WO2019149089A1 - 含有羧酸基团的苯并氮杂环类化合物及其制备方法和用途 - Google Patents

含有羧酸基团的苯并氮杂环类化合物及其制备方法和用途 Download PDF

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WO2019149089A1
WO2019149089A1 PCT/CN2019/072278 CN2019072278W WO2019149089A1 WO 2019149089 A1 WO2019149089 A1 WO 2019149089A1 CN 2019072278 W CN2019072278 W CN 2019072278W WO 2019149089 A1 WO2019149089 A1 WO 2019149089A1
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group
alkyl
compound
alkylene
alkyleneoxy
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PCT/CN2019/072278
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English (en)
French (fr)
Inventor
宋帅
田强
吴勇勇
赵明亮
王超磊
蔡家强
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to US16/959,691 priority Critical patent/US11292785B2/en
Priority to CN201980007236.9A priority patent/CN111630047B/zh
Priority to JP2020536998A priority patent/JP7263659B2/ja
Priority to EP19747600.5A priority patent/EP3747881B1/en
Priority to KR1020207019156A priority patent/KR20200116912A/ko
Publication of WO2019149089A1 publication Critical patent/WO2019149089A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to a benzo nitrogen heterocyclic compound containing a carboxylic acid group represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.
  • the compounds have excellent pharmacokinetic properties and extremely significant liver targeting and are useful as CCR antagonists, especially CCR2 and/or CCR5 antagonists.
  • the present application also relates to the use of said compounds for the prevention and/or treatment of CCR (especially CCR2 and/or CCR5) mediated related diseases, including but not limited to nonalcoholic fatty liver disease (NAFLD).
  • Non-alcohol fatty liver disease means that excess fat accumulates in the liver in the form of triglycerides (steatosis). It is defined as the first manifestation of hepatic steatosis by liver imaging or histology, followed by other factors that cause secondary hepatic steatosis, such as alcohol, drugs, genetic abnormalities, and the like.
  • the disease spectrum includes nonalcoholic simple fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and related liver cirrhosis and liver cancer.
  • NASH Newcastle disease virus
  • pathogenesis is most relevant to insulin resistance, obesity, and metabolic syndrome, not all patients in these states have NAFLD and/or NASH, and not all NAFLD and/or NASH patients experience these conditions. If NAFLD progresses to NASH, the risk of developing cirrhosis, liver failure and liver cancer will increase greatly.
  • NASH nonalcoholic steatohepatitis
  • the main targets for NASH are: peroxisome proliferator-activated receptor alpha (PPARA) and receptor delta (PPARD) agonists, farnesyl ester X receptor (FXR) agonists, inhibitory lysyl oxidative Monoclonal Antibody to Enzyme 2 (LOXL2) Protein, Apoptosis Signaling Regulator Protein Kinase (ASK1) Inhibitor, Acetyl-CoA Carboxylase (ACC) Protein Allosteric Inhibitor, Chemokine Receptor (CCR2/CCR5) Antagonist Wait.
  • PPARA peroxisome proliferator-activated receptor alpha
  • FXR farnesyl ester X receptor
  • L2 inhibitory lysyl oxidative Monoclonal Antibody to Enzyme 2
  • ASK1 Apoptosis Signaling Regulator Protein Kinase
  • ACC Acetyl-CoA Carboxylase
  • CCR2/CCR5 Antagonist Wait Antagonist Wait
  • WO03014105 describes a class of bicyclic compounds and their use in anti-HIV viruses, wherein R 1 is C 1-6 alkoxy-C 1-6 alkoxy, R 2 is tetrahydropyranylamino, alkyl substituted imidazole, triazole substituted alkyl, R 3 is halo, substituted alkyl, substituted alkoxy, Y a may be oxygen, sulfoxide, sulfone, amine substituted alkyl, Z 2a may be sulfur, sulfoxide , sulfone. It is considered that the detailed description in this patent is not part of the present invention, and its structural formula is as follows:
  • EP 1 359 681 describes a class of tricyclic compounds and their use in anti-HIV viruses, wherein R 1a is a C 1-6 alkoxy-C 1-6 alkoxy group, R 2a is a tetrahydropyranylamino group, an alkyl group Substituted imidazole, alkyl-substituted triazole, Z 2a may be sulfur, sulfoxide, sulfone, W is formula (a) or (b), and R 3 is halogen, substituted alkyl, substituted alkoxy. It is considered that the detailed description in this patent is not part of the present invention, and its structural formula is as follows:
  • WO03076411 describes a synthetic method of structural (c) optical isomers and their use for the treatment of HIV viruses. It is considered that the detailed description in this patent is not part of the present invention, and its structural formula is as follows:
  • WO2015143367 describes the use of Cenicriviroc for the treatment of HIV and fibrosis
  • WO2016105527 describes the synthesis of Cenicriviroc. It is considered that the detailed description in the above patents is not part of the invention.
  • the present application relates to the following:
  • the present application provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate thereof), stereoisomer, tautomer, prodrug thereof, or any of them. Crystal forms, metabolites, and mixtures thereof,
  • R 1 is selected from the group consisting of hydrogen, hydrazine, and C 1-6 alkyl, and the C 1-6 alkyl group is optionally substituted with R 2 ;
  • L 1 is selected from the group consisting of C 1-6 alkylene, C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene, and 3-10 membered heterocyclylene;
  • L 2 is absent or is selected from -NH-, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) Y2- , C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene; said -NH-, C 2-6 alkylene a group, a C 2-6 alkenylene group, a C 3-10 cycloalkylene group, a C 6-10 arylene group, a C 5-12 heteroarylene group, a 3-10 membered heterocyclylene group, optionally one or more Substituted independently by a substituent selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , -C(O)C 1-4 alkyl,
  • L 3 is absent or is selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, C 6-10 arylene, C 5 -12 heteroarylene and 3-10 membered heterocyclylene;
  • R 2 is selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, carboxyl, C 1-6 alkoxy, -(C 1-6 alkyleneoxy) m 1 -(C 1-6 alkyleneoxy) m 2 -C 1- a 6 alkyl group, a (C 1-6 alkyl) 2 amino group and a 5-6 membered heterocyclic group containing one or more N, O or S atoms; wherein m 1 and m 2 are each independently selected from 0, 1, 2, 3 or 4;
  • R 3 is selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, and C 3-6 cycloalkyl;
  • A is selected from a 4-7 membered heterocyclic group or a 5-10 membered heteroaryl ring group optionally substituted by a substituent selected from the group consisting of hydrazine, a C 1-6 alkyl group optionally substituted by R 6 and C 3-6 cycloalkyl, halogen, -CN, C 1-6 alkyl substituted by halogen, C 3-6 heterocycloalkyl, C 6-10 aryl and C 5-12 heteroaryl; R 6 Selected from hydrazine, hydroxy, -CN, C 1-6 alkoxy and C 3-6 cycloalkoxy;
  • n is selected from 0, 1 or 2.
  • R 1 is selected from hydrogen and C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with R 2;
  • R 2 is selected from hydroxy, carboxy, C 1-6 alkoxy Oxy, -(C 1-6 alkyleneoxy) m 1 -(C 1-6 alkyleneoxy) m 2 -C 1-6 alkyl and 5-6 containing one or more N, O or S atoms a heterocyclic group; wherein m 1 and m 2 are each independently selected from 0, 1 , 2 , 3 or 4.
  • R 1 is selected from C 1-4 alkyl, said C 1-4 alkyl is optionally substituted by R 2 ;
  • R 2 is selected from hydroxy, C 1-6 alkoxy, - (C 1-6 alkyleneoxy) m 1 -(C 1-6 alkyleneoxy) m 2 -C 1-6 alkyl and 5-6 membered heterocyclic group containing one or more N, O or S atoms Wherein m 1 and m 2 are each independently selected from 0, 1, or 2.
  • R 1 is selected from C 1-4 alkyl, said C 1-4 alkyl is optionally substituted by R 2 ;
  • R 2 is selected from C 1-4 alkoxy, -(C 1-4 alkyleneoxy) m1 -(C 1-4 alkyleneoxy) m 2 -C 1-4 alkyl and 5-6 membered heterocyclic group containing one or more N, O or S atoms;
  • m 1 and m 2 are each independently selected from 0, 1, or 2.
  • R 1 is selected from C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with R 2; R 2 is selected from C 1-4 alkoxy.
  • R 1 is
  • L 1 is selected from the group consisting of C 1-6 alkylene, C 3-10 cycloalkylene, C 6-10 arylene, and C 5-12 heteroarylene.
  • L 1 is selected from the group consisting of C 1-6 alkylene, C 3-7 cycloalkylene, C 6-8 arylene, and C 5-8 heteroarylene.
  • L 1 is selected from the group consisting of C 1-3 alkylene and C 3-5 cycloalkylene.
  • L 1 is selected from the group consisting of C 1-3 alkylene.
  • L 1 is selected from the group consisting of methylene and ethylene.
  • L 2 is absent or selected from the group consisting of -NH-, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) Y2- , C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene; the -NH-, C 2-6 -ene , -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 cycloalkylene, C 6-10 arylene, C 5-12
  • the heteroaryl and 3-10 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(O)C 1-4
  • L 2 is absent or selected from the group consisting of -NH-, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene; said -NH -, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 subring
  • the alkyl, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen , hydroxy, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy,
  • L 2 is absent or selected from the group consisting of -NH-, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene; said -NH -, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 subring
  • the alkyl, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, cyano, methyl, methyl halide group, a halogenated methoxy group, -C (O)
  • L 2 is absent or selected from the group consisting of -NH-, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene; said -NH -, C 2-6 alkenylene group, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 cycloalkylene group, C 6-10 sub
  • the aryl, C 5-12 heteroarylene and 3-10 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, and a group, a halomethylalkyl group, a halogenated methoxy group, -C(O
  • L 2 is absent or selected from the group consisting of -NH-, C 2-4 alkylene, C 2-3 alkenylene, -(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) y2 -, C 3-6 cycloalkylene, C 6-8 arylene, C 5-8 heteroarylene and 3-6 membered heterocyclylene; said -NH -, C 2-4 alkylene, C 2-3 alkenylene, -(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) y2 -, C 3-6 subring
  • the alkyl, C 6-8 arylene, C 5-8 heteroarylene and 3-6 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, cyano, methyl, methyl halide group, a halogenated methoxy group, -C (O) CH 3,
  • L 2 is absent or selected from the group consisting of -NH-, C 2-4 alkylene, C 2-3 alkenylene, -(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) y2 -, C 3-6 cycloalkylene, C 6-8 arylene, C 5-8 heteroarylene and 3-6 membered heterocyclylene; said -NH -, C 2-3 alkenylene, -(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) y2 -, C 3-6 cycloalkylene, C 6-8
  • the aryl, C 5-8 heteroarylene and 3-6 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, and a group, a halomethylalkyl group, a halogenated methoxy group, -C(O)CH 3 ,
  • L 2 is absent.
  • L 2 is selected from the group consisting of C 2-4 alkylene.
  • L 2 is selected from the group consisting of -NH-, -N(CH 3 )-, and -C(CH 3 ) 2 -.
  • L 2 is -C(CH 3 ) 2 -.
  • L 3 is absent or selected from C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, C 3-6 cycloalkylene, C 6 -8 arylene, C 5-8 heteroarylene and 3-7 membered heterocyclylene.
  • L 3 is absent or selected from the group consisting of C 1-6 alkylene and C 2-6 alkenylene.
  • L 3 is absent.
  • L 3 is -CH 2 -.
  • A is selected from a 4-7 membered heterocyclyl or a 5-10 membered heteroaryl ring.
  • A is selected from a 4-7 membered nitrogen-containing heterocyclic group or a 5-10 membered nitrogen-containing heteroaryl ring group.
  • A is selected from a 4-7 membered nitrogen-containing heterocyclic group or a 5-10 membered nitrogen-containing heteroaryl ring group optionally substituted with a substituent selected from the group consisting of hydrogen, hydrazine, and any of C 1-6 alkyl and C 3-6 cycloalkyl optionally substituted by R 6 , halogen, -CN, C 1-6 alkyl substituted by halogen, C 3-6 heterocycloalkyl, C 6- 10 aryl and C 5-12 heteroaryl; R 6 is selected from the group consisting of hydrazine, hydroxy, -CN, C 1-6 alkoxy and C 3-6 cycloalkoxy.
  • A is selected from a 5 or 6 membered nitrogen-containing heteroaryl ring group.
  • A is selected from optionally substituted 5 or 6 membered heteroaromatic ring-containing group, said substituents are selected from deuterium, R 6 is optionally substituted C 1-6 alkyl And C 3-6 cycloalkyl, halogen, -CN, C 1-6 alkyl substituted by halogen, C 3-6 heterocycloalkyl, C 6-10 aryl and C 5-12 heteroaryl; R 6 is selected from the group consisting of hydrazine, hydroxy, -CN, C 1-6 alkoxy and C 3-6 cycloalkoxy.
  • A is a 5-membered nitrogen-containing heteroaryl ring group.
  • A is a 5-membered nitrogen-containing heteroaryl ring optionally substituted with a substituent selected from the group consisting of hydrazine, C 1-6 alkyl optionally substituted by R 6 and C 3-6 cycloalkyl, halogen, -CN, halogenated C 1-6 alkyl, C 3-6 heterocycloalkyl, C 6-10 aryl and C 5-12 heteroaryl;
  • R 6 is selected from Anthracene, hydroxy, -CN, C 1-6 alkoxy and C 3-6 cycloalkoxy;
  • A is a 5-membered nitrogen-containing heteroaryl ring group substituted with a substituent which is a C 1-6 alkyl group (e.g., a propyl group).
  • A is wherein R 4 is selected from hydrogen, hydrazine or a C 1-6 alkyl group optionally substituted by R 6 and a C 3-6 cycloalkyl group, and R 6 is selected from the group consisting of hydrazine, hydroxy, -CN, C 1-4 alkoxy And C 3-6 cycloalkoxy, R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, -CN, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylene-CN , C 1-6 alkylene-OH, C 1-6 alkylene-C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl And C 5-12 heteroaryl, X is selected from N and CR 5 , and each R 5 is the same or different.
  • A is selected from
  • R 4 is C 1-6 alkyl optionally substituted by R 6 and R 6 is selected from the group consisting of hydrazine, hydroxy, -CN, and C 1-4 alkoxy.
  • R 4 is C 1-6 alkyl optionally substituted by R 6 and R 6 is selected from hydroxy and C 1-4 alkoxy.
  • R 4 is C 1-4 alkyl optionally substituted by R 6 and R 6 is selected from hydroxy and C 1-4 alkoxy.
  • R 4 is C 1-4 alkyl optionally substituted by R 6 and R 6 is selected from the group consisting of hydrogen, hydroxy, methoxy, and ethoxy.
  • R 4 is C 1-4 alkyl optionally substituted by R 6 and R 6 is selected from methoxy and ethoxy.
  • R 4 is selected from the group consisting of n-propyl and
  • R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene -C 1-6 alkoxy, C 3-6 cycloalkyl and C 3-6 heterocycloalkyl.
  • R 5 is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, halogenated C 1-6 alkyl, and C 3-6 cycloalkyl.
  • R 5 is selected from the group consisting of hydrogen, methyl, trifluoromethyl, and cyclopropane.
  • R 5 is hydrogen
  • X is selected from the group consisting of N and CR 5 and R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylene-OH C 1-6 alkylene-C 1-6 alkoxy, C 3-6 heterocycloalkyl and C 3-6 heterocycloalkyl.
  • X is selected from N and CR 5
  • R 5 is selected from hydrogen, deuterium, C 1-6 alkyl, halo C 1-6 alkyl and C 3-6 cycloalkyl.
  • X is selected from N and CR 5
  • R 5 is selected from hydrogen, methyl, trifluoromethyl, and cyclopropyl.
  • L 1 is selected from the group consisting of C 1-6 alkylene, C 3-10 cycloalkylene, C 6-10 arylene, and C 5-12 heteroarylene; preferably, L 1 is selected from C 1-3 alkylene and C 3-5 cycloalkylene; more preferably, L 1 is selected from the group consisting of methylene and ethylene;
  • L 2 is absent or is selected from -NH-, C 2-4 alkylene, C 2-3 alkenylene, -(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) Y2- , C 3-6 cycloalkylene, C 6-8 arylene, C 5-8 heteroarylene, and 3-6 membered heterocyclylene; the -NH-, C 2-4 alkylene , C 2-3 alkenylene, -(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) y2 -, C 3-6 cycloalkylene, C 6-8
  • the aryl, C 5-8 heteroarylene and 3-6 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, and a group, a halomethylalkyl group, a halogenated methoxy group, -C(O)CH 3 ,
  • n is selected from 1 or 2, preferably n is 1.
  • the present application provides the general formula I a or I b as shown in a compound or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer, Body, prodrug, or any of their crystal forms, metabolites, and mixtures thereof:
  • R 1 , R 4 , R 5 , L 1 , L 2 , L 3 , X and n are as defined above.
  • the present application provides a compound of Formula II a and Formula II a' , or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate thereof), stereoisomer, tautomer Isomers, prodrugs, or any of their crystal forms, metabolites, and mixtures thereof:
  • R 1 , R 4 , R 5 , X, L 1 , L 2 , L 3 or n are as defined above.
