WO2023134656A1 - 一种肽基腈类化合物及其应用 - Google Patents

一种肽基腈类化合物及其应用 Download PDF

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WO2023134656A1
WO2023134656A1 PCT/CN2023/071503 CN2023071503W WO2023134656A1 WO 2023134656 A1 WO2023134656 A1 WO 2023134656A1 CN 2023071503 W CN2023071503 W CN 2023071503W WO 2023134656 A1 WO2023134656 A1 WO 2023134656A1
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ring
alkyl
cycloalkyl
substituted
cycloalkenyl
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French (fr)
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叶斌
郑鸣芳
颜桃
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Shanghai Yidian Pharmaceutical Technology Development Co Ltd
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Shanghai Yidian Pharmaceutical Technology Development Co Ltd
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Priority claimed from CN202210028063.2A external-priority patent/CN116462672A/zh
Application filed by Shanghai Yidian Pharmaceutical Technology Development Co Ltd filed Critical Shanghai Yidian Pharmaceutical Technology Development Co Ltd
Priority to JP2024541912A priority Critical patent/JP7854219B2/ja
Priority to US18/728,249 priority patent/US20250101011A1/en
Priority to KR1020247026209A priority patent/KR20240147983A/ko
Priority to EP23739998.5A priority patent/EP4450497A4/en
Priority to CN202380016085.XA priority patent/CN118475575A/zh
Publication of WO2023134656A1 publication Critical patent/WO2023134656A1/zh
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of medicine, in particular to a novel peptidyl nitrile compound and its application.
  • Inflammatory diseases are currently an important area of drug research and development. Although interleukin-based antibody drugs and small molecule drugs such as JAK inhibitors have been used clinically, they all have defects of varying degrees. For example, antibody drugs can only Injection administration, low clinical compliance, JAK inhibitors are used for inflammatory diseases, because of the potential cardiovascular adverse reactions due to the target mechanism (Norman P, Expert Opinion on Investigational Drugs.2014,23(8):1067–77 ), so it is very necessary to explore new anti-inflammatory drugs.
  • Cathepsin C also known as dipeptidyl peptidase I (DPP-1), is a lysosomal cysteine protease belonging to the papain family with a molecular weight of 200KDa.
  • Cathepsin C acts to activate neutrophil and mast cell granule serine peptidases in inflammatory cells (such as four neutrophil proteases, elastase (NE), cathepsin G (CatG), protease 3 (PR3) and Key enzymes of neutrophil serine protease (NSP4), mast cell-associated chymase, tryptase and serine protease (Guay, D. et al, Curr. Top. Med. Chem.
  • cathepsin C may serve as potential therapeutic agents for the treatment of neutrophil-dominated inflammatory diseases, including chronic obstructive pulmonary disease (COPD), emphysema, asthma, multiple sclerosis , idiopathic pneumonia, cystic fibrosis, etc. (Laine et al, Expert Opin. Ther. Patents 2010, 20, 497).
  • COPD chronic obstructive pulmonary disease
  • the serine protease elastase downstream of cathepsin plays a very important role in the occurrence and metastasis of cancer, and cardiovascular and cerebrovascular diseases such as myocardial infarction, so theoretically inhibiting cathepsin also has the same pharmacological effect as inhibiting elastase, so theoretically Cathepsin inhibitors can also be used in the treatment of cancer diseases and cardiovascular and cerebrovascular diseases.
  • Cathepsin C has been discovered for more than 70 years, but clinical drugs for cathepsin C inhibitors are still very limited (Korkmaz B. et al, J. Med. Chem., 2020, 63, 13258; Shen, XB et al, E.J.Med.Chem., 2021, 225-113818).
  • the U.S. Food and Drug Administration granted breakthrough drug designation to the cathepsin C inhibitor Brensocatib, which had just completed phase II clinical trials, for the treatment of adults with non-cystic fibrosis bronchiectasis (NCFBE) (Doyle K et al, J. Med. Chem., 2016, 59, 9457).
  • NCFBE non-cystic fibrosis bronchiectasis
  • One object of the present invention is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof,
  • p 0-6;
  • W is selected from CH 2 -CH 2 -O-, -O-, -S-, -SO 2 -, -CH 2 -, -OCH 2 -, -CH 2 O-, -CH 2 S-, -SCH 2 -, -CH 2 SO 2 -, -SO 2 CH 2 -, -CH 2 -CH 2 -, -(CH 2 ) 3 -, -CH 2 -CH 2 -S-, -CH 2 -CH 2 -SO 2 -, -CH 2 -O-CH 2 -, -CH 2 -S-CH 2 -, -CH 2 -SO 2 -CH 2 -;
  • R a is each independently selected from deuterium, halogen, hydroxyl, cyano, mercapto, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 cycloalkane yloxy, heterocycloalkoxy, -SC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 N-, C 1-6 Alkyl-C(O)HN-, -C(O)NHC 1-6Alkyl , oxo, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl and heterocycloalkane Oxygen can be optionally substituted by halogen and deuterium; two R a can be connected to the same carbon atom, and can also be connected to different carbon atoms; R a or two R a together form C 1-4 alkylene Or an ether chain containing 1
  • a and B are each independently selected from hydrogen, deuterium, fluorine, or A and B form cyclopropane with the carbon atom to which both are attached;
  • X, Y, and Z are each independently selected from CH, N, S, O, Se, or one of X, Y, and Z is a bond in the ring, that is, the atoms on both sides of X, Y, or Z are directly connected, and the connected bond can be is a single or double bond;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are all optionally substituted by halogen and deuterium;
  • R 2 is not hydrogen and q is not 0;
  • a and B are not hydrogen at the same time
  • R is selected from cyclic groups, specifically aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl;
  • the cyclic group can be monocyclic or bicyclic, It can optionally contain one or more heteroatoms of N, O, S, Se, and the C and S in the ring can be selectively oxo or thio into -CO-, -CS-, -CO--SO-, -SO2-;
  • the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl can be selectively substituted by one or more R 1a ;
  • R 1a can be selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, not Saturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkane Oxy, Heterooxyl, Aryloxy, Heteroaryloxy, Benzyloxy, Alkylcarbonyl, Alkoxycarbonyl, Cycloalkylcarbonyl, Cycloalkoxycarbonyl, Aryloxycarbonyl, Heteroaryloxycarbonyl, -CONR 3 R 4 , Alkylcarbonyloxy, Cyclo
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxyl, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycle Alkyl, alkylcarbonyl, alkylsulfone, alkylC(O)NH-, alkylS(O)2NH-, carboxyl, alkylcarbonyl; where amino, hydroxyl, carboxyl, alkyl, cycloalkyl, Cycloalkoxy, heterocycloalkoxy, heterocycloalkyl can be further substituted by alkyl, halogen, cyano, hydroxyl, hydroxyalkyl, alkoxy; two R 3 can be connected to the same atom, or can be connected On different atoms; or two R 3 , or R 3 and R 4 , can optionally form a 3-10 membered cycloalkyl, heterocycloal
  • R is selected from pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycle Alkyl, heterocyclic alkenyl, of which pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl can be substituted by one or more R 1a (R 1a is defined as above), or wherein S or 1-2 carbon atoms can be selectively oxo;
  • R1 is selected from:
  • f 0-2;
  • g 0-3;
  • h 0-5;
  • k 0-2;
  • R 1a is as defined above, R 1a on the same ring can choose the same substituent or different substituents; two R 1a can optionally form a saturated or unsaturated ring with a carbon atom or a nitrogen atom in the original ring Group, the cyclic group includes but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and cyclic The group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be selectively substituted with -CO-, -SO-, -SO2-;
  • R 3 and R 4 are as defined above unless otherwise specified;
  • R 1b H, R 1a ; R 1b and R 1a , or two R 1a , can optionally form a saturated carbon atom or nitrogen atom in the original ring Or an unsaturated cyclic group including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heterocycloalkenyl, Aryl, and the cyclic group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be optionally substituted as -CO-, -SO-, -SO2-;
  • R 1b may be selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo , Thio, Nitro, Alkyl, Haloalkyl, Saturated Cycloalkyl, Unsaturated Cycloalkyl, Saturated Heterocyclyl, Unsaturated Heterocyclyl, Aralkyl, Heteroaralkyl, Alkenyl, Cycloalkenyl , heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxy Carbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryl
  • R 5a , R 5 and R 6 R 1a , or two of R 5a , R 5 , R 6 , and 1 to 2 R 1a can optionally be the same as the original
  • the carbon atom or nitrogen atom in the ring forms a saturated or unsaturated cyclic group, which includes but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, Spiro ring, fused ring, aryl group, heteroaryl group, and the cyclic group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be selectively substituted as -CO-, - SO-, -SO2-;
  • R 5a is deuterium, bromine, cyano, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, C 2-8 alkyl, haloalkyl, saturated ring Alkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy radical, cycloalkoxy, heterooxyl, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryl Oxycarbonyl, Heteroaryloxycarbonyl, -CONR 3 R 4 , Alkylcarbonyloxy, Cycloal
  • R 5 and R 6 R 1a
  • two of R 5 , R 6 , R 5a and 1 to 2 R 1a can optionally form a saturated or unsaturated ring with a carbon atom or a nitrogen atom in the original ring
  • said cyclic group includes but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and ring
  • the like group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be selectively substituted by oxygen as -CO-, -SO-, -SO2-;
  • R 5 R 1a
  • R 5 may be selected from deuterium, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkane group, 1-2 fluorine-substituted alkyl, 1-3 bromine-substituted alkyl, 1-3 chlorine-substituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclic, unsaturated heterocyclic radical, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyl, aryloxy, hetero Aryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxy, cycloalkoxy,
  • R 5a is H, chlorine, fluorine, CH 3 , R 1 is selected from
  • U is selected from -O-, -S-, -Se-, -CO-, -SO-, -S(O)2, -NR 7 -, -CR 8 R 9 -;
  • T is -O-, -S-, -CF 2 -, and U is -CO-, T is -O-, -S-, -Se-, -CO, -SO-, -S(O) 2.
  • X 1 , Y 1 , Z 1 can be independently selected from CH and N;
  • R 7 R 1a ;
  • R 8 , R 9 ⁇ R 1a , or R 8 , R 9 can optionally form a saturated or unsaturated cyclic group with the atoms to which they are originally attached, and the cyclic group includes but is not limited to cycloalkane Base, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, condensed ring, aryl, heteroaryl, and the cyclic group can be further selectively substituted by one or more R3 , And the C and S in the ring can also be selectively oxo-substituted as -CO-, -SO-, -SO2-; and/or its pharmaceutically acceptable salt or its prodrug, and/or its solvate, Hydrates, metabolites, nitrogen oxides, racemic mixtures, enantiomers, diastereoisomers and tautomers or mixtures thereof in any proportion including racemic mixtures, wherein:
  • p 0-6;
  • W is selected from CH 2 -CH 2 -O-, -O-, -S-, -SO 2 -, -CH 2 -, -OCH 2 -, -CH 2 O-, -CH 2 S-, -SCH 2 -, -CH 2 SO 2 -, -SO 2 CH 2 -, -CH 2 -CH 2 -, -(CH 2 ) 3 -, -CH 2 -CH 2 -S-, -CH 2 -CH 2 -SO 2 -, -CH 2 -O-CH 2 -, -CH 2 -S-CH 2 -, -CH 2 -SO 2 -CH 2 -;
  • R a is each independently selected from deuterium, halogen, hydroxyl, cyano, mercapto, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 cycloalkane yloxy, heterocycloalkoxy, -SC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 N-, C 1-6 Alkyl-C(O)HN-, -C(O)NHC 1-6Alkyl , oxo, thio, and the alkyl, cycloalkyl, alkoxy, heterocycloalkyl and heterocycloalkane Oxygen can be optionally substituted by halogen and deuterium; two R a can be connected to the same carbon atom, and can also be connected to different carbon atoms; R a or two R a together form C 1-4 alkylene Or an ether chain containing 1
  • a and B are each independently selected from hydrogen, deuterium, fluorine, or A and B form cyclopropane with the carbon atom to which both are attached;
  • X, Y, and Z are each independently selected from CH, N, S, O, Se, or one of X, Y, and Z is a bond in the ring, that is, the atoms on both sides of X, Y, or Z are directly connected, and the connected bond can be is a single or double bond;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, the alkyl, Alkoxy, cycloalkyl and cycloalkoxy are all optionally substituted by halogen and deuterium;
  • R 2 is not hydrogen and q is not 0;
  • a and B are not hydrogen at the same time
  • R is selected from cyclic groups, specifically aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl;
  • the cyclic group can be monocyclic or bicyclic, It can optionally contain one or more heteroatoms of N, O, S, Se, and the C and S in the ring can be selectively oxo or thio into -CO-, -CS-, -CO--SO-, -SO2-;
  • the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl can be selectively substituted by one or more R 1a ;
  • R 1a can be selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, alkyl, haloalkyl, saturated cycloalkyl, not Saturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkane Oxy, Heterooxyl, Aryloxy, Heteroaryloxy, Benzyloxy, Alkylcarbonyl, Alkoxycarbonyl, Cycloalkylcarbonyl, Cycloalkoxycarbonyl, Aryloxycarbonyl, Heteroaryloxycarbonyl, -CONR 3 R 4 , Alkylcarbonyloxy, Cyclo
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, halogen, hydroxyl, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, heterocycle Alkyl, alkylcarbonyl, alkylsulfone, alkylC(O)NH-, alkylS(O)2NH-, carboxyl, alkylcarbonyl; where amino, hydroxyl, carboxyl, alkyl, cycloalkyl, Cycloalkoxy, heterocycloalkoxy, heterocycloalkyl can be further substituted by alkyl, halogen, cyano, hydroxyl, hydroxyalkyl, alkoxy; two R 3 can be connected to the same atom, or can be connected On different atoms; or two R 3 , or R 3 and R 4 , can optionally form a 3-10 membered cycloalkyl, heterocycloal
  • R is selected from pyrimidine, pyrazine, pyridazine, pyrazole, furan, imidazole, thiazole, oxazole, isoxazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, heterocycle Alkyl, heterocyclic alkenyl, of which pyrimidine, pyrazine, pyridazine, triazinyl, pyrazole, furan, imidazole, thiazole, triazole, quinazoline, quinoline, cycloalkyl, cycloalkenyl, hetero Cycloalkyl, heterocycloalkenyl can be substituted by one or more R 1a (R 1a is defined as above), or wherein S or 1-2 carbon atoms can be selectively oxo;
  • R1 is selected from:
  • f 0-2;
  • g 0-3;
  • h 0-5;
  • k 0-2;
  • R 1a is as defined above, R 1a on the same ring can choose the same substituent or different substituents; two R 1a can optionally form a saturated or unsaturated ring with a carbon atom or a nitrogen atom in the original ring Group, the cyclic group includes but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and cyclic The group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be selectively substituted with -CO-, -SO-, -SO2-;
  • R 3 and R 4 are as defined above unless otherwise specified;
  • R 1b H, R 1a ; R 1b and R 1a , or two R 1a , can optionally form a saturated carbon atom or nitrogen atom in the original ring Or an unsaturated cyclic group including but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heterocycloalkenyl, Aryl, and the cyclic group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be optionally substituted as -CO-, -SO-, -SO2-;
  • R 1b may be selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo , Thio, Nitro, Alkyl, Haloalkyl, Saturated Cycloalkyl, Unsaturated Cycloalkyl, Saturated Heterocyclyl, Unsaturated Heterocyclyl, Aralkyl, Heteroaralkyl, Alkenyl, Cycloalkenyl , heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxy Carbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryl
  • R 5a , R 5 and R 6 R 1a , or two of R 5a , R 5 , R 6 , and 1 to 2 R 1a can optionally be the same as the original
  • the carbon atom or nitrogen atom in the ring forms a saturated or unsaturated cyclic group, which includes but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, Spiro ring, fused ring, aryl group, heteroaryl group, and the cyclic group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be selectively substituted as -CO-, - SO-, -SO2-;
  • R 5a is deuterium, bromine, cyano, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, C 2-8 alkyl, haloalkyl, saturated ring Alkyl, unsaturated cycloalkyl, saturated heterocyclyl, unsaturated heterocyclyl, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy radical, cycloalkoxy, heterooxyl, aryloxy, heteroaryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, aryl Oxycarbonyl, Heteroaryloxycarbonyl, -CONR 3 R 4 , Alkylcarbonyloxy, Cycloal
  • R 5 and R 6 R 1a
  • two of R 5 , R 6 , R 5a and 1 to 2 R 1a can optionally form a saturated or unsaturated ring with a carbon atom or a nitrogen atom in the original ring
  • said cyclic group includes but not limited to cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, fused ring, aryl, heteroaryl, and ring
  • the like group can be further selectively substituted by one or more R 3 , and the C and S in the ring can also be selectively substituted by oxygen as -CO-, -SO-, -SO2-;
  • R 5 R 1a
  • R 5 may be selected from deuterium, hydroxyl, amino, mercapto, carboxyl, sulfone, sulfoxide, oxo, thio, nitro, cyano, alkane group, 1-2 fluorine-substituted alkyl, 1-3 bromine-substituted alkyl, 1-3 chlorine-substituted alkyl, saturated cycloalkyl, unsaturated cycloalkyl, saturated heterocyclic, unsaturated heterocyclic radical, aralkyl, heteroaralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkoxy, heterocyclyl, aryloxy, hetero Aryloxy, benzyloxy, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, cycloalkoxy, cycloalkoxy,
  • R 5a is H, chlorine, fluorine, CH 3 , R 1 is selected from
  • U is selected from -O-, -S-, -Se-, -CO-, -SO-, -S(O)2, -NR 7 -, -CR 8 R 9 -;
  • T is -O-, -S-, -CF 2 -, and U is -CO-, T is -O-, -S-, -Se-, -CO, -SO-, -S(O) 2.
  • X 1 , Y 1 , Z 1 can be independently selected from CH and N;
  • R 7 R 1a ;
  • R 8 , R 9 ⁇ R 1a , or R 8 , R 9 can optionally form a saturated or unsaturated cyclic group with the atoms to which they are originally attached, and the cyclic group includes but is not limited to cycloalkane Base, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, bridged ring, spiro ring, condensed ring, aryl, heteroaryl, and the cyclic group can be further selectively substituted by one or more R3 , And the C and S in the ring can also be selectively oxo-substituted as -CO-, -SO-, -SO2-.
  • Ar is pyridine and benzene ring
  • R b is chlorine, fluorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoromethoxy
  • a preferred embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A and B are both selected from H, or both are selected from F.
  • a preferred embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X and Y are each independently selected from CH and N, and Z is selected from CH.
  • a preferred embodiment of the present invention a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is selected from
  • X 1 , Y 1 , Z 1 are independently selected from CH, N;
  • n, o are 0-3;
  • R 7 is selected from hydrogen, CH 3 OCH 2 CH 2 -, oxetane, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine, -C 1-3 Alkyl, C 3-6 cycloalkyl, wherein said C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, tetrahydrofuryl, tetrahydropyran, pyrrolidine, piperazine, morpholine, Piperidine is optionally substituted with 1, 2 or 3 fluorines, and/or is optionally substituted with one substituent selected from: C 1-3 alkyl, hydroxyl, -OC 1-3 alkyl, -N (C 1-3 alkyl) 2 , cyclopropyl; R 7 in different positions in the same structure can choose the same substituent, or can choose different substituents;
  • R 8 and R 9 are hydrogen, fluorine, -C 1-6 alkyl, -C 1-6 haloalkyl, or R 8 and R 9 form a C 3-6 cycloalkane together with the nitrogen atom or carbon atom to which they are attached base, oxetane, azetidine, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuryl, tetrahydropyranyl, the cyclopropane, oxetane, azetidine , pyrrolidine, piperidine ring, piperazine ring, morpholine ring, tetrahydrofuranyl, tetrahydropyranyl can be replaced by C 1-3 alkyl, cyclopropane, oxetane, azetidine, cyclopropyloxy base selective substitution;
  • C, D are independently selected from -NR 7 C(O)-, -C(O)NR 7 -, -CH 2 -CH 2 -, -C(O)-O-, -OC(O)-, - CH 2 -O-, -O-CH 2 -, -CH 2 -NR 7 -, -NR 7 -CH 2 -, -CH 2 -; or one of C and D is a bond (single bond in the ring or a double bond, where the atoms at both ends are directly connected);
  • R 5 is selected from -S(O)2C 1-3 alkyl, -CONH 2 , -SO 2 NHC 1-3 alkyl, -SO 2 NR 3 R 4 (wherein R 3 and R 4 if the N Atoms form a heterocyclic group, the heterocyclic group is selected from piperazinyl, morpholinyl, the piperazinyl and morpholinyl can be optionally substituted by C 1-3 alkyl, cyclopropyl);
  • R is selected from hydrogen, fluorine, chlorine, bromine, methyl
  • R 7a is selected from H, -CHF, -CF 2 , -CH 2 -CH(OH)-CH 3 , -CH 2 -CH(OCH 3 )-CH 3 , -C 4-8 alkyl, -cycloalkyl , -cycloalkoxy, -CH 2 -CH 2 -OCH 3 , -oxetane, -tetrahydrofuran, -tetrahydropyran, pyrrolidine, piperazine, morpholine, piperidine; wherein the C 4 -8 alkyl, tetrahydrofuran, pyrrolidine, piperazine, morpholine, piperidine are optionally substituted by 1, 2 or 3 fluorine and
  • a substituent selected from: hydroxyl, -OC 1-3 alkyl, -N(C 1-3 alkyl) 2 , cyclopropyl;
  • R 5 is selected from cyano, -SO 2 C 1-3 alkyl, -CONH 2 , -SO 2 NR 3 R 4 , wherein R 3 and R 4 are hydrogen, -C 1-6 alkyl, or R 3 and R together with the nitrogen atom to which they are attached form an azetidine, oxetane, pyrrolidine, piperidine ring, piperazine ring, morpholine ring, said azetidine, oxetane, Pyrrolidine, piperidine ring, piperazine ring, morpholine ring can be selectively substituted by C 1-3 alkyl, cyclopropyl;
  • R is selected from hydrogen, fluorine, chlorine, bromine, methyl
  • R7a R7 ;
  • a preferred embodiment of the present invention a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is selected from
  • R 7 is selected from hydrogen, -CF 2 , -CHF, CH 3 OCH 2 CH 2 -, oxetanyl, tetrahydrofuryl, tetrahydropyran, -C 1-3 alkyl, -C 3-6 ring Alkoxy; wherein said C 1-3 alkyl, oxetanyl, tetrahydrofuryl, tetrahydropyran can be optionally substituted by 1, 2 or 3 fluorines, and or optionally substituted by one selected Substituents from the following substituents: hydroxyl, -OC 1-3 alkyl, -N(C 1-3 alkyl) 2 , cyclopropyl; R 7 at different positions in the same structure can choose the same substituent, or can choose different substituents;
  • Typical compounds of the invention include, but are not limited to:
  • the beneficial effects of the present invention relate to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicines for treating and preventing diseases of cathepsin C and its downstream serine proteases NE, PR3, CaTG and NSP4.
  • It further relates to the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof for treating respiratory diseases, metabolic diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, cancer, infectious diseases and other inflammatory related diseases Disease is asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, pulmonary hypertension, noncystic fibrosis, cystic fibrosis, bronchiectasis, bronchitis, pneumonia, emphysema, acute lung injury (ALI), acute Respiratory distress syndrome (ARDS), sepsis, allergic disease, immune inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis, eosinophilic disease, neutrophil disease, ANCA-associated inflammation , antineutrophil cytoplasmic antibody-associated necrotizing crescentic glomerulonephritis, acute brain trauma, acute myocarditis, acute kidney injury, alpha-1-antitrypsin deficiency (AATD) and associated
  • the beneficial effect of the present invention relates to a pharmaceutical composition, which contains the compound of formula (I) and its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition contains one or more compounds of formula (I), and a pharmaceutically active compound selected from the group consisting of other compounds, including but not limited to: b mimetics, anticholinergic Functional drugs, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, NE inhibitors, MMP9 inhibitors , MMP12 inhibitors and combinations of two or three active substances.
  • a pharmaceutically active compound selected from the group consisting of other compounds, including but not limited to: b mimetics, anticholinergic Functional drugs, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, NE inhibitors, MMP9 inhibitors , MMP12 inhibitors and combinations of two or three active substances.
  • the pharmaceutical composition also includes combined use with small molecular compounds and/or macromolecular antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases.
  • the small molecular compounds and/or macromolecular antibodies Including but not limited to glucocorticoids, adrenergic agonists, cholinergic receptor antagonists, theophylline drugs, antioxidants, elastase inhibitors, metalloproteinase inhibitors, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors , CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, CCR9 antagonists and SYK inhibitors, chemokine receptor inhibitors, interleukin antibodies such as IL-6 antibody, IL-23 antibody, targeted anti Thymic stromal lymphopoietin (TSLP) antibodies such as tezepelumab, complement inhibitors.
  • TSLP Thymic stromal lymphopoietin
  • the beneficial effects of the present invention relate to the use of the composition of the compound of formula (I) in the treatment and prevention of diseases caused by cathepsin C and its downstream serine proteases NE, PR3, CaTG, NSP4, and the diseases are selected from respiratory diseases, metabolic disease, cardiovascular and cerebrovascular disease, autoimmune disease, cancer, infectious disease or inflammatory infectious disease.
  • the beneficial effects of the present invention relate to the solvates, racemic mixtures, enantiomers, diastereoisomers, tautomers or mixtures comprising racemic mixtures and any ratio thereof of the compound of formula (I) , characterized in that, the substituents of R 1 , R 2 , Cy, A, B, X, Y, Z and q are:
  • the compounds of the invention may be asymmetric, for example having one or more stereocenters. Unless otherwise specified, all stereoisomers, for example, are enantiomers and diastereomers. Containing asymmetrically substituted carbon atoms.
  • the compounds of the invention may be isolated in optically pure or racemic forms. Optically pure forms can be prepared by resolution of racemates, or by use of chiral synthons or chiral reagents.
  • the compounds of the present invention may also include tautomeric forms.
  • New forms of tautomers result from the interchange of a single bond with an adjacent double bond together with migration of a proton.
  • the compounds of the invention may also include all isotopic forms of atoms present in intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the present invention also includes pharmaceutically acceptable salts of compounds of formula (I).
  • Pharmaceutically acceptable salts are derivatives of compounds of formula (I) wherein the parent compound is modified by the presence of a base moiety into its salt form, or wherein the parent compound is converted into its salt form by the presence of an acid moiety and modified derivatives of compounds of formula (I).
  • examples of pharmaceutically acceptable salts include, but are not limited to: salts of inorganic or organic acids with basic groups such as amines, or salts of inorganic or organic bases with acidic groups such as carboxylic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds of formula (I) by reacting the free base forms of these compounds with 1-4 equivalents of the appropriate acid in a solvent system. Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • the compounds of the present invention and their pharmaceutically acceptable salts also include solvated or hydrated forms.
  • solvated or hydrated forms are equivalent to unsolvated or nonhydrated forms and are included within the scope of the present invention.
  • Some of the compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms of the compounds are included within the scope of the present invention.
  • the present invention also includes prodrugs of the compounds of formula (I).
  • a prodrug is a pharmacological substance (ie, a drug) derived from a parent drug. Once administered, the prodrug is metabolized in vivo to become the parent drug.
  • Prodrugs can be prepared by substituting one or more functional groups present on a compound, wherein the substituents in the prodrug are removed in vivo in such a way as to convert them to the parent compound. The preparation and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" Vol. 14 of the A.C.S. Symposium Series and Bioreversible.
  • the present invention is further illustrated by the examples below, and the examples are only used to more specifically illustrate preferred embodiments of the present invention, and are not intended to limit the technical solution of the present invention.
  • the above-mentioned solutions of the present invention are all technical solutions that can realize the object of the present invention.
  • the temperature and reagents used in the following examples can be replaced by the above-mentioned corresponding temperatures and reagents to achieve the purpose of the present invention.
  • a dash ("-") between two letters or symbols indicates the point of attachment of a substituent.
  • -O(C 1-4 alkyl) refers to a C 1-4 alkyl group attached to the rest of the molecule through an oxygen atom.
  • "-" can be omitted.
  • alkyl used in the present invention refers to a straight or branched chain containing 1-18 carbon atoms, such as 1-12 carbon atoms, another example 1-6 carbon atoms, and another example 1-4 carbon atoms of saturated hydrocarbon groups.
  • C1-6 alkyl within the scope of “alkyl” means the said alkyl group having 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), isopropyl (“i-Pr”), n-butyl ( “n-Bu”), isobutyl (“i-Bu”), sec-butyl (“sBu”) and tert-butyl (“t-Bu”).
  • C2-6 alkenyl within the scope of “alkenyl” means the said alkenyl group having 2-6 carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, and 2-butenyl.
  • alkynyl used in the present invention refers to a group containing one or more, such as 1, 2 or 3 carbon-carbon triple bonds (C ⁇ C), containing 2-10 carbon atoms, such as 2-6 carbon atoms , Another example is a linear or branched hydrocarbon group with 2-4 carbon atoms.
  • C 2-6 alkynyl means said alkynyl group containing 1 carbon-carbon triple bond (C ⁇ C) and having 2-6 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
  • halo used in the present invention refers to fluoro, chloro, bromo and iodo, and "halogen” refers to fluoro, chloro, bromo and iodo.
  • haloalkyl used in the present invention refers to an alkyl group defined in the present invention in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen When atoms are replaced by halogen atoms, the halogen atoms may be the same as or different from each other.
  • the term “haloalkyl” as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms , wherein the halogen atoms are identical to each other.
  • haloalkyl refers to an alkane as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms. group, wherein the halogen atoms are different from each other.
  • haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2CF3, and the like.
  • alkoxy refers to the group -O-alkyl, wherein alkyl is as defined above.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy, including their isomers.
  • cycloalkyl used in the present invention refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3-12 ring carbon atoms, such as 3-8 ring carbon atoms, and for example 3-6 ring carbon atoms, It may have one or more rings, for example 1 or 2 rings.
