WO2021136345A1 - Jak抑制剂化合物及其用途 - Google Patents

Jak抑制剂化合物及其用途 Download PDF

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WO2021136345A1
WO2021136345A1 PCT/CN2020/141251 CN2020141251W WO2021136345A1 WO 2021136345 A1 WO2021136345 A1 WO 2021136345A1 CN 2020141251 W CN2020141251 W CN 2020141251W WO 2021136345 A1 WO2021136345 A1 WO 2021136345A1
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alkyl
methyl
group
ethyl
indazol
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PCT/CN2020/141251
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English (en)
French (fr)
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路良
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路良
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Priority to JP2022564690A priority Critical patent/JP2023508772A/ja
Priority to EP20909530.6A priority patent/EP4071145A4/en
Publication of WO2021136345A1 publication Critical patent/WO2021136345A1/zh
Priority to US17/852,990 priority patent/US20220388992A1/en

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    • 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
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    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D471/08—Bridged systems

Definitions

  • This application provides a class of novel compounds with pharmacological activity, which can be used to inhibit Janus kinase (JAK).
  • the application also relates to a composition comprising the compound, and the use of the compound and the composition in the preparation of a medicament for the treatment and/or prevention of JAK-related diseases or disorders.
  • Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins, and are broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity caused by mutation, overexpression or inappropriate regulation, abnormal or dysregulation, and excessive or insufficient production of growth factors or cytokines is involved in many diseases, including but not limited to cancer, cardiovascular diseases, Allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders (e.g. Alzheimer's disease).
  • diseases including but not limited to cancer, cardiovascular diseases, Allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders (e.g. Alzheimer's disease).
  • Inappropriate kinase activity triggers a variety of biological cell responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility related to the aforementioned and related diseases. Therefore, protein kinases have become an important class of enzymes as targets for therapeutic intervention.
  • the JAK family of cellular protein tyrosine kinases plays an important role in cytokine signal transduction (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253).
  • JAK is a family of intracellular non-receptor tyrosine kinases, which play a role in the cytokine receptor signaling pathway by interacting with signal transducers and activators of transcription (STAT). Plays an important role.
  • JAK/STAT signaling pathway is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Compared with other signal pathways, the transmission process of this signal pathway is relatively simple. It mainly consists of three components, namely tyrosine kinase associated receptor, tyrosine kinase JAK and signal transducer. And the transcriptional activator STAT.
  • cytokines and growth factors conduct signals through the JAK-STAT signaling pathway, including interleukins (such as IL-2 ⁇ 7, IL-9, IL-10, IL-15, IL-21, etc.), GM-CSF ( Granulocyte/macrophage colony stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin), PDGF (platelet derived Factors) and interferons (including IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , etc.) and so on. These cytokines and growth factors have corresponding receptors on the cell membrane.
  • interleukins such as IL-2 ⁇ 7, IL-9, IL-10, IL-15, IL-21, etc.
  • GM-CSF Granulocyte/macrophage colony stimulating factor
  • GH growth hormone
  • EGF epidermal growth factor
  • PRL pro
  • the common feature of these receptors is that the receptor itself does not have kinase activity, but the intracellular segment has the binding site of the tyrosine kinase JAK. After the receptor binds to the ligand, the tyrosine residues of various target proteins are phosphorylated by the activation of JAK that binds to the receptor to realize the signal transfer from the extracellular to the intracellular.
  • JAK is a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors.
  • JAK is the abbreviation of Janus Kinase in English. In Roman mythology, Janus is the two-faced god in charge of the beginning and the end. The reason why it is called the double-faced god kinase is because JAK can phosphorylate the cytokine receptors that it binds to, and also phosphorylate multiple signal molecules containing specific SH2 domains.
  • the JAK protein family includes 4 members: JAK1, JAK2, JAK3, and TYK2. They have 7 JAK homology domains (JH) in structure.
  • JH1 domain is the kinase domain and the function is to encode the kinase protein.
  • JH2 domain is a "pseudo" kinase region, which regulates the activity of JH1;
  • JH3-JH7 constitute a four-in-one domain, which regulates the binding of JAK to the receptor.
  • STAT is a type of cytoplasmic protein that can bind to DNA in the regulatory region of target genes, and is a downstream substrate of JAK. Seven members of the STAT family have been discovered, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.
  • STAT protein can be divided into the following functional segments in structure: N-terminal conserved sequence, DNA binding region, SH3 domain, SH2 domain and C-terminal transcription activation region. Among them, the most conserved and functionally important segment in sequence is the SH2 domain, which has the same core sequence "GTFLLRFSS" as the SH2 domain of tyrosine kinase Src.
  • the JAK-STAT signaling pathway has a wide range of functions, and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
  • inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn’s disease; and neoplastic diseases mainly involve myelofibrosis, polycythemia vera and primary platelets Hyperplasia.
  • mutations in the JAK molecule itself can also cause acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ductal breast carcinoma and non-small cell lung cancer (NSCLC), polycythemia vera (PV), idiopathic Thrombocythemia (ET), Idiopathic Myelofibrosis (IMF), Chronic Myeloid Leukemia (CML), etc.
  • AML acute myeloid leukemia
  • ALL acute lymphocytic leukemia
  • NSCLC non-small cell lung cancer
  • PV polycythemia vera
  • ET idiopathic Thrombocythemia
  • IMF Idiopathic Myelofibrosis
  • CML Chronic Myeloid Leukemia
  • JAK is a very important drug target. JAK inhibitors developed for this target are mainly used to screen therapeutic drugs for blood system diseases, tumors, rheumatoid arthritis and psoriasis. JAK-1, JAK-2 and TYK-2 are expressed in all tissue cells of the human body. JAK-3 is mainly expressed in various hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes , T lymphocytes. Studies have shown that JAK2 inhibitors are suitable for myeloproliferative diseases (Santos et al., Blood, 2010, 115:1131; Barosi G. and Rosti V., Curr. Opin.
  • JAK3 inhibitors are suitable as immunosuppressive agents (for example, US Patent 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003, 4:1297).
  • JAK inhibitors approved by the FDA and EMA include Tofacitinib, Ruxolitinib, Oclacitinib, etc. JAK inhibitors in the middle and late stages of the clinic include Filgotinib, Peficitinib and so on.
  • Tofacitinib a JAK3 inhibitor
  • Pfizer was developed by Pfizer and was approved by the FDA in November 2012 for the treatment of moderate to severe rheumatoid patients with inadequate response or intolerance to methotrexate in adult patients arthritis. It is the first oral JAK inhibitor approved for RA treatment. After that, it was approved by Japan PMDA for listing in March 2013 under the trade name Xeljanz. On March 16, 2017, Pfizer China announced that CFDA has formally approved Pfizer’s application for the marketing of oral JAK inhibitors. It is reported that the drug is approved for the treatment of adult patients with moderate to severe rheumatoid arthritis who have insufficient efficacy or intolerance to methotrexate.
  • tofacitinib has been used for psoriasis, ulcerative colitis, juvenile idiopathic arthritis and other indications close to being approved; clinical trials for the treatment of Crohn's disease, alopecia areata and other indications have also entered the middle and late stages of clinical trials .
  • the main side effects of tofacitinib are serious infection rate and increased low-density lipoprotein levels.
  • the most common adverse reactions are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat and nasopharyngitis.
  • tofacitinib can cause side effects such as anemia and neutropenia.
  • Ruxolitinib an inhibitor of JAK1 and JAK2
  • Incyte and Novartis were jointly developed by Incyte and Novartis and was approved by the US FDA in November 2011. It is also the first approved drug specifically for the treatment of myelofibrosis. It was approved by EMA in August 2012 and approved by Japan PMDA for listing in July 2014. The drug is sold by Incyte in the United States under the trade name Jakafi; Novartis is sold in Europe and Japan under the trade name Jakavi. Ruxolitinib is carrying out a number of clinical trials in the middle and late stages.
  • the indications include a variety of cancers, GVHD (rejection reaction), alopecia areata, allergic dermatitis, rheumatoid arthritis, vitiligo, psoriasis, etc.
  • GVHD injection reaction
  • alopecia areata
  • allergic dermatitis rheumatoid arthritis
  • vitiligo vitiligo
  • psoriasis psoriasis
  • the most common hematological adverse reactions of ruxolitinib are platelet count reduction and anemia.
  • the most common non-hematological adverse reactions are ecchymosis, dizziness and headache.
  • Olatinib was approved by the US FDA in 2013 for the control of itching and atopic dermatitis caused by canine allergic dermatitis.
  • Olatinib is a new type of JAK and JAK1-dependent cytokine inhibitor.
  • Olatinib is not only a very effective JAK1 inhibitor, but also inhibits the functions of JAK1-dependent cytokines in some anti-allergic, inflammation and pruritic reactions. It has little effect on cytokines that are not involved in activating JAK1.
  • Oral route, 0.4-0.6mg/kg olatinib twice a day is safe and effective for the treatment of itching caused by allergic dermatitis.
  • the administration of olatinib can relieve itching within 24 hours. In the experiment, more than 70% of the experimental animals (dogs) alleviated more than 50% of the itching response on the 7th day. However, olatinib cannot yet be used to treat human diseases.
  • Filgotinib a JAK1 inhibitor
  • the study of Filgotinib for the treatment of ulcerative colitis and Crohn's disease is currently in clinical phase II/III trials.
  • Filgotinib is a selective JAK1 inhibitor with IC50 of 10nM, 28nM, 810nM and 116nM for JAK1, JAK2, JAK3 and TYK2, respectively.
  • Peficitinib, JAK1 and JAK3 inhibitors, developed by Astellas, are currently in Phase III clinical treatment for rheumatoid arthritis.
  • the Phase II clinical study for the treatment of psoriasis has now been completed.
  • Peficitinib is a new type of oral JAK inhibitor.
  • Peficitinib inhibits the enzyme activities of JAK1, JAK2, JAK3 and TYK2 with IC50 of 3.9nM, 5.0nM, 0.71nM and 4.8nM, respectively.
  • JAK inhibitors Although some JAK inhibitors have been approved for marketing, and there are still a large number of JAK inhibitors in clinical research, these JAK inhibitors are not satisfactory in terms of efficacy or safety. Therefore, there is always a need for JAK inhibitors with better efficacy and/or fewer side effects.
  • One purpose of this application is to provide a new type of JAK inhibitor that replaces the existing JAK inhibitor, so as to provide more options for the treatment of JAK-related diseases.
  • a further purpose of the present application is to provide a new type of JAK inhibitor with better efficacy and/or better safety than existing JAK inhibitors.
  • this application provides compounds of formula (I) as JAK inhibitors:
  • X 1 is N or CR 14 ;
  • X 2 is N or CR 15 ;
  • X 3 is N or CR 16 ;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently H or selected from the following group: C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, ( 4-10 membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl- and (5-10 membered heteroaryl)-C 1-4 alkane Group -, wherein each option in the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the following groups: halogen, -CF 3 , -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, oxo, C
  • this application relates to a compound of formula (I):
  • X 1 is N or CR 14 ;
  • X 2 is N or CR 15 ;
  • X 3 is N or CR 16 ;
  • R 13 is H, C 1-6 alkyl or C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, C 7-11 bicyclic aryl Group, 7-11 membered bicyclic heteroaryl group, 11-15 membered tricyclic group, C 5-11 bicyclic alkyl group, 5-11 membered bicyclic heteroalkyl group, and R 13 is divided by 0, 1, 2, 3 or 4 R 1 is substituted; and
  • R 18 and R 19 are each independently selected from the following group: H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkoxy Group, C 3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl -, (4-10 membered heterocycloalkyl) -C 1-4 alkyl -, (C 6- 10 aryl) -C 1-4 alkyl -, (5-10 membered heteroaryl) -C 1 -4 alkyl-, wherein each option in this group is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the following groups: halogen, -CF 3 , -OH,- NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, ox
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are each independently H or selected from the following group: C 1-6 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, ( 4-10 membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl- and (5-10 membered heteroaryl)-C 1-4 alkane Group -, wherein each option in the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the following groups: halogen, -CF 3 , -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, oxo, C
  • isotopically-labeled compounds of the above-mentioned compound of formula (I) are provided.
  • an isotopically labeled compound of the compound of formula (I) is provided, wherein all H are each independently and optionally replaced by D.
  • X 1 is N. In some preferred embodiments of the present application, in formula (I), X 2 is N. In some preferred embodiments of the present application, in formula (I), X 3 is N. In some preferred embodiments of the present application, in formula (I), X 1 is CR 14 , X 2 is CR 15 , and X 3 is CR 16 .
