WO2024109736A1 - 一种化合物、包含其的药物组合物及其合成方法和用途 - Google Patents

一种化合物、包含其的药物组合物及其合成方法和用途 Download PDF

Info

Publication number
WO2024109736A1
WO2024109736A1 PCT/CN2023/132911 CN2023132911W WO2024109736A1 WO 2024109736 A1 WO2024109736 A1 WO 2024109736A1 CN 2023132911 W CN2023132911 W CN 2023132911W WO 2024109736 A1 WO2024109736 A1 WO 2024109736A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
ring
independently
mmol
Prior art date
Application number
PCT/CN2023/132911
Other languages
English (en)
French (fr)
Inventor
曹斌
赵立雨
田野
窦国生
卢思竹
杨军
谢德伟
陈照强
张启花
王绍晖
陈斌
张佩宇
Original Assignee
深圳众格生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳众格生物科技有限公司 filed Critical 深圳众格生物科技有限公司
Publication of WO2024109736A1 publication Critical patent/WO2024109736A1/zh

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a compound, a pharmaceutical composition containing the compound, a synthesis method and use thereof.
  • ALS Amyotrophic lateral sclerosis
  • MND motor neurone disease
  • the core pathological finding of ALS is the death of motor neurons in the motor cortex and spinal cord, and the degeneration of corticospinal axons can lead to thinning and scarring (sclerosis) of the lateral aspect of the spinal cord.
  • the unfolded protein response comprises a set of signaling mechanisms that initiate gene expression programs to restore protein homeostasis or promote neuronal death when stress is chronic or excessive. This function of the UPR has been proposed to play a key role in ALS.
  • the integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that helps cells, tissues, and organisms adapt to changing environments and stay healthy.
  • the ISR responds to various changes and restores balance by reprogramming gene expression.
  • Long-term memory formation in the brain requires new protein synthesis, so inhibition of the ISR enhances long-term memory formation, while activation of the ISR blocks this process, and age-related cognitive impairment is often associated with ISR activation.
  • ISR activation occurs in a wide range of brain diseases. This activation was confirmed by measuring eIF2-P and PKR, PERK, and GCN2 phosphorylation in the brain, including samples from patients and animal models of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, Down syndrome, and Charcot-Marie-Tooth. Notably, ISR activation leads to cognitive deficits in traumatic brain injury, aging, and Alzheimer's disease mouse models.
  • eIF2B eukaryotic translation initiation factor 2B, eIF2B
  • eIF2B eukaryotic translation initiation factor 2B
  • GEF guanine nucleotide exchange factor
  • the eIF2B agonist ISRIB can restore protein translation, restore UPR transcription to the basal level, and reduce the integrated stress response (ISR).
  • eIF2B agonists ABBV-CLS-7262 AbbVie/Calico
  • DNL-343 Denali Therapeutics
  • eIF2B activator ISRIB can increase long-term memory in mouse models. After taking the eIF2B activator ABBV-CLS-7262 orally for 3 days, the brain function of the model animals can be restored to the level of youth. This means that this drug may be able to inhibit some neurodegenerative diseases in the later stages and has the potential to treat diseases such as Alzheimer's disease and Parkinson's disease.
  • the present application provides a compound, a pharmaceutical composition containing the same, and a synthesis method and use thereof, so as to provide a compound that can significantly weaken the integrated stress response (ISR) of cells, activate eIF2B activity, and make the intracellular protein tend to be synthesized normally, and treat diseases or disorders mediated by the integrated stress response (ISR) pathway, eIF2B-related diseases, and/or for the regulation of the activity or level of eIF2B, the activity or level of the eIF2 pathway or the ISR pathway.
  • ISR integrated stress response
  • the first aspect of the present application provides a compound represented by formula 0, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not And the * end is connected to L, The end is connected to the B ring, and the n 3 is any integer from 0 to 5;
  • Ring B is selected from 5-10 membered heteroarylene, n 4 is any integer from 0 to 4;
  • the C ring is selected from a 3-10 membered heterocycloalkylene group, a C3-C10 membered cycloalkylene group, or # B - X21 -C3-C12 cycloalkylene group-$ R1 , X21 is -NR3 or -C(O) NR3 , # B- is a connecting bond to the B ring, and -$ R1 is a connecting bond to R1 ; each R3 is independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and when the C ring is a C3-C10 membered cycloalkylene group, the A ring is not and cyclohexylene, and the * end is connected to L, The end is connected to the B ring, and n 5 is any integer from 0 to 5;
  • Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 membered heterocycloalkylene;
  • L is -L1 - L2 - L3- $ A or a 5-6 membered heteroaryl
  • L1 is a bond, -O-, -S- or -NR4-
  • L2 is a bond, a substituted or unsubstituted C1-C10 alkylene group
  • L3 is -C( X10 ) NR5- $ A or -C( X10 )-$ A
  • X10 is O or S
  • R4 and R5 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl
  • R4 and R5 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10
  • the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl of 5 can be substituted by 1 to 6 R 11s independently, L 1 is connected to the D ring, and L 3 is connected to the A ring; # D - is a connecting bond connected to the D ring, and -$ A is a connecting bond connected to the A ring;
  • R 1 , R 2 , R 9a , R 9b , and R 9c are each independently a substituent R 11 ;
  • Each R 20 and R 21 is independently selected from H, or a C1-C10 alkyl group optionally substituted with 1-6 carbonyl groups, halogen, hydroxyl or amino groups;
  • R 20 and R 21 form a heterocycloalkyl group with a common atom, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group optionally substituted by 1-6 carbonyl groups, halogens, hydroxyl groups or amino groups; each R 30 and R 31 are independently selected from H, or a C1-C10 alkyl group optionally substituted by 1-6 carbonyl groups, halogens, hydroxyl groups or amino groups;
  • R 30 and R 31 form a heterocycloalkyl group with the common atom, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group optionally substituted by 1-6 carbonyls, halogens, hydroxyls or aminos;
  • n1 and n2 are each independently any integer from 0 to 4.
  • ring A can be understood as selected from a trivalent or higher polyvalent ring according to the valence and quantity of R 9a , and the same applies to ring B; taking ring D as an example, when n2 is 0, ring D can be understood as a monovalent ring.
  • ring D can be understood as selected from a divalent or higher polyvalent ring according to the valence and quantity of R 2 ; taking ring C as an example, when n1 and n5 are 0, ring C can be understood as a monovalent ring.
  • ring C can be understood as selected from a divalent or higher polyvalent ring according to the valence and quantity of R 9c and R 2 ; when both n1 and n5 are not 0, ring C can be understood as selected from a trivalent or higher polyvalent ring according to the valence and quantity of R 9c and R 2.
  • ring A, ring B, ring C and ring D apply to the entire text.
  • the compound is as shown in Formula 0, wherein:
  • Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not Among them, the * end is connected to L, The end is connected to the B ring, and n3 is any integer from 0 to 5;
  • Ring B is selected from 5-10 membered heteroarylene, n4 is any integer from 0 to 4;
  • the C ring is selected from a 3-10 membered heterocycloalkylene, a C3-C10 cycloalkylene, or # B - X21 -C3-C12 cycloalkylene-$ R1 , X21 is -NR3 or -C(O) NR3 , # B- is a connecting bond to the B ring, -$ R1 is a connecting bond to R1 ; each R3 is independently H, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and C When the ring is a C3-C10 cycloalkylene group, the A ring is not a cyclohexylene group, and n5 is any integer from 0 to 5;
  • Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 membered heterocycloalkylene;
  • L is # D - L1 - L2 - L3- $ A , 5-6 membered heteroaryl or # D - NR14C (O)-C1-C6 alkylene-O-$ A
  • L1 is a bond, -O-, -S- or -NR4-
  • L2 is a bond, substituted or unsubstituted C1-C10 alkylene
  • L3 is -C( X10 ) NR5- $ A or -C( X10 )-$ A
  • X10 is O or S
  • R4 , R5 and R14 are each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl
  • R4, R5 and R14 are each independently selected from H,
  • the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl of 14 may each independently be substituted by 1 to 6 R 11 ;
  • # D - is a connecting bond to the D ring, -$ A is a connecting bond to the A ring;
  • R 1 , R 2 , R 9a , R 9b , and R 9c are each independently a substituent R 11 ,
  • each of R 6 , R 7 and R 8 is independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 , wherein the C1 - C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl as R 6 , R 7 and R 8 are each independently substituted by 1 to 6 R 13 ; or
  • R6 and R7 together with the atoms to which they are attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; or
  • R7 and R8 together with the atoms to which they are attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;
  • each R 20 and R 21 are independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or
  • R 20 and R 21 together with the atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;
  • each R 30 and R 31 are independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino; or
  • R 30 and R 31 together with the atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1 to 6 halogens, or by a C1-C10 alkyl group optionally substituted by 1 to 6 halogens, hydroxyl groups or amino groups;
  • n1 and n2 are each independently any integer from 0 to 4.
  • the compound is as shown in Formula 0, wherein:
  • Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not Among them, the * end is connected to L, The end is connected to the B ring, and n3 is any integer from 0 to 5;
  • Ring B is selected from 5-10 membered heteroarylene, n4 is any integer from 0 to 4;
  • the C ring is selected from a 3-10 membered heterocycloalkylene, a C3-C10 cycloalkylene, or # B - X21 -C3-C12 cycloalkylene-$ R1 , X21 is -NR3 or -C(O) NR3 , # B- is a connecting bond to the B ring, and -$ R1 is a connecting bond to R1 ; each R3 is independently H, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and when the C ring is a C3-C10 cycloalkylene, the A ring is not a cyclohexylene, and the A ring is When the * terminal is connected to L, The end is connected to the B ring, the C ring is a 3-10 membered heterocycloalkylene group, and n5 is any integer from 0 to 5;
  • Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 membered heterocycloalkylene;
  • L is # D - L1 - L2 - L3- $ A , 5-6 membered heteroaryl or # D - NR14C (O)-C1-C6 alkylene-O-$ A
  • L1 is a bond, -O-, -S- or -NR4-
  • L2 is a bond, substituted or unsubstituted C1-C10 alkylene
  • L3 is -C( X10 ) NR5- $ A or -C( X10 )-$ A
  • X10 is O or S
  • R4 , R5 and R14 are each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl
  • R4, R5 and R14 are each independently selected from H,
  • the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl of 14 may each independently be substituted by 1 to 6 R 11 ;
  • # D - is a connecting bond to the D ring, -$ A is a connecting bond to the A ring;
  • R 1 , R 2 , R 9a , R 9b , and R 9c are each independently a substituent R 11 ,
  • each of R 6 , R 7 and R 8 is independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 , wherein the C1 - C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl as R 6 , R 7 and R 8 are each independently substituted by 1 to 6 R 13 ; or
  • R6 and R7 together with the atoms to which they are attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; or
  • R7 and R8 together with the atoms to which they are attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;
  • each R 20 and R 21 are independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or
  • R 20 and R 21 together with the atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;
  • each R 30 and R 31 are independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino; or
  • R 30 and R 31 together with the atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1 to 6 halogens, or by a C1-C10 alkyl group optionally substituted by 1 to 6 halogens, hydroxyl groups or amino groups;
  • n1 and n2 are each independently any integer from 0 to 4.
  • the compound of formula 0 is not any of the following compounds
  • the aforementioned scheme does not include any of the following compounds, or their stereoisomers, or their tautomers, or their geometric isomers, or their enantiomers, or their diastereomers, or their racemates, or their polymorphs, or their solvates, or their hydrates, or their N-oxides, or their isotope-labeled compounds, or their metabolites, or their esters, or their prodrugs, or their pharmaceutically acceptable salts;
  • the compounds of the present application can significantly weaken the integrated stress response (ISR) of cells, activate eIF2B activity, and allow proteins in cells to tend to be synthesized normally.
  • ISR integrated stress response
  • n4 is 0, 1, 2 or 3;
  • each R 9b is independently halogen, cyano, nitro, carbonyl, -OH, C1-C3 alkyl, and more preferably each R 9b is independently halogen, cyano, nitro, -OH, C1-C3 alkyl;
  • each of the R 9b is independently halogen, -OH, methyl, ethyl or propyl;
  • n4 is 0.
  • the B ring is selected from
  • the B ring is selected from (For example )or (For example ), wherein X 7 is O or S, X 8 , X 9 , and X 10 are each independently CH or N, and the * end is connected to the C ring, The end is connected to the A ring;
  • X 8 , X 9 , and X 10 are N;
  • one of X 8 , X 9 and X 10 is N.
  • the B ring is selected from any one of the following groups:
  • the B ring is selected from any one of the following groups:
  • the B ring is selected from any one of the following groups:
  • the B ring is selected from any one of the following groups:
  • the B ring is
  • the compound has a structure shown in Formula I
  • Ring A, Ring C, Ring D, L, R 1 , R 2 , R 9a , R 9c , n2, n2, n3 and n5 are as defined in any one of the above embodiments, and X 7 is O or S. or Ring A, Ring D, L, R 1 , R 2 , R 9a , R 9c , n2, n2, n3 and n5 are as defined in any one of the above embodiments, and X 7 is O or S.
  • n1 and n2 are each independently an integer of 1-3;
  • n1 is 1, and n2 is an integer of 1-3.
  • the C ring may be substituted by 1 or 2 R 9c , preferably each of the R 9c is independently halogen, cyano, nitro, carbonyl, -OH, C1-C3 alkyl, more preferably each of the R 9c is independently halogen, cyano, nitro, -OH, C1-C3 alkyl;
  • each of the R 9c is independently halogen, -OH, methyl, ethyl or propyl;
  • the R 9c are each independently F or methyl.
  • n5 is 0, 1 or 2;
  • n5 is 0 or 1.
  • the 3-10 membered heterocycloalkylene group of the C ring is selected from wherein X 11 and X 23 are each N or B, X 12 is CH 2 , NH, O or S, q is an integer from 0 to 3, preferably q is 1 or 2; X 13 is N or B, s is an integer from 1 to 3, preferably s is 1 or 2; X 14 is O, S or NH, t is an integer from 1 to 3, preferably t is 1 or 2; the * end is connected to the B ring, The end is connected to R 1 ;
  • the 3-10 membered heterocycloalkylene group of the C ring is selected from wherein X 11 is N or B, X 12 is CH 2 , NH, O or S, q is 0 to 3, preferably q is 1 or 2; X 13 is N or B, s is an integer from 1 to 3, preferably s is 1 or 2; X 14 is O, S or NH, t is an integer from 1 to 3, preferably t is 1 or 2;
  • the 3-10 membered heterocycloalkylene group of the C ring is selected from
  • the # B - X21 -C3-C12cycloalkylene-$ R1 of the C ring is
  • R3 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl
  • p is an integer from 1 to 3, preferably 1 or 2
  • # B- is a connecting bond connected to the B ring
  • -$ R1 is a connecting bond connected to R1
  • the * end is connected to the B ring, The end is connected to R 1 ;
  • the # B - X21 -C3-C12cycloalkylene-$ R1 of the C ring is
  • the C ring is selected from * end is connected to the B ring, The end is connected to R1 .
  • the C ring is selected from
  • the C ring is selected from
  • the C ring is selected from Each of q, p, s, and t is independently 1 or 2.
  • the Selected from * end is connected to the B ring, The end is connected to R1 .
  • the Selected from * end is connected to the B ring, The end is connected to R1 .
  • the Selected from * end is connected to the B ring, The end is connected to R1 .
  • the Selected from * end is connected to the B ring, The end is connected to R1 .
  • the Selected from * end is connected to the B ring, The end is connected to R1 .
  • Each R 6 and R 7 are independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, wherein the C1 -C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, The C2-C10 alkynyl, C3-C10 cycloalkyl and 3-10 membered heterocycloalkyl groups may each be independently substituted by 1 to 3 R 13 ;
  • Each R 30 is independently selected from H, or C1-C3 alkyl optionally substituted by 1-6 carbonyls, halogens, hydroxyls or aminos, preferably each R 30 is independently selected from H, or C1-C3 alkyl optionally substituted by 1-6 halogens, hydroxyls or aminos.
  • the R 1 is selected from -OR 6 , C1-C3 alkyl, halogen, C2-C4 alkenyl, -S(O) 2 R 6 or -P(O)R 6 R 7 , preferably each R 6 and R 7 are independently selected from H, C1-C3 alkyl, wherein the C1-C3 alkyl as R 6 and R 7 may be substituted by 1 to 3 R 13 ; preferably each R 13 is independently halogen, cyano or nitro.
  • the R 1 is selected from -OR 6 , C1-C3 alkyl, halogen, -S(O) 2 R 6 or -P(O)R 6 R 7 , wherein the C1-C3 alkyl as R 1 is preferably substituted by 1-6 R 12 , R 12 is selected from halogen, -S(O) 2 R 30 , R 30 is selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; each R 6 is independently selected from C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, wherein the C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl as R 6 is independently substituted by 1-6 R 13 , R 13 is selected from halogen; R 7 is selected from C1-C3
  • the R 1 is selected from -OCF 3 , -CF 2 CF 3 , -OCH 3 , -F, -CF 3 ;
  • the R 1 is selected from -OCF 3 , -OCF 2 CF 3 ;
  • the R 1 is -OCF 3 .
  • n1 is preferably 0 or 1.
  • the compound has a structure shown in Formula II
  • Ring A, Ring D, L, R 2 , R 9a , n2 and n3 are as defined in any one of the embodiments above.
  • the R 1 is selected from -OCH 3 , -OCF 3 , -CF 2 CF 3 , -F, -CF 3 ;
  • the R 1 is -OCF 3 , -OCF 2 CF 3 ;
  • said R 1 is -OCF 3 ; preferably, n1 is 1;
  • n5 is 0, 1 or 2
  • each of the R 9c is independently halogen, cyano, nitro, carbonyl, -OH, C1-C3 alkyl, preferably each of the R 9c is independently halogen, cyano, nitro, -OH, C1-C3 alkyl;
  • each of the R 9c is independently halogen, -OH, methyl, ethyl or propyl;
  • each of the R 9c is independently F.
  • the compound has a structure shown in Formula II-1
  • Ring A, Ring D, L, R 2 , R 9a , n2 and n3 are as defined in any one of the embodiments above.
  • n5 is 0 or 1
  • n5 is 1
  • the R 9c is selected from halogen, cyano, nitro, carbonyl, -OH, C1-C3 alkyl; preferably, the R 9c is selected from halogen, cyano, nitro, -OH, C1-C3 alkyl;
  • said R 9c is selected from halogen, methyl or ethyl
  • said R 9c is F.
  • the R 1 is selected from -OCH 3 , -OCF 3 , -OCF 2 CF 3 ;
  • the R 1 is selected from -OCF 3 , -OCF 2 CF 3 ;
  • the R 1 is -OCF 3 .
  • n3 is 0, 1 or 2;
  • the A ring is selected from C5-C8 cycloalkylene or 5-8 membered heterocycloalkylene.
  • the A ring is selected from cyclohexylene or 6-membered heterocycloalkylene.
  • the A ring is selected from cyclohexane or * terminal is connected to L, The end is connected to the B ring.
  • the A ring is selected from C5-C8 sub-bridged cycloalkyl or 6-8-membered sub-bridged heterocycloalkyl, wherein X1 is CH or N, X2 , X3 , X4 , X5 , X6 are each independently CH2 , CH, NH, N or O, the * end is connected to L, The end is connected to the B ring.
  • the A ring is selected from C6-C8 sub-bridged cycloalkyl or 6-8-membered sub-bridged heterocycloalkyl, wherein X1 is CH or N, X2 , X3 , X4 , X5 , X6 are each independently CH2 , CH, NH, N or O, the * end is connected to L, The end is connected to the B ring.
  • X 5 is CH 2 or O
  • X 2 , X 3 , X 4 , and X 6 are each independently CH 2 or CH;
  • X 2 , X 3 and X 6 are CH 2
  • X 4 is CH.
  • the C6-C8 cycloalkylene or 6-8 membered heterocycloalkylene may each independently be substituted by 1 to 4 R 9a , preferably by 1 or 2 R 9a .
  • the A ring C5-C8 cycloalkylene or 6-8 membered heterocycloalkylene may each independently be substituted by 0-4 R 9a ;
  • the A ring is substituted by 0, 1 or 2 R 9a ;
  • the A ring is substituted with 0 or 1 R 9a .
  • the C6-C8 sub-bridged cycloalkyl is
  • the C5-C8 sub-bridged cycloalkyl is
  • the subbridged heterocycloalkyl is N-(2-aminoethyl)-2-aminoethyl
  • the subbridged heterocycloalkyl is N-(2-aminoethyl)-2-aminoethyl
  • each of R 6 , R 7 and R 8 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 , wherein the C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl as R 6 , R 7 and R 8 are each independently substituted by 1 to 4 R 13 ;
  • the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of 13 may be substituted by 1 to 6 halogens, or by C1-C6 alkyl which may be optionally substituted by 1 to 6 halogens, hydroxyl or amino groups,
  • Each R 20 and R 21 is independently selected from H, or a C1-C6 alkyl group optionally substituted by 1-6 carbonyl groups, halogen groups, hydroxyl groups or amino groups, preferably each R 20 and R 21 is independently selected from H, or a C1-C6 alkyl group optionally substituted by 1-6 halogen groups, hydroxyl groups or amino groups;
  • Each R 30 and R 31 is independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 carbonyls, halogens, hydroxyls or aminos.
  • each R 30 and R 31 is independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 halogens, hydroxyls or aminos.
  • each of the R 9a is independently -OH.
  • the compound has a structure shown in Formula III
  • X1 is CH or N
  • X2 , X3 , X4 , X5 , X6 are each independently CH2 , CH, NH, N or O; preferably X1 and X4 are each independently CH or N, X2 , X3 , X5 , X6 are each independently CH2 , CH, NH, N or C, and v is an integer from 0 to 2; and ring D, L, R1 , R2 , R9a , R9c , n1, n2, n3 and n5 are as defined in any of the above embodiments.
  • Ring D, L, R 1 , R 2 , R 9a , R 9c , n 1 , n 2 , n 3 and n 5 are as defined in any of the above embodiments.
  • the compound has a structure represented by any one of the general formulas III-1 to III-6.
  • Ring D, L, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any one of the above embodiments.
  • R 9a is hydroxy or halogen
  • R 9a is hydroxy
  • n3 is an integer of 0-3, more preferably 0, 1 or 2.
  • the compound has any one of the compounds having the structure shown in the following general formula:
  • the D ring, L, R 1 , R 2 , n1 and n2 are as defined in any one of the above embodiments.
  • the L is #D -L 1 -L 2 -L 3 -$ A or L1 is a bond, -O-, -S- or -NR4- , preferably L1 is -O-, -S- or -NR4- , L2 is a bond, a substituted or unsubstituted C1-C3 alkylene, preferably L2 is a substituted or unsubstituted C1-C3 alkylene, L3 is -C( X10 ) NR5- $ A or -C( X10 )-$ A , X10 is O or S, R4 and R5 are each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, and the C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkyl,
  • the L is # D - L1 - L2 - L3- $ A , or # D - NR14C (O)-C1-C6alkylene-O-$ A
  • L1 is a bond, -O-, -S- or -NR4-
  • L2 is a bond, substituted or unsubstituted C1-C3alkylene
  • L3 is -C( X10 ) NR5- $A or -C( X10 )-$ A
  • X10 is O or S
  • R4 , R5 and R14 are each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, and the C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • the compound has a structure shown in Formula IV-1 or IV-2
  • ring D, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any one of the above embodiments, and preferably ring A, ring C, ring D, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in the above embodiments.
  • X7 is O or S.
  • the compound has a structure shown in Formula V-1 or V-2
  • v is an integer from 0 to 2
  • ring D, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any one of the above embodiments, and X 7 is O or S.
  • X14 , X15 , X16 , X17 , and X18 are each independently selected from CH and N, and at least one is N, preferably there are at most three Ns, and more preferably there are at most two Ns;
  • X19 and X20 are each independently selected from CH, N, NH, O, and S, and they are not S or O at the same time, and m is 1 or 2;
  • X21 and X22 are each independently selected from CH, N, NH, O, and S, and they are not S or O at the same time, and m is 1 or 2; and u is 1, 2, or 3.
  • X14 , X15 , X16 , X17 , and X18 are each independently selected from CH and N, and at least one is N, preferably there are at most three Ns, and more preferably there are at most two Ns;
  • X19 and X20 are each independently selected from CH, N, NH, O, and S, and they are not S or O at the same time, and m is 1 or 2;
  • X21 and X22 are each independently selected from CH, N, NH, O, and S, and they are not S or O at the same time, and m is 1 or 2; and u is 1, 2, or 3.
  • each of R 6 , R 7 and R 8 is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl as R 6 , R 7 and R 8 may be independently substituted by 1 to 3 R 13 ;
  • the C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl as R 12 and R 13 are each independently substituted by 1 to 3 halogens, or by C1-C3 alkyl optionally substituted by 1 to 3 halogens, hydroxyls or amino groups.
  • Each R 20 and R 21 is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxyl or amino;
  • Each R 30 and R 31 is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxyl or amino;
  • n2 is 1 or 2 or 3.
  • each R 2 is independently selected from halogen, cyano, C1-C3 haloalkyl,
  • C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NR 6 R 7 , C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, R 6 , R 7 are each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, preferably, when R 2 is C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, n is 1, and R 2 and the D ring share two carbon atoms to form a condensed ring.
  • each R 2 is independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH 2 , Among them, it is preferred that when R 2 is hour, It shares two carbon atoms with the D ring to form a fused ring.
  • each R 2 is independently selected from F, Cl, Br, -CF 3 , -CH 3 , -CFH 2 , -CF 2 H, -OCH 3 , O-CF 3 , -NH 2 , and n2 is 1 or 2.
  • each R 2 is independently selected from F, Cl, Br, -CF 3 , -CH 3 , -CF 2 H, -OCF 3 , -NH 2 , and n2 is 1, 2 or 3.
  • the compound preferably has a structure shown in Formula VI
  • the A ring is selected from cyclohexane or 6-membered heterocycloalkylene; and L, R 1 , R 2 , R 9a , R 9c , n1 , n2, n3 and n5 are defined as in any one of the above embodiments.
  • the R 2 is independently selected from F, Cl, and Br.
  • n2 is 1 or 2.
  • R 2 is in a para and/or meta relationship with L.
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • said L is selected from
  • L is selected from * end is connected to the A ring, The end is connected to the D ring.
  • L is selected from
  • L is selected from
  • L is selected from
  • n1 and n5 are not 0 at the same time.
  • the R 1 is in a para position to the N on the C ring where it is located.
  • the R 1 is selected from -OR 6 , C1-C3 alkyl, halogen, C2-C4 alkenyl, -S(O) 2 R 6 or -P(O)R 6 R 7 , preferably each R 6 , R 7 is independently selected from H, C1-C3 alkyl, wherein the C1-C3 alkyl as R 6 , R 7 may be substituted by 1 to 3 R 13 ; preferably each R 13 is independently halogen, cyano, nitro;
  • the R 1 is selected from -OR 6 , C1-C3 alkyl, halogen, -S(O) 2 R 6 or -P(O)R 6 R 7 , wherein the C1-C3 alkyl as R 1 may be substituted by 1-6 R 12 , R 12 is selected from halogen, -S(O) 2 R 30 , R 30 is selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; each R 6 is independently selected from C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, wherein the C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl as R 6 may be independently substituted by 1-6 R 13 , R 13 is selected from halogen; R 7 is selected from C1-C3
  • the R 1 is -OCF 3 , -CF 2 CF 3 , -OCH 3 , -F, -CF 3 ;
  • the R 1 is -OCF 3 , -OCF 2 CF 3 ;
  • the R 1 is -OCF 3 .
  • R 1 , R 2 , R 9a , R 9b , R 9c are each independently a substituent R 11 .
  • R 11 When n1, n2, n3, n4, n5 are 0, it means that R 1 , R 2 , R 9a , R 9b , R 9c do not exist. Then the free bonds of C constituting the D ring, A ring, B ring and C ring are connected to H.
  • the compound has a structure shown in Formula VII
  • R 9a and X 10 are as defined in any of the above embodiments, R 21 is selected from halogen, R 22 is selected from H and halogen, and t is selected from an integer of 0-2;
  • R 21 is Cl
  • R 22 is selected from H, F, Cl, Br;
  • R 9a is selected from H, hydroxyl
  • t is 0 or 2.
  • the compound is selected from:
  • the compound is specifically selected from
  • the compound is specifically selected from
  • Another aspect of the present application provides a method for synthesizing a compound having a structure represented by the above general formula IV-1 or IV-2, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the synthetic method is selected from any one of synthetic routes 1 to 6;
  • compound 1-1 undergoes an amide condensation reaction with compound 1-2 to obtain compound 1-3; the compound 1-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 1-4; the compound 1-4 undergoes a cyclization reaction with N,N-carbonyldiimidazole to obtain compound 1-5; the compound 1-5 undergoes a condensation reaction with compound 1-6 to obtain compound IV-1-1, wherein R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiment;
  • compound 2-1 undergoes an amide condensation reaction with compound 2-2 to obtain compound 2-3; the compound 2-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 2-4; the compound 2-4 undergoes a cyclization reaction with N,N-carbonyldiimidazole to obtain compound 2-5; the compound 2-5 undergoes a condensation reaction with compound 2-6 to obtain compound IV-2-1; R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiment;
  • compound 3-1 reacts with hydrazine hydrate to obtain compound 3-2 through functional group transformation; the compound 3-2 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 3-3; the compound 3-3 undergoes condensation reaction with compound 3-4 to obtain compound 3-5; the compound 3-5 is deprotected under acidic conditions to obtain compound 3-6; the compound 3-6 undergoes amide condensation reaction with compound 3-7 to obtain compound IV-1-1, wherein R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiment;
  • compound 4-1 reacts with hydrazine hydrate to obtain compound 4-2 after functional group conversion; the compound 4-2 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 4-3; the compound 4-3 undergoes condensation reaction with compound 4-4 to obtain compound 4-5; the compound 4-5 is deprotected under acidic conditions to obtain compound 4-6; the compound 4-6 undergoes amide condensation reaction with compound 4-7 to obtain compound IV-2-1, R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiment;
  • compound 5-1 and compound 5-2 undergo amide condensation reaction to obtain compound 5-3; the compound 5-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 5-4; the compound 5-4 and compound 5-5 undergo condensation to obtain compound 5-6; the compound 5-6 undergoes ring-closure reaction to obtain compound IV-1-1, wherein R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiment;
  • compound 6-1 reacts with hydrazine hydrate to obtain compound 6-2 through functional group transformation; the compound 6-2 undergoes a ring-closing reaction to obtain compound 6-3; the compound 6-3 undergoes an oxidation reaction to obtain compound 6-4; the compound 6-4 reacts with compound 6-5 to obtain compound 6-6; the compound 6-6 is deprotected under acidic conditions to obtain compound 6-7; the compound 6-7 is condensed with compound 6-8 to obtain compound IV-1-1, wherein R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiment.
  • Another aspect of the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds, or its stereoisomers, or its tautomers, or its geometric isomers, or its enantiomers, or its diastereomers, or its racemates, or its polymorphs, or its solvates, or its hydrates, or its N-oxides.
  • the above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.
  • ISR integrated stress response
  • a method of treating a disease or condition mediated by an integrated stress response (ISR) pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of any of the above-mentioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of any of the above-mentioned pharmaceutical compositions.
  • ISR integrated stress response
  • a method for treating a disease associated with regulation of eIF2B activity or level, eIF2 pathway or ISR pathway activity or level comprising administering to a subject a therapeutically effective amount of any of the above-mentioned compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a therapeutically effective amount of any of the above-mentioned pharmaceutical compositions.
  • a method for preventing and/or treating the above-mentioned diseases comprises administering to a subject in need thereof an effective amount of any of the above-mentioned compounds, or its stereoisomers, or its tautomers, or its geometric isomers, or its enantiomers, or its diastereomers, or its racemates, or its polymorphs, or its solvates, or its hydrates, or its N-oxides, or its isotope-labeled compounds, or its metabolites, or its esters, or its prodrugs, or its pharmaceutically acceptable salts, or any of the above-mentioned pharmaceutical compositions.
  • a method for preventing and/or treating cancer comprising administering to a subject in need thereof an effective amount of any of the above compounds, or its stereoisomers, or its tautomers, or its geometric isomers, or its enantiomers, or its diastereomers, or its racemates, or its polymorphs, or its solvates, or its hydrates, or its N-oxides, or its isotope-labeled compounds, or its metabolites, or its esters, or its prodrugs, or its pharmaceutically acceptable salts, or any of the above pharmaceutical compositions.
  • Compound Compound.
  • the neurodegenerative disease includes, but is not limited to, leukodystrophy, leukoencephalopathy, myelin dysplasia or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glial cell dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, kuru, Lewy body dementia, Machado-
  • cancers include, but are not limited to: human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid cancers and lymphoid cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, gliomas, esophageal cancer, liver cancer (including hepatocarcinoma), lymphomas (including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma)
  • cancer refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer,
  • the above-mentioned inflammatory diseases include, but are not limited to: postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune Thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease,
  • musculoskeletal diseases include, but are not limited to, muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1 or myotonic dystrophy type 2), limb-girdle muscular dystrophy, multisystem proteinopathy, radiculopathy, X-linked recessive chondrodysplasia punctata, Connor-Schwitz syndrome (C onradi-Hünermann syndrome), autosomal dominant chondrodysplasia punctata, stress-induced bone disorders (e.g., stress-induced osteoporosis), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spin
  • muscular dystrophy
  • the above-mentioned metabolic diseases include, but are not limited to: non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (such as type 1 diabetes, type 2 diabetes or gestational diabetes), phenylketonuria, proliferative retinopathy or Kearns-Sayre disease.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • liver fibrosis obesity
  • heart disease atherosclerosis
  • arthritis cystinosis
  • diabetes such as type 1 diabetes, type 2 diabetes or gestational diabetes
  • phenylketonuria proliferative retinopathy
  • Kearns-Sayre disease Kearns-Sayre disease.
  • the above-mentioned mitochondrial diseases include, but are not limited to: Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Cohens-Sell syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), mitochondrial DNA deletion syndrome (MDDS, such as Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with fragmented red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON) and Pearson syndrome.
  • cPEO chronic progressive external ophthalmoplegia
  • KSS Cohens-Sell syndrome
  • Leigh syndrome e.g., MILS or maternally inherited Leigh syndrome
  • MDDS mitochondrial DNA deletion syndrome
  • the above-mentioned hearing loss diseases include, but are not limited to, mitochondrial non-syndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, inherited or genetic hearing loss, hearing loss experienced due to ototoxic exposure, hearing loss caused by disease, and hearing loss caused by trauma.
  • mitochondrial non-syndromic hearing loss and deafness is MT-RNR1-related hearing loss.
  • eye diseases include but are not limited to: cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy age-related macular degeneration (AMD), or diabetic retinopathy.
  • ER endoplasmic reticulum
  • AMD autophagy age-related macular degeneration
  • kidney diseases include, but are not limited to: Abderhalden-Kaufmann-Lignac syndrome (Y-pathogenic cystic acidosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure/acute kidney injury, acute lobar nephropathy, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenoviral nephritis, Alagille Syndrome, Alport Syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa nephropathy, vasoconstrictor peptide antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, glomerulonephritis associated with anti-TNF- ⁇ therapy, APOL1 mutation, apparent mineralocorticoid excess syndrome, a
  • the above skin diseases include, but are not limited to: acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic erythropoiesis, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), rash), extramammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infections of the nails, Hailey-Hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, dermatoderma melanogaster, mu
  • fibrotic diseases include, but are not limited to, adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scars, hepatitis C, hypertrophic cardiomyopathy, allergic pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloids, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, non-alcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, s
  • hemoglobin disorders include, but are not limited to, dominant ⁇ -thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS/ ⁇ -thalassemia, HbE/ ⁇ -thalassemia, HbSC disease, homozygous ⁇ +-thalassemia (phenotype of ⁇ 0-thalassemia), Hydrops fetalis with H b Bart's), sickle cell anemia/disease, sickle cell trait, sickle beta-thalassemia disease, alpha+-thalassemia, alpha0-thalassemia, alpha-thalassemia associated with myelodysplastic syndrome, alpha-thalassemia with mental retardation syndrome (ATR), beta0-thalassemia, beta+-thalassemia, delta-thalassemia, gamma-thalassemia, beta-thalassemia major, beta-thalassemia intermediate,
  • autoimmune diseases include, but are not limited to, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune scrotal inflammation, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Balódisease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, disease, CD), celiac disease, Chagas disease, chronic inflammatory demy
  • viral infections include, but are not limited to, influenza, human immunodeficiency virus (HIV), and herpes.
  • the above-mentioned malarial infections include, but are not limited to, infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium falciparum.
  • the above-mentioned diseases with mutations that lead to the induction of unfolded protein response include, but are not limited to: Marinesco-Sjogren syndrome, neuropathy pain, diabetic neuropathy pain, noise-induced hearing loss, non-syndromic sensorineural hearing loss, age-related hearing loss, Wolfram syndrome, Darier White disease, Usher syndrome, collagenosis, thin base nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid and pseudochondrodysplasia.
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that the hydrogen atom in a molecule is replaced by another different atom or group; or the lone pair of electrons in an atom in a molecule is replaced by another atom or group.
  • the lone pair of electrons on the S atom can be replaced by O Atomic substitution formation
  • C1-C6 alkyl indicates any alkyl group containing from “a” to "b” carbon atoms.
  • C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.
  • Alkyl refers to a saturated hydrocarbon chain with a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. For example, C1-C6 alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.
  • C1-C10 alkyl refers to any straight chain or branched group containing 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl and the following straight chain or branched alkyl groups: C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, etc.
  • C1-C10 alkyl includes a straight chain or branched chain group with any two integers between 1 and 10 as endpoints of the carbon number.
  • C1-C10 alkyl includes C1-C10 alkyl, C1-C8 alkyl, C1-C6 alkyl, C2-C10 alkyl, C2-C8 alkyl, C2-C6 alkyl, C6-C10 alkyl, etc.
  • the above list is only for example and is not a limitation of the above range.
  • alkoxy and its derivatives refer to any of the above alkyl groups (eg, C1-C10 alkyl, C1-C6 alkyl, etc.) that are attached to the rest of the molecule through an oxygen atom (-O-).
  • Alkylene refers to a divalent saturated aliphatic hydrocarbon radical having a specified number of member atoms.
  • C-C alkylene refers to an alkylene group having a to b carbon atoms.
  • Alkylene groups include branched and straight chain hydrocarbon groups.
  • the term "propylene” can be exemplified by the following structure:
  • the term "dimethylbutylene” can be exemplified, for example, by any of the following structures:
  • the C1-C4 alkylene group of the present invention may be a C1 alkylene group (eg, -CH 2 -), a C2 alkylene group (eg, -CH 2 CH 2 -, etc.), a C3 alkylene group or a C4 alkylene group.
  • cycloalkylene refers to a divalent saturated cyclic alkane having a single ring or multiple rings (condensed ring, spiro ring, bridged ring) with multiple carbon atoms and no ring heteroatoms.
  • monocarbocyclic groups include, for example, divalent cyclopropane, divalent cyclobutane, divalent cyclohexane, divalent cyclopentane, divalent cyclooctane, divalent cyclopentene and divalent cyclohexene.
  • bridged cycloalkane systems include bicyclo[3,1,0]hexane, bicyclo[3,1,1]hexane, bicyclo[2,2,1]hexane, bicyclo[2,2,2]hexane.
  • cycloalkylene described in the present invention includes but is not limited to wait.
  • C3-C10 cycloalkyl refers to a 3 to 10 membered all-carbon monocyclic, fused and bridged ring, which may contain 0, one or more double bonds, but does not have a completely conjugated ⁇ -electron system.
  • Examples of C3-C10 cycloalkyl are, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, and the like.
  • heterocycloalkyl refers to a single ring or multiple rings containing at least one heteroatom.
  • a univalent or bivalent saturated ring (a bivalent saturated ring of a heterocycloalkyl group is a heterocycloalkylene group) of a ring (a fused ring, a spiro ring, a bridged ring) is a saturated monocyclic ring or a bivalent saturated ring (a bivalent saturated ring of a heterocycloalkyl group is a heterocycloalkylene group); wherein a heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc.
  • heterocyclic groups may be oxetane, azetidinyl, oxolanyl, oxhexane, piperazinyl, piperidinyl, morpholinyl, trioxanyl, etc.
  • heterocycloalkyl described in the present invention include but are not limited to Or piperidinyl, etc.
  • the unsaturated mentioned in the present invention refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the groups or molecules.
  • aromatic ring refers to an aromatic hydrocarbon group having multiple carbon atoms.
  • Aryl is generally a monocyclic, bicyclic or tricyclic aromatic group having multiple carbon atoms.
  • aryl used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
  • the "5-10 membered heteroaryl" described in the present invention refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, and S. Preferably, there are one to three heteroatoms.
  • 5-6 membered heteroaryl represents, for example, pyridyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyranyl, thiopyranyl, piperazinyl, triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,2,3,4-tetrazolyl, 1,2,3,5-tetrazolyl, isoxazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-oxatriazolyl, 1,3,2-dioxazolyl 1,2,3-dioxazolyl, 1,2,3,4-dioxadiazolyl, 1,2,3,5-d
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halogen-substituted alkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen; for example, a halogen-substituted C1-4 alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.
  • the "-N(R) 2 " etc. mentioned in the present invention means that the R group is connected to the nitrogen atom by a single bond.
  • any group whose name is a composite name such as "6-10 membered aryl-D-C1-C6 alkyl"
  • stereoisomers refer to compounds with the same chemical structure but different spatial arrangements of atoms or groups, including enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
  • tautomers generally refer to structural isomers of different energies that can be mutually converted through a low energy barrier.
  • proton tautomers also known as proton shift
  • Prototropic tautomers include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations.
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • enantiomers refer to two isomers of a compound that are non-superimposable but mirror images of each other.
  • diastereomer refers to stereoisomers with two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical operations such as electrophoresis and chromatography, for example HPLC.
  • racemate refers to an equimolar mixture of two enantiomers lacking optical activity.
  • polymorph refers to a crystalline form of a compound (or its salt, hydrate or solvate) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may lead to one crystal form being dominant.
  • solvate in the present invention refers to a mixture produced by dissolving a compound in a solvent.
  • isotope-labeled compound refers to a molecule or group in which one or more atoms are replaced by their isotope atoms, such as hydrogen atoms replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature; or 12C replaced by 13C.
  • metabolites refer to substances generated by chemical structural transformation of drug molecules under the action of the body after the drug molecules are absorbed by the body.
  • prodrug refers to a compound that is obtained by chemically modifying a drug, is inactive or has low activity in vitro, and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its efficacy.
  • pharmaceutically acceptable means that a carrier, vehicle, diluent, excipient, and/or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.
  • salts and “pharmaceutically acceptable salts” refer to acidic and/or basic salts of the above compounds or their stereoisomers, formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compounds. They can also be obtained by mixing the above compounds, or their stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.
  • prevention includes inhibiting and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.
  • one or more compounds of the present invention may be used in combination with each other.
  • the compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be used together.
  • the drugs are administered to the subjects at the same time, separately or sequentially.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Bidex Pharmaceuticals, Leyan, Titan, Shaoyuan, Anaiji Chemical, Exploration Platform, Nanjing Yaoshi, Jiangsu Aikang, and Beijing Inokai Technology. Among them, tetrapropylammonium perruthenate was purchased from Exploration Platform, and 1-propylphosphoric acid cyclic anhydride was purchased from Beijing Inokai Technology Co., Ltd.
  • the reaction is carried out under a nitrogen atmosphere.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shift ( ⁇ ) is given in units of 10 -6 (ppm). NMR was measured using a (Bruker AvanceIII 400) nuclear magnetic spectrometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (Methanol-d 4 ), and the internal standard was tetramethylsilane (TMS).
  • LC-MS was measured using a Shimadzu LC-MS2020 (ESI) instrument. HPLC was measured using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
  • MPLC medium pressure preparative chromatography
  • Gilson GX-281 reverse phase preparative chromatograph used a Gilson GX-281 reverse phase preparative chromatograph.
  • the thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications used for thin layer chromatography separation and purification products were 0.4mm to 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • Dimethylformamide is abbreviated as DMF; N,N'-diisopropylethylamine (also known as diisopropylethylamine) is abbreviated as DIEA or DIPEA; 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is abbreviated as HATU; tetrapropylammonium perruthenate is abbreviated as TPAP; 1-propylphosphoric acid cyclic anhydride is abbreviated as T3P; N-methylmorpholine-N-oxide is abbreviated as NMO; trifluoroacetic acid is abbreviated as TFA. Tetrahydrofuran is abbreviated as THF.
  • compound 1a (BiDe Pharmaceuticals, catalog number: BD57204, 4.0g, 16.44mmol) and dimethylformamide (20.0mL), under stirring conditions, compound N, N'-thiocarbonyl diimidazole (4.1g, 23.02mmol) was added in sequence. After reacting at 25°C for 1 hour, the reaction temperature was raised to 100 degrees Celsius and stirred for 2 hours, then the reaction temperature was lowered to zero degrees Celsius and methyl iodide (2.33g, 16.44mmol) was added, and the reaction was completed by stirring at 25°C for 1 hour. 50mL of water was added to the resulting reaction solution, extracted with 50mL of ethyl acetate, and the extraction was repeated three times.
  • intermediate 1b (4.1 g, 13.71 mmol) and dichloromethane (20.0 mL) to a 100 mL single-mouth bottle, add compound m-chloroperbenzoic acid (4.2 g, 20.58 mmol) under ice bath and stirring conditions. After 16 hours of reaction at 25°C, the reaction is complete. Add saturated sodium bicarbonate aqueous solution to the resulting reaction solution to adjust the pH of the solution to about 8, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate the filtrate obtained after filtration under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography to obtain intermediate 1c. LC-MS: m/z: 275.9 (M+H-56) + .
  • compound 1d (BiDe Pharmaceuticals, item number: BD25596, 197 mg, 2.26 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL single-mouth bottle, and compound NaH (181 mg, 4.52 mmol) was added under stirring. After reacting at 25°C for 0.5 hours, intermediate 1c (500 mg, 1.51 mmol) was added, and the reaction was completed by stirring at 25°C for 16 hours.
  • intermediate 1e 270 mg, 0.80 mmol
  • dichloromethane 3.0 mL
  • trifluoroacetic acid 1.0 mL, 4.5 mmol
  • intermediate 1f 140 mg, 0.59 mmol
  • glacial acetic acid 3.5 mL
  • water 1.5 mL
  • sodium nitrite 121 mg, 1.75 mmol
  • LC-MS m/z: 268.0 (M+H) + .
  • intermediate 2f 26 mg, 0.06 mmol
  • dimethylformamide 3.0 mL
  • cesium carbonate 55 mg, 0.17 mmol
  • p-toluenesulfonyl chloride 22 mg, 0.11 mmol
  • the reaction was completed after 3 hours at 25°C.
  • 35 mL of water was added to the reaction solution, and 35 mL of ethyl acetate was used for extraction.
  • the organic phase was washed with 100 mL of saturated brine and dried over sodium sulfate.
  • the filtrate was filtered and concentrated under reduced pressure to obtain a crude product.
  • intermediate 21a (3.8 g, 13.29 mmol) and 1,2-dichloroethane (30.0 mL) were added to a 100 mL single-mouth bottle, and compound N,N'-carbonyldiimidazole (5.0 g, 26.58 mmol) was added in sequence under stirring.
  • the reaction was completed after 18 hours at 25°C.
  • 25 mL of water was added to the resulting reaction solution, the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by column chromatography to obtain intermediate 21c.
  • intermediate 21c (2.9 g, 9.26 mmol) and dimethylformamide (30 mL) were added to a 100 mL single-mouth bottle, and 3-(trifluoromethoxy)-azetidine (1.73 g, 12.28 mmol), diisopropylethylamine (6.65 g, 51.18 mmol) and Carter condensation agent (6.45 g, 15.53 mmol) were added in sequence under stirring. After sixteen hours of reaction at 25°C, the reaction was completed.
  • intermediate 21d 140 mg, 0.34 mmol
  • dichloromethane 6.0 mL
  • trifluoroacetic acid 2.0 mL, 4.5 mmol
  • compound 21f (BiDe Pharmaceuticals, product number: BD11064, 6 mg, 0.03 mmol) and intermediate 21b (5.1 mg, 0.02 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (4.048 mg, 0.04 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15.21 mg, 0.03 mmol) were added in sequence under stirring. The reaction was stirred at 25°C for 10 hours and ended. 20 mL of water was added to the reaction solution, and the mixture was extracted with 20 mL of ethyl acetate.
  • compound 22a (BiDe Pharmaceuticals, product number: BD21790, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was completed by stirring at 25°C for 10 hours. 20 mL of water was added to the reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 22.
  • compound 23a (BiDe Pharmaceuticals, item number: BD21634, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • compound 24a (Bi De Pharmaceutical, item number: BD45137, 25.5 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • intermediate 25b 60 mg, 0.23 mmol
  • dichloromethane 0.5 mL
  • trifluoroacetic acid 0.5 mL, 6.71 mmol
  • intermediate 25c (30.69 mg, 0.15 mmol) and intermediate Compound 21b (30 mg, 0.1 mmol) was dissolved in dimethylformamide (1.5 mL), and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the reaction solution, and the mixture was extracted with 20 mL of ethyl acetate.
  • intermediate 26b 200 mg, 0.62 mmol
  • dichloromethane 2 mL
  • trifluoroacetic acid 2 mL, 26.84 mmol
  • intermediate 26c 39.82 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • compound 27a (Leyan, 33.16 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was completed by stirring at 25°C for 10 hours. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • compound 28a (Bi De Pharmaceutical, item number: BD81648, 33.16 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • compound 29a (Bi De Pharmaceutical, product number BD75182, 25.5 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • intermediate 30b 200 mg, 0.82 mmol
  • dichloromethane 2 mL
  • trifluoroacetic acid 2 mL, 26.84 mmol
  • intermediate 30c 28.22 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • intermediate 31b 200 mg, 0.77 mmol
  • dichloromethane 2 mL
  • trifluoroacetic acid 2 mL, 26.84 mmol
  • intermediate 31c (30.69 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL), and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring.
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 31.
  • compound 32a (BiDe Pharmaceuticals, product number: BD65476, 33.16 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was completed by stirring at 25°C for 10 hours.
  • intermediate 33b 160 mg, 0.61 mmol
  • dichloromethane 1.5 mL
  • trifluoroacetic acid 0.5 mL, 6.71 mmol
  • intermediate 33c (30.69 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL), and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring.
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 33.
  • intermediate 34b (170 mg, 0.69 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-mouth bottle, and trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. After 1 hour at 25°C, the reaction was completed. The mixture was concentrated under reduced pressure to obtain intermediate 34c.
  • intermediate 34c 28.22 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 34.
  • intermediate 35b 50 mg, 0.20 mmol
  • dichloromethane 1.5 mL
  • trifluoroacetic acid 0.5 mL, 6.71 mmol
  • intermediate 35c 28.29 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 35.
  • compound 36a (Bi De Pharmaceutical, item number: BD11470, 29.5 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • compound 38a (BiDe Pharmaceuticals, product number: BD38284, 32.05 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was completed by stirring at 25°C for 10 hours.
  • compound 41a (Bi De Pharmaceutical, item number: BD260228, 21.98 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • compound 42a 21.47 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 42.
  • compound 44a (Bi De Pharmaceutical, item number: BD334736, 31.14 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and the reaction was completed.
  • compound 45a (Bi De Pharmaceutical, item number: BD232348, 26.12 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and the reaction was completed.
  • compound 46a (BiDe Pharmaceuticals, product number: BD160922, 26.73 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred at 25°C for 10 hours and the reaction was completed.
  • compound 47a (Bidec Pharmaceuticals, product number: BD9715, 0.4 g, 1.76 mmol), Rockphos-pd-G 3 (22.15 mg, 0.02 mmol) and cesium carbonate (1.7 g, 5.27 mmol) were added to a 50 mL three-necked flask, followed by dimethylformamide (4.0 mL) and water (0.15 mL). After nitrogen protection, the temperature was raised to 85°C and the reaction was continued for 5 hours. The crude reaction solution (containing intermediate 47b) was directly used in the next step without purification, LC-MS: m/z: 163.0 (MH) - .
  • tert-butyl bromoacetate 889 mg, 4.56 mmol was added to the reaction solution obtained in the previous step (containing intermediate 47b). The reaction was completed after 2 hours at 25°C. 5 mL of water and 15 mL of ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine (40 mL ⁇ 3), dried over sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 47c (80 mg, 0.28 mmol). LC-MS: m/z: 277.0 (M-H).
  • intermediate 47c 80 mg, 0.28 mmol
  • dichloromethane 1.0 mL
  • trifluoroacetic acid 0.3 mL, 4.03 mmol
  • intermediate 47d 33 mg, 0.1 mmol
  • intermediate 21b were mixed in an 8 mL reaction bottle.
  • (30 mg, 0.1 mmol) was dissolved in dimethylformamide (1.5 mL), and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring.
  • the reaction was stirred at 25 ° C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and 20 mL of ethyl acetate was used for extraction.
  • compound 48a (BiDe Pharmaceuticals, product number: BD297147, 0.8 g, 3.52 mmol), Rockphos-pd-G3 (44.29 mg, 0.05 mmol) and cesium carbonate (3.4 g, 10.55 mmol) were added to a 50 mL three-necked flask, and then dimethylformamide (8.0 mL) and water (0.3 mL) were added. After nitrogen protection, the temperature was raised to 85 degrees Celsius and the reaction was completed for 5 hours. The resulting reaction solution (containing intermediate 48b) was directly used in the next step without purification, LC-MS: m/z: 163.0 (MH) - .
  • tert-butyl bromoacetate 889 mg, 4.56 mmol was added to the reaction solution obtained in the previous step (containing intermediate 48b). After reacting at 25°C for 2 hours, the reaction was completed. 5 mL of water and 15 mL of ethyl acetate were added to the reaction solution, and the organic phase was washed with 40 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 48c.
  • intermediate 48c 200 mg, 0.72 mmol
  • dichloromethane 2.0 mL
  • trifluoroacetic acid 2.0 mL, 26.84 mmol
  • intermediate 48d 22.26 mg, 0.1 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was completed by stirring at 25°C for 10 hours. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • tert-butyl bromoacetate (727.47 mg, 3.73 mmol) was added to the reaction solution obtained in the previous step (containing intermediate 49b). After reacting at 25°C for 2 hours, the reaction was completed. 5 mL of water and 15 mL of ethyl acetate were added to the reaction solution, and the organic phase was washed with 40 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 49c.
  • intermediate 49c 200 mg, 0.68 mmol
  • dichloromethane 2.0 mL
  • trifluoroacetic acid 2.0 mL, 26.84 mmol
  • intermediate 49d (23.9 mg, 0.1 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL), and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring.
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the obtained reaction solution, and it was extracted with 20 mL of ethyl acetate.
  • compound 50a (BiDe Pharmaceuticals, product number: BD322259, 0.4 g, 1.76 mmol), Rockphos-pd-G3 (22.15 mg, 0.02 mmol) and cesium carbonate (1.7 g, 5.27 mmol) were added to a 50 mL three-necked flask, and then dimethylformamide (4.0 mL) and water (0.15 mL) were added. After nitrogen protection, the temperature was raised to 85 degrees Celsius and the reaction was completed for 5 hours. The resulting reaction solution (containing intermediate 50b) was directly used in the next step without purification, LC-MS: m/z: 163.0 (MH) - .
  • tert-butyl bromoacetate 889 mg, 4.56 mmol was added to the reaction solution obtained in the previous step (containing intermediate 50b). After reacting at 25°C for 2 hours, the reaction was completed. 5 mL of water and 15 mL of ethyl acetate were added to the obtained reaction solution, and the obtained organic phase was washed with 40 mL of saturated brine and dried over sodium sulfate. The filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 50c. LC-MS: m/z: 279.2 (M+H) + .
  • intermediate 50c (220 mg, 0.79 mmol) and dichloromethane (2.0 mL) were added to a 25 mL single-mouth bottle, and trifluoroacetic acid (2.0 mL, 26.84 mmol) was added under stirring. After reacting at 25°C for 1 hour, the reaction was completed. The mixture was concentrated under reduced pressure to obtain intermediate 50d.
  • intermediate 50d 33.15 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 15 mL of water was added to the obtained reaction solution, and 15 mL of ethyl acetate was used to extract.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried over sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 50.
  • compound 52a (Titan, 0.2 g, 1.15 mmol), tert-butyl bromoacetate (0.25 g, 1.27 mmol) and potassium carbonate (0.317 g, 9.84 mmol) were added to an 8 mL reaction tube, and then acetonitrile (2.0 mL) was added. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was spin-dried, and the crude product was purified by column chromatography to obtain intermediate 52b. LC-MS: m/z: 288.0 (M+H) + .
  • intermediate 52c 177 mg, 0.76 mmol
  • N,N-dimethylformamide 2.0 mL
  • intermediate 21b 60 mg, 0.196 mmol
  • the resulting reaction solution was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain intermediate 52d.
  • LC-MS m/z: 520.1 (M+H).
  • the intermediate 52d (20 mg, 0.038 mmol) was dissolved in methanol (1.5 mL) and water (0.5 mL), and iron powder (11 mg, 0.19 mmol) and ammonium chloride (10.29 mg, 0.19 mmol) were added in sequence under stirring.
  • the reaction was completed by stirring at 70°C for 1 hour.
  • the resulting reaction solution was filtered while hot, and the filtrate was dried to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 52.
  • compound 53a (Biode Pharmaceuticals, catalog number: BD222433, 100 mg, 0.45 mmol), tert-butyl bromoacetate (85.45 mg, 0.65 mmol), cesium carbonate (421.3 mg, 1.3 mmol) and methanesulfonyl (2-(di-tert-butylphosphino)-3-methoxy-6-methyl, 2,4,6-triisopropyl-1,1-biphenyl) (2-amino-1,1-biphenyl-2-yl) palladium (II) (7 mg, 0.009 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction was completed at 95 ° C overnight.
  • intermediate 53b (90 mg, 0.32 mmol) and dichloromethane (1 mL) were added to a 25 mL single-mouth bottle, and trifluoroacetic acid (1 mL, 13.42 mmol) was added under stirring. After 1 hour at 25°C, the reaction was complete. The mixture was concentrated under reduced pressure to obtain intermediate 53c.
  • intermediate 53c 34.07 mg, 0.15 mmol
  • intermediate 21b 30 mg, 0.1 mmol
  • triethylamine 40.48 mg, 0.4 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 57.03 mg, 0.15 mmol
  • the reaction was stirred at 25°C for 10 hours and the reaction was completed. 15 mL of water was added to the obtained reaction solution, and it was extracted with 15 mL of ethyl acetate.
  • the obtained organic phase was washed with 20 mL of saturated brine and dried with sodium sulfate.
  • the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 53.
  • compound 6a (BiDe Pharmaceuticals, product number: BD00841787, 1.50 g, 7.75 mmol) and dimethylformamide (30 mL) were added to a 50 mL single-mouth bottle, and compound 1i (1.58 g, 7.75 mmol), diisopropylethylamine (5.13 mL, 30.98 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.42 g, 11.62 mmol) were added in sequence under stirring. The reaction was completed after 18 hours at 25°C.
  • intermediate 6d 100 mg, 0.27 mmol
  • dimethylformamide 4 mL
  • diisopropylethylamine (0.18 mL, 1.08 mmol
  • 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate 179.41 mg, 0.41 mmol
  • compound 6f 71.50 mg, 0.40 mmol
  • the reaction was completed after 18 hours at 25°C.
  • the reaction solution was poured into 20 mL of water, and then extracted with 30 mL of ethyl acetate, and extracted twice in total.
  • the obtained organic phase was washed with 10 mL of saturated brine, dried with sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 6.
  • intermediate 11b 200 mg, 0.42 mmol
  • dioxane hydrochloride 5 mL
  • intermediate 6d 50 mg, 0.14 mmol
  • dimethylformamide (2 mL) 50 mg, 0.14 mmol
  • diisopropylethylamine 0.09 mL, 0.54 mmol
  • 1H-benzene Triazole-1-yloxytripyrrolidino hexafluorophosphate 89.71 mg, 0.20 mmol
  • intermediate 11c 28.22 mg, 0.20 mmol
  • the reaction was completed after 18 hours at 25°C.
  • the resulting reaction solution was poured into 20 mL of water, and then extracted with 30 mL of ethyl acetate each time, for a total of two extractions.
  • intermediate 6d 50 mg, 0.14 mmol
  • dimethylformamide (2 mL) 50 mg, 0.14 mmol
  • diisopropylethylamine 0.09 mL, 0.54 mmol
  • 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate 89.71 mg, 0.20 mmol
  • compound 14a Ba De Pharmaceutical, item number: BD00841787, 71.61 mg, 0.41 mmol
  • the resulting reaction solution was poured into 20 mL of water, and then extracted with 30 mL of ethyl acetate each time, for a total of two extractions.
  • the resulting organic phase was washed with 10 mL of saturated brine, dried with sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated by high-performance liquid chromatography (trifluoroacetic acid/acetonitrile/water system) to obtain compound 14.
  • intermediate 4b (5.023 g, 20.91 mmol), tetrahydrofuran (60 mL), methanol (15 mL) to a 250 mL single-mouth bottle, and then add LiOH (400 mg, 16.73 mmol) in water (15 mL). After stirring at 25°C for 16 hours, the reaction is complete. Concentrate under reduced pressure to remove tetrahydrofuran, add 2 mol/L HCl to adjust the pH to 2-3, solid precipitates, and filter the filter cake to obtain intermediate 4c.
  • intermediate 4c (2.15 g, 9.5 mmol) and tert-butyl alcohol (30 mL) were added to a 100 mL single-mouth bottle, followed by pyridine (5.37 mL, 66.53 mmol), DMAP (1.16 g, 9.5 mmol) and (Boc) 2 O (4.07 mL, 19.01 mmol).
  • the reaction was completed after stirring at 35°C for 16 hours. After concentration under reduced pressure, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3). The organic layers were combined, washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • intermediate 4d (1.204 g, 4.26 mmol), tetrahydrofuran (20 mL), methanol (5 mL) were added to a 100 mL single-necked bottle, and an aqueous solution (4 mL) of lithium hydroxide (100 mg, 4.26 mmol) was added.
  • the reaction was completed after stirring at 25°C for 16 hours.
  • the tetrahydrofuran was removed by concentration under reduced pressure, and 2M HCl was added to adjust the pH to 2-3, solid precipitated, and the filter cake was filtered to obtain intermediate 4e.
  • intermediate 4f 890 mg, 2.38 mmol
  • tetrahydrofuran 20 mL
  • palladium hydroxide 297.79 mg, 2.12 mmol
  • the hydrogen gas was replaced three times, and the reaction was completed after stirring at 25°C for 16 hours.
  • the filtrate was filtered and concentrated under reduced pressure to obtain intermediate 4g.
  • intermediate 4i 260 mg, 0.61 mmol
  • dichloromethane 5 mL
  • trifluoroacetic acid 5 mL
  • intermediate 4j 225.7 mg, 0.61 mmol
  • dimethylformamide 5 mL
  • tert-butyl carbazate (0.09 mL, 0.73 mmol
  • 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.02 mg, 1.22 mmol)
  • 1-hydroxybenzotriazole (315.54 mg, 2.44 mmol)
  • N,N-diisopropylethylamine (0.21 mL, 1.22 mmol
  • intermediate 4k (296 mg, 0.61 mmol) and dichloromethane (3 mL) were added to a 25 mL single-necked bottle, and 4 M dioxane hydrochloride (3 mL) was added under stirring. After stirring at 25°C for 1 hour, the reaction was completed. The solvent was removed by concentration under reduced pressure to obtain intermediate 4l.
  • the intermediate 41 obtained in the previous step and tetrahydrofuran (2 mL) were added to a 10 mL single-mouth bottle, and N, N-diisopropylethylamine (0.09 mL, 0.57 mmol) and thiocarbonyldiimidazole (61.29 mg, 0.34 mmol) were added under stirring.
  • the mixture was stirred at 25°C for 16 hours, and then stirred at 70°C for 3 hours to complete the reaction.
  • Water (3 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (5 ml ⁇ 3).
  • intermediate 4o 44 mg, 0.09 mmol
  • dimethylformamide 1 mL
  • compound 4p 65.78 mg, 0.47 mmol
  • potassium carbonate 90.20 mg, 0.65 mmol
  • the reaction was completed after stirring at 25°C for 4 hours.
  • Water (2 mL) was added to the reaction mixture, and ethyl acetate (5 mL ⁇ 3) was used for extraction.
  • the organic layers were combined and washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated.
  • intermediate 10c (1.6 g, 4.33 mmol) and ethanol (15 mL) were added to a 100 mL single-mouth bottle, and 50% hydrazine hydrate (3.61 g, 43.3 mmol) was added under stirring, and the temperature was raised to 80 degrees Celsius overnight to complete the reaction.
  • the crude product was concentrated under reduced pressure.
  • the crude product was purified by recrystallization using acetonitrile solvent to obtain intermediate 10d.
  • intermediate 10d (616 mg, 1.67 mmol) and 1,2-dichloroethane (5 mL) to a 100 mL single-mouth bottle, and add compound N,N'-carbonyldiimidazole (350 mg, 2.16 mmol) in sequence under stirring.
  • the reaction is completed after 18 hours at 25 degrees Celsius.
  • the crude product is purified by column chromatography to obtain intermediate 10e.
  • intermediate 8b 100 mg, 0.43 mmol
  • dichloromethane 1 mL
  • trifluoroacetic acid 0.3 mL, 4.03 mmol
  • intermediate 10e (30 mg, 0.08 mmol) and dimethylformamide (1 mL) were added to a 50 mL single-mouth bottle, and intermediate 8c (20.18 mg, 0.15 mmol), carter condensation agent (67.0 mg, 0.15 mmol) and diisopropylethylamine (0.08 mL, 0.45 mmol) were added in sequence under stirring.
  • the reaction was completed after 16 hours at 25 degrees Celsius.
  • the reaction solution was filtered and sent to the preparation, and the crude product was finally obtained by high performance liquid chromatography (formic acid/acetonitrile/water system).
  • LC-MS m/z: 511.0 (M+H) + .
  • intermediate 9b 200 mg, 1.50 mmol
  • sodium bicarbonate 378.62 mg, 4.51 mmol
  • tetrahydrofuran 20 mL
  • water 10 mL
  • benzyl chloroformate (0.32 mL, 2.25 mmol) dropwise under stirring.
  • the reaction is completed after 16 hours at 25 degrees Celsius.
  • the resulting reaction solution is poured into 100 mL of water, and then extracted twice with 200 mL of ethyl acetate each time.
  • the resulting organic phase is washed with 100 mL of saturated brine, dried with sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 9c.
  • LC-MS m/z: 268.0 (M+H) + .
  • intermediate 9c 100 mg, 0.37 mmol
  • 1 mol/L hydrochloric acid 2 mL
  • methanol 10 mL
  • 10% palladium carbon 39.82 mg, 0.37 mmol
  • the intermediate 9d is filtered and concentrated under reduced pressure.
  • LC-MS m/z: 134.0 (M+H) + .
  • intermediate 9d 15.98 mg, 0.12 mmol
  • intermediate 10e (30 mg, 0.08 mmol)
  • dimethylformamide (4 mL)
  • diisopropylethylamine 0.05 mL, 0.30 mmol
  • Carter condensation agent 50.28 mg, 0.11 mmol
  • the reaction was completed after 18 hours at 25 degrees Celsius.
  • the resulting reaction solution was poured into 20 mL of water, and then extracted twice with 30 mL of ethyl acetate each time.
  • compound 15a (BiDe Pharmaceuticals, item number: BD17826, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • 16a (BiDe Pharmaceuticals, product number: BD263092, 800 mg, 3.26 mmol) and anhydrous tetrahydrofuran (8 mL) were added to a 100 mL single-mouth bottle, and the compound N, N'-thiocarbonyldiimidazole (821 mg, 4.89 mmol) was added under stirring.
  • the reaction was stirred at 25°C for 16 hours, and then hydrazine hydrate (1.92 g, 32.6 mmol) was added and reacted for half an hour.
  • the crude product was concentrated under reduced pressure.
  • the crude product was recrystallized from acetonitrile to obtain intermediate 16b.
  • intermediate 16b 710 mg, 2.46 mmol
  • 1,2-dichloroethane (10.0 mL)
  • compound N,N'-carbonyldiimidazole 887 mg, 5.46 mmol
  • the reaction is complete.
  • the organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by column chromatography to obtain intermediate 16c.
  • intermediate 16c (680 mg, 2.03 mmol) and dimethylformamide (10 mL) were added to a 100 mL single-mouth bottle, and compound 3-(trifluoromethoxy)-azetidine (336 mg, 2.38 mmol), diisopropylethylamine (1.2 g, 9.53 mmol) and Carter condensation agent (1.6 g, 3.6 mmol) were added in sequence under stirring.
  • the reaction was completed after sixteen hours of reaction. 100 mL of water was added to the obtained reaction solution, and it was extracted with 100 mL of ethyl acetate.
  • intermediate 16d 70 mg, 0.17 mmol
  • dichloromethane 5.0 mL
  • trifluoroacetic acid 2.0 mL, 4.5 mmol
  • compound 17a (BiDe Pharmaceuticals, item number: BD01523901, 76 mg, 0.35 mmol) and intermediate 21b (90 mg, 0.22 mmol) were dissolved in dimethylformamide (5.0 mL) in an 8 mL reaction bottle, and triethylamine (101.0 mg, 0.95 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (167 mg, 0.47 mmol) were added in sequence under stirring. The reaction was stirred for 10 hours at 25°C and ended.
  • compound 18a (BiDe Pharmaceuticals, product number: BD00971063, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle, and triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added in sequence under stirring. The reaction was completed by stirring at 25°C for 10 hours.
  • intermediate 1c 1000 mg, 3.02 mmol
  • 3-(trifluoromethoxy)-azetidine (1277.25 mg, 9.06 mmol)
  • potassium carbonate 2085.15 mg, 15.1 mmol
  • N,N-dimethylformamide (20 mL)
  • Add 50 ml of water to the reaction solution extract three times with 50 ml of ethyl acetate, wash the combined organic layer with 50 ml of saturated brine, dry with sodium sulfate, filter and concentrate.
  • intermediate 7a (1100 mg, 2.80 mmol) and dichloromethane (3 mL) to a single-mouth bottle, add dioxane hydrochloride solution (4 M) (3 mL) under ice bath, and stir at room temperature for 2 hours.
  • the reaction solution is directly concentrated to obtain intermediate 7b.
  • 51a (Shaoyuan, 800 mg, 4.32 mmol) and 1,4-dioxane (2.0 mL) were added to a single-mouth bottle, and a hydrochloric acid/dioxane solution (4 M, 6.0 mL) was added under stirring, and the mixture was reacted at room temperature for 18 hours.
  • the reaction solution was concentrated under reduced pressure to obtain intermediate 51b.
  • intermediate 51b 350 mg, 4.11 mmol
  • dimethylformamide 8.0 mL
  • compound benzyl chloroformate (1.08 g, 6.34 mmol) and potassium carbonate (2.34 g, 16.92 mmol) were added in sequence under stirring, and stirred at room temperature for 18 hours.
  • 50 mL of water was added to the reaction solution, and it was extracted once with 50 mL of ethyl acetate.
  • the organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Step 4 Preparation of intermediates 51ea and 51eb
  • intermediate 51d 300 mg, 1.36 mmol
  • ethyl acetate 20 mL
  • intermediate 51ea 60 mg, 0.21 mmol
  • anhydrous methanol 5.0 mL
  • palladium carbon 12 mg
  • 2 drops of concentrated hydrochloric acid were added successively under stirring.
  • the reaction was carried out at room temperature under a hydrogen atmosphere for 16 hours.
  • the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 51-1a.
  • intermediate 51-1a (30 mg, 0.18 mmol) and dimethylformamide (5.0 mL) to a single-mouth bottle
  • Carter condensation agent 125 mg, 0.27 mmol
  • diisopropylethylamine 70 mg, 0.54 mmol
  • intermediate 6d 70 mg, 0.18 mmol
  • intermediate 51eb 70 mg, 0.24 mmol
  • anhydrous methanol 5.0 mL
  • palladium carbon (12 mg) and 2 drops of concentrated hydrochloric acid were added successively under stirring.
  • the reaction was carried out at room temperature under a hydrogen atmosphere for 16 hours.
  • the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 51-2a.
  • intermediate 51-2a 32 mg, 0.20 mmol
  • dimethylformamide 5.0 mL
  • Carter condensation agent 149 mg, 0.34 mmol
  • Diisopropylethylamine 88 mg, 0.68 mmol
  • intermediate 6d 83 mg, 0.22 mmol
  • 25 mL of water was added to the reaction solution, and 30 mL of ethyl acetate was used for extraction three times.
  • the combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • intermediate 90b (4.50 g, 16.52 mmol) and ethanol (40.0 mL) were added to a single-mouth bottle, and hydrazine hydrate (9.73 g, 165.16 mmol) was added at room temperature, and the mixture was reacted at 85 degrees Celsius for 18 hours.
  • the reaction solution was concentrated under reduced pressure to obtain intermediate 90c.
  • intermediate 90f (480 mg, 1.56 mmol) and N,N-dimethylformamide (6.0 mL) to a single-mouth bottle, add sodium hydride (125 mg, 3.12 mmol) and tert-butyl bromoacetate (456 mg, 2.34 mmol) under stirring, and react at 60 degrees Celsius for 18 hours.
  • compound 86a (Nanjing Yaoshi, 470 mg, 1.72 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-mouth bottle, and imidazole (334 mg, 4.91 mmol) and tert-butyldimethylsilyl chloride (370 mg, 2.45 mmol) were added under stirring, and the reaction was carried out at room temperature for 18 hours. 50 mL of water was added to the reaction solution, and it was extracted twice with 50 mL of ethyl acetate.
  • intermediate 86b (570 mg, 1.47 mmol) and ethanol (10.0 mL) were added to a single-mouth bottle, and hydrazine hydrate (836 mg, 14.19 mmol) was added at room temperature, and the mixture was reacted at 80°C for 18 hours.
  • the reaction solution was concentrated under reduced pressure to obtain white solid intermediate 86c, LC-MS: m/z: 410.2 (M+Na)+.
  • intermediate 86c (520 mg, 1.34 mmol) and 1,2-dichloroethane (10.0 mL) were added to a single-mouth bottle, and triethylamine (0.56 mL, 4.02 mmol) and N,N'-carbonyldiimidazole (326 mg, 2.01 mmol) were added under stirring, and the reaction was carried out at room temperature for 18 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • intermediate 86d (470 mg, 1.14 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-mouth bottle, and N,N-diisopropylethylamine (589 mg, 4.56 mmol), 3-(trifluoromethoxy)-azetidine (176 mg, 1.25 mmol) and Carter condensation agent (603 mg, 1.36 mmol) were added under stirring, and the reaction was carried out at room temperature for 18 hours. The reaction solution was poured into 50 mL of water and extracted with 50 mL of ethyl acetate. The reaction was repeated three times, and the organic phases were combined and dried over anhydrous sodium sulfate.
  • intermediate 86e 100 mg, 0.19 mmol
  • dichloromethane 2.0 mL
  • trifluoroacetic acid 0.5 mL
  • intermediate 86f (82 mg, 0.19 mmol) and N,N-dimethylformamide (2.0 mL) were added to a single-mouth bottle, and N,N-diisopropylethylamine (98 mg, 0.76 mmol), compound 1i (42 mg, 0.14 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (119 mg, 0.23 mmol) were added under stirring, and the reaction was carried out at room temperature for 18 hours.
  • reaction solution was poured into 30 mL of water, extracted three times with 30 mL of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • intermediate 86g (117mg, 0.19mmol) and tetrahydrofuran (2.0mL) were added to a single-mouth bottle, and tetrabutylammonium fluoride (0.38mL, 0.38mmol, 1M) was added under stirring, and the reaction was carried out at room temperature for 3 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product, which was prepared by high performance liquid chromatography (formic acid/acetonitrile/water system) to obtain compound 86.
  • the ATF4 luciferase reporter plasmid consists of two parts, the 5' untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the 5' untranslated region sequence of ATF4 containing two upstream open reading frames (uORFs) (NCBI database number BC022088.2) and the firefly luciferase coding gene were cloned into the pLVX-Puro vector (Ubao Bio, VT1465).
  • the packaging plasmids of the lentivirus are psPAX2 (Ubao Bio, VT1444) and pMD2.G (Ubao Bio, VT1443).
  • the above three plasmids were transfected simultaneously in HEK293T/17 cells with X-tremeGENE 9 DNA transfection reagent, and the culture medium containing the lentivirus was collected after 48 hours.
  • the virus-transduced HEK293T/17 cells were screened with 1 ⁇ g/mL of puromycin, and then monoclonal cells were obtained by limiting dilution.
  • the translational regulation of ATF4 can be detected and the activity of eIF2B activators can be tested by cold fluorescence readings.
  • the specific experimental process is as follows: 6000 HEK293T/17-ATF4uORF-Luc-Puro monoclonal cells are plated in a 384-well plate and allowed to adhere overnight. The test compound is dissolved in DMSO and added to the cell culture medium together with 50nM thapsigargin and incubated for 6 hours. Among them, the role of thapsigargin is to cause cell stress and upregulate the protein translation of ATF4. After 6 hours of drug addition, the cells were lysed using the One-Glo Luciferase Assay Kit (Promega #E6120), and the cold fluorescence value was then read using the LUM program of the EnVision 2104 plate reader.
  • ATF4 reporter expression The relative expression of ATF4 reporter gene (ATF4 reporter expression%) was calculated as follows:
  • ATF4 reporter expression% (ave_sample-ave_vc)/(ave_pc-ave_vc)*100%.
  • ave_vc average signal value of negative control
  • ave_pc average signal value of positive control
  • ave_sample average signal value of the sample
  • X-axis log value of compound concentration
  • Y-axis relative expression level of ATF4 reporter gene
  • Top estimated asymptote on the curve
  • Bottom estimated asymptote under the curve
  • Hillslope slope of the fitting curve.
  • the experimental results show that the compounds of the present application can enhance/activate eIF2B activity and reduce the expression of ATF4, thereby reducing the fluorescence intensity, indicating that the compounds of the present application can significantly relieve the cell stress caused by thapsigargin, weaken the integrated stress response of the cell, and make the intracellular protein tend to be synthesized normally, and are eIF2B agonists.
  • Most of the compounds of the present application have an EC 50 value of ⁇ 100nM for HEK293T/17 cells, many compounds have an EC 50 value of between 10nM and 100nM for HEK293T/17 cells, and many compounds have an EC 50 value of less than 10nM for HEK293T/17 cells.
  • Some preferred compounds have an EC 50 value of ⁇ 1nM for HEK293T/17 cells, and the most preferred compound has an EC 50 value of less than 10pM for HEK293T/17 cells.
  • Preheat 100 mM K-Mg-buffer containing 5 mM MgCl2 Prepare the spike solution by adding 5 ⁇ L of 10 mM compound and reference stock solutions to 95 ⁇ L of acetonitrile (ACN). Add 1.5 ⁇ L of 500 ⁇ M spike solution and 18.75 ⁇ L of 20 mg/mL liver microsomes to 479.8 ⁇ L of K-Mg buffer. NADPH stock solution (3 mM) is prepared by dissolving NADPH in K-Mg buffer. At different time points (0, 5, 15, 30 and 45 min), 30 ⁇ L of the 1.5 ⁇ M spike solution containing microsomes is evenly dropped into the assay plate. Preincubate at 37 °C for 5 min.
  • test compounds were diluted from a 10 mM stock solution to a concentration of 10 ⁇ M in transport buffer (HBSS + BSA) and applied to the apical or basolateral side of the cell monolayer.
  • transport buffer HBSS + BSA
  • the permeability of the test compounds from A to B or B to A was determined duplex after 120 min incubation at 37°C, 5% CO 2 and 95% relative humidity.
  • the efflux ratio of each compound was determined.
  • the analyte and reference were quantitatively analyzed by LC-MS/MS based on the analyte/IS peak area ratio.
  • quench the reaction by adding 400 ⁇ L of quenching solution (cold ACN containing 500 nM tolbutamine and 10 nM terfenadine). Centrifuge at 3220 g for 50 min at 4°C. Transfer 100 ⁇ L of supernatant to a new plate. Dilute the supernatant with 100 ⁇ L of purified water. Mix well and analyze the samples by UPLC-MS/MS.
  • quenching solution cold ACN containing 500 nM tolbutamine and 10 nM terfenadine.
  • the experimental results show that at least some of the compounds of the present application have weak inhibition on five major P450 enzymes (CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4), and the risk of drug-drug interactions is low.
  • the IC50 values of compound 6 for these five major P450 enzymes are basically >10 ⁇ M, especially the IC50 values of CYP2D6 and CYP3A4 are both greater than >30 ⁇ M.
  • mice in each group were given 1 mg/kg via the tail vein and 10 mg/kg orally (PO).
  • Blood was collected at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after intravenous administration, and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after oral administration.
  • Plasma samples were centrifuged and the supernatant was prepared for quantitative analysis by LC/MS/MS.
  • mice have excellent pharmacokinetic properties in mice (including but not limited to Cl (clearance rate), T 1/2 (half-life), C max (peak concentration), AUC (area under the drug-time curve), F (bioavailability), etc.).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本申请提供了一种式（0）所示的化合物、包含其的药物组合物及其合成方法和用途。本申请的化合物能明显减弱细胞的整合应激反应（ISR），激活eIF2B活性，使得细胞内蛋白质趋于正常合成，并为整合应激反应（ISR）路径介导的疾病或病症eIF2B相关疾病，和/或为与eIF2B活性或水平、eIF2通路或ISR通路的活性或水平的调节有关的疾病提供更多的可能药物。