  • C3-8 cycloalkyl means the cycloalkyl group having 3-8 ring carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • heterocyclyl or “heterocyclic” as used herein means a ring selected from 4 to 12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings, which, in addition to containing at least one, For example, 1-4, further such as 1-3 or further such as 1 or 2 heteroatoms selected from O, S and N, also contains at least one carbon atom.
  • the point of attachment of a heterocyclyl group can be at a heteroatom or at a carbon.
  • Heterocyclyl or “heterocyclic” also refers to a single ring containing at least one heteroatom selected from O, S and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S and N and the other ring is not heteroaryl or aryl, the point of attachment can be on the heterocycle or on the other ring.
  • cycloalkoxy refers to the group -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, including isomers thereof.
  • heterocycloalkoxy refers to the group -O-heterocycloalkyl, wherein heterocycloalkyl is as defined above.
  • examples of cycloalkoxy include, but are not limited to, aziridinyloxy, epoxypropyleneoxy, azetidinyloxy, oxetanyloxy, including isomers thereof.
  • cycloalkenyl refers to those containing one or more, such as 1, 2 or 3 carbon-carbon double bonds, containing 3-12 ring carbon atoms, preferably 3-8 ring carbon atoms, more Preference is given to non-aromatic cyclic hydroxyl groups of 3 to 6 ring carbon atoms which may have one or more rings, preferably one or two rings.
  • C 3-8 ring carbon atoms and cycloalkenyl preferably "C 3-6 cycloalkenyl” that is, the cycloalkenyl with 3-6 ring carbon atoms.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • heterocycloalkenyl means that one or more carbon atoms in the above “cycloalkenyl” are replaced by N, O, and S.
  • a heterocycloalkenyl group with C 3-8 ring atoms preferably a "C 3-6 heterocycloalkenyl group", that is, the aforementioned heterocycloalkenyl group with 3-6 ring atoms.
  • heterocycloalkenyl groups include, but are not limited to, azetidinyl, oxetenyl, azacyclopentenyl, oxolyl, oxenyl.
  • aryl used in the present invention, unless otherwise clearly defined, refers to a carbocyclic hydrocarbon group consisting of one or more rings condensed and containing 6-14 ring carbon atoms, such as 6-12 ring carbon atoms, Where at least one ring is aromatic and the other ring is not heteroaryl as defined below, the point of attachment may be on the aromatic ring or on the other ring.
  • aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl.
  • aryl or “aromatic” follows Hückel's rule, where the number of pi electrons is equal to 4n+2, n being zero or any positive integer up to six.
  • heterocyclyl or “heterocyclic” as used herein means a ring selected from 4 to 12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings, which, in addition to containing at least one, For example, 1-4, further such as 1-3 or further such as 1 or 2 heteroatoms selected from O, S and N, also contains at least one carbon atom.
  • the point of attachment of a heterocyclyl group can be at a heteroatom or at a carbon.
  • Heterocyclyl or “heterocyclic” also refers to a single ring containing at least one heteroatom selected from O, S and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S and N and the other ring is not heteroaryl or aryl, the point of attachment can be on the heterocycle or on the other ring.
  • heteroaryl used in the present invention, unless otherwise clearly defined, refers to: a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, for example, 6 ring atoms, which contains one or A plurality, such as 1, 2 or 3, such as 1 or 2 ring heteroatoms independently selected from N, O and S (such as N), the remaining ring atoms being carbon atoms; and having 8-12 ring atoms,
  • a bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, which contains one or more, such as 1, 2, 3 or 4, such as 1 or 2, independently selected from N, O and S (
  • N) is a ring heteroatom, the remaining ring atoms are carbon atoms, and at least one of the rings is aromatic.
  • a bicyclic heteroaryl includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cycloalkyl ring, heterocyclyl ring, or aryl ring, where the point of attachment can be at the heteroaryl ring or at On cycloalkyl ring/heterocyclyl ring/aryl ring.
  • the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other.
  • Heteroaryl also includes those in which the N-ring heteroatom is in the form of an N-oxide, eg, N-oxypyrimidinyl.
  • the ring heteroatoms in the above-mentioned heteroaryl groups are N atoms, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups".
  • Nitrogen-containing heteroaryl groups also include those in which the N-ring heteroatom is in the form of an N-oxide, such as pyridinyl N-oxide.
  • heteroaryl groups include, but are not limited to: pyridyl, pyridyl N-oxide; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; Diazolyl; tetrazolyl; triazolyl; thienyl; furyl; pyryl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; benzodioxolyl, e.g.
  • nitrogen-containing heteroaryl groups include, but are not limited to: pyrrolyl; pyrazolyl; imidazolyl; pyridyl; pyrazinyl; pyrimidinyl, N-oxypyrimidinyl; pyridazinyl; [3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; purinyl, such as 9H-purinyl and 7H-purinyl; quinolinyl; indolyl; and indazolyl .
  • hydroxyl in the present invention refers to the -OH group.
  • mercapto refers to a -SH group.
  • cyano refers to a -CN group.
  • amino refers to the -NH2 group.
  • group and “radical” used in the present invention are synonymous, and are used to indicate a functional group or molecular fragment that can be connected with other molecular fragments.
  • a structural formula of the present invention contains an asterisk "*"
  • the compound represented by the structural formula is a chiral compound, that is, the compound is in R-configuration or S-configuration.
  • the configuration of a compound can be determined by one skilled in the art using a variety of analytical techniques, such as single crystal X-ray crystallography and/or optical polarimetry, and according to routine protocols.
  • substitution pattern means that the subsequently described substitution pattern, event or circumstance may Occurs one or more times, or may not occur, and the description includes instances where the substitution pattern occurs and instances where the substitution pattern does not occur.
  • “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined in the present invention.
  • substituted or “substituted by” as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents , provided that the normal valence of that given atom is not exceeded.
  • Combinations of substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds.
  • a chemically correct and stable compound means that the compound is sufficiently stable that it can be isolated from a reaction mixture and the chemical structure of the compound can be determined, and subsequently formulated into a preparation that is at least practical.
  • substituents are named into the core structure.
  • (cycloalkyl)alkyl is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is at the alkyl moiety.
  • substituted by one or more substituents used in the present invention means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group.
  • substituted with one or more substituents means that a given atom or group is substituted with 1, 2, 3 or 4 substituents independently selected from the given group.
  • some compounds of formula (I) may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemic mixtures of these isomers, individual isomers and one enantiomerically enriched mixture, as well as diastereomers and specific diastereomers when there are two chiral centers Constructively partially enriched mixtures are within the scope of the present invention. Those skilled in the art will also understand that the present invention includes all individual stereoisomers (such as enantiomers), racemic mixtures or partially resolved mixtures of compounds of formula (I), and where appropriate In this case, the individual tautomers thereof are included.
  • the invention provides compounds that contain multiple stereoisomeric purities, ie, diastereomeric or enantiomeric purities expressed as different "ee” or “de” values.
  • the compound of formula (I) eg, as described herein
  • has at least 60% ee eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91% , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%ee, or any value between these recited values
  • enantiomeric purity eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91% , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%ee, or any value between these recited values
  • compounds of formula (I) have an enantiomeric purity of greater than 99.9% ee, up to 100% ee.
  • the compound of formula (I) eg, as described herein
  • has at least 60% de eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91% , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%de, or any value between these enumerated values
  • compounds of formula (I), such as described herein have a diastereomeric purity of greater than 99.9% de.
  • enantiomeric excess or "ee” means the amount of one enantiomer relative to the other.
  • the percentage of enantiomeric excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the mixture of enantiomers, [ a]max is the optical rotation of the pure enantiomer.
  • diastereomeric excess indicates the amount of one diastereoisomer relative to the other and is defined by analogy in terms of enantiomeric excess.
  • Diastereomers and/or enantiomeric excess can be determined using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography and/or optical polarimetry, and according to routine protocols familiar to those skilled in the art To be done.
  • Racemic mixtures can be used as such or resolved into individual isomers. Resolution may yield stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known and include physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral form may be prepared from chiral precursors. Alternatively, single enantiomers of 10-camphorsulfonic acid, camphoric acid, ⁇ -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.
  • the racemate can be covalently attached to a chiral compound (auxiliary) to give diastereoisomers, which can be separated by chromatography or fractional crystallization, followed by Chemical removal of the chiral auxiliary affords the pure enantiomer.
  • the "pharmaceutically acceptable salt” of the present invention refers to the free acid or base of the compound of formula (I) that is non-toxic, biologically tolerable or other biologically suitable for administering to an individual for treatment. Salt. .
  • “Pharmaceutically acceptable salts” include, but are not limited to: acid addition salts formed by compounds of formula (I) and inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, Sulfates, sulfites, nitrates, etc.; and acid addition salts of compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate , tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and Salts with alkanedicarboxylic acids of formula HOOC-(CH2)n-COOH wherein n is 0-4, and the like.
  • “Pharmaceutically acceptable salts” also include base addition salts of compounds of formula (I) bearing acidic groups with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.
  • the molar ratio of the compound of formula (I) to the acid or cation in the resulting pharmaceutically acceptable salt includes but is not limited to 1:1, 1:2, 1:3 and 1:4.
  • prodrug in the present invention refers to a pharmacological substance (ie drug) derived from a parent drug, which is metabolized into the parent drug in vivo after administration.
  • Prodrugs can be prepared by substituting one or more functional groups present on a compound, wherein the substituents in the prodrug are removed in vivo in such a way as to convert them to the parent compound.
  • the preparation and use of prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol.14 of the A.C.S. Symposium Series and Bioreversible.
  • Prodrugs include, but are not limited to: esters of compounds of formula (I) such as phosphates, formates, carbamates; amides such as formamide and acetamide.
  • a compound of the present invention is obtained in the form of an acid addition salt
  • its free base form can be obtained by basifying a solution of the acid addition salt.
  • its acid addition salts especially pharmaceutically acceptable acid addition salts, may be prepared by dissolving the free base in a suitable solvent and treating the solution with acid.
  • solvate means a solvent addition form comprising stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to recruit a fixed molar ratio of solvent molecules in the solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water and one molecule of said substance, wherein the water retains its molecular state of H2O, such combination can form one or more hydrates, such as hemihydrate, monohydrate and dihydrates, and variable hydrates.
  • group and “radical” used in the present invention are synonymous and are used to denote functional groups or molecular fragments that can be linked to other molecular fragments.
  • active ingredient is used to denote a chemical substance that has biological activity.
  • an “active ingredient” is a chemical substance that has pharmaceutical use.
  • actual drug activity may be determined by appropriate preclinical testing, either in vitro or in vivo.
  • drug activity that is sufficient to be accepted by regulatory agencies (such as the FDA in the United States) requires a higher standard than preclinical trials. The success of such a higher standard of drug activity cannot generally be reasonably expected from preclinical test results, but can be obtained through appropriate and effective randomized, double-blind, controlled clinical trials in humans to establish.
  • treating means giving the disease or disorder, or symptoms of, or predisposition to, the disease or disorder.
  • An individual with a disordered constitution such as a human, administers one or more drug substances, particularly the compound of formula (I) according to the present invention and/or a pharmaceutically acceptable salt thereof, to cure, heal, alleviate, relieve, Alter, cure, ameliorate, ameliorate or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition to the disease or disorder.
  • the disease or disorder is cancer.
  • treating when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction leading to the shown and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates formed in the mixture which forms ultimately lead to the formation of the shown and/or desired products.
  • the term "effective amount” refers to an amount or dose of a cathepsin C inhibitor generally sufficient to produce a beneficial therapeutic effect on a patient in need of treatment of a disease or disorder mediated by cathepsin C and downstream serine protease activity. It can be done by conventional methods (such as modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (such as the mode or route of administration or administration, pharmacokinetics of the pharmaceutical ingredients, the severity and course of the disease or disorder, individual The effective amount or dosage of the active ingredients in the present invention is determined based on previous or ongoing treatment, the individual's health status and response to the drugs, and the judgment of the attending physician. In the United States, the determination of effective doses is generally difficult to predict from preclinical trials. In fact, dosing is completely unpredictable, and new unpredictable dosing regimens are developed after the original dose was used in a randomized, double-blind, controlled clinical trial.
  • Typical dosage ranges are from about 0.0001 to about 200 mg active ingredient per kg body weight of the subject per day, for example from about 0.001 to 100 mg/kg/day, or from about 0.01 to 35 mg/kg/day, or from about 0.1 to 10 mg/kg once daily or in divided dosage units (eg, twice daily, three times daily, four times daily).
  • suitable dosages may range from about 0.05 to about 7 grams per day, or from about 0.2 to about 5 grams per day.
  • inhibitor refers to a reduction in the baseline activity of a biological activity or process.
  • inhibitor cathepsin C activity is the actual pharmaceutical activity used for the purpose of the present invention, and refers to the activity of cathepsin C when there is no compound of formula (I) and/or its pharmaceutically acceptable salt.
  • the reduction of cathepsin C activity caused by the direct or indirect response of the compound of formula (I) and/or its pharmaceutically acceptable salt according to the invention.
  • the reduction of activity may be caused by the direct interaction between the compound of formula (I) described in the present invention and/or its pharmaceutically acceptable salt and cathepsin C, or by the compound of formula (I) described in the present invention and/or Its pharmaceutically acceptable salt interacts with one or more other factors to affect cathepsin C activity.
  • the presence of the compound of formula (I) described in the present invention and/or its pharmaceutically acceptable salt can reduce the activity of cathepsin C by directly binding to cathepsin C, and can directly or indirectly affect another Factors to reduce the activity of cathepsin C, or reduce the activity of cathepsin C by directly or indirectly reducing the amount of cathepsin C present in cells or organisms.
  • the term "individual” as used herein refers to both mammals and non-mammals.
  • Mammal means any member of the class Mammalia, which includes, but is not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats and pigs; Domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs; etc.
  • Examples of non-mammals include, but are not limited to, birds and the like.
  • the term "individual” is not limited to a particular age or gender. In some embodiments, the individual is a human.
  • PG in the compound of formula II represents a protecting group, such as tert-butoxycarbonyl.
  • the compound of formula II is under basic conditions (such as using N,N-diisopropylethylamine as a base), which is obtained by 2-(7-azabenzotriazole)-N,N , N', N'-tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU) is activated to react with ammonia water to obtain the compound of formula III.
  • HATU 2-(7-azabenzotriazole)-N,N , N', N'-tetramethyluronium hexafluorophosphate
  • HBTU O-benzotriazole-tetramethyluronium hexafluorophosphate
  • the deprotection product of the compound of the formula III The compound of the formula IV and the acid of the compound of the formula V Utilize conventional methods reported in the literature, such as using N,N-diisopropylethylamine as the base, HATU or HBTU as the activating reagent, to obtain the amide formula VI compound of.
  • the Suzuki coupling reaction of the compound of formula VI with the borate compound of formula VIII utilizes a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in a suitable solvent such as dioxo Hexacyclic, and use of an appropriate base such as potassium acetate gives compounds of formula IX.
  • a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in a suitable solvent such as dioxo Hexacyclic
  • Another route is the conversion of compounds of formula VI to boronate compounds of formula VII.
  • the compound of formula VI reacts with bis-valeryl diboron under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and reacts with potassium acetate as base in dimethyl sulfoxide Borate ester compounds of formula VII.
  • the Suzuki coupling reaction of the compound of formula XI with the borate compound of formula VII utilizes a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in a suitable solvent such as dioxo Hexacyclic, and use of an appropriate base such as potassium acetate gives compounds of formula IX.
  • the amide of the compound of formula IX can be dehydrated with methyl N-(triethylammoniumsulfonyl)carbamate in dichloromethane to give the compound of formula X. Deprotection of compounds of formula X yields compounds of formula I as final products.
  • the compound of formula (I) of the present invention (for example, any compound in the present invention) and/or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition alone or in combination with one or more other active ingredients .
  • the pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) described in the present invention and/or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient agent (eg, a pharmaceutically acceptable carrier).
  • a pharmaceutically acceptable carrier is one that is compatible with (and, in some embodiments, stabilizes) the active ingredients in the composition and not deleterious to the individual being treated.
  • solubilizers such as cyclodextrins (which can form specific, more soluble complexes with compounds of formula (I) and/or pharmaceutically acceptable salts thereof according to the present invention) can be used as pharmaceutical excipients. formulations to deliver the active ingredient.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and colors such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in a standard reference text in the field (Remington's Pharmaceutical Sciences, A. Osol).
  • compositions comprising the compound of formula (I) according to the present invention (for example, any compound in the present invention) and/or its pharmaceutically acceptable salt can be administered in various known ways, such as oral, topical, rectal , parenteral, inhalation, or implantation.
  • parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.
  • the pharmaceutical composition of the present invention can be prepared in the form of tablets, capsules, bagged granules, sugar-coated pills, powders, granules, buccal tablets, powder injections, liquid preparations or suppositories.
  • the pharmaceutical composition comprising the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be formulated for intravenous infusion, topical administration or oral administration.
  • Compositions for oral administration may be in any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions.
  • Common tablet carriers include lactose and corn starch.
  • Lubricants such as magnesium stearate are also often added to tablets.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient When administered orally in the form of an aqueous suspension or emulsion, the active ingredient can be suspended or dissolved in the oily phase with emulsifying or suspending agents. Certain sweetening, flavoring or coloring agents can also be added, if desired.
  • the amount of the compound of formula (I) and/or its pharmaceutically acceptable salt in the tablet can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg. In some embodiments, the amount of the compound of formula (I) and/or its pharmaceutically acceptable salt in the capsule can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90 , 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg.
  • Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents.
  • the sterile injectable intermediate medium can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • suitable pharmaceutically acceptable carriers and solvents that can be used are mannitol, water, Ringer's solution and physiological saline.
  • sterile, fixed oils such as synthetic mono- or diglycerides, are conventionally employed as a solvent or suspending medium.
  • Fatty acids such as oleic acid and its glyceride derivatives
  • natural pharmaceutically-acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions, are commonly employed as intermediates for injectables.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • compositions for inhalation may be prepared according to techniques well known in the art of pharmaceutical formulation, using benzyl alcohol or other suitable preservatives, using absorption enhancers to enhance bioavailability, using fluorocarbons and/or other solubilizing or dispersing agents known in the art. It can also be prepared as a solution in saline.
  • Topical compositions may be formulated as oils, creams, lotions, ointments, and the like.
  • suitable carriers for the composition include vegetable or mineral oil, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (ie, those having greater than 12 carbon atoms).
  • a pharmaceutically acceptable carrier is one in which the active ingredient is soluble.
  • the composition if desired, may also contain emulsifiers, stabilizers, wetting agents and antioxidants, as well as substances imparting color or flavor thereto.
  • transdermal penetration enhancers may be added to topical formulations. Examples of such accelerators can be found in US Patent Nos. 3,989,816 and 4,444,762.
  • a cream may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, into which the active ingredient is incorporated dissolved in a small amount of fat, such as almond oil.
  • An example of a cream comprises, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil.
  • An ointment can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture.
  • An example of an ointment comprises, by weight, about 30% almond oil and about 70% white soft paraffin.
  • Appropriate in vitro experiments can be used to evaluate the practical use of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof of the present invention in inhibiting cathepsin C activity.
  • the compound of formula (I) described in the present invention and/or its pharmaceutically acceptable salt can be further detected by in vivo test in the treatment of pulmonary diseases, inflammatory diseases, metabolic diseases, infectious diseases, cardiovascular and cerebrovascular diseases or Additional practical use in autoimmune diseases.
  • the compound of formula (I) described in the present invention and/or its pharmaceutically acceptable salt can be administered to patients with pulmonary diseases, inflammatory diseases, metabolic diseases, infectious diseases, cardiovascular and cerebrovascular diseases, Animals (such as mouse models) of cancer, autoimmune diseases, and then evaluate its therapeutic effect.
  • the compounds of formula (I) and/or pharmaceutically acceptable salts thereof according to the present invention may show sufficient preclinical practical use to be worthy of clinical trials, and are expected to show beneficial therapeutic or preventive effects, for example, in Beneficial therapeutic or prophylactic effects are shown in individuals with pulmonary and inflammatory diseases.
  • pulmonary disease refers to pathological conditions associated with the lung organ.
  • diseases include bronchiectasis, idiopathic pulmonary fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, pneumonia, acute lung injury, acute respiratory distress syndrome.
  • inflammatory disease refers to a pathological state leading to an inflammatory response, especially due to neutrophil chemotaxis.
  • diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; and inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative Colitis)-related reactions; ischemia-reperfusion injury, including surgically induced tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and abnormalities of coronary vessels after percutaneous coronary angioplasty Systolic response, stroke, and abdominal aortic aneurysm surgical tissue reperfusion injury; cerebral edema secondary to stroke; traumatic head injury; hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; multiple myositis;
  • the compounds of formula (I) and/or their pharmaceutically acceptable salts according to the present invention can be used to achieve beneficial therapeutic or preventive effects, for example, in patients with metabolic diseases, infectious diseases, cardiovascular and cerebrovascular diseases, infection Beneficial therapeutic or prophylactic effects are achieved in individuals with a variety of diseases, cancers, autoimmune diseases.
  • autoimmune disease refers to a disease or disease caused by the body's immune response to self-antigens, resulting in damage to its own tissues or organs.
  • autoimmune diseases include, but are not limited to: Chronic Obstructive Pulmonary Disease (COPD), Allergic Rhinitis, Lupus Erythematosus, Myasthenia Gravis, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Psoriasis , inflammatory bowel disease (IBD), asthma, and idiopathic thrombocytopenic purpura, and myeloid proliferative disorders such as myelofibrosis, polycythemia vera/essential platelets Polycythemia vera/essential thrombocytosis myelofibrosis (PV/ET).
  • COPD Chronic Obstructive Pulmonary Disease
  • RA Rheumatoid Arthritis
  • IBD inflammatory bowel disease
  • myeloid proliferative disorders such as myel
  • metabolic disease refers to a disease caused by or related to metabolism, and non-limiting examples include non-alcoholic fatty liver, non-alcoholic steatohepatitis, AATD, obesity, diabetes, and the like.
  • infectious disease refers to a pathological state caused by infection by viruses, bacteria, parasites, etc.
  • Non-limiting examples of such diseases include leishmaniasis, novel coronavirus pneumonia, sepsis.
  • cardiovascular and cerebrovascular diseases refers to diseases related to the cardiovascular system and brain organs.
  • Non-limiting examples of such diseases are ischemia-reperfusion injury, acute brain injury, heart failure, myocarditis, myocardial infarction, and the like.
  • cancer refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth foci at other sites.
  • cancer includes, but is not limited to: solid tumors and hematological malignancies.
  • cancer includes cancers of the skin, tissues, organs, bones, cartilage, blood and blood vessels.
  • cancer includes both primary and metastatic cancers.
  • Non-limiting examples of solid tumors include lung cancer such as non-small cell lung cancer (NSCLC).
  • inflammatory diseases and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, systemic lupus erythematosus, psoriasis, and multiple hardening.
  • COPD chronic obstructive pulmonary disease
  • allergic rhinitis asthma, lupus erythematosus, systemic lupus erythematosus, psoriasis, and multiple hardening.
  • the compound of formula (I) of the present invention (for example, any compound in the present invention) and/or its pharmaceutically acceptable salt can be used in combination with other active ingredients for the treatment of respiratory diseases, inflammatory Or autoimmune diseases and cancer.
  • the additional active ingredient may be administered separately from the compound of formula (I) according to the present invention and/or a pharmaceutically acceptable salt thereof, or it may be included in a pharmaceutical composition according to the present disclosure, such as a fixed dose combination drug.
  • the additional active ingredients are those known or found to be effective in the treatment of diseases mediated by cathepsin C and its downstream serine protease activity, such as another cathepsin C modulator or A compound that effectively antagonizes another target associated with that particular disease.
  • the combination can be used to improve the therapeutic effect (for example, by including a compound that can enhance the potency or effectiveness of the compound of formula (I) described in the present invention and/or its pharmaceutically acceptable salt into the combination), To reduce one or more side effects, or to reduce the required dose of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof according to the present invention.
  • Pin 2 B 2 pinacol bis-boronate
  • Step 11 Step 11: Preparation of (2S, 6S)-4-(tert-butoxycarbonyl)-6-fluoro-1,4-oxazepanyl-2-carboxylic acid (D54-m):
  • Embodiment 1 the synthesis of compound D01
  • Example 1 the following compounds were prepared from different analogues of fluorine-substituted L-phenylalanine (L-2-Fluoro-Phenylalanine) in a similar manner.
  • Embodiment 2 the synthesis of compound D11
  • Embodiment 3 the synthesis of compound D15
  • D15a (22g, 158.3mmol) was dissolved in dry THF (150mL) at 0°C, and slowly added dropwise to THF (250mL) containing LiAlH 4 (24.06g, 633.1mmol). The reaction was stirred overnight, then cooled to 0 °C, diluted with Et2O (250 mL), quenched carefully with water (22.06 mL), 15% aq. NaOH (22.06 mL), and additional water (22.06 mL), filtered off solid and washed dropwise with MeOH (400 mL).