  • X 1 is CR 14
  • X 2 is CR 15
  • X 3 is CR 16
  • X 1 , X 2 , and X 3 are each independently selected from H , -OH, -CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl.
  • X 1 , X 2 , and X 3 are the same.
  • X 1 , X 2 , and X 3 are all CH.
  • X 1 , X 2 , and X 3 are all N.
  • an isotopically labeled compound of the compound of formula (I) is provided, wherein all H are each independently and optionally replaced by D, and X 1 , X 2 , X 3 are the same . In some more preferred embodiments of the present application, an isotopically labeled compound of the compound of formula (I) is provided, wherein all H are each independently and optionally replaced by D, and X 1 , X 2 , and X 3 are all CH .
  • X 1 , X 2 , and X 3 are all CH, and L is CH 2 .
  • X 1 , X 2 , and X 3 are all CH, and L is a connecting bond.
  • X 1 , X 2 , and X 3 are all N, and L is CH 2 .
  • X 1 , X 2 , and X 3 are all N, and L is a connecting bond.
  • X 1 , X 2 , and X 3 are all CR 14 , wherein R 14 is selected from -OH, -CN, halogen, and C 1-6 alkane Group, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, L is CH 2 .
  • X 1 , X 2 , and X 3 are all CR 14 , wherein R 14 is selected from -OH, -CN, halogen, and C 1-6 alkane Group, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, and L is a linkage.
  • R 13 is H, C 1-6 alkyl or C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclic group (wherein R 13 is optionally substituted by 1, 2, 3 One or four R 1 replaced).
  • R 13 is H, C 1-6 alkyl or C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 Aryl, 5-7 membered heteroaryl (wherein R 13 is optionally substituted with 1, 2, 3 or 4 R 1 ).
  • R 13 is C 1-6 alkyl or C 3-7 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 Member heteroaryl (wherein R 13 is optionally substituted with 1, 2, 3, or 4 R 1 ).
  • R 13 is C 1-4 alkyl or C 3-7 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 Member heteroaryl (wherein R 13 is optionally substituted with 1, 2, 3, or 4 R 1 ). In some preferred embodiments of the present application, in formula (I), R 13 is C 1-4 alkyl or C 3-7 cycloalkyl, 4-6 membered heterocycloalkyl (wherein R 13 optionally Replaced by 1, 2, 3, or 4 R 1 ).
  • R 13 is C 1-4 alkyl or C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl (wherein R 13 is optionally Replaced by 1, 2, 3, or 4 R 1 ). In some preferred embodiments of the present application, in formula (I), R 13 is C 1-3 alkyl, cyclopropyl or 6-membered heterocycloalkyl (wherein R 13 is optionally divided by 1, 2 , 3 or 4 R 1 ).
  • R 13 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl or pyrazinyl (wherein R 13 is optionally Replaced by 1, 2, 3, or 4 R 1 ).
  • R 13 is a methyl group.
  • R 13 is an ethyl group.
  • R 13 is n-propyl.
  • R 13 is isopropyl.
  • R 13 is cyclopropyl. In some particularly preferred embodiments of the present application, in formula (I), R 13 is pyrazinyl. In some particularly preferred embodiments of the present application, in formula (I), R 13 is pyrazinyl and is substituted by piperidinyl. In some particularly preferred embodiments of the present application, in formula (I), R 13 is a pyrazinyl group and is substituted by a morpholinyl group.
  • R 17 is H, -OH, -SH, -CN, halogen, -NO 2 , -SF 5 , -SC 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 4-14 membered heterocycloalkane Group, C 6-10 aryl group or 5-10 membered heteroaryl group, and is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the following groups: halogen, -CF 3 , -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 hydroxyalkyl, -
  • R 17 is H.
  • R 13 and R 17 and the L and N atoms connected to them together form a 4-6 membered azacycloalkyl group, and the 4-6 membered
  • the azacycloalkyl group is optionally substituted with 1, 2 or 3 substituents each independently selected from the following group: halogen, -CF 3 , -OH, -NH 2 , -NH(CH 3 ), -N (CH 3 ) 2 , -CN, oxo, C 1-4 alkyl.
  • R 18 and R 19 are each independently selected from the following groups: H, C 1-6 alkyl, C 1-4 haloalkyl, C 2- 8 -alkenyl, C 2-8 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl , Wherein each option in the group is optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the following groups: halogen, -CF 3 , -OH, -NH 2 , -NH (CH 3 ), -N(CH 3 ) 2 , -CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1 -4 hydroxyalkyl, -SC 1-4 alkyl.
  • R 18 and R 19 are each independently selected from the following group: H, C 1-6 alkyl, wherein each option in this group is optional Ground is substituted by 1, 2, 3 or 4 substituents each independently selected from the following group: halogen, -CF 3 , -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2. -CN, oxo.
  • R 18 is H.
  • R 19 is H.
  • both R 18 and R 19 are H.
  • R 18 and R 19 and the carbon atoms to which they are connected together form a C 3-6 cycloalkyl group, a 4-6 membered heterocycloalkyl group, and
  • the C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents each independently selected from the following groups: halogen, -CF 3 , -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, oxo, C 1-4 alkyl.
  • the number of R 2 is 1, 2 or 3, and each R 2 is independently selected from H, halogen, -OH, -NO 2 ,- CN, -SF 5 , -SH, -SC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, wherein the -SC 1-4 alkyl, C 1-6 alkyl, C 3-7 cycloalkyl, 4-10 Each membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 substituents each independently selected from the following group: halogen, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4
  • the number of R 2 is 1, 2, or 3, and each R 2 is independently selected from halogen, C 1-6 alkyl, and C 3- 6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 substituents each independently selected from the following groups: halogen,- OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 Haloalkoxy.
  • the number of R 2 is 1, 2 or 3, and each R 2 is independently selected from halogen, C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the following group: halogen, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy.
  • the number of R 2 is 1 or 2, and each R 2 is independently selected from halogen and C 1-6 alkyl.
  • the number of R 2 is 1 or 2, and each R 2 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl. In some preferred embodiments of the present application, in formula (I), the number of R 2 is 1 or 2, and each R 2 is independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, Isopropyl. In some preferred embodiments of the present application, in formula (I), the number of R 2 is 1 or 2, and each R 2 is independently selected from fluorine, methyl, and ethyl.
  • the number of R 2 is 1 or 2, and each R 2 is independently selected from fluorine and ethyl. In some preferred embodiments of the present application, in formula (I), the number of R 2 is one, and R 2 is selected from fluorine and ethyl. In some preferred embodiments of the present application, in formula (I), the number of R 2 is 2, and each R 2 is independently selected from fluorine and ethyl. In some particularly preferred embodiments of the present application, in formula (I), there are two R 2 , each of which is fluorine and ethyl.
  • R 2 there is one R 2 , and R 2 is an ethyl group. In some particularly preferred embodiments of the present application, in formula (I), there is one R 2 , and R 2 is fluorine.
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from H, halogen, -OH,- NO 2 , -CN, -SF 5 , -SH, -SC 1-4 alkyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl, C 7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, wherein
  • the -SC 1-4 alkyl group, C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 1-8 alkoxy group are optionally composed of 1, 2, 3 Or 4 R 3 substitutions, and wherein the C 3-7 cycloalkyl group, 3-10 membered heterocycloalkyl group, 3-10 membered heterocycloal
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from H, halogen, -OH,- NO 2 , -CN, -SF 5 , -SH, -SC 1-4 alkyl, C 1-8 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aromatic Group, 5-7 membered heteroaryl group, wherein said -SC 1-4 alkyl group, C 1-8 alkyl group is optionally substituted with 1, 2, 3 or 4 R 3 , and wherein said C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 R 4 .
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from halogen, -OH, C 1- 8 alkyl group, C 3-7 cycloalkyl group, 3-7 membered heterocycloalkyl group, C 5-7 aryl group, 5-7 membered heteroaryl group, wherein the C 1-8 alkyl group is optionally substituted by 1 One, two, three, or four R 3 substitutions, and wherein the C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 5-7 aryl, 5-7 membered heteroaryl group is any Optionally substituted by 1, 2, 3 or 4 R 4 .
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from halogen, -OH, C 1- 8 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, wherein the C 1-8 alkyl is optionally substituted with 1, 2, or 3 R 3 , and wherein C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R 4 .
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from halogen, -OH, C 1- 6 alkyl, C 3-7 cycloalkyl, 5-7 membered heterocycloalkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 3 , and wherein C 3-7 cycloalkyl, 5-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R 4 .
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from halogen, -OH, C 1- 4- alkyl, C 3-6 cycloalkyl, 5-7 membered heterocycloalkyl, wherein said C 1-4 alkyl is optionally substituted with 1 or 2 R 3 , and wherein said C 3- 6 cycloalkyl, 5-7 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R 4 .
  • R 13 is substituted with 0, 1, 2, 3 or 4 R 1 , and each R 1 is independently selected from 5-7 membered heterocycloalkyl , Wherein the 5-7 membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 R 4 .
  • R 13 is substituted with 0 or 1 R 1 , and R 1 is selected from piperidinyl or morpholinyl.
  • R 1 is absent.
  • R 13 is substituted by one R 1.
  • R 13 is substituted by one R 1 , and R 1 is piperidinyl. In some particularly preferred embodiments of the present application, in formula (I), R 13 is substituted by one R 1 , and R 1 is morpholinyl.
  • the compound of formula (I) is each specific compound shown in the various examples herein. That is, the compound of formula (I) is selected from:
  • optical isomers means that when a compound has one or more chiral centers, each chiral center may have an R configuration or an S configuration, and the various isomers formed thereby are optically different. Construct. Optical isomers include all diastereomers, enantiomers, mesoisomers, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatography columns or by chiral synthesis.
  • Geometric isomer means that when a double bond exists in a compound, the compound may exist in cis isomer, trans isomer, E isomer, and Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or mixtures thereof.
  • tautomer refers to an isomer produced by the rapid movement of an atom in two positions in a molecule. Those skilled in the art can understand that: tautomers can be transformed into each other, and in a certain state, they may reach an equilibrium state and coexist.
  • compound of formula (I) described herein also encompasses any tautomers of the compound of formula (I).
  • This application includes all pharmaceutically acceptable isotope-labeled compounds of the compound of formula (I), wherein one or more atoms have the same atomic number as the atoms normally found in nature but different atomic mass or mass number. Replaced.
  • isotopes suitable for inclusion in the compounds of this application include hydrogen isotopes such as 2 H(D) and 3 H(T), carbon isotopes such as 11 C, 13 C and 14 C, and chlorine isotopes such as 36 Cl, isotope of fluorine, such as 18 F, isotope of iodine, such as 123 I and 125 I, isotope of nitrogen, such as 13 N and 15 N, oxygen isotope, such as 15 O, 17 O and 18 O, and sulfur Isotope, such as 35 S.
  • hydrogen isotopes such as 2 H(D) and 3 H(T)
  • carbon isotopes such as 11 C, 13 C and 14 C
  • chlorine isotopes such as 36 Cl
  • isotope of fluorine such as 18 F
  • isotope of iodine such as 123 I and 125 I
  • isotope of nitrogen such as 13 N and 15 N
  • oxygen isotope such as 15
  • isotope-labeled compounds of formula (I) can be used in drug and/or substrate tissue distribution studies. Considering the ease of introduction and the convenience of detection means, the radioisotopes deuterium (ie 2 H) and carbon-14 (ie 14 C) are particularly useful for this purpose.
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic benefits and therefore may be preferred in certain situations, due to greater metabolic stability ( For example, increased in vivo half-life or reduced dosage requirements).
  • positron emission isotopes such as 11 C, 18 F, 15 O, and 13 N
  • PET Positron Emission Topography
  • the isotope-labeled compound of formula (I) can generally be used by conventional techniques known to those skilled in the art or by using a suitable isotope-labeled reagent to replace the previously used non-labeled reagent to be similar to that described in the examples and preparations attached herein. Method to prepare.
  • the compound of formula (I) may exist in the form of a pharmaceutically acceptable salt, for example, an acid addition salt and/or a base addition salt of the compound of formula (I).
  • pharmaceutically acceptable salts include acid addition salts or base addition salts that may appear in the compound of formula (I).
  • the pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts and base addition salts thereof.
