独立地选自氢或正丁基，所述正丁基可进一步被一个或多个F取代；优选的，R1和R2各自独立地选自氢、正丁基、-CH2OCH2CH3或-CH2CH2OCH3；
    或者，R1和R2以及与它们相连的碳原子一起形成C3-6环烷基或3-6元杂环基，所述C3-6环烷基或3-6元杂环基任选地可进一步被一个或多个Rbb取代；优选的，R1和R2以及与它们相连的碳原子一起形成环戊基，所述环戊基任选地可进一步被一个或多个Rbb取代；
    或者，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成3-6元杂环基，所述3-6元杂环基任选地可进一步被一个或多个Rbb取代；优选的，当X选自(NRc)q时，R2和Rc以及与它们相连的碳原子和氮原子一起形成吡咯烷基或哌啶基，所述吡咯烷基或哌啶基任选地可进一步被一个或多个Rbb取代。
  8. 根据权利要求1-7任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，R3选自氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)nORal、-(CH2)nNRa2Ra3或-(CH2)nS(O)mRal，所述氨基、C1-6烷基或C1-6烷氧基任选地可进一步被一个或多个Rf取代；优选的，R3选自卤素、羟基、NH2、氰基、C1-3烷基、C1-3烷氧基、C3-6环烷基、-(CH2)nORal、-(CH2)nNRa2Ra3或-(CH2)nS(O)mRal，所述C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个Rf取代；优选的，R3选自甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、-(CH2)nORal、-(CH2)nNRa2Ra3-(CH2)nS(O)mRal，所述甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选地可进一步被一个或多个Rf取代；优选的，R3选自-(CH2)nS(O)mRal；优选的，R3选自-SCH3。
  9. 根据权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，R5和R5’各自独立地选自氢、氘、卤素、氨基、C1-3烷基或C1-3烷氧基；所述氨基、C1-3烷基或C1-3烷氧基任选地可进一步被一个或多个Ri取代；优选的，R5和R5’各自独立地选自氢、氘、卤素、NH2、甲基、乙基、甲氧基或乙氧基，所述甲基、乙基、甲氧基或乙氧基任选地可进一步被一个或多个Ri取代；优选的，R5选自氢或F；优选的，A选自
  10. 根据权利要求1-9任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，A选自环B选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，所述C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基任选地可进一步被一个或多个Rg取代；优选的，A选自 环B选自C3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基，所述C3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基任选地可进一步被一个或多个Rg取代。
  11. 根据权利要求1-10任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，R4选自C3-10环烷基、3-10元杂环基、C6-12芳基或5-10元杂芳基，所述C3-10环烷基、3-10元杂环基、C6-12芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代；优选的，R4选自C5-8环烷基、5-8元杂环基、C6-12芳基或5-10元杂芳基，所述C5-8环烷基、5-8元杂环基、C6-12芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代；优选的，R4选自C5-8环烷基、C6-11芳基或5-10元杂芳基，所述C5-8环烷基、C6-11芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代；优选的，R4选自C5-8环烷基、苯基、C9-11芳基或5-10元杂芳基，所述C5-8环烷基、苯基、C9-11芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代；优选的，R4选自C5-8环烷基、C9-11芳基或5-10元杂芳基，所述C5-8环烷基、C9-11芳基或5-10元杂芳基任选地可进一步被一个或多个Rh取代；
    或者，R4选自环丁基、1,2-二氢吡啶基、金刚烷基、苯并环丁基、苯基、吲哚啉基、异吲哚啉基、苯并吡唑烷环基、苯并四氢呋喃环基、3H-螺[苯并呋喃-2,1'-环丙烷]、苯并四氢吡喃环基、苯并二氧戊环基、苯并四氢吡喃环基、苯并哌啶环基、呋喃基、噻吩基、吡啶基、苯并噻吩环基、苯并噻唑环基、苯并噁唑环基、吲哚基、苯并咪唑环基、噻吩并[3,2-b]吡啶环基、噻吩并[2,3-b]吡啶环基、喹啉基、异喹啉基、2,3-二氢呋喃并[2,3-b]吡啶环基、2,3-二氢呋喃并[3,2-b]吡啶环基、2,3-二氢苯并[b][1,4]二噁英基、6,7-二氢-4H-吡唑[5,1-c][1,4]噁嗪基、2,3-二氢呋喃并[3,2-c]吡啶环基或双环[1.1.1]戊烷基，所述R4任选地可进一步被一个或多个Rh取代；优选的，R4选自 所述R4任选地可进一步被一个或多个Rh取代。
  12. 根据权利要求1-11任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，选自式(I-1)化合物、式(I-2)化合物、其立体异构体或其药学上可接受的盐：
    其中，R1、R2、R3、R4、R5、X和环B的定义如权利要求1-10任一项所述；
    或者，选自式(II-1)化合物、式(II-2)化合物、其立体异构体或其药学上可接受的盐：
    其中，R2、R3、R4、R5、X和环B的定义如权利要求1-10任一项所述；
    或者，选自式(III-1)化合物、式(III-2)化合物、其立体异构体或其药学上可接受的盐：
    其中，R1、R2、R3、R4、R5和环B的定义如权利要求1-10任一项所述；
    或者，选自式(IV-1)化合物、式(IV-2)化合物、其立体异构体或其药学上可接受的盐：
    其中，R1、R2、R4、R5和环B的定义如权利要求1-10任一项所述。
  13. 以下化合物、其立体异构体或其药学上可接收的盐：














    优选的，选自以下化合物、其立体异构体或其药学上可接收的盐：






























  14. 药物组合物，其包含权利要求1-13任一项所述化合物、其立体异构体或其药学上可接受的盐。
  15. 权利要求1-13任一项所述化合物、其立体异构体或其药学上可接受的盐、权利要求14所述的药物组合物在制备治疗或预防疾病的药物中的用途；任选地所述疾病选自心血管疾病、脂肪酸代谢及葡萄糖利用病症、胃肠道疾病及肝病。
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102361860A (zh) * 2009-03-20 2012-02-22 瑟维尔实验室 用作ampa和nmda受体调节剂的苯并硫杂二氮杂*衍生物
CN112449637A (zh) * 2018-06-05 2021-03-05 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
WO2022029101A1 (en) * 2020-08-03 2022-02-10 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
CN114761079A (zh) * 2019-12-04 2022-07-15 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
CN114761080A (zh) * 2019-12-04 2022-07-15 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
CN114786772A (zh) * 2019-12-04 2022-07-22 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
WO2022253997A1 (en) * 2021-06-03 2022-12-08 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
WO2023164179A1 (en) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164183A1 (en) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102361860A (zh) * 2009-03-20 2012-02-22 瑟维尔实验室 用作ampa和nmda受体调节剂的苯并硫杂二氮杂*衍生物
CN112449637A (zh) * 2018-06-05 2021-03-05 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
CN114761079A (zh) * 2019-12-04 2022-07-15 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
CN114761080A (zh) * 2019-12-04 2022-07-15 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
CN114786772A (zh) * 2019-12-04 2022-07-22 阿尔比里奥公司 苯并硫杂(二)氮杂环庚三烯化合物及其作为胆汁酸调节剂的用途
WO2022029101A1 (en) * 2020-08-03 2022-02-10 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
WO2022253997A1 (en) * 2021-06-03 2022-12-08 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
WO2023164179A1 (en) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164183A1 (en) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv

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