Description

一种化合物、包含其的药物组合物及其合成方法和用途
相关申请的交叉引用
本申请文件要求享有申请日为2022年11月21日的中国发明专利申请202211455519.X和申请日为2023年6月19日的中国发明专利申请202310731972.7的优先权，并将它们的全部内容以援引的形式整体并入本申请。
技术领域
本发明涉及一种化合物、包含其的药物组合物及其合成方法和用途。
背景技术
肌萎缩侧索硬化(Amyotrophic Lateral Sclerosis,ALS)也叫运动神经元病(Motor neurone disease,MND)，俗称渐冻人症，这是一种不可逆的致死性运动神经元病，主要症状为四肢和躯干肌肉表现进行性加重的肌肉无力和萎缩，逐渐失去运动功能，像被“冻住”一般，所以俗称“渐冻人”。大多数ALS患者死于呼吸衰竭，通常在症状首次出现后的三到五年内死亡。目前，没有治愈ALS的方法，也没有有效的治疗方法来阻止或逆转疾病的进展。ALS的核心病理发现是运动皮层和脊髓的运动神经元死亡，皮质脊髓轴突的退化会导致脊髓侧向方面的变薄和疤痕(硬化)。
蛋白质折叠稳态的丧失是许多最普遍的神经退行性疾病的特征。作为应对内质网(ER)内折叠压力的机制，未折叠蛋白反应(UPR)包括一组信号机制，这些机制启动基因表达程序以恢复蛋白质稳态，或者当压力是慢性的或过载时会促进神经元死亡。UPR的这种功能已被提出在ALS中发挥关键作用。
综合应激反应(ISR)是一种进化上保守的细胞内信号网络，可帮助细胞、组织和生物体适应可变环境并保持健康。ISR响应各种变化，通过重编程基因表达恢复平衡。大脑中长期记忆形成需要新蛋白质合成，所以抑制ISR可增强长期记忆形成，而活化ISR会阻止这个过程，并且年龄相关的认知障碍通常与ISR激活相关。
作为蛋白质稳态的中央调节器，ISR激活发生在广泛的大脑疾病中。这一激活过程通过检测大脑中的eIF2-P和PKR、PERK和GCN2磷酸化得以证实，包括来自病人样本以及神经退行性疾病的动物模型样本，比如阿尔茨海默氏症疾病、帕金森病、亨廷顿病、创伤性脑损伤、唐氏综合症和Charcot-Marie-Tooth等神经退行性疾病。值得注意的是，ISR激活会导致创伤性脑损伤、衰老和阿尔茨海默病小鼠模型的认知缺陷。
eIF2B(真核翻译起始因子2B(eukaryotic translation initiation factor 2B，eIF2B)是调节蛋白质合成的关键酶，是一种专用于翻译起始因子2的鸟嘌呤核苷酸交换因子(Guanine Nucleotide Exchange Factor，GEF)，eIF2B激动剂ISRIB可以恢复蛋白质翻译，使UPR转录恢复到基础水平，降低综合应激反应(ISR)。
同时，eIF2B激动剂ABBV-CLS-7262(AbbVie/Calico)和DNL-343(Denali Therapeutics)适应症均为ALS，且均进入临床1期，其中DNL-343已公布健康人1期数据，其安全耐受。
大量动物实验证实了eIF2B激活剂ISRIB在小鼠模型中证明可增加长期记忆。而口服eIF2B激活剂ABBV-CLS-7262 3天后，模型动物的大脑功能可以恢复到年轻的水平。这意味着，这种药物或许能够在后期抑制一些神经退行性疾病，并具有治疗阿尔茨海默病、帕金森病等疾病的潜力。
发明内容
本申请提供了一种化合物、包含其的药物组合物及其合成方法和用途，以提供能明显减弱细胞的整合应激反应(ISR)，激活eIF2B活性，使得细胞内蛋白质趋于正常合成的化合物，并为整合应激反应(ISR)路径介导的疾病或病症eIF2B相关疾病，和/或为与eIF2B活性或水平、eIF2通路或ISR通路的活性或水平的调 节有关的疾病提供更多的可能药物。
本申请的第一方面提供了一种式0所示的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐：
其中，
A环选自C3-C10亚环烷基、或3-10元亚杂环烷基，且A环不为且*端与L连接，端与B环连接，所述n3为0-5的任意整数；
B环选自5-10元亚杂芳基，n4为0-4的任意整数；
C环选自3-10元亚杂环烷基、C3-C10元亚环烷基、或#B-X21-C3-C12亚环烷基-$R1，X21为-NR3或-C(O)NR3，#B-为与B环连接的连接键，-$R1为与R1连接的连接键；各R3各自独立地为H、卤素、C1-C6烷基或C1-C6卤代烷基，且C环为C3-C10元亚环烷基时A环不为和亚环己基，且*端与L连接，端与B环连接，n5为0-5的任意整数；
D环选自C6-C10亚芳基、5-10元亚杂芳基、C3-C10亚环烷基或3-10亚杂环烷基；
L为#D-L1-L2-L3-$A或5-6元杂芳基，L1为键、-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C10亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A，X10为O或S，R4和R5各自独立地选自H、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基，作为R4和R5的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R11取代，L1与D环连接，L3与A环连接；#D-为与D环连接的连接键，-$A为与A环连接的连接键；
R1、R2、R9a、R9b、R9c各自独立地为取代基R11；
各R11各自独立地选自卤素、氰基、硝基、羰基、＝O、-OR6、-SR6、SF5、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、NR6S(O)1- 2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7、-P(O)R6R7或-NR6C(O)OR7，其中作为R9a、R9b、R9c、R11的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R12取代；各R6、R7和R8各自独立地选自H、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R20、-C(O)OR20、-C(O)NR20R21、-S(O)1-2R20、-S(O)1-2NR20，其中作为R6、R7和R8的 C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R13取代；或者R6、R7和R8中的两个与共用原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C10的烷基取代；各R12和各R13各自独立地为H、卤素、氰基、硝基、羰基、＝O、-OR30、-SR30、SF5、NR30R31、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30、-C(O)NR30R31、-C(O)O NR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1-2NR30、NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31，其中作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C10的烷基取代；
各R20和R21各自独立地选自H、或可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C10的烷基；
R20和R21与共用原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C10的烷基取代；各R30和R31各自独立地选自H、或可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C10的烷基；
R30和R31与共用原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C10的烷基取代；
n1和n2各自独立为0-4的任意整数。
需要说明的是，虽然本申请以(R2)n2-D环-L-A环-B环-C环-(R1)n1为主链结构将式0中的A环、B环、C环和D环均描述为二价基团，但是本领域技术人员应该理解，由于取代基的变化，A环、B环、C环和D环的价态也根据化学价变化规则适应性改变。以A环为例，当n3为0时，则A环为二价环，当n3不为0时，则A环可理解为依据R9a的价态和数量从三价及以上的多价态环中选择，B环以此类推；以D环为例，当n2为0时，则D环可理解为一价环，当n2不为0时，则D环可理解为依据R2的价态和数量从二价及以上的多价态环中选择；以C环为例，当n1和n5为0时，则C环可理解为一价环，当n1和n5之一为0时，则C环可理解为依据R9c和R2的价态和数量从二价及以上的多价态环中选择；当n1和n5均不为0时，则C环可理解为依据R9c和R2的价态和数量从三价及以上的多价态环中选择。上述A环、B环、C环和D环的说明适用于全文。
在一些实施例中，所述化合物如式0所示，其中，
A环选自C3-C10亚环烷基、或3-10元亚杂环烷基，且A环不为其中，*端与L连接，端与B环连接，所述n3为0-5的任意整数；
B环选自5-10元亚杂芳基，n4为0-4的任意整数；
C环选自3-10元亚杂环烷基、C3-C10亚环烷基、或#B-X21-C3-C12亚环烷基-$R1，X21为-NR3或-C(O)NR3，#B-为与B环连接的连接键，-$R1为与R1连接的连接键；各R3各自独立地为H、氘、卤素、C1-C6烷基或C1-C6卤代烷基，且C 环为C3-C10亚环烷基时A环不为亚环己基，n5为0-5的任意整数；
D环选自C6-C10亚芳基、5-10元亚杂芳基、C3-C10亚环烷基或3-10元亚杂环烷基；
L为#D-L1-L2-L3-$A、5-6元杂芳基或#D-NR14C(O)-C1-C6亚烷基-O-$A，L1为键、-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C10亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A，X10为O或S，R4、R5和R14各自独立地选自H、氘、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基，作为R4、R5和R14的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R11取代；#D-为与D环连接的连接键，-$A为与A环连接的连接键；
R1、R2、R9a、R9b、R9c各自独立地为取代基R11，
各R11各自独立地选自氘、卤素、氰基、硝基、＝O、-OR6、-SR6、SF5、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、NR6S(O)1- 2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7、-P(O)R6R7或-NR6C(O)OR7，其中作为R9a、R9b、R9c、R11的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R12取代；
各R6、R7和R8各自独立地选自H、氘、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R20、-C(O)OR20、-C(O)NR20R21、-S(O)1-2R20、-S(O)1-2NR20，其中作为R6、R7和R8的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R13取代；或者
R6和R7与和它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；或者
R7和R8与和它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
各R12和各R13各自独立地为H、氘、卤素、氰基、硝基、＝O、-OR30、-SR30、SF5、NR30R31、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30、-C(O)NR30R31、-C(O)ONR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1- 2NR30、NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31，其中作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
各R20和R21各自独立地选自H、氘、或可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基；或者
R20和R21与它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
各R30和R31各自独立地选自H、氘、或可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基；或者
R30和R31与它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
n1和n2各自独立为0-4的任意整数。
在一些实施例中，所述化合物如式0所示，其中，
A环选自C3-C10亚环烷基、或3-10元亚杂环烷基，且A环不为 其中，*端与L连接，端与B环连接，所述n3为0-5的任意整数；
B环选自5-10元亚杂芳基，n4为0-4的任意整数；
C环选自3-10元亚杂环烷基、C3-C10亚环烷基、或#B-X21-C3-C12亚环烷基-$R1，X21为-NR3或-C(O)NR3，#B-为与B环连接的连接键，-$R1为与R1连接的连接键；各R3各自独立地为H、氘、卤素、C1-C6烷基或C1-C6卤代烷基，且C环为C3-C10亚环烷基时，A环不为亚环己基，A环为时，*端与L连接，端与B环连接，C环为3-10元亚杂环烷基，n5为0-5的任意整数；
D环选自C6-C10亚芳基、5-10元亚杂芳基、C3-C10亚环烷基或3-10元亚杂环烷基；
L为#D-L1-L2-L3-$A、5-6元杂芳基或#D-NR14C(O)-C1-C6亚烷基-O-$A，L1为键、-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C10亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A，X10为O或S，R4、R5和R14各自独立地选自H、氘、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基，作为R4、R5和R14的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R11取代；#D-为与D环连接的连接键，-$A为与A环连接的连接键；
R1、R2、R9a、R9b、R9c各自独立地为取代基R11，
各R11各自独立地选自氘、卤素、氰基、硝基、＝O、-OR6、-SR6、SF5、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、NR6S(O)1- 2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7、-P(O)R6R7或-NR6C(O)OR7，其中作为R9a、R9b、R9c、R11的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R12取代；
各R6、R7和R8各自独立地选自H、氘、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R20、-C(O)OR20、-C(O)NR20R21、-S(O)1-2R20、-S(O)1-2NR20，其中作为R6、R7和R8的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R13取代；或 者
R6和R7与和它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；或者
R7和R8与和它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
各R12和各R13各自独立地为H、氘、卤素、氰基、硝基、＝O、-OR30、-SR30、-SF5、NR30R31、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30、-C(O)NR30R31、-C(O)ONR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1- 2NR30、-NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31，其中作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
各R20和R21各自独立地选自H、氘、或可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基；或者
R20和R21与它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
各R30和R31各自独立地选自H、氘、或可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基；或者
R30和R31与它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
n1和n2各自独立为0-4的任意整数。
优选地，式0化合物不是下述任一种化合物
优选地，前述方案不包括下述任一种化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐；
本申请的化合物能明显减弱细胞的整合应激反应(ISR)，激活eIF2B活性，使得细胞内蛋白质趋于正常合成。
在一些实施方式中，所述n4为0、1、2或3；
优选地，各所述R9b各自独立地为卤素、氰基、硝基、羰基、-OH、C1-C3烷基，进一步优选各所述R9b各自独立地为卤素、氰基、硝基、-OH、C1-C3烷基；
更优选地，所述R9b各自独立地为卤素、-OH、甲基、乙基或丙基；
进一步优选地，所述n4为0。
优选地，所述B环选自
进一步优选所述B环选自(例如)或(例如)，其中，X7为O或S，X8、X9、X10各自独立地为CH或N，*端与C环连接，端与A环连接；
更优选地，X8、X9、X10中至多两个为N；
进一步优选地，X8、X9、X10中的一个为N。
在一些实施方式中，所述B环选自以下基团中的任意一种：
在一些实施方式中，所述B环选自以下基团中的任意一种：
(例如)、(例如)、(例如)、(例如)。
在一些实施方式中，所述B环选自以下基团中的任意一种：
在一些实施方式中，所述B环选自以下基团中的任意一种：
(例如)、(例如)。
在一些实施方式中，所述B环为
在一些实施方式中，所述化合物具有通式I所示结构
其中，A环、C环、D环、L、R1、R2、R9a、R9c、n2、n2、n3和n5如上文任意一个实施方式中所定义，X7为O或S。或者A环、D环、L、R1、R2、R9a、R9c、n2、n2、n3和n5如上文任意一个实施方式中所定义，X7为O或S。
优选地，n1和n2各自独立地为1-3的整数；
进一步优选地，n1为1，n2为1-3的整数。
在一些实施方式中，各所述R9c各自独立地为卤素、氰基、硝基、羰基、＝O、-OH、-NR30R31、C1-C3烷基、-C(O)R30、-C(O)OR30，优选各所述R9c各自独立地为卤素、氰基、硝基、＝O、-OH、-NR30R31、C1-C3烷基、-C(O)R30、-C(O)OR30，各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
优选地，所述C环可被1或2个R9c取代，优选各所述R9c各自独立地为卤素、氰基、硝基、羰基、-OH、C1-C3烷基，更优选各所述R9c各自独立地为卤素、氰基、硝基、-OH、C1-C3烷基；
更优选地，所述R9c各自独立地为卤素、-OH、甲基、乙基或丙基；
更优选地，所述R9c各自独立地为F、甲基。
优选地，n5为0、1或2；
进一步优选地，n5为0或1。
优选地，所述C环的3-10元亚杂环烷基选自 其中，X11、X23各自为N或B，X12为CH2、NH、O或S，q为0至3的整数，优选q为1或2；X13为N或B，s为1至3的整数，优选s为1或2；X14为O、S或NH，t为1至3的整数，优选t为1或2；*端与B环连接，端与R1连接；
优选所述C环的3-10元亚杂环烷基选自 其中，X11为N或B，X12为CH2、NH、O或S，q为0至3，优选q为1或2；X13为N或B，s为1至3的整数，优选s为1或2；X14为O、S或NH，t为1至3的整数，优选t为1或2；
进一步优选地，所述C环的3-10元亚杂环烷基选自
优选地，所述C环的#B-X21-C3-C12亚环烷基-$R1为其中，R3为H、卤素、C1-C3烷基或C1-C3卤代烷基，p为1至3的整数，优选为1或2；#B-为与B环连接的连接键，-$R1为与R1连接的连接键；*端与B环连接，端与R1连接；
进一步优选地，所述C环的#B-X21-C3-C12亚环烷基-$R1为
在一些实施方式中，所述C环选自 *端与B环连接，端与R1连接。
在一些实施方式中，所述C环选自
在一些实施方式中，所述C环选自
在一些实施方式中，所述C环选自 各q、p、s、t各自独立地为1或2。
在一些实施方式中，所述选自 *端与B环连接，端与R1连接。
在一些实施方式中，所述选自 *端与B环连接，端与R1连接。
在一些实施方式中，所述选自 *端与B环连接，端与R1连接。
在一些实施方式中，所述选自 *端与B环连接，端与R1连接。
在一些实施方式中，所述选自*端与B环连接，端与R1连接。
在一些实施方式中，各R1各自独立地为R11，各R1各自独立地为R11，各R11各自独立地选自卤素、氰基、硝基、羰基、＝O、-OR6、-SR6、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、-C(O)R6、-C(O)OR6、-OC(O)OR6、-S(O)1-2R6、-P(O)R6R7，优选各R11各自独立地选自卤素、氰基、硝基、＝O、-OR6、-SR6、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、-C(O)R6、-C(O)OR6、-OC(O)OR6、-S(O)1- 2R6、-P(O)R6R7，其中作为R11的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到6个R12取代，
各R6、R7各自独立地选自H、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基，其中作为R6、R7的C1-C10烷基、C2-C10烯 基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到3个R13取代；
各R12和各R13各自独立地为H、卤素、氰基、硝基、羰基、＝O、-OR30、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基，优选各R12和各R13各自独立地为H、卤素、氰基、硝基、＝O、-OR30、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基，其中作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到3个卤素取代、或被可选地被1-3个羰基、卤素、羟基或氨基取代的C1-C3烷基取代；优选作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到3个卤素取代、或被可选地被1-3个卤素、羟基或氨基取代的C1-C3烷基取代，
各R30各自独立地选自H、或可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C3烷基，优选各R30各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基。
在一些实施方式中，所述R1选自-OR6、C1-C3烷基、卤素、C2-C4烯基、-S(O)2R6或-P(O)R6R7，优选各R6、R7各自独立地选自H、C1-C3烷基，其中作为R6、R7的C1-C3烷基可被1到3个R13取代；优选各R13各自独立地为卤素、氰基、硝基。
在一些实施方式中，所述R1选自-OR6、C1-C3烷基、卤素、-S(O)2R6或-P(O)R6R7，其中优选作为R1的C1-C3烷基可被1-6个R12取代，R12选自卤素、-S(O)2R30，R30选自C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基；各R6各自独立地选自C1-C3烷基、C2-C4烯基、C3-C6环烷基，其中作为R6的C1-C3烷基、C2-C4烯基、C3-C6环烷基各自独立地可被1-6个R13取代，R13选自卤素；R7选自C1-C3烷基。
在一些实施方式中，所述R1为-OCH3、-OCF3、-CF2CF3、-CF3、-CHF2、-OCF2Cl、-CH2CF3、-CF3、-F、-OCF＝CF2、
在一些实施方式中，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、-F、-OCF＝CF2、
优选地，所述R1选自-OCF3、-CF2CF3、-OCH3、-F、-CF3；
进一步优选地，所述R1选自-OCF3、-OCF2CF3；
更优选地，所述R1为-OCF3。
在一些实施方式中，优选n1为0或1。
在一些实施方式中，所述化合物具有通式II所示结构
其中，A环、D环、L、R2、R9a、n2和n3如上文任意一个实施方式中所定义。
优选地，所述R1为-OCH3、-OCF3、-CF2CF3、-CF3、-CHF2、-OCF2Cl、-CH2CF3、-OCF＝CF2、
优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-CHF2、-OCF2Cl、-CH2CF3、F、-OCF＝CF2、
优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、F、-OCF＝CF2、
进一步优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-CHF2、-OCF2Cl、-CH2CF3、-CF3、-OCF＝CF2、
进一步优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-F、-CF3；
进一步优选地，所述R1为-OCF3、-OCF2CF3；
更优选地，所述R1为-OCF3；优选地，n1为1；
优选地，n5为0、1或2，各所述R9c各自独立地为卤素、氰基、硝基、羰基、-OH、C1-C3烷基，优选各所述R9c各自独立地为卤素、氰基、硝基、-OH、C1-C3烷基；
进一步优选地，所述R9c各自独立地为卤素、-OH、甲基、乙基或丙基；
更优选地，所述R9c各自独立地为F。
在一些实施方式中，所述化合物具有通式II-1所示结构
其中，A环、D环、L、R2、R9a、n2和n3如上文任意一个实施方式中所定义。
优选地，n5为0或1，优选n5为1，所述R9c选自卤素、氰基、硝基、羰基、-OH、C1-C3烷基；优选所述R9c选自卤素、氰基、硝基、-OH、C1-C3烷基；
进一步优选地，所述R9c选自卤素、甲基或乙基；
更优选地，所述R9c为F。
优选地，所述选自
进一步优选地，所述选自
优选地，n1为1，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-CHF2、-OCF2Cl、-CH2CF3、-OCF＝CF2、
进一步优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2Cl、-CH2CF3、-OCF2CF3、-OCF＝CF2、
进一步优选地，所述R1选自-OCH3、-OCF3、-OCF2CF3；
进一步优选地，所述R1选自-OCF3、-OCF2CF3；
更优选地，所述R1为-OCF3。
在一些实施方式中，n3为0、1或2；
优选地，所述A环选自C5-C8亚环烷基或5-8元亚杂环烷基。
在一些实施方式中，所述A环选自亚环己烷或6元亚杂环烷基。
在一些实施方式中，所述A环选自亚环己烷或*端与L连接，端与B环连接。
在一些实施方式中，所述A环选自C5-C8亚桥环烷基或6-8元亚桥杂环烷基，其中，X1为CH或N，X2、X3、X4、X5、X6各自独立地为CH2、CH、NH、N或O，*端与L连接，端与B环连接。
在一些实施方式中，所述A环选自C6-C8亚桥环烷基或6-8元亚桥杂环烷基，其中，X1为CH或N，X2、X3、X4、X5、X6各自独立地为CH2、CH、NH、N或O，*端与L连接，端与B环连接。
在一些实施方式中，所述中，X5为CH2或O，X2、X3、X4、X6各自独立地为CH2或CH；
优选地，所述X2、X3、X6为CH2，X4为CH。
在一些实施方式中，所述A环的C6-C8亚桥环烷基或6-8元亚桥杂环烷基各自独立地可被1-4个R9a取代，优选被1或2个R9a取代。
在一些实施方式中，所述A环的C5-C8亚桥环烷基或6-8元亚桥杂环烷基各自独立地可被0-4个R9a取代；
优选地，所述A环被0、1或2个R9a取代；
更优选地，所述A环被0或1个R9a取代。
在一些实施方式中，所述C6-C8亚桥环烷基为
在一些实施方式中，所述C5-C8亚桥环烷基为
在一些实施方式中，所述亚桥杂环烷基为
在一些实施方式中，所述亚桥杂环烷基为
在一些实施方式中，所述R9a各自独立地为卤素、氰基、硝基、羰基、＝O、-OR6、-SR6、SF5、-NR6R7、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、-NR6S(O)1-2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7或-NR6C(O)OR7，优选所述R9a各自独立地为卤素、氰基、硝基、＝O、-OR6、-SR6、-SF5、-NR6R7、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、-OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、-NR6S(O)1-2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7或-NR6C(O)OR7，其中作为R9a的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R12取代；
各R6、R7和R8各自独立地选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R20、-C(O)OR20、-C(O)NR20R21、-S(O)1-2R20、-S(O)1-2NR20，其中作为R6、R7和R8的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到4个R13取代；
各R12、各R13各自独立地为H、卤素、氰基、硝基、羰基、＝O、-OR30、-SR30、SF5、-NR30R31、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、-OC(O)R30、-C(O)NR30R31、-C(O)ONR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1- 2NR30、NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31， 优选各R12、各R13各自独立地为H、卤素、氰基、硝基、＝O、-OR30、-SR30、SF5、-NR30R31、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、-OC(O)R30、-C(O)NR30R31、-C(O)ONR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1- 2NR30、-NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31，其中作为R12和R13的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C6的烷基取代，优选作为R12和R13的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C6的烷基取代，
各R20和R21各自独立地选自H、或可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C6的烷基，优选各R20和R21各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C6的烷基；
各R30和R31各自独立地选自H、或可选地被1-6个羰基、卤素、羟基或氨基取代的C1-C6的烷基，优选各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C6的烷基。
在一些实施方式中，所述R9a各自独立地为卤素、氰基、硝基、羰基、＝O、-OH、-NR30R31、C1-C3烷基、C1-C3卤代烷基、-C(O)R30、-C(O)OR30，各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；优选所述R9a各自独立地为卤素、氰基、硝基、＝O、-OH、-NR30R31、C1-C3烷基、C1-C3卤代烷基、-C(O)R30、-C(O)OR30，各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基。
在一些实施方式中，所述R9a各自独立地为卤素、氰基、硝基、羰基、＝O、-OH、甲基、乙基、氟代甲基或氟代乙基；优选所述R9a各自独立地为卤素、氰基、硝基、＝O、-OH、甲基、乙基、氟代甲基或氟代乙基。
在一些实施方式中，所述R9a各自独立地为-OH、＝O。
在一些实施方式中，所述R9a各自独立地为-OH。
在一些实施方式中，所述选自
*端与L连接，端与B环连接。
在一些实施方式中，所述选自
*端与L连接，端与B环连接。
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述化合物具有通式III所示结构
其中，X1为CH或N，X2、X3、X4、X5、X6各自独立地为CH2、CH、NH、N或O；优选地X1和X4各自独立地为CH或N，X2、X3、X5、X6各自独立地为CH2、CH、NH、N或C，v为0至2的整数；D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如上述任意一个实施方式中所定义。
优选地，所述R9a各自独立地为卤素、＝O、-OH、C1-C3烷基，更优选为-OH。
D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如上述任意实施方式所定义。
在一些实施方式中，所述化合物具有通式III-1至III-6中任一通式所示结构

其中，D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如上述任意一个实施方式中所定义。
优选地，R9a为羟基或卤素；
更优选地，R9a为羟基；
优选地，n3为0-3的整数，更优选为0、1或2。
在一些实施方式中，所述化合物具有以下通式所示结构的化合物中的任意一种：