  • Appropriate acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate , Camphorsulfonate, citrate, cyclohexamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, six Fluorophosphate, 2-(4-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate , Malate, maleate, malonate, methanesulfonate, methylsulfate, na
  • base addition salts are formed from bases that form non-toxic salts. Examples thereof include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. It is also possible to form half salts of acids and bases, such as hemisulfate and hemicalcium salts. For an overview of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
  • Certain compounds of the present application may exist in different crystal forms or amorphous forms, and no matter what form they exist, the compounds of formula (I) are included in the scope of the present application.
  • pharmaceutically acceptable means that the corresponding compound, carrier or molecule is suitable for administration to humans.
  • the term refers to any national regulatory agency certified by regulatory agencies such as CFDA (China), EMEA (Europe), FDA (United States) for mammals, preferably humans.
  • prodrug refers to a derivative of the compound of the present application through a reaction with enzymes, gastric acid, etc., in the living body under physiological conditions, for example, through oxidation, reduction, and hydrolysis, respectively, catalyzed by enzymes.
  • Metal refers to all molecules derived from any compound of the present application in a cell or organism, preferably a human.
  • hydroxy refers to -OH.
  • halogen refers to -F, -Cl, -Br, or -I.
  • cyano refers to -CN.
  • each substituent is independently selected from each other, that is, these substituents may be the same or different.
  • these R 1s may be the same or different.
  • these R 2s may be the same or different.
  • R 1 and R 2 are both -N (R 9) (R 10 )
  • R is 2 R 1 and R 9 and R 10 may be independently selected, i.e., the R 1 R 2 R 9 and the R 9 may be the same or different
  • R 1 is R 10 and R 2 10 may be the same or different.
  • R 9 and R 10 in the two R 1s can be independently selected, that is, the first in R 1 and second R 9 and R 1 R 9 may be the same or different, R 1 is the first and the second R 10 and R 1 R 10 may be the same or different.
  • substituted means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.
  • the term “optional” or “optionally” means that the event described can occur or not occur.
  • a group “optionally substituted” means that the group may be unsubstituted or substituted.
  • heteroatom represents oxygen (O), nitrogen (N), or S(O) m (where m can be 0, 1, or 2, that is, sulfur atom S, or sulfoxide SO, Or sulfonyl S(O) 2 ).
  • alkyl refers to saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms.
  • C 1-8 alkyl refers to a linear or branched atomic group having 1-8 carbon atoms.
  • C 1-8 alkyl includes the terms “C 1-6 alkyl”, “C 1 -C 3 alkyl” and "C 1 -C 4 alkyl” in its definition.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopropyl Pentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3- Dimethylbutyl, hexyl, etc.
  • Alkyl groups may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.
  • alkenyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
  • alkenyl groups have 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms.
  • C 2-8 alkenyl refers to a linear or branched unsaturated atomic group (having at least one carbon-carbon double bond) having 2-8 carbon atoms.
  • the double bond may or may not be the point of attachment of another group.
  • Alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. Alkenyl groups may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents. When the compound of formula (I) contains an alkenyl group, the alkenyl group may be present in the pure E form, the pure Z form, or any mixture thereof.
  • alkynyl refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • an alkynyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms.
  • C 2-8 alkynyl refers to a linear or branched unsaturated atomic group (having at least one carbon-carbon triple bond) having 2-8 carbon atoms.
  • the triple bond may or may not be the point of attachment of another group.
  • Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like.
  • the alkynyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.
  • C 3-7 cycloalkyl refers to a cycloalkyl group having 3-7 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Hexenyl, cycloheptyl. Cycloalkyl groups may be optionally substituted with one or more suitable substituents.
  • n-membered heterocycloalkyl refers to a cycloalkyl group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms, the heteroatoms being selected from O, S and N.
  • 3-7 membered heterocycloalkyl groups include but are not limited to oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran , Piperidine, morpholine, piperazine, oxepane, thiepane, azepine.
  • the heterocycloalkyl group may be optionally substituted with one or more suitable substituents.
  • C 5-7 aryl refers to an aryl group having an aromatic ring containing 5-7 carbon atoms, preferably a phenyl group.
  • n-membered heteroaryl refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, the heteroatoms being selected from O, S And N.
  • 5-7 membered heteroaryl groups include but are not limited to pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine.
  • Heteroaryl groups may be optionally substituted with one or more suitable substituents.
  • C 7-11 bicyclic aryl group refers to a bicyclic aryl group having 7-11 carbon atoms, such as naphthalene, indene and the like.
  • the bicyclic aryl group may be optionally substituted with one or more suitable substituents.
  • n-membered bicyclic heteroaryl group refers to a bicyclic heteroaryl group having m carbon atoms forming an aromatic bicyclic ring and (nm) heteroatoms forming an aromatic bicyclic ring, the heteroatoms are selected from From O, S and N.
  • 7-11 membered bicyclic heteroaryl groups include, but are not limited to, quinoline, isoquinoline, benzothiazole, and the like.
  • the bicyclic heteroaryl group may be optionally substituted with one or more suitable substituents.
  • 11-15 membered tricyclic group includes but is not limited to acridine and the like.
  • the 11-15 membered tricyclic group may be optionally substituted with one or more suitable substituents.
  • haloalkyl refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl, that is, each hydrogen atom of the alkyl group is replaced by a halogen atom) .
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group having one or more halogen substituents (up to perhaloalkyl, that is, each hydrogen atom of the alkyl group is halogenated Replaced by atoms).
  • C 1-4 haloalkyl refers to a C 1-4 alkyl group with one or more halogen substituents (up to a perhaloalkyl group, that is, each hydrogen atom of the alkyl group is Substituted by a halogen atom);
  • C 1-3 haloalkyl refers to a C 1-3 alkyl group having one or more halogen substituents (up to a perhaloalkyl group, that is, each of the alkyl groups The hydrogen atoms are all replaced by halogen atoms);
  • C 1-2 haloalkyl refers to a C 1-2 alkyl group with one or more halogen substituents (ie, methyl or ethyl) (up to Perhaloalkyl, that is, each hydrogen atom of the alkyl group is replaced by a halogen atom).
  • C 1 haloalkyl refers to a methyl group with 1, 2, or 3 halogen substituents.
  • haloalkyl groups include: CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl and the like.
  • alkoxy refers to an alkyl group with a single bond attached to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. Alkoxy can be described as alkyl-O-.
  • C 1-6 alkoxy refers to a linear or branched alkoxy group containing 1 to 6 carbon atoms. The term “C 1-6 alkoxy” includes the term “C 1-3 alkoxy” in its definition.
  • Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexoxy and the like. The alkoxy group may be optionally substituted with one or more suitable substituents.
  • the number range related to the number of substituents, the number of carbon atoms, and the number of ring atoms means that all integers in the range are enumerated one by one, and the range is only used as a simplified notation.
  • 3-12 membered ring means 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring;
  • 3-8 membered ring means 3, 4, 5, 6, 7 or 8 membered ring
  • “1-12 carbon atoms” or C 1-12 means 1 (C 1 ), 2 (C 2 ), 3 (C 3 ), 4 (C 4 ), 5 (C 5 ), 6 (C 6 ), 7 (C 7 ), 8 (C 8 ), 9 (C 9 ), 10 (C 10 ), 11 (C 11 ) or 12 carbon atoms (C 12 ) ;
  • 1-6 carbon atoms or “C 1-6” means 1 (C 1 ), 2 (C 2 ), 3 (C 3 ), 4 (C 4 ), 5 (C 5 ) Or 6 carbon atoms (C 6 );
  • C 3-8 means 3 (C 3 ), 4 (C 4 ), 5 (C 5 ), 6 (C 6 ), 7 (C 7 ) or 8 carbon atoms (C 8 ) ;
  • 3-8 ring atoms means 3, 4, 5, 6, 7 or 8 ring atoms.
  • the number range related to the number of substituents, the number of carbon atoms, and the number of ring atoms also encompasses any of its sub-ranges, and each sub-range is also deemed to be disclosed herein.
  • the present application provides a pharmaceutical composition, which contains the above-mentioned compound or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer Body mixture, or a pharmaceutically acceptable salt thereof, or a prodrug, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
  • the pharmaceutical composition of the present application can be formulated as required for oral, external use (including but not limited to external application, spraying, etc.), parenteral (including subcutaneous, muscle, cortical and intravenous) administration, bronchial administration or nasal administration
  • the dosage form preferably, the pharmaceutical composition of the present application is formulated into a dosage form (preparation) suitable for oral or external use. More preferably, the pharmaceutical composition of the present application is formulated into a dosage form (formulation) suitable for oral administration.
  • the preparation can be in the form of tablets, placed in hard gel capsules in powder or granule form, or in the form of troches or lozenges.
  • the solid carrier may include conventional excipients such as binders, fillers, tableting lubricants, disintegrants, wetting agents, and the like. If necessary, the tablets can be film-coated by conventional techniques.
  • a liquid carrier the preparation may be in the form of syrup, emulsion, ointment, soft gel capsule, sterile carrier for injection, aqueous or non-aqueous liquid suspension, or it may be in the form of water or other appropriate Carrier-recovered dry product.
  • Liquid preparations may contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavoring and/or coloring agents.
  • the carrier usually at least mostly includes sterile water, but saline solution, glucose solution, etc. can also be used. Injectable suspensions can also be used, in which case conventional suspending agents can be used. Conventional preservatives, buffer reagents, etc. can also be added to parenteral dosage forms.
  • the pharmaceutical composition is prepared by conventional techniques suitable for the desired formulation containing an appropriate amount of the active ingredient (ie, the compound of formula (I) of the present application).
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, and solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectables Organic esters (for example, ethyl oleate).
  • compositions may also contain various excipients, for example, preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • Various antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, etc.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of injectable pharmaceutical dosage forms can be achieved through the use of agents that delay absorption (e.g., aluminum monostearate and gelatin).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert excipient (or carrier) (for example, sodium citrate or dicalcium phosphate), which may also include: (a) fillers or mixing agents (for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic); (c) Humectants (for example, glycerol); (d) disintegrants (for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution Blockers (for example, paraffin); (f) absorption enhancers (for example, quaternary ammonium compounds); (1) wetting agents (for example, cetyl alcohol and
  • Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gel capsules using, for example, lactose and high molecular weight polyethylene glycol as excipients.
  • Solid dosage forms e.g., tablets, dragees, capsules, pills, and granules
  • coatings and shells e.g., enteric coatings and others known in the art. They may contain sunscreens, and they may also be a combination of active compounds or various active compounds that release the active compound or various active compounds in a certain part of the intestinal tract in a delayed manner.
  • examples of embedding compositions that can be used are polymeric substances and waxes.
  • the active ingredient may also be in microencapsulated form, if appropriate, with one or more of the aforementioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene) commonly used in the art.
  • Methanol benzyl benzoate, propylene glycol, 1,3 butanediol, dimethylformamide), oil (specifically, cotton seed oil, groundnut oil, corn oil, olive oil, castor oil, sesame oil), propylene Fatty acid esters of triol, tetrahydrofuranol, polyethylene glycol and sorbitan or mixtures of these substances, etc.
  • oil specifically, cotton seed oil, groundnut oil, corn oil, olive oil, castor oil, sesame oil
  • composition may also include, for example, wetting agents, emulsifying and suspending agents, flavoring agents, flavoring agents, and perfuming agents.
  • the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline fibers, aluminum metahydroxide, bentonite, agar-agar and Tragacanth gum or a mixture of these substances, etc.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline fibers, aluminum metahydroxide, bentonite, agar-agar and Tragacanth gum or a mixture of these substances, etc.
  • Dosage forms for topical administration of the compound of the present application include ointments, powders, sprays and inhalants.
  • the active ingredient is mixed with a physiologically acceptable carrier and any required preservatives, buffers or propellants under sterile conditions.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also included in the scope of this application.
  • the topical dosage form of the compound of the present application may be in the form of a water-in-oil (W/O) or oil-in-water (O/W) emulsion, a multi-emulsion form, such as a water-in-oil-in-water (W/O/W) form or an oil-in-water It is prepared in the form of an oil-in-water (O/W/O) emulsion, or in the form of a water dispersion or a lipid dispersion, a gel or an aerosol.
  • W/O water-in-oil
  • O/W oil-in-water
  • the external dosage form of the compound of the present application may contain additives and formulation aids, such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilizers, dyes, fragrances, and preservatives.
  • emulsifiers include stearic acid, triethanolamine, and PEG-40-stearate.