  • the present application provides a compound of Formula II a and Formula II a' , wherein R 1 is selected from the group consisting of hydrogen, hydrazine, and C 1-6 alkyl, said C 1-6 alkane The group is optionally substituted by R 2 , and R 2 is selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, carboxy, C 1-6 alkoxy, -(C 1-6 alkyleneoxy) m 1 -(C 1-6 Alkoxy) m 2 -C 1-6 alkyl, (C 1-6 alkyl) 2 amino group and 5-6 membered heterocyclic group containing one or more N, O or S atoms; wherein m 1 , m 2 Individually selected from 0, 1, 2, 3 or 4;
  • R 1 is C 1-6 alkyl, and the C 1-6 alkyl group is optionally substituted by C 1-6 alkoxy;
  • R 1 is C 1-3 alkyl, and the C 1-3 alkyl group is optionally substituted by C 1-6 alkoxy;
  • R 1 is ethyl and the ethyl group is substituted by n-butoxy.
  • the present application provides a compound of Formula II a and Formula II a' wherein X is selected from N and CR 5 and R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, -CN, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylene-CN, C 1-6 alkylene-OH, C 1-6 alkylene-C 1-6 alkoxy a group, a C 3-6 cycloalkyl group, a C 3-6 heterocycloalkyl group, a C 6-10 aryl group, and a C 5-12 heteroaryl group;
  • X is selected from N and CR 5 and R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, halogenated C 1-6 alkyl and C 3-6 cycloalkyl;
  • X is selected from the group consisting of N and CR 5
  • R 5 is selected from the group consisting of hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, and C 3-6 cycloalkyl
  • X is selected from the group consisting of N and CR 5 and R 5 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and cyclopropyl;
  • X is CR 5 and R 5 is selected from the group consisting of hydrogen and methyl.
  • the present application provides a compound of Formula II a and Formula II a' , wherein R 4 is selected from hydrogen, hydrazine or C 1-6 alkane, optionally substituted by R 6 And a C 3-6 cycloalkyl group, R 6 is selected from the group consisting of hydrogen, hydrazine, hydroxy, -CN, C 1-4 alkoxy, and C 3-6 cycloalkoxy;
  • R 4 is selected from C 1-6 alkyl and C 3-6 cycloalkyl optionally substituted by R 6 , and R 6 is C 1-4 alkoxy;
  • R 4 is selected from C 1-3 alkyl optionally substituted by R 6 and R 6 is C 1-3 alkoxy;
  • R 4 is selected from the group consisting of a propyl group and an ethyl group substituted with a methoxy group;
  • R 4 is n-propyl.
  • the present application provides a compound of Formula II a and Formula II a' , wherein
  • L 1 is selected from the group consisting of C 1-6 alkylene, C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene, and 3-10 membered heterocyclylene;
  • L 1 is a C 1-3 alkylene group; preferably, L 1 is selected from the group consisting of methylene and ethylene.
  • the present application provides a compound of Formula II a and Formula II a' , wherein
  • L 2 is absent or is selected from -NH-, C 2-6 alkylene, C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) Y2- , C 3-10 cycloalkylene, C 6-10 arylene, C 5-12 heteroarylene and 3-10 membered heterocyclylene; said -NH-, C 2-6 alkylene , C 2-6 alkenylene, -(C 1-6 alkyleneoxy) y1 -(C 1-6 alkyleneoxy) y2 -, C 3-10 cycloalkylene, C 6-10
  • the aryl, C 5-12 heteroarylene and 3-10 membered heterocyclylene are optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, C 1 -3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, -C(O)C
  • L 2 is absent or selected from -NH-, -N(CH 3 )- and -C(CH 3 ) 2 -;
  • L 2 is selected from the group consisting of -NH-, -N(CH 3 )-, and -C(CH 3 ) 2 -.
  • L 2 is absent.
  • the present application provides a compound of Formula II a and Formula II a' , wherein
  • L 3 is absent or is selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, C 6-10 arylene, C 5 -12 heteroarylene and 3-10 membered heterocyclylene;
  • L 3 is absent or selected from C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, C 3-6 cycloalkylene, C 6-8 arylene a C 5-8 heteroarylene group and a 3-7 membered heterocyclylene group;
  • L 3 is absent or is selected from the group consisting of C 1-6 alkylene and C 2-6 alkenylene;
  • L 3 is absent.
  • the present application provides a compound of Formula II a and Formula II a' , wherein
  • n is selected from 0, 1 or 2; preferably, n is selected from 0 and 1; preferably, n is 1.
  • the present application provides a compound of Formula II a and Formula II a' , wherein
  • R 1 is C 1-3 alkyl, and the C 1-3 alkyl group is optionally substituted by C 1-6 alkoxy;
  • X is selected from N and CR 5 and R 5 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and cyclopropyl;
  • R 4 is selected from the group consisting of propyl and ethyl substituted by methoxy
  • L 1 is a C 1-3 alkylene group; preferably, L 1 is selected from the group consisting of a methylene group and an ethylene group;
  • L 2 is absent or selected from -NH-, -N(CH 3 )- and -C(CH 3 ) 2 -;
  • n is selected from 0 and 1; preferably, n is 1.
  • the present application provides a compound of Formula II b and Formula II b' , or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate thereof), stereoisomer, tautomer thereof Constructs, prodrugs, or any of their crystal forms, metabolites, and mixtures thereof,
  • R 1 , R 4 , R 5 , X, L 1 , L 2 , L 3 or n are as defined above.
  • the present application provides a compound, or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate), stereoisomer, tautomer, prodrug thereof, or any crystal thereof Types, metabolites, and mixtures thereof, the compounds selected from:
  • the atoms in the compounds of the invention may be replaced by their isotopes.
  • 12 C can be replaced by its isotope 13 C or 14 C;
  • 1 H can be replaced by 2 H (D, ⁇ ) or 3 H (T, ⁇ ).
  • the invention includes isotopically-labeled compounds obtained by the replacement of any of the compounds by their isotopes.
  • the application also relates to a process for the preparation of a compound of formula I, which comprises the following synthetic route:
  • L is a group having an aldehyde group at the terminal, and L can be converted to L 1 by the reaction (preferably, L 1 is C) 1-3 alkylene group, more preferably, L 1 is selected from the group consisting of methylene and ethylene), and the carboxy protecting group PG is selected from the group consisting of the following groups optionally substituted by one or more R 7 substituents: C 1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 aryl, C 1-6 alkylene -C 6-10 aryl, C 5-12 heteroaryl, R 7 is selected from the group consisting of hydrogen, hydrazine, halogen, C 1-6 alkyl and C 1-6 alkoxy.
  • the carboxy protecting group PG is preferably a C 1-6 alkyl
  • the method includes the following steps:
  • Step 1 Compound a is reacted with compound b to obtain compound c;
  • the reaction is preferably carried out in a suitable organic solvent, which may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-). Dichloroethane, etc.), nitriles (such as acetonitrile, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide and any In combination, dioxane or 1,2-dichloroethane is preferred.
  • a suitable organic solvent which may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-). Dichloroethane, etc.), nitriles (such
  • the reaction is preferably carried out in the presence of a suitable reducing agent which may be selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium borohydride.
  • a suitable reducing agent which may be selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium borohydride.
  • the reducing agent is cyano boron.
  • Sodium hydride is preferably carried out under suitable acidic conditions, which may be selected from the group consisting of hydrochloric acid, acetic acid and trifluoroacetic acid, preferably the acid is trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature, preferably at a temperature of from -50 to 100 ° C, more preferably from -20 to 70 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 1 to 24 hours, for example 1 to 6 hours.
  • Step 2 Compound c is reacted with compound d to give compound e.
  • the reaction is preferably carried out in a suitable organic solvent, which may be selected from the group consisting of halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (e.g., acetonitrile, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide, and any combination thereof are preferably dichloromethane.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • nitriles e.g., acetonitrile, etc.
  • N-methylpyrrolidone e.g., dimethylformamide, dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide, and any combination thereof are preferably dichloromethane.
  • the reaction is preferably carried out in the presence of a suitable condensing agent, which may be selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, ethyl chloroformate, chloroformic acid.
  • a suitable condensing agent which may be selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, ethyl chloroformate, chloroformic acid.
  • a suitable condensing agent which may be selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, ethyl chloroformate, chloroformic acid.
  • the reaction is preferably carried out under suitable basic conditions, the base being an organic base or an inorganic base, preferably the organic base is selected from the group consisting of triethylamine, DIPEA, pyridine, NMM or DMAP, preferably, said The inorganic base is selected from the group consisting of NaH, NaOH, Na 2 CO 3 or K 2 CO 3 .
  • the base is selected from the group consisting of triethylamine, DIPEA and DMAP.
  • the reaction is preferably carried out at a suitable temperature, preferably at a temperature of from 0 to 100 ° C, more preferably from 15 to 50 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 1 to 24 hours, for example 2 to 7 hours.
  • Step 3 Compound e is subjected to removal of the protecting group to give a compound of formula I.
  • the reaction is preferably carried out in a suitable water and/or organic solvent, which may be selected from the group consisting of halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (e.g. Acetonitrile, etc., alcohols (such as methanol, ethanol), ethers (such as tetrahydrofuran, dioxane), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and Any combination, preferably water and ethanol.
  • the reaction is preferably carried out under suitable acidic conditions, such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.
  • the reaction is preferably carried out under suitable basic conditions, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.
  • the base is selected from the group consisting of sodium hydroxide.
  • the reaction is preferably carried out at a suitable temperature, preferably at a temperature of from -20 to 100 ° C, more preferably from 0 to 60 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 1 to 24 hours.
  • the application also relates to a process for the preparation of a compound of formula I a :
  • L is a group having an aldehyde group at the terminal, and L can be converted into L 1 by the reaction.
  • L 1 is a C 1-3 alkylene group, more preferably, L 1 is selected from the group consisting of a methylene group and an ethylene group
  • a method for producing the compound of the formula I a is referred to a method for producing the compound of the formula I.
  • the application also relates to a process for the preparation of a compound of formula Ib :
  • L is a group having an aldehyde group at the terminal, and L can be converted into L 1 by the reaction.
  • L 1 is a C 1-3 alkylene group, more preferably, L 1 is selected from the group consisting of a methylene group and an ethylene group
  • a preparation method of the compound of the formula Ib is carried out with reference to a method for producing a compound of the formula I.
  • the present application provides processes for preparing the formula II a and a compound and / or the general formula II a 'is:
  • L is a group having an aldehyde group at the terminal, and L can be converted into L 1 by the reaction.
  • L 1 is a C 1-3 alkylene group, and more preferably, L 1 is selected from the group consisting of a methylene group and an ethylene group).
  • R 1 , R 4 , R 5 , n, L 1 , L 2 , L 3 and X are as defined above.
  • the method 2 includes the following steps:
  • Step 1 The compound of formula I a is isolated to give a compound of formula II a and formula II a' .
  • the separation method uses a commercially available chiral preparation column, preferably OD, OJ, AS, AD, IA, IB, IC, ID, etc., with alcohol (ethanol and isopropanol, etc.), weakly polar solvent (n-hexane, Petroleum ether, CO 2 , etc., co-solvent (dichloromethane, etc.) and alkali (ammonia, diethylamine, etc.) are classified and purified as a mobile phase, and components having an ee value of >99% are collected.
  • alcohol ethanol and isopropanol, etc.
  • weakly polar solvent n-hexane, Petroleum ether, CO 2 , etc.
  • co-solvent diichloromethane, etc.
  • alkali ammonia, diethylamine, etc.
  • R 1 , R 4 , R 5 , n, L 1 , L 2 , L 3 and X are as defined above.
  • the method three includes the following steps:
  • Step 1 Compound e is isolated to give compound h and compound h'.
  • the method uses a commercially available chiral preparative column, preferably OD, OJ, AS, AD, IA, IB, IC, ID, etc., with alcohol (ethanol and isopropanol, etc.), weak polar solvent (n-hexane, petroleum) Ether, CO 2 , etc., cosolvent (dichloromethane, etc.) and alkali (ammonia, diethylamine, etc.) are classified and purified as a mobile phase, and components having an ee value of >99% are collected.
  • alcohol ethanol and isopropanol, etc.
  • weak polar solvent n-hexane, petroleum
  • CO 2 etc.
  • cosolvent diichloromethane, etc.
  • alkali ammonia, diethylamine, etc.
  • Step 2 Compound h and compound h' are subjected to removal of the protecting group to give the compound of the formula II a and the formula II a' , respectively.
  • the reaction is preferably carried out in a suitable water and/or organic solvent, which may be selected from the group consisting of halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), nitriles (e.g. Acetonitrile, etc., alcohols (such as methanol, ethanol), ethers (such as tetrahydrofuran, dioxane), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and Any combination, preferably water and ethanol.
  • the reaction is preferably carried out under suitable acidic conditions, such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.
  • the reaction is preferably carried out under suitable basic conditions, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.
  • the base is selected from the group consisting of sodium hydroxide.
  • the reaction is preferably carried out at a suitable temperature, preferably at a temperature of from -20 to 100 ° C, more preferably from 0 to 60 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 1 to 24 hours.
  • the application provides a method of preparing a compound of Formula II b and/or Formula II b' , the method comprising the steps of:
  • L is a group having an aldehyde group at the terminal, and L can be converted into L 1 by the reaction.
  • L 1 is a C 1-3 alkylene group, and more preferably, L 1 is selected from the group consisting of a methylene group and an ethylene group).
  • the method of synthesis is carried out with reference to the synthetic step of the compound of formula Ib .
  • R 1 , R 4 , R 5 , n, L 1 , L 2 , L 3 and X are as defined above.
  • the method 2 includes the following steps:
  • Step 1 The compound of formula Ib is isolated to give a compound of formula II b and formula II b' .
  • the separation method uses a commercially available chiral preparation column, preferably OD, OJ, AS, AD, IA, IB, IC, ID, etc., with alcohol (ethanol and isopropanol, etc.), weakly polar solvent (n-hexane, Petroleum ether, CO 2 , etc., co-solvent (dichloromethane, etc.) and alkali (ammonia, diethylamine, etc.) are classified and purified as a mobile phase, and components having an ee value of >99% are collected.
  • alcohol ethanol and isopropanol, etc.
  • weakly polar solvent n-hexane, Petroleum ether, CO 2 , etc.
  • co-solvent diichloromethane, etc.
  • alkali ammonia, diethylamine, etc.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound encompassed by the first aspect, or a pharmaceutically acceptable salt, ester, solvate thereof (eg, hydrate), stereoisomer, tautomer Body, prodrug, or any of their crystal forms, metabolites, and mixtures thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is a tablet, a capsule, a troche, a hard candy, a powder, a spray, a cream, an ointment, a suppository, a gel, a paste, a lotion, Ointments, aqueous suspensions, injectable solutions, elixirs or syrups.
  • the pharmaceutical composition further comprises one or more additional agents that prevent or treat diseases or conditions mediated by CCR2 and/or CCR5, particularly diseases such as nonalcoholic fatty liver disease (NAFLD).
  • additional agents that prevent or treat diseases or conditions mediated by CCR2 and/or CCR5, particularly diseases such as nonalcoholic fatty liver disease (NAFLD).
  • NAFLD nonalcoholic fatty liver disease
  • the present application provides a pharmaceutical formulation comprising the compound of the first aspect, or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate thereof), stereoisomer, tautomer thereof And prodrugs, or any of their crystalline forms, metabolites, and mixtures thereof, or the compositions, and one or more pharmaceutically acceptable carriers.
  • kit product comprising:
  • a) a first container comprising at least one compound of the first aspect, or a pharmaceutically acceptable salt, ester, solvate (e.g., hydrate), stereoisomer, tautomer thereof, as a first therapeutic agent Body, prodrug, or any of their crystal forms, metabolites, and mixtures thereof, or the pharmaceutical composition as the first pharmaceutical composition;
  • a second container optionally present comprising at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising said other therapeutic agent as a second pharmaceutical composition;
  • the additional therapeutic agent is selected from the group consisting of a compound of the present disclosure that is useful for preventing or treating a disease or condition mediated by CCR2 and/or CCR5, particularly non-alcoholic fatty liver disease (NAFLD). Other drugs outside.
  • the application provides the compound of the first aspect, or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate), stereoisomer, tautomer, prodrug thereof, or any of them Forms, metabolites, and mixtures, pharmaceutical compositions, pharmaceutical preparations or kit products thereof for the preparation or use thereof for the prevention or treatment of diseases or conditions mediated by CCR2 and/or CCR5, especially nonalcoholic fatty liver disease (NAFLD) Use in medicines for diseases.
  • the application provides the compound of the first aspect, or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate), stereoisomer, tautomer, prodrug thereof, or any of them Crystal forms, metabolites, and mixtures thereof, pharmaceutical compositions, pharmaceutical preparations or kit products for use in the prevention or treatment of diseases or conditions mediated by CCR2 and/or CCR5, especially non-alcoholic fatty liver disease (NAFLD), etc. disease.
  • a pharmaceutically acceptable salt, ester, solvate eg, hydrate
  • stereoisomer e.g., hydrate
  • tautomer e.g., prodrug thereof
  • Crystal forms, metabolites, and mixtures thereof pharmaceutical compositions, pharmaceutical preparations or kit products for use in the prevention or treatment of diseases or conditions mediated by CCR2 and/or CCR5, especially non-alcoholic fatty liver disease (NAFLD), etc. disease.
  • NAFLD non-alcoholic fatty liver disease
  • the application provides a method of preventing or treating a CCR2 and/or CCR5 mediated disease or condition, particularly a disease such as nonalcoholic fatty liver disease (NAFLD), comprising administering to a subject in need thereof a therapeutically effective amount of the disease.
  • a CCR2 and/or CCR5 mediated disease or condition particularly a disease such as nonalcoholic fatty liver disease (NAFLD)
  • NAFLD nonalcoholic fatty liver disease
  • a prophylactic or therapeutic agent for a disease or condition mediated by CCR2 and/or CCR5 in particular a non-alcoholic fatty liver disease (NAFLD) Other drugs.