  • Intracellular enzyme activity assay was carried out in a 384-well plate, cell culture medium: 1640, 10% FBS, 1*PS. Add 30 ⁇ L of cell culture medium cell suspension containing U937 cells into a 384-well plate so that each well contains 2 ⁇ 10 4 cells; and add 30 nL of AZD7986, vehicle control (100% DMSO) or the serial dilution of the test compound by Echo After adding to the wells and incubating at 37°C for 1h, h-Gly-phe-AFC (10 ⁇ L) was added to each well to start the reaction, further incubated at 37°C for 1h, and then the fluorescence absorption was read by EX ⁇ 400nm and EM ⁇ 505nm. The above test results were calculated with Graphpad 8.0 IC50 value, the results are as follows:
  • Embodiment 5 the inhibitory effect test of DPP1 enzymatic activity
  • Recombinant human cathepsin rhCathepsin C/DPP1 purchased from R&D systems
  • AZD7986 purchased from MCE
  • Gly-Arg-AMC (hydrochloride) was purchased from Cayman chemical
  • DMSO was purchased from Sigma-Aldrich

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Abstract

提供了一种肽基腈类化合物及其应用，具体提供了式(I)的化合物和/或其药学上接受的盐、包含该化合物和/或其药学上接受的盐的药物组合物、制备该化合物的方法，以及该化合物用于治疗组织蛋白酶C及其下游丝氨酸蛋白酶导致的疾病的用途。

Description

[根据细则37.2由ISA制定的发明名称]　 一种肽基腈类化合物及其应用 技术领域
本发明涉及医药技术领域，尤其是一种新型肽基腈类化合物及其应用。
背景技术
炎症性疾病是目前药物研发的重要领域，虽然已有白介素类抗体药物在临床应用，也有小分子药物如JAK抑制剂等在临床应用，但他们都存着不同程度的缺陷，如抗体药物仅能注射给药，临床依从性较低，JAK抑制剂用于炎性疾病，因靶点机制有潜在的心血管不良反应(Norman P,Expert Opinion on Investigational Drugs.2014,23(8):1067–77)，因此还非常有必要探索新型抗炎药物。
组织蛋白酶C(CTSC)又称为二肽基肽酶I(DPP-1)，是一种属于木瓜蛋白酶家族具有200KDa分子量的溶酶体半胱氨酸蛋白酶。组织蛋白酶C充当激活炎性细胞中的中性粒细胞和肥大细胞颗粒丝氨酸肽酶(例如四种中性粒细胞蛋白酶，弹性蛋白酶(NE)，组织蛋白酶G(CatG)，蛋白酶3(PR3)和中性粒细胞丝氨酸蛋白酶(NSP4)，以及肥大细胞相关的糜酶、类胰蛋白酶和丝氨酸蛋白酶等)的关键酶(Guay,D.et al,Curr.Top.Med.Chem.2010,10,708-716；Korkmaz,B.et al,Pharmacol.Ther.2018,190,202-236)。这些蛋白酶一旦被组织蛋白酶C激活，便能够降解各种细胞外基质组分，这导致组织损伤和慢性炎症。因此，组织蛋白酶C的抑制剂可作为治疗嗜中性粒细胞主导炎症性疾病适用的潜在治疗药物，所述炎性疾病包括慢性阻塞性肺病(COPD)、肺气肿、哮喘、多发性硬化症、特发性肺炎、囊性纤维化等(Laine et al,Expert Opin.Ther.Patents 2010,20,497)。
其他免疫性疾病如炎性肠病、类风湿性关节炎、抗中性粒细胞胞浆抗体相关的坏死性新月形肾小球肾炎，ANCA介导的血管炎，还有较为严重的系统性炎症疾病如败血症、急性肺损伤(急性呼吸窘迫综合征)、急性胰腺炎等，其发病机理中的很大一部分是由这些炎性蛋白酶中的某些的活性增加引起的，因此组织蛋白酶C抑制剂也可作为治疗这些疾病的潜在药物。此外组织蛋白酶下游丝氨酸蛋白酶弹性蛋白酶在癌症的发生和转移，及心脑血管疾病如心肌梗死中有非常重要的作用，因此理论上抑制组织蛋白酶也具有抑制弹性蛋白酶的相同的药理作用，因此理论上组织蛋白酶抑制剂也可以用于癌症性疾病和心脑血管疾病的治疗。(Pharmacol Ther.2018Oct；190:202-236；Int J Mol Sci.2021Jan 13；22(2):722.)。
组织蛋白酶C从发现到现在已有超70年的历史，但组织蛋白酶C抑制剂的临床药物仍非常有限(Korkmaz B.et al,J.Med.Chem.,2020,63,13258；Shen,XB et al,E.J.Med.Chem.,2021,225-113818)。直到2020年6月，美国食品和药物管理局才授予刚完成II期临床试验的组织蛋白酶C抑制剂Brensocatib突破性药物资格，用于治疗成人非囊性纤维化支气管扩张症(NCFBE)(Doyle K.et al,J.Med.Chem.,2016,59,9457)。组织蛋白酶C抑制剂仍存在较大未满足的需求。现有的化合物很难抑制组织蛋白酶C和下游丝氨酸蛋白酶的活性，因此需要提供新型肽基腈类化合物及其应用。
发明内容
本发明的一个目的在于提供通式(I)化合物或其药学上可接受的盐，
Figure PCTCN2023071503-appb-000001
和/或其药学上可接受的盐或它的前药，和/或其溶剂合物、水合物、代谢产物、氮氧化物、外消旋混合物、对映异构体、非对映异构体和互变异构体或其任意比例的混合物包括外消旋混合物，其中：
Cy为
Figure PCTCN2023071503-appb-000002
p为0-6；
W选自CH 2-CH 2-O-、-O-、-S-、-SO 2-、-CH 2-、-OCH 2-、-CH 2O-、-CH 2S-、-SCH 2-、-CH 2SO 2-、-SO 2CH 2-、-CH 2-CH 2-、-(CH 2) 3-、-CH 2-CH 2-S-、-CH 2-CH 2-SO 2-、-CH 2-O-CH 2-、-CH 2-S-CH 2-、-CH 2-SO 2-CH 2-；
R a各自独立地选自氘、卤素、羟基、氰基、巯基、氨基、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6环烷基氧基、杂环烷氧基、-SC 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2N-、C 1-6烷基-C(O)HN-、-C(O)NHC 1-6烷基、氧代、硫代，并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的；两个R a可连在同一碳原子，也可以连在不同的碳原子；R a或两个R a一起形成C 1-4亚烷基或者含有1～4个碳原子的醚链如-CH 2-O-CH 2-CH 2-CH 2-、-CH 2-O-CH 2-，所述亚烷基或醚链可与原来环形成含有杂原子或者不含杂原子环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环，所述杂原子包括N、S、O，所述环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环可被氘、羟基、卤素、烷基和烷氧基选择性取代，且其中C、S可被选择性氧代为-C＝O、-S＝O、-S(O)2-；或两个R a与其各自附接的碳原子组成6元芳基、5元杂芳基、6元杂芳基，且与原来环形成并环，所述并环可被羟基、卤素、氰基、烷基、烷氧基选择性取代；并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的。
A和B各自独立的选自氢、氘、氟，或者A和B与两者附接的碳原子形成环丙烷；
X、Y、Z各自独立选自CH、N、S、O、Se，或者X、Y、Z其中1个为环中的键即X、Y或Z两侧的原子直接连接，连接的键可为单键或双键；
R 2选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基，所述烷基、烷氧基、环烷基和环烷氧基均可任选的被卤素和氘取代的；
q为0-3；
当在下述四种情况下(四种情况是和/或的关系)
1)Cy不为
Figure PCTCN2023071503-appb-000003
2)X、Y、Z不同时为CH；
3)R 2不为氢且q不为0；
4)A和B不同时为氢；
R 1选自环状基团具体为芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基；所述环状基团可为单环也可为双环，可选择性含有一个或者多个N、O、S、Se的杂原子，且环中的C、S可被选择性氧代或硫代为-CO-、-CS-、-CO--SO-、-SO2-；所述芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基可被一个或者多个R 1a选择性取代；
R 1a可选自氢、氘、卤素、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5～6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；两个R 1a可连在同一个碳原子或者氮原子，也可以连在不同的碳原子或者氮原子；两R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，环中的C、S也可被选择性氧代或硫代为-CO-、-CS-、-SO-、-SO2-；
R 3、R 4各自独立的选自氢、氘、卤素、氰基、卤素、羟基、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、环烷氧基、杂环烷基、烷基羰基、烷基砜基、烷基C(O)NH-、烷基S(O)2NH-、羧基、烷基羰基；其中氨基、羟基、羧基、烷基、环烷基、环烷氧基、杂环烷氧基、杂环烷基可被烷基、卤素、氰基、羟基、羟基烷基、烷氧基进一步取代；两R 3可连在相同原子上，也可连在不同原子上；或者两个R 3，或R 3和R 4，可选择性与各自共同连接的碳原子或者氮原子形成3-10元环烷基、杂环烷基、螺环、桥环、稠环，包括但不限于氧杂环丁烷、氮杂环丁烷、吗啉环、哌啶环、哌嗪环、氮杂氧杂环丁烷、呋喃环、吡咯烷，所述环烷基、杂环烷基、螺环、桥环、稠环中C和S可被选择性氧代为-CO-、-SO-、-SO2-，且可被一个或多个卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、C 3-8杂环基选择性取代；
当Cy为
Figure PCTCN2023071503-appb-000004
且X、Y、Z三者均为CH，且R 2为氢，且A/B均为H时：
R 1选自为嘧啶、吡嗪、哒嗪、吡唑、呋喃、咪唑、噻唑、噁唑、异噁唑、三氮唑、喹唑啉、喹 啉、环烷基、环烯基、杂环烷基、杂环烯基，其中嘧啶、吡嗪、哒嗪、三嗪基、吡唑、呋喃、咪唑、噻唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基可被一个或者多个R 1a取代(R 1a定义如上所述)，或者其中S或者1-2个碳原子可被选择性氧代；
和/或R 1选自：
Figure PCTCN2023071503-appb-000005
f为0-2；
g为0-3；
h为0-5；
k为0-2；
R 1a如上述定义，同环上的R 1a可同时选相同取代基也可选不同取代基；两个R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
R 3和R 4除非特殊说明，否则如上述定义；
当f和g不为0且R 1a不为氢时，R 1b＝H、R 1a；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
当f和g为0时，或者f和g不为0且R 1a为氢时，R 1b可选自氢、氘、卤素、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
当k不为0且R 1a不为氢时，R 5a、R 5和R 6＝R 1a，或R 5a、R 5、R 6、1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个 或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
当k为0，或者k不为0且R 1a为氢时：
如果R 5a为氘、溴、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、C 2-8烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
那么R 5和R 6＝R 1a，或者R 5、R 6、R 5a和1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
如果R 5a为氯、氟、CH 3时，那么R 5、R 6＝R 1a；
如果R 5a为H，那么R 6＝R 1a，R 5可选自选自氘、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、烷基、1～2个氟取代的烷基、1～3个溴取代烷基、1-3个氯取代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4(其中R 3和R 4不同时为H)、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2C 4-8烷基、-OS(O)2C 4-8环烷基、-OS(O)2C 4-8杂环烷基、-S(O)(NH)R 3、-S(O)(NR 4)R 3、S(O)2NR 3R 4(其中R 3和R 4与所附接的N原子可形成杂烯基、哌嗪基、含有至少1个O原子的5-7元氮杂烷基、吗啉基、桥环吗啉基，或R 3和R 4单独取代不构成环)、-S(O)2NH 2、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
或者R 5a为H、氯、氟、CH 3时，R 1选自
Figure PCTCN2023071503-appb-000006
其中
V选自-O-、-S-、-Se-、-CH 2-、-CF 2-、-CO-、-SO-、-SO2-、-N(R 7)-、-C(R 8R 9)-、-O-CH(烷基)-、-O-CH(环烷基)-、-S-CH(环烷基)-、-CH＝C(烷基)-、-N＝C(烷基)-、-CH＝C(环烷基)-、-N＝C(环烷基)-；
U选自-O-、-S-、-Se-、-CO-、-SO-、-S(O)2、-NR 7-、-CR 8R 9-；
当V为-O-、-S-、-CF 2-，且U为-CO-时，T为-O-、-S-、-Se-、-CO、-SO-、-S(O)2、-CR 8R 9-，-NH-、-N(CHF)-、-N(CF 2)-、-N(CH 2-CH(OH)-CH 3)-、-N(CH 2-CH(OCH 3)-CH 3)-、-N(CH 2-CH 2-OCH 3)-、-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)-，其中所述为-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)可选择性被C 1-3烷氧基、C 1-3烷基、C 3-6环烷基、NH(C 1-3烷基)、N(C 1-3烷基) 2或者1～3个卤素取代；否则T为-O-、-S-、-Se-、-CO-、-SO-、-SO2-、-C(R 8R 9)-、-N(R 7)-；
X 1、Y 1、Z 1可独立选自CH和N；
R 7＝R 1a；
R 8、R 9＝R 1a，或者R 8、R 9可选择性与两者原来所附接的原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；和/或其药学上可接受的盐或它的前药，和/或其溶剂合物、水合物、代谢产物、氮氧化物、外消旋混合物、对映异构体、非对映异构体和互变异构体或其任意比例的混合物包括外消旋混合物，其中：
Cy为
Figure PCTCN2023071503-appb-000007
p为0-6；
W选自CH 2-CH 2-O-、-O-、-S-、-SO 2-、-CH 2-、-OCH 2-、-CH 2O-、-CH 2S-、-SCH 2-、-CH 2SO 2-、-SO 2CH 2-、-CH 2-CH 2-、-(CH 2) 3-、-CH 2-CH 2-S-、-CH 2-CH 2-SO 2-、-CH 2-O-CH 2-、-CH 2-S-CH 2-、-CH 2-SO 2-CH 2-；
R a各自独立地选自氘、卤素、羟基、氰基、巯基、氨基、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6环烷基氧基、杂环烷氧基、-SC 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2N-、C 1-6烷基 -C(O)HN-、-C(O)NHC 1-6烷基、氧代、硫代，并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的；两个R a可连在同一碳原子，也可以连在不同的碳原子；R a或两个R a一起形成C 1-4亚烷基或者含有1～4个碳原子的醚链如-CH 2-O-CH 2-CH 2-CH 2-、-CH 2-O-CH 2-，所述亚烷基或醚链可与原来环形成含有杂原子或者不含杂原子环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环，所述杂原子包括N、S、O，所述环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环可被氘、羟基、卤素、烷基和烷氧基选择性取代，且其中C、S可被选择性氧代为-C＝O、-S＝O、-S(O)2-；或两个R a与其各自附接的碳原子组成6元芳基、5元杂芳基、6元杂芳基，且与原来环形成并环，所述并环可被羟基、卤素、氰基、烷基、烷氧基选择性取代；并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的。
A和B各自独立的选自氢、氘、氟，或者A和B与两者附接的碳原子形成环丙烷；
X、Y、Z各自独立选自CH、N、S、O、Se，或者X、Y、Z其中1个为环中的键即X、Y或Z两侧的原子直接连接，连接的键可为单键或双键；
R 2选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基，所述烷基、烷氧基、环烷基和环烷氧基均可任选的被卤素和氘取代的；
q为0-3；
当在下述四种情况下(四种情况是和/或的关系)
1)Cy不为
Figure PCTCN2023071503-appb-000008
2)X、Y、Z不同时为CH；
3)R 2不为氢且q不为0；
4)A和B不同时为氢；
R 1选自环状基团具体为芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基；所述环状基团可为单环也可为双环，可选择性含有一个或者多个N、O、S、Se的杂原子，且环中的C、S可被选择性氧代或硫代为-CO-、-CS-、-CO--SO-、-SO2-；所述芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基可被一个或者多个R 1a选择性取代；
R 1a可选自氢、氘、卤素、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5～6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；两个R 1a可连在同一个碳原子或者氮原子，也可以连在不同的碳原子或者氮原子；两R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或 者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，环中的C、S也可被选择性氧代或硫代为-CO-、-CS-、-SO-、-SO2-；
R 3、R 4各自独立的选自氢、氘、卤素、氰基、卤素、羟基、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、环烷氧基、杂环烷基、烷基羰基、烷基砜基、烷基C(O)NH-、烷基S(O)2NH-、羧基、烷基羰基；其中氨基、羟基、羧基、烷基、环烷基、环烷氧基、杂环烷氧基、杂环烷基可被烷基、卤素、氰基、羟基、羟基烷基、烷氧基进一步取代；两R 3可连在相同原子上，也可连在不同原子上；或者两个R 3，或R 3和R 4，可选择性与各自共同连接的碳原子或者氮原子形成3-10元环烷基、杂环烷基、螺环、桥环、稠环，包括但不限于氧杂环丁烷、氮杂环丁烷、吗啉环、哌啶环、哌嗪环、氮杂氧杂环丁烷、呋喃环、吡咯烷，所述环烷基、杂环烷基、螺环、桥环、稠环中C和S可被选择性氧代为-CO-、-SO-、-SO2-，且可被一个或多个卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、C 3-8杂环基选择性取代；
当Cy为
Figure PCTCN2023071503-appb-000009
且X、Y、Z三者均为CH，且R 2为氢，且A/B均为H时：
R 1选自为嘧啶、吡嗪、哒嗪、吡唑、呋喃、咪唑、噻唑、噁唑、异噁唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基，其中嘧啶、吡嗪、哒嗪、三嗪基、吡唑、呋喃、咪唑、噻唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基可被一个或者多个R 1a取代(R 1a定义如上所述)，或者其中S或者1-2个碳原子可被选择性氧代；
和/或R 1选自：
Figure PCTCN2023071503-appb-000010
f为0-2；
g为0-3；
h为0-5；
k为0-2；
R 1a如上述定义，同环上的R 1a可同时选相同取代基也可选不同取代基；两个R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
R 3和R 4除非特殊说明，否则如上述定义；
当f和g不为0且R 1a不为氢时，R 1b＝H、R 1a；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一 步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
当f和g为0时，或者f和g不为0且R 1a为氢时，R 1b可选自氢、氘、卤素、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
当k不为0且R 1a不为氢时，R 5a、R 5和R 6＝R 1a，或R 5a、R 5、R 6、1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
当k为0，或者k不为0且R 1a为氢时：
如果R 5a为氘、溴、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、C 2-8烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
那么R 5和R 6＝R 1a，或者R 5、R 6、R 5a和1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
如果R 5a为氯、氟、CH 3时，那么R 5、R 6＝R 1a；
如果R 5a为H，那么R 6＝R 1a，R 5可选自选自氘、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、烷基、1～2个氟取代的烷基、1～3个溴取代烷基、1-3个氯取代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯 基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4(其中R 3和R 4不同时为H)、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2C 4-8烷基、-OS(O)2C 4-8环烷基、-OS(O)2C 4-8杂环烷基、-S(O)(NH)R 3、-S(O)(NR 4)R 3、S(O)2NR 3R 4(其中R 3和R 4与所附接的N原子可形成杂烯基、哌嗪基、含有至少1个O原子的5-7元氮杂烷基、吗啉基、桥环吗啉基，或R 3和R 4单独取代不构成环)、-S(O)2NH 2、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
或者R 5a为H、氯、氟、CH 3时，R 1选自
Figure PCTCN2023071503-appb-000011
其中
V选自-O-、-S-、-Se-、-CH 2-、-CF 2-、-CO-、-SO-、-SO2-、-N(R 7)-、-C(R 8R 9)-、-O-CH(烷基)-、-O-CH(环烷基)-、-S-CH(环烷基)-、-CH＝C(烷基)-、-N＝C(烷基)-、-CH＝C(环烷基)-、-N＝C(环烷基)-；
U选自-O-、-S-、-Se-、-CO-、-SO-、-S(O)2、-NR 7-、-CR 8R 9-；
当V为-O-、-S-、-CF 2-，且U为-CO-时，T为-O-、-S-、-Se-、-CO、-SO-、-S(O)2、-CR 8R 9-，-NH-、-N(CHF)-、-N(CF 2)-、-N(CH 2-CH(OH)-CH 3)-、-N(CH 2-CH(OCH 3)-CH 3)-、-N(CH 2-CH 2-OCH 3)-、-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)-，其中所述为-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)可选择性被C 1-3烷氧基、C 1-3烷基、C 3-6环烷基、NH(C 1-3烷基)、N(C 1-3烷基) 2或者1～3个卤素取代；否则T为-O-、-S-、-Se-、-CO-、-SO-、-SO2-、-C(R 8R 9)-、-N(R 7)-；
X 1、Y 1、Z 1可独立选自CH和N；
R 7＝R 1a；
R 8、R 9＝R 1a，或者R 8、R 9可选择性与两者原来所附接的原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-。
本发明的优选方案，一种通式(I)所述化合物或其药学上可接受的盐，其中Cy选自
Figure PCTCN2023071503-appb-000012
Ar为吡啶和苯环；
R b为氯、氟、甲基、乙基、丙基、异丙基、环丙基、三氟甲基、三氟甲氧基
本发明的优选方案，一种式(I)所述化合物或其药学上可接受的盐，其中A和B均选自H，或均选自F。
本发明的优选方案，一种式(I)所述化合物或其药学上可接受的盐，其中X，Y各自独立选自CH、N，所述Z选自CH。
本发明的优选方案，一种式(I)所述化合物或其药学上可接受的盐，其中R 2选自氢、氟、甲基，所述q选自1。
本发明的优选方案，一种式(I)所述化合物或其药学上可接受的盐，其中R 1选自
Figure PCTCN2023071503-appb-000013
其中
X 1、Y 1、Z 1独立选自CH、N；
m、n、o为0-3；
U可选自-C(＝O)-,-S(O)2-、-O-、-NR 7-、-CR 8R 9-；
V可选自-C(＝O)-,-S(O)2-、-O-、-S-、-Se-、-NR 7-、-CR 8R 9-；
R 7选自氢、CH 3OCH 2CH 2-、氧杂环丁烷基、吖丁啶、四氢呋喃基、四氢吡喃、吡咯烷、哌嗪、吗啉、哌啶、-C 1-3烷基、C 3-6环烷基，其中所述C 1-3烷基、C 3-6环烷基、吖丁啶、四氢呋喃基、四氢吡喃、吡咯烷、哌嗪、吗啉、哌啶任选地被1、2或3个氟取代，和/或任选地被一个选自以下的取代基取代：C 1-3烷基、羟基、-OC 1-3烷基、-N(C 1-3烷基) 2、环丙基；同结构中不同位置的R 7可选择同样取代基，也可以选则不同的取代基；
R 8、R 9为氢、氟、-C 1-6烷基、-C 1-6卤代烷基，或R 8和R 9与其所附接的氮原子或者碳原子一起形成C 3-6环烷基、氧杂环丁烷、吖丁啶、吡咯烷、哌啶环、哌嗪环、吗啉环、四氢呋喃基、四氢吡喃基，所述环丙烷、氧杂环丁烷、吖丁啶、吡咯烷、哌啶环、哌嗪环、吗啉环、四氢呋喃基、四氢吡喃基可被C 1-3烷基、环丙烷、氧杂环丁烷、吖丁啶、环丙基氧基选择性取代；
C、D独立地选自-NR 7C(O)-、-C(O)NR 7-、-CH 2-CH 2-、-C(O)-O-、-O-C(O)-、-CH 2-O-、-O-CH 2-、-CH 2-NR 7-、-NR 7-CH 2-、-CH 2-；或者C和D中其中1个为键(环中的单键或者双键，两端的 原子直接连接)；
当Cy为
Figure PCTCN2023071503-appb-000014
且R 2为H，且X、Y、Z三者均选自CH，且如果结构中V存在则为-O-、-S-或者-CF 2-时：
R 5选自-S(O)2C 1-3烷基、-CONH 2、-SO 2NHC 1-3烷基、-SO 2NR 3R 4(其中R 3和R 4如果与其附接的N原子形成杂环基，所述杂环基选自哌嗪基、吗啉基，所述哌嗪基和吗啉基可选择性被C 1-3烷基、环丙基取代)；
R 6选自氢、氟、氯、溴、甲基；
R 7a选自H、-CHF、-CF 2、-CH 2-CH(OH)-CH 3、-CH 2-CH(OCH 3)-CH 3、-C 4-8烷基、-环烷基、-环烷氧基，-CH 2-CH 2-OCH 3、-氧杂环丁烷、-四氢呋喃、-四氢吡喃、吡咯烷、哌嗪、吗啉、哌啶；其中所述C 4-8烷基、四氢呋喃、吡咯烷、哌嗪、吗啉、哌啶任选地被1、2或3个氟取代和
/或任选地被一个选自以下的取代基取代：羟基、-OC 1-3烷基、-N(C 1-3烷基) 2、环丙基；
否则：R 5选自氰基、-SO 2C 1-3烷基、-CONH 2、-SO 2NR 3R 4，其中R 3、R 4为氢、-C 1-6烷基，或R 3和R 4与其所附接的氮原子一起形成吖丁啶、氧杂环丁烷、吡咯烷、哌啶环、哌嗪环、吗啉环，所述吖丁啶、氧杂环丁烷、吡咯烷、哌啶环、哌嗪环、吗啉环可被C 1-3烷基、环丙基选择性取代；
R 6选自氢、氟、氯、溴、甲基；
R 7a＝R 7；
本发明的优选方案，一种式(I)所述化合物或其药学上可接受的盐，其中R 1选自
Figure PCTCN2023071503-appb-000015
R 7选自氢、-CF 2、-CHF、CH 3OCH 2CH 2-、氧杂环丁烷基、四氢呋喃基、四氢吡喃、-C 1-3烷基、-C 3-6环烷氧基；其中所述C 1-3烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃可任选地被1、2或3 个氟取代，和或任选地被一个选自以下的取代基取代：羟基、-OC 1-3烷基、-N(C 1-3烷基) 2、环丙基；同结构中不同位置的R 7可选择同样取代基，也可以选则不同的取代基；
当Cy为
Figure PCTCN2023071503-appb-000016
且R 2为H，且X、Y、Z三者均选自CH，且A和B均为H时：R 7a选自H、-CHF、-CF 2、-CH 2-CH(OH)-CH 3、-CH 2-CH(OCH 3)-CH 3、-C 4-8烷基、-C 3-6环烷基、-C 3-6环烷氧基，-CH 2-CH 2-OCH 3、-氧杂环丁烷、-四氢呋喃、-四氢吡喃，所述氧杂环丁烷、四氢呋喃、四氢吡喃可被C 1-3烷基、环丙基选择性取代；否则R 7a＝R 7。
本发明的典型化合物包括，但不限于：
Figure PCTCN2023071503-appb-000017
Figure PCTCN2023071503-appb-000018
Figure PCTCN2023071503-appb-000019
Figure PCTCN2023071503-appb-000020
Figure PCTCN2023071503-appb-000021
Figure PCTCN2023071503-appb-000022
Figure PCTCN2023071503-appb-000023
或其药学上可接受的盐。
本发明的有益效果涉及式(I)化合物或其药学上可接受的盐在制备用于治疗和预防组织蛋白酶C及其下游丝氨酸蛋白酶NE、PR3、CaTG、NSP4疾病的药物中的用途。
进一步地涉及式(I)化合物或其药学上可接受的盐在制备用于在患有呼吸疾病、代谢疾病、心脑血管疾病、自身免疫性疾病、癌症、感染性疾病及其他炎性相关性疾病是哮喘、慢性阻塞性肺病、肺纤维化、肺高压、肺动脉高压、非囊性纤维化、囊性纤维化、支气管扩张、支气管炎、肺炎、肺气肿、急性肺损伤(ALI)、急性呼吸窘迫综合症(ARDS)、脓毒症、过敏性疾病、免疫性炎症性肠病、类风湿性关节炎、肾小球肾炎、嗜酸性粒细胞疾病、嗜中性粒细胞疾病、ANCA相关炎症、抗中性粒细胞胞浆抗体相关的坏死性新月形肾小球肾炎、急性脑创伤、急性心肌炎、急性肾损伤、a-1-抗胰蛋白酶缺乏症(AATD)及相关炎症、肝纤维化、脂肪肝及肝脂肪变性、肥胖症、胰岛素抗性、糖尿病、病原性微生物感染、感染性胃肠炎性疾病、肺癌和/或者放射性损伤综合征或者面临所述疾病危险的患者中治疗所述疾病的药物中的用途。
本发明的有益效果涉及一种药物组合物，其含有式(I)化合物其药学上可接受的盐、及至少一种药用载体或赋形剂。
进一步地，所述药物组合物其含有一种或多种式(I)化合物，以及选自由其他化合物组成的群的药学活性化合物，所述其他化合物包括但不限于：b模拟剂、抗胆碱能药物、皮质类固醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、CRTH2抑制剂、5-LO抑制剂、组织胺受体拮抗剂、CCR9拮抗剂及SYK抑制剂、NE抑制剂、MMP9抑制剂、MMP12抑制剂以及两种或三种活性物质的组合。
进一步地，所述药物组合物还包括与小分子化合物和/或大分子抗体联合使用，以治疗癌症、炎症、骨髓相关疾病和自身免疫性疾病，所述小分子化合物和/或大分子抗体、包括但不限于糖皮质激素、肾上腺素激动剂、胆碱能受体拮抗剂、茶碱类药物、抗氧化剂、弹性蛋白酶抑制剂、金属蛋白酶抑制剂、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、CRTH2抑制剂、5-LO抑制剂、组织胺受 体拮抗剂、CCR9拮抗剂及SYK抑制剂、趋化因子受体抑制剂、白介素抗体如IL-6抗体、IL-23抗体、靶向抗胸腺基质淋巴细胞生成素(TSLP)抗体如tezepelumab、补体抑制剂。
本发明的有益效果涉及式(I)化合物的组合物在治疗和预防由组织蛋白酶C及其下游丝氨酸蛋白酶NE、PR3、CaTG、NSP4疾病的药物中的用途，所述疾病选自呼吸疾病、代谢疾病、心脑血管疾病、自身免疫性疾病、癌症、感染性疾病或者炎性感染性疾病。
本发明的有益效果涉及式(I)化合物的溶剂合物、外消旋混合物、对映异构体、非对映异构体、互变异构体或包括外消旋混合物其任意比例的混合物，其特征在于，所述R 1、R 2、Cy、A、B、X、Y、Z和q各取代基：
Figure PCTCN2023071503-appb-000024
本发明的化合物可以是非对称的，例如具有一个或多个立体中心。除非有另外的限定，所有的立体异构体，例如是对映异构体和非对映异构体。含有非对称取代的碳原子的。本发明的化合物可以被分离成光学纯或外消旋形式。光学纯形式可以通过外消旋体的拆分来制备，或者通过使用手性合成子(synthon)或手性试剂来制备。
本发明的化合物也可以包括互变异构体形式。互变异构体新形式由单键和相邻的双键一起伴随质子的迁移而互换所产生的。
本发明的化合物也可以包括存在于中间体或最终化合物中的原子的所有同位素形式。同位素包括具有相同的原子序数但不同的质量数的那些原子。例如，氢的同位素包括氘和氚。
本发明还包括式(I)化合物的药用盐。药用盐是指，其中母体化合物通过所存在的碱部分转化成它的盐形式进行改性的式(I)化合物的衍生物，或者其中母体化合物通过所存在的酸部分转化成它的盐形式而进行改性的式(I)化合物化合物的衍生物。
具体地，药用盐的实例包括但不限于：碱性基团(如胺)的无机或有机酸的盐，或者酸性基团(如羧酸)的无机或有机碱的盐。本发明的药用盐可以由式(I)的母体化合物通过在溶剂体系中使这些化合物的游离碱形式与1-4当量适当的酸反应而合成。合适的盐被在Remington’s PharmaceuticalSciences,17th ed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中列出。
本发明的化合物以及其药用盐还包括溶剂化物形式或水合物形式。一般而言，溶剂化物形式或水合物形式与非溶剂化物形式或非水合物形式是等同的，均包括在本发明的范围内。本发明的一些化合物可以以多种晶型或非晶型形式存在。总体而言，化合物的所有的物理形式都包括在本发明的范围内。