  • Suitable thickeners include glyceryl monostearate and PEG600.
  • Suitable preservatives include propyl paraben and chlorocresol.
  • Suitable spreading agents include dimethicone and polydimethylcyclosiloxane.
  • Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.
  • the external dosage form of the compound of the present application may include ointments, lotions, gels, emulsions, microemulsions, sprays, skin patches, etc., which can be applied topically to treat atopic dermatitis, eczema, psoriasis, and scleroderma. Disease, itching, vitiligo, hair loss and other skin diseases.
  • the external dosage form of the compound of the present application is an ointment, which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and hair loss.
  • the amount of the compound of formula (I) in the pharmaceutical composition and dosage form can be appropriately determined by those skilled in the art according to needs.
  • the compound of formula (I) may be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.
  • the application provides the compound as described above or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable compound.
  • Disease or disorder related to JAK includes but is not limited to:
  • Autoimmune diseases or disorders including single organ or single cell type autoimmune disorders, such as Hashimoto’s thyroiditis, autoimmune hemolytic anemia, pernicious anemia, autoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmune Orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and Membranous glomerulopathy, those involving systemic autoimmune disorders (e.g.
  • Cancer or tumor including gastrointestinal/gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast and breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including Acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple Myeloma), myeloproliferative disorders, proliferative diabetic retinopathy or disorders related to angiogenesis (including solid tumors);
  • leukemia including Acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including Acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including Acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including Acute myeloid leukemia and chronic myeloid leukemia
  • Diabetes including type I diabetes or diabetic complications
  • Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis and lens uveitis associated with Behcet’s disease), keratitis, herpetic Keratitis, keratitis conus, corneal epithelial dystrophy, leukoplakia, ocular pemphigus, Moren ulcer, scleritis, Grave's eye disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye) , Blisters, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis or ocular neovascularization;
  • Intestinal inflammation allergies or conditions, including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis or mastocytosis;
  • Neurodegenerative diseases including motor neuron disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, neurodegenerative disease caused by cerebral ischemia or traumatic injury, stroke, glutamate neurotoxicity or Hypoxia; stroke ischemia/reperfusion injury, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation;
  • Skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, itching or other pruritic conditions, vitiligo, hair loss;
  • Allergies including mammalian allergic dermatitis (including equine allergic diseases, such as bite allergies), summer eczema, Culex mosquito itch syndrome (sweet itch), emphysema, inflammatory airway disease, recurrent Airway obstruction, airway overreaction, or chronic obstructive pulmonary disease;
  • mammalian allergic dermatitis including equine allergic diseases, such as bite allergies), summer eczema, Culex mosquito itch syndrome (sweet itch), emphysema, inflammatory airway disease, recurrent Airway obstruction, airway overreaction, or chronic obstructive pulmonary disease;
  • Asthma and other obstructive airway diseases including chronic or refractory asthma, advanced asthma, bronchitis, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma or dusty asthma;
  • Transplant rejection including islet transplant rejection, bone marrow transplant rejection, graft versus host disease, organ and cell transplant rejection (e.g. bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islets, kidney, limbs, liver, lung, muscle, myoblasts , Nerve, pancreas, skin, small intestine or trachea) or xenotransplantation.
  • organ and cell transplant rejection e.g. bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islets, kidney, limbs, liver, lung, muscle, myoblasts , Nerve, pancreas, skin, small intestine or trachea
  • xenotransplantation e.g. bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islets, kidney, limbs, liver, lung, muscle, myoblasts , Nerve, pancreas, skin, small intestine or trac
  • the present application provides a method for treating JAK-related diseases or disorders, the method comprising adding a therapeutically effective amount of the compound described above or its isotope-labeled compound, or its optical isomer , Geometric isomers, tautomers or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, or the composition as described above is administered to patients in need .
  • the patient is preferably a mammal, and more preferably a human patient.
  • the route of administration can be oral, topical (including but not limited to external application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical and intravenous) administration, bronchial administration or nasal administration. Among them, it is preferably administered orally or externally. It is more preferably administered orally.
  • the compound of the present application demonstrated excellent efficacy as a JAK kinase inhibitor in experiments (better than existing JAK kinase inhibitors, such as Filgotinib), and potentially has good safety.
  • the compound of formula (I) of the present application can be synthesized by various methods familiar to those skilled in the art of organic synthesis.
  • the following specific examples give some exemplary synthetic methods of compounds of formula (I), and these methods are well-known in the field of synthetic chemistry.
  • those skilled in the art can appropriately adjust the reactants, reaction conditions and protecting groups to easily design synthetic routes for other compounds of formula (I).
  • Example 1 N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl) Methyl)-5-(piperidin-1-yl)pyrazine-2-carboxamide (MDI-3)
  • the obtained product is dissolved in 2 ml of methanol and In 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 3ml methanol, add 0.5ml ammonia water, concentrate, and purify by preparation plate to obtain the final product 6mg with a yield of 32.8%.
  • the obtained product is dissolved in 2ml methanol and 1ml In concentrated hydrochloric acid, reacted at 50 degrees for 6 hours, concentrated, dissolved in 3ml methanol, added 0.5ml ammonia, concentrated, and purified by preparation plate to obtain 4mg of the final product with a yield of 34.9%.
  • Dissolve 11-1 (24.2mg, 0.03mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 3.4 mg, and the yield was 26.4%.
  • Synthesis intermediate 12-1 1-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl) -1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(Trimethylsilyl)ethoxy)methyl (Yl)-1H-imidazol-4-yl)methyl)pyrrolidine-3-carbonitrile
  • Dissolve 12-1 (20.0mg, 0.02mmol) in 2ml methanol solution, add 1ml concentrated hydrochloric acid, and react at 50°C for 6h.
  • the reaction solution was concentrated, dissolved in 3 ml of methanol, 0.5 ml of ammonia was added, and concentrated to prepare a silica gel plate for purification to obtain 3 mg of the final product with a yield of 28.6%.
  • the obtained product was dissolved in 2ml methanol and 1ml concentrated hydrochloric acid and reacted at 50°C. After 6 hours, concentrate, dissolve in 3ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain 8mg of the final product with a yield of 46.9%.
  • Dissolve 14-1 (23.0mg, 0.03mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 7.1 mg, and the yield was 59.0%.
  • Dissolve 15-1 (22.9mg, 0.03mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 5.4mg, and the yield was 45.0%.
  • the obtained product is dissolved in 2ml methanol and 1ml concentrated hydrochloric acid, reacted at 50°C for 6 hours, concentrated, and dissolved in 3ml methanol. Add 0.5 ml of ammonia water, concentrate, prepare a silica gel plate for purification, and obtain 7 mg of the final product with a yield of 45.9%.
  • the product was dissolved in 2ml methanol and 1ml concentrated hydrochloric acid was added. React at 50 degrees for 6 hours, concentrate, dissolve in 3ml of methanol, add 0.5ml of ammonia, concentrate, prepare a silica gel plate for purification, and obtain 6.4mg of the final product with a yield of 39.0%.
  • the obtained product was dissolved in 2ml methanol and 1ml concentrated hydrochloric acid, reacted at 50°C for 6 hours, concentrated, dissolved in 3ml methanol, and added 0.5ml ammonia water was concentrated, and a silica gel plate was prepared for purification to obtain 11mg of the final product with a yield of 47.0%.
  • Dissolve 22-1 (21.0mg, 0.02mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 6.7mg, and the yield was 58.6%.
  • Dissolve 23-1 (17.8mg, 0.02mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 4.2 mg, and the yield was 43.5%.
  • the purified concentrate Dissolve in 2ml of methanol, add 1ml of concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, and dissolve in 3ml of methanol, add 0.5ml of ammonia, concentrate, and purify on silica gel plate to obtain the final product 4.8mg with a yield of 43.4%.
  • Dissolve 26-1 (17.9mg, 0.02mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 3.9mg, and the yield was 42.5%.
  • Example 31 4-(3-(4-((Cyclobutylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl -2-Fluorophenol (Ex-31)
  • Example 32 5-Ethyl-2-fluoro-4-(3-(4-(((tetrahydrofuran-3-yl)amino)methyl)-1H-imidazol-2-yl) -1H-indazol-6-yl)phenol (Ex-32)
  • Dissolve 32-1 (15.0mg, 0.02mmol) in 2ml methanol, add 1ml concentrated hydrochloric acid, react at 50°C for 6 hours, concentrate, dissolve in 2ml methanol, add 0.5ml ammonia, concentrate, prepare a silica gel plate for purification, and obtain the final
  • the product was 4.3 mg, and the yield was 55.1%.
  • the obtained product is dissolved in 2ml methanol and 1ml concentrated hydrochloric acid, reacted at 50°C for 6 hours, concentrated, dissolved in 3ml methanol, added 0.5ml ammonia, concentrated, and purified on a preparation plate , The final product is 5mg, the yield is 32.0%.
  • the obtained product is dissolved in 2ml methanol and 1ml concentrated hydrochloric acid, reacted at 50°C for 6 hours, concentrated, dissolved in 3ml methanol, added 0.5ml ammonia and concentrated to prepare the plate. After purification, 6 mg of the final product was obtained with a yield of 37.3%.
  • a drug screening system based on JAK1, JAK2, JAK3, and TYK2 was used to detect the inhibitory ability of small molecule compounds on kinase activity.
  • Kinase and its substrates IRS1, IGF1Rtide, Poly(4:1Glu, Tyr) undergo an enzymatic reaction, consume ATP to produce ADP, and use ADP-Glo reagent and luminescence method to detect the amount of product to reflect the activity of the kinase.
  • a) Use 100% DMSO to dilute Filgotinib (10mM stock solution) to the original times, the test compound is diluted 5 times, and the test compound is diluted 4 times in a 96-well dilution plate. Add 1 ⁇ L of the compound to 49 ⁇ L of kinase reaction buffer, and add 1 ⁇ L of the compound to 49 ⁇ L of kinase reaction buffer. Shake on a microplate shaker for 20 minutes.
  • step b) Transfer 2 ⁇ L of kinase (prepared in step 2.2.1.2) to the 384 reaction plate, add 1 ⁇ L of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075), 1000rpm/min, centrifuge for 1min, Incubate at 25°C for 10 min.
  • Compound inhibition rate (%inh) (negative control-compound)/(negative control-positive control)*100%
  • Min is the 10uM/50uM Filgotinib RLU value of the positive control
  • Max is the negative control DMSO RLU value.
  • SD is the standard error
  • AVE is the average value of RLU.