  • NASH non-alcoholic fatty liver disease
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
  • the carrier described therein includes, but is not limited to, an ion exchanger, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants.
  • Partial glyceride mixture of fatty acids, water, salt or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fiber Substance, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • compositions, pharmaceutical preparations or kits can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, peritoneal Internal, intranasal, intramuscular route or as an inhaler.
  • the pharmaceutical composition may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases.
  • the application provides the compound of the first aspect, or a pharmaceutically acceptable salt, ester, solvate (eg, hydrate), stereoisomer, tautomer, prodrug thereof, or any crystalline form or metabolite thereof And mixtures or pharmaceutical compositions thereof may be formulated into various suitable dosage forms depending on the route of administration.
  • compositions or suitable dosage forms described herein may contain from 0.01 mg to 1000 mg of the compound.
  • compositions may be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension.
  • some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.
  • mixtures or pharmaceutical compositions thereof may be prepared in the form of a suitable ointment, lotion or cream preparation, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may also be administered in the form of a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • suitable in vitro or in vivo assays are performed to determine the effect of the pharmaceutical composition and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments.
  • an effective amount of the pharmaceutical composition sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day.
  • the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the dosage may range from about 0.01 to 1000 mg/kg of subject weight per day, every two days or every three days, more typically from 0.1 to 500 mg/kg of subject weight.
  • An exemplary treatment regimen is once every two days or once a week or once a month.
  • the formulation is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
  • the formulation may be administered in the form of a sustained release formulation, in which case less dosing frequency is required.
  • the dosage and frequency will vary depending on the half-life of the formulation in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment.
  • relatively low doses are administered chronically at relatively low frequency intervals.
  • alkyl is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 8, such as from 1 to 4 carbon atoms.
  • C1-6 alkyl refers to a straight or branched chain group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (at this time)
  • This group is referred to as "haloalkyl” such as -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH
  • alkylene is defined as a saturated divalent hydrocarbon radical derived from the removal of two hydrogen atoms from a linear or branched saturated hydrocarbon radical, the alkylene radical containing from 1 to 10 a carbon atom, 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 to 3 carbon atoms, such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene A group (-CH(CH 3 )CH 2 -) or the like wherein the alkylene group may be independently unsubstituted or substituted with one or more substituents described herein.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridging systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.), It is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused
  • the cycloalkyl group has 3 to 15, such as 3 to 10 carbon atoms, 3 to 7 carbon atoms or 3 to 6 carbon atoms such as as used herein, the term "C 3 - 7 cycloalkyl” means a 3-7 ring carbon atoms, a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic a hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl Substituted cyclopropyl.
  • a saturated or unsaturated non-aromatic monocyclic or polycyclic such as bicyclic a hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl)
  • C 3-10 cycloalkylene is defined as a C 3-10 alkyl residue having 2 unsaturation valences, such as a divalent methylene residue, such as a cyclopropylene group, Cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and especially cyclopentylene Base, cyclohexylene.
  • alkoxy refers to a linear, branched or cyclic saturated monovalent hydrocarbon radical of the formula -O-alkyl, wherein the term “alkyl” is as defined above or as defined below.
  • Cycloalkyl for example C 1-6 alkyl, C 1-3 alkyl or C 3-6 cycloalkyl, for example methoxy, ethoxy, n-propoxy, isopropoxy, ring Propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutoxy, pentyloxy, isopentyloxy or n-hexyloxy, or isomers thereof.
  • R a represents a hydrogen atom or a C 1-6 alkyl group or a halogenated-C 1-6 alkyl group; said heterocycloalkyl group may be passed through any one of said carbon atoms or a nitrogen atom, if present, and The rest of the molecule is connected.
  • a C 3-6 heterocyclic group, a C 5-6 or C 3-7 heterocyclic group is a heterocyclic group having 3 to 6 carbon atoms, 5 to 6 or 3 to 7 carbon atoms, and a 3 to 10 membered heterocyclic group is a group having 3 to 10 carbon atoms and a hetero atom in the ring, and a 4-7 membered heterocyclic group is a group having 4 to 7 carbon atoms and a hetero atom in the ring, such as, but not limited to, ethylene oxide.
  • Aziridine azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinone, imidazolidine Or pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heteroarylene refers to a heteroaryl group having 2 unsaturation valences, for example having 5 to 12, 5 to 10 or 5 to 8 carbon atoms.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C6-10 aromatic ring means an aromatic group containing from 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • arylene refers to an aryl group having 2 unsatisfied valencies, for example having from 6 to 10 or from 6 to 8 carbon atoms, for example, a phenylene group.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example having 5-10 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen) Or sulfur), and, in each case, may be benzo-fused.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia Diazolyl, etc. and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and their benzo derivatives.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and one of its hydrogen atoms replaced by a bond.
  • the alkenyl group can be a linear or branched alkenyl group and contains from about 2 to about 15 carbon atoms.
  • C 2-6 alkenyl herein has from about 2 to about 6 carbon atoms.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • the alkenyl group may be an unsubstituted alkenyl group or may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, Hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH( Cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH and -C(O)O-alkyl.
  • C 2-6 alkenyl refers to an alkenyl group of 2 to 6 carbon atoms.
  • alkenylene refers to a straight or branched divalent hydrocarbon that attaches the remainder of the molecule to a group, consisting solely of carbon and hydrogen atoms, containing at least one double bond and having two Six carbon atoms, such as ethenylene, propenylene, n-butenyl, and the like.
  • the alkenylene chain is attached to the remainder of the molecule via a double bond or a single bond and to the group via a double bond or a single bond.
  • the alkenylene chain and the remainder of the molecule and the point of attachment to the group may pass through one carbon or any two carbons in the chain.
  • alkynyl refers to a hydrocarbon group having one or more C ⁇ C triple bonds.
  • the alkynyl group has, but is not limited to, 2 to 18 carbon atoms, for example, it has 2 to 10 carbon atoms, for example 2 to 6 carbon atoms.
  • lower alkynyl herein is meant alkynyl having a lower carbon number, for example having from 2 to 8 carbon atoms, for example 2 to 6 carbon atoms, for example 2 to 4 carbon atoms.
  • alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like.
  • alkynyl groups as defined herein are in the numerical range, for example "C 2 -C 6 alkynyl” or "C 2-6 alkynyl” means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons
  • An alkynyl group consisting of an atom or 6 carbon atoms, the alkynyl group herein also covers the unspecified range of numbers.
  • alkynylene refers to an alkynyl group, as defined above, wherein one of the hydrogen atoms of the alkynyl group has been replaced by a bond.
  • alkynylene include -CH 2 C ⁇ C-, -CH 2 C ⁇ CCH 2 -, and -CH(CH 3 )C ⁇ C-, for example, alkynylene has 2 to 6 carbon atoms.
  • Alkynylene is branched or straight chain.
  • C 2-6 alkynylene refers to an alkynylene group having 2 to 6 carbon atoms
  • C 2-3 alkynylene group means an alkynylene group having 2 to 3 carbon atoms.
  • amino refers to a nitrogen-containing moiety having two further substituents wherein a chlorine or carbon atom is attached to the nitrogen.
  • representative amino groups include -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 and the like.
  • a compound of the invention containing an amino moiety can include a protected derivative thereof.
  • Suitable protecting groups for the amino moiety include acetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • carboxylic acid group also referred to as “carboxy” refers to a functional group of the formula -COOH.
  • carboxy also includes the related anion-COO- (carboxylate ion).
  • the functional group may be present in the form -COOH or -COO-.
  • halo C 1-6 alkyl refers to one or more of the C 1-6 alkyl groups as described above (eg, 1, 2, 3 or 4) a group obtained by substituting a hydrogen atom with a halogen such as fluorine, chlorine, bromine or iodine, for example, a halogenated C 1-3 alkyl group, a halogenated methyl group, a halogenated ethyl group, a halogenated C 3 alkyl group, or a halogenated group.
  • a halogen such as fluorine, chlorine, bromine or iodine
  • C 4 alkyl fluoro C 1-3 alkyl, fluoromethyl, fluoroethyl, fluoro C 3 alkyl, fluoro C 4 alkyl, chloro C 1-3 alkyl, chloro Base, chloroethyl, chloro C 3 alkyl, chloro C 4 alkyl.
  • Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, chloroethyl, and the like.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded.
  • the normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • optionally substituted refers to being optionally substituted with a particular group, radical or moiety.
  • the compounds of the invention may also comprise one or more (e.g., one, two, three or four) isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or ⁇ ) and 3 H (T or ⁇ );
  • C may be in any isotopic form, including 12 C, 13 C and 14 C;
  • O can be any isotopic form, including 16 O and 18 O.
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • compounds having one or more (eg, one, two, three, or four) asymmetric centers which can produce racemates, racemic mixtures, single enantiomers, diastereoisomers The mixture of the constructs and the individual diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • the present application encompasses all possible crystalline forms or polymorphs of the compounds, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compound or a pharmaceutically acceptable salt thereof may also form a solvate such as an alcoholate or the like.
  • the compound may also be in the form of a prodrug or the release of the active ingredient after or after metabolic changes in the body.
  • suitable prodrug derivatives are well known to those skilled in the art.
  • the compound may also be in a chemically protected form which is protected on a reactive group (e.g., an amino group) of the compound which is metabolized in vivo to release the active ingredient.
  • a reactive group e.g., an amino group
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other components that make up the formulation and/or the mammals treated therewith.
  • pharmaceutically acceptable salt includes a conventional salt formed with a pharmaceutically acceptable inorganic or organic acid, or an inorganic or organic base.
  • suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and Inorganic salts of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • compositions of the present application may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • Pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, when administered to a patient in need thereof, are capable of providing the compound directly or indirectly Its metabolite or residue.
  • Pharmaceutically acceptable salts of the compounds include the acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Suitable base addition salts are formed from bases which form non-toxic salts.
  • Acceptable inorganic bases include aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include tromethamine, N-methylglucamine, and the like.
  • the compound may exist in the form of a hydrate or solvate wherein the compound of the invention comprises a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention i.e., compounds formed in vivo upon administration of the drug.
  • composition includes a product comprising a therapeutically effective amount of the compound, as well as any product produced directly or indirectly from a combination of the compounds.
  • an effective amount refers to an amount sufficient to achieve the desired therapeutic effect, for example, to achieve a reduction in the symptoms associated with the condition to be treated.
  • treatment is intended to alleviate or eliminate the disease state or condition to which it is directed. If the subject receives a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, the subject exhibits one or more indications and symptoms Observable and/or detectable reduction or improvement, the subject is successfully "treated”. It will also be appreciated that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medical related results.
  • Treatment means any administration of the compound, including:
  • the nuclear magnetic resonance ( 1 H NMR) measuring instrument used a Bruker 400 MHz nuclear magnetic resonance apparatus; the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), and hexa- dimethyl sulfoxide (DMSO-d 6). ); the internal standard substance is tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometer
  • ESI Agilent 6120B
  • Step 1 Synthesis of 3-hydroxy-2,2-dimethylpropionic acid ethyl ester
  • Oxalyl chloride (522 mg, 4.1 mmol) was dissolved in dichloromethane (5 mL), the system was cooled to -78 ° C, dimethyl sulfoxide (640 mg, 8.2 mmol) was added dropwise thereto, and the reaction was kept for 30 min. Then, a solution of the compound 1-2 (500 mg, 3.4 mmol) in dichloromethane (5 mL) was added dropwise thereto, and the mixture was diluted at -78 ° C for 2 h, and triethylamine (1.03 g, 10.2 mmol) was added dropwise thereto. After completion, the reaction was carried out at -78 ° C for 1 h, and returned to room temperature for 30 min.
  • Step 3 (E)-8-(4-(2-Butoxyethoxy)phenyl)-1-(3-ethoxy-2,2-dimethyl-3-oxopropyl) Synthesis of -1,2,3,4-tetrahydrobenzo[b]azetidin-4-ene-5-carboxylic acid
  • Step 4 (S,E)-3-(8-(4-(2-Butoxyethoxy)phenyl)-5-((4-(((1-propyl-1H-imidazole-5) -yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidin-4-ene-1(2H)-yl)-2,2-dimethyl Synthesis of ethyl propyl propionate
  • Step 5 (S,E)-3-(8-(4-(2-Butoxyethoxy)phenyl)-5-((4-(((1-propyl-1H-imidazole-5) -yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidin-4-ene-1(2H)-yl)-2,2-dimethyl Synthesis of propyl propionic acid
  • the compound 1-5 (15 mg, 0.02 mmol) was dissolved in anhydrous ethanol (0.5 mL), water (1 mL), and then added with sodium hydroxide (8 mg, 0.2 mmol). The reaction was kept for 20 hours, and the reaction was completed by LC-MS. The mixture was cooled to room temperature, and the mixture was diluted with EtOAc (20 mL ⁇ 2). The solvent was distilled off under reduced pressure, and purified by preparative liquid chromatography to give the title compound 1.
  • Step 6 (E)-3-(8-(4-(2-Butoxyethoxy)phenyl)-5-((4-(((4-methyl-1-propyl-1H-)-) Imidazol-5-yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidinyl-1(2H)-yl)-2,2 -Synthesis of methyl dimethylpropionate
  • Step 7 (E)-3-(8-(4-(2-Butoxyethoxy)phenyl)-5-((4-(((4-methyl-1-propyl-1H-)-) Imidazol-5-yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidinyl-1(2H)-yl)-2,2 - Synthesis of dimethylpropionic acid
  • the compound 1-5 was replaced with the compound 2-7 by a similar synthetic method in the first step of Example 1 to give the title compound 2, 60 mg.
  • Example 2 The compound 2 (260 mg) obtained in Example 2 was separated by chiral column chiral isomers by SFC method, and the corresponding components were collected. The solvent was removed by rotary evaporation to give a pure optical isomer.
  • Example 2 The compound 2 (260 mg) obtained in Example 2 was separated by chiral column chiral isomers by SFC method, and the corresponding components were collected. The solvent was removed by rotary evaporation to give a pure optical isomer.
  • Step 6 (E)-3-(8-(4-(2-Butoxyethoxy)phenyl)-5-((4-(((5-methyl-1-propyl-1H-)) Imidazolyl-4-yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidinyl-1(2H)-yl)-2,2 -Synthesis of methyl dimethylpropionate
  • Step 7 (E)-3-(8-(4-(2-Butoxyethoxy)phenyl)-5-((4-(((5-methyl-1-propyl-1H-)- Imidazolyl-4-yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidinyl-1(2H)-yl)-2,2 - Synthesis of dimethylpropionic acid
  • the compound 5-7 (230 mg, 0.30 mmol) was dissolved in tetrahydrofuran / methanol (10 mL / 10 mL), and a lithium hydroxide solution (5 mL, 1 M) was added, and the mixture was warmed to 70 ° C and reacted for 2 h. After the reaction was cooled to room temperature, the pH was adjusted to 7 with 1M hydrochloric acid, water (50 mL) was added to the mixture, ethyl acetate (30 mL ⁇ 3), and the organic phase was washed with saturated brine (30 mL ⁇ 2) and dried over anhydrous sodium sulfate Purification by preparative liquid chromatography gave the title compound 5, 60 mg.
  • Step 3 (E)-8-(4-(2-methoxyethoxy)phenyl)-1-(3-methoxy-2,2-dimethyl-3-oxopropyl) Synthesis of -1,2,3,4-tetrahydrobenzo[b]azetidin-4-ene-5-carboxylic acid
  • Oxalyl chloride (3.818 g, 30 mmol) was dissolved in methylene chloride, cooled to -78 ° C, and then evaporated, and dimethyl sulfoxide (3.12 g, 40 mmol) was added dropwise, and the reaction was kept for 30 minutes.
  • a dichloromethane solution of methyl 2,2-dimethyl-3-hydroxypropionate (1.32 g, 10 mmol) was added dropwise to the above reaction mixture, and the reaction was kept for 2 hours.
  • Triethylamine (10 g, 100 mmol) was added and incubated for 1 hour.
  • Step 4 (E)-3-(8-(4-(2-methoxyethoxy)phenyl)-5-((4-((1-(2-methoxyethyl))-) 1H-imidazol-5-yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidin-4-ene-2(2H)-yl)-2 Synthesis of methyl 2-dimethylpropionate
  • Step 5 (E)-3-(8-(4-(2-methoxyethoxy)phenyl)-5-((4-((1-(2-methoxyethyl))-) 1H-imidazol-5-yl)methyl)sulfinyl)phenyl)carbamoyl)-3,4-dihydrobenzo[b]azetidin-4-ene-2(2H)-yl)-2 Synthesis of 2-dimethylpropionic acid
  • HEK293 cells stably expressing CCR2 and CCR5 receptor proteins were first calibrated with calcium-sensitive fluorescent probes and then stimulated with the corresponding ligands (MCP1 and RANTES). After stimulation, receptor activation triggers the release of calcium ions from the endoplasmic reticulum.
  • the fluorescent probe captures calcium ions and triggers a fluorescent signal. The inhibitory effect of the compound on CCR2 and CCR5 can be judged by detecting the intensity of the fluorescent signal.
  • HEK293 cells Shanghai WuXi PharmaTech.
  • MCP1 Monocyte chemoattractant protein 1
  • RANTES normal T-cell expression secreting factor
  • Percentage of relative inhibitory activity 1 - (fluorescence signal in each concentration group - blank group fluorescence signal) / (vehicle group fluorescence signal - blank group fluorescence signal) * 100%
  • the concentration of the inhibitory activity was plotted against the concentration of the compound in each concentration group, and the IC 50 value was calculated by fitting the curve according to the four-parameter model:
  • y is the relative inhibitory activity percentage
  • max, min are the maximum and minimum values of the fitted curve
  • x is the compound concentration
  • Hillslope is the slope of the curve.