其中，所述D环、L、R1、R2、n1、n2如上述任意一个实施方式中所定义。
在一些实施方式中，所述L为#D-L1-L2-L3-$A或L1为键、-O-、-S-或-NR4-，优选L1为-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C3亚烷基，优选L2为取代或未取代的C1-C3亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A， X10为O或S，R4和R5各自独立地选自H、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环烷基，作为R4和R5的C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环烷基各自独立地可被1到3个R11取代；各R11各自独立地选自卤素、氰基、硝基、羰基、＝O、-OH、-SH、-NH2，优选各R11各自独立地选自卤素、氰基、硝基、＝O、-OH、-SH、-NH2，优选各R11各自独立地选自卤素、氰基、硝基、-OH、-SH、-NH2；#D-为与D环连接的连接键，-$A为与A环连接的连接键；*端与A环连接，端与D环连接。
在一些实施方式中，所述L为#D-L1-L2-L3-$A、或#D-NR14C(O)-C1-C6亚烷基-O-$A，L1为键、-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C3亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A，X10为O或S，R4、R5和R14各自独立地选自H、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环烷基，作为R4、R5和R14的C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环烷基各自独立地可被1到3个R11取代；各R11各自独立地选自卤素、氰基、硝基、＝O、-OH、-SH、-NH2，优选各R11各自独立地选自卤素、氰基、硝基、-OH、-SH、-NH2；#D-为与D环连接的连接键，-$A为与A环连接的连接键，*端与A环连接，端与D环连接。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述化合物具有通式IV-1或IV-2所示结构
其中，D环、R1、R2、R9a、R9c、n1、n2、n3和n5如上述任意一个实施方式所定义，优选A环、C环、D环、R1、R2、R9a、R9c、n1、n2、n3和n5如上述 任意一个实施方式所定义，X7为O或S。
在一些实施方式中，所述化合物具有通式V-1或V-2所示结构
其中，v为0至2的整数，D环、R1、R2、R9a、R9c、n1、n2、n3和n5如上述任意一个实施方式所定义，X7为O或S。
在一些实施方式中，选自 其中，X14、X15、X16、X17、X18各自独立地选自CH、N，且至少一个为N，优选至多有三个N，进一步优选至多有两个N；X19、X20各自独立地选自CH、N、NH、O、S，且不同时为S或O，m为1或2；X21、X22各自独立地选自CH、N、NH、O、S，且不同时为S或O，m为1或2；u为1或2或3。
在一些实施方式中，选自 其中，X14、X15、X16、X17、X18各自独立地选自CH、N，且至少一个为N，优选至多有三个N，进一步优选至多有两个N；X19、X20各自独立地选自CH、N、NH、O、S，且不同时为S或O，m为1或2；X21、X22各自独立地选自CH、N、NH、O、S，且不同时为S或O，m为1或2；u为1或2或3。
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，R2为R11，各R11各自独立地选自卤素、氰基、硝基、羰基、＝O、-OR6、-SR6、-NR6R7、C1-C6烷基、C3-C6环烷基、3-8元杂环烷基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7，优选各R11各自独立地选自卤素、氰基、硝基、＝O、-OR6、-SR6、-NR6R7、C1-C6烷基、C3-C6环烷基、3-8元杂环烷基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7，其中作为R11的C1-C6烷基、C2-C6烯基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到6个R12取代，
各R6、R7和R8各自独立地选自H、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、-C(O)R20、-C(O)OR20、-C(O)NR20R21，其中作为R6、R7和R8的C1-C6烷基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到3个R13取代；
各R12和各R13各自独立地为H、卤素、氰基、硝基、羰基、＝O、-OR30、NR30R31、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30，优选各R12和各R13各自独立地为H、卤素、氰基、硝基、＝O、-OR30、NR30R31、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30，其中作为R12和R13的C1-C6烷基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到3个卤素取代、或被可选地被1-3个羰基、卤素、羟基或氨基取代的C1-C3的烷基取代，优选作为R12和R13的C1-C6烷基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到3个卤素取代、或被可选地被1-3个卤素、羟基或氨基取代的C1-C3烷基取代，
各R20和R21各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
n2为1或2或3。
在一些实施方式中，各R2各自独立地选自卤素、氰基、C1-C3卤代烷基、
C1-C3烷基、-OC1-C3烷基、-O C1-C3卤代烷基、-NR6R7、C3-C6环烷基、3-6元杂环烷基，R6、R7各自独立地选自H、C1-C3烷基、C1-C3卤代烷基、C3-C6环烷基、C3-C6卤代环烷基，优选地，所述R2为C3-C6环烷基、3-6元杂环烷基时，n为1，且所述R2与所述D环共用两个碳原子形成稠环。
在一些实施方式中，各R2各自独立地选自卤素、C1-C3卤代烷基、C1-C3烷基、-OC1-C3烷基、-O C1-C3卤代烷基、-NH2、其中，优选当R2为时，与所述D环共用两个碳原子形成稠环。
在一些实施方式中，各R2各自独立地选自F、Cl、Br、-CF3、-CH3、-CFH2、-CF2H、-OCH3、O-CF3、-NH2，n2为1或2。
在一些实施方式中，各R2各自独立地选自F、Cl、Br、-CF3、-CH3、-CF2H、-OCF3、-NH2，n2为1、2或3。
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，所述选自
在一些实施方式中，优选所述化合物具有通式VI所示结构
其中，所述A环选自亚环己烷或6元亚杂环烷基；所述L、R1、R2、R9a、R9c、n1、n2、n3和n5如上述任意一个实施方式所定义。
在一些实施方式中，所述R2各自独立的选自F、Cl、Br。
在一些实施方式中，所述n2为1或2。
在一些实施方式中，所述R2与L呈对位和/或间位关系。
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
优选地，所述L选自
在一些实施方式中，所述L选自 *端与A环连接，端与D环连接。
在一些实施方式中，所述L选自
在一些实施方式中，所述L选自
在一些实施方式中，所述L选自
在一些实施方式中，所述n1和n5不同时为0。
在一些实施方式中，所述R1与其所在C环上的N呈对位关系。
在一些实施方式中，所述R1选自-OR6、C1-C3烷基、卤素、C2-C4烯基、-S(O)2R6或-P(O)R6R7，优选各R6、R7各自独立地选自H、C1-C3烷基，其中作为R6、R7的C1-C3烷基可被1到3个R13取代；优选各R13各自独立地为卤素、氰基、硝基；
优选地，所述R1为-OCH3、-OCF3、-CF2CF3、-CF3、-CHF2、-OCF2Cl、-CH2CF3、-CF3、-F、-OCF＝CF2、
在一些实施方式中，所述R1选自选自-OR6、C1-C3烷基、卤素、-S(O)2R6或-P(O)R6R7，其中作为R1的C1-C3烷基可被1-6个R12取代，R12选自卤素、-S(O)2R30，R30选自C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基；各R6各自独立地选自C1-C3烷基、C2-C4烯基、C3-C6环烷基，其中作为R6的C1-C3烷基、C2-C4烯基、C3-C6环烷基各自独立地可被1-6个R13取代，R13选自卤素；R7选自C1-C3烷基。
在一些实施方式中，所述R1为-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、-F、-OCF＝CF2、
在一些实施方式中，所述R1为-OCF3、-CF2CF3、-OCH3、-F、-CF3；
在一些实施方式中，所述R1为-OCF3、-OCF2CF3；
在一些实施方式中，所述R1为-OCF3。
各实施方式中，R1、R2、R9a、R9b、R9c各自独立地为取代基R11，当n1、n2、n3、n4、n5为0时说明R1、R2、R9a、R9b、R9c不存在，那么组成D环、A环、B环和C环的C的自由键与H连接。
在一些实施方式中，所述化合物具有通式VII所示结构
其中，R9a、X10的定义如上述任意实施方式所定义，R21选自卤素，R22选自H、卤素，t选自0-2的整数；
优选地，R21为Cl；
优选地，R22选自H、F、Cl、Br；
优选地，R9a选自H、羟基；
优选地，t为0或2。
在一些实施方式中，化合物选自：





在一些实施方式中，化合物具体选自

在一些实施方式中，化合物具体选自
本申请的另一方面提供了一种具有上述通式IV-1或IV-2所示结构的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐的合成方法，所述合成方法选自合成路线1至6中任意一种；
合成路线1：
其中，化合物1-1与化合物1-2发生酰胺缩合反应得到化合物1-3；所述化合物1-3与水合肼反应，经官能团转化得到化合物1-4；所述化合物1-4与N,N-羰基二咪唑发生环合得到化合物1-5；所述化合物1-5与化合物1-6发生缩合反应得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如上述实施方式所定义；
合成路线2：
其中，化合物2-1与化合物2-2发生酰胺缩合反应得到化合物2-3；所述化合物2-3与水合肼反应，经官能团转化得到化合物2-4；所述化合物2-4与N,N-羰基二咪唑发生环合得到化合物2-5；所述化合物2-5与化合物2-6发生缩合反应得到化合物IV-2-1；R1、R2、R9a、R9c、n1和n2如上述实施方式所定义；
合成路线3：