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Abstract

公开了一类JAK 抑制剂化合物及其用途。具体地，公开了如式(I)所示的化合物、或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物。还公开了所述化合物在医学方面的应用。

Description

JAK抑制剂化合物及其用途
相关申请的交叉引用
本申请要求享有于2019年12月30日提交的名称为“JAK抑制剂化合物及其用途”的中国专利申请201911394671.X的优先权，该申请的全部内容通过引用并入本文中。
技术领域
本申请提供了一类具有药学活性的新颖化合物，所述化合物可用于抑制Janus激酶(JAK)。本申请还涉及包含所述化合物的组合物，以及所述化合物和所述组合物在制备用于治疗和/或预防与JAK相关的疾病或病症的药物中的用途。
背景技术
蛋白质激酶是催化蛋白质中特定残基磷酸化的酶家族，并广义地分类为酪氨酸和丝氨酸/苏氨酸激酶。由于突变、过度表达或不适当调节、调节异常或失调，以及生长因子或细胞因子的过度产生或产生不足所导致的不适当的激酶活性涉及许多疾病，其包括但不限于癌症、心血管疾病、变态反应、哮喘和其它呼吸疾病、自身免疫病、炎症疾病、骨病、代谢紊乱及神经病症和神经变性病症(例如阿尔茨海默病)。不适当的激酶活性触发多种生物细胞反应，所述生物细胞反应与涉及上述和相关疾病的细胞生长、细胞分化、细胞功能、存活、凋亡和细胞运动性有关。因此，蛋白质激酶已成为一类重要的作为治疗性介入的靶点的酶。特别地，细胞蛋白质酪氨酸激酶的JAK家族在细胞因子信号转导中扮演重要的角色(Kisseleva等人,Gene,2002,285,1；Yamaoka等人,Genome Biology 2004,5,253)。
从20世纪90年代初首个JAK被发现以来，JAK抑制剂的开发走过了近30年的历程。JAK是一类胞内非受体酪氨酸激酶家族，其通过与信号转 导子和转录激活子(signal transducer and activator of transcription；STAT)之间的相互作用在细胞因子受体信号通路中发挥着重要作用。JAK/STAT信号通路参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。与其它信号通路相比，这条信号通路的传递过程相对简单，它主要由三个成分组成，即酪氨酸激酶相关受体(tyrosine kinase associated receptor)、酪氨酸激酶JAK和信号转导子和转录激活子STAT。
许多细胞因子和生长因子通过JAK-STAT信号通路来传导信号，这包括白介素类(如IL-2～7，IL-9，IL-10，IL-15，IL-21等)、GM-CSF(粒细胞/巨噬细胞集落刺激因子)、GH(生长激素)、EGF(表皮生长因子)、PRL(催乳素)、EPO(促红细胞生成素)、TPO(促血小板生成素)、PDGF(血小板衍生因子)以及干扰素类(包括IFN-α，IFN-β，IFN-γ等)等等。这些细胞因子和生长因子在细胞膜上有相应的受体。这些受体的共同特点是受体本身不具有激酶活性，但胞内段具有酪氨酸激酶JAK的结合位点。受体与配体结合后，通过与之相结合的JAK的活化，来磷酸化各种靶蛋白的酪氨酸残基以实现信号从胞外到胞内的转递。
JAK是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶。如上所述，JAK是英文Janus kinase的缩写，Janus在罗马神话中是掌管开始和终结的两面神。之所以称为两面神激酶，是因为JAK既能磷酸化与其相结合的细胞因子受体，又能磷酸化多个含特定SH2结构域的信号分子。JAK蛋白家族共包括4个成员：JAK1、JAK2、JAK3以及TYK2，它们在结构上有7个JAK同源结构域(JAK homology domain，JH)，其中JH1结构域为激酶区，功能是编码激酶蛋白；JH2结构域是“假”激酶区，对JH1的活性起调节作用；JH3-JH7组成一个四合一结构域，调节JAK与受体的结合。
STAT是一类能与靶基因调控区DNA结合的胞质蛋白，是JAK的下游底物。目前已发现STAT家族的7个成员，即STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B及STAT6。STAT蛋白在结构上可分为以下几个功能区段：N-端保守序列、DNA结合区、SH3结构域、SH2结构域及C-端的转录激活区。其中，序列上最保守和功能上最重要的区段是SH2结构 域，它具有与酪氨酸激酶Src的SH2结构域完全相同的核心序列“GTFLLRFSS”。
JAK-STAT信号通路功能广泛，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程，目前与疾病及药物创新相关的研究大都集中于炎症性疾病及肿瘤性疾病。其中，炎症性疾病主要包括类风湿性关节炎、犬皮炎、银屑病、溃疡性结肠炎及克罗恩病；而肿瘤性疾病则主要涉及骨髓纤维化、真性红细胞增多症及原发性血小板增多症。另外，JAK分子自身的突变也会导致急性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)、真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓纤维化(IMF)、慢性粒细胞白血病(CML)等。
JAK是一类非常重要的药物靶点，针对这一靶点而研发的JAK抑制剂主要用于筛选血液系统疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。JAK-1、JAK-2和TYK-2在人体各组织细胞中均有表达，JAK-3主要表达于各造血组织细胞中，主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。研究表明：JAK2抑制剂适用于骨髓增殖性疾病(Santos等人,Blood,2010,115:1131；Barosi G.和Rosti V.,Curr.Opin.Hematol.,2009,16:129；Atallah E.和Versotvsek S.,2009 Exp.Rev.Anticancer Ther.9:663)，JAK3的抑制剂适用作免疫抑制剂(例如美国专利6,313,129；Borie等人,Curr.Opin.Investigational Drugs,2003,4:1297)。
目前，获得FDA、EMA批准的JAK抑制剂有Tofacitinib(托法替尼)、Ruxolitinib(鲁索利替尼)、Oclacitinib(奥拉替尼)等。处于临床中后期的JAK抑制剂有例如Filgotinib、Peficitinib等。
托法替尼，JAK3抑制剂，由辉瑞公司研发，于2012年11月获FDA批准上市，用于治疗成人患者的对甲氨喋呤应答不充分或不耐受的中度至重度类风湿性关节炎。系首个获批用于RA治疗的口服JAK抑制剂。之后于2013年3月获得日本PMDA批准上市，商品名为Xeljanz。2017年3月16日，辉瑞中国宣布，CFDA已正式批准辉瑞公司的口服JAK抑制剂的上市申请。据悉，该药物被批准用于对甲氨蝶呤疗效不足或对其无法耐受的 中度至重度类风湿关节炎成年患者的治疗。目前，托法替尼用于银屑病、溃疡性结肠炎、青少年特发性关节炎等适应症已接近获批；治疗克罗恩病、斑秃等适应症的临床试验也已经进入临床中后期。托法替尼的主要副作用有严重感染率和低密度脂蛋白水平提高，最常见的不良反应为上呼吸道感染、头痛、腹泻、鼻充血、咽喉痛和鼻咽炎。此外，有临床研究报道，托法替尼可引起贫血和中性粒细胞减少症等副作用。
Figure PCTCN2020141251-appb-000001
鲁索利替尼，JAK1及JAK2的抑制剂，由Incyte和诺华联合开发，于2011年11月获得美国FDA批准上市，其也是第一个获准的专门治疗骨髓纤维化的药物。2012年8月获得EMA批准，2014年7月获得日本PMDA批准上市。该药由Incyte在美国销售，商品名为Jakafi；由诺华在欧洲和日本销售，商品名为Jakavi。鲁索利替尼正开展多项处于临床中后期的试验，适应症囊括多种癌症、GVHD(排异反应)、斑秃、过敏性皮炎、类风湿性关节炎、白癜风、银屑病等。鲁索利替尼的最常见血液学不良反应(发生率>20％)是血小板计数减低和贫血。最常见非血液学不良反应(发生率>10％)是瘀斑、眩晕和头痛。
Figure PCTCN2020141251-appb-000002
奥拉替尼，于2013年获得美国FDA批准，用于控制犬类过敏性皮炎 引起的瘙痒及特应性皮炎。奥拉替尼是一种新型的JAK以及JAK1依赖性细胞因子抑制剂。奥拉替尼不仅是非常有效的JAK1抑制剂，而且还抑制JAK1依赖性细胞因子在一些抗过敏、炎症及瘙痒反应中的功能。它对不参与激活JAK1的细胞因子影响甚微。通过口服途径，每天处理以0.4-0.6mg/kg的奥拉替尼两次，对于治疗由于变应性皮炎带来的瘙痒是安全有效的。在治疗期间，施以奥拉替尼可在24小时内缓解发痒，在实验中，超过70％的实验动物(狗)在第7天时减轻了大于50％的瘙痒反应。然而，奥拉替尼尚不能用于治疗人类疾病。
Figure PCTCN2020141251-appb-000003
Filgotinib，JAK1抑制剂，已于2018年9月完成三期临床试验，用于治疗风湿性关节炎。同时，Filgotinib用于治疗溃疡性结肠炎和克罗恩病的研究目前正处于临床二/三期试验中。Filgotinib是一种选择性JAK1抑制剂，其对JAK1、JAK2、JAK3和TYK2的IC50分别为10nM、28nM、810nM和116nM。
Figure PCTCN2020141251-appb-000004
Peficitinib，JAK1及JAK3抑制剂，由安斯泰来公司研发，目前处于三期临床用于治疗风湿性关节炎。用于治疗银屑病的临床二期研究目前已经完成。Peficitinib是一种新型口服的JAK抑制剂，Peficitinib抑制JAK1、JAK2、JAK3和TYK2酶活性，IC50分别为3.9nM、5.0nM、0.71nM和4.8nM。
Figure PCTCN2020141251-appb-000005
虽然目前已有一些JAK抑制剂获批准上市，并且还有大量JAK抑制剂处于临床研究阶段，但这些JAK抑制剂在疗效或安全性方面并不尽如人意。因此，始终存在对疗效更好和/或副作用更少的JAK抑制剂的需求。
发明内容
本申请的一个目的是提供一类替代现有JAK抑制剂的新型JAK抑制剂，从而为JAK相关疾病的治疗提供更多的选择。
本申请的进一步目的是提供一类比现有JAK抑制剂功效更好和/或安全性更佳的新型JAK抑制剂。
在第一个方面，本申请提供了作为JAK抑制剂的式(I)的化合物：
Figure PCTCN2020141251-appb-000006
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中：
L为C＝O、O＝S＝O、CH 2或连接键；且
X 1为N或CR 14；且
X 2为N或CR 15；且
X 3为N或CR 16；且
R 13为H、-C(＝O)-R 20、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5- 7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环 基、C 5-11双环烷基、5-11元双环杂烷基，且R 13被0、1、2、3或4个R 1取代；且
R 17选自以下群组：H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；或者
R 13和R 17以及与它们相连的L和N原子共同形成4-10元杂环烷基,并且所述4-10元杂环烷基任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
R 18、R 19各自独立地选自以下群组：H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、- CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；或者
R 18和R 19以及与它们相连的碳原子共同形成C 3-10环烷基、4-10元杂环烷基，并且所述C 3-10环烷基、4-10元杂环烷基任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
R 2的个数为0、1、2、3或4个，并且各个R 2独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 3-7环烷基、4-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、以及7-11元双环杂芳基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CN、-OH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-OR 12、-C(＝O)H、-C(＝O)R 12、-C(＝O)-N(R 9)(R 10)、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12；且
各个R 1独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基、C 5-11双环烷基、5-11元双环杂烷基、-N(R 9)(R 10)、- N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基任选地被1个、2个、3个或4个R 3取代，并且其中所述C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基任选地被1个、2个、3个或4个R 4取代；且
R 14、R 15、R 16各自独立地选自H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基任选地被1个、2个或3个选自卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基的取代基取代；且
R 20选自以下群组：H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
R 3、R 4各自独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-N(R 5)(R 6)、-N(R 11)(C(＝O)R 12)、-CON(R 7)(R 8)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述C 1-6烷基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、以及7-11元双环杂芳基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CN、-OH、C 1-4烷基、C 1-6烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-OR 12、-C(＝O)H、-C(＝O)R 12、-C(＝O)-N(R 9)(R 10)、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12；且
R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立地是H或选自以下群组：C 1-6烷基、C 1-4卤代烷基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-以及(5-10元杂芳基)-C 1-4烷基-，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
优选地，本申请涉及一种式(I)的化合物：
Figure PCTCN2020141251-appb-000007
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中：
L为C＝O、O＝S＝O、CH 2或连接键；且
X 1为N或CR 14；且
X 2为N或CR 15；且
X 3为N或CR 16；且
R 13为H、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基、C 5-11双环烷基、5-11元双环杂烷基，且R 13被0、1、2、3或4个R 1取代；且
R 17选自以下群组：H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-S(＝O) 2-N(R 9)(R 10)，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；或者
R 13和R 17以及与它们相连的L和N原子共同形成4-10元杂环烷基,并且所述4-10元杂环烷基任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
R 18、R 19各自独立地选自以下群组：H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6- 10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、 -CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；或者
R 18和R 19以及与它们相连的碳原子共同形成C 3-10环烷基、4-10元杂环烷基，并且所述C 3-10环烷基、4-10元杂环烷基任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
R 2的个数为0、1、2、3或4个，并且各个R 2独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 3-7环烷基、4-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、以及7-11元双环杂芳基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CN、-OH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-OR 12、-C(＝O)H、-C(＝O)R 12、-C(＝O)-N(R 9)(R 10)、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12；且