本发明还包括式(I)化合物的前药。前药是一种由母体药物衍生的药理学物质(即药物)一旦给药之后，前药在体内被代谢成为母体药物。前药可以通过取代在化合物中存在的一个或多个官能团来制备，其中前药中的取代基在体内以这样一种方式被去除而转化成母体化合物。关于前药的制备和 使用如T.Higuchi and V.Stella,“Pro-drugs as Novel Delivery Systems”Vol.14of the A.C.S.Symposium Series和Bioreversible所记载。
具体实施方式
下面结合具体实施例对本发明进一步说明：
以下通过实施例进一步说明本发明，实施例仅用于更具体的说明本发明优选地实施方案，不用于对本发明的技术方案进行限定。上述本发明的方案均为可实现本发明目的之技术方案。以下实施例所采用温度和试剂，均可以用上述相应温度和试剂替代以实现本发明之目的。
本发明中所用的下列术语、短语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。
在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-O(C 1-4烷基)是指通过氧原子与分子的其余部分连接的C 1-4烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。
除非另有明确说明，使用“一”之类的术语是指一个或多个。
本发明所用的术语“烷基”是指含有1-18个碳原子、例如1-12个碳原子、再例如1-6个碳原子、再例如1-4个碳原子的直链或支链的饱和烃基。例如，“C1-6烷基”在“烷基”的范围内，表示所述的具有1-6个碳原子的烷基。烷基的例子包括但不限于甲基(“Me”)、乙基(“Et”)、正丙基(“n-Pr”)、异丙基(“i-Pr”)、正丁基(“n-Bu”)、异丁基(“i-Bu”)、仲丁基(“sBu”)和叔丁基(“t-Bu”)。
本发明所用的术语“烯基”是指含有一个或多个、例如1、2或3个碳碳双键(C＝C)的、含有2-10个碳原子、例如2-6个碳原子、再例如2-4个碳原子的直链或支链的烃基。例如，“C2-6烯基”在“烯基”的范围内，表示所述的具有2-6个碳原子的烯基。烯基的例子包括但不限于乙烯基、2-丙烯基和2-丁烯基。
本发明所用的术语“炔基”是指含有一个或多个、例如1、2或3个碳碳三键(C≡C)的、含有2-10个碳原子、例如2-6个碳原子、再例如2-4个碳原子的直链或支链的烃基。例如，“C 2-6炔基”表示所述的包含1个碳碳三键(C≡C)并具有2-6个碳原子的炔基。炔基的例子包括但不限于乙炔基、2-丙炔基和2-丁炔基。
本发明所用的术语“卤代”是指氟代、氯代、溴代和碘代，“卤素”是指氟、氯、溴和碘。
本发明所用的术语“卤代烷基”是指其中一个或多个氢原子、例如1、2、3、4或5个氢原子被卤素原子替代的本发明所定义的烷基，并且当超过一个氢原子被卤素原子替代时，所述卤素原子可以彼此相同或不同。在一个实施方案中，本发明所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本发明所定义的烷基，其中所述卤素原子彼此相同。在另一个实施方案中，本发明所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本发明所定义的烷基，其中所述卤素原子彼此不同。卤代烷基的例子包括但不限于-CF3、-CHF2、-CH2CF3等。
本发明所用的术语“烷氧基”是指基团-O-烷基，其中烷基如上文所定义。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基和己氧基，包括它们的异构体。
本发明所用的术语“环烷基”是指含有3-12个环碳原子、例如3-8个环碳原子、再例如3-6个环碳原子的饱和或部分不饱和的环状烃基，其可以具有一个或多个环，例如具有1个或2个环。例如，“C3-8环烷基”表示所述的具有3-8个环碳原子的环烷基。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基，以及类似的基团。
本发明所用的术语“杂环基”或“杂环的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂环基的连接点可以在杂原子上或在碳上。“杂环基”或“杂环的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂环上或在其它环上。
本发明所用的术语“环烷氧基”是指基团-O-环烷基，其中环烷基如上文所定义。环烷氧基的例子包括但不限于环丙基氧基、环丁基氧基，包括它们的异构体。
本发明所用的术语“杂环烷氧基”是指基团-O-杂环烷基，其中杂环烷基如上文所定义。环烷氧基的例子包括但不限于氮杂环丙基氧基、环氧丙烷氧基、氮杂环丁基氧基、氧杂环丁基氧基，包括它们的异构体。
本发明所述的“环烯基”是指含有一个或多个，例如1、2或3个碳碳双键的、含有3-12个环碳原子、优选3-8个环碳原子、更优选3-6个环碳原子的非芳族的环状羟基，其可以具有一个或多个环，优选具有1个或2个环。例如，C 3-8个环碳原子和环烯基，优选“C 3-6环烯基”，即所述的具有3-6个环碳原子的环烯基。环烯基的例子包括但不限于环丙烯及、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环庚烯基和环辛烯基。
本发明所述的“杂环烯基”是指上述“环烯基”中的一个或者多个碳原子被N、O、S替换。例如，C 3-8个环原子的杂环烯基，优选“C 3-6杂环烯基”，即所述的具有3-6个环原子的杂环烯基。杂环烯基的例子包括但不限于氮杂环丁烯及、氧杂环丁烯基、氮杂环戊烯基、氧杂环戊烯基、氧杂环己烯基。
本发明所用的术语“芳基”除非有明确定义，否则是指由一个环或多个环稠合组成的含有6-14个环碳原子，例如6-12个环碳原子的碳环烃基，其中至少一个环是芳族环并且其它环不是如下文所定义的杂芳基，其连接点可以在芳族环上或在其它环上。芳基的例子包括但不限于苯基、萘基、1,2,3,4-四氢萘基、茚基、茚满基、薁基，优选苯基和萘基。如本发明所用，“芳基”或“芳族的”遵循休克尔规则(Hückel's rule)，其中π电子数等于4n+2，n为零或任何最多为6的正整数。
本发明所用的术语“杂环基”或“杂环的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂环基的连接点可以在杂原子上或在碳上。“杂环基”或“杂环的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂环上或在其它环上。
本发明所用的术语“杂芳基”除非有明确定义，否则，是指：具有5、6或7个环原子、例如具有6个环原子的单环芳族烃基，其在环中包含一个或多个、例如1、2或3个、例如1或2个独立地选 自N、O和S(例如N)的环杂原子，其余环原子是碳原子；和具有8-12个环原子、例如具有9或10个环原子的二环芳族烃基，其在环中包含一个或多个、例如1、2、3或4个、例如1或2个独立地选自N、O和S(例如N)的环杂原子，其余环原子是碳原子，其中至少一个环是芳族环。例如，二环杂芳基包括与5-6元环烷基环、杂环基环或芳基环稠合的5-6元杂芳基环，其中连接点可以在杂芳基环上或在环烷基环/杂环基环/芳基环上。当杂芳基中的S和O原子的总数超过1时，这些S和O杂原子彼此不相邻。杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化嘧啶基。在一些实施方案中，上述杂芳基中的环杂原子是N原子，这类杂芳基称为“含氮杂芳基”。含氮杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化吡啶基。
杂芳基的例子包括但不限于：吡啶基、N-氧化吡啶基；吡嗪基；嘧啶基；吡唑基；咪唑基；噁唑基；异噁唑基；噻唑基；异噻唑基；噻二唑基；四唑基；三唑基；噻吩基；呋喃基；吡喃基；吡咯基；哒嗪基；苯并[d]噻唑基；苯并间二氧杂环戊烯基，例如苯并[d][1,3]间二氧杂环戊烯基；苯并噁唑基，例如苯并[d]噁唑基；咪唑并吡啶基，例如咪唑并[1,2-a]吡啶基；三唑并吡啶基，例如[1,2,4]三唑并[4,3-a]吡啶基和[1,2,4]三唑并[1,5-a]吡啶基；吲唑基；2H-吲唑基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；吡唑并嘧啶基，例如吡唑并[1,5-a]嘧啶基；四唑并吡啶基，例如四唑并[1,5-a]吡啶基；苯并噻吩基；苯并呋喃基；苯并咪唑啉基；吲哚基；吲哚啉基；嘌呤基，例如9H-嘌呤基和7H-嘌呤
含氮杂芳基的实例包括但不限于：吡咯基；吡唑基；咪唑基；吡啶基；吡嗪基；嘧啶基、N-氧化嘧啶基；哒嗪基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；嘌呤基，例如9H-嘌呤基和7H-嘌呤基；喹啉基；吲哚基；以及吲唑基。
本发明所述的术语“羟基”是指–OH基团。
本发明所用的术语“巯基”是指–SH基团。
本发明所用的术语“氧代”是指＝O基团。
本发明所用的术语“羧基”是指–C(O)-OH基团。
本发明所用的术语“氰基”是指-CN基团。
本发明所用的术语“氨基”是指-NH2基团。
本发明所用的“基团”和“基”是同义词，用于表示可与其他分子片段连接的官能团或分子片段。
本发明所述的p、q、f、g、h、k、m、n、o的数值范围是指包含该范围内的任意整数，举例如0-6是指0、1、2、3、4、5、6中的任意整数。
如果本发明的某个结构式包含星号“*”，则该结构式所表示的化合物是手性化合物，即该化合物是R-构型或S-构型。化合物的构型可以由本领域技术人员使用多种分析技术、例如单晶X-射线晶体学和/或光学旋光测定法并根据常规方案来确定。
本发明所用的术语“选择性”、“选择性的”、“选择性地”、“任选”、“任选的”或“任选地”意指随后描述的取代模式、事件或情况可以发生一次或者多次、或可以不发生，并且该描述包括所述取代模式发生的情形以及所述取代模式不发生的情形。例如，“任选被取代的烷基”包括本发明定义的“未被取代的烷基”和“被取代的烷基”。本领域技术人员应当理解的是，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在 不稳定的取代模式。
本发明所用的术语“包括但不限于”意指所选择的范围优先后续例举的基团，但没有被例举的基团也可以使用。
本发明所用的术语“被取代的”或“被……取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定的取代基组的取代基替换，条件是不超过该给定原子的正常化合价。当取代基是氧代(即＝O)时，则单个原子上的两个氢原子被氧替换。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时，这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定，以至于能从反应混合物中被分离出来并能确定化合物的化学结构，并且随后能被配制成至少具有实际效用的制剂。
除非另有说明，取代基被命名入核心结构中。例如，应当理解的是，当(环烷基)烷基被列为一种可能的取代基时，其表示该取代基与核心结构的连接点在烷基部分。
本发明所用的术语“被一个或多个取代基取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个选自给定基团的取代基替换。在一些实施方案中，“被一个或多个取代基取代”意指给定的原子或基团被1、2、3或4个独立地选自给定基团的取代基取代。
本领域技术人员应当理解的是，一些式(I)的化合物可以包含一个或多个手性中心，因此存在两个或更多个立体异构体。这些异构体的外消旋混合物、单个异构体和一种对映异构体富集的混合物，以及当有两个手性中心时的非对映异构体和特定的非对映异构体部分富集的混合物均在本发明的范围内。本领域技术人员还应当理解的是，本发明包括式(I)的化合物的所有单个立体异构体(例如对映异构体)、外消旋混合物或部分拆分的混合物，以及在适当的情况下，包括其单个互变异构体。
换言之，在一些实施方案中，本发明提供了含有多种立体异构体纯度的化合物，即以不同“ee”或“de”值表示的非对映体或对映体纯度。在一些实施方案中，式(I)的化合物(例如如本发明所述)有至少60％ee(例如60％、65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％、99.9％ee，或任何在这些列举的数值之间的数值)的对映体纯度。在一些实施方案中，式(I)的化合物(例如如本发明所述)有大于99.9％ee、达到100％ee的对映体纯度。在一些实施方案中，式(I)的化合物(例如如本发明所述)有至少60％de(例如60％、65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％、99.9％de，或任何在这些列举的数值之间的数值)的非对映体纯度。在一些实施方案中，式(I)的化合物(例如本发明所述)有大于99.9％de的非对映体纯度。
术语“对映体过量”或“ee”表示一种对映异构体相对于另一种对映异构体的多少。对于R和S对映异构体的混合物，对映体过量的百分数定义为│R-S│*100，其中R和S为混合物中各自对映异构体的摩尔或重量分数，R+S＝1。若已知一手性物质的旋光度，则对映体过量的百分数定义为([a]obs/[a]max)*100，其中[a]obs为对映异构体混合物的旋光度，[a]max为纯的对映异构体的旋光度。
术语“非对映体过量”或“de”表示一种非对映异构体相对于另一种非对映异构体的多少，并用类推的方法根据对映体过量来定义。因此，对于非对映异构体D1和D2的混合物，非对映体过量的百分数定义为│D1–D2│*100，其中D1和D2为混合物中各自非对映异构体的摩尔或重量分数，D1+D2＝1。
非对映体和/或对映体过量的测定可采用多种分析技术，包括核磁共振光谱法、手性柱色谱法和/或光学旋光测定法，并根据本领域技术人员所熟悉的常规方案来完成。
外消旋混合物可以以其本身的形式使用或者拆分成单个异构体使用。通过拆分可以得到立体化学上的纯的化合物或者富集一种或多种异构体的混合物。分离异构体的方法是众所周知的，包括物理方法，例如使用手性吸附剂的色谱法。可以由手性前体制备得到手性形式的单个异构体。或者，可以通过与手性酸(例如10-樟脑磺酸、樟脑酸、α-溴樟脑酸、酒石酸、二乙酰基酒石酸、苹果酸、吡咯烷酮-5-羧酸等的单个对映异构体)形成非对映异构体盐而由混合物化学分离得到单个异构体，将所述的盐分级结晶，然后游离出拆分的碱中的一个或两个，任选地重复这一过程，从而得到一个或两个基本上不包含另一种异构体的异构体，即光学纯度以重量计为例如至少91％、92％、93％、94％、95％、96％、97％、98％、99％或99.5％的所需的立体异构体。或者，如本领域技术人员所熟知的，可以将外消旋物共价连接到手性化合物(辅助物)上，得到非对映异构体，可通过色谱法或分级结晶法将其分离，之后化学除去手性辅助物，得到纯的对映异构体。
本发明所述“药学上可接受的盐”，指的是无毒的、生物学上可耐受的或其他生物学上适合于给予治疗个体的式(I)的化合物的游离酸或碱的盐。。
“药学上可接受的盐”包括但不限于：式(I)的化合物与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及式(I)的化合物与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH2)n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。“药学上可接受的盐”也包括带有酸性基团的式(I)的化合物与药学上可接受的阳离子例如钠、钾、钙、铝、锂和铵形成的碱加成盐。所得的药学上可接受的盐中的式(I)的化合物与酸或阳离子的摩尔比包括但不限于1:1、1:2、1:3和1:4。
本发明所述“前药”，指的是一种由母体药物衍生的药理学物质(即药物)一旦给药之后，前药在体内被代谢成为母体药物。前药可以通过取代在化合物中存在的一个或多个官能团来制备，其中前药中的取代基在体内以这样一种方式被去除而转化成母体化合物。关于前药的制备和使用可以在T.Higuchi and V.Stella,“Pro-drugs as Novel Delivery Systems,”Vol.14of the A.C.S.Symposium Series和Bioreversible。“前药”包括但不限于：式(I)的化合物的酯类如磷酸酯、甲酸酯、氨基甲酸酯；酰胺如甲酰胺、乙酰胺。
此外，如果本发明所述的化合物是以酸加成盐的形式得到的，其游离碱形式可以通过碱化该酸加成盐的溶液获得。相反地，如果产物是游离碱形式，则其酸加成盐、特别是药学上可接受的酸加成盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。
术语“溶剂合物”意指包含化学计量的或非化学计量的溶剂的溶剂加成形式。一些化合物具有在固体状态中网罗固定摩尔比的溶剂分子的倾向，从而形成溶剂合物。如果溶剂是水，则形成的溶剂合物是水合物，当溶剂是乙醇时，则形成的溶剂合物是乙醇合物。水合物是通过一个或多个分子的 水与一分子所述物质形成的，其中水保留其H2O的分子状态，这样的组合能形成一种或多种水合物，例如半水合物、一水合物和二水合物，以及可变的水合物。
本发明所用的术语“基团”和“基”是同义词，用于表示可与其它分子片段连接的官能团或分子片段。
术语“活性成分”用来表示具有生物活性的化学物质。在一些实施方案中，“活性成分”是具有制药用途的化学物质。在美国，实际的药物活性可通过适当的无论是体外的或体内的临床前试验来确定。但是能够足以被监管机构(例如美国的FDA)接受的药物活性，要有比临床前试验更高的标准。这样一种更高标准的药物活性，其是否能成功获得一般不能从临床前的试验结果合理地预期到，但可以通过在人体中进行的适当并有效的随机、双盲、可控的临床试验来确立。
术语“处置”或“治疗”疾病或障碍，在达到有益治疗效果的情况下，是指给患有所述疾病或障碍、或者具有所述疾病或障碍的症状、或者具有易患所述疾病或障碍的体质的个体、例如人施用一种或多种药物物质、特别是本发明所述的式(I)化合物和/或其药学上可接受的盐，用以治愈、愈合、缓解、减轻、改变、医治、改善、改进或影响所述疾病或障碍、所述疾病或障碍的症状或者易患所述疾病或障碍的体质。在一些实施方案中，所述疾病或障碍是癌症。
当涉及化学反应时，术语“处理”、“接触”和“反应”意指在适当的条件下加入或混合两种或更多种试剂，以产生所示的和/或所需的产物。应当理解的是，产生所示的和/或所需的产物的反应可能不一定直接来自最初加入的两种试剂的组合，即，在混合物中可能存在生成的一个或多个中间体，这些中间体最终导致了所示的和/或所需的产物的形成。
本发明所用的术语“有效量”是指通常足以对需要治疗具有由组织蛋白酶C及下游丝氨酸蛋白酶活性介导的疾病或障碍的患者产生有益治疗效果的组织蛋白酶C抑制剂的量或剂量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药或施药的方式或途径、药物成分的药代动力学、疾病或障碍的严重程度和病程、个体先前的或正在进行的治疗、个体的健康状况和对药物的反应、以及主治医生的判断)来确定本发明中活性成分的有效量或剂量。在美国，有效剂量的确定一般难以从临床前试验中预知。事实上，剂量是完全不可预知的，剂量在原始用于随机的、双盲的、可控的临床试验后会发展出新的不可预知的剂量方案。
典型的剂量范围是从约0.0001至约200毫克活性成分每公斤个体体重每天，例如从约为0.001至100毫克/公斤/天，或者约为0.01至35毫克/公斤/天，或者约为0.1至10毫克/公斤，每日一次或分剂量单位服用(例如，每日两次、每日三次、每日四次)。对于一个70公斤的人而言，合适剂量范围可以是约0.05至约7克/天，或者约为0.2至约5克/天。一旦患者的疾病或障碍出现改善，可以调整剂量以维持治疗。例如，根据症状的变化可以将给药剂量或给药次数，或者将给药剂量和给药次数减少至维持所期望的治疗效果的水平。当然，如果症状减轻到了适当的水平，可以停止治疗。然而，对于症状的复发，患者可能需要间歇性长期治疗。
术语“抑制”是指生物活动或过程的基线活性的降低。术语“抑制组织蛋白酶C活性”是用于本发明目的的实际药物活性，是指相对于不存在式(I)化合物和/或其药学上可接受的盐时的组织蛋白酶C活性，对存在本发明所述的式(I)化合物和/或其药学上可接受的盐的直接或间接响应导致的组织蛋白酶C活性的降低。活性的降低可以是由本发明所述的式(I)化合物和/或其药学上可接受的盐与组织蛋 白酶C直接相互作用引起的，或者是由本发明所述的式(I)化合物和/或其药学上可接受的盐与一种或多种其它因子相互作用进而影响组织蛋白酶C活性引起的。例如，本发明所述的式(I)化合物和/或其药学上可接受的盐的存在可通过直接与组织蛋白酶C结合而降低组织蛋白酶C的活性、可通过直接或间接地影响另一种因子来降低组织蛋白酶C的活性，或者通过直接或间接地减少存在于细胞或机体中的组织蛋白酶C的量来降低组织蛋白酶C的活性。
本发明所用的术语“个体”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳类的任何成员，其包括但不限于：人；非人灵长类动物，如黑猩猩及其它猿类和猴类物种；农场动物，如牛、马、绵羊、山羊和猪；家畜，如兔、狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠；等。非哺乳动物的例子包括但不限于鸟等。术语“个体”并不限定特定的年龄或性别。在一些实施方案中，个体是人。
一般而言，术语“约”在本发明中用于将所给出的数值调整至高于或低于该数值20％。
式(I)化合物通用合成方法：
Scheme 1
Figure PCTCN2023071503-appb-000025
在路线1中，式II的化合物中PG代表保护基，如叔丁氧基羰基。如路线1所示，式II的化合物在碱性条件下(如用N,N-二异丙基乙胺做碱)，被2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)或O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)激活与氨水反应得式III的化合物。 式III的化合物的脱保护产物式IV的化合物与式V的化合物酸利用常规的文献报道方法如用N,N-二异丙基乙胺做碱，HATU或HBTU做活化试剂，得到酰胺式VI的化合物。
式VI的化合物与式VIII的硼酸酯化合物Suzuki偶联反应利用钯催化剂如[1,1'-双(二苯基膦基)二茂铁]二氯化钯在合适的溶剂中如二氧六环，和使用适当的碱如醋酸钾而得到式IX的化合物。
另外一条路线是将式VI的化合物转化成式VII的硼酸酯化合物。式VI的化合物与双戊酰二硼在[1,1'-双(二苯基膦基)二茂铁]二氯化钯催化下用醋酸钾做碱在二甲基亚砜中反应而得式VII的硼酸酯化合物。式XI的化合物与式VII的硼酸酯化合物Suzuki偶联反应利用钯催化剂如[1,1'-双(二苯基膦基)二茂铁]二氯化钯在合适的溶剂中如二氧六环，和使用适当的碱如醋酸钾而得到式IX的化合物。
式IX的化合物的酰胺可以在二氯甲烷中利用N-(三乙基铵磺酰)氨基甲酸甲酯脱水得式X的化合物。式X的化合物的脱保护反应得到最终产物式I的化合物。
本发明所述的式(I)的化合物(例如，本发明中的任何化合物)和/或其药学上可接受的盐可单独或者与一种或多种另外的活性成分联合配制成药物组合物。药物组合物包括：(a)有效量的本发明所述的一种式(I)的化合物和/或一种其药学上可接受的盐；和(b)一种药学上可接受的赋形剂(例如，一种药学上可接受的载体)。
药学上可接受的载体是指能与组合物中的活性成分相容(在一些实施方案中，能稳定活性成分)并且对所治疗的个体无害的载体。例如，增溶剂如环糊精(其能与本发明所述的式(I)的化合物和/或其药学上可接受的盐形成特定的、溶解性更强的复合物)可用作药物赋形剂来递送活性成分。其它载体的例子包括胶态二氧化硅、硬脂酸镁、纤维素、十二烷基硫酸钠以及色素如D&C黄色10号(D&C Yellow#10)。合适的药学上可接受的载体在本领域一本标准的参考书(Remington's Pharmaceutical Sciences,A.Osol)中公开。
包含本发明所述的式(I)化合物(例如，本发明中的任何化合物)和/或其药学上可接受的盐的药物组合物可以以各种已知的方式、例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。本发明所用的术语“肠胃外”包括皮下、皮内、静脉、肌内、关节内、动脉内、滑膜内、胸骨内、脊椎内、患处内以及颅内注射或输注。
本发明所述的药物组合物被制备成的形式可以是片剂、胶囊、袋装冲剂、糖衣丸、散剂、颗粒剂、含片、粉针剂、液体制剂或栓剂。在一些实施方案中，包含式(I)化合物和/或其药学上可接受的盐的药物组合物可被配制成用于静脉滴注、局部给药或口服给药的形式。
口服施用的组合物可以是任何口服可接受的剂型，包括但不限于：片剂、胶囊、乳剂以及水性的混悬剂、分散剂和溶液。常用的片剂载体包括乳糖和玉米淀粉。润滑剂如硬脂酸镁也常加入到片剂中。以胶囊形式口服施用时，有用的稀释剂包括乳糖和干燥的玉米淀粉。当以水性混悬剂或乳剂形式口服施用时，可用乳化剂或助悬剂使活性成分混悬或溶解于油相中。若有需要，还可添加某些甜味剂、矫味剂或色素。
在一些实施方案中，式(I)的化合物和/或其药学上可接受的盐在片剂中的量可以是1、5、10、15、20、25、50、75、80、85、90、95、100、125、150、200、250、300、400和500毫克。在一些实施方案中，式(I)的化合物和/或其药学上可接受的盐在胶囊中的量可以是1、5、10、15、20、 25、50、75、80、85、90、95、100、125、150、200、250、300、400和500毫克。
无菌可注射组合物(如水性或油性混悬剂)可按照本领域已知的技术，使用适合的分散剂或润湿剂(例如，吐温80)以及助悬剂来配制。无菌可注射中间介质也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液，例如在1,3-丁二醇中的溶液。药学上可接受的载体和溶剂尤其可使用的是甘露醇、水、林格氏液和生理盐水。此外，无菌的不易挥发的油例如合成的单或二甘油酯通常用作溶剂或混悬介质。脂肪酸例如油酸及其甘油酯衍生物以及天然的药学上可接受的油例如橄榄油或蓖麻油(尤其是其聚氧乙基化形式)常用作可注射中间介质。这些油溶液或混悬液也可含有长链的醇类稀释剂或分散剂、或羧甲基纤维素或类似的分散剂。
使用苯甲醇或其它适宜的防腐剂、使用提高生物利用度的吸收促进剂、使用碳氟化合物和/或其它本领域已知的增溶剂或分散剂，可以根据药物制剂领域众所周知的技术制备吸入组合物，也可将其制成在盐水中的溶液。
局部组合物可配制为油、乳膏剂、洗剂、软膏剂等形式。用于组合物的适合载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量的醇(即，碳原子数大于12的醇)。在一些实施方案中，药学上可接受的载体是活性成分能溶解于其中的载体。如有需要，组合物还可以包含乳化剂、稳定剂、湿润剂和抗氧化剂，以及赋予其颜色或香味的物质。此外，局部制剂中还可加入透皮渗透促进剂。这类促进剂的例子可见于美国专利US No.3,989,816和4,444,762。
乳膏剂可以由矿物油、自乳化蜂蜡和水的混合物配制，将溶解于少量油脂例如杏仁油中的活性成分混合在其中。乳膏剂的一个例子包含以重量计约40份水、约20份蜂蜡、约40份矿物油以及约1份杏仁油。软膏剂可通过将活性成分在植物油例如杏仁油中的溶液与温热的软石蜡混合并将混合物冷却来配制。软膏剂的一个例子包含以重量计约30％杏仁油和约70％白软石蜡。
合适的体外实验可用于评价本发明所述的式(I)的化合物和/或其药学上可接受的盐在抑制组织蛋白酶C活性中的实际用途。可进一步通过体内试验检测本发明所述的式(I)的化合物和/或其药学上可接受的盐在治疗肺部疾病、炎症性疾病、代谢疾病、感染性疾病、心脑血管性疾病或自身免疫性疾病中的另外的实际用途。例如，可将本发明所述的式(I)的化合物和/或其药学上可接受的盐施用给患有肺部疾病、炎症性疾病、代谢疾病、感染性疾病、心脑血管性疾病、癌症、自身免疫性疾病的动物(如小鼠模型)，然后评估其治疗效果如果临床前试验的结果是成功的，还可以预测其对动物例如人的剂量范围和施用途径；或给非疾病模型动物(如大鼠)给药经评估其对组织蛋白酶C下游的丝氨酸蛋白酶的抑制效果来预测其对尚无验证疾病模型的肺部疾病的如支气管扩张的获益。
本发明所述的式(I)的化合物和/或其药学上可接受的盐可显示有足够的临床前的实际用途以值得进行临床试验，并期望显示有益的治疗或预防效果，例如，在患有肺部疾病和炎症性疾病的个体中显示有益的治疗或预防效果。
术语“肺部疾病”指的是肺部器官相关的病理状态。这种疾病的非限制性例子包括支气管扩张、特发性肺纤维化、肺动脉高压、哮喘、慢性阻塞性肺部疾病、肺炎、急性肺损伤、急性呼吸窘迫综合征。
术语“炎症性疾病”或“炎性疾病”指的是导致炎症反应的病理状态，尤其是由于嗜中性粒细胞趋化引起的。这种疾病非限制性例子包括炎性皮肤疾病(包括银屑病和特应性皮炎)；系统性硬皮病和 硬化症；与炎性肠病(IBD)(例如克罗恩病和溃疡性结肠炎)有关的反应；缺血再灌注损伤，包括手术引起组织再灌注损伤、心肌缺血如心肌梗死、心脏骤停、心脏术后再灌注和经皮冠状动脉成形术后冠脉血管的异常收缩反应、中风和腹主动脉瘤手术组织再灌注损伤；中风继发脑水肿；颅外伤；失血性休克；窒息；成人呼吸窘迫综合征；急性肺损伤；白塞氏病；皮肌炎；多发性肌炎；自身免疫性疾病如类风湿性关节炎(RA)；肺部炎症，包括胸膜炎、肺泡炎、脉管炎、肺炎、慢性支气管炎、支气管扩张、弥漫性泛细支气管炎、过敏性肺炎、特发性肺纤维化(IPF)以及囊性纤维化等；其他炎症ANCA相关炎症、抗中性粒细胞胞浆抗体相关的坏死性新月形肾小球肾炎。
本发明所述的式(I)的化合物和/或其药学上可接受的盐可用来达到有益的治疗或预防效果，例如，在患有代谢性疾病、感染性疾病、心脑血管疾病、感染性疾病、癌症、自身免疫性疾病的个体中达到有益的治疗或预防效果。
术语“自身免疫性疾病”是指机体对自身抗原发生免疫反应而导致自身组织或器官损害所引起的疾病或病症。自身免疫性疾病的例子包括但不限于：慢性阻塞性肺病(COPD)、变应性鼻炎、红斑狼疮、重症肌无力、多发性硬化(MS)、类风湿性关节炎(RA)、银屑病、炎性肠病(IBD)、哮喘和特发性血小板减少性紫癜(idiopathic thrombocytopenicpurpura)以及骨髓增生性疾病(myeloid proliferative disorder)，例如骨髓纤维化(myelofibrosis)、真性红细胞增多症/原发性血小板增多症性骨髓纤维化(postpolycythemia vera/essential thrombocytosis myelofibrosis,PV/ET)。
术语“代谢性疾病”指的是因代谢紊乱导致的疾病或者与代谢有关的疾病，非限制性例子包括非酒精性脂肪肝、非酒精性脂肪肝炎、AATD、肥胖、糖尿病等。
术语“感染性疾病”指的病毒、细菌、寄生虫等感染导致的病理状态。这种疾病的非限制性例子包括利什曼病、新型冠状病毒感染肺炎、脓毒症。
术语“心脑血管疾病”指的是心血管系统、脑部器官相关的疾病。这种疾病的非限制性例子缺血再灌注损伤、急性脑损伤、心衰、心肌炎、心肌梗塞等。
本发明所用的术语“癌症”是指以失控或失调的细胞增殖、减少的细胞分化、不恰当的侵入周围组织的能力和/或在其它部位建立新生长灶的能力为特征的细胞障碍。术语“癌症”包括但不限于：实体瘤和血液系统恶性肿瘤。术语“癌症”包括皮肤、组织、器官、骨骼、软骨、血液和血管的癌症。术语“癌症”既包括原发性癌症，也包括转移性癌症。实体瘤的非限制性例子包括肺癌例如非小细胞肺癌(NSCLC)。
在一些实施方案中，炎症性疾病和自身免疫性疾病包括类风湿性关节炎、慢性阻塞性肺病(COPD)、变应性鼻炎、哮喘、红斑狼疮、系统性红斑狼疮、银屑病和多发性硬化。
此外，本发明所述的式(I)的化合物(例如，本发明中的任何化合物)和/或其药学上可接受的盐可与另外的活性成分联合用药，用于治疗呼吸疾病、炎症性或自身免疫性疾病和癌症。另外的活性成分可以与本发明所述的式(I)的化合物和/或其药学上可接受的盐分开给药，或者可以根据本公开将其包含在药物组合物中，例如固定剂量的复方药品。在一个典型的实施方案中，另外的活性成分是那些已知的或已被发现对治疗组织蛋白酶C及其下游丝氨酸蛋白酶活性介导的疾病有效的成分，例如另一种组织蛋白酶C调节剂或一种能有效拮抗与该特定的疾病相关的另一个靶点的化合物。联合用药可用于提高疗效(例如，通过将一种能增强本发明所述的式(I)的化合物和/或其药学上可接受的盐 的效力或有效性的化合物包含入联合用药中)，降低一种或多种副作用，或者减少所需的本发明所述的式(I)的化合物和/或其药学上可接受的盐的剂量。
实施例
下述实施例是对本发明的示例性说明，不以任何方式限制本发明。除非另外说明，否则所有分数均是重量分数，温度为摄氏温度。压力为大气压或接近大气压。所有数据均由安捷伦(Agilent 6120和/或1100)测得。除了合成的中间体外，本发明所用的所有试剂均为商业渠道获得。除试剂外所有化合物的名称均由ChemDrew 20.0生成。
使用以下缩写：
ACN        乙腈
Boc        叔丁氧基羰基
(Boc) 2O    焦碳酸而叔丁酯
BH 3        硼烷
DAST       二乙氨基三氟化硫
DCM        二氯甲烷
DEA        二乙氨
DMF         N,N-二甲基甲酰胺
DMA        二甲基乙酰胺
DIBAL-H    二异丁基氢化铝
DIEPA      N,N-二异丙基乙胺
EDCI       1-(3-二甲基胺基丙基)-3-乙基碳二亚胺盐酸盐
EA         乙酸乙酯
Et3N       三乙胺
HATU       2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HBTU       O-苯并三氮唑-四甲基脲六氟磷酸酯
HOAc       乙酸
HOBt       1-羟基苯并三唑
ee         对映异构体过量
mL         毫升
g          克
mg         毫克
ng         纳克
mol        摩尔
mmol       毫摩尔
h          小时
MeOH       甲醇
NaH        氢化钠
NCS            N-氯代琥珀酰亚胺
NMP            N-甲基-2-吡咯烷酮
PE             石油醚
Pd(dppf) 2Cl 2   [1,1'-双(二苯基膦基)二茂铁]二氯化钯
Pd 2(dba) 3      三二亚苄基丙酮二钯
Pd(PPh 3) 4      四(三苯基膦)钯
PMB            对甲氧基氰苄基
PPh 3           三苯基膦
Pin 2B 2         频哪醇联硼酸酯
THF            四氢呋喃
TFA            三氟乙酸
TsOH           4-甲苯磺酸
Xphos          2-二环己基膦-2’，4’，6’-三异丙基联苯
Burgess试剂    N-(三乙基铵磺酰)氨基甲酸甲酯
1.中间体1：
Figure PCTCN2023071503-appb-000026
a)室温条件氮气保护下，向化合物2-氨基-4-溴苯酚(20.0g,106.4mmol)的2-MeTHF(300mL)溶液中加入CDI(20.7g,127.7mmol)，然后进入回流1小时，冷至室温，依次用2M HCl(aq.)(300mL),8％NaHCO 3(aq.)(300mL)，和饱和食盐水(150mL)洗，Na 2SO 4干燥，浓缩得浅棕色固体产物1a(21.9g,96％).MS(ESI):m/z＝215.9[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ11.85(s,1H)；7.26-7.23(m,3H)。
b)室温下氮气保护下，向化合物1a(1.0g,4.7mmol)的DMF(15.0mL)溶液中,依次加入氯二氟乙酸钠(3.6g,23.5mmol),S 8(6.0g,23.5mmol),叔丁醇钠(1.8g,18.8mmol),
Figure PCTCN2023071503-appb-000027
分子筛(200mg,干粉)，然后加热到70℃，并继续搅拌6小时。冷至室温，过滤除去分子筛，并用EA(50mL)洗涤，进一步用EA(100mL)稀释，用饱和食盐水(50mL×5)洗,Na 2SO 4干燥，浓缩得粗品。粗品用制备HPLC纯化(用TFA缓冲液:A：0.05％TFA水溶液；B:0.05％TFA乙腈溶液；色谱柱:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000028
)的白色固体产物1(660mg,53％)。MS(ESI):m/z＝266.0[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.73(t,J＝57.4Hz,1H),7.58-7.57(m,1H),7.50(dd,J＝8.4,2.0Hz,1H),7.45(d,J＝8.4Hz,1H)。
2.中间体2：
Figure PCTCN2023071503-appb-000029
a)室温下,将1a(1.0g,4.7mmol)和甲醛(37％水溶液,610μL)加入水中(5mL)。反应液在80℃下搅拌过夜，然后冷至室温，过滤，并用水洗(3×10mL).所得粗品真空干燥得浅棕色固体2a(960mg,84％).MS(ESI):m/z＝228.1[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.60(t,J＝1.2Hz,1H)；7.33(br,3H)；5.21(s,2H).