  • the compounds of the present application e.g., Compounds 1, 2, 3, and 4 have a strong inhibitory effect on CCR2/CCR5.
  • Probe substrate phenacetin, laboratory, 100095.
  • Probe substrate dextromethorphan hydrobromide, Beijing Jinbao, 100201.
  • Ketoconazole purchased from Dangdang Chemical, DTYC 0516-17.
  • Probe substrate testosterone: European Pharmacopoeia (EP) Reference Standard, Sigma-Aldrich, T0100000.
  • Probe substrate 50 ⁇ l
  • PBS 49 ⁇ l
  • different concentrations of test compound 0.05 ⁇ M, 0.15 ⁇ M, 0.5 ⁇ M, 1.5 ⁇ M, 5 ⁇ M, 15 ⁇ M, 50 ⁇ M
  • positive control (1 ⁇ l) with human liver microparticles
  • the mixture (HLM, 50 ⁇ l) was mixed to obtain 150 ⁇ l of the mixture, which was preincubated (37 ° C) for 5 min, then added with NADPH (50 ⁇ l) for 30 min, and 200 ⁇ l of ice acetonitrile was added to terminate the reaction. Add an appropriate volume of internal standard, vortex, centrifuge to take the supernatant.
  • LC-MS/MS Detection by LC-MS/MS.
  • the mass spectrum was API 5500 and the liquid phase was the Waters ACQUITY UPLC I-CLASS system.
  • the column was Hypersil GOLD C 18 with a particle size of 1.9 ⁇ m, 50 ⁇ 2.1 mm; mobile phase A was water + 0.1% formic acid, phase B was acetonitrile; flow rate was 0.4 ml/min, and column temperature was 40 °C.
  • the ion source is used as the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).
  • the concentration of the main metabolite produced by the probe substrate under different concentrations of the test compound was determined by the vehicle group (DMSO), and the half inhibitory concentration (IC 50 ) of the compound was determined.
  • the results of the half-inhibitory concentration (IC 50 ) of the compounds are shown in Table 2-3.
  • HEK293 cells overexpressing the hERG potassium channel were cultured in a 37 ° C, 5% CO 2 incubator.
  • PBS phosphate buffer solution
  • trypsin/EDTA trypsin/EDTA for 2-3 minutes
  • add the cell culture medium to stop digestion and remove the supernatant after transfer and centrifugation.
  • Cell culture medium (DMEM, 15% fetal bovine serum and 1% 100x penicillin-streptomycin) was added, and after mixing, the cells were dropped on a circular slide and cultured in a Petri dish to obtain cells to be tested.
  • the electrophysiological manual patch clamp whole-cell recording mode was used to record the channel current: the extracellular fluid was perfused until the current was stable, and the tail current peak (control current value) was recorded, and the extracellular fluid containing the different concentrations of the test drug was perfused and continuously recorded until the drug was administered.
  • the compounds in the present application have a weak induction effect on the CYP enzyme, no hERG channel inhibition, no significant cardiotoxicity, and compounds in the present application (for example, Compound 1, Compound 2, Compound 3 and Compound 4) has good properties in both CYP and hERG and has good safety.
  • the test compound was administered to male SD rats by gavage (po), the dose administered by po was 5 mg/kg, and the vehicle system at the time of po administration was 0.5% MC.
  • Blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after po administration for PK study.
  • Liver tissues were collected at 15 min, 1 h, 4 h, 8 h, and 24 h after po administration. Liver tissue samples were subjected to protein precipitation treatment and analyzed by LC-MS/MS.
  • the mass spectrometer is API 5500, the liquid chromatograph is Waters ACQUITY I CLASS system; the column is Agela ASB C18 column (2.1 mm ⁇ 50 mm, 1.9 ⁇ m); the mobile phase A phase is water + 0.1% formic acid, and the phase B is acetonitrile; The flow rate was 0.4 mL/min and the column temperature was 40 °C.
  • the ion source is used as the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).
  • MRM multiple reaction monitoring
  • the exposure of the compound described herein (for example, Compound 3) in the liver of rats is about 2345 times that in plasma; the concentration of the drug in the liver is about 530 times that in plasma; in the liver T 1/2 is 7.20 ⁇ 0.50 h.
  • the compounds described herein have extremely low exposure (AUC last ) and drug concentration (C max ) in plasma, and have extremely high exposure and drug concentrations in the liver, thus having extremely significant liver targeting and Good pharmacokinetic properties.
  • the compounds described in the present application show good activity in vitro, have excellent pharmacokinetic properties and extremely significant liver targeting, and can be applied to CCR2 and CCR5 mediated related diseases, especially It is used for the preparation of therapeutic drugs for diseases such as nonalcoholic fatty liver disease (NAFLD).
  • NAFLD nonalcoholic fatty liver disease

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Abstract

涉及一种通式(I)所示的含有羧酸基团的苯并氮杂环类化合物、其立体异构体或药学上可以接受的盐，所述化合物具有优秀的药代性质和极为显著的肝靶向性，以及含有它们的药物组合作为CCR拮抗剂尤其是CCR2和/或CCR5拮抗剂在其介导的相关疾病中的用途，包括但不限于非酒精性脂肪肝病(NAFLD)等疾病治疗中的药物用途，

Description

含有羧酸基团的苯并氮杂环类化合物及其制备方法和用途 技术领域
本申请涉及一种通式(I)所示的含有羧酸基团的苯并氮杂环类化合物、其立体异构体或药学上可以接受的盐，以及含有它们的药物组合物。所述化合物具有优秀的药代性质和极为显著的肝靶向性，可作为CCR拮抗剂尤其是CCR2和/或CCR5拮抗剂。因此，本申请还涉及所述化合物在预防和/或治疗CCR(尤其是CCR2和/或CCR5)介导的相关疾病中的用途，包括但不限于非酒精性脂肪肝病(NAFLD)。
背景技术
非酒精性脂肪性肝病(non-alcohol fatty liverdisease，NAFLD)是指过多的脂肪以甘油三酯(脂肪变性)的形式在肝脏中堆积。其定义为首先肝脏影像学或组织学证实存在肝脂肪变性，其次无导致继发性肝脂肪变性的其他因素，例如饮酒、药物、遗传基因异常等。疾病谱包括非酒精性单纯性脂肪肝(nonalcoholic simple fatty liver，NAFL)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis，NASH)及其相关肝硬化和肝癌。
NASH的确切致病机制尚未阐明，几乎每个患者都有所差异。尽管致病与胰岛素抵抗、肥胖及代谢综合征最为相关，但是并非所有处于这些状态的患者都有NAFLD和(或)NASH，也并非所有NAFLD和(或)NASH患者都会经历这些状态。NAFLD若进展为NASH，发生肝硬化，肝衰竭和肝癌的危险将大大增加。
随着非酒精性脂肪性肝炎(NASH)发病机制研究的深入，在此基础上寻找一些新的治疗靶点或药物成为当前的一个热点。NASH的新药机理主要分为四类：糖尿病/脂质、胆汁酸/胆汁酸受体通路、细胞凋亡、抗炎症/纤维化。针对NASH的主要靶点为：过氧化物酶体增殖物激活受体α(PPARA)和受体δ(PPARD)激动剂、法尼酯X受体(FXR)激动剂、抑制类赖氨酰氧化酶2(LOXL2)蛋白的单克隆抗体、凋亡信号调节蛋白激酶(ASK1)抑制剂、乙酰辅酶A羧化酶(ACC)蛋白别构抑制剂、趋化因子受体(CCR2/CCR5)拮抗剂等。
目前，针对NASH尚无药物上市，化合物全部处于临床研究阶段。进展最快的为Intercept公司的奥贝胆酸，处于临床III期研究，日本武田公司的Cenicriviroc已经完成临床II期研究，Gilead、Bristol-Myers Squibb、Astra Zeneca等国际制药公司均有化合物进入临床II期研究，关于NASH的药物治疗已经成为全球医药领域的研究热点。WO03014105描述了一类双环类化合物及其在抗HIV病毒方面的应用，其中R 1为C 1-6烷氧基-C 1-6烷氧基，R 2为四氢吡喃氨基、烷基取代的咪唑、烷基取代的三氮唑，R 3为卤素、取代烷基、取代烷氧基，Y a可以为氧、亚砜、砜、烷基取代的胺，Z 2a可以为硫、亚砜、 砜。认为此专利中具体描述不是本发明的一部分，其结构式如下：
Figure PCTCN2019072278-appb-000001
EP1593681描述了一类三环类化合物及其在抗HIV病毒方面的应用，其中R 1a为C 1-6烷氧基-C 1-6烷氧基，R 2a为四氢吡喃氨基、烷基取代的咪唑、烷基取代的三氮唑，Z 2a可以为硫、亚砜、砜，W为式(a)或者(b)，R 3为卤素、取代烷基、取代烷氧基。认为此专利中具体描述不是本发明的一部分，其结构式如下：
Figure PCTCN2019072278-appb-000002
WO03076411描述了结构式(c)光学异构体的合成方法及其用于治疗HIV病毒的医药用途。认为此专利中具体描述不是本发明的一部分，其结构式如下：
Figure PCTCN2019072278-appb-000003
WO2015143367描述了Cenicriviroc用于HIV及纤维化治疗的应用，WO2016105527描述了Cenicriviroc的合成方法。认为上述专利中具体描述不是本发明的一部分。
发明内容
通过深入的研究，本发明人惊奇的发现，在苯并氮杂环类化合物中引入羧酸基团，所得化合物对CCR2/CCR5具有极强的抑制作用，而对CYP及hERG无明显抑制作用，具有很好的安全性，同时具有极为显著的肝靶向性和极为优良的药代动力学性质。本申请中所述的化合物可用于CCR2和/或CCR5介导的相关疾病的治疗，包括但不限于非酒精性脂肪肝病(NAFLD)等病毒性疾病的治疗。本申请即是基于以上发现完成的。
具体而言，本申请涉及以下：
第一方面，本申请提供通式I所示的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，
Figure PCTCN2019072278-appb-000004
其中，R 1选自氢、氘和C 1-6烷基，所述C 1-6烷基任选地被R 2取代；
L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；
L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基、3-10元亚杂环基任选被一个或多个独立选自以下的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、-C(O)C 1-4烷基、-COOR 3、-N(R 3) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、-CON(R 3) 2和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；
L 3不存在或者选自C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；
R 2选自氢、氘、羟基、氨基、羧基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基、(C 1-6烷基) 2氨基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1，2，3或4；
R 3选自氢、氘、C 1-4烷基和C 3-6环烷基；
A选自任选被取代基取代的4-7元杂环基或者5-10元杂芳环基，所述取代基选自氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、被卤素取代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基；
n选自0，1或2。
在一些优选的实施方案中，R 1选自氢和C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自羟基、羧基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1，2，3或4。
在一些优选的实施方案中，R 1选自C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自羟基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1或2。
在一些优选的实施方案中，R 1选自C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自C 1-4烷氧基、-(C 1-4亚烷氧基) m1-(C 1-4亚烷氧基) m2-C 1-4烷基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1或2。
在一些优选的实施方案中，R 1选自C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自C 1-4烷氧基。
在一些优选的实施方案中，R 1为
Figure PCTCN2019072278-appb-000005
在一些优选的实施方案中，L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基和C 5-12亚杂芳基。
在一些优选的实施方案中，L 1选自C 1-6亚烷基、C 3-7亚环烷基、C 6-8亚芳基和C 5-8亚杂芳基。
在一些优选的实施方案中，L 1选自C 1-3亚烷基和C 3-5亚环烷基。
在一些优选的实施方案中，L 1选自C 1-3亚烷基。
在一些优选的实施方案中，L 1选自亚甲基和亚乙基。
在一些优选的实施方案中，L 2不存在或者选自-NH-、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选被一个或多个独立选自以下的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、-C(O)C 1-4烷基、-COOR 3、-N(R 3) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、-CON(R 3) 2和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立地选自0，1，2，3或4；z选自0，1或2。
在一些优选的实施方案中，L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3卤代烷氧基、-C(O)C 1-4烷基、-COOR 3和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、C 1-4烷基和C 3-6环烷基。
在一些优选的实施方案中，L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基。
在一些优选的实施方案中，L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基。
在一些优选的实施方案中，L 2不存在或者选自-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基；所述-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-6元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基。
在一些优选的实施方案中，L 2不存在或者选自-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基；所述-NH-、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-6元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基。
在一些优选的实施方案中，L 2不存在或者选自-NH-、-N(CH 3)-、-C(CH 3) 2-、-CH＝CH-、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元 亚杂环基，其中y 1、y 2各自独立的选自0，1或2。
在一些优选的实施方案中，L 2不存在。
在一些优选的实施方案中，L 2选自C 2-4亚烷基。
在一些优选的实施方案中，L 2选自-NH-、-N(CH 3)-和-C(CH 3) 2-。
在一些优选的实施方案中，L 2为-C(CH 3) 2-。
在一些优选的实施方案中，L 3不存在或者选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-7元亚杂环基。
在一些优选的实施方案中，L 3不存在或者选自C 1-6亚烷基和C 2-6亚烯基。
在一些优选的实施方案中，L 3不存在或者选自-C(CH 3) 2-、-CH 2-和-CH＝CH-。
在一些优选的实施方案中，L 3不存在。
在一些优选的实施方案中，L 3为-CH 2-。
在一些优选的实施方案中，A选自4-7元杂环基或者5-10元杂芳环基。
在一些优选的实施方案中，A选自4-7元含氮杂环基或者5-10元含氮杂芳环基。
在一些优选的实施方案中，A选自任选被取代基取代的4-7元含氮杂环基或者5-10元含氮杂芳环基，所述取代基选自氢、氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、被卤素取代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基。
在一些优选的实施方案中，A选自5或6元含氮杂芳环基。
在一些优选的实施方案中，A选自任选被取代基取代的5或6元含氮杂芳环基，所述取代基选自氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、被卤素取代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基。
在一些优选的实施方案中，A为5元含氮杂芳环基。
在一些优选的实施方案中，A为任选被取代基取代的5元含氮杂芳环基，所述取代基选自氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、卤代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基；
优选地，A为被取代基取代的5元含氮杂芳环基，所述取代基为C 1-6烷基(例如丙基)。
在一些优选的实施方案中，A为
Figure PCTCN2019072278-appb-000006
其中R 4选自氢、氘或任选地被R 6所取代的C 1-6烷基和C 3-6环烷基，R 6选自氘、羟基、-CN、C 1-4烷氧基和C 3-6环烷 氧基，R 5选自氢、氘、卤素、-CN、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-CN、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6环烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基，X选自N和C-R 5，各R 5相同或不同。
在一些优选的实施方案中，A选自
Figure PCTCN2019072278-appb-000007
Figure PCTCN2019072278-appb-000008
在一些优选的实施方案中，R 4为任选地被R 6取代的C 1-6烷基，R 6选自氘、羟基、-CN和C 1-4烷氧基。