各个R 1独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基、C 5-11双环烷基、5-11元双环杂烷基、-N(R 9)(R 10)、- N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基任选地被1个、2个、3个或4个R 3取代，并且其中所述C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基任选地被1个、2个、3个或4个R 4取代；且
R 14、R 15、R 16各自独立地选自H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基任选地被1个、2个或3个选自卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基的取代基取代；且
R 3、R 4各自独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-N(R 5)(R 6)、-N(R 11)(C(＝O)R 12)、-CON(R 7)(R 8)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述C 1-6烷基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、以及7-11元双环杂芳基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CN、-OH、C 1-4烷基、C 1-6烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-OR 12、-C(＝O)H、-C(＝O)R 12、-C(＝O)-N(R 9)(R 10)、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12；且
R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立地是H或选自以下群组：C 1-6烷基、C 1-4卤代烷基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-以及(5-10元杂芳基)-C 1-4烷基-，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
在本申请的一些优选实施方式中，提供了上述式(I)的化合物的同位素标记化合物。在本申请的一些更优选的实施方式中，提供了式(I)的化合物的同位素标记化合物，其中所有H各自独立地任选地被D代替。
在本申请的一些优选实施方式中，在式(I)中，X 1为N。在本申请的一些优选实施方式中，在式(I)中，X 2为N。在本申请的一些优选实施方式中，在式(I)中，X 3为N。在本申请的一些优选实施方式中，在式(I)中，X 1为CR 14、X 2为CR 15、X 3为CR 16。在本申请的一些优选实施方式中，在式(I)中，X 1为CR 14、X 2为CR 15、X 3为CR 16，且X 1、X 2、X 3各自独立地选自H、-OH、-CN、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基。在本申请的一些优选实施方式中，在式(I)中，X 1、X 2、X 3是相同的。在本申请的一些优选实施方式中，在式(I)中，X 1、X 2、X 3均为CH。在本申请的一些优选实施方式中，在式(I)中，X 1、X 2、X 3均为N。
在本申请的一些更优选的实施方式中，提供了式(I)的化合物的同位素标记化合物，其中所有H各自独立地任选地被D代替，并且X 1、X 2、X 3是相同的。在本申请的一些更优选的实施方式中，提供了式(I)的化合物的同位素标记化合物，其中所有H各自独立地任选地被D代替，并且X 1、X 2、X 3均为CH。
在本申请的一些优选实施方式中，在式(I)中，L为C＝O、O＝S＝O或CH 2。在本申请的一些特别优选的实施方式中，在式(I)中，L为C＝O。 在本申请的一些特别优选的实施方式中，在式(I)中，L为O＝S＝O。在本申请的一些特别优选的实施方式中，在式(I)中，L为CH 2。在本申请的另一些实施方式中，在式(I)中，L为连接键。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CH，L为C＝O。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CH，L为O＝S＝O。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CH，L为CH 2。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CH，L为连接键。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为N，L为C＝O。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为N，L为O＝S＝O。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为N，L为CH 2。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为N，L为连接键。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CR 14，其中R 14选自-OH、-CN、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基，L为C＝O。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CR 14，其中R 14选自-OH、-CN、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基，L为O＝S＝O。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CR 14，其中R 14选自-OH、-CN、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基，L为CH 2。
在本申请的一些特别优选的实施方式中，在式(I)中，X 1、X 2、X 3均为CR 14，其中R 14选自-OH、-CN、卤素、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基，L为连接键。
在本申请的一些优选实施方式中，在式(I)中，R 13为H、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些优选实施方式中，在式(I)中，R 13为H、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些优选实施方式中，在式(I)中，R 13为C 1-6烷基或者C 3-7环烷基、4-6元杂环烷基、苯基、5-6元杂芳基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些优选实施方式中，在式(I)中，R 13为C 1-4烷基或者C 3-7环烷基、4-6元杂环烷基、苯基、5-6元杂芳基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些优选实施方式中，在式(I)中，R 13为C 1-4烷基或者C 3-7环烷基、4-6元杂环烷基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些优选实施方式中，在式(I)中，R 13为C 1-4烷基或者C 3-6环烷基、5-6元杂环烷基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些优选实施方式中，在式(I)中，R 13为C 1-3烷基、环丙基或者6元杂环烷基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为甲基、乙基、正丙基、异丙基、环丙基或吡嗪基(其中R 13任选地被1个、2个、3个或4个R 1所取代)。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为甲基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为乙基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为正丙基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为异丙基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为环丙基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为吡嗪基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13为吡嗪基，且被哌啶基取代。在 本申请的一些特别优选的实施方式中，在式(I)中，R 13为吡嗪基，且被吗啉基取代。
在本申请的一些优选实施方式中，在式(I)中，R 17为H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基或者5-10元杂芳基，并任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些优选实施方式中，在式(I)中，R 17为H、-OH、C 1-6烷基、C 3-7环烷基、4-6元杂环烷基、苯基或者5-6元杂芳基，并任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些优选实施方式中，在式(I)中，R 17为H、-OH或者C 1-6烷基，并任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些特别优选的实施方式中，在式(I)中，R 17为H。
在本申请的一些优选实施方式中，在式(I)中，R 13和R 17以及与它们相连的L和N原子共同形成4-6元杂环烷基,并且所述4-6元杂环烷基任选地被1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6 炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些优选实施方式中，在式(I)中，R 13和R 17以及与它们相连的L和N原子共同形成4-6元氮杂环烷基,并且所述4-6元氮杂环烷基任选地被1、2或3个各自独立选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基。在本申请的一些优选实施方式中，在式(I)中，R 13和R 17以及与它们相连的L和N原子共同形成5元杂环烷基,并且所述5元杂环烷基任选地被1、2或3个各自独立选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13和R 17以及与它们相连的L和N原子共同形成吡咯烷基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13和R 17以及与它们相连的L和N原子共同形成吡咯烷基，且吡咯烷基被-OH取代。
在本申请的一些优选实施方式中，在式(I)中，R 18、R 19各自独立地选自以下群组：H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基以及5-10元杂芳基，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基。在本申请的一些优选实施方式中，在式(I)中，R 18、R 19各自独立地选自以下群组：H、C 1-6烷基，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代。在本申请的一些特别优选的实施方式中，在式(I)中，R 18为H。在本申请的一些特别优选的实施方式中，在式(I)中，R 19为H。在本申请的一些特别优选的实施方式中，在式(I)中，R 18和R 19均为H。
在本申请的一些优选实施方式中，在式(I)中，R 18和R 19以及与它们相连的碳原子共同形成C 3-6环烷基、4-6元杂环烷基，并且所述C 3-6环烷基、 4-6元杂环烷基任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基。
在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1、2或3个，并且各个R 2独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-10元杂环烷基，其中所述-S-C 1-4烷基、C 1-6烷基、C 3-7环烷基、4-10元杂环烷基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1、2或3个，并且各个R 2独立地选自卤素、C 1-6烷基以及C 3-6环烷基，其中所述C 1-6烷基及C 3-6环烷基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1、2或3个，并且各个R 2独立地选自卤素、C 1-6烷基，其中所述C 1-6烷基任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1个或2个，并且各个R 2独立地选自卤素、C 1-6烷基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1或2个，并且各个R 2独立地选自氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1或2个，并且各个R 2独立地选自氟、氯、甲基、乙基、正丙基、异丙基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1或2个，并且各个R 2独立地选自氟、甲基、乙基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1或2个，并且各个R 2独立地选自氟、乙基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数为1个，并且R 2选自氟、乙基。在本申请的一些优选实施方式中，在式(I)中，R 2的个数 为2个，并且各个R 2独立地选自氟、乙基。在本申请的一些特别优选的实施方式中，在式(I)中，存在2个R 2，分别为氟、乙基。在本申请的一些特别优选的实施方式中，在式(I)中，存在1个R 2，并且R 2为乙基。在本申请的一些特别优选的实施方式中，在式(I)中，存在1个R 2，并且R 2为氟。
在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基，其中所述-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基任选地被1个、2个、3个或4个R 3取代，并且其中所述C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基任选地被1个、2个、3个或4个R 4取代。在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-8烷基、C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基，其中所述-S-C 1-4烷基、C 1-8烷基任选地被1个、2个、3个或4个R 3取代，并且其中所述C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基任选地被1个、2个、3个或4个R 4取代。在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自卤素、-OH、C 1-8烷基、C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基，其中所述C 1-8烷基任选地被1个、2个、3个或4个R 3取代，并且其中所述C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基任选地被1个、2个、3个或4个R 4取代。在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自卤素、-OH、C 1-8烷基、C 3-7环烷基、3-7元杂环烷基，其中所述C 1-8烷基任选地被1个、2个或3个R 3取代，并且其中所述C 3-7环烷基、3-7元杂环烷基任选地被1个、2个或3个R 4取代。在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自卤素、-OH、C 1-6烷基、C 3-7环烷基、5-7元杂环 烷基，其中所述C 1-6烷基任选地被1个、2个或3个R 3取代，并且其中所述C 3-7环烷基、5-7元杂环烷基任选地被1个、2个或3个R 4取代。在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自卤素、-OH、C 1-4烷基、C 3-6环烷基、5-7元杂环烷基，其中所述C 1-4烷基任选地被1个或2个R 3取代，并且其中所述C 3-6环烷基、5-7元杂环烷基任选地被1个、2个或3个R 4取代。在本申请的一些优选实施方式中，在式(I)中，R 13被0、1、2、3或4个R 1取代，且各个R 1独立地选自5-7元杂环烷基，其中所述5-7元杂环烷基任选地被1个、2个或3个R 4取代。在本申请的一些特别优选的实施方式中，在式(I)中，R 13被0个或1个R 1取代，且R 1选自哌啶基或吗啉基。在本申请的一些特别优选的实施方式中，在式(I)中，R 1不存在。在本申请的一些特别优选的实施方式中，在式(I)中，R 13被1个R 1取代。在本申请的一些特别优选的实施方式中，在式(I)中，R 13被1个R 1取代，且R 1为哌啶基。在本申请的一些特别优选的实施方式中，在式(I)中，R 13被1个R 1取代，且R 1为吗啉基。