b)在-50℃氮气保护下，向2a(312mg,1.3mmol)的二氯甲烷溶液(5mL)滴加DAST(265μL,2.0mmol)。加完后，让反应液慢慢升至室温，并搅拌过夜，然后用饱和NaHCO 3(10mL)淬灭，二氯甲烷萃取，饱和食盐水洗(10mL),Na 2SO 4干燥，浓缩得浅棕色固体2(306mg,95％).MS(ESI):m/z＝246.1[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.86(brs,1H)；7.41-7.39(m,2H)；6.02(d,J＝52Hz,2H)。
3.中间体3：
Figure PCTCN2023071503-appb-000030
a)室温下，将化合物2-氨基-4-溴苯酚(1.0g,5.3mmol)和化合物3-氧杂环丁酮(764mg,10.6mmol)溶解于干燥的THF(15.0mL)中。冰浴冷却下，慢慢滴加BH 3·THF(1M,5.3mL)。加完后，让反应液升至室温，继续搅拌6h。然后，再补加化合物3-氧杂环丁酮(764mg,10.6mmol)和BH 3·THF(1M,5.3mL)，并搅拌过夜。反应液冰浴冷却，慢慢滴加NaOH水溶液(1M,20mL)去淬灭多余的BH 3.分离出有机相，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(eluted with DCM/MeOH＝50/1)得浅棕色固体产物3a(640mg,50％).MS(ESI):m/z＝246.2[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ9.64(s,1H),6.61-6.56(m,2H),6.32-6.28(m,1H),5.6(brs,1H),4.82-4.78(m,2H),4.53-4.45(m,3H)。
b)室温下氮气保护下，向化合物3a(603mg,2.5mmol)的2-MeTHF(10mL)溶液中加入CDI(535mg,3.3mmol)。加热回流一小时后，反应液降到室温，依次用2M HCl(aq.)(15mL),8％NaHCO 3(aq.)(15mL)和饱和食盐水(8mL)洗涤。分离出有机相，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝10:1～2:1,V/V)得浅棕色固体产物3(230mg,35％)。MS(ESI):m/z＝270.0[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.68-7.66(m,1H),7.36-7.35(m,2H),5.42-5.37(m,1H),5.04-5.01(m,2H),4.93-4.88(m,2H)。
4.中间体4和5：
Figure PCTCN2023071503-appb-000031
a)在0℃氮气保护下，向1a(1.1g,5.1mmol)的DMF(15mL)溶液中依次加入Cs 2CO 3(1.6g,5.1mmol)in DMF(15mL)和MeI(658μL,10.2mmol)。升至室温，并搅拌过夜。冷至0℃，滴加水(15mL)。过滤，水洗，在55℃真空干燥得浅棕色固体4(826mg,71％).MS(ESI):m/z＝230.3 [M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.55-7.54(m,1H),7.29-7.28(m,2H),3.32(s,3H)。
b)在氩气保护下，将4(228mg,1.0mmol),Pin 2B 2(305mg,1.2mmol)，Pd(OAc) 2(7mg,0.03mmol)，XPhos(29mg,0.06mmol)和KOAc(294mg,3.0mmol)加入到二氧六环(5mL)中，加热至75℃，并继续搅拌1小时。冷至室温，过滤，用EA(3×5mL)洗涤固体。浓缩滤液，柱层析纯化(洗脱液PE/DCM＝0％～100％,V/V)得灰色固体产物5(232mg,84.4％).MS(ESI):m/z＝276.4[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.47(dd,J＝8.0,1.2Hz,1H),7.44(s,1H),7.33(d,J＝8.0Hz,1H),3.35(s,3H),1.30(s,12H)。
5.中间体6和7：
Figure PCTCN2023071503-appb-000032
a)在70℃下，将AIBN(524mg,3.2mmol)将入含有of 3-甲基噻吩-2-甲酸甲酯(5g,32.05mmol)和NBS(5.7g,32.02mmol)的CCl 4(80mL)悬浮液中。继续搅拌3小时，冷至40℃加入NBS(2.85g,16mmol)。然后再升温至70℃，继续搅拌1小时。冷至室温，过滤去固体，滤液旋干，所得残余物溶解在EA(100mL),依次用饱和NaHCO 3(30mL)，和水(30mL)洗涤，Na 2SO 4干燥，浓缩得油状产物6a(10g).该粗品直接用于下一步反应。MS(ESI):m/z＝155.4[M-Br] +。
b)室温下，将7N NH 3in MeOH(100mL)滴加到6a(粗品10g,约32.05mmol)的DMF(50mL)溶液中,并继续搅拌2小时。然后向反应液中加入水H 2O(200mL)和EA(3×150mL),并用固体NaHCO 3调节酸碱度到pH 8。之后再依次加入二氧六环(50mL)和Boc 2O(5g,22.9mmol).室温搅拌3小时。减压浓缩蒸去二氧六环，用EA(3×100mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE:EA＝6:1～5:1～4:1,产物Rf＝0.7在PE/EA4/1中)得油状产物6b(4g,带有一些Boc 2O).MS(ESI):m/z＝294.3[M+Na] +。
c)室温下，向6b(crude 4g,about 14mmol)的二氯甲烷溶液(60mL)中加入TFA(20mL)，并继续搅拌1小时。减压浓浓去除溶剂和TFA。所得残留物溶解在二氯甲烷(100mL)，并再次旋干。粗产物溶解在MeOH(10mL)中，再加入7N NH3/MeOH调整酸碱度到pH10。该液体用制备HPLC纯化(C18,CH 3CN,10mM NH 4HCO 3水溶液)而得浅白色固体6c(1.75g,4步产率31％).MS(ESI):m/z＝171.9[M+H] +. 1HNMR(400MHz,CDCl 3):δ7.94(d,J＝4.8Hz,1H),7.5(brs,2H),7.32(d,J＝4.8Hz,1H),4.29(s,2H),3.83(s,3H)。
d)让化合物6c(1.55g,9.06mmol)和K 2CO 3(1.25g,9.06mmol)混合在MeOH(120mL)和EtOH(120mL)中，并回流过夜。冷至室温后，旋干得粗品。柱层析纯化(洗脱液DCM:MeOH＝20:1～15:1,在DCM/MeOH 20/1溶液中Rf＝0.2)得浅棕色固体产物6d(680mg,53％).MS(ESI):m/z ＝140.1[M+H] +。
e)在0℃，将Br 2(300uL,5.85mmol)慢慢滴入6d(745mg,5.36mmol)的AcOH(10mL)/H 2O(10mL)溶液中，并继续搅拌2小时。然后，依次加入10％Na 2SO 3(20mL)和饱和NaHCO 3并调整酸碱度到pH 7。EA(3×50ml)萃取，干燥，浓缩浅白色固体6(1.09g,93％).MS(ESI):m/z＝218.2[M+H] +. 1HNMR(400MHz,CD3OD):δ7.29(s,1H),4.39(s,2H)。
f)在0℃，将NaH(60％in oil,122mg,3.05mmol)加入到6(600mg,2.75mmol)的DMF(10mL)溶液中。搅拌半小时后，滴加入MeI(205uL,3.29mmol)，然后室温搅拌2小时。反应液用水H 2O(100mL)淬灭，饱和NH 4Cl溶液中和至pH 7，EA(50mL*3)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(EA:PE＝2:1to EA,Rf＝0.5in EA)得到浅棕色固体7(400mg,62％).MS(ESI):m/z＝232.1[M+H] +。
6.中间体8和9：
Figure PCTCN2023071503-appb-000033
a)在0℃，2-氨基-4-溴苯甲酸甲酯(20g,87mmol)加入含有10％H 2SO 4(500mL)的烧瓶中，然后滴加70mL NaNO 2(12g,173.9mmol)的水溶液。搅拌40分钟后，滴加70mL KI(57.73g,347.8mmol)的水溶液，继续搅拌1小时。反应用饱和Na 2SO 3(200mL)淬灭，EA(3×500mL)萃取。Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝10:1,V/V)得油状产物8a(25g,84％).MS(ESI):m/z＝342.8[M+H] +. 1H NMR(400MHz,CDCl 3):δ8.19(d,J＝1.6Hz,1H),7.71(d,J＝8.4Hz,1H),7.57-7.54(m,1H),3.94(s,3H)。
b)在-70℃，向8a(11g,32.3mmol)和3-氧代氮杂环丁烷-1-羧酸叔丁酯(6.08g,35.5mmol) 的THF(230mL)溶液中慢慢滴加 iPrMgCl-LiCl(27.3ml,35.5mmol,1.3mol/L in THF)，并继续搅拌半小时。移去干冰浴，升至室温，并继续搅拌1小时。反应液用饱和NaHCO 3(200mL)水溶液淬灭，EA(3×500mL)萃取。Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝10:1,V/V)得黄色固体产物8b(6g,53％).MS(ESI):m/z＝298.1[M-55] +. 1H NMR(400MHz,CDCl 3):δ7.93-7.91(m,1H),7.75(d,J＝1.2Hz,2H),4.55-4.52(m,2H),4.28-4.26(m,2H),1.51(s,9H)。
c)室温下，向8b(0.8g,2.35mmol)的二氯甲烷(20mL)溶液中加TFA(2mL)。搅拌7小时后，减压浓缩的棕色油状产物8c(1g,91％)。MS(ESI):m/z＝256.0[M+H] +。
d)室温下，将8c(1g,2.82mmol)和多聚甲醛(1.69g,56.3mmol)加入MeOH(40mL)和AcOH(5mL)中，搅拌1小时后，加入NaBH(OAc) 3(600mg,2.82mmol)，并继续搅拌半小时。该步骤重复9次，然后搅拌过夜。反应液减压浓缩，向残留物中加入饱和NaHCO 3(150mL)，EA(3×200mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(eluted with PE/EA＝3:1to 1:1,V/V)得白色固体产物8(400mg,66.7％).MS(ESI):m/z＝270.0[M+H] +. 1H NMR(400MHz,CDCl 3):δ8.15-8.14(m,1H),7.70-7.69(m,2H),3.74-3.72(m,2H),3.67-3.65(m,2H),2.52(s,3H)。
e)室温下，向8b(6g,16.9mmol)的THF(100mL)溶液中加入LiBH 4(1.49g,67.8mmol)in THF(100mL)。搅拌24h后，反应液用水(200mL)淬灭，EA(3×500mL)萃取，Na 2SO 4干燥，浓缩得粗品9a。制备HPLC纯化(用NH 4HCO 3水溶液:A作为缓冲液:10mM NH 4HCO 3水溶液；B:乙腈；Column:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000034
)得白色固体产物9a(4.5g,75％).MS(ESI):m/z＝380.2[M+Na] +。
f)在0℃，向9a(2.5g,7.0mmol)和TEA(3.53g,35mmol)的THF(100mL)溶液中，分批加入对甲苯磺酸酐(2.73g,8.4mmol).搅拌30分钟后，升至室温，继续搅拌48h。减压浓缩，加水(200mL)，EA(3×200mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(eluted with PE/EA＝5:1,V/V)得白色固体产物9b(1.9g,80％).MS(ESI):m/z＝284.2[M-55] +. 1H NMR(400MHz,CDCl 3):δ7.62(d,J＝1.6Hz,1H),7.48-7.46(m,1H),7.10(d,J＝8.0Hz,1H),5.07(s,2H),4.32(d,J＝10.0Hz,2H),4.13(d,J＝10.0Hz,2H),1.50(s,9H)。
g)室温下，将TFA(3mL)滴加到9b(1g,2.95mmol)的二氯甲烷(20mL)溶液中。搅拌3h后，减压浓缩得棕色油9c(1.05g,99％)MS(ESI):m/z＝242.1[M+H] +。
h)室温下，将9c(1.05g,2.97mmol)和多聚甲醛(1.78g)加入含有MeOH(60mL)与AcOH(10mL)的烧瓶中，搅拌1h后，加入NaBH(OAc) 3(629mg,2.97mmol)，并继续搅拌30分钟。该步骤重复9次，反应液搅拌过夜。减压浓缩，加入饱和NaHCO 3(200mL)，EA(3×200mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝2:1～1:1,V/V)无色油状产物9(650mg,86％).MS(ESI):m/z＝256.0[M+H] +. 1H NMR(400MHz,CDCl 3):δ7.88(d,J＝1.6Hz,1H),7.45-7.42(m,1H),7.06(d,J＝8.0Hz,1H),5.02(s,2H),3.69-3.66(m,2H),3.43-3.40(m,2H),2.46(s,3H)。
7.中间体10：
Figure PCTCN2023071503-appb-000035
a)在70℃下，将AIBN(840mg，5.1mmol)加入到2-甲基噻吩-3-甲酸甲酯(8g，51.3mmol)/NBS(9.1g，51.1mmol)的四氯化碳(120mL)悬浮液中。将反应混合物在70℃下搅拌4h。将反应混合物冷却至室温并过滤。滤液用饱和NaHCO 3(50mL)/水(50mL)洗涤。分离有机层，用Na 2SO 4干燥，过滤并蒸发以得到呈浅棕色油状的10a粗产物(13g)。该粗产物将直接用于下一步。MS(ESI)：m/z＝155.4[M-Br]+。
b)将7N NH 3(30mL，210mmol)MeOH溶液加入到10a(粗品13g，约51.3mmol)的THF(100mL)溶液中。将反应混合物在室温搅拌1h。蒸发反应混合物，用EA/MeOH 10/1(50mL)洗涤残余的浅棕色固体并过滤，得到呈白色固体状的10b(3.5g，产率39％)。MS(ESI)：m/z＝172.0[M+H]+。 1HNMR(400MHz,CD3OD):δ7.59-7.55(m,2H),4.61(s,2H),3.94(s,3H)
c)将10b(3.3g，19.3mmol)/K 2CO 3(2.66g，19.3mmol)混合物的MeOH(120mL)溶液回流24h，然后将反应混合物冷却至室温并蒸发。残余物用硅胶色谱法分离(DCM:MeOH＝20:1，DCM/MeOH20/1中Rf＝0.5)纯化，得到10c白色固体(890mg，33％)。MS(ESI)：m/z＝140.4[M+H]+。 1HNMR(400MHz,MeOD):δ7.56(d,J＝5.2Hz,1H),7.21(d,J＝5.2Hz,1H),4.53(s,2H)。
d)在0℃下将Br 2(320uL，6.24mmol)加入到10c(0.86g，6.19mmol)的AcOH(10mL)/H 2O(10mL)溶液中。然后将反应混合物在0℃搅拌1h。向反应混合物中再加入Br 2(40uL，0.78mmol)并在0℃下再搅拌1h。向反应混合物中加入10％Na 2SO 3(20mL)至无色，然后加入饱和NaHCO 3至pH7并用EA(3×50mL)萃取。合并EA层，用Na 2SO 4干燥，过滤并蒸发。残余物用EA(10mL)/PE(5mL)洗涤，得到10白色固体(1.22g，产率90％)。MS(ESI)：m/z＝218.2[M+H]+。 1HNMR(400MHz,CD3OD):δ7.27(s,1H),4.49(s,2H)。
8.中间体11：
Figure PCTCN2023071503-appb-000036
a)将CH 3NH 2(2N，THF溶液，20mL，40mmol)加入到10a(粗品3g，约11.54mmol)的THF(20mL)溶液中。将反应混合物在室温搅拌2h。过滤反应混合物并蒸发滤液。残余物用硅胶色谱法纯化(EA:PE＝1:1～2:1～100％EA，在EA中Rf＝0.1)以得到呈棕色油状的11a(1.4g，两步的产率66％)。MS(ESI):m/z＝186.4[M+H] +。
b)将11a(1.4g,7.57mmol)/K 2CO 3(1.05g,7.6mmol)在MeOH(40mL)中的混合物回流过夜。将反应混合物冷却至室温并蒸发至干。向残余物中加入水(10mL)并用EA(3×20mL)萃取。合并所有EA层，用Na 2SO 4干燥，过滤并蒸发。残余物用硅胶色谱法(EA:PE＝1:1～2:1～100％EA，Rf＝0.5，在EA/PE 2/1中)得到11b，为白色固体(500mg，43％)。MS(ESI):m/z＝154.3[M+H] +. 1HNMR(400MHz,MeOD):δ7.55(d,J＝4.8Hz,1H),7.19(d,J＝4.8Hz,1H),4.56(s,2H),3.17(s,3H)。
c)在0℃下将Br 2(168uL，3.27mmol)加入到11b(500mg，3.27mmol)的AcOH(5mL)/H2O(5mL)溶液中。将反应混合物在0℃搅拌1h。向反应混合物中加入Br 2(35uL，0.68mmol)并在0℃下再搅拌2h。向反应混合物中加入10％Na 2SO 3(10mL)至无色，然后加入饱和溶液。NaHCO 3至pH7并用EA(3×30mL)萃取。合并EA层，用Na  2SO  4干燥，过滤并蒸发。残余物用硅胶色谱法纯化(EA:PE＝1:1～2:1，Rf＝0.4，在EA/PE 2/1中)得到11，为浅色固体(400mg，52％)。
9.中间体12和13：
Figure PCTCN2023071503-appb-000037
a)在-70℃，向化合物8a(1g,2.9mmol)和3-氧杂环丁酮(232mg,3.2mmol)的THF(25mL)溶液中，滴加iPrMgCl-LiCl(2.5ml,3.2mmol,1.3mol/L in THF).搅拌半小时后，升至室温，加入饱和NaHCO 3(40mL)，EA(3×100mL)萃取，Na 2SO 4干燥，浓缩得粗品。制备HPLC纯化(用TFA为缓冲液:A:0.05％TFA水溶液；B:乙腈；Column:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000038
))得白色固体产物12(300mg,40％).MS(ESI):m/z＝257.0[M+H] +. 1H NMR(400MHz,CDCl 3):δ8.12(s,1H),7.77-7.73(m,2H),5.24(d,J＝8.0Hz,2H),4.91(d,J＝7.6Hz,1H).
b)室温下，向化合物12的THF(70mL)溶液中加入LiBH 4(621mg,28.2mmol)。搅拌24h后，加入水(200mL)，EA(3×300mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝ 2:1,V/V)得白色固体产物13a(1.6g,89％).MS(ESI):m/z＝281.0[M+Na] +.
c)在0℃，向13a(1g,3.9mmol)和TEA(19.5g,19.3mmol)的THF(50mL)溶液中分批加入对甲苯磺酸酐(1.51g,4.6mmol).搅拌半小时后，升至室温，继续搅拌48h。减压浓缩，加入水(100mL)，EA(3×300mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝10:1,V/V)得白色固体产物13(440mg,47％)MS(ESI):m/z＝243.1[M+H] +. 1H NMR(400MHz,DMSO-d 6):δ7.88(d,J＝1.6Hz,1H),7.56-7.54(m,1H),7.28(d,J＝8.0Hz,1H),5.00(s,2H),4.83-4.77(m,4H)。
10.中间体D54-m：
Figure PCTCN2023071503-appb-000039
1)二苄基-D-丝氨酸甲酯(D54-b)的制备：
Figure PCTCN2023071503-appb-000040
室温下，向DMF(250mL)中，依次加入无水K 2CO 3(31.0g,224.1mmol)，D-serine methyl ester hydrochloride(D54-a,23.25g,149.4mmol),KI(12.4g,74.7mol)，和benzyl bromide(44.4mL,373.6mol)。室温搅拌过夜，然后将反应液倒入水(l L)中。乙酸乙酯(500mL x 3)萃取，依次用水(300mL)饱和食盐水(300mL)洗，无水Na 2SO 4干燥，浓缩，柱层析纯化PE/EA(9/1to 8/2)得无色油状液体产物(D54-b，42.3g,88％).MS(ESI):m/z＝300.2[M+H] +.
2)(S)-3-(二苄氨基)-2-氟丙酸甲酯(D54-c)的制备:
Figure PCTCN2023071503-appb-000041
室温下,向diethylamine sulphur trifluoride(18.23mL,138mmol)的THF(500mL)溶液中,在3小时内加入54-b(41.3g,138mmol)。室温搅拌1小时后，加入乙酸乙酯(500mL)，并用饱和NaHCO 3溶液中和至pH 7。无水Na 2SO 4干燥，浓缩，柱层析纯化PE/EA(9/1to 8/2)得无色油状液体产物(D54-c,38.1g,92％)。
3)(S)-3-(二苄氨基)-2-氟丙醇(D54-d)的制备:
Figure PCTCN2023071503-appb-000042
在0℃，向54-c(37.8g,125mmol)的THF(500mL)溶液中，滴加LAH(60mL,2.5M in THF,150mmol).反应1小时后，小心加入水5.7mL。反应30分钟后，加入5.7mL 15％NaOH.搅拌10分钟后，加入水17mL。加入无水Na 2SO 4,滤去固体，浓缩得无色油状液体产物(D54-d,34.2g,99％).MS(ESI):m/z＝274.1[M+H] +.
4)(S)-苄基(2-氟-3-羟丙基)氨基甲酸叔丁酯(D54-e)的制备:
Figure PCTCN2023071503-appb-000043
室温下,将54-d(33.9g,124mmol)和10％Pd/C(2.4g)在乙醇(500mL)中的混合物放置在1大气压的氢气中。反应过夜，滤去固体，浓缩得无色油状液体产物.柱层析纯化得(D54-e,33.6g,95％).MS(ESI):m/z＝306.2[M+Na] +.
5)(S)-3-(苄基氨基)-2-氟-1-丙醇(D54-f)的制备:
Figure PCTCN2023071503-appb-000044
室温下,向D54-e(10g,35.3mmol)的DCM(120mL)中，加入(20mL)。反应3小时后，浓缩，再用DCM溶解，加入30g K 2CO 3.搅拌20分钟后，滤去固体，浓缩，反相柱纯化得(C18,using 10nm NH 4HCO 3buffer)(D54-f,6.5g,91％).MS(ESI):m/z＝184.1[M+H] +.
6)(S)-3-(苄基((S)-3-(苄氧基)-2-羟丙基)氨基)-2-氟-1-丙醇(D54-h)的制备:
Figure PCTCN2023071503-appb-000045
室温下,将54-f(6.3g,34.4mmol)和(S)-2-((benzyloxy)methyl)oxirane(D54-g,6.77g,41.3mmol)混合于iPrOH(500mL)中。在55℃搅拌过夜.冷至室温，浓缩，柱层析纯化得无色油状产物(D54-h,4.5g,38％).MS(ESI):m/z＝348.2[M+H] +.
7)(S)-3-(苄基((S)-3-(苄氧基)-2-羟丙基)氨基)-2-氟丙基甲磺酸酯(D54-i)的制备:
Figure PCTCN2023071503-appb-000046
在–10℃，将MsCl(346mg,3.02mmol)在DCM(3mL)的溶液滴加到54-h(1.0g,2.88mmol)和DIPEA(447mg,3.46mmol)的DCM(12mL)溶液中。反应在-2℃进行1小时，加入水(5mL)，用DCM(10mL x 3)萃取。无水Na 2SO 4干燥，浓缩，得无色油状液体产物(D54-i，1.2g).MS(ESI):m/z＝348.2[M+H] +.
8)(2S，6S)-4-苄基-2-((苄氧基)甲基)-6-氟-1,4-氧杂氮杂环庚烷(D54-j)的制备:
Figure PCTCN2023071503-appb-000047
在0℃，将NaH(60％in oil,276mg,6.91mmol)分批加入到D54-h(1.2g,2.88mmol)的THF(15mL)溶液中。升至室温，搅拌过夜。加入饱和NaHCO3(5mL)溶液，浓缩去除THF。残留物用乙酸乙酯萃取(50mL x 3),依次用水(50mL)和饱和食盐水(50mL)洗，无水Na 2SO 4干燥，浓缩，柱层析纯化得无色油状液体产物(54-j,350mg,37％).MS(ESI):m/z＝330.2[M+H] +.
9)((2S，6S)-6-氟-1,4-氧杂氮杂环庚基-2-基)甲醇(D54-k)的制备:
Figure PCTCN2023071503-appb-000048
室温下,将D54-i(680mg,2.06mmol),10％Pd/C(100mg)和4M HCl in dioxane(1.03mL,4.12mmol)在ethanol(20mL)中的化合物放置在氢化装置中。氢化4小时后，滤去固体，滤液浓缩得无色油状液体产物(54-k，0.4g).MS(ESI):m/z＝150.1[M+H] +.
10)(2S，6S)-6-氟-2-(羟甲基)-1,4-氧杂氮杂环庚基-4-羧酸叔丁酯(D54-l)的制备:
Figure PCTCN2023071503-appb-000049
室温下,向D54-k(382mg,2.0mmol)DCM(20mL)溶液中，依次加入(Boc) 2O(919μL,4.0mmol)和TEA(1.4mL,10.0mmol)。搅拌4小时后，加入水(50mL)，用DCM(3×20mL)萃取，饱和食盐水(20mL)洗,无水Na 2SO 4干燥，浓缩得无色油状液体产物(D54-l，0.50g,100％).MS(ESI):m/z＝194.1[M-tBu+H] +.
11)Step 11:Step 11:(2S，6S)-4-(叔丁氧羰基)-6-氟-1,4-氧杂氮杂环庚基-2-甲酸 (D54-m)的制备:
Figure PCTCN2023071503-appb-000050
室温下,向D54-l(475mg,1.9mmol)的DCM(13mL)溶液中，依次加入水(3mL)TEMPO(5.9mg,0.038mmol)和Bu 4NHSO 4(45mg,0.133mmol).用饱和NaHCO 3调节6.8mL of NaClO溶液(10-15％)的酸碱度到pH of 8-9.将NaBr(60mg,5.8mmol)的水溶液(1.2mL)加入到配制的缓冲溶液中。取出10mL缓冲溶液,在0℃下，滴加到反应体系中。室温搅拌3小时，用KHSO 4(2N)溶液调节酸碱度到pH2-3.DCM(3×20mL)萃取，无水Na 2SO 4干燥，浓缩，反相柱层析纯化得白色固体产物(D54-m,385mg,3步总产率68％).MS(ESI):m/z＝208.3[M-tBu+H] +.
■中间体(2S，6R)-4-(叔丁氧羰基)-6-氟-1,4-氧杂氮杂环庚基-2-甲酸用类似的方法合成而得：
Figure PCTCN2023071503-appb-000051
11.中间体D62-f:
Figure PCTCN2023071503-appb-000052
1)1-甲基-1H-咪唑-4-胺基盐酸盐(D62-b)的制备：
Figure PCTCN2023071503-appb-000053
室温下，向D62-a(530mg,4.17mmol)的EtOH(20mL)溶液中，加入Pd(OH) 2/C(65mg).该反应液放置在氢气下过夜，滤去固体，向滤液中加入HCl(4M in dioxane,2mL)，浓缩得黄色固体产物(D62-b,575mg.).MS(ESI):m/z＝98.2[M+H] +.