其中，化合物3-1与水合肼反应，经官能团转化得到化合物3-2；所述化合物3-2与N,N-羰基二咪唑发生环合得到化合物3-3；所述化合物3-3与化合物3-4发生缩合反应得到化合物3-5；所述化合物3-5在酸性条件下脱去保护基得到化合物3-6；所述化合物3-6与化合物3-7发生酰胺缩合反应得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如上述实施方式所定义；
合成路线4：
其中，化合物4-1与水合肼反应，经官能团转化得到化合物4-2；所述化合物4-2与N,N-羰基二咪唑发生环合得到化合物4-3；所述化合物4-3与化合物4-4发生缩合反应得到化合物4-5；所述化合物4-5在酸性条件下脱去保护基得到化合物4-6；所述化合物4-6与化合物4-7发生酰胺缩合反应得到化合物IV-2-1，R1、R2、R9a、R9c、n1和n2如上述实施方式所定义；
合成路线5：
其中，化合物5-1与化合物5-2发生酰胺缩合反应得到化合物5-3；所述化合物5-3与水合肼反应，经官能团转化得到化合物5-4；所述化合物5-4与化合物5-5发生缩合得到化合物5-6；所述化合物5-6发生关环反应得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如上述实施方式所定义；
合成路线6：
其中，化合物6-1与水合肼反应，经官能团转化得到化合物6-2；所述化合物6-2发生关环反应得到化合物6-3；所述化合物6-3发生氧化反应得到化合物6-4；所述化合物6-4与化合物6-5发生反应得到化合物6-6；所述化合物6-6在酸性条件下脱去保护基得到化合物6-7；所述化合物6-7与化合物6-8发生缩合得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如上述实施方式所定义。
本申请的又一方面提供了一种药物组合物，包含上述任一种的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化 物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐所制备而成的制剂，或上述任一种的合成方法得到的化合物。
在一些实施方式中，上述药物组合物进一步包括药学上可接受的载体、辅料、媒介物。
在一些实施方式中，提供了上述任一种所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐、或上述任一种的药物组合物在制备预防和/或治疗神经退行性疾病(例如脑白质营养不良、脑白质病变、髓鞘发育不良或脱髓鞘疾病、智力障碍综合征、认知功能障碍、神经胶质细胞功能异常或脑损伤(例如外伤性脑损伤或毒素诱发的脑损伤)、癌症、炎症性疾病、自身免疫性疾病、病毒感染、皮肤疾病、纤维化疾病、血红蛋白疾病、肾脏疾病、听力损失疾病、眼部疾病、具有导致未折叠蛋白质反应(UPR)诱导的突变疾病、疟疾感染、肌肉骨骼疾病、代谢性疾病或线粒体疾病的药物中的用途。
在一些实施方式中，提供了上述任一种所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐、或上述任一种的药物组合物在制备预防和/或治疗由整合应激反应(ISR)路径介导的疾病或病症的药物中的用途。
在一些实施方式中，提供了一种治疗有需要个体的由整合应激反应(ISR)路径介导的疾病或病症的方法，所述方法包含向所述个体施用治疗有效量的任一上述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐、或治疗有效量的任一上述的药物组合物。
在一些实施方式中，提供了一种治疗与eIF2B活性或水平、eIF2通路或ISR通路的活性或水平的调节有关的疾病的方法，所述方法包含向受试者施用治疗有效量的任一上述的化合物、或其立体异构体、或其药学上可接受的盐、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯或其前药、或治疗有效量的任一上述的药物组合物。
在一些实施方式中，提供了一种预防和/或治疗上述各疾病的方法，其包括向有此需要的受试者施用有效量的任一上述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐、或任一上述的药物组合物。
在一些实施方式中，提供了一种预防和/或治疗癌症的方法，其包括向有此需要的受试者施用有效量的任一上述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐、或任一上述的药物组 合物。
在一些实施方式中，所述神经退行性疾病包括但不限于：脑白质营养不良、脑白质病变、髓鞘发育不良或脱髓鞘疾病、智力障碍综合征、认知功能障碍、神经胶质细胞功能异常或脑损伤(例如外伤性脑损伤或毒素诱发的脑损伤)、亚历山大病(Alexander's disease)、阿耳珀氏病(Alper'sdisease)、阿尔茨海默病、肌萎缩性侧索硬化(ALS)、共济失调微血管扩张、巴顿病(Batten disease)(也称为Spielmeyer-Vogt-Sjogren-Batten病)、牛海绵状脑病变(BSE)、卡纳万病(Canavandisease)、科凯恩综合征(Cockayne syndrome)、皮质基底核变性、克雅病(CreutzfeldtJakob disease)、肌张力障碍、额颞叶痴呆(FTD)、Gerstmann-Straussler-Scheinker综合征、亨廷顿病(Huntington'sdisease)、HIV相关痴呆、肯尼迪病(Kennedy's disease)、克拉伯病(Krabbe disease)、库鲁病(kuru)、路易体痴呆(Lewy body dementia)、马查多-约瑟夫病(Machado-Joseph disease)(3型脊髓小脑性失调症)、多系统萎缩、多系统蛋白质病变、发作性睡病、神经疏螺旋体病(Neuroborreliosis)、帕金森病、佩梅病(PelizaeusMerzbacher Disease)、皮克氏病(Pick's disease)、原发性侧索硬化、航病毒病(Priondisease)、雷弗素姆氏病(Refsum's disease)、山德霍夫病(Sandhoff disease)、谢耳德病(Schilder's disease)、恶性贫血继发性脊髓亚急性联合变性(Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia)、精神分裂症、脊髓小脑性失调症(具有不同特征的多种类型,例如2型脊髓小脑性失调症或8型脊髓小脑性失调症)、脊髓性肌萎缩、Steele-Richardson-01szewski病、进行性核上性麻痹、皮质基底核变性、肾上腺脑白质营养不良、X连锁肾上腺脑白质营养不良、脑肾上腺脑白质营养不良、佩梅病、克拉伯病、由于DARS2基因中的突变所致的脑白质营养不良(有时称为伴脑干与脊髓受累以及乳酸升高的脑白质病(LBSL)、DARS2相关谱系障碍或脊髓痨(Tabes dorsalis))。
上述的癌症包括但不限于：人类癌症和癌瘤、肉瘤、腺癌、淋巴瘤、白血病、黑色素瘤等,包括实体癌症和淋巴样癌症、肾癌、乳腺癌、肺癌、膀胱癌、结肠癌、卵巢癌、前列腺癌、胰腺癌、胃癌、脑癌、头颈癌皮肤癌、子宫癌、翠丸癌、神经胶质瘤、食道癌、肝癌(liver cancer)(包括肝癌(hepatocarcinoma))、淋巴瘤(包B-急性淋巴母细胞性淋巴瘤、非霍奇金淋巴瘤(non-Hodgkin's 1ymphoma)(例如伯基特淋巴瘤(Burkitt's 1ymphoma)、小细胞淋巴瘤和大细胞淋巴瘤)、霍奇金淋巴瘤、白血病(包括AML、ALL和CML)和/或多发性骨髓瘤。在一些其他情形中,“癌症”是指肺癌、乳腺癌、卵巢癌、白血病、淋巴瘤、黑色素瘤、胰腺癌、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食道癌、胃癌、肝癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、前列腺癌、转移性癌症或癌瘤。
上述的白血病包括但不限于：急性非淋巴细胞性白血病、慢性淋巴细胞性白血病、急性粒细胞性白血病、慢性粒细胞性白血病、急性早幼粒细胞白血病、成人T细胞白血病、非白血性白血病、白细胞不增多性白血病、嗜碱性白血病、母细胞白血病、牛科动物白血病、慢性髓细胞性白血病、皮肤白血病、干细胞性白血病、嗜酸细胞性白血病、格罗斯白血病(Gross'leukemia)、毛细胞白血病、血母细胞性白血病、成血细胞性白血病、组织细胞性白血病、干细胞白血病、急性单核细胞性白血病、白细胞减少性白血病、淋巴性白血病、淋巴母细胞性白血病、淋巴细胞性白血病、淋巴源性白血病、淋巴样白血病、淋巴肉瘤细胞白血病、肥大细胞白血病、巨核细胞白血病、小骨髓母细胞性白血病、单核细胞性白血病、骨髓母细胞性白血病、骨髓细胞性白血病、骨髓样粒细胞性白血病、骨髓单核细胞性白血病、内格利白血病(Naegeli leukemia)、浆细胞白血病、多发性骨髓瘤、 浆球性白血病、早幼粒细胞性白血病、李德尔氏细胞白血病(Rieder cellleukemia)、席林氏白血病(Schilling's leukemia)、干细胞白血病、亚白血病性白血病或未分化细胞白血病。
上述的炎性疾病包括但不限于：手术后认知功能障碍、关节炎(例如类风湿性关节炎、牛皮癣性关节炎、青少年特发性关节炎)、全身性红斑狼疮(SLE)重症肌无力、幼发型糖尿病、1型糖尿病、格林-巴利综合征、桥本氏脑炎(HashimotoSencephalitis)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、强直性脊柱炎、牛皮癣、干燥综合征(Sjogren's syndrome)、血管炎、肾小球肾炎、自身免疫性甲状腺炎、白塞病(Behcet's disease)、克罗恩病(Crohn's disease)、溃疡性结肠炎、大疱性类天疱疮、类肉瘤病、鱼鳞癣、格雷夫斯眼病(Graves'ophthalmopathy)、炎症性肠病、艾迪生病(Addison'sdisease)、白癫风、哮喘(例如过敏性哮喘)、寻常痤疮、乳糜泻、慢性前列腺炎、炎症性肠病盆腔炎性疾病、再灌注损伤、类肉瘤病、移植排斥、间质性膀胱炎、动脉粥样硬化和特应性皮炎。
上述的肌肉骨骼疾病包括但不限于：肌营养不良症(例如杜氏肌营养不良症(Duchenne muscular dystrophy)、贝克氏肌营养不良症(Becker muscular dystrophy)、远端肌营养不良症、先天性肌营养不良症、埃-德二氏肌营养不良症(Emery-Dreifuss muscular dystrophy)、面肩胛臂肌营养不良症、1型强直性肌营养不良症或2型强直性肌营养不良症)、肢带肌营养不良症、多系统蛋白质病变、肢根性点状软骨发育异常、X连锁隐性点状软骨发育异常、康-休二氏综合征(Conradi-Hünermann syndrome)、常染色体显性点状软骨发育异常、应激诱发的骨酷病症(例如应激诱发的骨质疏松症)、多发性硬化、肌萎缩性侧索硬化(ALS)、原发性侧索硬化、进行性肌萎缩、进行性延髓麻痹、假延髓性麻痹、脊髓性肌萎缩、进行性脊髓延髓性肌萎缩、脊髓痉挛、脊髓性肌萎缩、重症肌无力、神经痛、纤维肌痛、马查多-约瑟夫病、骨佩吉特氏病、疼挛肌束震颤综合征、弗雷德里希共济失调(Freidrich'sataxia)、肌肉消耗性病症(例如肌萎缩、肌少症、恶病质)、包涵体肌病、运动神经元病或瘫痪。
上述的代谢性疾病包括但不限于：非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、肝纤维化、肥胖症、心脏病、动脉粥样硬化、关节炎、胱氨酸病、糖尿病(例如I型糖尿病、II型糖尿病或妊娠糖尿病)、苯丙酮尿症、增殖性视网膜病变或科恩斯-塞尔病(Kearns-Sayre disease)。
上述的线粒体疾病包括但不限于：巴斯综合征(Barth syndrome)、慢性进行性眼外肌麻痹(cPEO)、科恩斯-塞尔综合征(KSS)、利氏综合征(Leigh syndrome)(例如MILS或母系遗传利氏综合征)、线粒体DNA缺失综合征(MDDS,例如阿尔佩斯综合征(Alpers syndrome))、线粒体脑肌病(例如线粒体脑肌病伴乳酸性酸中毒和中风样发作(MELAS))、线粒体神经胃肠脑肌病(MNGIE)、肌阵挛性癫病伴破碎样红纤维(MERRF)、神经病变、共济失调、色素性视网膜炎(NARP)、莱伯氏遗传性视神经病变(Leber's hereditary optic neuropathy,LHON)和皮尔逊综合征(Pearson syndrome)。
上述的听力损失疾病包括但不限于：线粒体非综合征型听力损失和耳聋、毛细胞死亡、年龄相关性听力损失、噪音诱发的听力损失、遗传的或遗传性听力损失、由于耳毒性暴露而经历的听力损失、疾病导致的听力损失和创伤导致的听力损失。在一些实施方案中,线粒体非综合征型听力损失和耳聋是MT-RNR1相关的听力损失。
上述的眼部疾病包括但不限于：白内障、青光眼、内质网(ER)应激、自体吞 噬缺陷、年龄相关性黄斑变性(AMD)或糖尿病性视网膜病变。
上述的肾脏疾病包括但不限于：阿博赫登-考夫曼-利尼亚克综合征(Abderhalden-Kaufmann-Lignac syndrome)(Y病性胱氢酸症)、腹腔间隔室综合征、乙酰氨酚诱发的肾毒性、急性肾衰竭/急性肾损伤、急性大叶性肾病、急性磷酸盐肾病变、急性肾小管坏死、腺嘌吟磷酸核糖基转移酶缺乏症、腺病毒肾炎、阿拉杰里综合征(Alagille Syndrome)、奥尔波特综合征(Alport Syndrome)、淀粉样变性、与心内膜炎和其他感染相关的ANCA血管炎、血管肌脂肪瘤、镇痛药性肾病变、神经性厌食症性肾病、血管收缩肽抗体和局灶节段性肾小球硬化、抗磷脂质综合征、抗TNF-α疗法相关的肾小球肾炎、APOL1突变、表观盐皮质激素过多综合征、马兜铃酸肾病变、中草药肾病变、巴尔干半岛地方性肾病变(Balkan Endemic Nephropathy)、泌尿道动静脉畸形和痿、常染色体显性低钙血症、巴尔得-别德尔综合征(Bardet-Biedl Syndrome)、巴特综合征(Bartter Syndrome)、浴盐性急性肾损伤、嗜啤酒癖(Beer Potomania)、甜菜尿、β-地中海贫血肾病、胆汁管型肾病变、自体肾BK多瘤病毒肾病变、膀胱破裂、膀胱括约肌协同失调、膀胱填塞、跨界肾病变(Border-Crossers'Nephropathy)、波旁病毒(Bourbon Virus)性急性肾损伤、燃烧式甘蔗收割型急性肾功能障碍、Byetta肾衰竭、Clq肾病变、C3肾小球病变、C3肾小球病变伴单克隆丙种球蛋白病、C4肾小球病变、钙调神经磷酸酶抑制剂肾毒性、苍术苷(CallilepsisLaureola)中毒、大麻素剧吐急性肾衰竭、心肾综合征、卡非佐米(Carfilzomib)诱发的肾损伤、CFHR5肾病变、恰克-马里-杜斯病(Charcot-Marie-Tooth Disease)伴肾小球病变、中草药肾毒性、樱桃浓缩物急性肾损伤、胆固醇栓塞、查格-施特劳斯综合征(Churg-Strausssyndrome)、乳糜尿、纤毛病变、可卡因(Cocaine)性肾病、冷利尿、粘菌素肾毒性、胶原纤维性肾小球病变、塌陷性肾小球病变、与CMV相关的塌陷性肾小球病变、联合抗反转录病毒(cART)相关性肾病变、先天性肾脏和泌尿道畸形(CAKUT)、先天性肾病综合征、充血性肾衰竭、锥形骨骺肾病综合征(Mainzer-Saldino综合征或Saldino-Mainzer病)、显影剂肾病变、硫酸铜中毒、皮质坏死、克唑替尼(Crizotinib)相关的急性肾损伤、晶体型冷球蛋白血症、冷球蛋白血症、晶体球蛋白诱发的肾病变、晶体诱发的急性肾损伤、晶体储备性组织细胞增生症、获得性囊性肾病、胱氨酸尿、达沙替尼(Dasatinib)诱发的肾病变范围蛋白尿、致密沉积物病(2型MPGN)、登特病(Dent Disease)(X连锁隐性肾石病)、DHA结晶肾病变、透析失衡综合征、糖尿病和糖尿病性肾病、糖尿病尿崩症、膳食补充剂肾衰竭、弥漫性系膜硬化、利尿、缅甸臭豆(Djenkol Bean)中毒(臭豆果毒症(Djenkolism))、唐氏综合征(DownSyndrome)性肾病、药物滥用性肾病、重复输尿管、EAST综合征、伊波拉病(Ebola)性肾病、异位肾、异位输尿管、水肿、肿胀、埃德海姆-切斯特病(Erdheim-Chester Disease)、法布里病(Fabry's Disease)、家族性低尿钙性高钙血症、范可尼综合征(Fanconi Syndrome)、弗雷泽综合征(Fraser syndrome)、纤连蛋白肾小球病变、原纤维性肾小球肾炎和免疫触须样肾小球病变、弗雷利综合征(Fraley syndrome)、体液过多、高血容量症、局灶节段性肾小球硬化、局灶性硬化、局灶性肾小球硬化、加洛韦-莫厄特综合征(Galloway Mowat syndrome)、累及肾脏的巨细胞(题)动脉炎、妊娠高血压、吉特曼综合征(Gitelman Syndrome)、肾小球疾病、肾小球肾小管反流、糖尿、古德帕斯彻综合征(Goodpasture Syndrome)、蔬果奶昔排毒性Y病变(Green Smoothie Cleanse Nephropathy)、HANAC综合征、Harvoni(迪帕韦(Ledipasvir)和索非布韦(Sofosbuvir))诱发的肾损伤、染发剂摄入性急性肾损伤、汉坦病毒感染性足细胞病变(Hantavirus Infection Podocytopathy)、热应激肾病变、血尿症(尿中 带血)、溶血性尿毒综合征(HUS)、非典型溶血性尿毒综合征(aHUS)、噬血综合征、出血性膀胱炎、肾综合征性出血热(HFRS,汉坦病毒肾病、朝鲜出血热、流行性出血热、流行性肾病(Nephropathis Epidemica))、含铁血黄素尿症、与阵发性夜间血红蛋白尿和溶血性贫血相关的含铁血黄素沉着症、肝肾小球病变、肝静脉闭塞性疾病、肝窦阻塞综合征、丙型肝炎相关的肾病、肝细胞核因子1B相关的肾病、肝肾综合征、草药补充剂性肾病、高海拔性肾综合征、高血压性肾病、HIV相关的免疫复合物肾病(HIVICK)、HIV相关的肾病变(HIVAN)、HNF1B相关的常染色体显性小管间质性肾病、马蹄肾(肾融合)、亨纳氏溃疡(Hunner's Ulcer)、羟基氯喹诱发的肾磷脂质病、高醛固酮症、高钙血症、高钟血症、高镁血症、高钠血症、高草酸尿症、高磷酸盐血症、低钙血症、低补体型尊麻疹性血管炎综合征、低钟血症、低钟血症诱发的肾功能障碍、低钟性周期性麻痹、低镁血症、低钠血症、低磷酸盐血症、大麻使用者的低磷酸盐血症、高血压、单基因高血压、冰茶肾病变、异环磷酰胺肾毒性、IgA肾病变、IgG4肾病变、浸泡利尿、免疫检查点疗法相关的间质性肾炎、英利昔单抗(Infliximab)相关的肾病、间质性膀胱炎、膀胱疼痛综合征(问卷)、间质性肾炎、巨核细胞性间质性肾炎、伊维马克氏综合征(Ivemark's syndrome)、JC病毒肾病变、朱伯特综合征(Joubert Syndrome)、氯胺酮相关的膀胱功能障碍、肾结石、肾石病、康普茶(Kombucha Tea)毒性、铅肾病变和铅相关的肾毒性、卵磷脂胆固醇酰基转移酶缺乏症(LCAT缺乏症)、钩端螺旋体病肾病、轻链沉积病、单克隆免疫球蛋白沉积病、轻链近端肾小管病变、利德尔综合征(Liddle Syndrome)、莱特伍德-奥尔布赖特综合征(Lightwood-Albright Syndrome)、脂蛋白肾小球病变、锂肾毒性、LMX1B突变引起的遗传性FSGS、腰痛血尿症、狼疮、全身性红斑狼疮、狼疮性肾病、狼疮性肾炎、狼疮性肾炎伴抗中性粒细胞细胞质抗体血清阳性、狼疮性足细胞病变、莱姆病(Lyme·Disease)相关的肾小球肾炎、赖氨酸尿蛋白不耐受症、溶菌酶肾病变、疟疾性肾病变、恶性病相关的肾病、恶性高血压、软斑病(Malakoplakia)、McKittrick-Wheelock综合征、MDMA(莫利(Molly)；狂喜(Ecstacy)；3,4-亚甲基二氧基甲基安非他命)性肾衰竭、尿道口狭窄、髓质囊性肾病、尿调节素相关的肾病变、青少年1型高尿酸血症肾病变、髓质海绵肾、巨输尿管症、三聚氧胺毒性性肾病、MELAS综合征、膜性增殖性肾小球肾炎、膜性肾病变、伴有隐蔽性IgGk沉积的膜样肾小球病变、中美洲肾病变(MesoAmerican Nephropathy)、代谢性酸中毒、代谢性碱中毒、氢甲蝶吟相关的肾衰竭、显微镜下多血管炎、乳碱综合征、微小病变肾病、肾脏意义的单克隆丙种球蛋白病、异常蛋白血症、漱口剂毒性、MUC1肾病变、多囊性发育不良肾、多发性骨髓瘤、骨髓增殖性赘瘤性肾小球病变、指甲-髌骨综合征、NARP综合征、肾钙质沉着症、肾源性系统性纤维化、肾下垂(Nephroptosis)(浮游肾、肾下垂症(RenalPtosis))、肾病综合征、神经源性膀胱、9/11和肾病、结节性肾小球硬化、非淋球菌性尿道炎、胡桃夹综合征(Nutcracker syndrome)、肾单位稀少巨大症、口面指综合征、乳清酸尿症、直立性低血压、直立性蛋白尿、渗透性利尿、渗透性肾变病、卵巢过度刺激综合征、草酸盐肾病变、佩吉氏肾(Page Kidney)、乳头坏死、乳头肾综合征(Papillorenal Syndrome)(肾缺损综合征、孤立肾发育不全)、PARN突变性肾病、细小病毒B19性肾病、腹膜-肾综合征、后尿道瓣膜POEMS综合征、足细胞内折性肾小球病变、感染后肾小球肾炎、链球菌感染后肾小球肾炎、非典型性感染后肾小球肾炎、感染后肾小球肾炎(IgA显性)、模仿IgA肾病变、结节性多动脉炎、后尿道瓣膜多囊性肾病、阻塞后利尿、子病前症、丙泊酚输注综合征、增殖性肾小球肾炎伴单克隆IgG沉积(纳萨病(Nasr Disease))、 蜂胶(蜜蜂树脂)相关的肾衰竭、蛋白尿(尿中带蛋白质)、假性高醛固酮症、假性低碳酸氢盐血症、假性甲状旁腺功能减退症,肺肾综合征、肾孟肾炎(肾感染)、肾积脓、非那吡啶(Pyridium)性肾衰竭、放射性肾病变、雷诺嗉(Ranolazine)性肾病、再喂食综合征、反流性肾病变、急进性肾小球肾炎、肾脓肿、肾周围脓肿、肾发育不全、肾弓形静脉微血栓相关的急性肾损伤、肾动脉瘤、自发性肾动脉剥离、肾动脉狭窄、肾细胞癌、肾囊肿、肾低尿酸血症伴运动诱发的急性肾衰竭、肾梗塞、肾性骨营养不良、肾小管性酸中毒、肾素突变和常染色体显性小管间质性肾病、肾素分泌肿瘤(近肾小球细胞瘤)、渗透调定点重设(Reset Osmostat)、腔静脉后输尿管、腹膜后纤维化、横纹肌溶解、与肥胖症治疗手术相关的横纹肌溶解、类风湿性关节炎相关的肾病、类肉瘤病肾病、肾和脑的盐流失、血吸虫病性肾小球病、施沐克免疫-骨发育不良(Schimke immunoosseous dysplasia)、硬皮病肾危象、蛇纹石肺骨-多囊性肾综合征、埃克纳综合征(ExnerSyndrome)、镰状细胞肾病变、二氧化硅暴露性慢性肾病、斯里兰卡农民肾病(Sri LankanFarmers'Kidney Disease)、干燥综合征性肾病、使用合成大麻素导致的急性肾损伤、造血细胞移植后肾病、与干细胞移植有关的肾病、TAFRO综合征、茶和吐司性低钠血症、泰诺福韦(Tenofovir)诱发的肾毒性、薄基底膜病、良性家族性血尿症、与单克隆丙种球蛋白病相关诺嗉(Ranolazine)性肾病、再喂食综合征、反流性肾病变、急进性肾小球肾炎、肾脓肿、肾周围脓肿、肾发育不全、肾弓形静脉微血栓相关的急性肾损伤、肾动脉瘤、自发性肾动脉剥离、肾动脉狭窄、肾细胞癌、肾囊肿、肾低尿酸血症伴运动诱发的急性肾衰竭、肾梗塞、肾性骨营养不良、肾小管性酸中毒、肾素突变和常染色体显性小管间质性肾病、肾素分泌肿瘤(近肾小球细胞瘤)、渗透调定点重设(Reset Osmostat)、腔静脉后输尿管、腹膜后纤维化、横纹肌溶解、与肥胖症治疗手术相关的横纹肌溶解、类风湿性关节炎相关的肾病、类肉瘤病肾病、肾和脑的盐流失、血吸虫病性肾小球病、施沐克免疫-骨发育不良(Schimke immunoosseous dysplasia)、硬皮病肾危象、蛇纹石肺骨-多囊性肾综合征、埃克纳综合征(ExnerSyndrome)、镰状细胞肾病变、二氧化硅暴露性慢性肾病、斯里兰卡农民肾病(Sri LankanFarmers'Kidney Disease)、干燥综合征性肾病、使用合成大麻素导致的急性肾损伤、造血细胞移植后肾病、与干细胞移植有关的肾病、TAFRO综合征、茶和吐司性低钠血症、泰诺福韦(Tenofovir)诱发的肾毒性、薄基底膜病、良性家族性血尿症、与单克隆丙种球蛋白病相关的血栓性微血管病变、战壤肾炎、膀胱三角区炎、泌尿生殖器结核症、结节性硬化、肾小管发育不全、针对近端小管刷缘的自身抗体所致的免疫复合物小管间质性肾炎、肿瘤溶解综合征、尿毒症、尿毒症视神经病变、囊性输尿管炎、输尿管疝、尿道肉阜、尿道狭窄、尿失禁、尿路感染、尿路梗阻、泌尿生殖痿、尿调节素相关的肾病、万古霉素(Vancomycin)相关的管型肾病变、血管舒缩肾病变、膀胱肠痿、膀胱输尿管反流、VGEF抑制性肾血栓微血管病变、挥发性麻醉剂性急性肾损伤、逢希伯-林道病(Von Hippel-Lindau Disease)、华氏巨球蛋白血症肾小球肾炎(Waldenstrom's Macroglobulinemic Glomerulonephritis)、华法林(Warfarin)相关的肾病变、黄蜂蜇伤性急性肾损伤、韦格纳氏肉芽肿病(Wegener'sGranulomatosis)、肉芽肿伴多血管炎、西尼罗河病毒(West Nile Virus)性慢性肾病、冯德利希综合征(Wunderlich syndrome)、柴尔维格氏综合征(Zellweger Syndrome)或脑肝肾综合征。
上述的皮肤疾病包括但不限于：痤疮、斑秃、基底细胞癌、鲍温病(Bowen's disease)、先天性红细胞生成性叶琳症、接触性皮炎、达里埃氏病(Darier'sdisease)、播散性浅表光化性汗孔角化症、营养不良型大疱性表皮松解症、湿疹(特应性湿 疹)、乳腺外佩吉特氏病、单纯型大疱性表皮松解症、红细胞生成性原卟琳症、指(趾)甲的真菌感染、黑利-黑利病(Hailey-Hailey disease)、单纯型疱疹、化脓性汗腺炎、多毛症、多汗症、鱼鳞癣、脓疱病、癫痕疙瘩、毛角化病、扁平苔藓、硬化性苔藓、黑色素瘤、黑皮病、粘膜类天疱疮、类天疱疮、寻常天疱疮、苔藓样糠疹、毛发红糠疹、足跖疣(疣)、多形性日光疹、牛皮癣、斑块状牛皮癣、坏疽性脓皮病、酒渣鼻、疥疮、硬皮病、带状疱疹、鳞状细胞癌、斯威特氏综合征(sweet's syndrome)、尊麻疹和血管性水肿和白癫风。
上述的纤维化疾病包括但不限于：粘连性肩关节囊炎、动脉僵硬、关节纤维化、心房纤维化、心脏纤维化、硬化、先天性肝纤维化、克罗恩病、囊性纤维化、杜普伊特伦氏挛缩(Dupuytren's contracture)、心肌内膜纤维化、胶质癫痕、丙型肝炎、肥厚性心肌病、过敏性肺炎、特发性肺纤维化、特发性间质性肺炎、间质性肺病、癫痕疙瘩、纵膈纤维化、骨髓纤维化、肾源性系统性纤维化、非酒精性脂肪肝病、陈旧性心肌梗塞、佩罗尼氏病(Peyronie's disease)、尘肺症、肺炎、进行性大块纤维化、肺纤维化、辐射诱发的肺损伤、腹膜后纤维化、硬皮病/系统性硬化、硅肺病和心室重塑。
上述的血红蛋白病症包括但不限于：“显性”β-地中海贫血、获得性(毒性)高铁血红蛋白血症、碳氧血红蛋白血症、先天性亨氏小体(Heinz body)溶血性贫血、HbH病、HbS/β-地中海贫血、HbE/β-地中海贫血、HbSC病、纯合型α+-地中海贫血(α0-地中海贫血的表型)、巴氏血红蛋白胎儿水肿(Hydrops fetalis with Hb Bart's)、镰状细胞贫血/疾病、镰状细胞性状、镰状β-地中海贫血病、α+-地中海贫血、α0-地中海贫血、与骨髓发育不良综合征相关的α-地中海贫血、α-地中海贫血伴智力迟钝综合征(ATR)、β0-地中海贫血、β+-地中海贫血、δ-地中海贫血、γ-地中海贫血、重度β-地中海贫血、中度β-地中海贫血、δβ-地中海贫血和εγδβ-地中海贫血。
上述的自身免疫性疾病包括但不限于：弛缓不能(Achalasia)、艾迪生病、成人斯蒂尔病(Adult Still'sdisease)、无丙种球蛋白血症(Agammaglobulinemia)、斑秃、淀粉样变性、强直性脊柱炎、抗GBM/抗TBM肾炎、抗磷脂质综合征、自身免疫性血管性水肿、自身免疫性自主神经机能异常、自身免疫性脑脊髓炎、自身免疫性肝炎、自身免疫性内耳病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性串丸炎、自身免疫性胰腺炎、自身免疫性视网膜病变、自身免疫性尊麻疹、轴突和神经元神经病变(AMAN)、巴洛病(Balódisease)、白塞病、良性粘膜类天疱疮、大疱性类天疱疮、卡斯尔曼病(Castleman disease，CD)、乳糜泻、查加斯病(Chagasdisease)、慢性发炎性脱髓鞘型多发性神经病变(CIDP)、慢性复发性多灶性骨髓炎(CRMO)查格-施特劳斯综合征(CSS)或嗜酸细胞性肉芽肿病(EGPA)、癫痕性类天疱疮、科根综合征(Cogan's syndrome)、冷凝集素病、先天性心脏传导阻滞、柯萨奇病毒性心肌炎(Coxsackiemyocarditis)、CREST综合征、克罗恩病、疱疹样皮炎、皮肌炎、德维克氏病(视神经脊髓炎)盘状狼疮、德雷斯勒氏综合征(Dressler's syndrome)、子宫内膜异位症、嗜酸细胞性食管炎(EoE)、嗜酸细胞性筋膜炎、结节性红斑、原发性混合型冷球蛋白血症、埃文斯综合征(Evans syndrome)、纤维肌痛、纤维化肺泡炎、巨细胞性动脉炎(题动脉炎)、巨细胞性心肌炎、肾小球肾炎、古德帕斯彻综合征、肉芽肿伴多血管炎、格雷夫斯病(Graves'disease)、格林-巴利综合征、桥本氏甲状腺炎、溶血性贫血、亨诺-许兰紫癫(Henoch-Schonleinpurpura,HSP)、妊娠性疱疹或妊娠性类天疱疮(PG)、化脓性汗腺炎(HS)(反常性座疮)、低丙种球蛋白血症、IgA肾病变、IgG4相关的硬化性疾病、 免疫性血小板减少性紫癫(ITP)、包涵体肌炎(IBM)、间质性膀胱炎(IC)、青少年关节炎、青少年糖尿病(1型糖尿病)、青少年肌炎(JM)、川崎病(Kawasaki disease)、兰伯特-伊顿综合征(Lambert-Eaton syndrome)、白细胞碎裂性血管炎、扁平苔薛、硬化性苔薛、木样结膜炎、线性IgA病(LAD)、狼疮、慢性莱姆病、梅尼埃氏病(Meniere's disease)、显微镜下多血管炎(MPA)、混合性结缔组织疾病(MCTD)莫伦氏溃疡(Mooren's ulcer)、穆夏-哈伯曼病(Mucha-Habermann disease)、多灶性运动神经病变(MMN)或MMNCB、多发性硬化、重症肌无力、肌炎、发作性睡病、新生儿狼疮、视神经脊髓炎、中性粒细胞减少症、眼部疲痕性类天疱疮、视神经炎、复发性风湿症(PR)、PANDAS、副赘瘤性小脑变性(PCD)、阵发性夜间血红蛋白尿(PNH)、帕罗综合征(Parry Rombergsyndrome)、睫状体扁平部炎(周边葡萄膜炎)、帕森-特纳综合征(Parsonnage-Turnersyndrome)、天疱疮、外周神经病变、静脉周围性脑脊髓炎、恶性贫血(PA)、POEMS综合征、结节性多动脉炎、I型多腺性综合征、II型多腺性综合征、III型多腺性综合征、风湿性多肌痛、多发性肌炎、心肌梗塞后综合征、心包切开术后综合征、原发性胆汁性肝硬化、原发性硬化性胆管炎、孕酮皮炎、牛皮癣、牛皮癣性关节炎、纯红细胞再生障碍(PRCA)、坏疽性脓皮病、雷诺氏现象(Raynaud's phenomenon)、反应性关节炎、反射性交感神经营养不良、复发性多发性软骨炎、不宁腿综合征(RLS)、腹膜后纤维化、风湿热、类风湿性关节炎、类肉瘤病、施密特综合征(Schmidt syndrome)、巩膜炎、硬皮病、干燥综合征、精液和睾丸自身免疫性、僵人综合征(SPS)、亚急性细菌性心内膜炎(SBE)、苏萨克氏综合征(Susac's syndrome)、交感性眼炎(SO)、高安氏动脉炎(Takayasu's arteritis)、题动脉炎/巨细胞性动脉炎、血小板减少性紫癫(TTP)、妥洛沙-韩特综合征(Tolosa-Hunt syndrome,THS)、横贯性脊髓炎、1型糖尿病、溃疡性结肠炎(UC)、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、白癫风、伏格特-小柳-原田病(Vogt-Koyanagi-Harada Disease)和韦格纳氏肉芽肿病(或肉芽肿伴多血管炎(GPA))。
上述的病毒感染包括但不限于：流行性感冒、人类免疫缺陷病毒(HIV)和疱疹。
上述的疟疾感染包括但不限于：由间日原虫(Plasmodium vivax)、卵形症原虫(Plasmodium ovale)、三日疟原虫(Plasmodium malariae)和恶性原虫(Plasmodium falciparum)引起的感染。
上述的具有导致未折叠蛋白质反应(UPR)诱导的突变疾病包括但不限于：Marinesco-Sjogren综合征、神经病性疼痛、糖尿病性神经病性疼痛、噪音诱发的听力损失、非综合征性感觉神经听力损失、年龄相关性听力损失、沃尔弗拉姆综合征(Wolfram syndrome)、达里尔-怀特病(Darier White disease)、乌谢尔综合征(Usher syndrome)、胶原蛋白病变、薄基底肾病变、奥尔波特综合征、骨胳软骨发育不良、施密德型干骺端软骨发育不良(metaphysealchondrodysplasia type Schmid)和假软骨发育不良。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或基团所替换；或者是分子中原子的孤对电子被其它的原子或基团替换，例如S原子上的孤对电子可被O 原子取代形成
“可被……取代”、“可选地被……取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca-Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C1-C6烷基是指包含1～6个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。比如C1-C6烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。
术语“C1-C10烷基”指的是任意的含有1-10个碳原子的直链或支链基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基以及直链或支链的以下烷基:C7烷基、C8烷基、C9烷基、C10烷基等。
而且，所述“C1-C10烷基”包括碳原子数为1-10之间的任意两个整数为端点的区间的直链或支链基团。例如，“C1-C10烷基”包括C1-C10烷基、C1-C8烷基、C1-C6烷基、C2-C10烷基、C2-C8烷基、C2-C6烷基、C6-C10烷基、等等，以上所列仅仅为举例而言，并不是对于所述区间的限定。
术语“烷氧基”及其衍生物指的是任意上述烷基(例如C1-C10烷基、C1-C6烷基等)，其通过氧原子(-O-)连接到分子的其余部分。
“亚烷基”是指具有指定数目的成员原子的二价饱和脂族烃基。Ca-Cb亚烷基是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如，术语“亚丙基”可以通过下列结构例举:同样地，术语“二甲基亚丁基”可以例如通过下列结构的任一种例举:
本发明的C1-C4亚烷基可以为C1亚烷基(例如-CH2-)、C2亚烷基(例如-CH2CH2-等)、C3亚烷基或C4亚烷基。
本发明中所述的“亚环烷基”是指具有多个碳原子且没有环杂原子的具有单个环或多个环(稠环、螺环、桥环)的二价饱和环状烷烃。单碳环基基团的实例包括例如二价环丙烷基、二价环丁烷基、二价环己烷基、二价环戊烷基、二价环辛烷基、二价环戊烯烃基和二价环己烯烃基等。桥环亚烷烃体系的实例包含二环[3,1,0]己烷、二环[3,1,1]己烷、二环[2,2,1]己烷、二环[2,2,2]己烷。
本发明中所述的“亚环烷基”实施包括但不限于 等。
术语“C3-C10环烷基”指的是3至10元全碳单环、稠环和桥环，其可以包含0个、一个或多个双键，但不具有完全共轭的π-电子系统。C3-C10环烷基的实例是但不限于环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环己二烯等等。
本发明中所述的“杂环烷基”是指包含至少一个杂原子的具有单个环或多个 环(稠环、螺环、桥环)的一价或二价饱和环(杂环烷基的二价饱和环即为亚杂环烷基)；其中杂原子指氮原子、氧原子、硫原子等。3-10元杂环基实例可以是氧杂环丁烷基、氮杂环丁烷基、氧杂环戊烷基、氧杂环己烷基、哌嗪基、哌啶基、吗啉基、均三噁烷基等。本发明中所述的“杂环烷基”实施包括但不限于 或哌啶基等。
本发明中所述的不饱和是指基团或者分子中含有碳碳双键、碳碳三键、碳氧双键、碳硫双键、碳氮三键等。
本发明中所述的“芳环”是指具有多个碳原子的芳烃基团。芳基通常是具有多个碳原子的单环、二环或三环芳基。此外，本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。
本发明中所述的“5-10元杂芳基”是指包含至少一个杂原子的芳香性不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。其中比如5-6元杂芳基例如代表:吡啶基、吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、吡喃基、噻喃基、哌嗪基、连三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、1,2,3,4-四唑基、1,2,3,5-四唑基、异噁唑基、噁唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、呋咱基、1,2,3,5-噁三唑基、1,2,3,4-噁三唑基、1,3,2-二噁唑基、1,2,3-二噁唑基、1,2,3,4-二噁二唑基、1,2,3,5-二噁二唑基、1,3,3,4-二噁二唑基、1,3,4,5-二噁二唑基、1,2,3,4-二噁二唑基、异噻唑基、哒嗪基、连三嗪基、1,2,4-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、1,2,4-噁嗪基、1,2,6-噁嗪基、1,3,2-噁嗪基、1,3,6-噁嗪基、1,4,2-噁嗪基、1,2-异噁嗪基、1,4-异噁嗪基。
本发明中所述的“卤素”是指氟、氯、溴或碘。
本发明中所述的“卤素取代的烷基”是指烷基中的一个或多个氢原子被卤素取代；例如卤素取代的C1～4烷基指氢原子被一个或多个卤素原子取代的包含1～4个碳原子的烷基；还例如单氟甲基、双氟甲基、三氟甲基。
本发明中所述的“-N(R)2”等是指R基团与氮原子以单键相连。
本发明中所述的“＝O”是指氧原子通过双键取代分子中的两个氢原子。
本发明中，对本领域技术人员显而易见的是，其名称是复合名称的任意基团，例如“6-10元芳基-D-C1-C6烷基”，应该指的是常规地从左向右从其衍生的部分例如C1-C6烷基来构建，应该理解的是这里的烷基为二价烷基。
本发明中“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物，包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体等等。。
本发明中“互变异构体”通常是指可通过低能垒(low energybarrier)互相转化的不同能量的结构异构体。例如，质子互变异构体(protontautomer)(也称为质子移 变互变异构体(prototropic tautomer))包括通过质子迁移进行的互相转化，诸如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valencetautomer)包括通过一些成键电子的重组进行的互相转化。
本发明中“几何异构体”也称“顺反异构体”，因双键(包括烯烃的双键、C＝N双键和N＝N双键)或环碳原子的单健不能自由旋转而引起的异构体。
本发明中“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
本发明中“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明中“消旋体”、“外消旋物”或“外消旋混合物”是指缺少光学活性的两个对映异构体的等摩尔混合物。
本发明中“多晶型物”是指呈特定晶体堆积排列的化合物(或其盐、水合物或溶剂化物)的结晶形式。所有多晶型物具有相同的元素组成。不同的晶型通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光学和电学性质、稳定性和溶解度。重结晶溶剂、结晶速率、储存温度和其它因素可能导致一种晶型占优势。
本发明中“溶剂合物”即化合物溶解于溶剂后产生的混合物。
本发明中“N-氧化物”又称氧化胺，是一类通式为R3N+-O-(也写作R3N＝O或R3N→O)的有机化合物。
本发明中“同位素标记化合物”是指分子或基团中的1个或多个原子被其同位素原子取代，比如氢原子被氘原子取代，其中氘原子的占比大于氘在自然界中的丰度；又比如12C被13C取代。
本发明中“代谢产物”指的是药物分子被机体吸收后，在机体作用下发生的化学结构转化生成的物质。
本发明中“前药”是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。
术语“预防”包括抑制和延迟疾病的发作，并且不仅包括在发展疾病之前的预防，还包括在治疗后预防疾病的复发。
术语“治疗”意指逆转、减轻或清除这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同 时、分别或有序地对受试对象进行给药。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
下面结合实施例对本申请的实施方式作进一步详细描述。以下实施例的详细描述和附图用于示例性地说明本申请的原理，但不能用来限制本申请的范围，即本申请不限于所描述的实施例。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于毕得医药、乐研、泰坦、韶远、安耐吉化学、探索平台、南京药石、江苏艾康、北京伊诺凯科技等公司。其中，四丙基高钌酸铵购自探索平台、1-丙基磷酸环酐购自北京伊诺凯科技有限公司。
实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。室温为最适宜的反应温度，为20℃～30℃。实施例中无特殊说明，M是摩尔每升。
化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(Methanol-d4)，内标为四甲基硅烷(TMS)。LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
二甲基甲酰胺简称DMF；N,N'-二异丙基乙胺(又称二异丙基乙胺)简称DIEA或DIPEA；2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯简称HATU；四丙基高钌酸铵简称TPAP；1-丙基磷酸环酐简称T3P；N-甲基吗啉-N-氧化物简称NMO；三氟乙酸简称TFA。四氢呋喃简称THF。
实施例1：化合物1的合成
步骤1:中间体1b的合成
25℃条件下，向100mL的单口瓶中加入化合物1a(毕得医药，货号：BD57204， 4.0g，16.44mmol)和二甲基甲酰胺(20.0mL)，搅拌条件下依次加入化合物N,N'-硫羰基二咪唑(4.1g，23.02mmol)。25℃反应1小时后将反应温度提高至100摄氏度搅2小时，随后将反应温度降至零摄氏度加入碘甲烷(2.33g，16.44mmol)，在25℃下搅1小时反应完成。向所得反应液中加入50mL水，用50mL的乙酸乙酯萃取，重复萃取三次，所得有机相合并后用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品经柱层析纯化得到中间体1b。LC-MS:m/z:243.9(M+H-56)+。
步骤2:中间体1c的合成
25℃下，向100mL的单口瓶中加入中间体1b(4.1g，13.71mmol)和二氯甲烷(20.0mL)，冰浴并搅拌条件下加入化合物间氯过氧苯甲酸(4.2g，20.58mmol)。25℃反应16小时后反应完成。向所得反应液中加入饱和碳酸氢钠水溶液调节溶液pH至8左右，用乙酸乙酯萃取，无水硫酸钠干燥，将过滤之后得到的滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体1c。LC-MS:m/z:275.9(M+H-56)+。
步骤3:中间体1e的合成
25℃下，向100mL的单口瓶中加入化合物1d(毕得医药，货号：BD25596，197mg，2.26mmol)和四氢呋喃(10mL)，搅拌条件下加入化合物NaH(181mg，4.52mmol)。25℃反应0.5小时后加入中间体1c(500mg，1.51mmol)，在25℃下搅16小时反应完成。向所得反应液中加入25mL水，用25mL乙酸乙酯萃取，所得有机相用50mL饱和食盐水洗涤，无水硫酸钠干燥，将过滤之后得到的滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体1e。LC-MS:m/z:283.0(M+H-56)+。
步骤4:中间体1f的合成
25℃下，向100mL的单口瓶中加入中间体1e(270mg，0.80mmol)和二氯甲烷(3.0mL)，搅拌条件下加入三氟乙酸(1.0mL，4.5mmol)。25℃反应2小时后反应完成。减压浓缩得到中间体1f。LC-MS:m/z:239.0(M+H)+。
步骤5:中间体1g的合成
冰浴下，向100mL的单口瓶中加入中间体1f(140mg，0.59mmol)和冰醋酸(3.5mL)，水(1.5mL)，搅拌条件下加入亚硝酸钠(121mg，1.75mmol)，反应1小时后提高温度至25℃继续反应1小时反应完成。减压浓缩所得反应液得到中间体1g。LC-MS:m/z:268.0(M+H)+。
步骤6:中间体1h的合成
冰浴下，向100mL的单口瓶中加入中间体1g(80mg，0.30mmol)和冰醋酸(1.0mL)，甲醇(3.0mL)，搅拌条件下加入锌粉(97mg，1.48mmol)，25℃反应2小时后反应完成。减压浓缩所得反应液得到中间体1h。LC-MS:m/z:254.0(M+H)+。