在以上各种优选实施方式中分别提到的各个取代基的优选选项可以相互组合，其各种组合形式都在本申请的范围内。
在本申请的最优选的实施方式中，式(I)的化合物是本文各实施例所示的各个具体化合物。即，式(I)的化合物选自：
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-5-(哌啶-1-基)吡嗪-2-甲酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)丙酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丙烷甲酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)异丁酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)甲磺酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-5-吗啉并吡嗪-2-甲酰胺；
(S)-1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吡咯烷-3-醇；
1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)哌啶-4-醇；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-N-甲基环丙烷甲酰胺(Ex-10)
1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)哌啶-4-腈；
1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吡咯烷-3-甲腈；
5-乙基-2-氟-4-(3-(4-(吗啉代甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
5-乙基-2-氟-4-(3-(4-((吡啶-3-基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
5-乙基-2-氟-4-(3-(4-(((1-甲基-1H-吡唑-4-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
3-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-(2-羟基乙基)-1-甲基脲；
4-(3-(4-(((环丙基甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丙烷磺酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)乙磺酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-4-羟基哌啶-1-甲酰胺；
(R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基-N-甲基吡咯烷-1-甲酰胺；
(R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺；
(S)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺；
5-乙基-2-氟-4-(3-(4-(((2-羟乙基)(甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)丙烷-2-磺酰胺；
((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)氨基甲酸甲酯；
2-氰基乙基((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)氨基甲酸酯；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丁烷甲酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-甲基吡咯烷-3-甲酰胺；
4-(3-(4-((2-氮杂双环[2.2.2]辛烷-2-基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚；
4-(3-(4-((环丁基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚；
5-乙基-2-氟-4-(3-(4-(((四氢呋喃-3-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
5-乙基-2-氟-4-(3-(4-((吡啶-2-基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-甲基-1H-吡唑-4-甲酰胺；
5-乙基-2-氟-4-(3-(4-(((1-甲基吡咯烷-3-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吗啉-4-甲酰胺；
N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-4-甲基哌嗪-1-甲酰胺；
5-乙基-4-(3-(4-((4-乙基哌嗪-1-基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-2-氟苯酚。
为了简明起见，后文所述“式(I)所示的化合物”或“式(I)的化合物”或“本申请的化合物”也涵盖式(I)的化合物的任意光学异构体、几何异构体、互变异构体或异构体的混合物。
术语“光学异构体”意指，当化合物具有一个或更多个手性中心时，每个手性中心可以存在R构型或S构型，由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如，通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指，当化合物中存在双键时，该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解：互变异构体之间可以互相转变，在在某一状态下可能会达到一种平衡状态而共存。本文所述“式(I)所示的化合物”也涵盖式(I)的化合物的任意互变异构体。
除非另有指明，本文提到“式(I)所示的化合物”或“式(I)的化合物”或“本申请的化合物”时也涵盖该化合物中任一个原子被其同位素原子代替而得到的同位素标记化合物。
本申请包括式(I)的化合物的所有药学上可接受的同位素标记化合物，其中，一个或者多个原子被具有与通常在自然界中所发现的原子相同原子序数但是不同原子质量或者质量数的原子所替换。
适用于包含在本申请的化合物中的同位素的实例包括氢的同位素，诸如 2H(D)和 3H(T)，碳的同位素，诸如 11C、 13C和 14C，氯的同位素， 诸如 36Cl，氟的同位素，诸如 18F，碘的同位素，诸如 123I和 125I，氮的同位素，诸如 13N和 15N，氧的同位素，诸如 15O、 17O和 18O，以及硫的同位素，诸如 35S。
式(I)的某些同位素标记化合物(例如包含放射性同位素的那些)可用于药物和/或底物组织分布研究。考虑到引入的容易性和检测手段的方便性，放射性同位素氘(即 2H)和碳-14(即 14C)对于该目的是特别有用的。
利用诸如氘(即 2H)的较重同位素进行取代可以提供某些治疗方面的好处并且因此在某些情况下可能是优选的，所述治疗方面的好处是由更大的代谢作用稳定性(例如，增长的体内半衰期或者减小的剂量要求)带来的。
利用正电子放射同位素(诸如 11C、 18F、 15O和 13N)进行取代可以用于正电子放射受体图像(Positron Emission Topography(PET))研究，用于检测底物受体占用状态。
式(I)的同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂以类似于在本文所附的实例和制备中所描述的方法来进行制备。
式(I)的化合物可以药学上可接受的盐的形式存在，比如，式(I)的化合物的酸加成盐和/或碱加成盐。除非另有指明，否则本文所用的“药学上可接受的盐”包括可出现于式(I)的化合物内的酸加成盐或碱加成盐。
式(I)的化合物的药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于：乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石 酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于：铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。关于合适的盐的综述，参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahl and Wermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
本申请的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。一般而言，式(I)的化合物，无论以溶剂化形式存在或以未溶剂化形式存在，其都包括在本申请的范围内。
本申请的某些化合物可以不同晶型或不定型形式存在，无论以何种形式存在，式(I)的化合物都包括在本申请的范围内。
为了避免歧义，下面对本文中所使用的术语给出定义。除非另有说明，本文所用术语的含义如下。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地，该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
“前体药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本申请的化合物的衍生物。
“代谢物”是指在细胞或有机体优选人中源自本申请任意化合物的所有分子。
术语“羟基”是指-OH。
术语“卤素”或“卤“是指-F,-Cl,-Br,或-I。
术语“氰基”是指-CN。
在本申请中，当某类取代基存在多个时，每个取代基是彼此独立地选择的，即这些取代基可以相同也可以不同。例如，当存在2个、3个或4个R 1时，这些R 1可以相同也可以不同。例如，当存在2个、3个或4个R 2时，这些R 2可以相同也可以不同。例如，当R 1和R 2均为-N(R 9)(R 10)时， R 1和R 2中的R 9和R 10可以独立地选择，即，R 1中的R 9与R 2中的R 9可以相同也可以不同，R 1中的R 10与R 2中的R 10可以相同也可以不同。例如，当存在2个R 1，这2个R 1均为-N(R 9)(R 10)时，这2个R 1中的R 9和R 10可以独立地选择，即，第一个R 1中的R 9与第二个R 1中的R 9可以相同也可以不同，第一个R 1中的R 10与第二个R 1中的R 10可以相同也可以不同。以上说明适用于R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20。
在本文中使用时，术语“被取代”是指基团中的一个或多个(优选1至5个，更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时，术语“独立地”是指当取代基的个数超过一个时，这些取代基可以相同也可以不同。
在本文中使用时，术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如，一个基团“任选地被取代”表示：该基团可以是未被取代的，也可以是被取代的。
在本文中使用时，术语“杂原子”代表氧(O)、氮(N)、或S(O) m(其中m可以是0、1或2，即硫原子S、或亚砜基SO、或磺酰基S(O) 2)。
在本文中使用时，术语“烷基”是指饱和的脂族烃，包括直链及支链。在一些实施方式中，烷基基团具有1-8个、或1-6个、或1-3个碳原子。例如，术语“C 1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C 1-8烷基”在其定义中包括术语“C 1-6烷基”、“C 1-C 3烷基”和“C 1-C 4烷基”。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。
在本文中使用时，术语“烯基”是指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链及支链。在一些实施方式中，烯基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如，术语“C 2-8烯基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具 有至少一个碳-碳双键)。所述双键可以是或者可以不是另一基团的连接点。烯基包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-甲基-2-丙烯基、丁烯基、戊烯基、3-己烯基等。烯基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。当式(I)的化合物含有烯基基团时，该烯基基团可以纯E形式、纯Z形式、或其任何混合物存在。
在本文中使用时，术语“炔基”是指具有至少一个碳-碳三键的脂族烃，包括具有至少一个碳-碳三键的直链及支链。在一些实施方式中，炔基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如，术语“C 2-8炔基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳三键)。所述三键可以是或者可以不是另一基团的连接点。炔基包括但不限于乙炔基、1-丙炔基、2-丙炔基、2-甲基-2-丙炔基、丁炔基、戊炔基、3-己炔基等。炔基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。
在本文中使用时，术语“C 3-7环烷基”是指具有3-7个形成环的碳原子的环烷基，例如环丙基、环丁基、环戊基、环己基、环己烯基、环庚基。环烷基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“n元杂环烷基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的环烷基，所述杂原子选自O、S及N。例如，3-7元杂环烷基包括但不限于氧杂环丁烷、硫杂环丁烷、氮杂环丁烷、四氢呋喃、四氢噻吩、吡咯烷、四氢吡喃、四氢噻喃、哌啶、吗啉、哌嗪、氧杂环庚烷、硫杂环庚烷、氮杂环庚烷。杂环烷基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“C 5-7芳基”是指具有含5-7个碳原子的芳环的芳基，优选为苯基。
在本文中使用时，术语“n元杂芳基”是指具有m个形成芳环的碳原子和(n-m)个形成芳环的杂原子的杂芳基，所述杂原子选自O、S及N。例如，5-7元杂芳基包括但不限于吡嗪、吡唑、吡咯、呋喃、噻吩、噻唑、吡啶。杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“C 7-11双环芳基”是指具有7-11个碳原子的双 环芳基，例如萘、茚等。双环芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“n元双环杂芳基”是指具有m个形成芳族双环的碳原子和(n-m)个形成芳族双环的杂原子的双环杂芳基，所述杂原子选自O、S及N。例如，7-11元双环杂芳基包括但不限于喹啉、异喹啉、苯并噻唑等。双环杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“11-15元三环基”包括但不限于吖啶等。11-15元三环基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“卤代烷基”是指具有一或多个卤素取代基的烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。例如，术语“C 1-6卤代烷基”是指具有一或多个卤素取代基的C 1-6烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。另举一例，术语“C 1-4卤代烷基”是指具有一或多个卤素取代基的C 1-4烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；术语“C 1-3卤代烷基”是指具有一或多个卤素取代基的C 1-3烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；且术语“C 1-2卤代烷基”是指具有一或多个卤素取代基的C 1-2烷基基团(即，甲基或乙基)(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。再另举一例，术语“C 1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括：CF 3、C 2F 5、CHF 2、CH 2F、CH 2CF 3、CH 2Cl等。
在本文中使用时，术语“烷氧基”是指单键连接至氧原子的烷基。烷氧基与分子的连接点是通过氧原子。烷氧基可被描述为烷基-O-。术语“C 1-6烷氧基”是指包含1-6个碳原子的直链或支链的烷氧基。术语“C 1-6烷氧基”在其定义中包括术语“C 1-3烷氧基”。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、己氧基等。烷氧基可任选地被一或多个适当的取代基所取代。
本文中，与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举，而范围仅是作为一种简化的表示法。例如：
“1-4个取代基”表示1、2、3或4个取代基；
“1-3个取代基”表示1、2或3取代基；
“3-12元环”表示3、4、5、6、7、8、9、10、11或12元环；
“3-8元环”表示3、4、5、6、7或8元环；
“1-12个碳原子”或C 1-12”表示1个(C 1)、2个(C 2)、3个(C 3)、4个(C 4)、5个(C 5)、6个(C 6)、7个(C 7)、8个(C 8)、9个(C 9)、10个(C 10)、11个(C 11)或12个碳原子(C 12)；