2)N-(5-氯-2-甲氧基苯基)-1-甲基-1H-咪唑-4-胺(D62-d)的制备
Figure PCTCN2023071503-appb-000054
室温下氩气下,将4-chloro-2-iodo-1-methoxybenzene(D62-c,1.07g,3.99mmol),D62-b(280mg,2.1mmol),Pd 2(dba) 3(261mg,0.285mmol),XPhos(272mg,0.571mmol)和NaOtBu(549mg,5.7mmol)加入到Dioxane(15ml)中。反应液在110℃搅拌4小时，冷至室温，浓缩，直接柱层析纯化得棕色固体产物(D62-d，235mg,47％)。MS(ESI):m/z＝238.2[M+H] +.
3)4-氯-2-((1-甲基-1H-咪唑-4-基)氨基)苯酚(D62-e)的制备：
Figure PCTCN2023071503-appb-000055
在0℃,向D62-d(130mg,0.55mmol)得DCM(4mL)溶液中，加入BBr 3(2mL,17％Wt in DCM)，然后室温反应过夜。加入饱和NaHCO 3aq.(20mL)，DCM(3x10mL)萃取，无水Na 2SO 4干燥，浓缩，反相柱层析纯化得产物(D62-e,165mg).MS(ESI):m/z＝224.1[M+H] +.
4)5-氯-3-(1-甲基-1H-咪唑-4-基)苯并[d]噁唑-2(3H)-酮(D62-f)的制备:
Figure PCTCN2023071503-appb-000056
在0℃,向D62-e(165mg crude,0.55mmol)的DCM(3mL)溶液中，依次加入Et 3N(206μL,1.48mmol)和triphosgene(109mg,0.37mmol)。室温搅拌过夜，加入饱和NH 4Cl aq.(20mL)，DCM(20mL x 3)萃取。无水Na 2SO 4干燥，浓缩，反相柱层析(C18,TFA buffer)纯化棕色固体得产物(D62-f,21mg,2步总产率15％).MS(ESI):m/z＝250.3[M+H] +.
12.中间体D63-e:
Figure PCTCN2023071503-appb-000057
1)N-(5-氯-2-甲氧基苯基)-1-甲基-1H-吡唑-4-胺(D63-c)的制备:
Figure PCTCN2023071503-appb-000058
将D63-a(473mg,3.0mmol),D63-b(483mg,3.0mmol),XPhos Pd G3(51.0mg,0.06mmol)和NaOtBu(576mg,6.0mmol)在Dioxane(10ml)中的混合物在氩气下110℃搅拌7小时。冷至室温，浓缩，柱层析纯化得棕色固体产物(D63-c,546mg,77％).MS(ESI):m/z＝238.1[M+H] +.
2)4-氯-2-((1-甲基-1H-吡唑-4-基)氨基)苯酚(D63-d)的制备:
Figure PCTCN2023071503-appb-000059
在0℃，向D63-c(546mg,2.3mmol)的DCM(20mL)溶液中，滴加入BBr 3(5mL,17％Wt in DCM)。室温搅拌过夜，加入饱和NaHCO 3(20mL).DCM(20mL x 3)萃取。无水Na 2SO 4干燥，浓缩得产物(D63-d，450mg crude).MS(ESI):m/z＝224.0[M+H] +.
3)5-氯-3-(1-甲基-1H-吡唑-4-基)苯并[d]噁唑-2(3H)-酮(D63-e)的制备
Figure PCTCN2023071503-appb-000060
在0℃,向D63-d(450mg crude,2.0mmol)的DCM(5mL)溶液中，依次加入Et 3N(840uL,6mmol)和triphosgene(297mg,1.0mmol)。室温搅拌过夜，加入饱和NH 4Cl(20mL)水溶液。DCM(20mL x 3)萃取。无水Na 2SO 4干燥，浓缩，柱层析纯化得黄色固体(D63-e，194mg,)。MS(ESI):m/z＝250.1[M+H] +.
13.中间体D64-e:
Figure PCTCN2023071503-appb-000061
1)N-(5-氯-2-甲氧基苯基)-1-甲基-1H-1,2,4-三唑-3-胺(D64-c)的制备：
Figure PCTCN2023071503-appb-000062
将D64-a(486mg,3.1mmol,1eq.),D64-b(500mg,3.1mmol,1eq.),Pd 2(dba) 3(283mg,0.3mmol,0.1eq.),XPhos(294mg,0.6mmol,0.2eq.)和NaOtBu(593mg,6.2mmol,2eq.)在Dioxane(20mL)中的混合物，在110℃氩气下搅拌4小时。冷至室温，浓缩，柱层析纯化得棕色固体产物(D64-c,340mg,46％yield).MS(ESI):m/z＝239.2[M+H] +.
2)4-氯-2-((1-甲基-1H-1,2,4-三唑-3-基)氨基)苯酚(D64-d)的制备:
Figure PCTCN2023071503-appb-000063
在0℃,向D64-c(340mg,1.42mmol,1eq.)的DCM(5mL)溶液中，滴加BBr 3(2.5mL,17％Wt in DCM)。室温搅拌过夜，加入饱和NaHCO 3(20mL).DCM(20mL x 3)萃取。无水Na 2SO 4干燥，浓缩得产物(D64-d，340mg crude)。MS(ESI):m/z＝225.1[M+H] +.
3)5-氯-3-(1-甲基-1H-1,2,4-三唑-3-基)苯并[d]噁唑-2(3H)-酮(D64-e)的制备,
Figure PCTCN2023071503-appb-000064
在0℃,向D64-d(340mg crude,1.4mmol,1.0eq.)的DCM(20mL)溶液中，依次加入Et 3N(418μL,3.0mmol,2.0eq.)和triphosgene(222mg,0.75mmol,0.5eq.)。室温搅拌过夜，加入饱和NH 4Cl(20mL)。DCM(20mL x 3)萃取。无水Na 2SO 4干燥，浓缩，柱层析纯化得黄色固体产物(D64-e，234mg,42％).
14.中间体D68-b:
Figure PCTCN2023071503-appb-000065
5-溴-3-(3-氧代环丁基)苯并[d]噁唑-2(3H)-酮(D68-b)的制备：
Figure PCTCN2023071503-appb-000066
室温下，将NaH(376mg,9.4mmol,60％in oil)加入到1-a(1.0g,4.7mmol)的DMF(15mL)溶液中。搅拌30分钟后，加入D68-a(1.4g,9.4mmol)。搅拌3小时后，冷至0℃，加入水(20mL,1/1,v/v)。DCM(20mL x 3)萃取。无水Na 2SO 4干燥，浓缩，相柱层析纯化得黄色固体产物(D68-b，550mg,42％).MS(ESI):m/z＝284.0[M+H] +.
15.中间体D73-b:
Figure PCTCN2023071503-appb-000067
5-溴-3-甲基异苯并呋喃-1(3H)-酮(D73-b)的制备：
Figure PCTCN2023071503-appb-000068
在-78℃,向D73-a(1.5g,7mmol)的THF(40mL)溶液中，在15分钟内，滴加入LDA(8.8mL,17.6mmol,2mol/L)。搅拌15分钟后，加入MeI(10g,70.4mmol)。反应液升至0℃，并继续搅拌6小时。加入水(100mL)，乙酸乙酯萃取(250mL x 3)，用Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D73-b，528mg)。MS(ESI):m/z＝227.1[M+H] +. 1H NMR(400MHz,CDCl 3):δ7.77(s,1H),7.70-7.67(m,1H),7.63(d,J＝0.8Hz,1H),5.58-5.53(m,1H),1.65(d,J＝6.4Hz,3H).
16.中间体D75-c:
Figure PCTCN2023071503-appb-000069
1)(R)-1-(2-溴-5-氯苯基)乙醇(D75-b)的制备：
Figure PCTCN2023071503-appb-000070
室温下，将Trimethylborate(161mg,1.5mmol)加入到
(S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol(297mg,1.3mmol)的tetrahydrofuran(35mL)溶液中。搅拌1.25小时后,borane-methyl sulfide complex(7.1mL of a 2M solution in tetrahydrofuran,14.2mmol)慢慢滴加入。将反应液冷室至0℃，在1小时内滴加入D122-a(3g,12.8mmol)的tetrahydrofuran(15mL)溶液。升至室温，并搅拌过夜。浓缩去除大部分THF,倒入1N HCl溶液中。乙酸乙酯(200ml x 3)萃取，饱和食盐数水(200ml)洗,Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D122-b,2.9g,97％).MS(ESI):m/z＝217.1[M-17] +.
2)(R)-5-氯-3-甲基异苯并呋喃-1(3H)-酮(D75-c)的制备：
Figure PCTCN2023071503-appb-000071
室温下,向D122-b(200mg,0.85mmol)的DMF(10mL)溶液中，依次加入Pd(dppf)Cl 2(62mg,0.09mmol)，和TEA(171mg,1.7mmol).反应体系，充氮3次后，充入一氧化碳。在130℃下，搅拌16小时。冷至室温，浓缩，柱层析纯化得白色固体产物(D122-c，80mg,52％).MS(ESI):m/z＝183.1[M+H] +.
■中间体中间体(S)-5-氯-3-甲基异苯并呋喃-1(3H)-酮用类似的方法合成而得：
Figure PCTCN2023071503-appb-000072
17.中间体D76-b:
Figure PCTCN2023071503-appb-000073
5-溴-3-((二甲基氨基)甲基)异苯并呋喃-1(3H)-酮(D76-b)的制备：
Figure PCTCN2023071503-appb-000074
在-78℃,向D73-a(1.035g,4.86mmol)的THF(20mL)溶液中，滴加入LiHMDS(4.8mL,4.8mmol,1M in THF/hexane).搅拌1小时后，一次加入D76-b(900mg,4.86mmol).在-78℃，继续搅拌2小时。加入饱和NH 4Cl aq.(100mL)，用DCM/MeOH(9:1)(3*20mL)萃取。Na 2SO 4干燥，浓缩，反相柱层析纯化得白色固体产物(D76-b,0.6g，47％)。MS(ESI):m/z＝272.1[M+H] +.
18.中间体D77-a:
Figure PCTCN2023071503-appb-000075
5-溴-3-(甲氧甲基)异苯并呋喃-1(3H)-酮(D77-a)的制备：
Figure PCTCN2023071503-appb-000076
在-78℃,向D73-a(1.0g,4.69mmol)的THF(20mL)溶液中，滴加入LiHMDS(5.6mL,5.63mmol,1M in THF/hexane).搅拌15分钟后，滴加入bromo(methoxy)methane(417.88μL,5.15mmol).在-78℃，继续搅拌1小时，加入饱和NH 4Cl aq.(100mL)，用DCM/MeOH(9:1)(3x20mL)萃取。Na 2SO 4干燥，浓缩，反柱层析纯化得白色固体产物(D77-a，0.6g,50％)。MS(ESI):m/z＝257.0[M+H] +.
19.中间体D81-c:
Figure PCTCN2023071503-appb-000077
1)2-(5-溴-2-氧代苯并[d]噁唑-3(2H)-基)乙酸乙酯(D81-a)的制备:
Figure PCTCN2023071503-appb-000078
在0℃下，向1-a(5g,23.48mmol)在DMF(40mL)的溶液中，加入NaH(1.03g,25.83mmol).搅拌30分钟后，滴加入BrCH2CO2Et(3.9g,23.48mmol)。室温搅拌3小时，加入水，乙酸乙酯萃取，Na 2SO 4干燥，浓缩，反柱层析纯化得黄色固体产物(D81-a，4.8g,68.47％)。
2)1-(5-溴-2-羟基苯基)咪唑啉-2,4-二酮(D81-b)的制备:
Figure PCTCN2023071503-appb-000079
室温下，向D81-a(4.8g,16.05mmol)的EtOH(30mL)溶液中，加入NH4OH(300ml)。室温搅拌24小时，减压除去乙醇，加入冰水，过滤得黄色固体产物(D81-b，2.4g,55.42％).
3)6-溴苯并[d]咪唑[2,1-b]噁唑-2(3H)-酮(D81-c)的制备:
Figure PCTCN2023071503-appb-000080
在0℃，向D81-b(2.4g,8.89mmol)的甲苯e(25mL)溶液中，加入POCl3(25ml).在110℃，搅拌1小时，冷至室温，加入冰水，乙酸乙酯萃取，Na 2SO 4干燥，浓缩，反相柱层析纯化得黄色固体产物(D81-c，1.4g,5.56mmol,62.5％). 1H NMR(400MHz,DMSO-d 6)δ7.75(s,1H),7.44–7.31(m,2H),5.13(s,2H).
20.中间体D84-n:
Figure PCTCN2023071503-appb-000081
1)2-羟基-3-甲氧基苯甲醛(D84-b)的制备：
Figure PCTCN2023071503-appb-000082
室温下，向D84-b(10g,65.77mmol)的DCM(100mL)溶液中，依次加入Ac2O(10.07g,98.65mmol)，TEA(6.92g,68.40mmol)和DMAP(0.8g,6.58mmol)。搅拌30分钟后，加入水，并用二氯甲烷萃取，依次用稀盐酸HCl(4.0M)和饱和食盐水洗，Na 2SO 4干燥，浓缩得白色固体产物(D84-b，12g,94％)。1H NMR(400MHz,DMSO-d 6)δ10.10(s,1H),7.51–7.42(m,3H),3.84(s,3H),2.34(s,3H).
2)6-甲酰基-2-甲氧基-3-硝基苯基乙酸酯(D84-c)的制备：
Figure PCTCN2023071503-appb-000083
在-40℃，向D84-b(10g,51.50mmol),KNO3(5.31g,52.53mmol)在DCM(40mL)中的混合物，滴加入TFAA:TFA(3:1,37.5mL)。让反应液慢慢升至室温，并搅拌过夜。加入冰水，二氯甲烷萃取。Na 2SO 4干燥，浓缩，柱层析纯化得红色固体产物(D84-c，10.3g,83.6％)。
3)2-羟基-3-甲氧基-4-硝基苯甲酸(D84-d)的制备：
Figure PCTCN2023071503-appb-000084
室温下,向D84-c(10g,41.81mmol)的MeOH(150mL)溶液中，依次加入NaOH(6.8g,171.42mmol)和水(800mL).搅拌5分钟后，加入AgNO3(8.5g,50.17mmol)，并在85℃搅拌过夜。滤去固体，滤液，pH调节到2.乙酸乙酯萃取，饱和食盐水洗，Na 2SO 4干燥，浓缩得黄色固体产物(D84-d，7g,78.5％)(RT＝0.483min,m/z＝211.9)。LCMS:211.9[M-H] +；
4)2,3-二羟基-4-硝基苯甲酸(D84-e)的制备:
Figure PCTCN2023071503-appb-000085
室温下,向D84-d(13.45g,63.10mmol)的HOAc(158mL)溶液中，加入47％aq.HBr(79mL)。反应回流16小时，冷至室温。乙酸乙酯萃取，水洗，Na 2SO 4干燥，浓缩得黄色固体产物(D84-e，9g,71.6％).
5)4-氨基-2,3-二羟基苯甲酸(D84-f)的制备:
Figure PCTCN2023071503-appb-000086
室温下,将D84-d(7.2g,36.16mmol)溶于MeOH(120mL)，加入10％Pd/C(0.6g)，然后放置于40Psi的氢气中。氢气压力不继续下降时，滤去固体，滤液浓缩得黄色固体产物(D84-f，3.6g,58.9％)。LCMS:170.2[M+H] +。
6)4-溴-2,3-二羟基苯甲酸(D84-g)的制备:
Figure PCTCN2023071503-appb-000087
在0℃下，向D84-f(3.9g,23.06mmol)在H2O(8mL)中的悬浮液中，加入48％aq.HBr(6mL)，然后加入NaNO2(1.2g,17.29mmol)的水(8mL)溶液。零度搅拌2小时后，加入CuBr(2.5g,17.29mmol)在HBr(6mL)的溶液。零度搅拌1小时后，室温搅拌过夜。乙酸乙酯萃取，水洗，Na 2SO 4干燥，浓缩得黑色固体产物(D84-g，2.5g,46.5％)。LCMS:231.0[M-H] +；
7)4-溴-2,3-二羟基苯甲酸乙酯(D84-h)的制备:
Figure PCTCN2023071503-appb-000088
室温下,向(D84-g，1.2g,5.15mmol)的EtOH(38mL)溶液中，加入浓H2SO4(2mL)，然后搅拌回流过夜。冷至室温，减压去除EtOH.加入乙酸乙酯，依次用饱和NaHCO3和食盐水洗。Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D84-h，0.537g,39.9％)。LCMS:261.0[M+H] +；
8)7-溴苯并[d][1,3]二氧杂环戊基-4-羧酸乙酯(D84-i)的制备:
Figure PCTCN2023071503-appb-000089
室温下,向D84-h(1.0g,3.83mmol)的DMF(8mL)溶液中，加入Cs 2CO 3(2.7g,8.43mmol)，搅拌1小时后，加入CH 2I 2(1.7g,6.21mmol)，并在75℃反应12小时。冷至室温，加入乙酸乙酯和水。Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D84-i，598mg,57.2％)。LCMS:275.0[M+H] +；
9)乙基(7-溴苯并[d][1,3]-二氧杂环戊基-4-基)甲醇(D84-j)的制备:
Figure PCTCN2023071503-appb-000090
在-78℃，向D84-i(4.9g,17.94mmol)的THF(80mL)溶液中，滴加入LiAlH4(35.89mL,35.89mmoL)at-78℃.让反应液升至室温，并继续搅拌2小时。加入水，乙酸乙酯萃取，Na 2SO 4干燥，浓缩得产物(D84-j，3.8g，92％)。GCMS:230.0[M] +；
10)4-溴-7-(溴甲基)苯并[d][1,3]二氧呃(D84-k)的制备:
Figure PCTCN2023071503-appb-000091
在0℃，向D84-j(3800mg,16.45mmol)的THF(40mL)溶液中，加入PBr3(4897.14mg,18.09mmoL)的THF(20mL)溶液。零度搅拌2小时，加入饱和NH4Cl，乙酸乙酯萃取(300mL×4)，Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D84-k，2.6g,54％)。GCMS:294[M] +；
11)(5R)-2-((7-溴苯并[d][1,3]二氧杂环戊基-4-基)甲基)-5-异丙基-3,6-二甲氧基-2,5-二氢吡嗪(D84-m)的制备:
Figure PCTCN2023071503-appb-000092
在-78℃,向D84-l(2895.79mg,15.72mmol)的tetrahydrofuran(dry,60mL)溶液中，滴加n-butyllithium(2.5Min hexanes,6.29mL,15.72mmol)。搅拌30分钟后，滴加入D84-j(4200mg,14.29mmol)的THF(dry,20mL)溶液，继续搅拌1小时后，加入饱和NH4Cl溶液，乙酸乙酯萃取，Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D84-m，1800mg,32％)。LCMS:[M+H] +:397.1
12)(S)-2-氨基-3-(7-溴苯并[d][1,3]二氧杂戊基-4-基)丙酸甲酯(D84-n)的制备:
Figure PCTCN2023071503-appb-000093
室温下，向D84-m(1800mg,4.53mmol)的acetonitrile(60mL)溶液中，加入aq.0.2M HCl(47.57mL,9.51mmol)。搅拌12小时后，用饱和NaHC03溶液调节pH至8，乙酸乙酯萃取，Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D84-n 1300.0mg,95％)。1H NMR(400MHz,CDCl3)δ6.87(d,J＝8.4Hz,1H),6.54(d,J＝8.4Hz,1H),6.01–5.94(m,2H),3.74(dd,J＝7.5,5.6Hz,1H),3.68(s,3H),2.99(dd,J＝13.8,5.3Hz,1H),2.77(dd,J＝13.8,8.0Hz,1H).
21.中间体D98-k:
Figure PCTCN2023071503-appb-000094
1)(3-(溴甲基)氧杂环丁烷-3-基)甲氧基)(叔丁基)二苯基硅烷(D98-b)的制备：
Figure PCTCN2023071503-appb-000095
室温下，向D98-b(25g,138.1mmol)的DCM(600mL)溶液中，依次加入TBDPSCl(45.6g,165.7mmol)和imidazole(37.6g,552.5mmol)。室温搅拌16小时，浓缩除去二氯甲烷。加入EtOAc(1000mL),依次用水water(250mLx3)和食盐水(250mL)洗，Na 2SO 4干燥，浓缩，柱层析纯化得无色油状产物(D98-b，60.1g,96％)。MS(ESI):m/z＝441.1[M+Na] +.
2)N-苄基-1-(3-(((叔丁基二苯基硅基)氧基)甲基)氧杂环丁烷-3-基)甲酰胺(D98-c)的制备
Figure PCTCN2023071503-appb-000096
氮气下，将D98-b(70g,143.2mmol),BnNH 2(38.3g,358mmol),K 2CO 3(39.8g,286.4mmol)和KI(23.8g,143.2mmol)在DMF(600mL)的混合物，在70℃搅拌24小时.冷至室温，加入EtOAc(1500mL)，用饱和食盐水(350mLx4)洗，Na 2SO 4干燥，浓缩，柱层析纯化得无色油状产物(D98-c，41.5g,65％).MS(ESI):m/z＝446.3[M+H] +.
3)(S)-1-(苄基((3-(((叔丁基二苯基硅基)氧基)甲基)氧杂环丁烷-3-基)甲基)氨基)-3-(苄基氧基)丙-2-醇(D98-e)的制备：
Figure PCTCN2023071503-appb-000097
氮气下，将D98-c(40g,89.9mmol)and D98-D(29.5g,179.8mmol)在 iPrOH(200mL)中的混合物，在75℃搅拌72小时。冷至室温，浓缩，柱层析纯化得无色油状产物(D98-e,58.4g,95％).MS(ESI):m/z＝610.2[M+H] +.
4)(S)-1-(苄基((3-(羟甲基)氧杂环丁烷-3-基)甲基)氨基)-3-(苄氧基)丙-2-醇 (D98-f)的制备:
Figure PCTCN2023071503-appb-000098
氮气下,将D98-e(58.4g,95.9mmol),KF(55.6g,959mmol)和TBAF(4mL,1mol/l)在THF(1000mL)中的化合物，室温搅拌48小时。浓缩，加入水(300mL)。乙酸乙酯(500mLx3)萃取，Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D98-f，18g,50.6％).MS(ESI):m/z＝372.3[M+H] +.
5)(S)-(3-((苄基(3-(苄氧基)-2-羟丙基)氨基)甲基)氧杂环丁烷-3-基)甲磺酸甲酯(D98-g)的制备:
Figure PCTCN2023071503-appb-000099
在-8℃，在10分钟内向D98-f(15.3g,41.2mmol)的DCM(250mL)溶液中，依次滴加入DIPEA(6.92g,53.6mmol)和MsCl(4.96g,43.3mmol)的DCM(50mL)溶液。在-8℃，继续搅拌2小时，加入冰水(150mL)，DCM(200mLx3)萃取,Na 2SO 4干燥，过滤，浓缩得无色油状粗产物(D98-g，18.5g,99％).MS(ESI):m/z＝450.1[M+H] +.
6)(S)-9-苄基-7-((苄氧基)甲基)-2,6-二氧杂-9-氮杂螺环[3.6]癸烷(D98-h)的制备:
Figure PCTCN2023071503-appb-000100
在-0℃,向NaH(8.24g,206mmol,purity:60％)在THF(200mL)的悬浮液中，滴加入D98-g(18.5g,41.2mmol)的THF(100mL)溶液。然后，在50℃搅拌16小时.冷至0℃,加入饱和NaHCO 3(500ml)溶液，乙酸乙酯(500mLx3)萃取，Na 2SO 4干燥，浓缩，柱层析纯化得无色油体产物(D98-h，12.5g,86％).MS(ESI):m/z＝354.2[M+H] +.
7)(S)-(2,6-二氧杂-9-氮螺环[3.6]癸烷-7-基)甲醇TFA盐(D98-i)的制备:
Figure PCTCN2023071503-appb-000101
室温下，将D98-h(5g,14.2mmol),Pd/C(2g,10％on C),TFA(1.61g,14.2mmol)和AcOH(10mL)在 iPrOH(200mL)中的混合物，放置在氢化装置中。室温搅拌吸氢16小时后，滤去固体，滤液浓缩得棕色油状粗产物(D98-i，4.5g,95％)。MS(ESI):m/z＝174.2[M+H] +.
8)(S)-7-(羟甲基)-2,6-二氧杂-9-氮杂螺环[3.6]癸烷-9-羧酸叔丁酯(D98-j)的制备：
Figure PCTCN2023071503-appb-000102
室温下，将D98-i(Crude 4.5g,14.2mmol),(Boc) 2O(6.18g,28.3mmol)和饱和NaHCO 3(150ml)在dioxane(150mL))中的混合物，搅拌4小时。乙酸乙酯(3×200mL)萃取，Na 2SO 4干燥，浓缩，柱层析纯化得棕色油体产物(D98-j，3.5g,90％)。MS(ESI):m/z＝274.2[M+H] +.
9)(S)-9-(叔丁氧羰基)-2,6-二氧杂-9-氮杂螺[3.6]癸烷-7-甲酸(D98-k)的制备：
Figure PCTCN2023071503-appb-000103
室温下，向DCM(20mL)和water(9mL)中，依次加入D98-j(1g,3.7mmol),TEMPO(11mg,0.07mmol)，和Bu 4NHSO 4(87mg,0.3mmol).同时，用饱和NaHCO 3(liquid+solids)(approx 15mL)去调节7.4mL of NaClO solution,10-15％的酸碱度到to pH8-9，再将NaBr(64mg,0.6mmol)的水溶液(1mL)加入到该缓充溶液中。在0℃，将新制的缓冲溶液滴加到反应液中。室温搅拌3小时后，加入KHSO 4(2N)溶液,调节pH到2-3。用DCM(100mLx3)萃取，Na 2SO 4干燥，浓缩得白色固体产物(D98-k，850mg,81％).MS(ESI):m/z＝310.2[M+Na] +.
22.中间体D100-f:
Figure PCTCN2023071503-appb-000104
1)4-((5-溴-2-羟基苯基)氨基)-3,3-二氟哌啶-1-羧酸叔丁酯(D100-c)的制备；
Figure PCTCN2023071503-appb-000105
在0℃，向D100-b(1.0g,4.0mmol,4eq.)和D100-a(376mg,2.0mmol,1eq.)的DMF(10mL)溶液中，加入TMSCl(1.0mL,8.0mmol,4.0eq.).零度搅拌2小时后，滴加入BH 3·THF(1M,10mL,5eq.).室温搅拌3小时后，加入饱和Na 2CO 3(200mL)和水(10mL)。乙酸乙酯(100mL x 2)萃取，水洗，Na 2SO 4干燥，浓缩，柱层析纯化得橙色油体产物(D100-c，730mg,90％)。MS(ESI):m/z＝353.0[M-tBu+H] +.
2)4-(5-溴-2-氧代苯并[d]噁唑-3(2H)-基)-3,3-二氟哌啶-1-羧酸叔丁酯(D100-d)的制备
Figure PCTCN2023071503-appb-000106
氩气下，将D100-c(690mg,1.69mmol),CDI(330mg,2.03mmol)在dioxane(20mL)中的混合物，在110℃下搅拌6小时.冷至室温，浓缩，柱层析纯化得黄色固体产物(D100-d，586mg,76％yield)。MS(ESI):m/z＝455.0[M+Na] +.
3)5-溴-3-(3,3-二氟哌啶-4-基)苯并[d]噁唑-2(3H)-酮(D100-e)的制备:
Figure PCTCN2023071503-appb-000107
氩气下,将D100-d(566mg,1.3mmol)在TFA/DCM(1:6,7mL)中的混合物，室温搅拌2小时，浓缩得产物并直接用于下一步反应。MS(ESI):m/z＝334.9[M+H] +.
4)5-溴-3-(3,3-二氟-1-甲基哌啶-4-基)苯并[d]噁唑-2(3H)-酮(D100-f)的制备:
Figure PCTCN2023071503-appb-000108
室温下，向D100-e(490mg crude,TFA salt,1.1mmol)在MeOH/HCHO aq.(10mL,1:1)中的混合物加入250μL HCOOH.反应液，在65℃下搅拌24小时。冷至室温，浓缩，冻干得黄色固体产物(D100-f,390mg,99％yield)。MS(ESI):m/z＝347.1[M+H] +.
23.中间体D115-j:
Figure PCTCN2023071503-appb-000109
1)(5-氯-2-碘苯基)甲醇(D115-b)的制备：
Figure PCTCN2023071503-appb-000110
在0℃，向D115-a(2.0g,7.1mmol,1.0eq.)的THF(20mL)溶液,滴加入BH 3·THF(1M in THF,17.8mL,2.5eq.),然后室温搅拌过夜。向反应液中加入MeOH(25mL)，浓缩得白色固体产物(D115-b，1.9g,99％)。MS(ESI):m/z＝251.0[M-OH] +.
2)2-(溴甲基)-4-氯-1-碘苯(D115-c)的制备：
Figure PCTCN2023071503-appb-000111
在0℃,向D115-b(1.34g,5.0mmol,1.0eq.)的DCM(50mL)溶液中，滴加入PBr 3(522μL,5.5mmol,1.1eq.).零度搅拌1小时，室温搅拌2小时后，加入饱和NaHCO 3aq.(100mL)。二氯甲烷(20mLx2)萃取，Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D115-c，0.92g,56％)。
3)5'-氯-1'-氧-1'，3'-二氢螺环[氮杂环丁烷-3,2'-茚]-1-羧酸叔丁酯(D115-f)的制备：
Figure PCTCN2023071503-appb-000112
在-78℃,向D115-d(420mg,2.3mmol)的THF(40ml)溶液中，滴加入LiHMDS(1M in hexane,2.3mL).继续在在-78℃搅拌30分钟后，一次加入D115-c(713mg,2.15mmol)。让反应慢慢升至室温，并继续搅拌3小时。再次冷至-78℃，滴加入nBuLi(2.5M in hexane,1.9mL)。让反应慢慢升至室温，并继续搅拌过夜。然后加入水H 2O(100mlL)，乙酸乙酯EtOAc(30mL x 3)萃取，Na 2SO 4干燥，浓缩，反相柱层析纯化得淡黄色油状产物(D115-f，570mg,86％)。MS(ESI):m/z＝252.2,330.1[M-tBu+H] +,[M+Na] +.