在一些优选的实施方案中，R 4为任选地被R 6取代的C 1-6烷基，R 6选自羟基和C 1-4烷氧基。
在一些优选的实施方案中，R 4为任选地被R 6取代的C 1-4烷基，R 6选自羟基和C 1-4烷氧基。
在一些优选的实施方案中，R 4为任选地被R 6取代的C 1-4烷基，R 6选自氢、羟基、甲氧基和乙氧基。
在一些优选的实施方案中，R 4为任选地被R 6取代的C 1-4烷基，R 6选自甲氧基和乙氧基。
在一些优选的实施方案中，R 4选自正丙基和
Figure PCTCN2019072278-appb-000009
在一些优选的实施方案中，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6环烷基和C 3-6杂环烷基。
在一些优选的实施方案中，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基和C 3-6环烷基。
在一些优选的实施方案中，R 5选自氢、甲基、三氟甲基和环丙烷基。
在一些优选的实施方案中，R 5为氢。
在一些优选的实施方案中，X选自N和C-R 5，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6杂环烷基和C 3-6杂环烷基。
在一些优选的实施方案中，X选自N和C-R 5，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基和C 3-6环烷基。
在一些优选的实施方案中，X选自N和C-R 5，R 5选自氢、甲基、三氟甲基和环丙烷基。
在一些优选的实施方案中，L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基和C 5-12亚杂芳基；优选地，L 1选自C 1-3亚烷基和C 3-5亚环烷基；更优选地，L 1选自亚甲基和亚乙基；
L 2不存在或者选自-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、 C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基；所述-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-6元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基；优选地，L 2不存在或者选自-NH-、-N(CH 3)-、-C(CH 3) 2-、-CH＝CH-、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基，其中y 1、y 2各自独立的选自0，1或2；更优选地，L 2不存在或者选自-NH-、-N(CH 3)-和-C(CH 3) 2-；
L 3不存在或者选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-7元亚杂环基；优选地，L 3不存在或者选自C 1-6亚烷基和C 2-6亚烯基；更优选地，L 3不存在或者选自-C(CH 3) 2-、-CH 2-和-CH＝CH-；特别优选地，L 3不存在或-CH 2-。
在一些优选的实施方案中，n选自1或2，优选地，n为1。
在一些优选的实施方案中，本申请提供了通式I a或I b所示的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物：
Figure PCTCN2019072278-appb-000010
其中，R 1、R 4、R 5、L 1、L 2、L 3、X和n如上文所定义。
在一些优选的实施方案中，本申请提供了通式II a和式II a'所示的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物：
Figure PCTCN2019072278-appb-000011
其中：R 1、R 4、R 5、X、L 1、L 2、L 3或n如上文中所定义。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，R 1选自氢、氘和C 1-6烷基，所述C 1-6烷基任选地被R 2取代，R 2选自氢、氘、羟基、氨基、羧基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基、(C 1-6烷基) 2氨基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1，2，3或4；
优选地，R 1为C 1-6烷基，所述C 1-6烷基任选地被C 1-6烷氧基取代；
优选地，R 1为C 1-3烷基，所述C 1-3烷基任选地被C 1-6烷氧基取代；
优选地，R 1为乙基，所述乙基被正丁氧基取代。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，X选自N和C-R 5，R 5选自氢、氘、卤素、-CN、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-CN、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6环烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；
优选地，X选自N和C-R 5，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基和C 3-6环烷基；
优选地，X选自N和C-R 5，R 5选自氢、C 1-3烷基、卤代的C 1-3烷基和C 3-6环烷基；
优选地，X选自N和C-R 5，R 5选自氢、甲基、三氟甲基和环丙基；
优选地，X为C-R 5，R 5选自氢和甲基。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，R 4选自氢、氘或任选地被R 6所取代的C 1-6烷基和C 3-6环烷基，R 6选自氢、氘、羟基、-CN、C 1-4烷氧基和C 3-6环烷氧基；
优选地，R 4选自任选地被R 6所取代的C 1-6烷基和C 3-6环烷基，R 6为C 1-4烷氧基；
优选地，R 4选自任选地被R 6所取代的C 1-3烷基，R 6为C 1-3烷氧基；
优选地，R 4选自丙基和被甲氧基取代的乙基；
优选地，R 4为正丙基。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，
L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；
优选地，L 1为C 1-3亚烷基；优选地，L 1选自亚甲基和亚乙基。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，
L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3卤代烷氧基、-C(O)C 1-4烷基、-COOR 3和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立地选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、C 1-4烷基和C 3-6环烷基；
优选地，L 2不存在或者选自-NH-、-N(CH 3)-、-C(CH 3) 2-、-CH＝CH-、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基，其中y 1、y 2各自独立的选自0，1或2；
优选地，L 2不存在或者选自-NH-、-N(CH 3)-和-C(CH 3) 2-；
优选地，L 2选自-NH-、-N(CH 3)-和-C(CH 3) 2-。
在一些优选的实施方案中，L 2不存在。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，
L 3不存在或者选自C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；
优选地，L 3不存在或者选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-7元亚杂环基；
优选地，L 3不存在或者选自C 1-6亚烷基和C 2-6亚烯基；
优选地，L 3不存在或者选自-C(CH 3) 2-、-CH 2-和-CH＝CH-；
优选地，L 3不存在。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，
n选自0，1或2；优选地，n选自0和1；优选地，n为1。
在一些优选的实施方案中，本申请提供了通式II a和式II a’所示的化合物，其中，
R 1为C 1-3烷基，所述C 1-3烷基任选地被C 1-6烷氧基取代；
X选自N和C-R 5，R 5选自氢、甲基、三氟甲基和环丙基；
R 4选自丙基和被甲氧基取代的乙基；
L 1为C 1-3亚烷基；优选地，L 1选自亚甲基和亚乙基；
L 2不存在或者选自-NH-、-N(CH 3)-和-C(CH 3) 2-；
L 3不存在或者选自-C(CH 3) 2-、-CH 2-和-CH＝CH-；
n选自0和1；优选地，n为1。
在一些优选的实施方案中，本申请提供通式II b和式II b’所示的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，
Figure PCTCN2019072278-appb-000012
其中：R 1、R 4、R 5、X、L 1、L 2、L 3或n如上文中所定义。
在一些优选的实施方案中，本申请提供了化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，所述的化合物选自：
Figure PCTCN2019072278-appb-000013
Figure PCTCN2019072278-appb-000014
Figure PCTCN2019072278-appb-000015
本发明所述化合物中的原子可以被其同位素替代。例如 12C可被其同位素 13C或 14C替代； 1H可被 2H(D，氘)或 3H(T，氚)替代等。本发明包括所述化合物中任意原子经其同位素替换后得到的同位素标记的化合物。
本申请还涉及制备式I化合物的方法，其包括以下合成路线：
Figure PCTCN2019072278-appb-000016
其中，R 1、n、L 1、L 2、L 3或A如上文中所定义，L为末端带有醛基的基团，L通过反应以后可以转化为L 1(优选地，L 1为C 1-3亚烷基，更优选地，L 1选自亚甲基和亚乙基)，羧基保护基PG选自任选地被一个或多个R 7取代基取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10杂环烷基、C 6-10芳基、C 1-6亚烷基-C 6-10芳基、C 5-12杂芳基，R 7选自氢、氘、卤素、C 1-6烷基和C 1-6烷氧基。在一些优选的实施方案中，羧基保护基PG优选为C 1-6烷基。
具体地，所述方法包括以下步骤：
步骤一：化合物a与化合物b反应得到化合物c；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1,4-二氧六环、二甲基亚砜及其任意组合，优选二氧六环或1,2-二氯乙烷。所述反应优选在适合的还原剂存在下进行，所述还原剂可选自硼氢化钠、硼氢化钾、氰基硼氢化钠和醋酸硼氢化钠，优选地，所述还原剂为氰基硼氢化钠。所述反应优选在适合的酸性条件下进行，所述酸可选自盐酸、醋酸和三氟醋酸，优选地，所述酸为三氟醋酸。所述反应优选在适合的温度下进行，优选反应温度为-50-100℃，更优选-20-70℃。所述反应优选进行合适的时间，例如1-24小时，例如1-6小时。
步骤二：化合物c经过与化合物d反应得到化合物e。
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1,4-二氧六环、二甲基亚砜及其任意组合，优选二氯甲烷。所述反应优选在适合的缩合剂存在下进行，所述缩合剂可选自氯化亚砜、草酰氯、三氯氧磷、三氯化磷、五氯化磷、氯甲酸乙酯、氯甲酸异丙酯、HATU、HBTU、EEDQ、DEPC、DCC、DIC、 EDC、BOP、PyAOP或PyBOP，优选地，所述缩合剂为氯化亚砜、草酰氯。所述反应优选在适合的碱性条件下进行，所述的碱为有机碱或无机碱，优选的，所述有机碱选自三乙胺、DIPEA、吡啶、NMM或DMAP，优选的，所述无机碱选自NaH、NaOH、Na 2CO 3或K 2CO 3，优选的，所述的碱选自三乙胺、DIPEA和DMAP。所述反应优选在适合的温度下进行，优选反应温度为0-100℃，更优选15-50℃。所述反应优选进行合适的时间，例如1-24小时，例如2-7小时。
步骤三：化合物e经过脱除保护基得到通式I化合物。
所述反应优选在适合的水和/或有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、醇类(例甲醇、乙醇)、醚类(例四氢呋喃、二氧六环)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜及其任意组合，优选水和乙醇。所述反应优选在适合的酸性条件下进行，所述的酸为盐酸、硫酸或三氟醋酸。所述反应优选在适合的碱性条件下进行，所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯，优选的，所述的碱选自氢氧化钠。所述反应优选在适合的温度下进行，优选反应温度为-20-100℃，更优选0-60℃。所述反应优选进行合适的时间，例如1-24小时。
本申请还涉及制备式I a化合物的方法：
Figure PCTCN2019072278-appb-000017
其中，R 1、R 4、R 5、n、L 1、L 2、L 3、PG和X如上文中所定义，L为末端带有醛基的基团，L通过反应以后可以转化为L 1(优选地，L 1为C 1-3亚烷基，更优选地，L 1选自亚甲基和亚乙基)，式I a化合物制备方法参照式I化合物的制备方法。
本申请还涉及制备通式I b化合物的方法：
Figure PCTCN2019072278-appb-000018
其中，R 1、R 4、R 5、n、L 1、L 2、L 3、PG和X如上文中所定义，L为末端带有醛基的基团，L通过反应以后可以转化为L 1(优选地，L 1为C 1-3亚烷基，更优选地，L 1选自亚甲基和亚乙基)，式I b化合物制备方法参照式I化合物的制备方法。
在一些实施方案中，本申请提供制备所述通式II a和/或通式II a’的化合物的方法：
方法一：
Figure PCTCN2019072278-appb-000019
其中，R 1、R 4、R 5、n、L 1、L 2、L 3、PG和X如上文中所定义，L为末端带有醛基的基团，L通过反应以后可以转化为L 1(优选地，L 1为C 1-3亚烷基，更优选地，L 1选自亚甲基和亚乙基)。
所述方法的合成步骤参照通式I a化合物的合成步骤。
方法二：
Figure PCTCN2019072278-appb-000020
其中，R 1、R 4、R 5、n、L 1、L 2、L 3和X如上文中所定义。
具体地，所述方法二包括以下步骤：
步骤一：通式I a化合物经过分离得到通式II a和通式II a’的化合物。
所述分离方法选用可采购的手性制备柱，优选OD、OJ、AS、AD、IA、IB、IC、ID等，以醇(乙醇和异丙醇等)、弱极性溶剂(正己烷、石油醚、CO 2等)、助溶剂(二氯甲烷等)和碱(氨水、二乙胺等)为流动相进行分类纯化，收集ee值>99％的成分。
方法三：
Figure PCTCN2019072278-appb-000021
其中，R 1、R 4、R 5、n、L 1、L 2、L 3和X如上文中所定义。
具体地，所述方法三包括以下步骤：
步骤一：化合物e经过分离得到化合物h和化合物h’。
所述方法选用可采购的手性制备柱，优选OD、OJ、AS、AD、IA、IB、IC、ID等，以醇(乙醇和异丙醇等)、弱极性溶剂(正己烷、石油醚、CO 2等)、助溶剂(二氯甲烷等)和碱(氨水、二乙胺等)为流动相进行分类纯化，收集ee值>99％的成分。
步骤二：化合物h和化合物h’经过脱除保护基分别得到通式II a和通式II a’的化合物。
所述反应优选在适合的水和/或有机溶剂中进行，所述有机溶剂可选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、醇类(例甲醇、乙醇)、醚类(例 四氢呋喃、二氧六环)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜及其任意组合，优选水和乙醇。所述反应优选在适合的酸性条件下进行，所述的酸为盐酸、硫酸或三氟醋酸。所述反应优选在适合的碱性条件下进行，所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯，优选的，所述的碱选自氢氧化钠。所述反应优选在适合的温度下进行，优选反应温度为-20-100℃，更优选0-60℃。所述反应优选进行合适的时间，例如1-24小时。
在一些实施方案中，本申请提供制备所述通式II b和/或通式II b’的化合物的方法，所述方法包括以下步骤：
方法一：
Figure PCTCN2019072278-appb-000022
其中，R 1、R 4、R 5、n、L 1、L 2、L 3、PG和X如上文中所定义，L为末端带有醛基的基团，L通过反应以后可以转化为L 1(优选地，L 1为C 1-3亚烷基，更优选地，L 1选自亚甲基和亚乙基)。
所述方法合成步骤参照通式I b化合物的合成步骤。
方法二：
Figure PCTCN2019072278-appb-000023
其中，R 1、R 4、R 5、n、L 1、L 2、L 3和X如上任意一项所定义。
具体地，所述方法二包括以下步骤：
步骤一：通式I b化合物经过分离得到通式II b和通式II b’的化合物。
所述分离方法选用可采购的手性制备柱，优选OD、OJ、AS、AD、IA、IB、IC、ID等，以醇(乙醇和异丙醇等)、弱极性溶剂(正己烷、石油醚、CO 2等)、助溶剂(二氯甲烷等)和碱(氨水、二乙胺等)为流动相进行分类纯化，收集ee值>99％的成分。
在另一个方面，本申请提供一种药物组合物，其包含第一方面所包含的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，以及一种或多种药学可接受的载体。
在一些优选的实施方案中，所述药物组合物为片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂或糖浆剂。
在一些优选的实施方案中，所述药物组合物进一步包含一种或多种预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的其它药物。
在另一个方面，本申请提供一种药物制剂，其含有第一方面所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，或者所述组合物，以及一种或多种药学可接受的载体。
在另一个方面，本申请提供一种药盒产品，其包括：
a)第一容器，其包括作为第一治疗剂的至少一种第一方面所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，或作为第一药物组合物的所述药物组合物；
b)任选存在的第二容器，其包括作为第二治疗剂的至少一种其他治疗剂，或者作为第二药物组合物的含有所述其他治疗剂的药物组合物；和
c)任选存在的包装说明书。
在一些优选的实施方案中，所述其他治疗剂选自可用于预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的除本公开所述化合物外的其它药物。
在另一个方面，本申请提供第一方面所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、药物组合物、药物制剂或者药盒产品在制备用于预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的药物中的用途。
在另一个方面，本申请提供第一方面所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、药物组合物、药物制剂或者药盒产品，其用于预防或治疗由CCR2和/或CCR5 介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病。
在另一个方面，本申请提供CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的预防或治疗方法，其包括向需要其的个体给药治疗有效量的所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、药物组合物、药物制剂或药盒产品，并任选地包括向需要其的个体另外给药预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的其它药物。
本申请中，所述药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。其中所述的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
本申请提供第一方面所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、药物组合物、药物制剂或者药盒可以通过以下途径给药：胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。
本申请提供第一方面所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物或者药物组合物可根据给药途径配成各种适宜的剂型。
本申请所述的药物组合物或适宜的剂型可以含有0.01mg至1000mg的所述化合物。
当口服用药时，所述所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物或者药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时，所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物或者药物组合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙 二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
所述化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物或者药物组合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在本申请的实施方案中，进行合适的体外或体内测定来确定所述药物组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的所述药物组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下，剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg受试者体重，更通常为0.1至500mg/kg受试者体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以以缓释制剂的形式给予所述制剂，在这种情况下，需要较少的给药频率。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用，术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“烷基”定义为直链或支链的饱和脂肪族烃基。在一些实施方案中，烷基具有1至8个，例如1至4个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指具有1至6个碳原子的直链或支链的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被一个或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”，例如-CF 3、-C 2F 5、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等)。
如本文中所使用，术语“亚烷基”定义为从直链或支链的饱和烃基中去掉两个氢原子所得到的饱和的二价烃基基团，亚烷基基团含有1-10个碳原子、1-6个碳原子、1-4个碳原子或1-3个碳原子，例如亚甲基(-CH 2-)，亚乙基(-CH 2CH 2-)，亚异丙基(-CH(CH 3)CH 2-)等等，其中所述亚烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
如本文中所使用，术语“环烷基”指饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基等)，其任选地被一个或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个，例如3至10个碳原子、3至7个碳原子或3至6个碳原子。例如，如本文中所使用，术语“C 3- 7环烷基”指具有3至7个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基、环己基、环庚基)，其任选地被一个或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“C 3-10亚环烷基”定义为具有2个不饱和化合价的C 3-10烷基残基，例如二价亚甲基残基，例如亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基或亚环辛基，例如亚环丙基、亚环丁基、亚环戊基、亚环己基，且特别是亚环戊基、亚环己基。