步骤7:化合物1的合成
冰浴下，向50mL的单口瓶中加入化合物1i(毕得医药，货号：BD00901377，71mg，0.35mmol)和二甲基甲酰胺(3.0mL)，搅拌条件下依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(180mg，0.47mmol)，二异丙基乙胺(123mg，0.95mmol)。25℃反应半小时后反应，向所得反应液中加入中间体1h(55mg，0.22mmol)，25℃下过夜反应结束。向所得反应液中加入25mL水，用50mL乙酸乙酯萃取，重复萃取三次，所得有机相合并后用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后得到的滤液减压浓缩得到粗品。粗品用高效液相 (碳酸氢胺/乙腈/水体系)分离纯化得到化合物1。1H NMR(400MHz,CDCl3)δ7.28–7.26(m,1H),6.78–6.73(m,1H),6.71–6.66(m,1H),4.81(s,1H),4.50(s,2H),4.38–4.28(m,3H),4.08–4.12(m,2H),3.33(s,3H),3.14–3.12(m,2H),2.88–2.84(m,1H),2.78–2.72(m,2H),2.14–2.10(m,4H)。LC-MS:m/z:440.0(M+H)+。
实施例2：化合物2的合成
步骤1:中间体2c的合成
冰浴下，向100mL的单口瓶中加入化合物1i(467mg，2.29mmol)和二甲基甲酰胺(8.0mL)，搅拌条件下依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.08g，2.86mmol)，二异丙基乙胺(986mg，7.64mmol)。25℃反应半小时后反应，向所得反应液中加入化合物2a(毕得医药，货号：BD283560，300mg，1.91mmol)，25℃反应过夜。向所得反应液中加入100mL水，每次用50mL乙酸乙酯萃取，共萃取两次，所得有机相合并后用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体2c。LC-MS:m/z:344.0(M+H)+。
步骤2:中间体2d的合成
25℃向100mL的单口瓶中加入中间体2c(360mg，1.05mmol)和乙醇(3.0mL)，搅拌条件下加入水合肼(969mg，10.50mmol)，提高温度至80摄氏度过夜反应完成。向所得反应液中加入25mL水，用25mL乙酸乙酯萃取，所得有机相用25mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体2d。LC-MS:m/z:344.0(M+H)+。
步骤3:中间体2f的合成
25℃向50mL的单口瓶中加入化合物1d(17mg，0.2mmol)和四氢呋喃(3.0mL)，搅拌条件下加入三光气(181mg，0.61mmol)，25℃反应2小时后，加入中间体2d(70mg，0.2mmol)。提高温度至80摄氏度过夜反应，反应体系存在大量固体，随后加入二甲基甲酰胺(3.0mL)，继续在80摄氏度反应过夜反应结束，向所得反应液中加入50mL水，用50mL乙酸乙酯萃取，所得有机相用100mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后得到的滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体2f。LC-MS:m/z:457.0(M+H)+。
步骤4:化合物2的合成
25℃下，向50mL的单口瓶中加入中间体2f(26mg，0.06mmol)和二甲基甲酰胺(3.0mL)，搅拌条件下依次加入碳酸铯(55mg，0.17mmol)，对甲苯磺酰氯(22mg，0.11mmol)。25℃反应3小时后反应完成。向所得反应液中加入35mL水，用35mL乙酸乙酯萃取，所得有机相用100mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)分离纯化得到化合物2。1H NMR(400MHz,CDCl3)δ7.33(t,J＝8.6Hz,1H),6.93–6.67(m,3H),6.65–6.63(m,2H),4.77–4.72(m,1H),4.52–4.47 (m,1H),4.43(s,2H),3.71–3.56(m,3H),3.48–3.33(m,3H),2.42–2.38(m,2H),1.80–1.68(m,4H),1.61–1.56(m,2H).LC-MS:m/z:439.1(M+H)+。
实施例3：化合物21的合成
步骤1:中间体21a的制备
25℃下，向100mL的单口瓶中加入化合物21g(毕得医药，BD212373，5.00g，19.42mmol)和乙醇(50.0mL)，搅拌条件下加入化合物水合肼(7.75g，84.00mmol)，提高温度至80摄氏度过夜反应完成。将反应液冷却后减压浓缩得到粗品。粗品经过柱机分离纯化得到中间体21a。LC-MS:m/z:202.0(M+H-56)+。
步骤2:中间体21c的制备
25℃下，向100mL的单口瓶中加入中间体21a(3.8g，13.29mmol)和1,2-二氯乙烷(30.0mL)，搅拌条件下依次加入化合物N,N'-羰基二咪唑(5.0g，26.58mmol)。25℃反应18小时后反应完成。向所得反应液中加入25mL水，有机相用100mL饱和食盐水洗涤，无水硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品通过过柱机纯化得到中间体21c。LC-MS:m/z:228.0(M+H-56)+。
步骤3:中间体21d的制备
25℃下，向100mL的单口瓶中加入中间体21c(2.9g，9.26mmol)和二甲基甲酰胺(30mL)，搅拌条件下依次加入3-(三氟甲氧基)-氮杂环丁烷(1.73g，12.28mmol)，二异丙基乙胺(6.65g，51.18mmol)和卡特缩合剂(6.45g，15.53mmol)。25℃反应十六小时后反应完成。向所得反应液中加入100mL水，分离得到的有机相用100mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)分离纯化得到中间体21d。LC-MS:m/z:407.2(M+H)+。
步骤4:中间体21b的制备
25℃下，向100mL的单口瓶中加入中间体21d(140mg，0.34mmol)和二氯甲烷(6.0mL)，搅拌条件下加入三氟乙酸(2.0mL，4.5mmol)。25℃反应2小时后反应完成。减压浓缩得到中间体21b。LC-MS:m/z:307.2(M+H)+。
步骤5:化合物21的合成。
25℃下，在8mL的反应瓶中将化合物21f(毕得医药，货号：BD11064，6mg，0.03mmol)和中间体21b(5.1mg，0.02mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(4.048mg，0.04mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(15.21mg，0.03mmol)。25℃下搅拌10小时反应结束。向反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20 mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物21。1H NMR(400MHz,MeOD)δ7.15–6.89(m,4H),5.37–5.20(m,1H),4.60–4.51(m,2H),4.49(s,2H),4.33(dd,J＝9.4,4.0Hz,2H),3.84(ddd,J＝15.6,7.9,4.0Hz,1H),2.81(tt,J＝12.1,3.5Hz,1H),2.17(d,J＝12.1Hz,2H),2.03(d,J＝9.8Hz,2H),1.76–1.60(m,2H),1.59–1.42(m,2H).LC-MS:m/z:459.1(M+H)+。
实施例4：化合物22的合成
25℃下，在8mL的反应瓶中将化合物22a(毕得医药，货号：BD21790，28mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物22。1H NMR(400MHz,DMSO)δ7.90(d,J＝7.9Hz,1H),7.45(dd,J＝7.9,1.6Hz,1H),7.36–7.22(m,1H),7.09–6.91(m,2H),5.39–5.23(m,1H),4.59(s,2H),4.46(dd,J＝9.6,6.8Hz,2H),4.19(dd,J＝9.6,4.0Hz,2H),3.63(ddd,J＝11.3,7.5,3.8Hz,1H),2.74(ddd,J＝11.8,7.7,3.5Hz,1H),2.03(d,J＝11.3Hz,2H),1.88(dd,J＝12.8,3.1Hz,2H),1.58–1.45(m,2H),1.43–1.30(m,2H).LC-MS:m/z:475.2(M+H)+。
实施例5：化合物23的合成
步骤1:化合物23的合成
25℃条件下，在8mL的反应瓶中将化合物23a(毕得医药，货号：BD21634，28mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物23。1H NMR(400MHz,DMSO)δ8.04(d,J＝8.0Hz,1H),7.32(t,J＝8.1Hz,1H),7.03(t,J＝5.5Hz,2H),6.93(dd,J＝8.3,2.0Hz,1H),5.37–5.26(m,1H),4.50(s,2H),4.46(dd,J＝9.4,6.9Hz,2H),4.19(dd,J＝9.5,3.9Hz,2H),3.74(s,1H),2.78–2.67(m,1H),2.03(d, J＝11.5Hz,2H),1.85(d,J＝9.7Hz,2H),1.51(dd,J＝25.0,10.9Hz,2H),1.44–1.31(m,2H).LC-MS:m/z:475.2(M+H)+。
实施例6：化合物24的合成
步骤1:化合物24的合成
25℃下，在8mL的反应瓶中将化合物24a(毕得医药，货号：BD45137，25.5mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物24。1H NMR(400MHz,MeOD)δ7.37–7.26(m,1H),6.92–6.70(m,3H),5.32–5.28(m,1H),4.58–4.53(m,2H),4.53(s,2H),4.31(dd,J＝9.6,4.1Hz,2H),3.84(s,1H),2.81(s,1H),2.17(d,J＝11.8Hz,2H),2.09–1.98(m,2H),1.67(dd,J＝12.6,2.7Hz,2H),1.58–1.39(m,2H).LC-MS:m/z:459.2(M+H)+。
实施例7：化合物25的合成
步骤1:中间体25b的合成
25℃下，在50mL反应瓶中将化合物25a(毕得医药，货号：BD9830，500mg，3.41mmol)、溴乙酸叔丁酯(997.68mg，5.11mmol)和碳酸铯(2.2g，6.82mmol)溶于乙腈(7mL)中。25℃反应2小时后反应完成。向所得反应液中加入15mL二氯甲烷，过滤之后滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体25b。1H NMR(400MHz,CDCl3)δ7.07(t,J＝8.8Hz,1H),6.95(dd,J＝5.9,3.1Hz,1H),6.78(dt,J＝9.1,3.4Hz,1H),4.49(s,2H),1.51(s,9H).
步骤2:中间体25c的合成
25℃下，向25mL的单口瓶中加入中间体25b(60mg，0.23mmol)和二氯甲烷(0.5mL)，搅拌条件下加入三氟乙酸(0.5mL，6.71mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体25c。LCMS:m/z:203.0(M-H)-。
步骤3:化合物25的合成
25℃下，在8mL的反应瓶中将中间体25c(30.69mg，0.15mmol)和中间 体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物25。1H NMR(400MHz,MeOD)δ7.24–7.13(m,2H),6.97(dt,J＝9.1,3.4Hz,1H),5.30(ddd,J＝10.9,6.8,4.3Hz,1H),4.60–4.46(m,4H),4.29(dd,J＝9.6,4.1Hz,2H),3.84(tt,J＝11.5,3.9Hz,1H),2.80(tt,J＝12.1,3.5Hz,1H),2.24–2.08(m,2H),2.03(dd,J＝12.7,2.8Hz,2H),1.67(qd,J＝13.2,3.0Hz,2H),1.49(ddd,J＝25.5,12.8,3.2Hz,2H).LC-MS:m/z:493.2(M+H)+。
实施例8：化合物26的合成
步骤1:中间体26b的合成
25℃下，在50mL反应瓶中将化合物26a(毕得医药，货号BD85025，500mg，2.41mmol)、溴乙酸叔丁酯(517.08mg，2.65mmol)和碳酸铯(1.57g，4.82mmol)溶于乙腈(7mL)中。25℃反应2小时后反应完成。向所得反应液中加入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体26b。1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.9Hz,1H),7.17(d,J＝2.9Hz,1H),6.83(dd,J＝8.9,2.9Hz,1H),4.51(s,2H),1.51(s,9H)。
步骤2:中间体26c的合成
25℃下，向25mL的单口瓶中加入中间体26b(200mg，0.62mmol)和二氯甲烷(2mL)，搅拌条件下加入三氟乙酸(2mL，26.84mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体26c。LC-MS:m/z:262.9(M-H)-。
步骤3:化合物26的合成
25℃下，在8mL的反应瓶中将中间体26c(39.82mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物26。1H NMR(400MHz,MeOD)δ7.19–6.98(m,2H),6.69(d,J＝8.9Hz,1H),4.97(s,1H),4.28–4.11(m,4H),3.95(s,2H),3.51(s,1H),2.48(s,1H),1.76(d,J＝54.4Hz,4H),1.25(dd,J＝72.6,11.6Hz,4H).LC-MS:m/z:555.2(M+H)+。
实施例9：化合物27的合成
25℃下，在8mL的反应瓶中将化合物27a(乐研，33.16mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物27。1H NMR(400MHz,DMSO)δ7.90(d,J＝7.9Hz,1H),7.45(dd,J＝7.9,1.6Hz,1H),7.36–7.22(m,1H),7.09–6.91(m,2H),5.39–5.23(m,1H),4.59(s,2H),4.46(dd,J＝9.6,6.8Hz,2H),4.19(dd,J＝9.6,4.0Hz,2H),3.63(ddd,J＝11.3,7.5,3.8Hz,1H),2.74(ddd,J＝11.8,7.7,3.5Hz,1H),2.03(d,J＝11.3Hz,2H),1.88(dd,J＝12.8,3.1Hz,2H),1.58–1.45(m,2H),1.43–1.30(m,2H)。LC-MS:m/z:509.2(M+H)+。
实施例10：化合物28的合成
25℃下，在8mL的反应瓶中将化合物28a(毕得医药，货号：BD81648，33.16mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物28。1H NMR(400MHz,MeOD)δ7.46(d,J＝8.9Hz,1H),7.22(d,J＝2.9Hz,1H),6.97(dd,J＝8.9,2.9Hz,1H),5.36–5.22(m,1H),4.61–4.44(m,4H),4.28(dd,J＝9.6,4.2Hz,2H),3.84(t,J＝4.0Hz,1H),2.94–2.68(m,1H),2.29–2.09(m,2H),2.03(dd,J＝13.1,3.2Hz,2H),1.73–1.58(m,2H),1.56–1.41(m,2H)。LC-MS:m/z:475.2(M+H)+。
实施例11：化合物29的合成
25℃下，在8mL的反应瓶中将化合物29a(毕得医药，货号BD75182，25.5mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物29。1H NMR(400MHz,MeOD)δ7.22–7.06(m,3H),7.06–6.97(m,1H),5.29(dd,J＝9.3,5.3Hz,1H),4.58(s,2H),4.54(dd,J＝9.2,7.1Hz,2H),4.29(dd,J＝9.6,4.0Hz,2H),3.90–3.79(m,1H),2.87–2.75(m,1H),2.16(d,J＝12.1Hz,2H),2.10–1.99(m,2H),1.75–1.59(m,2H),1.51(dd,J＝17.3,7.4Hz,2H)。LC-MS:m/z:459.2(M+H)+。
实施例12：化合物30的合成
步骤1:中间体30b的合成
25℃下，在50mL反应瓶中将化合物30a(毕得医药，货号：BD33414，500mg，3.84mmol)、溴乙酸叔丁酯(1.1mg，5.76mmol)和碳酸铯(2.5g，7.68mmol)溶于乙腈(7mL)中。25℃反应2小时后反应完成。向所得反应液中加入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体30b。1H NMR(400MHz,CDCl3)δ6.88–6.75(m,2H),6.71(dd,J＝11.4,5.3Hz,1H),4.48(s,2H),1.41(s,9H)。
步骤2:中间体30c的合成
25℃下，向25mL的单口瓶中加入中间体30b(200mg，0.82mmol)和二氯甲烷(2mL)，搅拌条件下加入三氟乙酸(2mL，26.84mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体30c。LC-MS:m/z:187.0(M-H)-。
步骤3:化合物30的合成
25℃下，在8mL的反应瓶中将中间体30c(28.22mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物30。1H NMR(400MHz,MeOD)δ7.05(d,J＝84.8Hz,3H),5.33(s,2H),4.58(s,4H),4.32(s,2H),3.87(s,1H),2.84(s,1H),2.13(d,J＝47.5Hz,4H),1.61(d,J＝65.3Hz,4H)。LC-MS:m/z:477.2(M+H)+。
实施例13：化合物31的合成
步骤1:中间体31b的合成
25℃下，在50mL反应瓶中将化合物31a(毕得医药，货号：BD19192，500mg，3.41mmol)、溴乙酸叔丁酯(731.63mg，3.75mmol)和碳酸铯(2.2g，6.82mmol)溶于乙腈(7mL)中。25℃反应2小时后反应完成。向所得反应液中加入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体31b。1H NMR(400MHz,CDCl3)δ7.17(dd,J＝8.0,3.0Hz,1H),6.93(ddd,J＝9.1,7.8,3.0Hz,1H),6.83(dd,J＝9.1,4.8Hz,1H),4.58(s,2H),1.50(s,9H)。
步骤2:中间体31c的合成
25℃下，向25mL的单口瓶中加入中间体31b(200mg，0.77mmol)和二氯甲烷(2mL)，搅拌条件下加入三氟乙酸(2mL，26.84mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体31c。LC-MS:m/z:202.9(M-H)-。
步骤3:化合物31的合成
25℃下，在8mL的反应瓶中将中间体31c(30.69mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物31。1H NMR(400MHz,MeOD)δ7.29(dd,J＝8.2,2.7Hz,1H),7.09(dt,J＝8.3,3.3Hz,2H),5.36–5.24(m,1H),4.60–4.48(m,4H),4.29(dd,J＝9.6,4.2Hz,2H),3.89–3.73(m,1H),2.83(tt,J＝12.0,3.4Hz,1H),2.25–2.02(m,4H),1.77–1.40(m,4H)。LC-MS:m/z:493.2(M+H)+。
实施例14：化合物32的合成
25℃下，在8mL的反应瓶中将化合物32a(毕得医药，货号：BD65476，33.16mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相 用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物32。1H NMR(400MHz,DMSO)δ7.96(d,J＝7.8Hz,1H),7.32(t,J＝8.2Hz,1H),7.28–7.20(m,1H),7.08–6.92(m,1H),5.36–5.28(m,1H),4.64(s,2H),4.46(dd,J＝9.4,6.9Hz,2H),4.19(dd,J＝9.6,3.9Hz,2H),3.69–3.56(m,1H),2.82–2.68(m,1H),2.03(d,J＝11.4Hz,2H),1.95–1.80(m,2H),1.60–1.44(m,2H),1.36(dt,J＝24.1,6.2Hz,2H)。LC-MS:m/z:509.2(M+H)+。
实施例15：化合物33的合成
步骤1:中间体33b的合成
25℃下，在10mL反应瓶中将化合物33a(毕得医药，货号：BD9831，250mg，1.71mmol)、溴乙酸叔丁酯(498.84mg，2.55mmol)和碳酸铯(1.1g，3.41mmol)溶于乙腈(3mL)中。25℃反应2小时后反应完成。向所得反应液中加入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体33b。LC-MS：m/z:261.1(M+H)+。
步骤2:中间体33c的合成
25℃下，向10mL的单口瓶中加入中间体33b(160mg，0.61mmol)和二氯甲烷(1.5mL)，搅拌条件下加入三氟乙酸(0.5mL，6.71mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体33c。LC-MS:m/z:203.0(M-H)-。
步骤3:化合物33的合成
25℃下，在8mL的反应瓶中将中间体33c(30.69mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物33。1H NMR(400MHz,MeOD)δ7.26(dd,J＝11.0,2.4Hz,1H),7.18-7.13(m,1H),7.09(t,J＝8.7Hz,1H),5.33-5.25(m,1H),4.59(s,2H),4.53(dd,J＝9.6,6.8Hz,2H),4.29(dd,J＝9.6,4.2Hz,2H),3.90-3.75(m,1H),2.85-2.75(m,1H),2.25-2.10(m,2H),2.09–1.95(m,2H),1.67(qd,J＝13.2,3.1Hz,2H),1.48(qd,J＝12.8,3.3Hz,2H)。LC-MS:m/z:493.2(M+H)+。
实施例16：化合物34的合成
步骤1:中间体34b的合成
25℃下，在10mL反应瓶中将化合物34a(毕得医药，货号：BD9841，250mg，1.92mmol)、溴乙酸叔丁酯(412.50mg，2.11mmol)和碳酸铯(1.87g，5.76mmol)溶于乙腈(4mL)中。25℃反应2小时后反应完成。向所得反应液中加入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到中间体34b。LC-MS：m/z:245.1(M+H)+。
步骤2:中间体34c的合成
25℃下，向10mL的单口瓶中加入中间体34b(170mg，0.69mmol)和二氯甲烷(1.5mL)，搅拌条件下加入三氟乙酸(0.5mL，6.71mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体34c。LC-MS:m/z:189.0(M-H)-。
步骤3:化合物34的合成
25℃下，在8mL的反应瓶中将中间体34c(28.22mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物34。1H NMR(400MHz,MeOD)δ7.22(dd,J＝19.5,9.2Hz,1H),6.98(ddd,J＝12.2,6.6,3.0Hz,1H),6.84–6.77(m,1H),5.34–5.23(m,1H),4.53(dd,J＝9.9,7.0Hz,2H),4.51(s,2H),4.29(dd,J＝9.7,4.2Hz,2H),3.84(tt,J＝11.6,3.9Hz,1H),2.81(tt,J＝12.1,3.5Hz,1H),2.25–2.11(m,2H),2.07-1.98(m,2H),1.67(qd,J＝13.2,3.2Hz,2H),1.49(qd,J＝12.8,3.3Hz,2H)。LC-MS:m/z:477.1(M+H)+。
实施例17：化合物35的合成
步骤1:中间体35b的合成
25℃下，在25mL反应瓶中将化合物35a(毕得医药，货号：BD9390，750mg，4.54mmol)、溴乙酸叔丁酯(970.01mg，5.00mmol)和碳酸铯(2.98g，9.09mmol)溶于乙腈(10mL)中。25℃反应2小时后反应完成。向所得反应液中加 入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体35b。LC-MS：m/z:189.0(M-56+H)+。
步骤2:中间体35c的合成
25℃下，向10mL的单口瓶中加入中间体35b(50mg，0.20mmol)和二氯甲烷(1.5mL)，搅拌条件下加入三氟乙酸(0.5mL，6.71mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体35c。LC-MS:m/z:189.0(M+H)+。
步骤3:化合物35的合成
25℃下，在8mL的反应瓶中将中间体35c(28.29mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物35。1H NMR(400MHz,MeOD)δ8.63(s,1H),5.35–5.24(m,1H),4.85(s,1H),4.52(dd,J＝9.7,6.8Hz,1H),4.28(dd,J＝9.7,4.2Hz,1H),3.90–3.68(m,1H),2.91–2.73(m,1H),2.16(d,J＝12.0Hz,1H),2.03(dd,J＝13.4,3.4Hz,1H),1.66(qd,J＝13.3,3.1Hz,1H),1.44(qd,J＝12.9,3.4Hz,1H)。LC-MS:m/z:477.1(M+H)+。
实施例18：化合物36的合成
25℃下，在8mL的反应瓶中将化合物36a(毕得医药，货号：BD11470，29.5mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物36。1H NMR(400MHz,MeOD)δ7.77(d,J＝2.0Hz,1H),7.61(d,J＝8.9Hz,1H),7.48(d,J＝0.9Hz,1H),7.47–7.44(m,1H),5.40–5.20(m,1H),4.54(dd,J＝9.7,6.8Hz,2H),4.30(dd,J＝9.7,4.2Hz,2H),4.05–3.90(m,1H),2.90–2.77(m,1H),2.21(d,J＝12.3Hz,2H),2.17–2.06(m,2H),1.78–1.66(m,2H),1.66–1.53(m,2H)。LC-MS:m/z:485.2(M+H)+。
实施例19：化合物37的合成
25℃下，在8mL的反应瓶中将化合物37a(毕得医药，货号BD182201，31.9mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)， 搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物37。1H NMR(400MHz,MeOD)δ7.92(dd,J＝5.2,3.1Hz,3H),7.45(dd,J＝8.7,2.0Hz,1H),5.39–5.21(m,1H),4.54(dd,J＝9.7,6.8Hz,2H),4.30(dd,J＝9.7,4.2Hz,2H),4.03–3.82(m,1H),2.91–2.77(m,1H),2.30–2.08(m,4H),1.79–1.65(m,2H),1.58(dt,J＝13.0,9.8Hz,2H)。LC-MS:m/z:501.2(M+H)+。
实施例20：化合物38的合成
25℃下，在8mL的反应瓶中将化合物38a(毕得医药，货号：BD38284，32.05mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物38。1H NMR(400MHz,MeOD)δ8.17(d,J＝2.0Hz,1H),8.10(d,J＝8.7Hz,1H),7.57(dd,J＝8.7,2.0Hz,1H),5.39–5.20(m,1H),4.54(dd,J＝9.6,6.8Hz,2H),4.30(dd,J＝9.6,4.2Hz,2H),3.97(t,J＝7.5Hz,1H),2.86(ddd,J＝11.7,7.7,3.5Hz,1H),2.23(d,J＝12.2Hz,2H),2.15(d,J＝11.1Hz,2H),1.73(dd,J＝25.4,11.2Hz,2H),1.63(dd,J＝18.6,8.5Hz,2H)。LC-MS:m/z:502.2(M+H)+。
实施例21：化合物40的合成
25℃下，在8mL的反应瓶中将40a(毕得医药，货号：BD28605，29.49mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物40。1H NMR(400MHz,MeOD)δ7.67(dd,J＝14.0,5.3Hz,2H),7.35(dd,J＝8.7,2.0Hz,1H),5.34–5.28(m,1H),4.55(dd,J＝9.6,6.8Hz,2H),4.31(dd,J＝9.7,4.2Hz,2H),4.03–3.89(m,1H),2.88(ddd,J＝12.1,7.8,3.4Hz,1H),2.20(t,J＝14.9Hz,4H),1.81–1.53(m,4H)。LC-MS:m/z:485.1(M+H)+。
实施例22：化合物41的合成
25℃下，在8mL的反应瓶中将化合物41a(毕得医药，货号：BD260228，21.98mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物41。1H NMR(400MHz,MeOD)δ7.21(s,1H),5.29(td,J＝6.8,3.6Hz,1H),4.53(dd,J＝9.7,6.8Hz,2H),4.29(dd,J＝9.7,4.2Hz,2H),3.95–3.81(m,1H),2.84(ddd,J＝11.8,7.7,3.5Hz,1H),2.20(d,J＝11.6Hz,2H),2.11(d,J＝9.8Hz,2H),1.77–1.63(m,2H),1.55(dt,J＝12.8,6.1Hz,2H)。LC-MS:m/z:435.1(M+H)+。
实施例23：化合物42的合成
25℃下，在8mL的反应瓶中将化合物42a(21.47mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物42。1H NMR(400MHz,MeOD)δ7.41(d,J＝0.7Hz,1H),5.34–5.25(m,1H),4.58–4.48(m,2H),4.30(dd,J＝9.6,4.1Hz,2H),3.91(ddt,J＝11.1,7.6,3.9Hz,1H),2.85(tt,J＝11.9,3.4Hz,1H),2.50(d,J＝0.6Hz,3H),2.20(d,J＝11.9Hz,2H),2.12(dd,J＝12.8,2.8Hz,2H),1.76–1.52(m,4H)。LC-MS:m/z:432.1(M+H)+。
实施例24：化合物43的合成
25℃下，在8mL的反应瓶中将化合物43a(毕得医药，货号：BD95552，21.83mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)， 搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢铵/乙腈/水体系)分离纯化得到化合物43。1H NMR(400MHz,MeOD)δ6.88(d,J＝1.6Hz,1H),6.77(d,J＝1.6Hz,1H),5.34–5.25(m,1H),4.53(dd,J＝9.6,6.9Hz,2H),4.29(dd,J＝9.6,4.2Hz,2H),3.87(ddd,J＝11.5,7.7,4.0Hz,1H),2.82(ddd,J＝12.1,8.7,3.5Hz,1H),2.23–2.04(m,4H),1.80–1.40(m,4H)。LC-MS:m/z:434.2(M+H)+。
实施例25：化合物44的合成
25℃下，在8mL的反应瓶中将化合物44a(毕得医药，货号：BD334736，31.14mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物44。1H NMR(400MHz,MeOD)δ8.46(d,J＝8.5Hz,1H),8.22(dd,J＝21.6,8.8Hz,2H),8.08(d,J＝2.3Hz,1H),7.83(dd,J＝9.1,2.4Hz,1H),5.31(s,1H),4.60–4.48(m,2H),4.30(dd,J＝9.8,4.2Hz,2H),4.02(s,1H),2.90(t,J＝11.4Hz,1H),2.21(dd,J＝20.6,14.6Hz,4H),1.85–1.59(m,4H)。LC-MS:m/z:496.1(M+H)+。
实施例26：化合物45的合成
25℃下，在8mL的反应瓶中将化合物45a(毕得医药，货号：BD232348，26.12mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物45。1H NMR(400MHz,MeOD)δ9.32(s,1H),8.98(s,1H),6.94(t,J＝54.3Hz,1H),5.34–5.26(m,1H),4.54(dd,J＝9.7,6.8Hz,2H),4.30(dd,J＝9.6,4.2Hz,2H),4.02(qd,J＝11.6,3.6Hz,1H),2.87(tt,J＝11.9,3.5Hz,1H),2.22(d,J＝12.2Hz,2H),2.18–2.07(m,2H),1.81–1.53(m,4H)。LC-MS:m/z:463.1(M+H)+。
实施例27：化合物46的合成
25℃下，在8mL的反应瓶中将化合物46a(毕得医药，货号：BD160922，26.73mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物46。1H NMR(400MHz,MeOD)δ7.62–7.49(m,2H),6.79(dd,J＝8.6,4.0Hz,1H),5.34–5.27(m,1H),4.53(dd,J＝9.7,6.8Hz,2H),4.29(dd,J＝9.6,4.2Hz,2H),4.25–4.17(m,2H),3.91(ddd,J＝15.4,7.7,3.9Hz,1H),2.83(dt,J＝8.7,5.7Hz,3H),2.19(d,J＝12.1Hz,2H),2.15–2.07(m,2H),2.07–1.99(m,2H),1.70(qd,J＝13.2,3.0Hz,2H),1.53(qd,J＝12.8,3.2Hz,2H)。LC-MS:m/z:467.1(M+H)+。
实施例28：化合物47的合成
步骤1:中间体47b的合成
25℃下，向50mL的三口瓶中加入化合物47a(毕得医药，货号：BD9715，0.4g，1.76mmol)、Rockphos-pd-G3(22.15mg,0.02mmol)和碳酸铯(1.7g，5.27mmol)，再加入二甲基甲酰胺(4.0mL)和水(0.15mL)。用氮气保护后温度提高至85摄氏度反应5小时。反应液粗品(含中间体47b)直接用于下一步不需要纯化，LC-MS：m/z:163.0(M-H)-。
步骤2:中间体47c的合成
25℃下，向上一步的所得反应液(含中间体47b)中加入溴乙酸叔丁酯(889mg，4.56mmol)。25℃反应2小时后反应完成。向所得反应液中加入5mL水和15mL乙酸乙酯，所得有机相用饱和食盐水洗涤(40mL×3)，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体47c(80mg，0.28mmol)。LC-MS:m/z:277.0(M-H)。
步骤3:中间体47d的合成
25℃下，向10mL的单口瓶中加入中间体47c(80mg，0.28mmol)和二氯甲烷(1.0mL)，搅拌条件下加入三氟乙酸(0.3mL，4.03mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体47d。LC-MS:m/z:220.9(M-H)-。
步骤4:化合物47的合成
25℃下，在8mL的反应瓶中将中间体47d(33mg，0.1mmol)和中间体21b (30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物47。1H NMR(400MHz,MeOD)δ6.94–6.70(m,2H),5.41–5.13(m,1H),4.55(s,2H),4.54–4.37(m,2H),4.28(dd,J＝9.6,4.2Hz,2H),4.11–3.68(m,1H),2.81(ddd,J＝12.1,8.6,3.7Hz,1H),2.22–2.10(m,2H),2.10–1.91(m,2H),1.74–1.58(m,2H),1.54-1.38(m,2H)。LC-MS:m/z:511.1(M+H)+。
实施例29：化合物48的合成
步骤1:中间体48b的合成
25℃下，向50mL的三口瓶中加入化合物48a(毕得医药，货号：BD297147，0.8g，3.52mmol)、Rockphos-pd-G3(44.29mg,0.05mmol)和碳酸铯(3.4g，10.55mmol)，再加入二甲基甲酰胺(8.0mL)和水(0.3mL)。用氮气保护后温度提高至85摄氏度反应5小时反应完成。所得反应液(含中间体48b)直接用于下一步不需要纯化，LC-MS：m/z:163.0(M-H)-。
步骤2:中间体48c的合成
25℃下，向上一步的所得反应液(含中间体48b)中加入溴乙酸叔丁酯(889mg，4.56mmol)。25℃反应2小时后反应完成。向所得反应液中加入5mL水和15mL乙酸乙酯，所得有机相用40mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体48c。1H NMR(400MHz,CDCl3)：δ7.09(dd,J＝10.4,6.9Hz,1H),6.67(dd,J＝9.8,7.3Hz,1H),4.49(s,1H),1.42(s,9H)。
步骤3:中间体48d的合成
25℃下，向25mL的单口瓶中加入中间体48c(200mg，0.72mmol)和二氯甲烷(2.0mL)，搅拌条件下加入三氟乙酸(2.0mL，26.84mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体48d。LC-MS:m/z:220.9(M-H)-。
步骤4:化合物48的合成
25℃下，在8mL的反应瓶中将中间体48d(22.26mg，0.1mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物48。1H NMR(400MHz,MeOD)δ7.38(dd,J＝10.6, 7.0Hz,1H),7.11(dd,J＝10.3,7.4Hz,1H),5.34–5.24(m,1H),4.62(s,2H),4.53(dd,J＝9.7,6.8Hz,2H),4.29(dd,J＝9.6,4.2Hz,2H),3.89–3.75(m,1H),2.87–2.75(m,1H),2.21–2.12(m,2H),2.05(dd,J＝13.1,3.4Hz,2H),1.67(qd,J＝13.2,3.1Hz,2H),1.48(qd,J＝12.8,3.3Hz,2H)。LC-MS:m/z:511.2(M+H)+。
实施例30：化合物49的合成
步骤1:中间体49b的合成
25℃下，向50mL的三口瓶中加入化合物49a(毕得医药，货号：BD66669，0.8g，3.28mmol)、Rockphos-pd-G3(41.3mg,0.05mmol)和碳酸铯(3.2g，9.84mmol)，再加入二甲基甲酰胺(8.0mL)和水(0.3mL)。用氮气保护后温度提高至85摄氏度反应5小时反应完成。所得反应液(含中间体49b)直接用于下一步不需要纯化，LC-MS：m/z:179.0(M-H)-。
步骤2:中间体49c的合成
25℃下，向上一步所得的反应液(含中间体49b)中加入溴乙酸叔丁酯(727.47mg，3.73mmol)。25℃反应2小时后反应完成。向所得反应液中加入5mL水和15mL乙酸乙酯，所得有机相用40mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体49c。1H NMR(400MHz,CDCl3)δ7.35(d,J＝7.6Hz,1H),6.58(d,J＝10.2Hz,1H),4.50(s,2H),1.42(d,J＝2.1Hz,9H).
步骤3:中间体49d的合成
25℃下，向25mL的单口瓶中加入中间体49c(200mg，0.68mmol)和二氯甲烷(2.0mL)，搅拌条件下加入三氟乙酸(2.0mL，26.84mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体49d。LC-MS:m/z:236.9(M-H)-。
步骤4:化合物49的合成
25℃下，在8mL的反应瓶中将中间体49d(23.9mg，0.1mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物49。1H NMR(400MHz,DMSO)δ7.96(d,J＝7.8Hz,1H),7.80(d,J＝7.8Hz,1H),7.22(d,J＝11.2Hz,1H),5.32(dd,J＝8.9,5.4Hz,1H),4.66(s,2H),4.51–4.37(m,2H),4.19(dd,J＝9.6,3.8Hz,2H),3.63–3.60(m,1H),2.83–2.69(m,1H),2.03(d,J＝11.7Hz,2H),1.89(d,J＝10.0Hz,2H),1.51(q,J＝10.6Hz,2H),1.35(dd,J＝24.1,9.9Hz,2H)。LC-MS:m/z:527.2(M+H)+。
实施例31：化合物50的合成
步骤1:中间体50b的合成
25℃下，向50mL的三口瓶中加入化合物50a(毕得医药，货号：BD322259，0.4g，1.76mmol)、Rockphos-pd-G3(22.15mg,0.02mmol)和碳酸铯(1.7g，5.27mmol)，再加入二甲基甲酰胺(4.0mL)和水(0.15mL)。用氮气保护后温度提高至85摄氏度反应5小时反应完成。所得反应液(含中间体50b)直接用于下一步不需要纯化，LC-MS：m/z:163.0(M-H)-。
步骤2:中间体50c的合成
25℃下，向上一步所得的反应液(含中间体50b)中加入溴乙酸叔丁酯(889mg，4.56mmol)。25℃反应2小时后反应完成。向所得反应液中加入5mL水和15mL乙酸乙酯，所得有机相用40mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体50c。LC-MS：m/z:279.2(M+H)+。
步骤3:中间体50d的合成
25℃下，向25mL的单口瓶中加入中间体50c(220mg，0.79mmol)和二氯甲烷(2.0mL)，搅拌条件下加入三氟乙酸(2.0mL，26.84mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体50d。LC-MS:m/z:223.0(M+H)+。
步骤4:化合物50的合成
25℃下，在8mL的反应瓶中将中间体50d(33.15mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入15mL水，用15mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物50。1H NMR(400MHz,MeOD)δ7.32–7.16(m,1H),6.99–6.83(m,1H),5.39–5.23(m,1H),4.64(s,2H),4.53(dd,J＝9.6,6.9Hz,2H),4.28(dd,J＝9.6,4.2Hz,2H),3.83(dd,J＝13.6,9.6Hz,1H),2.80(tt,J＝12.0,3.4Hz,1H),2.18(t,J＝12.7Hz,2H),2.10–1.95(m,2H),1.66(qd,J＝13.2,3.1Hz,2H),1.47(qd,J＝12.8,3.2Hz,2H)。LC-MS:m/z:511.1(M+H)+。
实施例32：化合物52的合成