4)5'-氯螺[氮杂环丁烷-3,2'-茚]-1'(3'H)-酮(D115-g)的制备:
Figure PCTCN2023071503-appb-000113
室温下，将D115-f(570mg,1.85mmol)溶解于TFA/DCM(1:10,5.5mL)中，搅拌2小时后，浓缩得产物(D115-g，0.6g,TFA salt)。MS(ESI):m/z＝208.1[M+H] +.
5)5'-氯-1-甲基-1'，3'-二氢螺环[氮杂环丁烷-3,2'-茚]-1'-醇(D115-h)的制备:
Figure PCTCN2023071503-appb-000114
室温下,向D115-g(0.6g crude,1.85mmol,1.0eq.)的MeOH/AcOH(5:1,24mL)溶液中，加入多聚甲醛(555mg,18.5mmol,10.0eq.).搅拌5小时后，加入NaBH 3CN(465mg,7.4mmol,4.0eq.).室温搅拌过夜，滤去固体，浓缩。向残留物中加入饱和NaHCO 3aq.(50mL)，二氯甲烷/甲醇(9/1,20mLx6)混合溶剂萃取。Na 2SO 4干燥，浓缩得淡黄色油状产物(D115-h，330mg).MS(ESI):m/z＝224.2[M+H] +.
6)5'-氯-1-甲基螺环[氮杂环丁烷-3,2'-茚]-1'(3'H)-酮(D115-i)的制备:
Figure PCTCN2023071503-appb-000115
室温下，向D115-h(308mg,1.38mmol,1.0eq.)的DCM(20mL)溶液中，加入Dess-Martin periodinane(642mg,1.51mmol,1.1eq.).搅拌1小时后，加入饱和NaHCO 3aq.(30mL),DCM(20mLx3)萃取。Na 2SO 4干燥，浓缩，反相柱层析纯化得白色固体产物(D115-i，280mg).MS(ESI):m/z＝222.1[M+H] +.
24.中间体D121-f:
Figure PCTCN2023071503-appb-000116
1)2-溴硒吩(D121-b)的制备：
Figure PCTCN2023071503-appb-000117
在0℃，向D121-a(5000mg,38.15mmol)在DCM(60mL)和CH 3COOH(60mL)的溶液中，加入NBS(6791mg,38.15mmol)。零度搅拌2小时，加入水，二氯甲烷萃取，Na 2SO 4干燥，浓缩，柱层析纯化得白色油状产物(D121-b,5100mgl,63.7％).
2)5-溴硒吩-2-甲醛(D121-c)的制备：Page:IDSU22-32-060
Figure PCTCN2023071503-appb-000118
在-78℃下，向D121-b(6100mg,29.06mmol)的THF(60mL)溶液中滴加入LDA(43.6mL,43.58mmol).搅拌30分钟后，滴加DMF(2mL)。继续在在-78℃搅拌4小时，加入水，二氯甲烷萃取，Na 2SO 4干燥，浓缩，柱层析纯化得棕色油状产物(D121-c，2100mg,30.4％)。GCMS:237[M]
3)(5-溴硒吩-2-基)甲醇(D121-c)的制备：
Figure PCTCN2023071503-appb-000119
在0℃下，向D121-b(2600mg,10.93mmol)的MeOH(50mL)溶液中加入NaBH 4(827mg,21.85mmol).零度搅拌2小时后，加入水，二氯甲烷萃取，Na 2SO 4干燥，浓缩得棕色油状产物YD02-I46-4(D121-c，2100mg)。
4)2-溴-5-(溴甲基)硒吩(D121-d)的制备：
Figure PCTCN2023071503-appb-000120
在0℃下，向D121-c(2100mg,8.75mmol)的diethyl ether(20mL)溶液中，滴加入PBr 3(3079mg,11.37mmol).零度搅拌2小时后，加入水，二氯甲烷萃取，Na 2SO 4干燥，浓缩得棕色油状产物(D121-d,2500mg).
5)(5R)-2-((5-溴硒吩-2-基)甲基)-5-异丙基-3,6-二甲氧基-2,5-二氢吡嗪(D121-e)的制备:
Figure PCTCN2023071503-appb-000121
在-78℃下,向D84-l(1825mg,9.91mmol)的THF(50mL)溶液中，滴加入n-BuLi(4.95mL,12.38mmol)at-78℃.继续搅拌1小时后，滴加入D121-f(2500mg,8.25mmol)的THF(10mL).在-78℃下反应2小时后，加入饱和NH 4Cl水溶液，乙酸乙酯萃取，Na 2SO 4干燥，浓缩，柱层析纯化得白色固体产物(D121-e，2000mg,59.7％).LCMS:407.0[M+H] +
6)2-氨基-3-(5-溴硒吩-2-基)丙酸甲酯(D121-f)的制备:
Figure PCTCN2023071503-appb-000122
室温下，向D121-e(2000mg,4.92mmol)的CH3CN(20mL)溶液中，加入HCl(52mL,0.2mol/L).搅拌半小时后，浓缩，HPLC纯化后得白色固体产物(D121-f，1002mg,65.4％)。LCMS:312.0[M+H] +
实施例1：化合物D01的合成
Figure PCTCN2023071503-appb-000123
a)室温下，将化合物D01a(1g,2.6mmol)溶解于二氯甲烷(30mL)中，然后滴加三氟醋酸(6mL)。搅拌2h，旋干得棕色固体产物D01b(1g,96.5％)。MS(ESI):m/z＝291.0[M+H] +.
b)(S)-4-(叔丁氧基羰基)-1,4-氧氮杂环庚烷-2-羧酸：冰浴冷却下，将化合物(S)-4-(叔丁氧基羰基)-1,4-氧氮杂环庚烷-2-甲醇(7.9g,34.2mmol)溶解于二氯甲烷(134mL)和水(28mL)中。(S)-4-(叔丁氧基羰基)-1,4-氧氮杂环庚烷-2-甲醇按专利(WO2015110826)报道的路线合成。然后依次加入TEMPO(107mg,0.68mmol)和Bu 4NHSO 4(812mg,2.4mmol)。与此同时，配制缓冲溶液。向68mL of NaClO溶液(10-15％)中加入饱和的NaHCO3溶液(大约100mL)调整酸碱性至pH8-9。然后，将NaBr(599mg,5.8mmol)溶解于水中(11.6mL)，并加入以上缓冲溶液。将如此配成的缓冲溶液慢慢滴进反应液中。注意，该反应放热，请保持瓶内温度在10℃以下1h。室温搅拌过夜，并用KHSO 4(2N)调整酸碱性至pH2-3，反应液用二氯甲烷萃取(3×500mL)，干燥，浓缩 得粗品。柱层析纯化(eluted with PE/EA＝2:1to 1:1,V/V)得白色固体产物(S)-4-(叔丁氧基羰基)-1,4-氧氮杂环庚烷-2-羧酸(30.9g,65％)。MS(ESI):m/z＝268.1[M+Na] +. 1H NMR(400MHz,CDCl3):δ9.14(m,1H)；4.34-4.00(m,3H)；3.76-3.34(m,3H)；3.28-3.16(m,1H)；1.93-1.92(m,2H)；1.46(s,9H)。
c)室温下，将化合物D01b(10.16g,25mmol)和(S)-4-(叔丁氧基羰基)-1,4-氧氮杂环庚烷-2-羧酸(5.56g,22.7mmol)，溶于DCM(300mL)，依次加入DIPEA(11.71g,90.8mmol),HOBt(3.06g,22.7mmol)和HBTU(9.46g,25mmol)，并搅拌过夜。向该反应液中加水(200mL)，再用二氯甲烷(3×400mL)萃取，干燥，浓缩得粗品。柱层析纯化.(洗脱液PE/EA＝1:1～1:4,V/V)得白色固体产物D01c(10.6g,91％)。MS(ESI):m/z＝540.1[M+Na] +. 1H NMR(400MHz,CDCl 3):δ7.61(s,2H)；7.20-7.11(m,1H)；6.98(d,J＝8.4Hz,2H)；6.29(s,0.5H)；5.96(s,0.5H)；5.45(d,J＝8.0Hz,1H)；4.63-4.55(m,1H)；4.18-3.97(m,3H)；3.81-3.77(m,0.5H)；3.50-2.93(m,5.5H)；2.00-1.86(m,2H)；1.45(s,9H)。
d)室温下氩气中，将化合物D01c(9.7g,18.8mmol)和Pin 2B 2(9.53g,37.5mmol)，溶于DMSO(250mL)中，然后加入Pd(dppf)Cl 2(960mg,1.3mmol)和KOAc(5.52g,56.3mmol)。将反应液加热至85℃，并继续搅拌8h。冷至室温，用EA(1000mL)稀释，饱和食盐水洗(5×200mL),Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝1:1～1:6,V/V)得白色固体产物D01d(8.5g,87.6％)。MS(ESI):m/z＝540.3[M+Na] +. 1H NMR(400MHz,CDCl 3):δ7.76(d,J＝7.2Hz,2H)；7.25(d,J＝8.0Hz,2H)；7.18(d,J＝7.2Hz,1H)；6.15(s,0.5H)；5.88(s,0.5H)；5.48(d,J＝18Hz,1H)；4.67-4.61(m,1H)；4.20-3.99(m,3H)；3.85-3.80(m,0.5H)；3.54-3.11(m,5H)；2.96-2.90(m,0.5H)；2.02-1.96(m,2H)；1.46(s,9H),1.34(s,12H)。
e)室温下氩气中，将化合物D01d(200mg,0.39mmol),6-溴咪唑并[1,2-a]吡啶(115mg,0.58mmol)溶于二氧六烷(8mL)和水(0.8mL)，然后进入PdCl 2dppf(30mg,0.04mmol)和KOAc(115mg,1.17mmol)，升温85℃，并继续搅拌4h。将反应液冷至室温，加入EA(50mL)，萃取，饱和食盐水洗(10mL)，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液EA～EA:MeOH＝10:1,Rf＝0.3in EA/MeOH 10/1)得棕色油状产物D01e(120mg,60％).MS(ESI):m/z＝508.3[M+H] +. 1HNMR(400MHz,CDCl 3):δ8.35-8.31(m,1H),7.76-7.70(m,3H),7.66-7.41(m,3H),7.38-7.36(m,2H),7.26-7.19(m,1H),6.24(brs,0.5H),5.93(brs,0.5H),5.45(brs,1H),4.71-4.64(m,1H),4.22-4.02(m,3H),3.80-3.76(m,0.5H),3.52-3.02(m,5.5H),1.92-1.90(m,2H),1.47(s,9H)。
f)室温下，向D01e(120mg,0.237mmol)的二氯甲烷(10mL)溶液中加入Burgess试剂(338mg,1.42mmol)。室温续搅拌4小时后，反应液用二氯甲烷(20mL)稀释，水洗(10mL)，Na 2SO 4干燥，浓缩得粗品。粗品用-HPLC(用TFA缓冲液:A:0.05％TFA水溶液；B:0.05％TFA乙腈溶液；Column:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000124
)纯化，冻干。所得产品用饱和NaHCO 3，中和至pH7，所得溶液用EA(3×50mL)萃取，Na 2SO 4干燥，浓缩棕色固体产物D01f(15mg,yield 12％).MS(ESI):m/z＝490.3[M+H] +。
g)室温下，向化合物D01f(10mg,0.02mmol)加入HCOOH(3mL)，然后生温至50℃，并继续搅拌10min分钟。反应液浓缩得粗品，粗品用-HPLC纯化(用HCOOH缓冲液:A:0.1％HCOOH水溶液；B:乙腈；Column:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000125
)白色固体产 物D01(1.5mg,产率17％)。 1H NMR(400MHz,DMSO-d 6):δ8.91(s,1H),8.71(d,J＝8.4Hz,1H),8.20(s,1H),7.95(s,1H),7.68-7.55(m,5H),7.41(d,J＝8Hz,2H),5.07-5.01(m,1H),4.09-4.06(m,1H),3.88-3.83(m,1H),3.79-3.70(m,1H),3.26-3.18(m,2H),3.12-3.08(m,1H),2.88-2.82(m,1H),2.72-2.66(m,1H),2.63-2.57(m,1H),1.80-1.73(m,2H)。
Figure PCTCN2023071503-appb-000126
按照实施例1的方法，用不同的溴代物替换6-溴咪唑并[1,2-a]吡啶反应制得以下化合物：
Figure PCTCN2023071503-appb-000127
Figure PCTCN2023071503-appb-000128
Figure PCTCN2023071503-appb-000129
Figure PCTCN2023071503-appb-000130
Figure PCTCN2023071503-appb-000131
Figure PCTCN2023071503-appb-000132
进一步的，按照实施例1的方法，用不同的溴代物替换6-溴咪唑并[1,2-a]吡啶反应还可制得以下化合物：
Figure PCTCN2023071503-appb-000133
Figure PCTCN2023071503-appb-000134
Figure PCTCN2023071503-appb-000135
进一步的，按照实施例1的方法，以下化合物按类似方法从不同的氟取代L-苯丙胺酸(L-2-Fluoro-Phenylalanine)的类似物制得。
Figure PCTCN2023071503-appb-000136
Figure PCTCN2023071503-appb-000137
Figure PCTCN2023071503-appb-000138
Figure PCTCN2023071503-appb-000139
Figure PCTCN2023071503-appb-000140
Figure PCTCN2023071503-appb-000141
Figure PCTCN2023071503-appb-000142
Figure PCTCN2023071503-appb-000143
Figure PCTCN2023071503-appb-000144
Figure PCTCN2023071503-appb-000145
Figure PCTCN2023071503-appb-000146
Figure PCTCN2023071503-appb-000147
Figure PCTCN2023071503-appb-000148
Figure PCTCN2023071503-appb-000149
Figure PCTCN2023071503-appb-000150
Figure PCTCN2023071503-appb-000151
Figure PCTCN2023071503-appb-000152
Figure PCTCN2023071503-appb-000153
Figure PCTCN2023071503-appb-000154
实施例2：化合物D11的合成
Figure PCTCN2023071503-appb-000155
a)室温下氩气中，将D01d(200mg,0.387mmol)，2-溴-4,5-二氢-6H-噻吩并[2,3-c]吡咯-6-酮(170mg,0.78mmol)，PdCl 2dppf(60mg,0.08mmol)和KOAc(114mg,1.16mmol)加入二氧六环(8mL)/和H 2O(0.8mL)中。在90℃下，搅拌过夜。反应液冷至室温，加入EA(50mL)和饱和食盐水(10mL).EA(3×300mL)萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液EA,EA:MeOH＝20:1～10:1,Rf＝0.5in EA/MeOH 10/1)得到相对纯的产物，制备HPLC(C18,CH 3CN,10mM NH 4HCO 3水溶液)进一步纯化得白色固体产物D11a(120mg,yield 58％).MS(ESI):m/z＝551.2[M+Na] +。
1HNMR(400MHz,CDCl 3):δ7.56-7.52(m,2H),7.32-7.20(m,3H),6.33-6.28(m,1.5H),5.97(brs,0.5H),5.46-5.35(m,1H),4.69-4.63(m,1H),4.40(s,2H),4.22-4.01(m,3H),3.81-3.76(m,0.5H),3.53-2.99(m,5.5H),2.03-1.82(m,2H),1.47(s,9H)。
b)室温下，将Burgess试剂(325mg,1.36mmol)加入到D11a(120mg,0.227mmol)的二氯甲烷(15mL)和THF(5mL)的溶液中，搅拌4h，用二氯甲烷DCM(20mL)稀释，水洗(10mL)，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液EA to EA:MeOH＝20:1,Rf＝0.1in EA)白色固体产物D11b(130mg,产率88％).MS(ESI):m/z＝548.2[M-Boc] +. 1HNMR(400MHz,DMSO-d 6):δ8.78(d,J＝8Hz,1H),7.70(d,J＝8.4Hz,2H),7.62(s,1H),7.38(d,J＝8Hz,2H),5.05-4.99(m,1H),4.86(s,2H),4.12-4.08(m,1H),3.95-3.76(m,2H),3.57-3.47(m,2H),3.37(s,3H),3.26-2.95(m,4H),1.80-1.69(m,2H),1.39-1.34(m,9H)。
c)室温下，向D11b(50mg,0.077mmol)的MeOH(0.5mL)和CH 3CN(3mL)的溶液中，滴加入4N HCl(0.2mL)甲醇溶液(0.5mL)。搅拌2h后，补加4N HCl(0.2mL)，并继续搅拌2h。然后，向反应液中加入Et 2O(40mL),部分白色沉定析出。离心分离2分钟，去除液体，残留物用制备HPLC纯化(用NH 4HCO 3水溶液为缓冲液：A:10mM NH 4HCO 3水溶液；B:乙腈；Column:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000156
)得白色固体产物D11，白色固体(20mg,产率47％)MS(ESI):m/z＝548.1[M+H] +。 1H NMR(400MHz,DMSO-d 6):δ8.96(d,J＝8.4Hz,1H),8.2(brs,1H),7.67 (d,J＝8.4Hz,2H),7.56(s,1H),7.36(d,J＝8.4Hz,2H),5.09-5.03(m,1H),4.82(s,2H),4.37-4.34(m,1H),3.92-3.86(m,1H),3.79-3.73(m,1H),3.40-3.38(m,1H),3.31(s,3H),3.26-3.19(m,3H),3.09-3.03(m,1H),2.82-2.76(m,1H),1.96-1.93(m,2H)
实施例3：化合物D15的合成
Figure PCTCN2023071503-appb-000157
a)室温下，将化合物氰基乙酸乙酯(20g,177mmol),1,2-dibromoethane(66.5g,354mmol)和 K 2CO 3(73.3g,531mmol)依次加入丙酮(300mL)中。加热回流过夜，然后冷至室温，滤去固体。浓缩滤液得黄色油状产物D15a(22g,89％).MS(ESI):m/z＝140.4[M+H] +。
b)在0℃，将D15a(22g,158.3mmol)溶于干燥得THF(150mL)，并慢慢滴加到含有LiAlH 4(24.06g,633.1mmol)的THF(250mL)中。反应液搅拌过夜，然后冷至0℃，用Et 2O(250mL)稀释，小心用水(22.06mL),15％aq.NaOH(22.06mL)，和追加的水(22.06mL)淬灭，滤去固体，并用MeOH(400mL)洗滴。滤液用Na2SO 4干燥，滤去固体，加入HCl(100ml,4mol/L二氧六烷溶液)，浓缩得棕色油状粗产物D15b(22g,80％). 1H NMR(400MHz,DMSO-d 6):δ8.09(s,3H)；3.32(s,2H)；2.79-2.75(m,2H)；0.58-0.55(m,2H)；0.45-0.42(m,2H)。
c)室温下，将D15b(5g,purity:80％,29.1mmol)，苯甲醛(4.63g,43.6mmol)和TEA(2.94g,29.1mmol)加入in MeOH(100mL)，搅拌2h后，分批加入NaBH 4(2.21g,58.2mmol)。搅拌2h后，滤去固体，滤液浓缩，柱层析纯化(洗脱液MeOH/DCM＝1:15,V/V)的棕色油状产物D15c(4.8g,87％).MS(ESI):m/z＝192.4[M+H] +. 1H NMR(400MHz,CDCl 3):δ7.37-7.26(m,5H)；3.82(s,2H)；3.58(s,2H)；2.76(s,2H)；0.52-0.50(m,2H)；0..41-0.39(m,2H)。
d)室温下，将化合物D15c(9.3g,48.7mmol)和(S)-苄氧甲基环氧乙烷(8.38g,51.1mmol)加入到 iPrOH(100mL)中，并在50℃搅拌16h。冷至室温，浓缩，柱层析纯化(洗脱液PE/EA＝1:1to 1:2,V/V)得棕色油状产物D15d(14g,81％)。MS(ESI):m/z＝356.2[M+H] +. 1H NMR(400MHz,CDCl 3):δ7.38-7.26(m,10H)；4.52(s,2H)；4.09-4.03(m,1H)；3.86(d,J＝13.2Hz,1H)；3.59-3.36(m,5H)；2.87(d,J＝13.2Hz,1H)；2.77-2.71(m,1H)；2.52-2.48(m,1H)；2.35(d,J＝13.2Hz,1H)；0.60-0.56(m,1H)；0.47-0.40(m,2H)；0.35-0.31(m,1H)。
e)冰浴中，向D15d(11g,31mmol)的二氯甲烷(100mL)溶液中，加入DIPEA(5.6g,43.4mmol)，然后在1h内慢慢滴加MsCl(3.9g,34.1mmol)。搅拌1h后，加入冰水(100mL)，二氯甲烷(3×200mL)萃取。Na 2SO 4干燥，浓缩得棕色油状粗品D15e。MS(ESI):m/z＝434.2[M+H] +。
f)在0℃，向NaH(3.88g,97mmol,purity:60％in oil)在THF(300mL)的悬浮液中，慢慢滴加溶于THF(100mL)的D15e(14g,32.3mmol)的溶液。在50℃搅拌16h，冷至0℃,加入sat.NaHCO 3(200ml)，EA(3×400mL)萃取。Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝6:1to 5:1,V/V)得棕色油状产物D15f(8g,73％).MS(ESI):m/z＝338.2[M+H] +. 1H NMR(400MHz,CDCl 3):δ7.36-7.23(m,10H)；4.57-4.49(m,2H)；4.15-4.08(m,1H)；3.75-3.62(m,3H)；3.56-3.49(m,2H)；3.40-3.36(m,1H)；2.97(d,J＝13.6Hz,1H)；2.70-2.60(m,2H)；2.34(d,J＝12.4Hz,1H)；0.58-0.44(m,3H)；0.35-0.30(m,1H)。
g)室温下，将D15f(4g,11.9mmol)溶解于含甲醇(100mL)的氢化装置中，然后加入Pd/C(800mg,10％on C)和AcOH(4mL)。氢化装置的空气被氢化置换4次后，加氢并晃动7h。然后加入HCl(1ml,12mol/L,12mmol)，继续氢化16h。滤去Pd/C，浓缩的棕色油状产物D15g(2.4g,90％).MS(ESI):m/z＝158.2[M+H] +。
h)室温下，将D15g(4.8g,24.8mmol)溶于二氧六环(150mL)和水(150mL)中，然后加入(Boc) 2O(10.82g,49.6mmol)和NaHCO 3(10.42g,124mmol)。搅拌16h后，EA(3×500mL)萃取.Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝2:1to 1:1,V/V)得无色油状产物D15h(5.7g, 90％).MS(ESI):m/z＝280.0[M+Na] +. 1H NMR(400MHz,CDCl 3):δ3.85-2.92(m,9H)；1.58-1.40(m,9H)；0.66-0.45(m,4H)。
i)室温下，将D15h(2g,7.78mmol)溶于二氯甲烷(35mL)中，依次加入水(7,TEMPO(24mg,0.16mmol)，Bu 4NHSO 4(185mg,0.54mmol).与此同时，将15.5mL of NaClO solution(10-15％)用sat.NaHCO 3(liquid+solids)(大约30mL)调节至to pH 8-9.将NaBr(136mg,1.32mmol)的水溶液(1mL)，加入到缓充溶液中。将所得溶液，冷至0℃，并慢慢滴加至反应液中。在0℃反应1h后，搅拌过夜。反应液KHSO 4(2N)用调节酸碱度至pH to 2-3。二氯甲烷萃取，Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝2:1to 1:1,V/V)得白色固体产物D15i(1.08g,40％).MS(ESI):m/z＝294.2[M+Na] +。
j)室温下，向(S)-2-氨基-3-(4-碘苯基)丙酰胺三氟乙酸盐(1.79g,4.4mmol)的二氯甲烷(40mL)溶液中，依次加入D15i(1g,3.7mmol),DIPEA(1.9g,14.8mmol),HOBt(498mg,3.7mmol)和HBTU(1.68g,4.4mmol)。搅拌5h后，加入水(50mL)，用二氯甲烷(3×150mL)萃取。Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝1:1to 1:5,V/V)然后用快速柱层析纯化得到粗品，(C18,CH 3CN,10mM NH 4HCO 3水溶液)，白色固体产物D15j(1g,50％).MS(ESI):m/z＝566.0[M+Na] +. 1H NMR(400MHz,CDCl 3):δ7.66-7.64(m,2H)；7.19(d,J＝8.4Hz,0.5H)；7.10(d,J＝8.4Hz,0.5H)；7.00(d,J＝8.4Hz,2H)；6.23(s,0.5H)；5.89(s,0.5H)；5.37(s,1H)；4.66-4.59(m,1H)；4.30-4.06(m,2H)；3.88(d,J＝13.6Hz,0.5H)；3.76-3.71(m,1H)；3.51(d,J＝14Hz,0.5H)；3.38-3.34(m,0.5H)；3.30(d,J＝12.8Hz,1H)；3.14-3.00(m,3H)；2.84(d,J＝14Hz,0.5H)；1.49(s,5H)；1.47(s,4H)；0.66-0.47(m,4H)。
k)室温下，向D15j(1g,1.84mmol)的DMSO(30mL)溶液中，加入Pin 2B 2(936mg,3.68mmol),Pd(dppf)Cl 2(269mg,0.37mmol)和KOAc(541mg,5.52mmol)。反应瓶利用减压去除空气，然后再注入氩气。重复3遍后，在85℃搅拌反应5h。冷至室温，用EA(500mL)稀释，饱和食盐水洗(5×100mL)。Na 2SO 4干燥，浓缩得粗品。柱层析纯化(洗脱液PE/EA＝1:2to 1:6,V/V)得棕色固体产物D15k(900mg,90％).MS(ESI):m/z＝566.3[M+Na] +. 1H NMR(400MHz,CDCl 3):δ7.73-7.75(m,2H)；7.26(d,J＝7.6Hz,2H)；7.22-7.15(m,1H)；6.15(s,0.5H)；5.84(s,0.5H)；5.44(s,1H)；4.71-4.61(m,1H)；4.29-4.06(m,2H)；3.86(d,J＝13.6Hz,0.5H)；3.71-3.65(m,1H)；3.49(d,J＝14Hz,0.5H)；3.33-3.27(m,1.5H)；3.15-3.04(m,3H)；2.81(d,J＝13.6Hz,0.5H)；1.48(s,5H)；1.46(s,4H)；1.35(s,12H)；0.65-0.46(m,4H)。
l)室温下，将D15k(200mg,0.37mmol)溶于二氧六环(10mL)中，然后依次加入5-溴-3-甲基苯并[d]噁唑-2(3H)-酮(126mg,0.55mmol),Pd(dppf)Cl 2(54mg,0.07mmol)，KOAc(108mg,1.1mmol)和水(1mL)，反应瓶利用减压去除空气，然后再注入氩气。反应化合物在85℃搅拌6h。冷至室温，浓缩，柱层析纯化(洗脱液PE/EA＝1:1to 1:6to MeOH/DCM＝1:10,V/V)得相对较纯的产物。进一步柱纯化(C18,CH 3CN,10mM NH 4HCO 3水溶液)得到棕的固体产物D15l(150mg,72％).MS(ESI):m/z＝587.3[M+Na] +。
m)室温下，将D15l(140mg,0.25mmol)溶于二氯甲烷(10mL)中，然后加入Burgess试剂(354mg,1.49mmol)。室温搅拌3h后，浓缩，制备HPLC纯化(Using NH 4HCO 3buffer:A:10mM NH 4HCO 3水溶液；B:acetonitrile；Column:Waters XBridge Peptide BEH C18,19×250mm,10μm,
Figure PCTCN2023071503-appb-000158
)得棕色固体产物D15m(80mg,59％).MS(ESI):m/z＝569.3[M+Na] +。
n)室温下，将HCl-二氧六环(1.172mmol,4mol/L,0.293mL)滴入D15m(80mg,0.147mmol)的MeCN(4.8mL)溶液中。室温搅拌1.5h后，加入冷的Et 2O(45mL)，离心分离，去除液相。残留物，用Et 2O(15mL)洗两次。制备-HPLC纯化(A:0.8％NH 4HCO 3水溶液，B:CH 3CN；Column:Xbridge BEH peptide C18,19mm×250mm)得白色固体产物D15(35mg,53％).HPLC纯度:99.46％。
Figure PCTCN2023071503-appb-000159
以下化合物按类似方法从不同的L-苯丙胺酸(L-Phenylalanine)的类似物制得：
Figure PCTCN2023071503-appb-000160
Figure PCTCN2023071503-appb-000161
以下化合物按类似方法从不同的6元环和7元环胺基酸制得：
Figure PCTCN2023071503-appb-000162
Figure PCTCN2023071503-appb-000163
实施例4：U937细胞抑制DPP1活性测试
胞内酶活测定在384孔板中进行，细胞培养基：1640，10％FBS，1*PS。将含有U937细胞的30μL细胞培养基细胞悬液加入384孔板中，使每孔含有2×10 4个细胞；并通过Echo将30nL AZD7986、vehicle对照(100％DMSO)或被测化合物连续稀释液加入孔中，在37℃下孵育1h后，每个孔加入h-Gly-phe-AFC(10μL)，并开始反应，在37℃下进一步孵育1h，然后通过EXλ400nm和EMλ505nm读取荧光吸收。以上检测结果用Graphpad 8.0计算IC50值，结果如下表：
Figure PCTCN2023071503-appb-000164
Figure PCTCN2023071503-appb-000165
Figure PCTCN2023071503-appb-000166
Figure PCTCN2023071503-appb-000167
Figure PCTCN2023071503-appb-000168
“++”：75％≤抑制率<100％；“+”：30％≤抑制率<75％；“-”：抑制率<30％；“/”：未测试。
实施例5：DPP1酶活性的抑制效应测试
实验材料：
重组人源组织蛋白酶rhCathepsin C/DPP1，购自R&D systems
重组人源组织蛋白酶rhCathepsin L，购自R&D systems
AZD7986,购自MCE
Gly-Arg-AMC(hydrochloride)购自Cayman chemical
DMSO购自Sigma-Aldrich
实验方法：
1)化合物的准备与处理：称量精确的化合物的量并将其溶解在10mL的DMSO中制备10mL的原液，该原液按要求进行进一步稀释。
2)筛选测试：使用激活缓冲剂溶液将重组人源组织蛋白酶rhCathepsin C/DPP1和重组人源组织蛋白酶rhCathepsin L稀释，并再37℃孵育60分钟。加4uL测试化合物到含有384孔的板的白色微孔中。取4uL孵育结束后的酶混合液加到白色微孔中。封闭384孔板，并在室温放置30分钟，加入8uL 2倍稀释的Gly-Arg-AMC(hydrochloride).封闭384孔板，并在室温放置2小时。制备4x的终止液，加入4uL终止液到白色微孔中。在萤光仪Victor Nivo35上读取萤光数据。
3)数据分析：
所有的IC50值是使用Prism Graphpad 8.0将抑制百分率换算过来。结果如下表：
化合物 IC50(nM)