如本文中所使用，术语“烷氧基”指式-O-烷基的线性的、支化的或环状的饱和一价烃基，其中术语“烷基”如上所定义或者为下文所定义的“环烷基”，例如C 1-6烷基、C 1-3烷基或C 3-6环烷基，例如是甲氧基、乙氧基、正丙氧基、异丙氧基、环丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、环丁氧基、戊氧基、异戊氧基或正己氧基，或它们的异构体。
如本文中所使用，术语“杂环基”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(＝O)、O、S、S(＝O)、S(＝O) 2和NR a的含杂原子的基团，其中R a表示氢原子或C 1-6烷基或卤代-C 1-6烷基；所述杂环烷基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。例如C 3-6杂环基、C 5-6或C 3-7杂环基为碳原子数为3-6、5-6或3-7的杂环基，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，4-7元杂环基为在环中具有4-7个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用，术语“亚杂芳基”指具有2个不饱和化合价的杂芳基，例如具有碳原 子数为5-12个、5-10个或5-8个。
如本文中所使用，术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-10芳环”意指含有6至10个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基取代。
如本文中所使用，术语“亚芳基”指具有2个不饱和化合价的芳基，例如具有碳原子数为6-10个或6-8个，例如为亚苯基。
如本文中所使用，术语“杂芳基”指单环、双环或三环芳族环系统，其具有5、6、8、9、10、11、12、13或14个环原子，例如具有5-10个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、等以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“烯基”是指含有至少一个碳-碳双键并且其一个氢原子被键代替的脂肪烃基团。烯基可以是直链或支链烯基，并且含有大约2至大约15个碳原子。例如本文中“C 2-6烯基”为含有大约2至大约6个碳原子。烯基的非限制性例子包括乙烯基，丙烯基，正丁烯基，3-甲基丁-2-烯基，正戊烯基，辛烯基和癸烯基。烯基可以是未取代的烯基，或被一个或多个相同或不同的取代基取代，每个取代基独立地选自卤素，烯基，炔基，芳基，环烷基，氰基，羟基，-O-烷基，-O-芳基，-亚烷基-O-烷基，烷硫基，-NH 2，-NH(烷基)，-N(烷基) 2，-NH(环烷基)，-O-C(O)-烷基，-O-C(O)-芳基，-O-C(O)-环烷基，-C(O)OH和-C(O)O-烷基。术语“C 2-6烯基”是指2至6个碳原子的烯基。
如本文中所使用，术语“亚烯基”是指将分子的剩余部分与基团相连的直链或支链二价烃，只由碳和氢原子组成，包含至少一个双键并具有二至六个碳原子，例如亚乙烯基、亚丙烯基、亚正丁烯基等。所述亚烯基链通过双键或单键与分子的剩余部分相连和通过双键或单键与基团相连。亚烯基链与分子的剩余部分和与基团的连接点可以经过所述链中的一个碳或任何两个碳。除非说明书中另有具体说明，亚烯基链可以独立地被选自下列的一个或多个取代基任选取代：卤代、氰基、硝基、芳基、环烷基、杂环基、杂芳基、氧代、三甲基甲硅烷基、-OR 8、-OC(＝O)R 8、-N(R 8) 2、-C(＝O)R 8、-C(＝O)OR 8、-C(＝O)N(R 8) 2、-N(R 8)C(＝O)OR 8、-N(R 8)C(＝O)R 8、-N(R 8)S(＝O) tR 8(其中t是1或2)、-S(＝O) tOR 8(其中t是1或2)、-S(＝O) pR 8(其中p是0、1或2)和-S(＝O) tN(R 8) 2(其中t是1或2)，其中每个R 8独立地为氢、烷基、卤代烷基、环烷基、环烷基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基，且其中上述取代基各自可如本文所定义地任选被取代。
如本文中所使用，术语“炔基”是指具有一个或多个C≡C三键的烃基。所述炔基具有但不限于2-18个碳原子，例如其具有2-10个碳原子，例如2-6个碳原子。本文的“低级炔基”是指碳数较少的炔基，例如其具有2-8个碳原子，例如2-6个碳原子，例如2-4个碳原子。本文的炔基实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。本文定义的炔基出现数字范围时，例如“C 2-C 6炔基”或“C 2-6炔基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的炔基基团，本文的炔基也涵盖未指定数字范围的情况。
如本文中所使用的，术语“亚炔基”是指其中炔基的氢原子之一已被键替代的如上定义的炔基。亚炔基的非限制性实例包括-CH 2C≡C-、-CH 2C≡CCH 2-和-CH(CH 3)C≡C-，例如亚炔基具有2至6个碳原子。亚炔基是支链或直链的。术语“C 2-6亚炔基”是指具有2至6个碳原子的亚炔基，术语“C 2-3亚炔基”是指具有2至3个碳原子的亚炔基。
如本文中所使用的，术语“氨基”是指具有两个进一步的取代基的含氮部分，其中氯或碳原子与氮连接。例如，代表性氨基包括-NH 2、-NHCH 3、-N(CH 3) 2、-NHC 1-3烷基、-N(C 1-3烷基) 2等。除非另有指示，含有氨基部分的本发明化合物可以包括其被保护的衍生物。适合氨基部分的保护基团包括乙酰基、叔丁氧羰基、苄氧羰基等。
如本文中所使用的，术语“羧酸基”也称“羧基”，是指化学式为-COOH的官能团。在本发明的意义上，术语“羧基”还包括相关的阴离子-COO-(羧酸根离子)。取决于环境条件，例如环境的pH值，该官能团可以以-COOH或-COO-形式存在。
如本文中所使用，术语“卤代C 1-6烷基”是指如前文所述的C 1-6烷基中的一个或多个(例如1个、2个、3个或4个)氢原子被卤素(例如氟、氯、溴或碘)取代后得到的基团，例如卤代C 1-3烷基、卤代甲基、卤代乙基、卤代C 3烷基、卤代C 4烷基、氟代C 1-3烷基、氟代甲基、氟代乙基、氟代C 3烷基、氟代C 4烷基、氯代C 1-3烷基、氯代甲基、氯代乙基、氯代C 3烷基、氯代C 4烷基。具体的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氟乙基、氯代乙基等。
术语“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
术语“任选地取代”指任选地被特定的基团、原子团或部分取代。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明的化合物还可以包含一个或多个(例如一个、两个、三个或四个)同位素置换。例如，在所述化合物中，H可是任何同位素形式，包括 1H、 2H(D或氘)和 3H(T或氚)；C 可是任何同位素形式，包括 12C、 13C和 14C；O可是任何同位素形式，包括 16O和 18O等。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋体、外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本申请涵盖所述化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
所述化合物或其药学上可接受的盐还可以形成溶剂合物，例如醇合物等。
所述化合物还可以是前药或以或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
所述化合物还可以是化学保护的形式，所述保护基可保护在化合物的活性基团(如氨基)上，所述保护基可在体内代谢释放出活性成分。选择和制备适当的化学保护的形式是本领域技术人员公知技术。
本申请中所用术语“药学上可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。
本申请中所用术语“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。适合的盐的示例性实例包括但不限于，得自氨基酸例如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺以及环胺例如哌啶、吗啉和哌嗪的有机盐，以及得自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
还应当理解，本申请中的某些化合物可以游离形式存在，或适当时，以其药学上可接受的衍生物形式存在。药学上可接受的衍生物包括但不限于，药学上可接受的盐、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供所述化合物或其代谢物或残余物。
所述化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成无毒盐的酸来形成。
适合的碱加成盐由形成无毒盐的碱来形成。可接受的无机碱包括氢氧化铝和氢氧化钙。可接受的有机碱包括氨丁三醇、N-甲基葡糖胺等。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备所述化合物的药学上可接受 的盐的方法为本领域技术人员已知的。
所述化合物可以水合物或溶剂合物的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药药物时体内形成的化合物。
本申请中所用术语“药物组合物”包括包含治疗有效量的所述化合物的产品，以及直接地或间接地由所述化合物的组合产生的任何产品。
本申请中所用术语“有效量”是指足以实现所需治疗效果的量，例如，实现减轻与待治疗疾病相关的症状的量。
本申请中所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其光学异构体或其药学上可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
“治疗”表示所述化合物的任何给药，包括：
(1)在可能有疾病倾向、但是尚未经历或显示疾病病理学或症状学的动物中防止疾病发生；
(2)在正在经历或显示疾病病理学或症状学的动物中抑制疾病(也就是阻止病理学和/或症状学的进一步发展)；或者
(3)在正在经历或显示疾病病理学或症状学的动物中改善疾病(也就是逆转病理学和/或症状学)。
技术效果
通过深入的研究，获得一类含有羧酸基团的苯并氮杂环类化合物。通过羧酸基团的引入，使得化合物能够实现下述至少一种技术效果：
(1)具有极为显著的肝靶向性；
(2)优良的药代动力学性质；
(3)对CCR2/CCR5具有极强的抑制作用；以及
(4)对CCR2和/或CCR5介导的相关疾病尤其是非酒精性脂肪肝病(NAFLD)等疾病具有显著的治疗作用。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
在常规的合成法以及实施例、和中间体合成例中，各缩写的意思如以下所示。
Figure PCTCN2019072278-appb-000024
Figure PCTCN2019072278-appb-000025
以下列举实施例和试验例，进而详细地说明本发明，但它们不限定本发明，另外在不脱离本发明的范围下可进行变化。
以下的实施例中记载的化合物的结构通过核磁共振( 1H NMR)或质谱(MS)来确定。
核磁共振( 1H NMR)的测定仪器使用Bruker 400MHz核磁共振仪；测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)，六氘代二甲基亚砜(DMSO-d 6)；内标物质为四甲基硅烷(TMS)。
实施例中使用的核磁共振(NMR)图谱中的缩写示于以下。
s：单峰(singlet)、d：二重峰(doublet)、t：三重峰(triplet)、q：四重峰(quartet)、dd：双二重峰(double doublet)、qd：四二重峰(quartet doublet)、ddd：双双二重峰(double double doublet)、ddt：双双三重峰(double double triplet)、dddd：双双双二重峰(double double double doublet)、m：多重峰(multiplet)、br：宽峰(broad)、J：偶合常数、Hz：赫兹、DMSO-d 6：氘化二甲基亚砜。
将全部δ值用ppm值表示。
质谱(MS)的测定仪器使用Agilent(ESI)质谱仪，型号为Agilent 6120B。
实施例
实施例一(S,E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((1-丙基-1H-咪唑-5-基)甲基)亚 磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸(化合物1)的合成
Figure PCTCN2019072278-appb-000026
步骤一：3-羟基-2,2-二甲基丙酸乙酯的合成
室温下，将化合物1-1(1.0g，8.5mmol)，碳酸铯(3.3g，10.2mmol)，N,N-二甲基甲酰胺(15mL)加入三颈瓶中，接着室温搅拌下加入碘乙烷(2.6g，17.0mmol)，氮气置换三次，升温至55℃，保温反应16h。降至室温，将体系倒入冰水中(80mL)，乙酸乙酯(30mL×3)萃取，有机相用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，柱层析纯化(THF:PE＝1：10)得标题化合物，1.0g。ESI-MS(m/z):147.1[M+H] +。
步骤二：2,2-二甲基-3-氧代丙酸乙酯的合成
将草酰氯(522mg，4.1mmol)，溶于二氯甲烷(5mL)中，体系降至-78℃，向其中滴加二甲基亚砜(640mg，8.2mmol)，滴毕，保温反应30min，然后向其中滴加化合物1-2(500mg，3.4mmol)的二氯甲烷(5mL)溶液，滴毕，-78℃反应2h，再向其中滴加三乙胺(1.03g，10.2mmol)，滴毕，-78℃反应1h，回至室温反应30min。向体系中加水(30mL)淬灭反应，二氯甲烷(20mL×2)萃取，有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，柱层析纯化(THF:PE＝1：15)得标题化合物，200mg。ESI-MS(m/z):145.1[M+H] +。
步骤三：(E)-8-(4-(2-丁氧基乙氧基)苯基)-1-(3-乙氧基-2,2-二甲基-3-氧代丙基)-1,2,3,4-四氢苯并[b]氮杂环辛四烯-5-甲酸的合成
室温下，将(E)-8-(4-(2-丁氧基乙氧基)苯基)-1,2,3,4-四氢苯并[b]氮杂环辛四烯-5-甲酸(80mg，0.2mmol)，化合物1-3(432mg，3.0mmol)溶于二氧六环(4.5mL)中，室 温向其中加入三氟乙酸(1.5mL)，搅拌5min，再向其中加入氰基硼氢化钠(252mg，4.0mmol)，加毕，微波60℃反应2.5h。向体系中加入水(30mL)，乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥。滤除干燥剂，减压蒸除溶剂，制备液相纯化得标题化合物，150mg。ESI-MS(m/z):524.3[M+H] +。
步骤四：(S,E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸乙酯的合成
将化合物1-4(60mg，0.11mmol)溶于二氯甲烷(2mL)中，室温向其中加入二氯亚砜(0.5mL)，反应1h，将体系抽干，加入二氯甲烷(2mL)溶解，并将其滴入到(S)-4-(((1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯胺(46mg，0.16mmol)和4-二甲氨基吡啶(84mg，0.66mmol)的二氯甲烷(2mL)溶液中，滴毕，室温反应3h。向其中加水(10mL)淬灭反应，二氯甲烷(20mL×2)萃取，有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，高效制备液相色谱纯化，得标题化合物，15mg。ESI-MS(m/z):769.4[M+H] +.
步骤五：(S,E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸的合成
室温下，将化合物1-5(15mg，0.02mmol)溶于无水乙醇(0.5mL)，水(1mL)中，室温搅拌下向其中加入氢氧化钠(8mg，0.2mmol)，升温至45℃，保温反应20h，LC-MS检测反应完成。降至室温，向体系加入1N的盐酸水溶液调节pH至5-6，乙酸乙酯(20mL×2)萃取，有机相用饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，滤除干燥剂，减压蒸除溶剂，高效制备液相色谱纯化，得标题化合物1，5mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ10.07(s,1H),7.89(d,J＝8.5Hz,2H),7.63(s,1H),7.55(d,J＝8.6Hz,2H),7.51(d,J＝2.4Hz,1H),7.47(d,J＝9.2Hz,4H),7.12(d,J＝8.8Hz,1H),7.00(d,J＝8.5Hz,2H),6.48(s,1H),4.35(d,J＝14.3Hz,1H),4.17(d,J＝14.3Hz,1H),4.11(dd,J＝5.8,3.6Hz,2H),3.80(td,J＝7.1,2.2Hz,2H),3.74-3.68(m,2H),3.49-3.42(m,6H),2.38(d,J＝6.2Hz,2H),1.65(q,J＝7.3Hz,2H),1.55-1.45(m,4H),1.39-1.27(m,2H),1.17(s,6H),0.88(t,J＝7.3Hz,3H),0.81(t,J＝7.4Hz,3H).ESI-MS(m/z):741.4[M+H] +.
实施例二(E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((4-甲基-1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸(化合物2)的合成
Figure PCTCN2019072278-appb-000027
步骤一：4-甲基-1-丙基-1H-咪唑-5-甲醛的合成
室温下，将化合物2-1(500mg，4.5mmol)，碳酸钾(941mg，6.8mmol)，N,N-二甲基甲酰胺(10mL)加入三颈瓶中，加入碘丙烷(1.5g，9.1mmol)，氮气保护，升温至50℃，保温反应16h降至室温，将体系倒入冰水中(100mL)，乙酸乙酯萃取(40mL×3)，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，浓缩，柱层析纯化得标题化合物，260mg。ESI-MS(m/z):153.1[M+H] +。
步骤二：(4-甲基-1-丙基-1H-咪唑-5-基)甲醇的合成
将化合物2-2(210mg，1.4mmol)溶于无水甲醇(5mL)中，降温至0℃，分批加入硼氢化钠(66mg，1.7mmol)，保温反应30min。向体系中加水(10mL)淬灭反应，浓缩，向其中加入乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，浓缩，得标题化合物，155mg。ESI-MS(m/z):155.1[M+H] +。
步骤三：5-(氯甲基)-4-甲基-1-丙基-1H-咪唑的合成
将化合物2-3(155mg，1.0mmol)溶于乙腈(3mL)中，室温加入二氯亚砜(1mL)，然后升温至70℃反应2h。降温至室温，浓缩，向其中加入乙酸乙酯(5mL)，室温搅拌30分钟，抽滤得标题化合物盐酸盐，175mg。 1H NMR(400MHz,DMSO-d 6)δ14.93(s,1H),9.14(s,1H),5.06(s,2H),4.15(t,J＝7.4Hz,2H),2.34(s,3H),1.86(h,J＝7.4Hz,2H),0.91(t,J＝7.4Hz,3H).
步骤四：4-(((4-甲基-1-丙基-1H-咪唑-5-基)甲基)硫代)苯胺的合成
室温下，将4-氨基苯硫酚(240mg，1.9mmol)，三乙胺(576mg，5.7mmol)，四氢呋喃(10mL)加入三颈瓶中，降温至0℃，向其中滴加化合物2-4(400mg，1.9mmol) 的四氢呋喃水(5mL：0.5mL)溶液，滴毕，回至室温反应2h。将体系倒入水中(50mL)，乙酸乙酯萃取(40mL×3)，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，浓缩，制备液相纯化得标题化合物，160mg。ESI-MS(m/z):262.1[M+H] +。
步骤五：4-(((4-甲基-1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯胺的合成
将化合物2-5(160mg，0.61mmol)溶于二氯甲烷(5mL)中，降温至0℃，分批次向其中加入间氯过氧苯甲酸(105mg，0.61mmol)，加毕，保温反应30min。向体系中加入饱和无水亚硫酸钠溶液(10mL)淬灭反应，加入二氯甲烷萃取(20mL×3)，有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，浓缩，制备液相纯化得标题化合物，180mg。ESI-MS(m/z):278.1[M+H] +。
步骤六：(E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((4-甲基-1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸甲酯的合成
采用实施例一步骤四类似的合成方法，将(S)-4-(((1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯胺替换为化合物2-6，柱层析纯化得标题化合物，230mg。ESI-MS(m/z):769.4[M+H] +
步骤七：(E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((4-甲基-1-丙基-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸的合成
采用实施例一步骤五类似的合成方法，将化合物1-5替换为化合物2-7，制备液相色谱纯化得标题化合物2，60mg。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ12.45(s,1H),10.08(s,1H),7.87(d,J＝8.5Hz,2H),7.53(t,J＝9.2Hz,4H),7.50–7.44(m,2H),7.39(d,J＝8.5Hz,2H),7.12(d,J＝8.9Hz,1H),7.00(d,J＝8.6Hz,2H),4.26(d,J＝14.3Hz,1H),4.16(d,J＝14.3Hz,1H),4.13–4.07(m,2H),3.79(ddd,J＝18.6,13.9,6.8Hz,2H),3.73–3.66(m,2H),3.52–3.40(m,4H),3.29(s,2H),2.38(s,2H),1.70–1.63(m,2H),1.61(s,3H),1.50(dt,J＝13.8,6.2Hz,4H),1.36–1.29(m,2H),1.17(s,6H),0.88(t,J＝7.3Hz,3H),0.82(t,J＝7.1Hz,3H).ESI-MS(m/z):755.3[M+H] +.
实施例三
将实施例二得到的化合物2(260mg)，采用SFC法，经手性柱对手性异构体分离，收集其相应组分。旋转蒸发除去溶剂，得到光学异构体的纯品。制备条件为，手性柱：CHIRALPAK ID；手性柱型号：0.46cm I.D.×15cm L，进样量：0.5uL,流动相：CO 2/(EtOH:DCM:NH 4OH＝60:40:0.1)＝55/45(V/V)，流速：2.0ml/min；波长：UV 254nm；得化合物2-异构体A 100mg，保留时间4.773min。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ12.45(s,1H),10.09(s,1H),7.87(d,J＝8.7Hz,2H),7.58–7.50(m,4H),7.49(s,1H),7.48–7.44(m,1H),7.39(d,J＝8.7Hz,2H),7.12(d,J＝8.8Hz,1H),7.02–6.97(m,2H),4.26(d,J＝14.4Hz,1H),4.16(d,J＝14.4Hz,1H),4.13–4.08(m,2H),3.84–3.75(m,2H),3.70(dd,J＝5.6,3.7Hz,2H),3.50–3.42(m,4H),3.29(s,2H),2.38(s,2H),1.70–1.63(m,2H),1.61(s,3H),1.54–1.45(m,4H),1.36–1.30(m,2H),1.17(s,6H),0.88(t,J＝7.4Hz,3H),0.82(t,J＝7.3Hz,3H).ESI-MS(m/z):755.3[M+H] +.