步骤1:中间体52b的合成
25℃下，向8mL的反应管中加入化合物52a(泰坦，0.2g，1.15mmol)、溴乙酸叔丁酯(0.25g,1.27mmol)和碳酸钾(0.317g，9.84mmol)，再加入乙腈(2.0mL)。在常温下反应3小时。将反应液旋干，粗品用过柱机纯化得到中间体52b。LC-MS：m/z:288.0(M+H)+。
步骤2:中间体52c的合成
25℃下，向中间体52b(240mg，0.83mmol)中加入三氟醋酸1mL和二氯甲烷1mL。25℃反应2小时后反应完成。所得反应液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体52c。LC-MS:m/z:232.0(M+H)+。
步骤3:中间体52d的合成
25℃下，向25mL的单口瓶中加入中间体52c(177mg，0.76mmol)和N,N-二甲基甲酰胺(2.0mL)，搅拌条件下加入中间体21b(60mg，0.196mmol)。25℃反应4小时后反应完成。所得反应液用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到中间体52d。LC-MS:m/z:520.1(M+H)。
步骤4:化合物52的合成
25℃下，在25mL的反应瓶中将中间体52d(20mg，0.038mmol)溶于甲醇(1.5mL)和水(0.5mL)中，搅拌条件下依次加入铁粉(11mg，0.19mmol)，氯化铵(10.29mg，0.19mmol)。70度下搅拌1小时反应结束。将所得反应液趁热过滤，滤液旋干得到粗品。粗品用用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物52。1H NMR(400MHz,DMSO)δ8.00(d,J＝8.2Hz,1H),6.76(d,J＝8.6Hz,1H),6.66(d,J＝2.5Hz,1H),6.49(d,J＝8.5Hz,1H),5.32(td,J＝6.5,3.4Hz,1H),4.46(dd,J＝9.7,6.8Hz,3H),4.40(s,2H),4.20(dd,J＝9.7,4.1Hz,3H),3.89(s,1H),2.71(d,J＝11.7Hz,1H),2.05(d,J＝11.7Hz,2H),1.85(d,J＝10.2Hz,2H),1.60–1.38(m,4H)。LC-MS:m/z 490.2(M+H)+。
实施例33：化合物53的合成
步骤1:中间体53b的合成
25℃下，在25mL反应瓶中将化合物53a(毕得医药，货号：BD222433， 100mg，0.45mmol)、溴乙酸叔丁酯(85.45mg，0.65mmol)，碳酸铯(421.3mg，1.3mmol)和甲烷磺酸基(2-(二叔丁基膦)-3-甲氧基-6-甲基,2,4,6-三异丙基-1,1-联苯基)(2-氨基-1,1-联苯基-2-基)钯(II)(7mg，0.009mmol)溶于1,4-二氧六环(5mL)中。95℃反应过夜反应完成。向所得反应液中加入15mL二氯甲烷，将过滤之后所得滤液减压浓缩得到粗品。粗品经柱层析分离纯化得到中间体53b。1H NMR(400MHz,CDCl3)δ7.37(s,1H),4.81(s,2H),1.41(s,9H).
步骤2:中间体53c的合成
25℃下，向25mL的单口瓶中加入中间体53b(90mg，0.32mmol)和二氯甲烷(1mL)，搅拌条件下加入三氟乙酸(1mL，13.42mmol)。25℃反应1小时后反应完成。减压浓缩得到中间体53c。LC-MS:m/z:225.9(M-H)-。
步骤3:化合物53的合成
25℃下，在8mL的反应瓶中将中间体53c(34.07mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入15mL水，用15mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物53。1H NMR(400MHz,MeOD)δ8.16(d,J＝8.1Hz,1H),7.52(d,J＝1.4Hz,1H),5.17(ddd,J＝10.9,6.8,4.3Hz,1H),4.85(s,2H),4.40(dd,J＝9.7,6.8Hz,2H),4.16(dd,J＝9.6,4.2Hz,2H),3.68(td,J＝11.6,5.9Hz,1H),2.68(ddd,J＝12.1,8.6,3.5Hz,1H),2.12–1.99(m,2H),1.97–1.86(m,2H),1.54(ddd,J＝25.6,13.2,3.1Hz,2H),1.33(ddd,J＝25.4,13.1,3.5Hz,2H)。LC-MS:m/z 516.2(M+H)+。
实施例34和35：化合物6和化合物12的合成
步骤1:中间体6b的合成
25℃下，向50mL的单口瓶中加入化合物6a(毕得医药，货号：BD00841787，1.50g,7.75mmol)和二甲基甲酰胺(30mL)，搅拌条件下依次加入化合物1i(1.58g,7.75mmol)，二异丙基乙胺(5.13mL,30.98mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.42g,11.62mmol)。25℃反应18小时后反应完成。将所得反应液倒入200mL水中，然后用300mL乙酸乙酯萃取两次。所得 有机相用100mL饱和食盐水洗涤，无水硫酸钠干燥过夜，过滤，滤液减压浓缩得到粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯＝10：1～1：2)得到中间体6b。LC-MS:m/z:344.0(M+H)+。
步骤2:中间体6c的合成
25℃下，向50mL的单口瓶中加入化合物6b(2.2g,6.40mmol)和乙醇(20mL)，搅拌条件下滴加水合肼(20mL)。85摄氏度下反应16小时后反应完成。将所得反应液冷却至室温，然后减压浓缩得到粗品。粗品悬浮在乙腈(50mL)中，悬浮液在25℃下搅拌2小时，过滤洗涤得到中间体6c。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.99(d,J＝8.1Hz,1H),7.50(t,J＝8.9Hz,1H),7.07(dd,J＝11.4,2.8Hz,1H),6.88-6.77(m,1H),4.49(s,2H),3.56(tt,J＝8.0,4.0Hz,1H),3.18(d,J＝6.9Hz,1H),2.00(s,1H),1.79-1.62(m,4H),1.46-1.22(m,4H).LC-MS:m/z:344.0(M+H)+。
步骤3:中间体6d的合成
25℃下，向50mL的单口瓶中加入中间体6c(1g，2.91mmol)和二氯甲烷(30mL)，搅拌条件下加入N,N'-羰基二咪唑(0.71g，4.37mmol)。25℃下反应16小时后反应完成，减压浓缩得到粗品。粗品经柱层析分离纯化(二氯甲烷：甲醇＝10：1～5：1)得到中间体6d。LC-MS:m/z:370.0(M+H)+。
步骤4:化合物6的合成
25℃下，向50mL的单口瓶中加入中间体6d(100mg,0.27mmol)和二甲基甲酰胺(4mL),搅拌条件下依次加入二异丙基乙胺(0.18mL,1.08mmol)，1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(179.41mg,0.41mmol)和化合物6f(71.50mg,0.40mmol)。25℃反应18小时后反应完成。将反应液倒入20mL水中，然后用30mL乙酸乙酯萃取，共萃取两次。所得有机相用10mL饱和食盐水洗涤，硫酸钠干燥，过滤，所得滤液减压浓缩得到粗品。粗品通过高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物6。1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝8.0Hz,1H),7.50(t,J＝8.9Hz,1H),7.07(dd,J＝11.4,2.9Hz,1H),6.85(dd,J＝8.7,2.9Hz,1H),5.37-5.24(m,1H),4.56-4.37(m,4H),4.19(dd,J＝9.7,4.0Hz,2H),3.66(t,J＝3.8Hz,1H),2.73(td,J＝11.9,10.1,6.1Hz,1H),2.09-1.97(m,2H),1.90-1.79(m,2H),1.55-1.35(m,4H)。LC-MS:m/z:493.1(M+H)+。
步骤5:化合物12的合成
25℃向50mL的单口瓶中加入化合物6(40mg,0.08mmol)和甲苯(3mL)，搅拌条件下加入劳森试剂(32.82mg,0.08mmol)。120摄氏度反应1小时后反应完成。待冷却至25℃后，将所得反应液倒入20mL水中，然后每次用30mL乙酸乙酯萃取，共萃取两次。所得有机相用10mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品通过高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物12。1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝8.0Hz,1H),7.50(t,J＝8.9Hz,1H),7.07(dd,J＝11.4,2.9Hz,1H),6.85(dd,J＝8.7,2.9Hz,1H),5.37-5.24(m,1H),4.56-4.37(m,4H),4.19(dd,J＝9.7,4.0Hz,2H),3.66(t,J＝3.8Hz,1H),2.73(td,J＝11.9,10.1,6.1Hz,1H),2.09-1.97(m,2H),1.90-1.79(m,2H),1.55-1.35(m,4H)。LC-MS:m/z:509.0(M+H)+。
实施例36：化合物13的合成
25℃下，向50mL的单口瓶中加入化合物12(80mg,0.16mmol)和甲苯(5mL)，搅拌条件下加入劳森试剂(64.71mg,0.16mmol)。120摄氏度反应18小时后反应完成。待冷却至25℃后，将所得反应液倒入20mL水中，然后每次用30mL乙酸乙酯萃取，共萃取两次。所得有机相用10mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品通过高效液相(三氟乙酸/乙腈/水体系)分离得到化合物13。1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝8.0Hz,1H),7.50(t,J＝8.9Hz,1H),7.07(dd,J＝11.4,2.9Hz,1H),6.85(dd,J＝8.7,2.9Hz,1H),5.37-5.24(m,1H),4.56-4.37(m,4H),4.19(dd,J＝9.7,4.0Hz,2H),3.66(t,J＝3.8Hz,1H),2.73(td,J＝11.9,10.1,6.1Hz,1H),2.09-1.97(m,2H),1.90-1.79(m,2H),1.55-1.35(m,4H)。LC-MS:m/z:525.0(M+H)+。
实施例37：化合物11的合成
步骤1:中间体11b的合成
25℃下，向50mL的单口瓶中加入化合物11a(毕得医药，货号：BD254006，150mg,0.89mmol)，叔丁醇(0.5mL)和甲苯(3mL)，搅拌条件下依次加入化合物叠氮磷酸二苯酯(0.25mL,1.16mmol)，和三乙胺(0.27mL,1.96mmol)。85摄氏度反应8小时后反应完成。将所得反应液减压浓缩得到粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯＝100：1～10：1)得到中间体11b。LC-MS:m/z:240.1(M+H)+。
步骤2:中间体11c的合成
25℃下，向50mL的单口瓶中加入中间体11b(200mg,0.42mmol)和盐酸二氧六环(5mL)。25℃反应3小时后反应完成。将所得反应液减压浓缩得到中间体11c。LC-MS:m/z:140.0(M+H)+。
步骤3:化合物11的合成
25℃下，向50mL的单口瓶中加入中间体6d(50mg,0.14mmol)和二甲基甲酰胺(2mL)，搅拌条件下依次加入二异丙基乙胺(0.09mL,0.54mmol),1H-苯 并三唑-1-基氧三吡咯烷基六氟磷酸盐(89.71mg,0.20mmol)和中间体11c(28.22mg,0.20mmol)。25℃反应18小时后反应完成。将所得反应液倒入20mL水中，然后每次用30mL乙酸乙酯萃取，共萃取两次。所得有机相用10mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品通过高效液相(三氟乙酸/乙腈/水体系)分离得到化合物11。1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝67.1Hz,1H),7.50(s,1H),7.08(s,1H),6.85(d,J＝9.0Hz,1H),4.50(s,2H),3.97(s,2H),3.72-3.59(m,1H),3.11(s,1H),2.92(s,1H),2.68(s,1H),2.36(s,1H),1.91(d,J＝64.6Hz,6H),1.43(d,J＝30.2Hz,4H).。LC-MS:m/z:491.0(M+H)+。
实施例38：化合物14的合成
25℃下，向50mL的单口瓶中加入中间体6d(50mg,0.14mmol)和二甲基甲酰胺(2mL)，搅拌条件下依次加入二异丙基乙胺(0.09mL,0.54mmol),1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(89.71mg,0.20mmol)和化合物14a(毕得医药，货号：BD00841787，71.61mg,0.41mmol)。25℃反应18小时后反应完成。将所得反应液倒入20mL水中，然后每次用30mL乙酸乙酯萃取，共萃取两次。所得有机相用10mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品通过高效液相(三氟乙酸/乙腈/水体系)分离得到化合物14。1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.1Hz,1H),7.36(s,1H),6.94(dd,J＝11.1,2.9Hz,1H),6.83-6.74(m,1H),4.46(s,2H),4.02(d,J＝7.1Hz,1H),3.78-3.62(m,1H),2.95(d,J＝14.9Hz,3H),2.81(q,J＝8.7Hz,1H),2.13-2.03(m,2H),1.90(dd,J＝13.2,3.8Hz,2H),1.61-1.13(m,9H)。LC-MS:m/z:505.2(M+H)+。
实施例39：化合物4的合成

步骤1:中间体4b的合成
25℃下，向500mL的单口瓶中加入化合物4a(毕得医药，货号：BD163186，15.5g,68.5mmol)和冰醋酸(125mL)，搅拌条件下加入化合物三氧化铬(13.70g,137mmol)。在90℃下搅拌16小时后反应完成。往反应混合物中加入乙酸乙酯(100mL)，倒入H2O(200mL)中，加入NaHCO3固体调节pH至9后进行萃取，将有机层合并后用盐水(200mL)洗涤，用Na2SO4干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝10:1)得到中间体4b。LC-MS:m/z:241.0(M+H)+。
步骤2:中间体4c的合成
25℃下向250mL的单口瓶中加入中间体4b(5.023g,20.91mmol)和四氢呋喃(60mL)、甲醇(15mL)，然后加入LiOH(400mg，16.73mmol)的水溶液(15mL)。25℃下搅拌16小时后反应完成。减压浓缩除去四氢呋喃，加入2mol/L HCl调pH至2-3，有固体析出，过滤取滤饼得到中间体4c。LC-MS:m/z:225.0(M-H)-。
步骤3:中间体4d的合成
25℃下，向100mL的单口瓶中加入中间体4c(2.15g，9.5mmol)和叔丁醇(30mL)，加入吡啶(5.37mL,66.53mmol)，DMAP(1.16g,9.5mmol)和(Boc)2O(4.07mL，19.01mmol)。在35℃下搅拌16小时后反应完成。减压浓缩后倒入水(50mL)中，并用乙酸乙酯(50mL×3)萃取。将有机层合并后用盐水(50mL)洗涤，用Na2SO4干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝10：1)，得到中间体4d。LC-MS:m/z:283.10(M+H)+。
步骤4:中间体4e的合成
25℃下，向100mL的单口瓶中加入中间体4d(1.204g,4.26mmol)和四氢呋喃(20mL)、甲醇(5mL)，加入氢氧化锂(100mg,4.26mmol)的水溶液(4mL)。25℃下搅拌16小时后反应完成。减压浓缩除去四氢呋喃，加入2M HCl调pH至 2-3，有固体析出，过滤取滤饼得到中间体4e。LC-MS:m/z:269.10(M+H)+。
步骤5:中间体4f的合成
25℃下，向100mL的单口瓶中加入中间体4e(800mg,2.98mmol)和甲苯(50mL),搅拌条件下加入三乙胺(1.24mL,8.94mmol)，叠氮磷酸二苯酯(1641.09mg,5.96mmol)，在120℃下搅拌2小时。随后加入苄醇(0.93mL,8.94mmol)，在120℃下搅拌12小时后反应完成。往反应混合物中加入水(50mL)，乙酸乙酯(60mL×3)萃取，将有机层合并后用盐水(50mL)洗涤，用Na2SO4干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝10：1)，得到中间体4f。LC-MS:m/z:374.2(M+H)+
步骤6:中间体4g的合成
25℃下，向100mL的单口瓶中加入中间体4f(890mg,2.38mmol)和四氢呋喃(20mL)，搅拌条件下加入氢氧化钯(297.79mg,2.12mmol)，氢气置换三次，25℃下搅拌16小时后反应完成。过滤，滤液减压浓缩除，得到中间体4g。LC-MS:m/z:240.1(M+H)+。
步骤7:中间体4i的合成
25℃下，向25mL的单口瓶中加入上一步得到的中间体4g和二氯甲烷(6mL)，搅拌条件下加入中间体1i(300.39mg,1.26mmol),二异丙基乙胺(0.83mL,5.02mmol)和1-丙基磷酸酐(1597.59mg,2.51mmol)，25℃下搅拌16小时后反应完成。往反应混合物中加入水(10mL)，乙酸乙酯(15ml×3)萃取，将有机层合并后用盐水(10mL)洗涤，用无水硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝4：1)，得到中间体4i。LC-MS:m/z:426.2(M+H)+。
步骤8:中间体4j的合成
0℃下，向25mL的单口瓶中加入中间体4i(260mg,0.61mmol)和二氯甲烷(5mL)，搅拌条件下加入三氟乙酸(5mL)，在50℃下搅拌1小时后反应完成。减压浓缩除去溶剂，得到中间体4j。LC-MS:m/z:370.1(M+H)+。
步骤9:中间体4k的合成
25℃下，向25mL的单口瓶中加入中间体4j(225.7mg,0.61mmol)和二甲基甲酰胺(5mL),搅拌条件下加入肼基甲酸叔丁酯(0.09mL,0.73mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(234.02mg,1.22mmol)，1-羟基苯并三唑(315.54mg,2.44mmol)和N,N-二异丙基乙胺(0.21mL,1.22mmol)，25℃下搅拌16小时后反应完成。往反应混合物中加入水(10mL)，用乙酸乙酯(15ml×3)萃取，将有机层合并后用盐水(10mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝1：1)，得到中间体4k。LC-MS:m/z:484.2(M+H)+。
步骤10:中间体4l的合成
0℃下，向25mL的单口瓶中加入中间体4k(296mg,0.61mmol)和二氯甲烷(3mL)，搅拌条件下加入4M盐酸二氧六环(3mL)，在25℃下搅拌1小时后反应完成。减压浓缩除去溶剂，得到中间体4l。LC-MS:m/z:385.8(M+H)。
步骤11:中间体4m的合成
25℃下，向10mL的单口瓶中加入上一步得到的中间体4l和四氢呋喃(2mL)，搅拌条件下加入N,N-二异丙基乙胺(0.09mL,0.57mmol)和硫羰基二咪唑(61.29mg,0.34mmol)，在25℃下搅拌16小时，然后在70℃下搅拌3小时后反应完成。往反应混合物中加入水(3mL)，乙酸乙酯(5ml×3)萃取，将有机层合并后用盐水(3mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(纯 乙酸乙酯)得到中间体4m。LC-MS:m/z:426.1(M+H)。
步骤12:中间体4n的合成
25℃下，向10mL的单口瓶中加入中间体4m(122mg,0.29mmol)和二甲基甲酰胺(1.5mL),搅拌条件下加入碳酸钾(79.18mg,0.57mmol)和碘甲烷(35.68μL,0.57mmol)，在25℃下搅拌3小时后反应完成。往反应混合物中加入水(5mL)，乙酸乙酯(6mL×3)萃取，将有机层合并后用盐水(5mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝1：1)，得到中间体4n。LC-MS:m/z:440.1(M+H)+。
步骤13:中间体4o的合成
0℃下，向10mL的单口瓶中加入中间体4n(65mg,0.15mmol)和二氯甲烷(1mL),搅拌条件下加入间氯过氧苯甲酸(105.00mg,0.52mmol)，在25℃下搅拌16小时后反应完成。往反应混合物中加入饱和硫代硫酸钠溶液，然后加入水(3mL)，乙酸乙酯(5mL×3)萃取，将有机层合并后用盐水(3mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝1：1)，得到中间体4o。LC-MS:m/z:472.1(M+H)+。
步骤14:中间体4q的合成
25℃下，向10mL的单口瓶中加入中间体4o(44mg,0.09mmol)和二甲基甲酰胺(1mL),搅拌条件下加入化合物4p(65.78mg,0.47mmol)和碳酸钾(90.20mg,0.65mmol)，在25℃下搅拌4小时后反应完成。往反应混合物中加入水(2mL)，乙酸乙酯(5mL×3)萃取，将有机层合并后用盐水(3mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝2：1)，得到中间体4q。LC-MS:m/z:533.2(M+H)+。
步骤15:化合物4的合成
0℃下，向10mL的单口瓶中加入中间体4q(35mg,0.07mmol)和甲醇(1mL),搅拌条件下加入硼氢化钠(4.97mg,0.13mmol)，在25℃下搅拌1小时后反应完成。往反应混合物中加入2M盐酸溶液至pH＝7，然后加入水(2mL)，乙酸乙酯(3mL×3)萃取，将有机层合并后用盐水(3mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经制备薄层层析(石油醚：乙酸乙酯＝3：1)，得到化合物4。LC-MS:m/z:535.2(M+H)+。1H NMR(DMSO-d6)δ:7.55(t,J＝8.9Hz,1H),7.42(s,1H),7.13(dd,J＝11.4,2.8Hz,1H),6.90(dd,J＝8.9,2.7Hz,1H),5.33-5.41(m,1H),5.12-5.32(m,1H),4.55(s,2H),4.51(dd,J＝9.4,6.9Hz,2H),4.25(dd,J＝9.6,3.9Hz,2H),4.17(br d,J＝7.1Hz,1H),2.23-2.37(m,1H),2.13(br d,J＝5.0Hz,1H),1.80-2.05(m,7H),1.74(dd,J＝13.6,2.5Hz,1H)。
实施例40：化合物3的合成