AZD7986 4.2
D02 4.1
D04 3.9
D09 5.4
D15 1.4
D19 3.5
D20 3.6
D21 8
D26 3.1
D44 5.2
D46 0.45
D57 2.2
D59 0.79
D60 3.7
D61 2.5
D63 1.7
D67 0.18
D70 0.58
D73 2.5
D74 2.9
D75 2.3
D78 0.72
D85 3.2
D67 0.18
D92 0.32
D106 1.36
D118 1.6
D120 2.3
D123 1.4
D124 11.2
D125 6.7
D126 10.8
D127 4.2
本专利的实施例仅以说明而非限制的方式提供。本领域技术人员将容易地认识到可以改变或修改各种非关键参数以产生基本上相似的结果。
尽管已经对本发明的技术方案做了较为详细的阐述和列举，应当理解，对于本领域技术人员来说，对上述实施例做出修改或者采用等同的替代方案，这对本领域的技术人员而言是显而易见，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (15)

  1. 一种式(I)化合物或其药学上可接受的盐，其特征在于：
    Figure PCTCN2023071503-appb-100001
    和/或其药学上可接受的前药，和/或其溶剂合物、水合物、代谢产物、氮氧化物、外消旋混合物、对映异构体、非对映异构体和互变异构体或其任意比例的混合物包括外消旋混合物，其中：
    Cy为
    Figure PCTCN2023071503-appb-100002
    p为0-6；
    W选自CH 2-CH 2-O-、-O-、-S-、-SO 2-、-CH 2-、-OCH 2-、-CH 2O-、-CH 2S-、-SCH 2-、-CH 2SO 2-、-SO 2CH 2-、-CH 2-CH 2-、-(CH 2) 3-、-CH 2-CH 2-S-、-CH 2-CH 2-SO 2-、-CH 2-O-CH 2-、-CH 2-S-CH 2-、-CH 2-SO 2-CH 2-；
    R a各自独立地选自氘、卤素、羟基、氰基、巯基、氨基、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6环烷基氧基、杂环烷氧基、-SC 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2N-、C 1-6烷基-C(O)HN-、-C(O)NHC 1-6烷基、氧代、硫代，并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的；两个R a可连在同一碳原子，也可以连在不同的碳原子；R a或两个R a一起形成C 1-4亚烷基或者含有1～4个碳原子的醚链如-CH 2-O-CH 2-CH 2-CH 2-、-CH 2-O-CH 2-，所述亚烷基或醚链可与原来环形成含有杂原子或者不含杂原子环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环，所述杂原子包括N、S、O，所述环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环可被氘、羟基、卤素、烷基和烷氧基选择性取代，且其中C、S可被选择性氧代为-C＝O、-S＝O、-S(O)2-；或两个R a与其各自附接的碳原子组成6元芳基、5元杂芳基、6元杂芳基，且与原来环形成并环，所述并环可被羟基、卤素、氰基、烷基、烷氧基选择性取代；并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的；
    A和B各自独立的选自氢、氘、氟，或者A和B与两者附接的碳原子形成环丙烷；
    X、Y、Z各自独立选自CH、N、S、O、Se，或者X、Y、Z其中1个为环中的键即X、Y或Z两侧的原子直接连接，连接的键可为单键或双键；
    R 2选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基，所述烷基、烷氧基、环烷基和环烷氧基均可任选的被卤素和氘取代的；
    q为0-3；
    当在下述四种情况下(四种情况是和/或的关系)
    1)Cy不为
    Figure PCTCN2023071503-appb-100003
    2)X、Y、Z不同时为CH；
    3)R 2不为氢且q不为0；
    4)A和B不同时为氢；
    R 1选自环状基团具体为芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基；所述环状基团可为单环也可为双环，可选择性含有一个或者多个N、O、S、Se的杂原子，且环中的C、S可被选择性氧代或硫代为-CO-、-CS-、-SO-、-SO2-；所述芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基可被一个或者多个R 1a选择性取代；
    R 1a可选自氢、氘、卤素、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5～6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；两个R 1a可连在同一个碳原子或者氮原子，也可以连在不同的碳原子或者氮原子；两R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，环中的C、S也可被选择性氧代或硫代为-CO-、-CS-、-SO-、-SO2-；
    R 3、R 4各自独立的选自氢、氘、卤素、氰基、卤素、羟基、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、环烷氧基、杂环烷基、烷基羰基、烷基砜基、烷基C(O)NH-、烷基S(O)2NH-、羧基、烷基羰基；其中氨基、羟基、羧基、烷基、环烷基、环烷氧基、杂环烷氧基、杂环烷基可被烷基、卤素、氰基、羟基、羟基烷基、烷氧基进一步取代；两R 3可连在相同原子上，也可连在不同原子上；或者两个R 3，或R 3和R 4，可选择性与各自共同连接的碳原子或者氮原子形成3-10元环烷基、杂环烷基、螺环、桥环、稠环，包括但不限于氧杂环丁烷、氮杂环丁烷、吗啉环、哌啶环、哌嗪环、氮杂氧杂环丁烷、呋喃环、吡咯烷，所述环烷基、杂环烷基、螺环、桥环、稠环中C和S可被选择性氧代为-CO-、-SO-、-SO2-，且可被一个或多个卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、C 3-8杂环基选择性取代；
    当Cy为
    Figure PCTCN2023071503-appb-100004
    且X、Y、Z三者均为CH，且R 2为氢，且A/B均为H时：
    R 1选自为嘧啶、吡嗪、哒嗪、吡唑、呋喃、咪唑、噻唑、噁唑、异噁唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基，其中嘧啶、吡嗪、哒嗪、三嗪基、吡唑、呋喃、咪唑、噻唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基可被一个或者多个R 1a取代(R 1a定义如上所述)，或者其中S或者1-2个碳原子可被选择性氧代；
    和/或R 1选自：
    Figure PCTCN2023071503-appb-100005
    f为0-2；
    g为0-3；
    h为0-5；
    k为0-2；
    R 1a如上述定义，同环上的R 1a可同时选相同取代基也可选不同取代基；两个R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    R 3和R 4除非特殊说明，否则如上述定义；
    当f和g不为0且R 1a不为氢时，R 1b＝H、R 1a；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    当f和g为0时，或者f和g不为0且R 1a为氢时，R 1b可选自氢、氘、卤素、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    当k不为0且R 1a不为氢时，R 5a、R 5和R 6＝R 1a，或R 5a、R 5、R 6、1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    当k为0，或者k不为0且R 1a为氢时：
    如果R 5a为氘、溴、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰 基、C 2-8烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
    那么R 5和R 6＝R 1a，或者R 5、R 6、R 5a和1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    如果R 5a为氯、氟、CH 3时，那么R 5、R 6＝R 1a；
    如果R 5a为H，那么R 6＝R 1a，R 5可选自选自氘、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、烷基、1～2个氟取代的烷基、1～3个溴取代烷基、1-3个氯取代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4(其中R 3和R 4不同时为H)、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2C 4-8烷基、-OS(O)2C 4-8环烷基、-OS(O)2C 4-8杂环烷基、-S(O)(NH)R 3、-S(O)(NR 4)R 3、S(O)2NR 3R 4(其中R 3和R 4与所附接的N原子可形成杂烯基、哌嗪基、含有至少1个O原子的5-7元氮杂烷基、吗啉基、桥环吗啉基，或R 3和R 4单独取代不构成环)、-S(O)2NH 2、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
    或者R 5a为H、氯、氟、CH 3时，R 1选自
    Figure PCTCN2023071503-appb-100006
    其中
    V选自-O-、-S-、-Se-、-CH 2-、-CF 2-、-CO-、-SO-、-SO2-、-N(R 7)-、-C(R 8R 9)-、-O-CH(烷基) -、-O-CH(环烷基)-、-S-CH(环烷基)-、-CH＝C(烷基)-、-N＝C(烷基)-、-CH＝C(环烷基)-、-N＝C(环烷基)-；
    U选自-O-、-S-、-Se-、-CO-、-SO-、-S(O)2、-NR 7-、-CR 8R 9-；
    当V为-O-、-S-、-CF 2-，且U为-CO-时，T为-O-、-S-、-Se-、-CO、-SO-、-S(O)2、-CR 8R 9-，-NH-、-N(CHF)-、-N(CF 2)-、-N(CH 2-CH(OH)-CH 3)-、-N(CH 2-CH(OCH 3)-CH 3)-、-N(CH 2-CH 2-OCH 3)-、-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)-，其中所述为-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)可选择性被C 1-3烷氧基、C 1-3烷基、C 3-6环烷基、NH(C 1-3烷基)、N(C 1-3烷基) 2或者1～3个卤素取代；否则T为-O-、-S-、-Se-、-CO-、-SO-、-SO2-、-C(R 8R 9)-、-N(R 7)-；
    X 1、Y 1、Z 1可独立选自CH和N；
    R 7＝R 1a；
    R 8、R 9＝R 1a，或者R 8、R 9可选择性与两者原来所附接的原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；和/或其药学上可接受的盐或它的前药，和/或其溶剂合物、水合物、代谢产物、氮氧化物、外消旋混合物、对映异构体、非对映异构体和互变异构体或其任意比例的混合物包括外消旋混合物，其中：
    Cy为
    Figure PCTCN2023071503-appb-100007
    p为0-6；
    W选自CH 2-CH 2-O-、-O-、-S-、-SO 2-、-CH 2-、-OCH 2-、-CH 2O-、-CH 2S-、-SCH 2-、-CH 2SO 2-、-SO 2CH 2-、-CH 2-CH 2-、-(CH 2) 3-、-CH 2-CH 2-S-、-CH 2-CH 2-SO 2-、-CH 2-O-CH 2-、-CH 2-S-CH 2-、-CH 2-SO 2-CH 2-；
    R a各自独立地选自氘、卤素、羟基、氰基、巯基、氨基、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、C 3-6环烷基氧基、杂环烷氧基、-SC 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2N-、C 1-6烷基-C(O)HN-、-C(O)NHC 1-6烷基、氧代、硫代，并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的；两个R a可连在同一碳原子，也可以连在不同的碳原子；R a或两个R a一起形成C 1-4亚烷基或者含有1～4个碳原子的醚链如-CH 2-O-CH 2-CH 2-CH 2-、-CH 2-O-CH 2-，所述亚烷基或醚链可与原来环形成含有杂原子或者不含杂原子环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环，所述杂原子包括N、S、O，所述环烷基、环烯基、杂环烷基、杂环烯基、桥环、稠环和螺环可被氘、羟基、卤素、烷基和烷氧基选择性取代，且其中C、S可被选择性氧代为-C＝O、-S＝O、-S(O)2-；或两个R a与其各自附接的碳原子组成6元芳基、5元杂芳基、6元杂芳基，且与原来环形成并环，所述并环可被羟基、卤素、氰基、烷基、烷氧基选择性取代；并且所述烷基、环烷基、烷氧基、杂环烷基和杂环烷氧基均可任选的被卤素和氘取代的；
    A和B各自独立的选自氢、氘、氟，或者A和B与两者附接的碳原子形成环丙烷；
    X、Y、Z各自独立选自CH、N、S、O、Se，或者X、Y、Z其中1个为环中的键即X、Y或Z两侧的原子直接连接，连接的键可为单键或双键；
    R 2选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基，所述烷基、烷氧基、环烷基和环烷氧基均可任选的被卤素和氘取代的；
    q为0-3；
    当在下述四种情况下(四种情况是和/或的关系)
    1)Cy不为
    Figure PCTCN2023071503-appb-100008
    2)X、Y、Z不同时为CH；
    3)R 2不为氢且q不为0；
    4)A和B不同时为氢；
    R 1选自环状基团具体为芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基；所述环状基团可为单环也可为双环，可选择性含有一个或者多个N、O、S、Se的杂原子，且环中的C、S可被选择性氧代或硫代为-CO-、-CS-、-CO--SO-、-SO2-；所述芳基、杂芳基、环烷基、环烯基、杂环烷基和杂环烯基可被一个或者多个R 1a选择性取代；
    R 1a可选自氢、氘、卤素、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5～6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；两个R 1a可连在同一个碳原子或者氮原子，也可以连在不同的碳原子或者氮原子；两R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，环中的C、S也可被选择性氧代或硫代为-CO-、-CS-、-SO-、-SO2-；
    R 3、R 4各自独立的选自氢、氘、卤素、氰基、卤素、羟基、氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、环烷氧基、杂环烷基、烷基羰基、烷基砜基、烷基C(O)NH-、烷基S(O)2NH-、羧基、烷基羰基；其中氨基、羟基、羧基、烷基、环烷基、环烷氧基、杂环烷氧基、杂环烷基可被烷基、卤素、氰基、羟基、羟基烷基、烷氧基进一步取代；两R 3可连在相同原子上，也可连在不同原子上；或者两个R 3，或R 3和R 4，可选择性与各自共同连接的碳原子或者氮原子形成3-10元环烷基、杂环烷基、螺环、桥环、稠环，包括但不限于氧杂环丁烷、氮杂环丁烷、吗啉环、哌啶环、哌嗪环、氮杂氧杂环丁烷、呋喃环、吡咯烷，所述环烷基、杂环烷基、螺环、桥环、稠环中C和S可 被选择性氧代为-CO-、-SO-、-SO2-，且可被一个或多个卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、C 3-8杂环基选择性取代；
    当Cy为
    Figure PCTCN2023071503-appb-100009
    且X、Y、Z三者均为CH，且R 2为氢，且A/B均为H时：
    R 1选自为嘧啶、吡嗪、哒嗪、吡唑、呋喃、咪唑、噻唑、噁唑、异噁唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基，其中嘧啶、吡嗪、哒嗪、三嗪基、吡唑、呋喃、咪唑、噻唑、三氮唑、喹唑啉、喹啉、环烷基、环烯基、杂环烷基、杂环烯基可被一个或者多个R 1a取代(R 1a定义如上所述)，或者其中S或者1-2个碳原子可被选择性氧代；
    和/或R 1选自：
    Figure PCTCN2023071503-appb-100010
    f为0-2；
    g为0-3；
    h为0-5；
    k为0-2；
    R 1a如上述定义，同环上的R 1a可同时选相同取代基也可选不同取代基；两个R 1a可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    R 3和R 4除非特殊说明，否则如上述定义；
    当f和g不为0且R 1a不为氢时，R 1b＝H、R 1a；R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    当f和g为0时，或者f和g不为0且R 1a为氢时，R 1b可选自氢、氘、卤素、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代； R 1b与R 1a，或者两个R 1a，可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    当k不为0且R 1a不为氢时，R 5a、R 5和R 6＝R 1a，或R 5a、R 5、R 6、1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    当k为0，或者k不为0且R 1a为氢时：
    如果R 5a为氘、溴、氰基、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、C 2-8烷基、卤代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2R 3、-S(O)(NH)R 3、-S(O)(NR 4)R 3、-S(O)2NR 3R 4、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
    那么R 5和R 6＝R 1a，或者R 5、R 6、R 5a和1～2个R 1a中的两个可选择性与原来环中的碳原子或者氮原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-；
    如果R 5a为氯、氟、CH 3时，那么R 5、R 6＝R 1a；
    如果R 5a为H，那么R 6＝R 1a，R 5可选自选自氘、羟基、氨基、巯基、羧基、砜基、亚砜基、氧代、硫代、硝基、氰基、烷基、1～2个氟取代的烷基、1～3个溴取代烷基、1-3个氯取代烷基、饱和环烷基、不饱和环烷基、饱和杂环基、不饱和杂环基、芳烷基、杂芳烷基、烯基、环烯基、杂环烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、杂环氧基、芳基氧基、杂芳基氧基、苄基氧基、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基、芳基氧基羰基、杂芳基氧基羰基、-CONR 3R 4(其中R 3和R 4不同时为H)、烷基羰基氧基、环烷基羰基氧基、杂环基羰基氧基、-SOR 3、-S(O)2C 4-8烷基、-OS(O)2C 4-8环烷基、-OS(O)2C 4-8杂环烷基、-S(O)(NH)R 3、-S(O)(NR 4)R 3、S(O)2NR 3R 4(其中R 3和R 4与所附接的N原子可形成杂烯基、哌嗪基、含有至少1个O原子的5-7元氮杂烷基、吗啉基、桥环吗啉基，或R 3和R 4单独取代不构成环)、-S(O)2NH 2、-OS(O)2R 3、-NR 3R 4、-NR 3(CO)R 4、-NR 3(SO 2)R 4、-NR 3R 4取代的烷基、-CR 3R 4、-SR 3、芳基、5-6元杂芳基；其中所述的烷基、烷氧基、烯基、环烯基、杂环烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 3取代；
    或者R 5a为H、氯、氟、CH 3时，R 1选自
    Figure PCTCN2023071503-appb-100011
    其中
    V选自-O-、-S-、-Se-、-CH 2-、-CF 2-、-CO-、-SO-、-SO2-、-N(R 7)-、-C(R 8R 9)-、-O-CH(烷基)-、-O-CH(环烷基)-、-S-CH(环烷基)-、-CH＝C(烷基)-、-N＝C(烷基)-、-CH＝C(环烷基)-、-N＝C(环烷基)-；
    U选自-O-、-S-、-Se-、-CO-、-SO-、-S(O)2、-NR 7-、-CR 8R 9-；
    当V为-O-、-S-、-CF 2-，且U为-CO-时，T为-O-、-S-、-Se-、-CO、-SO-、-S(O)2、-CR 8R 9-，-NH-、-N(CHF)-、-N(CF 2)-、-N(CH 2-CH(OH)-CH 3)-、-N(CH 2-CH(OCH 3)-CH 3)-、-N(CH 2-CH 2-OCH 3)-、-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)-，其中所述为-N(C 4-8烷基)-、-N(环烷基)-、-N(环烷氧基)-、-N(氧杂环丁烷)-、-N(四氢呋喃)-、-N(四氢吡喃)可选择性被C 1-3烷氧基、C 1-3烷基、C 3-6环烷基、NH(C 1-3烷基)、N(C 1-3烷基) 2或者1～3个卤素取代；否则T为-O-、-S-、-Se-、-CO-、-SO-、-SO2-、-C(R 8R 9)-、-N(R 7)-；
    X 1、Y 1、Z 1可独立选自CH和N；
    R 7＝R 1a；
    R 8、R 9＝R 1a，或者R 8、R 9可选择性与两者原来所附接的原子形成饱和或者不饱和的环状基团，所述环状基团包括但不限于环烷基、环烯基、杂环烷基、杂环烯基、桥环、螺环、稠环、芳香基、杂芳基，且环状基团可被一个或者多个R 3进一步选择性取代，且环中的C、S也可被选择性氧代为-CO-、-SO-、-SO2-。
  2. 根据权利要求1所述式(I)化合物或其药学上可接受的盐，其特征在于：所述Cy选自
    Figure PCTCN2023071503-appb-100012
    Ar为吡啶和苯环；
    R b为氯、氟、甲基、乙基、丙基、异丙基、环丙基、三氟甲基、三氟甲氧基。
  3. 根据权利要求1所述式(I)化合物或其药学上可接受的盐，其特征在于：所述A和B均选自H，或均选自F。
  4. 根据权利要求1所述式(I)化合物或其药学上可接受的盐，其特征在于：所述X，Y各自独立选自CH、N，所述Z选自CH。
  5. 根据权利要求1所述式(I)化合物或其药学上可接受的盐，其特征在于：所述R 2选自氢、氟、甲基，所述q选自1。
  6. 根据权利要求1所述式(I)化合物或其药学上可接受的盐，其特征在于：所述R 1选自
    Figure PCTCN2023071503-appb-100013
    其中
    X 1、Y 1、Z 1独立选自CH、N；
    m、n、o为0-3；
    U可选自-C(＝O)-,-S(O)2-、-O-、-NR 7-、-CR 8R 9-；
    V可选自-C(＝O)-,-S(O)2-、-O-、-S-、-Se-、-NR 7-、-CR 8R 9-；
    R 7选自氢、CH 3OCH 2CH 2-、氧杂环丁烷基、吖丁啶、四氢呋喃基、四氢吡喃、吡咯烷、哌嗪、吗啉、哌啶、-C 1-3烷基、C 3-6环烷基，其中所述C 1-3烷基、C 3-6环烷基、吖丁啶、四氢呋喃基、四氢吡喃、吡咯烷、哌嗪、吗啉、哌啶任选地被1、2或3个氟取代，和/或任选地被一个 选自以下的取代基取代：C 1-3烷基、羟基、-OC 1-3烷基、-N(C 1-3烷基) 2、环丙基；同结构中不同位置的R 7可选择同样取代基，也可以选则不同的取代基；
    R 8、R 9为氢、氟、-C 1-6烷基、-C 1-6卤代烷基，或R 8和R 9与其所附接的氮原子或者碳原子一起形成C 3-6环烷基、氧杂环丁烷、吖丁啶、吡咯烷、哌啶环、哌嗪环、吗啉环、四氢呋喃基、四氢吡喃基，所述环丙烷、氧杂环丁烷、吖丁啶、吡咯烷、哌啶环、哌嗪环、吗啉环、四氢呋喃基、四氢吡喃基可被C 1-3烷基、环丙烷、氧杂环丁烷、吖丁啶、环丙基氧基选择性取代；
    C、D独立地选自-NR 7C(O)-、-C(O)NR 7-、-CH 2-CH 2-、-C(O)-O-、-O-C(O)-、-CH 2-O-、-O-CH 2-、-CH 2-NR 7-、-NR 7-CH 2-、-CH 2-；或者C和D中其中1个为键(环中的单键或者双键，两端的原子直接连接)；
    当Cy为
    Figure PCTCN2023071503-appb-100014
    且R 2为H，且X、Y、Z三者均选自CH，且如果结构中V存在则为-O-、-S-或者-CF 2-时：
    R 5选自-S(O)2C 1-3烷基、-CONH 2、-SO 2NHC 1-3烷基、-SO 2NR 3R 4(其中R 3和R 4如果与其附接的N原子形成杂环基，所述杂环基选自哌嗪基、吗啉基，所述哌嗪基和吗啉基可选择性被C 1-3烷基、环丙基取代)；
    R 6选自氢、氟、氯、溴、甲基；
    R 7a选自H、-CHF、-CF 2、-CH 2-CH(OH)-CH 3、-CH 2-CH(OCH 3)-CH 3、-C 4-8烷基、-环烷基、-环烷氧基，-CH 2-CH 2-OCH 3、-氧杂环丁烷、-四氢呋喃、-四氢吡喃、吡咯烷、哌嗪、吗啉、哌啶；其中所述C 4-8烷基、四氢呋喃、吡咯烷、哌嗪、吗啉、哌啶任选地被1、2或3个氟取代和/或任选地被一个选自以下的取代基取代：羟基、-OC 1-3烷基、-N(C 1-3烷基) 2、环丙基；
    否则：R 5选自氰基、-SO 2C 1-3烷基、-CONH 2、-SO 2NR 3R 4，其中R 3、R 4为氢、-C 1-6烷基，或R 3和R 4与其所附接的氮原子一起形成吖丁啶、氧杂环丁烷、吡咯烷、哌啶环、哌嗪环、吗啉环，所述吖丁啶、氧杂环丁烷、吡咯烷、哌啶环、哌嗪环、吗啉环可被C 1-3烷基、环丙基选择性取代；
    R 6选自氢、氟、氯、溴、甲基；
    R 7a＝R 7。
  7. 根据权利要求1所述式(I)化合物或其药学上可接受的盐，其特征在于：所述R 1选自
    Figure PCTCN2023071503-appb-100015
    R 7选自氢、-CF 2、-CHF、CH 3OCH 2CH 2-、氧杂环丁烷基、四氢呋喃基、四氢吡喃、-C 1-3烷基、-C 3-6环烷氧基；其中所述C 1-3烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃可任选地被1、2或3 个氟取代，和或任选地被一个选自以下的取代基取代：羟基、-OC 1-3烷基、-N(C 1-3烷基) 2、环丙基；同结构中不同位置的R 7可选择同样取代基，也可以选则不同的取代基；
    当Cy为
    Figure PCTCN2023071503-appb-100016
    且R 2为H，且X、Y、Z三者均选自CH，且A和B均为H时：R 7a选自H、-CHF、-CF 2、-CH 2-CH(OH)-CH 3、-CH 2-CH(OCH 3)-CH 3、-C 4-8烷基、-C 3-6环烷基、-C 3-6环烷氧基，-CH 2-CH 2-OCH 3、-氧杂环丁烷、-四氢呋喃、-四氢吡喃，所述氧杂环丁烷、四氢呋喃、四氢吡喃可被C 1-3烷基、环丙基选择性取代；否则R 7a＝R 7。
  8. 以下式(I)化合物或其药学上可接受的盐：
    Figure PCTCN2023071503-appb-100017
    Figure PCTCN2023071503-appb-100018
    Figure PCTCN2023071503-appb-100019
    Figure PCTCN2023071503-appb-100020
    Figure PCTCN2023071503-appb-100021
    Figure PCTCN2023071503-appb-100022
    Figure PCTCN2023071503-appb-100023
  9. 根据权利要求1-8任一项所述式(I)化合物或其药学上可接受的盐在制备用于治疗和预防组织蛋白酶C及其下游丝氨酸蛋白酶NE、PR3、CaTG、NSP4疾病的药物中的用途。
  10. 根据权利要求1-8任一项所述式(I)化合物或其药学上可接受的盐在制备用于在患有呼吸疾病、代谢疾病、心脑血管疾病、自身免疫性疾病、癌症、感染性疾病及其他炎性相关性疾病是哮喘、慢性阻塞性肺病、肺纤维化、肺高压、肺动脉高压、非囊性纤维化、囊性纤维化、支气管扩张、支气管炎、肺炎、肺气肿、急性肺损伤(ALI)、急性呼吸窘迫综合症(ARDS)、脓毒症、过敏性疾病、免疫性炎症性肠病、类风湿性关节炎、肾小球肾炎、嗜酸性粒细胞疾病、嗜中性粒细胞疾病、ANCA相关炎症、抗中性粒细胞胞浆抗体相关的坏死性新月形肾小球肾炎、急性脑创伤、急性心肌炎、急性肾损伤、a-1-抗胰蛋白酶缺乏症(AATD)及相关炎症、肝纤维化、脂肪肝及肝脂肪变性、肥胖症、胰岛素抗性、糖尿病、病原性微生物感染、感染性胃肠炎性疾病、肺癌和/或者放射性损伤综合征或者面临所述疾病危险的患者中治疗所述疾病的药物中的用途。
  11. 一种药物组合物，其含有如权利要求1-8中任一项所述式(I)化合物其药学上可接受的盐、及至少一种药用载体或赋形剂。
  12. 根据权利要求11所述的一种药物组合物，其特征在于：所述其含有一种或多种如权利要求1-8任一项的式(I)化合物，以及选自由其他化合物组成的群的药学活性化合物，所述其他化合物包括但不限于：b模拟剂、抗胆碱能药物、皮质类固醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、CRTH2抑制剂、5-LO抑制剂、组织胺受体拮抗剂、CCR9拮抗剂及SYK抑制剂、NE抑制剂、MMP9抑制剂、MMP12抑制剂以及两种或三种活性物质的组合。
  13. 根据权利要求11-12任一项所述的一种药物组合物，其特征在于：所述药物组合物还包括与小分子化合物和/或大分子抗体联合使用，以治疗癌症、炎症、骨髓相关疾病和自身免疫性疾病，所述小分子化合物和/或大分子抗体、包括但不限于糖皮质激素、肾上腺素激动剂、胆碱能受体拮抗剂、茶碱类药物、抗氧化剂、弹性蛋白酶抑制剂、金属蛋白酶抑制剂、PDE4抑制剂、LTD4拮抗剂、EGFR 抑制剂、CRTH2抑制剂、5-LO抑制剂、组织胺受体拮抗剂、CCR9拮抗剂及SYK抑制剂、趋化因子受体抑制剂、白介素抗体如IL-6抗体、IL-23抗体、靶向抗胸腺基质淋巴细胞生成素(TSLP)抗体如tezepelumab、补体抑制剂。
  14. 根据权利要求13所述的一种药物组合物，其特征在于：所述组合物在治疗和预防由组织蛋白酶C及其下游丝氨酸蛋白酶NE、PR3、CaTG、NSP4疾病的药物中的用途，所述疾病选自呼吸疾病、代谢疾病、心脑血管疾病、自身免疫性疾病、癌症、感染性疾病或者炎性感染性疾病。
  15. 根据权利要求1-8任一项所述式(I)化合物的溶剂合物、外消旋混合物、对映异构体、非对映异构体、互变异构体或包括外消旋混合物其任意比例的混合物，其特征在于，所述R 1、R 2、Cy、A、B、X、Y、Z和q各取代基：
    Figure PCTCN2023071503-appb-100024
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US12479837B2 (en) 2023-01-06 2025-11-25 Insmed Incorporated Reversible DPP1 inhibitors and uses thereof
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WO2026002203A1 (zh) * 2024-06-27 2026-01-02 北京泰德制药股份有限公司 组织蛋白酶c抑制剂化合物及其应用

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