比旋光度：
Figure PCTCN2019072278-appb-000028
实施例四
将实施例二得到的化合物2(260mg)，采用SFC法，经手性柱对手性异构体分离，收集其相应组分。旋转蒸发除去溶剂，得到光学异构体的纯品。制备条件为，手性柱：CHIRALPAK ID；手性柱型号：0.46cm I.D.×15cm L，进样量：0.5uL,流动相：CO 2/(EtOH:DCM:NH 4OH＝60:40:0.1)＝55/45(V/V)，流速：2.0ml/min；波长：UV 254nm；得化合物2-异构体B 103mg，保留时间7.107min。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ12.35(brs,1H),10.16(s,1H),7.88(d,J＝8.7Hz,2H),7.56(s,1H),7.53(s,2H),7.50(d,J＝1.9Hz,1H),7.48–7.44(m,2H),7.39(d,J＝8.7Hz,2H),7.12(d,J＝8.8Hz,1H),6.99(d,J＝8.8Hz,2H),4.26(d,J＝14.3Hz,1H),4.16(d,J＝14.4Hz,1H),4.13–4.08(m,2H),3.86–3.73(m,2H),3.73–3.68(m,2H),3.46(t,J＝6.5Hz,4H),3.30(s,2H),2.38(s,2H),1.66(q,J＝7.4Hz,2H),1.61(s,3H),1.55–1.44(m,4H),1.36–1.30(m,2H),1.16(s,6H),0.88(t,J＝7.4Hz,3H),0.82(t,J＝7.3Hz,3H).ESI-MS(m/z):755.3[M+H] +.
比旋光度：
Figure PCTCN2019072278-appb-000029
实施例五
(E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((5-甲基-1-丙基-1H-咪唑-4-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸(化合物5)
Figure PCTCN2019072278-appb-000030
步骤一：5-甲基-1-丙基-1H-咪唑-4-甲醛的合成
室温下，将化合物2-1(500mg，4.5mmol)，碳酸钾(941mg，6.8mmol)，N,N-二甲基甲酰胺(10mL)加入三颈瓶中，加入碘丙烷(1.5g，9.1mmol)，氮气保护，升温至50℃，保温反应16h降至室温，将体系倒入冰水中(100mL)，乙酸乙酯萃取(40mL×3)，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，浓缩，柱层析纯化得标题化合物，230mg。ESI-MS(m/z):153.1[M+H] +。
步骤二：(5-甲基-1-丙基-1H-咪唑-4-基)甲醇的合成
将化合物5-2(210mg，1.4mmol)溶于无水甲醇(5mL)中，降温至0℃，分批加入硼氢化钠(66mg，1.7mmol)，保温反应30min。向体系中加水(10mL)淬灭反应，浓缩，向其中加入乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，浓缩，得标题化合物，155mg。ESI-MS(m/z):155.1[M+H] +。
步骤三：4-(氯甲基)-5-甲基-1-丙基-1H-咪唑盐酸盐的合成
将化合物5-3(155mg，1.0mmol)溶于乙腈(3mL)中，室温加入二氯亚砜(1mL)，然后升温至70℃反应2h。降温至室温，浓缩，向其中加入乙酸乙酯(5mL)，室温搅拌30分钟，抽滤得标题化合物，175mg。ESI-MS(m/z):173.1[M+H] +。
步骤四：4-(((5-甲基-1-丙基-1H-咪唑-4-基)甲基)硫基)苯胺的合成
室温下，将4-氨基苯硫酚(240mg，1.9mmol)，三乙胺(576mg，5.7mmol)，四氢呋喃(10mL)加入三颈瓶中，降温至0℃，向其中滴加化合物5-4(400mg，1.9mmol) 的四氢呋喃水(5mL：0.5mL)溶液，滴毕，回至室温反应2h。将体系倒入水中(50mL)，乙酸乙酯萃取(40mL×3)，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，浓缩，制备液相纯化得标题化合物，160mg。ESI-MS(m/z):262.1[M+H] +。
步骤五：4-(((5-甲基-1-丙基-1H-咪唑-4-基)甲基)亚磺酰基)苯胺的合成
将化合物5-5(160mg，0.61mmol)溶于二氯甲烷(5mL)中，降温至0℃，分批次向其中加入间氯过氧苯甲酸(105mg，0.61mmol)，加毕，保温反应30min。向体系中加入饱和无水亚硫酸钠溶液(10mL)淬灭反应，加入二氯甲烷萃取(20mL×3)，有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，浓缩，制备液相纯化得标题化合物，180mg。ESI-MS(m/z):278.1[M+H] +。
步骤六：(E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((5-甲基-1-丙基-1H-咪唑-4-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸甲酯的合成
将化合物5-6(330mg，0.65mmol)溶于二氯甲烷(10mL)中，将(S)-4-{[(4-甲基-1-丙基-1H-咪唑-5-基)甲基]亚硫酰基}苯胺(180mg,0.65mmol)加入反应体系中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(376mg，1.95mmol)，4-二甲氨基吡啶(237mg，1.95mmol)室温反应过夜。加入水(20mL)，二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，浓缩，柱层析纯化得标题化合物，230mg。ESI-MS(m/z):770.3[M+H] +
步骤七：(E)-3-(8-(4-(2-丁氧基乙氧基)苯基)-5-((4-(((5-甲基-1-丙基-1H-咪唑-4-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸的合成
将化合物5-7(230mg，0.30mmoL)，溶于四氢呋喃/甲醇(10mL/10mL)中，加入氢氧化锂溶液(5mL，1M)，体系升温至70℃，反应2h。待反应冷却至室温，用1M盐酸调节pH＝7，向体系中加水(50mL)，乙酸乙酯萃取(30mL×3)，有机相用饱和食盐水洗涤(30mL×2)，无水硫酸钠干燥，浓缩，制备液相色谱纯化得标题化合物5，60mg。
其结构表征如下：
1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),7.91(s,2H),7.54(dd,J＝14.8,3.9Hz,4H),7.41(dd,J＝13.6,6.1Hz,4H),7.02(s,2H),6.93(s,1H),4.26(d,J＝15.2Hz,1H),4.20(s,2H),4.10(d,J＝10.4Hz,1H),3.89(s,2H),3.85(s,2H),3.59(s,2H),3.42(s,2H),3.14(s,2H),2.68(s,2H),2.21(s,3H),1.82(s,2H),1.10(s,6H),1.02–0.97(m,6H).ESI-MS(m/z):755.4[M+H] +.
实施例六
(E)-3-(8-(4-(2-甲氧基乙氧基)苯基)-5-((4-(((1-(2-甲氧基乙基)-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸(化合 物6)的合成
Figure PCTCN2019072278-appb-000031
步骤一：(E)-8-(4-(2-甲氧基乙氧基)苯基)-1,2,3,4-四氢化苯[b]氮杂环辛四烯-5-甲酸甲酯的合成
将化合物6-1(816mg，2.55mmoL)，4-(2-甲氧基乙氧基)苯硼酸(500mg,2.55mmol),醋酸钯(20mg，0.085mmoL)，磷酸钾(540mg，2.53mmol)，三叔丁基磷四氟硼酸盐(98mg，0.35mmoL)甲苯/水10：1(5mL)加入微波管中，氮气保护，100℃微波条件下反应3h。降至室温，将体系倒入水中(50mL)，乙酸乙酯萃取(30mL×3)，有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，浓缩，柱层析纯化得标题化合物，530mg。ESI-MS(m/z):410.2[M+H] +。
步骤二：(E)-8-(4-(2-甲氧基乙氧基)苯基)-1,2,3,4-四氢化苯[b]氮杂环辛四烯-5-甲酸的合成
将化合物6-2(530mg，1.45mmoL)，溶于四氢呋喃/甲醇(10mL/10mL)中，加入氢氧化钠溶液(5mL，1M)，体系升温至70℃，反应2h。待反应冷却至室温，用1M盐酸调节pH＝7，向体系中加水(50mL)，乙酸乙酯萃取(30mL×3)，有机相用饱和食盐水洗涤(30mL×2)，无水硫酸钠干燥，浓缩，柱层析纯化得标题化合物，388mg。ESI-MS(m/z):396.2[M+H] +。
步骤三：(E)-8-(4-(2-甲氧基乙氧基)苯基)-1-(3-甲氧基-2,2-二甲基-3-氧代丙基)-1,2,3,4-四氢苯并[b]氮杂环辛四烯-5-甲酸的合成
将草酰氯(3.818g，30mmol)溶于二氯甲烷中，降温到-78℃，氮气保护，滴加二甲亚砜(3.12g，40mmol)，保温反应30分钟。将2,2-二甲基-3-羟基丙酸甲酯(1.32g，10mmol)的二氯甲烷溶液滴加到上述反应液中，保温反应2小时。三乙胺(10g，100mmol)加入，保温1小时。升温到-20℃，滴加三氟乙酸，使反应体系酸性(pH＝1.0)，化合物6-3(388mg，1.1mmol)和三乙酰氧基硼氢化钠(2.2g，10mmol)加入到反应体系，保温反应1小时。向反应液中加入蒸馏水(100mL)，二氯甲烷萃取(30mL×3)，合并有机相，饱和 碳酸氢钠洗涤(100mL×1)，饱和食盐水洗涤(100mL×1)，水洗(100mL×1)，无水硫酸钠干燥，柱层析分离纯化得标题化合物，300mg。ESI-MS(m/z):510.3[M+H] +
步骤四：(E)-3-(8-(4-(2-甲氧基乙氧基)苯基)-5-((4-(((1-(2-甲氧基乙基)-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸甲酯的合成
将化合物6-4(300mg，0.65mmol)溶于二氯甲烷(10mL)中，将(S)-4-{[(1-(2-甲氧基乙基)-1H-咪唑-5-基)甲基]亚硫酰基}苯胺(180mg,0.65mmol)加入反应体系中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(376mg，1.95mmol)，4-二甲氨基吡啶(237mg，1.95mmol)室温反应过夜。加入水(20mL)，二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，浓缩，柱层析纯化得标题化合物，155mg。ESI-MS(m/z):771.3[M+H] +
步骤五：(E)-3-(8-(4-(2-甲氧基乙氧基)苯基)-5-((4-(((1-(2-甲氧基乙基)-1H-咪唑-5-基)甲基)亚磺酰基)苯基)氨基甲酰基)-3,4-二氢苯并[b]氮杂环辛四烯-1(2H)-基)-2,2-二甲基丙酸的合成
将化合物6-5(155mg，0.20mmoL)，溶于四氢呋喃/甲醇(10mL/10mL)中，加入氢氧化钠溶液(5mL，1M)，体系升温至70℃，反应2h。待反应冷却至室温，用1M盐酸调节pH＝7，向体系中加水(50mL)，乙酸乙酯萃取(30mL×3)，有机相用饱和食盐水洗涤(30mL×2)，无水硫酸钠干燥，浓缩，制备液相色谱纯化得标题化合物6，8mg。
其结构表征如下：
1H NMR(400MHz,Chloroform-d)δ9.37(s,1H),8.29(s,1H),7.96(d,J＝8.3Hz,2H),7.57(dd,J＝8.4,2.2Hz,1H),7.52(d,J＝8.2Hz,2H),7.41(s,1H),7.37(d,J＝8.5Hz,1H),7.28(d,J＝8.3Hz,2H),7.03(d,J＝8.3Hz,2H),6.88(s,1H),6.58(s,1H),4.37(d,J＝14.6Hz,1H),4.32–4.25(m,1H),4.20(t,J＝4.9Hz,2H),4.11(d,J＝15.7Hz,1H),3.95(d,J＝14.7Hz,1H),3.85(t,J＝5.0Hz,2H),3.64(d,J＝8.4Hz,2H),3.59(d,J＝6.7Hz,2H),3.44(d,J＝15.9Hz,2H),3.34(s,3H),3.15(s,2H),2.68(d,J＝7.6Hz,2H),1.65(t,J＝7.5Hz,4H),1.46–1.42(m,2H),1.13(s,3H),1.09(s,3H),0.98(d,J＝7.4Hz,3H).ESI-MS(m/z):757.4[M+H] +.