步骤1:中间体3b的合成
向3a(毕得医药，货号：BD234253，1g，5.46mmol)和1i(1g,4.96mmol)的DCM(20mL)溶液中加入DIEA(3.28mL,19.84mmol)和T3P(3.16g,9.92mmol)，将混合物在室温下搅拌16小时。将反应混合物倒入水(20mL)中，并用DCM(20mL×3)萃取。将所得到的有机层合并后用盐水(20mL)洗涤，用Na2SO4干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝1：1)，得到中间体3b。m/z ES+[M+H]+＝370.1。
步骤2:中间体3c的合成
向中间体3b(1.13g,3.06mmol)在EtOH(8mL)的溶液中加入N2H4·H2O(9mL)，将混合物在100℃下搅拌过夜。将反应混合物倒入水(30mL)中，并用二氯甲烷(30mL×3)萃取。将所得到的有机层合并后用盐水(30mL)洗涤，用Na2SO4干燥，过滤浓缩。粗品经硅胶色谱柱(二氯甲烷：甲醇＝10：1)纯化得到中间体3c。m/z ES+[M+H]+＝370.1。
步骤3:中间体3d的合成
向中间体3c(100mg,0.27mmol)和DIEA(90μL,0.54mmol)在THF(1.5mL)的溶液中加入CDI(48mg,0.30mmol)，将所得混合物在室温下搅拌1小时。将所得反应混合物倒入水(5mL)中，并用二氯甲烷(5mL×3)萃取。将有机层合并后用盐水(5mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(纯乙酸乙酯)，得到中间体3d。m/z ES+[M+H]+＝396.1。
步骤4:化合物3的合成
向中间体3d(75mg,0.19mmol)和3-(三氟甲氧基)-氮杂环丁烷(67mg,0.38mmol)在二甲基甲酰胺(1.5mL)的溶液中加入DIEA(94μL,0.57mmol)，将所得混合物在室温下搅拌10分钟后加入卡特缩合剂(92mg,0.21mmol)，将混合物在室温下搅拌过夜。将所得反应混合物倒入水(5mL)中，并用二氯甲烷(5mL×3)萃取。将有机层合并后用盐水(5mL)洗涤，用硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝1：1)纯化，得到化合物3，m/z ES+[M+H]+＝519.1。1H NMR(DMSO-d6)δ:7.58(s,1H),7.48(t,J＝8.8Hz,1H),7.03(dd,J＝11.4,2.6Hz,1H),6.82(d,J＝9.1Hz,1H),5.26-5.35(m,1H),4.46(s,2H),4.40-4.45(m,2H),4.18(br dd,J＝9.5,3.6Hz,2H),1.90(br d,J＝5.1Hz,12H)。
实施例41：化合物10的合成

步骤1：中间体10b的制备
25摄氏度下，向100mL的单口瓶中加入化合物10a(毕得医药，货号：BD234295，2g，7.06mmol)和二氯甲烷(15mL)，搅拌条件下加入三氟乙酸(5.0mL)。25摄氏度反应3小时后反应完成。减压浓缩得到中间体10b。
步骤2：中间体10c的制备
冰浴下，向100mL的单口瓶中加入化合物1i(1.74g，8.51mmol)和二甲基甲酰胺(15mL)，搅拌条件下依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.04g，10.64mmol)，二异丙基乙胺(3.69g，28.83mmol)。25摄氏度反应半小时后反应，向所得反应液中加入中间体10b(1.3g，7.09mmol)，25摄氏度下过夜反应结束。向所得反应液中加入150mL水，用150mL乙酸乙酯萃取，有机相用150mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)最后得到中间体10c。LC-MS:m/z:393.0(M+Na)+。
步骤3：中间体10d的制备
25摄氏度下，向100mL的单口瓶中加入中间体10c(1.6g，4.33mmol)和乙醇(15mL)，搅拌条件下加入50％水合肼(3.61g，43.3mmol)，升温80摄氏度过夜反应完成。减压浓缩得到粗品。粗品通过使用乙腈溶剂重结晶纯化得到中间体10d。LC-MS:m/z:370.2(M+H)+。
步骤4：中间体10e的制备
25摄氏度下，向100mL的单口瓶中加入中间体10d(616mg，1.67mmol)和1,2-二氯乙烷(5mL)，搅拌条件下依次加入化合物N,N'-羰基二咪唑(350mg，2.16mmol)。25摄氏度反应18小时后结束。向反应液中加入50mL水，用50mL乙酸乙酯萃取，所得有机相用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过过柱机纯化得到中间体10e。LC-MS:m/z:396.0(M+H)+。
步骤5：中间体10g的制备
冰浴下，向100mL的三口瓶中加入化合物10f(1.0g，4.83mmol)和乙酸乙酯(20mL)，用锡箔纸将三口瓶包住遮光后，搅拌条件下加入三氟甲磺酸银(3.72g，14.48mmol)，1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(2.56g，7.24mmol)，氟化钾(1.12g，19.32mmol)，2-氟吡啶(1.34g，14.48mmol)，(五氟乙基)三甲基硅烷(2.78mg，11.48mmol)。25摄氏度反应16小时后TLC检测反应完成。将所得反应液过滤之后滤液减压浓缩得到粗品。粗品通过过柱机纯化得到中间体10g。1H NMR(400MHz,DMSO-d6)δ7.32–7.18(m,5H),5.13–5.10(s,2H),4.97–4.98(m,1H),4.28–4.26(m,2H),4.04–4.02(m,2H).
步骤6：中间体10h的制备
25摄氏度下，向50mL的单口瓶中加入中间体10g(110mg，0.34mmol) 和无水甲醇(5.0mL)，搅拌条件下依次加入钯碳(22mg)，几滴浓盐酸，用氢气置换三次后，在氢气球氛围下，25摄氏度反应16小时后反应完成。过滤之后滤液减压浓缩得到中间体10h。
步骤7：化合物10的制备
冰浴下，向50mL的单口瓶中加入中间体10h(51mg，0.13mmol)和二甲基甲酰胺(5.0mL)，搅拌条件下依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(86mg，0.19mmol)，二异丙基乙胺(68mg，0.78mmol),中间体10e(22mg，0.12mmol)，25摄氏度下过夜反应结束。向反应液中加入25mL水，用25mL乙酸乙酯萃取，所得有机相用50mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)最后得到化合物10。1H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.53–7.48(m,1H),7.06–7.02(m,1H),6.87–6.84(m,1H),5.48–5.45(m,1H),4.49–4.45(m,4H),4.20–4.16(m,2H),1.93–1.86(m,12H)，LC-MS:m/z:569.0(M+H)+。
实施例42：化合物8的合成
步骤1:中间体8b的合成
冰浴下，向250mL的单口瓶中加入化合物8a(毕得医药，货号：BD159912，1000mg，4.73mmol)和二氯甲烷(50mL)，搅拌条件下缓慢滴加二乙胺基三氟化硫(2.5mL，18.93mmol)。25摄氏度反应十六小时后反应完成。将所得反应液慢慢滴加到20mL冰水中淬灭，用20mL二氯甲烷萃取，有机相用无水硫酸钠干燥，浓缩得到中间体8b。1H NMR(400MHz,MeOD)δ＝3.99(s,4H),2.75(t,J＝12.1Hz,4H),1.43(s,9H).
步骤2:中间体8c的合成
25摄氏度下，向50mL的单口瓶中加入中间体8b(100mg,0.43mmol)和二氯甲烷(1mL)，搅拌条件下加入三氟乙酸(0.3mL，4.03mmol)。反应十六小时后反应完成。将溶剂旋干得到中间体8c。1H NMR(400MHz,CDCl3)δ＝4.57-3.89(m,4H),3.13-2.57(m,4H)。
步骤3:化合物8的合成
25摄氏度下，向50mL的单口瓶中加入中间体10e(30mg，0.08mmol)，二甲基甲酰胺(1mL)，搅拌条件下依次加入中间体8c(20.18mg，0.15mmol)，卡特缩合剂(67.0mg，0.15mmol)和二异丙基乙胺乙胺(0.08mL，0.45mmol)。25摄氏度反应十六小时后反应完成。反应液过滤送制备，粗品通过高效液相(甲酸/乙腈/水体系)最后得到化合物8。LC-MS:m/z:511.0(M+H)+。1H NMR(400MHz,MeOD)δ＝7.37(t,J＝8.7Hz,1H),6.91(dd,J＝2.8,11.0Hz,1H),6.80(ddd,J＝1.3,2.9,8.9Hz,1H),4.43(s,2H),4.21(s,4H),2.84(t,J＝12.1Hz,4H),2.09-1.98 (m,12H)。
实施例43：化合物9的合成
步骤1：中间体9b的制备
25℃下，向50mL的单口瓶中加入化合物二甲基氧化膦(0.55g,7.06mmol)和四氢呋喃(30mL)，冰浴搅拌条件下加入化合物双(三甲基硅基)氨基钠(3.53mL,7.06mmol)。25℃反应1小时后加入化合物9a(毕得医药，货号：BD32891，1g，3.53mmol)。25℃下反应16小时后反应完成。将所得反应液倒入100mL水中，然后每次用200mL乙酸乙酯萃取两次，所得有机相用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤之后滤液减压浓缩得到中间体9b。LC-MS:m/z:134.0(M+H)+。
步骤2：化合物9c的制备
25摄氏度下，向50mL的单口瓶中加入中间体9b(200mg,1.50mmol),碳酸氢钠(378.62mg，4.51mmol)，四氢呋喃(20mL)和水(10mL)，搅拌条件下滴加氯甲酸苄酯(0.32mL,2.25mmol)。25摄氏度下反应16小时后反应完成。将所得反应液倒入100mL水中，然后每次用200mL乙酸乙酯萃取两次，所得有机相用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到中间体9c。LC-MS:m/z:268.0(M+H)+。
步骤3：中间体9d的制备
25摄氏度下，向50mL的单口瓶中加入中间体9c(100mg，0.37mmol),1mol/L盐酸(2mL)，甲醇(10mL)和10％钯碳(39.82mg，0.37mmol)。加完后用氢气置换三次，然后在氢气下25摄氏度反应16小时后反应完成，减压过滤浓缩得到中间体9d。LC-MS:m/z:134.0(M+H)+。
步骤4：化合物9的制备
25摄氏度下，向50mL的单口瓶中加入中间体9d(15.98mg,0.12mmol),中间体10e(30mg,0.08mmol)和二甲基甲酰胺(4mL)，搅拌条件下依次加入二异丙基乙胺(0.05mL,0.30mmol)和卡特缩合剂(50.28mg,0.11mmol)。25摄氏度下反应18小时后反应完成。将所得反应液倒入20mL水中，然后每次用30mL乙酸乙酯萃取两次，所得有机相用10mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过高效液相(三氟乙酸/乙腈/水体系)分离得到化合物9。1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.60(s,1H),7.49(t,J＝8.9Hz,1H),7.04(dd,J＝11.4,2.9Hz,1H),6.85–6.80(m,1H),4.46(s,2H),4.30–4.03(m,4H),3.12(d,J＝9.3Hz,1H),1.90(d,J＝5.9Hz,11H),1.41(d,J＝13.1Hz,6H)。LC-MS:m/z:511.2(M+H)+。
实施例44：化合物15的合成
25℃条件下，在8mL的反应瓶中将化合物15a(毕得医药，货号：BD17826，28mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物15。1H NMR(400MHz,DMSO-d6)δ＝8.00(d,J＝8.0Hz,1H),7.39-7.28(m,2H),7.04-6.90(m,2H),5.35-5.24(m,1H),4.48-4.41(m,4H),4.19(dd,J＝3.9,9.5Hz,2H),3.70-3.59(m,1H),2.71(tt,J＝3.4,11.7Hz,1H),2.02(br d,J＝11.9Hz,2H),1.84(br dd,J＝2.9,12.5Hz,2H),1.56-1.32(m,4H).LC-MS:m/z:475.2(M+H)+。
实施例45：化合物16的合成
步骤1：中间体16b的制备
25℃下，向100mL的单口瓶中加入16a(毕得医药，货号：BD263092，800mg，3.26mmol)和无水四氢呋喃(8mL)，搅拌条件下加入化合物N,N'-硫羰基二咪唑(821mg，4.89mmol)。25℃搅拌反应16小时，随后加入水合肼(1.92g，32.6mmol)，反应半小时。减压浓缩得到粗品。粗品通过乙腈重结晶得到中间体16b。LC-MS:m/z:260.0(M+H)+。
步骤2：中间体16c的制备
25℃，向100mL的单口瓶中加入中间体16b(710mg，2.46mmol)和1,2-二氯乙烷(10.0mL)，搅拌条件下依次加入化合物N,N'-羰基二咪唑(887mg，5.46mmol)。25℃反应18小时后反应完成。向所得反应液中加入25mL水，有 机相用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过过柱机纯化得到中间体16c。LC-MS:m/z:230.0(M+H-56)+。
步骤3：中间体16d的制备
25℃下，向100mL的单口瓶中加入中间体16c(680mg，2.03mmol)和二甲基甲酰胺(10mL)，搅拌条件下依次加入化合物3-(三氟甲氧基)-氮杂环丁烷(336mg，2.38mmol)，二异丙基乙胺(1.2g，9.53mmol)和卡特缩合剂(1.6g，3.6mmol)。反应十六小时后反应完成。向所得反应液中加入100mL水，用100mL乙酸乙酯萃取，所得有机相用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)纯化得到中间体16d。LC-MS:m/z:409.0(M+H)+。
步骤4：中间体16e的制备
25℃下，向100mL的单口瓶中加入中间体16d(70mg，0.17mmol)和二氯甲烷(5.0mL)，搅拌条件下加入三氟乙酸(2.0mL，4.5mmol)。2小时后反应完成。减压浓缩得到中间体16e，LC-MS:m/z:309.1(M+H)+。
步骤5：化合物16的制备
冰浴下，向50mL的单口瓶中加入化合物1i(47mg，0.23mmol)和二甲基甲酰胺(5.0mL)，搅拌条件下依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(110mg，0.29mmol)，二异丙基乙胺(101mg，0.78mmol)和16e(65mg，0.21mmol)，室温下过夜反应结束。向所得反应液中加入25mL水，25mL乙酸乙酯萃取，所得有机相用50mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)最后得到化合物16.1H NMR(400MHz,DMSO-d6)δ8.08–8.01(m,1H),7.53–7.48(m,1H),7.10–7.06(m,1H),6.87–6.84(m,1H),5.35–5.31(m,1H),4.55–4.49(m,5H),4.26–4.21(m,2H),3.88–3.80(m,2H),3.29–3.26(m,1H),2.04–2.0(m,2H),1.90–1.86(m,1H),1.69–1.65(m,1H)，LC-MS:m/z:495.0(M+H)+。
实施例46：化合物17的合成
25℃条件下，在8mL的反应瓶中将化合物17a(毕得医药，货号：BD01523901，76mg，0.35mmol)和中间体21b(90mg，0.22mmol)溶于二甲基甲酰胺(5.0mL)，搅拌条件下依次加入三乙胺(101.0mg，0.95mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(167mg，0.47mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物17。1H NMR(400MHz,DMSO-d6)δ7.65–7.63(m,1H),5.33–5.30(m,1H),4.50–4.43(m,3H),4.20–4.17(m,2H),3.76(s,2H),3.73–3.69(m,1H),3.64–3.62(m,1H),2.78–2.72(m,3H),2.17–2.14(m,2H)，1.84–1.80(m,2H)，1.52–1.48(m,2H),1.46–1.38(m,4H).LC-MS:m/z:503.02(M+H)+。
实施例47：化合物18的合成
25℃条件下，在8mL的反应瓶中将化合物18a(毕得医药，货号：BD00971063，28mg，0.15mmol)和中间体21b(30mg，0.1mmol)溶于二甲基甲酰胺(1.5mL)，搅拌条件下依次加入三乙胺(40.48mg，0.4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.03mg，0.15mmol)。25℃下搅拌10小时反应结束。向所得反应液中加入20mL水，用20mL乙酸乙酯萃取，所得有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，将过滤之后所得滤液减压浓缩得到粗品。粗品用高效液相(三氟乙酸/乙腈/水体系)分离纯化得到化合物18。1H NMR(400MHz,Methanol-d4)δ8.09(d,J＝2.7Hz,1H),7.72(dd,J＝8.8,2.7Hz,1H),6.94(d,J＝8.9Hz,1H),5.44–5.21(m,2H),4.75(s,2H),4.50(dd,J＝9.7,6.7Hz,2H),4.25(dd,J＝9.6,4.2Hz,2H),3.77(t,J＝4.0Hz,1H),2.92–2.64(m,1H),2.20–2.09(m,2H),2.00(ddd,J＝13.6,8.9,4.7Hz,2H),1.63(qd,J＝13.1,3.3Hz,2H),1.43(td,J＝12.4,12.0,3.5Hz,2H).LC-MS:m/z:476.1(M+H)+。
实施例48：化合物7的合成
步骤1：中间体7a的制备
室温下，向单口瓶中加入中间体1c(1000mg,3.02mmol)、3-(三氟甲氧基)-氮杂环丁烷(1277.25mg,9.06mmol)、碳酸钾(2085.15mg,15.1mmol)和N,N-二甲基甲酰胺(20mL)，在室温下搅拌12小时。向反应液中加入50毫升水，用50毫升乙酸乙酯萃取三次，将合并的有机层用50毫升饱和食盐水洗涤，硫酸钠干燥，过滤浓缩。粗品经硅胶色谱柱纯化(石油醚：乙酸乙酯＝100：1～1：1)得到中间体7a。LC-MS:m/z:393.2(M+H)+。
步骤2：中间体7b的制备
室温下，向单口瓶中加入中间体7a(1100mg,2.80mmol)和二氯甲烷(3mL)，在冰浴下加入盐酸二氧六环溶液(4M)(3mL)，室温搅拌2小时。反应液直接浓缩得中间体7b。LC-MS:m/z:293.2(M+H)+。
步骤3：中间体7c的制备
室温下，向单口瓶中加入7b(230mg,0.79mmol)和水(1mL)，在冰浴下加入醋酸(3mL)和亚硝酸钠(162.88mg,2.36mmol)，冰浴下搅拌1小时后反应完 成。反应液直接减压浓缩得到中间体7c。LC-MS:m/z:322.1(M+H)+。
步骤4：中间体7d的制备
室温下，向单口瓶中加入7c(890mg,2.77mmol)、醋酸(2mL)和甲醇(6mL)，在冰浴下加入锌粉(905.62mg,13.85mmol)，室温下搅拌2小时。反应液直接过滤，滤液减压浓缩得到中间体7d。LC-MS:m/z:308.1(M+H)+。
步骤5：化合物7的制备
室温下，向单口瓶中加入中间体7d(100mg,0.33mmol)，1i(66.58mg,0.33mmol)和N,N-二甲基甲酰胺(1mL)，搅拌条件下依次加入1-丙基磷酸酐(414.19mg,0.65mmol)和N,N-二异丙基乙胺(126.19mg,0.98mmol)，在室温下搅拌12小时。反应液直接减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)纯化最后得到化合物7(6mg)。LC-MS:m/z:494.5(M+H)+。1H NMR(DMSO-d6)δ:8.77-9.19(m,1H),7.32-7.48(m,1H),6.90-7.03(m,1H),6.68-6.80(m,1H),5.22-5.29(m,1H),4.84(s,1H),4.35-4.44(m,3H),4.13(m,2H),2.87(d,J＝11.1Hz,1H),2.56-2.81(m,3H),1.83-2.00(m,3H),1.60-1.78(m,2H).
实施例49：化合物51-1、51-2的合成
步骤1：中间体51b的制备
室温下，向单口瓶中加入51a(韶远，800mg，4.32mmol)和1,4-二氧六环(2.0mL)，搅拌条件下加入盐酸/二氧六环溶液(4M,6.0mL，)，室温反应18小时。反应液减压浓缩得到中间体51b。
步骤2：中间体51c的制备
室温下，单口瓶中加入中间体51b(350mg，4.11mmol)和二甲基甲酰胺(8.0mL)，搅拌条件下依次加入化合物氯甲酸苄酯(1.08g，6.34mmol),碳酸钾(2.34g，16.92mmol)，在室温下搅18小时。向反应液中加入50mL水，用50毫升乙酸乙酯萃取一次，有机相用100mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～5：1)纯化得到中间体51c。
步骤3：中间体51d的制备
室温下，向单口瓶中加入51c(620mg，2.83mmol)和无水甲醇(10.0mL)， 搅拌条件下加入硼氢化钠(214mg,5.63mmol，)。提高温度至50摄氏度反应3小时。将反应液用50毫升氯化铵水溶液淬灭，每次用30毫升乙酸乙酯萃取，合并的有机相用50毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤之后滤液减压浓缩得到中间体51d。
步骤4：中间体51ea和51eb的制备
冰浴下，向三口瓶中加入中间体51d(300mg，1.36mmol)和乙酸乙酯(20mL)，用锡箔纸将三口瓶包住遮光后，搅拌条件下加入三氟甲磺酸银(1.05g，4.07mmol)，1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(0.72g，2.03mmol)，氟化钾(0.32g，5.42mmol)，2-氟吡啶(0.38g，4.07mmol)和(三氟甲基)三甲基硅烷(0.58mg，4.07mmol)，室温反应16小时。将反应液过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～8：1)纯化得到中间体51ea(60mg)和中间体51eb(110mg)(通过1H-1H NOESY(二维核磁)确认)。
51ea:1H NMR(400MHz,DMSO)δ7.40–7.30(m,5H),5.06(s,2H),4.79–4.75(m,1H),4.38–4.35(m,1H),4.21–4.17(m,1H),3.92–3.90(m,1H),1.37(d,J＝6.6Hz,3H).
51eb:1H NMR(400MHz,DMSO)δ7.46–7.21(m,5H),5.19–5.15(m,1H),5.05(s,2H),4.65–4.62(m,1H),4.28–4.25(m,1H),3.92–3.90(m,1H),1.30(d,J＝6.6Hz,3H)。
步骤5：中间体51-1a的制备
室温下，向单口瓶中加入中间体51ea(60mg，0.21mmol))和无水甲醇(5.0mL)，搅拌条件下依次加入钯碳(12mg)和2滴浓盐酸，用氢气球置换三次后，在氢气氛围下室温反应16小时后。将反应液过滤之后滤液减压浓缩得到中间体51-1a。
步骤6：化合物51-1的制备
冰浴下，向单口瓶中加入中间体51-1a(30mg，0.18mmol)和二甲基甲酰胺(5.0mL)，搅拌条件下依次加入卡特缩合剂(125mg，0.27mmol)，二异丙基乙胺(70mg，0.54mmol),中间体6d(70mg，0.18mmol)，室温下过夜反应结束。向反应液中加入25mL水，每次用30毫升乙酸乙酯萃取，有机相用50mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)最后得到化合物51-1(7.34mg)。1H NMR(400MHz,DMSO)δ8.02(d,J＝8.0Hz,1H),7.50(t,J＝8.9Hz,1H),7.07(dd,J＝11.4,2.9Hz,1H),6.87–6.85(m,1H),4.98–4.94(m,1H),4.51(s,2H),4.48–4.45(m,1H),4.30–4.26(m,1H),4.03–4.00(m,1H),3.67–3.63(m,1H),2.86–2.61(m,1H),2.06–2.01(m,2H),1.87–1.83(m,2H),1.56–1.47(m,2H),1.44(t,J＝5.8Hz,3H),1.41–1.29(m,2H)，LC-MS:m/z:507.0(M+H)+。
步骤7：中间体51-2a的制备
室温下，向单口瓶中加入中间体51eb(70mg，0.24mmol))和无水甲醇(5.0mL)，搅拌条件下依次加入钯碳(12mg)和2滴浓盐酸，用氢气球置换三次后，在氢气氛围下室温反应16小时后。将反应液过滤之后滤液减压浓缩得到中间体51-2a。
步骤8：化合物51-2的制备
冰浴下，向50mL的单口瓶中加入中间体51-2a(32mg，0.20mmol)和二甲基甲酰胺(5.0mL)，搅拌条件下依次加入卡特缩合剂(149mg，0.34mmol)， 二异丙基乙胺(88mg，0.68mmol)和中间体6d(83mg，0.22mmol)，室温下过夜反应结束。向反应液中加入25mL水，每次用30mL乙酸乙酯萃取三次，合并有机相用50mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品用高效液相(碳酸氢胺/乙腈/水体系)最后得到化合物51-2(4.54mg)。1H NMR(400MHz,DMSO)δ8.02(d,J＝8.0Hz,1H),7.50(t,J＝8.9Hz,1H),7.08–7.06(m,1H),7.05–6.86(m,1H),5.26–5.22(m,1H),4.75–4.73(m,1H),4.40(s,2H),4.39–4.36(m,1H),4.03–4.02(m,1H),3.65–3.63(m,1H),2.74–2.70(m,1H),2.04–2.01(m,2H),1.86–1.83(m,2H),1.55–1.49(m,2H),1.48–1.42(m,2H),1.37(t,J＝5.8Hz,3H)，LC-MS:m/z:507.1(M+H)+。
实施例50：化合物90的合成
步骤1：中间体90b的制备
室温下，向单口瓶中加入90a(毕得医药，货号：BD253909，5.0g，31.61mmol)和N,N-二甲基甲酰胺(40.0mL)，搅拌条件下加入咪唑(4.30g，63.22mmol)和叔丁基二甲基氯硅烷(5.24g，34.77mmol)，室温反应3小时。向反应液中加入200毫升水，每次用100毫升乙酸乙酯萃取三次，合并有机相用100毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～10：1)纯化得到中间体90b。1H NMR(400MHz,CDCl3)δ3.65(s,3H),3.59-3.51(m,1H),2.30-2.15(m,1H),2.00-1.84(m,4H),1.54-1.40(m,2H),1.36-1.23(m,2H),0.87(s,9H),0.04(s,6H)。
步骤2：中间体90c的制备
室温下，向单口瓶中加入中间体90b(4.50g，16.52mmol)和乙醇(40.0mL)，室温条件下加入水合肼(9.73g，165.16mmol)，85摄氏度反应18小时。反应液减压浓缩得到中间体90c。LC-MS:m/z:273.3(M+H)+。
步骤3：中间体90d的制备
室温下，向单口瓶中加入中间体90c(1.80g，6.61mmol)和1，2-二氯乙烷(20.0mL)，搅拌条件下加入三乙胺(2.75mL，19.82mmol)和N,N'-羰基二咪唑(1.50g，9.25mmol)，室温反应18小时。将反应液倒入80毫升水中，每次用50毫升乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～1：1)纯化得到中间体90d。LC-MS:m/z:299.3(M+H)+，1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),3.69-3.57(m,1H),2.63-2.52(m,1H),2.00-1.88(m,2H),1.87-1.78(m,2H),1.51-1.38(m,2H),1.37-1.25(m,2H),0.86(s,9H),0.04(d,J＝3.0Hz,6H)。
步骤4：中间体90e的制备
室温下，向单口瓶中加入90d(900mg，3.02mmol)和N,N-二甲基甲酰胺 (10.0mL)，搅拌条件下加入N,N-二异丙基乙胺(2.00mL，12.06mmol)，3-(三氟甲氧基)-氮杂环丁烷(425mg，3.02mmol)和卡特缩合剂(1.60g，3.62mmol)，室温反应18小时。将反应液倒入60mL水中，每次用50毫升乙酸乙酯萃取三次，无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～2：1)纯化得到中间体90e。LC-MS:m/z:422.4(M+H)+，1H NMR(400MHz,DMSO-d6)δ5.38-5.26(m,1H),4.50-4.40(m,2H),4.24-4.14(m,2H),3.73-3.58(m,1H),2.83-2.64(m,1H),2.01-1.93(m,2H),1.90-1.80(m,2H),1.57-1.28(m,4H),0.87(s,9H),0.06(s,6H)。
步骤5：中间体90f的制备
室温下，向50mL的单口瓶中加入中间体90e(850mg，2.02mmol)和四氢呋喃(10.0mL)，搅拌条件下加入四丁基氟化铵(6.05mL，6.05mmol，1M)，室温反应5小时。将反应液倒入60mL水中，每次用50毫升乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～1：1)纯化得到中间体90f。LC-MS:m/z:308.2(M+H)+。
步骤6：中间体90g的制备
室温下，向单口瓶中加入中间体90f(480mg，1.56mmol)和N,N-二甲基甲酰胺(6.0mL)，搅拌条件下氢化钠(125mg，3.12mmol)和溴乙酸叔丁酯(456mg，2.34mmol)，60摄氏度下反应18小时。将反应液倒入40mL冰水中，每次用30毫升乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～3：1)纯化得到中间体90g。LC-MS:m/z:422.3(M+H)+。
步骤7：中间体90h的制备
室温下，向单口瓶中加入中间体90g(70mg，0.17mmol)和二氯甲烷(2.0mL)，搅拌条件下加入三氟乙酸(0.5mL)，室温反应2小时。将反应液滤液减压浓缩得到中间体90h。LC-MS:m/z:366.2(M+H)+。
步骤8：化合物90的制备
室温下，向单口瓶中加入中间体90h(50mg，0.14mmol)和N,N-二甲基甲酰胺(1.0mL)，搅拌条件下加入N,N-二异丙基乙胺(53mg，0.41mmol)，化合物90i(20mg，0.14mmol)和(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐(86mg，0.16mmol)。室温反应3小时。将反应液减压浓缩得到粗品。粗品通过高效液相色谱制备(甲酸/乙腈/水体系)得到化合物90。LC-MS:m/z:493.3(M+H)+，1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.84(dd,J＝12.0,2.0Hz,1H),7.59-7.40(m,2H),5.37-5.23(m,1H),4.52-4.40(m,2H),4.23-4.15(m,2H),4.11(s,2H),3.47-3.37(m,1H),2.82-2.70(m,1H),2.17-1.94(m,4H),1.60-1.30(m,4H)。
实施例51：化合物19的合成
室温下，向单口瓶中加入19a(毕得医药，货号：BD00755909，16mg,0.13mmol) 和二甲基甲酰胺(3mL)，搅拌条件下依次加入二异丙基乙胺(52mg,0.40mmol),1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(90mg,0.20mmol)和化合物6d(50mg,0.14mmol)，室温反应18小时。将反应液倒入30mL水中，每次用30mL乙酸乙酯萃取两次。有机相用30mL饱和食盐水洗涤，硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过高效液相(甲酸/乙腈/水体系)分离得到化合物19。LC-MS:m/z:475.0(M+H)+，1H NMR(400MHz,DMSO)δ8.02(d,J＝8.0Hz,1H),7.50(t,J＝8.9Hz,1H),7.07(dd,J＝11.4,2.9Hz,1H),6.97–6.57(m,2H),5.15–5.04(m,1H),4.51(s,2H),4.40–4.36(m,2H),4.07–4.04(m,2H),3.73–3.57(m,1H),2.83–2.63(m,1H),2.05–2.01(m,2H),1.87–1.85(m,2H),1.61–1.43(m,2H),1.43–1.28(m,2H)。
实施例52：化合物86的合成
步骤1：中间体86b的制备
室温下，向单口瓶中加入化合物86a(南京药石，470mg，1.72mmol)和N,N-二甲基甲酰胺(10.0mL)，搅拌条件下加入咪唑(334mg，4.91mmol)和叔丁基二甲基氯硅烷(370mg，2.45mmol)，室温反应18小时。向反应液中加入水50mL，用50mL乙酸乙酯萃取两次，合并的有机相用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～10：1)纯化得到中间体86b。LC-MS:m/z:424.2(M+Na)+。
步骤2：中间体86c的制备
室温下，向单口瓶中加入中间体86b(570mg，1.47mmol)和乙醇(10.0mL)，室温条件下加入水合肼(836mg，14.19mmol)，80摄氏度反应18小时。反应液减压浓缩得到白色固体中间体86c，LC-MS:m/z:410.2(M+Na)+。
步骤3：中间体86d的制备
室温下，向单口瓶中加入中间体86c(520mg，1.34mmol)和1，2-二氯乙烷(10.0mL)，搅拌条件下加入三乙胺(0.56mL，4.02mmol)和N,N'-羰基二咪唑(326mg，2.01mmol)，室温反应18小时。反应液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～1：1)纯化得到中间体86d。LC-MS:m/z:436.2(M+Na)+。
步骤4：中间体86e的制备
室温下，向单口瓶中加入中间体86d(470mg，1.14mmol)和N,N-二甲基甲酰胺(10.0mL)，搅拌条件下加入N,N-二异丙基乙胺(589mg，4.56mmol)，3-(三氟甲氧基)-氮杂环丁烷(176mg，1.25mmol)和卡特缩合剂(603mg，1.36mmol)，室温反应18小时。将反应液倒入50mL水中，用50mL乙酸乙酯萃取 三次，合并有机相用无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～2：1)纯化得到中间体86e。LC-MS:m/z:537.4(M+H)+。
步骤5：中间体86f的制备
室温下，向单口瓶中加入中间体86e(100mg，0.19mmol)和二氯甲烷(2.0mL)，然后加入三氟乙酸(0.5mL)，室温反应2小时。反应液滤液减压浓缩得到中间体86f。LC-MS:m/z:437.4(M+H)+。
步骤6：中间体86g的制备
室温下，向单口瓶中加入中间体86f(82mg，0.19mmol)和N,N-二甲基甲酰胺(2.0mL)，搅拌条件下加入N,N-二异丙基乙胺(98mg，0.76mmol)，化合物1i(42mg，0.14mmol)和(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐(119mg，0.23mmol)，室温反应18小时。将反应液倒入30mL水中，用30mL乙酸乙酯萃取三次，合并有机相用无水硫酸钠干燥，过滤之后滤液减压浓缩得到粗品。粗品通过快速柱色谱(石油醚：乙酸乙酯＝100：1～3：1)纯化得到中间体86g。LC-MS:m/z:623.4(M+H)+。
步骤7：化合物86的制备
室温下，向单口瓶中加入中间体86g(117mg，0.19mmol)和四氢呋喃(2.0mL)，搅拌条件下加入四丁基氟化铵(0.38mL，0.38mmol，1M)，室温反应3小时。将反应液减压浓缩得到粗品，粗品通过高效液相色谱制备(甲酸/乙腈/水体系)得到化合物86。LC-MS:m/z:509.2(M+H)+，1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝7.7Hz,1H),7.49(t,J＝8.9Hz,1H),7.08(dd,J＝11.4,2.8Hz,1H),6.87(dd,J＝8.9,1.9Hz,1H),5.36-5.27(m,1H),4.83(d,J＝5.0Hz,1H),4.52(s,2H),4.49-4.42(m,2H),4.23-4.16(m,2H),3.58-3.41(m,2H),2.91-2.80(m,1H),2.24-2.16(m,1H),1.99-1.90(m,1H),1.88-1.80(m,1H),1.50-1.30(m,3H)。
本发明的其他化合物可以通过与以上实施例所述的方法类似的方法(必要时，进行适当的修改)制备。
生物测试
1、细胞活性测试
ATF4荧光素酶报告质粒是由两部分组成，ATF4基因的5’非翻译区序列和荧光素酶编码序列。具体来讲，将含有两个上游开放阅读框(uORF)的ATF4的5’非翻译区序列(NCBI数据库编号BC022088.2)及萤火虫萤光素酶编码基因克隆到pLVX-Puro载体(优宝生物，VT1465)中。慢病毒的包装质粒为psPAX2(优宝生物，VT1444)及pMD2.G(优宝生物，VT1443)。在HEK293T/17细胞中用X-tremeGENE 9 DNA转染试剂同时转染以上三个质粒，并于48小时后收集含慢病毒的培养液。用1μg/mL的嘌呤霉素来筛选病毒转导的HEK293T/17细胞，此后用有限稀释法获得单克隆细胞。
利用该细胞系，可以通过冷荧光读数来检测ATF4的翻译调控并测试eIF2B激活剂的活性。具体实验流程如下：在384孔板在铺6000个HEK293T/17-ATF4uORF-Luc-Puro单克隆细胞，过夜贴壁。将测试化合物溶解在DMSO中，与50nM的毒胡萝卜素共同加入细胞培养液中，孵育6小时。其中，毒胡萝卜素的作用是造成细胞压力，上调ATF4的蛋白翻译。加药6小时后，使用One-Glo荧光素酶检测试剂盒(Promega#E6120)来裂解细胞，随后用EnVision 2104读板器的LUM程序来读取冷荧光值。
按如下方法计算ATF4报告基因的相对表达量(ATF4 reporter expression％)：
ATF4 reporter expression％＝(ave_sample-ave_vc)/(ave_pc-ave_vc)*100％.
ave_vc：阴性对照的平均信号值
ave_pc：阳性对照的平均信号值
ave_sample：样品的平均信号值
拟合剂量-效应曲线，计算EC50值：
用GraphPad 9软件的nonlinear regression log(inhibitor)vs.response--variable slope(four parameters)方法来拟合ATF4报告基因的相对表达量与化合物浓度之间的对应关系。
X轴：化合物浓度的log值；Y轴：ATF4报告基因的相对表达量；Top：曲线上渐近线估值；Bottom：曲线下渐近线估值；Hillslope：拟合曲线的斜率。
公式：Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50-X)×HillSlope))，即LogEC50＝X+(1/HillSlope)×log((Top-Y)/(Y-Bottom))。
在表1中，“+”表示＞100nM的EC50，“++”表示在10nM至100nM的EC50，“+++”表示在1nM至10nM的EC50，“++++”表示小于1nM的EC50。
表1示例性化合物的结构及HEK293T/17-ATF4uORF-Luc-Puro单克隆细胞活性