药理活性测试
以下实施例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
实验例一.细胞CCR2/CCR5活性抑制试验
试验原理
稳定表达CCR2和CCR5受体蛋白的HEK293细胞首先用钙离子敏感的荧光探针 标定，然后用相应配体(MCP1和RANTES)刺激，刺激之后，受体激活引发钙离子从内质网释放到胞浆，荧光探针捕获到钙离子后可引发荧光信号。通过检测荧光信号的强度可判断化合物对CCR2和CCR5的抑制作用。
实验所用材料：
HEK293细胞：上海药明康德。
384孔板(384 well Poly-D-Lysine protein coating plate),Greiner #781946。
单核细胞趋化蛋白1(MCP1)：CCR2 Agonist,PeproTech-300-04。
调节激活正常T-细胞表达分泌因子(RANTES)：CCR5 Agonist,PeproTech-300-06。
于384孔板中每孔加入2×10 4个HEK293细胞，培养过夜。经荧光探针标记后，加入不同浓度的MCP1和RANTES，读取荧光信号。以荧光信号对配体浓度作图，按照四参数模型计算IC 50值，作为后续检测化合物时CCR2和CCR5的配体浓度。
参考上述结果，将不同浓度(5000nM、1250nM、313nM、78nM、20nM、4.8828nM、1.2207nM、0.3052nM、0.0763nM、0.0191nM)的待测化合物与细胞孵育，加入MCP1和RANTES后读取荧光信号，以溶媒组(不含化合物)为阴性对照，Buffer组(不含配体)为空白对照计算各浓度组抑制活性：
相对抑制活性百分比＝1-(各浓度组荧光信号-空白组荧光信号)/(溶媒组荧光信号-空白组荧光信号)*100％
以各浓度组抑制活性百分比对化合物浓度作图，按照四参数模型拟合曲线，计算IC 50值：
y＝min+(max-min)/(1+(x/IC 50)^(-Hillslope))
其中y为相对抑制活性百分比，max，min分别为拟合曲线的最大值与最小值，x为化合物浓度，Hillslope为曲线斜率。
试验结果
按照上述方法测定化合物对CCR2/CCR5的抑制活性，结果见表1：
表1 化合物对细胞CCR2/CCR5抑制结果
Figure PCTCN2019072278-appb-000032
由表1可以看出，本申请中的化合物(例如化合物1、2、3和4)，对CCR2/CCR5具 有极强的抑制作用。
实验例二：CYP 1A2、CYP 2D6、CYP 3A4M、CYP 3A4T及hERG抑制实验
1.CYP 1A2、CYP 2D6、CYP 3A4M、CYP 3A4T抑制实验
CYP1A2:
探针底物：非那西汀，中检所，100095。
阳性对照：α-萘黄酮(alpha-naphthoflavone)，ACRas，A0331533。
CYP2D6：
探针底物:氢溴酸右美沙芬，北京金宝，100201。
阳性对照：奎尼丁(Quinidine)，Damas-bata，P1176507。
CYP3A4M：
探针底物：咪达唑仑，中检所，171265。
阳性对照：酮康唑(Ketoconazole)，购自叮当化学，DTYC0516-17。
CYP3A4T:
探针底物：睾酮:European Pharmacopoeia(EP)Reference Standard，Sigma-Aldrich,T0100000。
阳性对照：酮康唑(Ketoconazole)，叮当化学，DTYC0516-17。
将探针底物(50μl)、PBS(49μl)和不同浓度的待测化合物(0.05μM、0.15μM、0.5μM、1.5μM、5μM、15μM、50μM)或阳性对照(1μl)，与人肝微粒体(HLM,50μl)进行混合得到混合液150μl，将其预孵(37℃)5min后，加入NADPH(50μl)孵育30min，加入200μl冰乙腈终止反应。加入适当体积内标，涡旋、离心取上清。
采用LC-MS/MS检测。质谱为API 5500，液相为Waters ACQUITY UPLC I-CLASS系统。色谱柱为Hypersil GOLD C 18，1.9μm粒径，50×2.1mm；流动相A相为水+0.1％甲酸，B相为乙腈；流速为0.4ml/min，柱温为40℃。采用离子源为ESI源正离子模式，扫描方式为多重反应监测(MRM)。
以溶媒组(DMSO)为阴性，测定不同浓度待测化合物下探针底物产生的主要代谢物的浓度，判断化合物的半数抑制浓度(IC 50)。化合物的半数抑制浓度(IC 50)结果参见表2-3。
2.hERG抑制实验:
配制不同浓度(1μM和10μM)的待测化合物和30μM阳性对照奎尼丁(Quinidine)溶液，将过表达hERG钾离子通道的HEK293细胞培养在37℃、5％CO 2的培养箱中，当细胞密度达培养皿80％时，分别用磷酸盐缓冲液(PBS)清洗后，胰蛋白酶/EDTA消化细胞2-3分钟，加入细胞培养基停止消化后，经转移、离心移除上清液后，加入细胞培养基(DMEM、15％胎牛血清和1％100x青霉素-链霉素)，混匀后将细胞滴 于圆形玻片上并置于培养皿中培养，得到待测细胞。
采用电生理手动膜片钳全细胞记录模式记录通道电流：灌流细胞外液至电流稳定，记录尾电流峰值(对照电流值)后，灌流含不同浓度待测药物的细胞外液并持续记录直到药物对hERG电流的抑制作用到达稳定状态，记录尾电流峰值(加药后电流值)。
该实验结果参见表4。
表2 化合物对CYP的抑制结果
Figure PCTCN2019072278-appb-000033
表3 化合物对CYP的抑制结果
Figure PCTCN2019072278-appb-000034
表4 化合物对hERG的抑制结果
化合物 hERG(μM)
化合物2 >10
化合物3 >10
化合物4 >10
由表2-4可以看出，本申请中的化合物对CYP酶的诱导作用较弱，无hERG通道抑制作用，无明显心脏毒性，本申请中的化合物(例如化合物1、化合物2、化合物3和化合物4)在CYP和hERG方面均具有较好的性质，具有较好的安全性。
实验例三.大鼠药代动力学(PK)研究
通过灌胃(po)向雄性SD大鼠给药待测化合物，通过po给药的剂量是5mg/kg，po 给药时溶媒系统为0.5％MC。po给药后在5min、15min、30min、1h、2h、4h、6h、8h、24h收集血液，用于PK研究。po给药后在15min、1h、4h、8h、24h收集肝组织，肝组织样品经蛋白沉淀处理后进行LC-MS/MS分析。质谱仪为API 5500，液相色谱仪为Waters ACQUITY I CLASS系统；色谱柱为Agela ASB C18柱(2.1mm×50mm,1.9μm)；流动相A相为水+0.1％甲酸，B相为乙腈；流速为0.4mL/min，柱温为40℃。采用离子源为ESI源正离子模式，扫描方式为多重反应监测(MRM)。试验结果见表5。
表5 化合物大鼠药代动力学数据
Figure PCTCN2019072278-appb-000035
“/”表示不存在
由表5可以看出，本申请所述化合物(例如化合物3)在大鼠体内肝脏中的暴露量是血浆中的约2345倍；肝脏中的药物浓度是血浆中的约530倍；肝脏中的T 1/2为7.20±0.50h。本申请所述化合物在血浆中具有极低的暴露量(AUC last)和药物浓度(C max)，而在肝脏中具有极高的暴露量和药物浓度，因而具有极为显著的肝靶向性和良好的药代动力学性质。
本申请中的其他化合物也具有与上述化合物相近的AUC last值、C max值以及T 1/2，在大鼠体内具有与上述相类似的药代动力学性质。
综上所述，本申请中所述化合物在体外药效方面显示出良好的活性、同时具有优秀的药代性质和极为显著的肝靶向性，可应用于CCR2和CCR5介导的相关疾病尤其是制备非酒精性脂肪肝病(NAFLD)等疾病治疗药物中的用途。
除本文中描述的那些实施方案外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (26)

  1. 通式I所示的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，
    Figure PCTCN2019072278-appb-100001
    其中，R 1选自氢、氘和C 1-6烷基，所述C 1-6烷基任选地被R 2取代；
    L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；
    L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基、3-10元亚杂环基任选被一个或多个独立选自以下的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、-C(O)C 1-4烷基、-COOR 3、-N(R 3) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、-CON(R 3) 2和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；
    L 3不存在或者选自C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；
    R 2选自氢、氘、羟基、氨基、羧基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基、(C 1-6烷基) 2氨基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1，2，3或4；
    R 3选自氢、氘、C 1-4烷基和C 3-6环烷基；
    A选自任选被取代基取代的4-7元杂环基或者5-10元杂芳环基，所述取代基选自氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、被卤素取代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6 环烷氧基；
    n选自0，1或2。
  2. 权利要求1所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中R 1选自氢和C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自羟基、羧基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1，2，3或4；
    优选地，R 1选自C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自羟基、C 1-6烷氧基、-(C 1-6亚烷氧基) m1-(C 1-6亚烷氧基) m2-C 1-6烷基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1或2；
    优选地，R 1选自C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自C 1-4烷氧基、-(C 1-4亚烷氧基) m1-(C 1-4亚烷氧基) m2-C 1-4烷基和含一个或多个N、O或S原子的5-6元杂环基；其中m 1、m 2各自独立的选自0，1或2；
    优选地，R 1选自C 1-4烷基，所述C 1-4烷基任选地被R 2取代；R 2选自C 1-4烷氧基；
    优选地，R 1为
    Figure PCTCN2019072278-appb-100002
  3. 权利要求1-2任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基和C 5-12亚杂芳基；
    优选地，L 1选自C 1-6亚烷基、C 3-7亚环烷基、C 6-8亚芳基和C 5-8亚杂芳基；
    优选地，L 1选自C 1-3亚烷基和C 3-5亚环烷基；
    优选地，L 1选自-CH 2-或-CH 2-CH 2-。
  4. 权利要求1-3任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中
    L 2不存在或者选自-NH-、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选被一个或多个独立选自以下的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、-C(O)C 1-4烷基、-COOR 3、-N(R 3) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、-CON(R 3) 2和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立地选自0，1，2，3或4；z选自0，1或2；
    优选地，L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3卤代烷氧基、-C(O)C 1-4烷基、-COOR 3和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、C 1-4烷基和C 3-6环烷基；
    优选地，L 2不存在或者选自-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基；所述-NH-、C 2-6亚烷基、C 2-6亚烯基、-(C 1-6亚烷氧基) y1-(C 1-6亚烷氧基) y2-、C 3-10亚环烷基、C 6-10亚芳基、C 5-12亚杂芳基和3-10元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-10元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基；
    优选地，L 2不存在或者选自-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基；所述-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-6元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基；
    优选地，L 2不存在或者选自-NH-、-N(CH 3)-、-C(CH 3) 2-、-CH＝CH-、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基，其中y 1、y 2各自独立的选自0，1或2；
    优选地，L 2不存在或者选自-NH-、-N(CH 3)-、和-C(CH 3) 2-。
  5. 权利要求1-4任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中L 3不存在或者选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-7元亚杂环基；
    优选地，L 3不存在或者选自C 1-6亚烷基和C 2-6亚烯基；
    优选地，L 3不存在或者选自-C(CH 3) 2-、-CH 2-和-CH＝CH-；
    优选地，L 3不存在或者为-CH 2-。
  6. 权利要求1-5任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中A选自4-7元杂环基或者5-10元杂芳环基
    优选地，A选自4-7元含氮杂环或者5-10元含氮杂芳环；
    优选地，A选自任选被取代基取代的4-7元含氮杂环基或者5-10元含氮杂芳环基，所述取代基选自氢、氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、被卤素取代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基；
    优选地，A选自5或6元含氮杂芳环基；
    优选地，A选自任选被取代基取代的5或6元含氮杂芳环基，所述取代基选自氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、被卤素取代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基；
    优选地，A为5元含氮杂芳环基；
    优选地，A为任选被取代基取代的5元含氮杂芳环基，所述取代基选自氘、任选地被R 6取代的C 1-6烷基和C 3-6环烷基、卤素、-CN、卤代的C 1-6烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基；R 6选自氘、羟基、-CN、C 1-6烷氧基和C 3-6环烷氧基；
    优选地，A为被取代基取代的5元含氮杂芳环基，所述取代基为C 1-6烷基(例如丙基)；
    优选地，A为
    Figure PCTCN2019072278-appb-100003
    其中R 4选自氢、氘或任选地被R 6所取代的C 1-6烷基和C 3-6环烷基，R 6选自氘、羟基、-CN、C 1-4烷氧基和C 3-6环烷氧基，R 5选自氢、氘、卤素、-CN、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-CN、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6环烷基、C 3-6杂环烷基、C 6-10芳基和C 5-12杂芳基，X选自N和C-R 5，各R 5相同或不同。
  7. 权利要求6所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中R 4为任选地被R 6取代的C 1-6烷基，R 6选自氘、羟基、-CN和C 1-4烷氧基；
    优选地，R 4为任选地被R 6取代的C 1-6烷基，R 6选自羟基和C 1-4烷氧基；
    优选地，R 4为任选地被R 6取代的C 1-4烷基，R 6选自羟基和C 1-4烷氧基；
    优选地，R 4为任选地被R 6取代的C 1-4烷基，R 6选自羟基、甲氧基和乙氧基；
    优选地，R 4为任选地被R 6取代的C 1-4烷基，R 6选自甲氧基和乙氧基；
    优选地，R 4选自正丙基和
    Figure PCTCN2019072278-appb-100004
  8. 权利要求6-7任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中各R 5独立地选自氢、氘、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6环烷基和C 3-6杂环烷基；
    优选地，各R 5独立地选自氢、氘、C 1-6烷基、卤代的C 1-6烷基和C 3-6环烷基；
    优选地，各R 5独立地选自氢、甲基、三氟甲基和环丙烷基；
    优选地，R 5为氢。
  9. 权利要求6-8任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中
    X选自N和C-R 5，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基、C 1-6亚烷基-OH、C 1-6亚烷基-C 1-6烷氧基、C 3-6杂环烷基和C 3-6杂环烷基；
    优选地，X选自N和C-R 5，R 5选自氢、氘、C 1-6烷基、卤代的C 1-6烷基和C 3-6环烷基；
    X选自N和C-R 5，R 5选自氢、甲基、三氟甲基和环丙烷基。
  10. 权利要求1-9任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中A选自
    Figure PCTCN2019072278-appb-100005
    Figure PCTCN2019072278-appb-100006
  11. 权利要求1-10任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中L 1选自C 1-6亚烷基、C 3-10亚环烷基、C 6-10亚芳基和C 5-12亚杂芳基；优选地，L 1选自C 1-3亚烷基和C 3-5亚环烷基；更优选地，L 1选自亚甲基和亚乙基；
    L 2不存在或者选自-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基；所述-NH-、C 2-4亚烷基、C 2-3亚烯基、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基任选地被一个或多个独立选自下列的取代基所取代：氢、氘、卤素、羟 基、氰基、甲基、卤代甲烷基、卤代甲氧基、-C(O)CH 3、-COOR 3和-NR 3CO 2R 3；所述3-6元亚杂环基含有一个或多个选自N、NR 3、O、P和S(O) z的环成员；其中y 1、y 2各自独立的选自0，1，2，3或4；z选自0，1或2；R 3选自氢、氘、甲基和环丙烷基；优选地，L 2不存在或者选自-NH-、-N(CH 3)-、-C(CH 3) 2-、-CH＝CH-、-(C 1-3亚烷氧基) y1-(C 1-3亚烷氧基) y2-、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-6元亚杂环基，其中y 1、y 2各自独立的选自0，1或2；更优选地，L 2不存在或者选自-NH-、-N(CH 3)-、和-C(CH 3) 2-；
    L 3不存在或者选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基、C 3-6亚环烷基、C 6-8亚芳基、C 5-8亚杂芳基和3-7元亚杂环基；优选地，L 3不存在或者选自C 1-6亚烷基和C 2-6亚烯基；更优选地，L 3不存在或者选自-C(CH 3) 2-、-CH 2-和-CH＝CH-；特别优选地，L 3不存在或-CH 2-。
  12. 权利要求1-11任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中所述化合物具有式I a或式I b所示结构：
    Figure PCTCN2019072278-appb-100007
    其中，R 1、R 4、R 5、L 1、L 2、L 3、X和n如权利要求1-11任一项所定义。
  13. 权利要求1-12任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中所述化合物具有式II a或式II a’所示结构：
    Figure PCTCN2019072278-appb-100008
    其中：R 1、R 4、R 5、X、L 1、L 2、L 3或n如权利要求1-12任一项中所定义。
  14. 权利要求1-12任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水 合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中所述化合物具有式II b或式II b’所示结构：
    Figure PCTCN2019072278-appb-100009
    其中：R 1、R 4、R 5、X、L 1、L 2、L 3或n如权利要求1-12任一项中所定义。
  15. 权利要求1-14任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中n选自1或2，优选地，n为1。
  16. 权利要求1-15任一项所述的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，其中化合物选自：
    Figure PCTCN2019072278-appb-100010
    Figure PCTCN2019072278-appb-100011
    Figure PCTCN2019072278-appb-100012
  17. 药物组合物，其含有至少一种权利要求1-16中任一项的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，以及一种或多种药学可接受的载体。
  18. 权利要求17所述的药物组合物，其进一步含有一种或多种预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的其它药物。
  19. 权利要求17-18任一项所述的药物组合物，其选自以下的形式：片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂和糖浆剂。
  20. 一种药物制剂，其含有权利要求1-16任一项的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，或者权利要求17-19任一项所述的药物组合物，以及一种或多种药学可接受的载体。
  21. 药盒产品，其包括：
    a)第一容器，其包括作为第一治疗剂的至少一种权利要求1-16中任一项的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物，或作为第一药物组合物的权利要求17-19任一项所述的药物组合物或者权利要求20所述的药物制剂；
    b)任选存在的第二容器，其包括作为第二治疗剂的至少一种其他治疗剂，或者作为第二药物组合物的含有所述其他治疗剂的药物组合物；和
    c)任选存在的包装说明书。
  22. 权利要求1-16中任一项的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、或者权利要求17-19任一项所述的药物组合物或者权利要求20所述的药物制剂，或者权利要求21所述的药盒产品在制备用于预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病的药物中的用途。
  23. 预防或治疗由CCR2和/或CCR5介导的疾病或病症的方法，其包括向需要的个体给药治疗有效量的权利要求1-16中任一项的化合物或其药学可接受的盐、酯、溶剂化物(例 如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、或者权利要求14-19任一项所述的药物组合物或者权利要求20所述的药物制剂或者使用权利要求21所述的药盒产品。
  24. 权利要求23所述的方法，其中CCR2和/或CCR5介导的疾病或病症优选为非酒精性脂肪肝病(NAFLD)等疾病。
  25. 权利要求1-16中任一项的化合物或其药学可接受的盐、酯、溶剂化物(例如水合物)、立体异构体、互变异构体、前药，或它们的任意晶型、代谢物，以及它们的混合物、或者权利要求17-19任一项所述的药物组合物或者权利要求20所述的药物制剂，或者权利要求21所述的药盒产品，其用于预防或治疗由CCR2和/或CCR5介导的疾病或病症尤其是非酒精性脂肪肝病(NAFLD)等疾病。
  26. 制备权利要求1-16任一项的式I化合物的方法，其包括以下合成路线：
    Figure PCTCN2019072278-appb-100013
    其中，R 1、n、L 1、L 2、L 3或A如权利要求1-11任一项中所定义，L为末端带有醛基的基团，L通过反应以后可以转化为L 1(优选地，L 1为C 1-3亚烷基，更优选地，L 1选自亚甲基和亚乙基)，羧基保护基PG选自任选地被一个或多个R 7取代基取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10杂环烷基、C 6-10芳基、C 1-6亚烷基-C 6-10芳基、C 5-12杂芳基，R 7选自氢、氘、卤素、C 1-6烷基和C 1-6烷氧基；优选地，羧基保护基PG为C 1-6烷基；
    具体地，所述方法包括以下步骤：
    步骤一：化合物a与化合物b反应得到化合物c；
    所述反应在适合的有机溶剂中进行，所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1,4-二氧六环、二甲基亚砜及其任意组合，优选地，有机溶剂为二氧六环或1,2-二氯乙烷，所述反应在适合的还原剂存在下进行， 所述还原剂选自硼氢化钠、硼氢化钾、氰基硼氢化钠和醋酸硼氢化钠，优选地，所述还原剂为氰基硼氢化钠；所述反应在适合的酸性条件下进行，所述酸选自盐酸、醋酸和三氟醋酸，优选地，所述酸为三氟醋酸；所述反应在适合的温度下进行，优选反应温度为-50-100℃，更优选-20-70℃；所述反应进行合适的时间，例如1-24小时，例如1-6小时；
    步骤二：化合物c经过与化合物d反应得到化合物e；
    所述反应在适合的有机溶剂中进行，所述有机溶剂选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1,4-二氧六环、二甲基亚砜及其任意组合，优选地，所述有机溶剂为二氯甲烷；所述反应在适合的缩合剂存在下进行，所述缩合剂选自氯化亚砜、草酰氯、三氯氧磷、三氯化磷、五氯化磷、氯甲酸乙酯、氯甲酸异丙酯、HATU、HBTU、EEDQ、DEPC、DCC、DIC、EDC、BOP、PyAOP或PyBOP，优选地，所述缩合剂为氯化亚砜、草酰氯；所述反应在适合的碱性条件下进行，所述的碱为有机碱或无机碱，优选地，所述有机碱选自三乙胺、DIPEA、吡啶、NMM或DMAP，优选地，所述无机碱选自NaH、NaOH、Na 2CO 3或K 2CO 3，优选的，所述的碱选自三乙胺、DIPEA和DMAP；所述反应在适合的温度下进行，优选反应温度为0-100℃，更优选15-50℃；所述反应进行合适的时间，例如1-24小时，例如2-7小时；
    步骤三：化合物e经过脱除保护基得到通式I化合物；
    所述反应在适合的水和/或有机溶剂中进行，所述有机溶剂选自卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、腈类(例如乙腈等)、醇类(例甲醇、乙醇)、醚类(例四氢呋喃、二氧六环)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜及其任意组合，优选水和乙醇；所述反应在适合的酸性条件下进行，所述的酸为盐酸、硫酸或三氟醋酸；所述反应在适合的碱性条件下进行，所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾或碳酸铯，优选地，所述的碱选自氢氧化钠；所述反应在适合的温度下进行，优选反应温度为-20-100℃，更优选0-60℃；所述反应进行合适的时间，例如1-24小时。
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