实验结果(部分未示出)显示，本申请的化合物可提升/激活eIF2B活性，能降低ATF4表达量，从而使得荧光强度减弱，表明本申请的化合物能明显缓解由毒胡萝卜素造成的细胞压力，减弱细胞的整合应激反应，使得细胞内蛋白质趋于正常合成，属于eIF2B激动剂。本申请大部分的化合物对HEK293T/17细胞的EC50值＜100nM，有许多化合物对HEK293T/17细胞的EC50值在10nM至100nM之间，有不少的化合物对HEK293T/17细胞的EC50值在10nM以下，部分优选化合物对HEK293T/17细胞的EC50值＜1nM，最优选的化合物对HEK293T/17细胞的EC50值小于10pM。
2、动力学溶解性评价
将测试化合物的溶解在DMSO中，制备称浓度为10mM储备液。将8.71g K2HPO4加入500mL去离子水中，制备100mM K2HPO4溶液。将2.05g磷酸二氢钾加入150mL去离子水中，制备100mM磷酸二氢钾溶液。将405mL 100mM K2HPO4和95mL 100mM KH2PO4混合，用100mM K2HPO4/KH2PO4溶液调整混合溶液的pH值为7.4。向240.3g去离子水中加入10.41g FaSSIF缓冲液浓缩液，制成缓冲液(禁食状态下模拟肠液，pH＝6.5)。将4.071g FeSSIF缓冲液浓缩物加入45.97g去离子水中，制成缓冲液(进食状态下模拟肠液，pH＝5.0)。
用96孔板，将16μL 10mM的化合物储备液加入到784μL不同缓冲液中(n＝3)，将板密封并在25℃(PBS)、37℃(其他)1000rpm振荡1.5h。孵育后，将溶液转移到滤板中。过滤所有样品。取滤液5μL，加入5μL DMSO和490μL含有内标的乙腈水溶液(1:1)中，混匀。再根据化合物性质及其在质谱的响应以含有内标的乙腈水溶液(1:1)进行稀释。根据溶解度值和UPLC-MS/MS信号响应改变稀释因子。
实验表明本申请的至少部分化合物在上述不同的模拟环境下均具有较好的溶解性，例如化合物6在禁食物状态下模拟肠液(pH＝6.5)环境下的溶解度＞10μg/mL，在进食状态下模拟肠液(pH＝5.0)环境下的溶解度＞80μg/mL。
3、体外肝微粒体稳定性评价
预热含5mM MgCl2的100mM K-Mg-缓冲液。将5μL的10mM化合物和参考品储备液加入95μL的乙腈(ACN)中制成加标溶液。在479.8μL的K-Mg缓冲液中加入1.5μL 500μM的加标溶液和18.75μL的20mg/mL的肝微粒体。NADPH储备液(3mM)通过将NADPH溶解到K-Mg缓冲液中来制备。在不同时间点(0、5、15、30和45分钟)将30μL的含微粒体的1.5μM加标液均匀滴入检测板中。37℃预孵育5分钟。0min时，在孔中加入200μL含IS(内标，甲苯磺丁脲/特非那定，tolbutamid/terfenadine)的ACN，再加入15μLNADPH储备液(6mM)。对于其他时间点，在孔中加入15μL NADPH储备液(6mM)启动反应并计时。分别于5、15、30、45min时在相应板孔中加入200μL含IS的ACN停止反应。淬火后，600rpm摇板10分钟，然后在4000rmp离心50分钟。每孔吸取80μL上清液转移到含有160μL纯水的96孔样品板中用于UPLC/MS/MS分析。
表2示例化合物的体外肝微粒体稳定性

实验表明本申请的至少部分化合物具有良好的体外肝微粒体稳定性。
4、细胞膜渗透性评价
用运输缓冲液(HBSS+BSA)将测试化合物从10mM的储备液稀释到10μM的浓度，并将其作用于细胞单层的顶端或基底外侧。在37℃和5％CO2且相对湿度为95％条件下，经120分钟孵育双重测定测试化合物从A到B方向或B到A方向的渗透性。此外，还测定了各化合物的外排比。采用LC-MS/MS方法，根据分析物/IS峰面积比值对被测物和参比物进行定量分析。
表3示例化合物的细胞膜渗透性
实验结果表明本申请的至少部分化合物具有良好的细胞膜渗透性，且不是P-糖蛋白底物。
5、P450酶抑制性评价
配置肝微粒体的磷酸缓冲液。将169μL肝微粒体的磷酸缓冲液和1μL多个浓度的测试化合物或阳性对照化合物工作液加入到96孔板中。将培养板置于水浴中并在37℃预热15分钟。孵育结束后，向培养板中加入10μL底物(CYP3A4-T向培养板中加入1μL底物和9μL K-Mg缓冲液)，在旋转混合器上混合孵育混合物10秒，然后加入20μL 10mM NADPH溶液，以终浓度1mM启动反应。实验重复两次。在表4中列出的预定时间点，通过加入400μL的淬灭溶液(冷ACN含500nM甲苯丁胺和10nM特非那定)来淬灭反应。在4℃下以3220g离心50分钟。将100μL上清液转移到新的平板上。上清液用100μL纯水稀释。混合均匀并用UPLC-MS/MS分析样品。
表4底物储备液的配置

实验结果表明本申请的至少部分化合物对5种主要的P450酶(CYP1A2、CYP2C9、CYP2D6、CYP2C19、CYP3A4)抑制较弱，产生药物-药物相互作用的风险较低，例如化合物6对这5种主要的P450酶的IC50值基本都＞10μM，尤其是CYP2D6和CYP3A4的IC50均大于＞30μM。
6、小鼠药代动力学评价
用溶媒溶解测试化合物制成澄清溶液或均一悬浮液。每组3只小鼠，经尾静脉给药1mg/kg，经口服给药(PO)10mg/kg。在静脉给药后0.083h,0.25h,0.5h,1h,2h,4h,8h和24h取血,口服给药后0.25h、0.5h、1h、2h、4h、6h、8h和24h取血。血浆样本通过离心，取上清液制成样品，用LC/MS/MS进行定量分析。
表5化合物6的小鼠PK性质
实验结果表明本申请的至少部分化合物(例如化合物6)在小鼠体内具有优秀的药代动力学性质(包括但不限于Cl(清除率)、T1/2(半衰期)、Cmax(峰值浓度)、AUC(药时曲线下面积)、F(生物利用度)等)。
虽然已经参考优选实施例对本申请进行了描述，但在不脱离本申请的范围的情况下，可以对其进行各种改进并且可以用等效物替换其中的部件。尤其是，只要不存在结构冲突，各个实施例中所提到的各项技术特征均可以任意方式组合起来。本申请并不局限于文中公开的特定实施例，而是包括落入权利要求的范围内的所有技术方案。

Claims (22)

  1. 式0所示的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐：
    其中，
    A环选自C3-C10亚环烷基、或3-10元亚杂环烷基，且A环不为 其中，*端与L连接，端与B环连接，所述n3为0-5的任意整数；
    B环选自5-10元亚杂芳基，n4为0-4的任意整数；
    C环选自3-10元亚杂环烷基、C3-C10亚环烷基、或#B-X21-C3-C12亚环烷基-$R1，X21为-NR3或-C(O)NR3，#B-为与B环连接的连接键，-$R1为与R1连接的连接键；各R3各自独立地为H、氘、卤素、C1-C6烷基或C1-C6卤代烷基，且C环为C3-C10亚环烷基时，A环不为亚环己基，A环为时，*端与L连接，端与B环连接，C环为3-10元亚杂环烷基，n5为0-5的任意整数；
    D环选自C6-C10亚芳基、5-10元亚杂芳基、C3-C10亚环烷基或3-10元亚杂环烷基；
    L为#D-L1-L2-L3-$A、5-6元杂芳基或#D-NR14C(O)-C1-C6亚烷基-O-$A，L1为键、-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C10亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A，X10为O或S，R4、R5和R14各自独立地选自H、氘、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基，作为R4、R5和R14的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R11取代；#D-为与D环连接的连接键，-$A为与A环连接的连接键；
    R1、R2、R9a、R9b、R9c各自独立地为取代基R11，
    各R11各自独立地选自氘、卤素、氰基、硝基、＝O、-OR6、-SR6、SF5、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、NR6S(O)1- 2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7、-P(O)R6R7或-NR6C(O)OR7，其中作为R9a、R9b、R9c、R11的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R12取代；
    各R6、R7和R8各自独立地选自H、氘、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R20、-C(O)OR20、-C(O)NR20R21、-S(O)1-2R20、-S(O)1-2NR20，其中作为R6、R7和R8的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R13取代；或者
    R6和R7与和它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；或者
    R7和R8与和它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
    各R12和各R13各自独立地为H、氘、卤素、氰基、硝基、＝O、-OR30、-SR30、-SF5、NR30R31、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30、-C(O)NR30R31、-C(O)ONR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1- 2NR30、-NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31，其中作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
    各R20和R21各自独立地选自H、氘、或可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基；或者
    R20和R21与它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
    各R30和R31各自独立地选自H、氘、或可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基；或者
    R30和R31与它们同时相连的原子形成杂环烷基，且该杂环烷基可被1-6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C10烷基取代；
    n1和n2各自独立为0-4的任意整数。
  2. 根据权利要求1所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    n4为0、1、2或3；各所述R9b各自独立地为卤素、氰基、硝基、-OH、C1-C3烷基；优选地，所述R9b各自独立地为卤素、-OH、甲基、乙基或丙基；
    优选地，所述n4为0；
    优选地，所述B环选自 其中，X7为O或S，X8、X9、X10各自独立地为CH或N，*端与C环连接，端与A环连接；
    更优选地，X8、X9、X10中至多两个为N；
    进一步优选地，X8、X9、X10中的一个为N；
    优选地，所述B环选自以下基团中的任意一种：
    进一步优选地，所述B环选自以下基团中的任意一种：
    更优选地，所述B环为
  3. 根据权利要求1或2所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式I所示结构
    其中，A环、C环、D环、L、R1、R2、R9a、R9c、n1、n2、n2、n3和n5如权利要求1或2所定义，X7为O或S；
    优选地，n1和n2各自独立地为1-3的整数；
    进一步优选地，n1为1，n2为1-3的整数。
  4. 根据权利要求1至3中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    各所述R9c各自独立地为卤素、氰基、硝基、＝O、-OH、-NR30R31、C1-C3烷基、-C(O)R30、-C(O)OR30，各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
    优选地，所述C环可被1或2个R9c取代，各所述R9c各自独立地为卤素、氰基、硝基、-OH、C1-C3烷基；
    进一步优选地，所述R9c各自独立地为卤素、-OH、甲基、乙基或丙基；
    更优选地，所述R9c各自独立地为F、甲基；
    优选地，n5为0、1或2；
    进一步优选地，n5为0或1；
    优选地，所述C环的3-10元亚杂环烷基选自 其中，X11、X23各自为N或B，X12为CH2、NH、O或S，q为0至3的整数，优选q为1或2；X13为N或B，s为1至3的整数，优选s为1或2；X14为O、S或NH，t为1至3的整数，优选t为1或2；*端与B环连接，端与R1连接；
    进一步优选地，所述C环的3-10元亚杂环烷基选自
    优选地，所述C环的#B-X21-C3-C12亚环烷基-$R1为其中，R3为H、卤素、C1-C3烷基或C1-C3卤代烷基，p为1至3的整数，优选为1或2；*端与B环连接，端与R1连接；
    进一步优选地，所述C环的#B-X21-C3-C12亚环烷基-$R1为
    优选地，所述C环选自 *端与B环连接，端与R1连接；
    进一步优选地，所述C环选自
    更优选地，所述C环选自 各q、p、s、t各自独立地为1或2；
    优选地，所述选自 *端与B环连接，端与R1连接；
    进一步优选地，所述选自
    更优选地，所述选自
  5. 根据权利要求1至4中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    各所述R1各自独立地为R11，
    各R11各自独立地选自卤素、氰基、硝基、＝O、-OR6、-SR6、-NR6R7、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基、-C(O)R6、-C(O)OR6、-OC(O)OR6、-S(O)1-2R6、-P(O)R6R7，其中作为R11的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到6个R12取代；
    各R6、R7各自独立地选自H、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基，其中作为R6、R7的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到3个R13取代；
    各R12和各R13各自独立地为H、卤素、氰基、硝基、＝O、-OR30、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基，其中作为R12和R13的C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环烷基各自独立地可被1到3个卤素取代、或被可选地被1-3个卤素、羟基或氨基取代的C1-C3烷基取代，
    各R30各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
    优选地，所述R1选自-OR6、C1-C3烷基、卤素、-S(O)2R6或-P(O)R6R7，其中作为R1的C1-C3烷基可被1-6个R12取代，R12选自卤素、-S(O)2R30，R30选自C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基；各R6各自独立地选自C1-C3烷基、C2-C4烯基、C3-C6环烷基，其中作为R6的C1-C3烷基、C2-C4烯基、C3-C6环烷基各自独立地可被1-6个R13取代，R13选自卤素；R7选自C1-C3烷基；
    进一步优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、-F、-OCF＝CF2、
    进一步优选地，所述R1选自-OCF3、-CF2CF3、-OCH3、-F、-CF3；
    进一步优选地，所述R1选自-OCF3、-OCF2CF3；
    更优选地，所述R1为-OCF3；
    优选地，n1为0或1。
  6. 根据权利要求1至5中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式II所示结构
    其中，A环、D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如权利要求1至5中任一项所定义；
    优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、F、-OCF＝CF2、
    进一步优选地，所述R1选自-OCH3、-OCF3、-CF2CF3、-F、-CF3；
    进一步优选地，所述R1为-OCF3、-OCF2CF3；
    更优选地，所述R1为-OCF3；
    优选地，n1为1；
    优选地，n5为0、1或2，各所述R9c各自独立地为卤素、氰基、硝基、-OH、C1-C3烷基；
    进一步优选地，所述R9c各自独立地为卤素、-OH、甲基、乙基或丙基；
    更优选地，所述R9c各自独立地为F。
  7. 根据权利要求1至6中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式II-1所示结构
    其中，A环、D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如权利要求1至6中任一项所定义；
    优选地，n5为0或1；
    优选地，所述R9c选自卤素、氰基、硝基、-OH、C1-C3烷基；
    进一步优选地，所述R9c选自卤素、甲基或乙基；
    更优选地，所述R9c为F；
    优选地，所述选自
    优选地，n1为1，所述R1选自-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2Cl、-CH2CF3、-OCF2CF3、-OCF＝CF2、
    进一步优选地，所述R1选自-OCH3、-OCF3、-OCF2CF3；
    进一步优选地，所述R1选自-OCF3、-OCF2CF3；
    更优选地，所述R1为-OCF3。
  8. 根据权利要求1至7中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    n3为0、1或2；
    优选地，所述A环选自C5-C8亚环烷基或5-8元亚杂环烷基；
    进一步优选地，所述A环选自亚环己烷或6元亚杂环烷基；
    进一步优选地，所述A环选自亚环己烷或*端与L连接，端与B环连接；
    优选地，所述A环选自C5-C8亚桥环烷基或6-8元亚桥杂环烷基，其中，X1为CH或N，X2、X3、X4、X5、X6各自独立地为CH2、CH、NH、N或O，*端与L连接，端与B环连接；
    进一步优选地，所述中，X5为CH2或O，X2、X3、X4、X6各自独立地为CH2或CH；
    进一步优选地，所述中X2、X3、X6为CH2，X4为CH；
    优选地，所述A环的C5-C8亚桥环烷基或6-8元亚桥杂环烷基各自独立地可被0-4个R9a取代；
    进一步优选地，所述A环被0、1或2个R9a取代；
    更优选地，所述A环被0或1个R9a取代；
    进一步优选地，所述C5-C8亚桥环烷基为
    进一步优选地，所述6-8元亚桥杂环烷基为
    优选地，所述R9a各自独立地为卤素、氰基、硝基、＝O、-OR6、-SR6、SF5、-NR6R7、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7、-NR6C(O)NR7R8、-S(O)1-2R6、-S(O)1-2NR6、NR6S(O)1- 2R7、-NR6S(O)1-2NR7R8、-NR6C(O)R7或-NR6C(O)OR7，其中作为R9a的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个R12取代；
    各R6、R7和R8各自独立地选自H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R20、-C(O)OR20、-C(O)NR20R21、-S(O)1-2R20、-S(O)1-2NR20，其中作为R6、R7和R8的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到4个R13取代；
    各R12、各R13各自独立地为H、卤素、氰基、硝基、＝O、-OR30、-SR30、SF5、-NR30R31、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30、-C(O)NR30R31、-C(O)ONR30R31、-NR30C(O)NR30R31、-S(O)1-2R30、-S(O)1- 2NR30、NR30S(O)1-2R31、-NR30S(O)1-2NR30R31、-NR30C(O)R31或-NR30C(O)OR31，其中作为R12和R13的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基、5-10元杂芳基各自独立地可被1到6个卤素取代、或被可选地被1-6个卤素、羟基或氨基取代的C1-C6的烷基取代，
    各R20和R21各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C6的烷基；
    各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C6的烷基；
    进一步优选地，所述R9a各自独立地为卤素、氰基、硝基、＝O、-OH、-NR30R31、C1-C3烷基、C1-C3卤代烷基、-C(O)R30、-C(O)OR30，各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
    更优选地，所述R9a各自独立地为卤素、氰基、硝基、＝O、-OH、甲基、乙基、氟代甲基或氟代乙基；
    更优选地，所述R9a各自独立地为-OH、＝O；
    更优选地，所述R9a各自独立地为-OH；
    优选地，所述选自
    *端与L连接，端与B环连接；
    进一步优选地，所述选自
    进一步优选地，所述选自
    更优选地，所述选自
    更优选地，所述选自
    更优选地，所述选自
  9. 根据权利要求1至8中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式III所示结构
    其中，D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如权利要求1至8中任一项所定义；X1和X4各自独立地为CH或N，X2、X3、X5、X6各自独立地为CH2、CH、NH、N或C，v为0至2的整数；
    优选地，所述R9a各自独立地为卤素、＝O、-OH、C1-C3烷基，更优选为-OH。
  10. 根据权利要求1至9中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式III-1至III-6中任一通式所示结构
    其中，D环、L、R1、R2、R9a、R9c、n1、n2、n3和n5如权利要求1至9中任一项所定义；
    优选地，R9a为羟基或卤素；
    更优选地，R9a为羟基；
    优选地，n3为0-3的整数；
    更优选地，n3为0、1或2。
  11. 根据权利要求1至10中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述L为#D-L1-L2-L3-$A、或#D-NR14C(O)-C1-C6亚烷基-O-$A，L1为键、-O-、-S-或-NR4-，L2为键、取代或未取代的C1-C3亚烷基，L3为-C(X10)NR5-$A或-C(X10)-$A，X10为O或S，R4、R5和R14各自独立地选自H、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环烷基，作为R4、R5和R14的C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、3-6元杂环烷基各自独立地可被1到3个R11取代；各R11各自独立地选自卤素、氰基、硝基、＝O、-OH、-SH、-NH2，优选各R11各自独立地选自卤素、氰基、硝基、-OH、-SH、-NH2；#D-为与D环连接的连接键，-$A为与A环连接的连接键，*端与A环连接，端与D环连接；
    优选地，所述L选自 *端与A环连接，端与D环连接；
    进一步优选地，所述L选自
    进一步优选地，所述L选自
    更优选地，所述L选自
  12. 根据权利要求1至9、11中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式IV-1或IV-2所示结构
    其中，A环、C环、D环、R1、R2、R9a、R9c、n1、n2、n3和n5如权利要求1至9中任一项所定义，X7为O或S；
    优选地，所述化合物具有通式V-1或V-2所示结构
    其中，v为0至2的整数，D环、R1、R2、R9a、R9c、n1、n2、n3和n5如 权利要求1至9中任一项所定义，X7为O或S，X1和X4各自独立地为CH或N，X2、X3、X5、X6各自独立地为CH2、CH、NH、N或C。
  13. 根据权利要求1至12中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述选自 其中，X14、X15、X16、X17、X18各自独立地选自CH、N，且至少一个为N，优选至多有三个N，进一步优选至多有两个N；X19、X20各自独立地选自CH、N、NH、O、S，且不同时为S或O，m为1或2；X21、X22各自独立地选自CH、N、NH、O、S，且不同时为S或O，m为1或2；u为1或2或3；
    优选地，所述选自
    进一步优选地，所述选自
    进一步优选地，所述选自
    进一步优选地，所述选自
    更优选地，所述选自
  14. 根据权利要求1至13中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    R2为R11，
    各R11各自独立地选自卤素、氰基、硝基、＝O、-OR6、-SR6、-NR6R7、C1-C6烷基、C3-C6环烷基、3-8元杂环烷基、-C(O)R6、-C(O)OR6、-OC(O)OR6、OC(O)R6、-C(O)NR6R7、-C(O)ONR6R7，其中作为R11的C1-C6烷基、C2-C6烯基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到6个R12取代；
    各R6、R7和R8各自独立地选自H、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、-C(O)R20、-C(O)OR20、-C(O)NR20R21，其中作为R6、R7和R8的C1-C6烷基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到3个R13取代；
    各R12和各R13各自独立地为H、卤素、氰基、硝基、＝O、-OR30、NR30R31、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、-C(O)R30、-C(O)OR30、-OC(O)OR30、OC(O)R30，其中作为R12和R13的C1-C6烷基、C3-C8环烷基、3-8元杂环烷基各自独立地可被1到3个卤素取代、或被可选地被1-3个卤素、羟基或氨基取代的C1-C3烷基取代，
    各R20和R21各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代的C1-C3烷基；
    各R30和R31各自独立地选自H、或可选地被1-6个卤素、羟基或氨基取代 的C1-C3烷基；
    n2为1或2或3；
    优选地，各R2各自独立地选自卤素、氰基、C1-C3卤代烷基、C1-C3烷基、-OC1-C3烷基、-O C1-C3卤代烷基、-NR6R7、C3-C6环烷基、3-6元杂环烷基，R6、R7各自独立地选自H、C1-C3烷基、C1-C3卤代烷基、C3-C6环烷基、C3-C6卤代环烷基，优选地，所述R2为C3-C6环烷基、3-6元杂环烷基时，n为1，且所述R2与所述D环共用两个碳原子形成稠环；
    进一步优选地，各R2各自独立地选自卤素、C1-C3卤代烷基、C1-C3烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-NH2、其中，当R2为时，与所述D环共用两个碳原子形成稠环；
    进一步优选地，各R2各自独立地选自F、Cl、Br、-CF3、-CH3、-CF2H、-OCF3、-NH2，n2为1、2或3；
    优选地，所述选自
    进一步优选地，所述选自
    进一步优选地，所述选自
    进一步优选地，所述选自
    更优选地，所述选自
  15. 根据权利要求1至14中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，
    所述化合物具有通式VI所示结构
    其中，所述A环选自亚环己烷或6元亚杂环烷基；所述L、R1、R2、R9a、R9c、n1、n2、n3和n5如权利要求1至14中任一项所定义；
    优选地，所述R2各自独立的选自F、Cl、Br；
    优选地，所述n2为1或2；
    优选地，所述R2与L呈对位和/或间位关系；
    优选地，所述L选自 *端与A环连接，端与D环连接；
    进一步优选地，所述L选自
    进一步优选地，所述L选自
    更优选地，所述L选自
    优选地，所述n1和n5不同时为0；
    优选地，所述R1与其所在C环上的N呈对位关系；
    优选地，所述R1选自-OR6、C1-C3烷基、卤素、-S(O)2R6或-P(O)R6R7，其中作为R1的C1-C3烷基可被1-6个R12取代，R12选自卤素、-S(O)2R30，R30选自C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基；各R6各自独立地选自C1-C3烷基、C2-C4烯基、C3-C6环烷基，其中作为R6的C1-C3烷基、C2-C4烯基、C3-C6环烷基各自独立地可被1-6个R13取代，R13选自卤素；R7选自C1-C3烷基；
    进一步优选地，所述R1为-OCH3、-OCF3、-CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、-F、-OCF＝CF2、
    进一步优选地，所述R1为-OCF3、-CF2CF3、-OCH3、-F、-CF3；
    进一步优选地，所述R1为-OCF3、-OCF2CF3；
    更优选地，所述R1为-OCF3。
  16. 根据权利要求1至15中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，所述化合物具有通式VII所示结构
    其中，R9a、X10的定义如权利要求1所述，R21选自卤素，R22选自H、卤素，t选自0-2的整数；
    优选地，R21为Cl；
    优选地，R22选自H、F、Cl、Br；
    优选地，R9a选自H、羟基；
    优选地，t为0或2。
  17. 根据权利要求1至16中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐，其中，所述化合物选自：





    优选地，所述化合物选自：

  18. 一种具有权利要求12所述的通式IV-1或IV-2所示结构的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐的合成方法，所述合成方法选自合成路线1至6中任意一种；
    合成路线1：
    其中，化合物1-1与化合物1-2发生酰胺缩合反应得到化合物1-3；所述化合物1-3与水合肼反应，经官能团转化得到化合物1-4；所述化合物1-4与N,N-羰基二咪唑发生环合得到化合物1-5；所述化合物1-5与化合物1-6发生缩合反应得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如权利要求12所定义；
    合成路线2：
    其中，化合物2-1与化合物2-2发生酰胺缩合反应得到化合物2-3；所述化合物2-3与水合肼反应，经官能团转化得到化合物2-4；所述化合物2-4与N,N-羰基二咪唑发生环合得到化合物2-5；所述化合物2-5与化合物2-6发生缩合反应得到化合物IV-2-1；R1、R2、R9a、R9c、n1和n2如权利要求12所定义；
    合成路线3：
    其中，化合物3-1与水合肼反应，经官能团转化得到化合物3-2；所述化合物3-2与N,N-羰基二咪唑发生环合得到化合物3-3；所述化合物3-3与化合物3-4发生缩合反应得到化合物3-5；所述化合物3-5在酸性条件下脱去保护基得到化合物3-6；所述化合物3-6与化合物3-7发生酰胺缩合反应得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如权利要求12所定义；
    合成路线4：

    其中，化合物4-1与水合肼反应，经官能团转化得到化合物4-2；所述化合物4-2与N,N-羰基二咪唑发生环合得到化合物4-3；所述化合物4-3与化合物4-4发生缩合反应得到化合物4-5；所述化合物4-5在酸性条件下脱去保护基得到化合物4-6；所述化合物4-6与化合物4-7发生酰胺缩合反应得到化合物IV-2-1，R1、R2、R9a、R9c、n1和n2如权利要求12所定义；
    合成路线5：
    其中，化合物5-1与化合物5-2发生酰胺缩合反应得到化合物5-3；所述化合物5-3与水合肼反应，经官能团转化得到化合物5-4；所述化合物5-4与化合物5-5发生缩合得到化合物5-6；所述化合物5-6发生关环反应得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如权利要求12所定义；
    合成路线6：

    其中，化合物6-1与水合肼反应，经官能团转化得到化合物6-2；所述化合物6-2发生关环反应得到化合物6-3；所述化合物6-3发生氧化反应得到化合物6-4；所述化合物6-4与化合物6-5发生反应得到化合物6-6；所述化合物6-6在酸性条件下脱去保护基得到化合物6-7；所述化合物6-7与化合物6-8发生缩合得到化合物IV-1-1，R1、R2、R9a、R9c、n1和n2如权利要求12所定义。
  19. 一种药物组合物，包含权利要求1至17中任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐所制备而成的制剂，或权利要求18所述的合成方法得到的化合物。
  20. 根据权利要求19所述的药物组合物，其特征在于：进一步包括药学上可接受的载体、辅料、媒介物。
  21. 权利要求1至17任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐或权利要求19或20所述的药物组合物在制备预防和/或治疗神经退行性疾病、癌症、炎症性疾病、自身免疫性疾病、病毒感染、皮肤疾病、纤维化疾病、血红蛋白疾病、肾脏疾病、听力损失疾病、眼部疾病、具有导致未折叠蛋白质反应(UPR)诱导的突变疾病、疟疾感染、肌肉骨骼疾病、代谢性疾病或线粒体疾病的药物中的用途。
  22. 权利要求1至17任一项所述的化合物、或其立体异构体、或其互变异构体、或其几何异构体、或其对映异构体、或其非对映异构体、或其消旋体、或其多晶型物、或其溶剂合物、或其水合物、或其N-氧化物、或其同位素标记化合物、或其代谢产物、或其酯、或其前药、或其药学上可接受的盐、或权利要求19或20所述的药物组合物在制备预防和/或治疗由整合应激反应(ISR)路径介导的疾病或病症的药物中的用途。
PCT/CN2023/132911 2022-11-21 2023-11-21 一种化合物、包含其的药物组合物及其合成方法和用途 WO2024109736A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202211455519.X 2022-11-21
CN202211455519 2022-11-21
CN202310731972 2023-06-19
CN202310731972.7 2023-06-19

Publications (1)

Publication Number Publication Date
WO2024109736A1 true WO2024109736A1 (zh) 2024-05-30

Family

ID=91195294

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/132911 WO2024109736A1 (zh) 2022-11-21 2023-11-21 一种化合物、包含其的药物组合物及其合成方法和用途

Country Status (1)

Country Link
WO (1) WO2024109736A1 (zh)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109641853A (zh) * 2016-05-05 2019-04-16 卡里科生命科学有限责任公司 整合应激通路的调节剂
CN111094233A (zh) * 2017-08-09 2020-05-01 戴纳立制药公司 化合物、组合物及方法
CN112204012A (zh) * 2017-11-02 2021-01-08 卡里科生命科学有限责任公司 整合应激通路的调节剂
CN113993850A (zh) * 2019-04-23 2022-01-28 埃沃特克国际有限责任公司 整合应激反应途径的调节剂
CN114008041A (zh) * 2019-04-23 2022-02-01 埃沃特克国际有限责任公司 整合应激反应路径的调节剂
CN114206848A (zh) * 2019-04-30 2022-03-18 卡里科生命科学有限责任公司 作为整合应激通路的调节剂的被取代的环烷基化合物
WO2022084447A1 (en) * 2020-10-22 2022-04-28 Evotec International Gmbh Modulators of the integrated stress response pathway
WO2022094244A1 (en) * 2020-10-30 2022-05-05 Calico Life Sciences Llc Modulators of the integrated stress pathway
CN114980894A (zh) * 2020-01-28 2022-08-30 埃沃特克国际有限责任公司 整合应激反应途径的调节剂
WO2022212902A1 (en) * 2021-04-02 2022-10-06 Altos Labs, Inc. Modulators of integrated stress response pathway
CN115190813A (zh) * 2020-03-11 2022-10-14 埃沃特克国际有限责任公司 整合应激反应途径的调节剂

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109641853A (zh) * 2016-05-05 2019-04-16 卡里科生命科学有限责任公司 整合应激通路的调节剂
CN111094233A (zh) * 2017-08-09 2020-05-01 戴纳立制药公司 化合物、组合物及方法
CN112204012A (zh) * 2017-11-02 2021-01-08 卡里科生命科学有限责任公司 整合应激通路的调节剂
CN113993850A (zh) * 2019-04-23 2022-01-28 埃沃特克国际有限责任公司 整合应激反应途径的调节剂
CN114008041A (zh) * 2019-04-23 2022-02-01 埃沃特克国际有限责任公司 整合应激反应路径的调节剂
CN114206848A (zh) * 2019-04-30 2022-03-18 卡里科生命科学有限责任公司 作为整合应激通路的调节剂的被取代的环烷基化合物
CN114980894A (zh) * 2020-01-28 2022-08-30 埃沃特克国际有限责任公司 整合应激反应途径的调节剂
CN115190813A (zh) * 2020-03-11 2022-10-14 埃沃特克国际有限责任公司 整合应激反应途径的调节剂
WO2022084447A1 (en) * 2020-10-22 2022-04-28 Evotec International Gmbh Modulators of the integrated stress response pathway
WO2022094244A1 (en) * 2020-10-30 2022-05-05 Calico Life Sciences Llc Modulators of the integrated stress pathway
WO2022212902A1 (en) * 2021-04-02 2022-10-06 Altos Labs, Inc. Modulators of integrated stress response pathway

Similar Documents

Publication Publication Date Title
AU2020200407B2 (en) Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof
JP5504252B2 (ja) ５−ｈｔ６アンタゴニストとしてのアリールスルホニルピラゾリンカルボキシアミジン誘導体
CN109906224A (zh) 三唑吡啶化合物及其应用
AU2013227024A1 (en) Novel piperidine compound or salt thereof
US11634432B2 (en) mTORC1 modulators and uses thereof
CN112165944A (zh) 转录激活蛋白的咪唑并哌嗪抑制剂
WO2022089454A1 (zh) 一种高活性Wnt通路抑制剂化合物
KR101905295B1 (ko) 나프티리딘디온 유도체
CN115605463A (zh) 用于治疗疾病的受体相互作用蛋白激酶i的抑制剂
WO2023083201A1 (zh) 一种氨基吡唑衍生物及其制备方法和用途
WO2015064714A1 (ja) オートタキシン阻害活性を有する１－置換イミダゾピリミジノン誘導体
WO2023078451A1 (zh) 用作cdk7激酶抑制剂的化合物及其应用
WO2022117075A1 (zh) 氮杂并环化合物、其制备方法及其用途
CN108929307A (zh) 一类异吲哚酮-酰亚胺环-1,3-二酮-2-烯化合物、其组合物和用途
WO2021027647A1 (zh) 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途
JP6526064B2 (ja) ピリドピリミジンジオン誘導体
WO2024109736A1 (zh) 一种化合物、包含其的药物组合物及其合成方法和用途
WO2023143147A1 (zh) 一种哒嗪并吡啶酮类化合物、其药物组合物及应用
TW202322819A (zh) 含氮的四環化合物、其製備方法及其在醫藥上的應用
JP2016540031A (ja) ＲＯＲ−ガンマ阻害剤としてのテトラヒドロ−テトラゾロ［１，５−ａ］ピラジン
CN115215862A (zh) 嘧啶酮化合物及其用途
WO2024032501A1 (zh) 一种化合物、包含其的药物组合物及其用途
TWI848162B (zh) 橋雜環基取代的嘧啶類化合物及其製備方法和醫藥用途
WO2023116763A1 (zh) 一种哒嗪类化合物、其药物组合物及应用
WO2023143546A1 (zh) Wnt通路抑制剂化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23893826

Country of ref document: EP

Kind code of ref document: A1