“1-6个碳原子”或“C 1-6”表示1个(C 1)、2个(C 2)、3个(C 3)、4个(C 4)、5个(C 5)或6个碳原子(C 6)；
“1-4个碳原子”或“C 1-4”表示1个(C 1)、2个(C 2)、3个(C 3)或4个碳原子(C 4)；
“2-6个碳原子”或“C 2-6”表示2个(C 2)、3个(C 3)、4个(C 4)、5个(C 5)或6个碳原子(C 6)；
“C 3-8”表示3个(C 3)、4个(C 4)、5个(C 5)、6个(C 6)、7个(C 7)或8个碳原子(C 8)；
“3-8个环原子”表示3个、4个、5个、6个、7个或8个环原子。
因此，与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围，且每一个子范围也视为被本文公开。
在第二个方面，本申请提供了一种药物组合物，其含有如上文所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，以及一种或多种药学上可接受的载体、佐剂或赋形剂。
本申请的药物组合物可根据需要配制成适用于口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予的剂型。其中，优选地，本申请的药物组合物被配制成 适用于口服或外用的剂型(制剂)。更优选地，本申请的药物组合物被配制成适用于口服的剂型(制剂)。
如果使用固体载剂，则该制剂可以成片，以粉末或颗粒形式置于硬质凝胶胶囊中，或以糖锭或锭剂形式。固体载剂可以包括常规的赋形剂，诸如粘合剂、填料、成片润滑剂、崩解剂、润湿剂等等。如果需要可以通过常规技术膜包衣该片剂。如果使用液体载剂，则该制剂可以是糖浆、乳液、膏剂、软凝胶胶囊、用于注射的无菌载体、水性或非水性液体悬浮液形式的，或者可以是在使用前用水或其他适当载体复原的干品。液体制剂可以包含常规添加剂，诸如悬浮剂、乳化剂、润湿剂、非水性载体(包括可食用油)、防腐剂以及香味剂和/或着色剂。为了胃肠外施予，通常载体至少大部分包括无菌水，但也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液，在这种情况下，可以使用常规悬浮剂。常规防腐剂、缓冲试剂等也可以添加到胃肠外剂型中。药物组合物通过对包含适量的活性成分(即本申请的式(I)的化合物)的所需制剂合适的常规技术制备。
适于非肠道注射的组合物可以包括生理学上可接受无菌水性或非水性溶液、分散液、悬浮液或乳液和用于无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、丙三醇等)、其合适的混合物、植物油(例如，橄榄油)和可注射有机酯(例如，油酸乙酯)。
这些组合物还可以包含各种赋形剂，例如，防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌剂和抗真菌剂(例如，对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)来确保对微生物的作用的抑制。还可以包括等渗剂，例如，糖、氯化钠等。可以通过使用延迟吸收试剂(例如，单硬脂酸铝和凝胶)来延长可注射药学剂型的吸收。
用于口服的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中，将活性化合物与至少一种惰性赋型剂(或载体)(例如，柠檬酸钠或磷酸二钙)混合，其中还可以包括：(a)填料或混合剂(例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸)；(b)粘结剂(例如，羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树 胶)；(c)保湿剂(例如，丙三醇)；(d)崩解剂(例如，琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠)；(e)溶液阻滞剂(例如，石蜡)；(f)吸收促进剂(例如，季铵化合物)；(I)润湿剂(例如，十六烷醇和单硬脂酸丙三醇酯)；(h)吸附剂(例如，高岭土和斑脱土)和(i)润滑剂(例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
类似类型的固体组合物还可以在使用例如乳糖以及高分子量聚乙二醇等作为赋型剂的软填充和硬填充凝胶胶囊中作为填料。
固体剂型(例如，药片、糖衣丸、胶囊、药丸和颗粒)可以采用涂层和外壳(例如，肠道涂层和本领域已知的其它)来制备。它们可以包含遮光剂，它们还可以是以延迟方式在肠道的某一部分中释放活性化合物或各种活性化合物的组合物。可用的包埋组合物的实例是聚合物质和蜡。活性组分还可以以微胶囊化形式，如果适当的话，可以具有一种或更多种上述赋型剂。
用于口服的液体剂型包括药学上可接受乳液、溶液、分散液、糖浆和酏剂。除了活性化合物以外，液体剂型可以包含本领域中通常所用的惰性稀释剂(例如，水或其它溶剂)、增溶剂和乳化剂(例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3丁二醇、二甲基甲酰铵)、油(具体为，棉花子油、落花生油、玉米油、橄榄油、蓖麻油、芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂，组合物还可以包括，例如，润湿剂、乳化和悬浮剂、香化剂、调味剂和加香剂。
除了活性化合物，悬浮液可以包含悬浮剂，例如乙氧基化异十八烷醇、聚氧化乙烯山梨醇、山梨聚糖酯、微晶纤维、偏氢氧化铝、斑脱土、琼脂-琼脂和黄芪胶或这些物质的混合物等。
本申请的化合物的局部给药用剂型包括膏剂、粉末、喷雾和吸入剂。该活性组分在无菌条件下与生理学上可接受载体和任何所需要的防腐剂、 缓冲剂或推进剂混合。眼用配方、眼药膏、粉末和溶液也包括在本申请的范围内。
本申请的化合物的外用剂型可以呈油包水(W/O)或水包油(O/W)乳液的形式，多乳液形式，如水包油包水(W/O/W)形式或油包水包油(O/W/O)乳液形式，或者以水分散体或脂分散体、凝胶或气溶胶形式制得。
本申请的化合物的外用剂型可以包含添加剂和制剂助剂，如乳化剂、增稠剂、胶凝剂、水固定剂、铺展剂、稳定剂、染料、香料和防腐剂。合适的乳化剂包括硬脂酸、三乙醇胺和PEG-40-硬脂酸酯。合适的增稠剂包括单硬脂酸甘油酯和PEG600。合适的防腐剂包括对羟苯甲酸丙酯和氯甲酚。适的铺展剂包括二甲聚硅氧烷和聚二甲基环硅氧烷。合适的水固定剂包括聚乙二醇，优选聚乙二醇600。
本申请的化合物的外用剂型可以包括膏剂、洗剂、凝胶、乳液、微乳剂、喷雾剂、皮肤贴剂等，其可局部施用，以治疗特应性皮炎、湿疹、银屑病、硬皮病、瘙痒、白癜风、脱发等皮肤疾病。特别地，本申请的化合物的外用剂型是膏剂，其可局部外敷施用，以治疗特应性皮炎、湿疹、银屑病、硬皮病、瘙痒、白癜风、脱发等皮肤疾病。
在药物组合物和剂型中式(I)的化合物的量可以由本领域技术人员根据需要适当地确定，例如式(I)的化合物可以治疗有效量存在于药物组合物或剂型中。
在第三个方面，本申请提供了如上文所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，或如上文所述的组合物在制备用于治疗和/或预防与JAK相关的疾病或病症的药物中的用途。
“与JAK相关的疾病或病症”包括但不限于：
关节炎，包括类风湿性关节炎、幼年型关节炎和银屑病关节炎；
自身免疫疾病或病症，包括单一器官或单一细胞类型自身免疫病症，例如桥本甲状腺炎、自身性免疫溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯彻病、自身 免疫性血小板减少症、交感性眼炎、重症肌无力、格雷夫斯病、原发性胆汁性肝硬变、慢性侵袭性肝炎、溃疡性结肠炎和膜性肾小球病、涉及全身性自身免疫病症的那些(例如全身性红斑狼疮、类风湿性关节炎、干燥综合征、莱特尔综合征、多肌炎-皮肌炎、系统性硬化病、结节性多动脉炎、多发性硬化和大疱性类天疱疮)以及其它O-细胞(体液)型或T细胞型自身免疫病(包括寇甘综合征)、强直性脊椎炎、Wegener’s氏肉芽肿、自身免疫性脱发、I型糖尿病或幼年发病型糖尿病或甲状腺炎；
癌症或肿瘤，包括消化道/胃肠道癌、结直肠癌、肝癌、皮肤癌(包括肥大细胞瘤和鳞状细胞癌)、乳房和乳腺癌、卵巢癌、前列腺癌、淋巴瘤、白血病(包括急性髓性白血病和慢性髓性白血病)、肾癌、肺癌、肌癌、骨癌、膀胱癌、脑癌、黑色素瘤(包含口腔和转移性黑色素瘤)、卡波西肉瘤、骨髓瘤(包括多发性骨髓瘤)、骨髓增殖性病症、增生型糖尿病视网膜病变或与血管生成相关的病症(包括实体瘤)；
糖尿病，包括I型糖尿病或糖尿病并发症；
眼疾病、病症或病况，包括眼的自身免疫病、角膜结膜炎、春季结膜炎、葡萄膜炎(包括与贝切特病相关的葡萄膜炎和晶状体性葡萄膜炎)、角膜炎、疱疹性角膜炎、圆锥形角膜炎、角膜上皮营养障碍、角膜白斑、眼天疱疮、莫伦溃疡、巩膜炎、格雷夫眼病、Vogt-Koyanagi-Harada综合征、干燥性角结膜炎(干眼症)、水疱、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、变应性结膜炎或眼部新生血管形成；
肠炎症、变态反应或病况，包括克罗恩氏病和/或溃疡性结肠炎、炎性肠病、乳糜泻、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症；
神经变性疾病，包括运动神经元病、阿尔茨海默病、帕金森病、肌萎缩侧索硬化、亨廷顿病、脑缺血或创伤性损伤引发的神经变性疾病、卒中、谷氨酸神经毒性或缺氧；卒中的缺血/再灌注损伤、心肌缺血、肾缺血、心脏病发作、心脏肥大、动脉粥样硬化和动脉硬化、器官缺氧或血小板聚集；
皮肤疾病、病况或病症，包括特应性皮炎、湿疹、银屑病、硬皮病、瘙痒或其它瘙痒病况、白癜风、脱发；
变态反应，包括哺乳动物的变应性皮炎(包括马变应性疾病，例如叮 咬过敏)、夏季湿疹、库蚊叮痒综合症(sweet itch)、肺气肿、炎症性气道疾病、复发性气道阻塞、气道反应过度或慢性阻塞性肺疾病；
哮喘和其它阻塞性气道疾病，包括慢性或顽固型哮喘、晚期哮喘、支气管炎、支气管性哮喘、变应性哮喘、内源性哮喘、外源性哮喘或粉尘性哮喘；
移植排斥，包括胰岛移植排斥、骨髓移植排斥、移植物抗宿主病、器官和细胞移植排斥(例如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、四肢、肝、肺、肌肉、成肌细胞、神经、胰脏、皮肤、小肠或气管)或者异种移植。
在第四个方面，本申请提供了一种治疗与JAK相关的疾病或病症的方法，所述方法包括将治疗有效量的如上文所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，或如上文所述的组合物给予有需要的患者。其中，所述患者优选是哺乳动物，更优选是人类患者。其中给药途径可以是口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予等。其中，优选地通过口服或外用施予。更优选地通过口服施予。
出人意料地，本申请的化合物在实验中展示出作为JAK激酶抑制剂的优异功效(优于现有的JAK激酶抑制剂，例如Filgotinib)，而且潜在具有良好的安全性。
下面结合具体实施例对本申请做进一步的说明和描述。
实施例
本申请的式(I)的化合物可以用有机合成领域的技术人员所熟悉的多种方法合成。以下具体实施例中给出了一些示例性的式(I)的化合物的合成方法，这些方法是合成化学领域所公知的。显然，参照本专利中的示例性方案，本领域技术人员可以适当调整反应物、反应条件和保护基团而容易地设计其他式(I)的化合物的合成路线。
下面进一步结合实施例来阐述本申请；但这些实施例并不限制本申请 的范围。
实施例1：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-5-(哌啶-1-基)吡嗪-2-甲酰胺(MDI-3)
Figure PCTCN2020141251-appb-000008
目标化合物16(即，MDI-3)的合成路线：
Figure PCTCN2020141251-appb-000009
中间体17的合成路线
Figure PCTCN2020141251-appb-000010
中间体19的合成路线
Figure PCTCN2020141251-appb-000011
中间体21的合成路线
Figure PCTCN2020141251-appb-000012
合成方法：
合成中间体1：5-乙基-2-氟苯酚
将5-溴-2-氟苯酚(200.0mg，1.05mmol)和二(三叔丁基磷)钯(10.7mg,0.02mmol)溶于10ml THF。氮气置换3次，降温至10～20℃，缓慢滴加1mol/L的二乙基锌溶液(2.3ml,2.30mmol),滴加完毕，升温至50℃。反应过夜，降温至0℃，加水淬灭，用硅藻土过滤，硅藻土垫用乙酸乙酯洗涤，用乙酸乙酯萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥。干燥后浓缩柱层析分离得到油状液体，收率65.1％。
1H NMR(400MHz,CDCl 3)δ6.97(d,J＝8.0Hz,1H),6.85(d,J＝12.0Hz,1H),6.69-6.65(m,1H),2.61-2.55(m,2H),1.21(t,J＝8.0Hz,3H).
合成中间体2：4-溴-5-乙基-2-氟苯酚
将中间体1(200.1mg,1.43mmol)溶于6ml乙腈中，加入CuBr2(957.5mg,4.29mmol),室温搅拌3小时，加水淬灭，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物，收率:78.1％。
1H NMR(400MHz,CDCl 3)δ7.25(d,J＝12.0Hz,1H),6.89(d,J＝12.0Hz, 1H),2.69-2.63(m,2H),1.19(t,J＝12.0Hz,3H).
合成中间体3：2-((4-溴-5-乙基-2-氟苯氧基)甲氧基)乙基)三甲基硅烷
将中间体2(220.0mg,1.00mmol)溶于6ml DCM中，加入DIPEA(130.5mg,1.10mmol),降温到0℃。在0℃下滴加SEMCl(168.2mg,1.10mmol),滴加完毕升至室温，反应8小时，加水淬灭，用DCM萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩得到无色油状物，粗品收率:99.1％。
1H NMR(400MHz,CDCl 3)δ7.26(d,J＝12.0Hz,1H),6.89(d,J＝12.0Hz,1H),5.24(s,2H)3.82-3.78(m,2H)2.67-2.62(m,2H),1.19(t,J＝12.0Hz,3H),0.98-0.94(m,2H),0.01(s,9H).
合成中间体4：(2-((5-乙基-2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)甲氧基)乙基)三甲基硅烷
将中间体3(280.0mg,0.80mmol),频哪醇硼酸酯(206.1mg,0.80mmol),Pd(dppf)Cl 2(59.2mg,0.08mmol)和KOAc(237.5mg,2.40mmol)溶于1,4-二氧六环(6ml)中，氮气置换3次。加热到100℃反应过夜。反应完成后加水淬灭，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物，收率:56.2％。
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝12.0Hz,1H),7.02(d,J＝8.0Hz,1H),5.28(s,2H),3.82-3.78(m,2H),2.89-2.83(m,2H),1.35(s,12H),1.17(t,J＝8.0Hz,3H),0.98-0.94(m,2H),0.01(s,9H).
合成中间体17：6-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑
向体系中加入化合物6-碘引唑(200mg,0.82mmol),5ml THF,将体系降温至0℃。在0℃下，向体系中分批加入NaH(32.8mg(60％),0.82mmol),加入完毕后在0℃下反应1h。然后向体系中滴加SEMCl(143.5mg,0.86mmol),滴加完毕后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到产物252mg，收率:82.2％.
1H NMR(400MHz,CDCl 3)δ8.16(s,1H),8.07(s,1H),8.21(d,J＝1.4Hz,1H),7.47-7.43(m,1H),5.69(s,2H),3.63-3.58(m,2H),0.96-0.91(m,2H),-0.04 (s,9H).
合成中间体5：6-(2-乙基-5-氟-4–((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1–((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑
N 2保护下，向体系中加入中间体4(85mg,0.21mmol),中间体17(80mg,0.21mmol),Pd(dppf)Cl 2(15.6mg,0.021mmol),K 3PO 4(136.3mg,0.64mmol),1,4-dioxane(2ml)。加入完毕后升至100℃过夜反应。反应完成后加入水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物66.9mg，收率:60.6％。
1H NMR(400MHz,CDCl 3)δ8.14(s,1H),7.69(d,J＝8.0Hz,1H),7.61(s,1H),7.15(d,J＝8.0Hz,1H),7.05-7.01(m,2H),5.74(s,2H),5.31(s,2H),3.88-3.84(m,2H),3.70-3.65(m,2H),2.61-2.52(m,2H),1.09(t,J＝8.0Hz,3H),1.03-0.96(m,4H),0.01(s,9H),-0.03(s,9H).
合成中间体6：5-乙基-2-氟-4-(1H-吲唑-6-基)苯酚
向体系中加入中间体5(30mg,0.12mmol),2ml甲醇，1ml浓盐酸，加入完毕后升至60℃反应。反应完成后加入饱和NaHCO 3溶液调节pH＝7，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到白色固体12mg，收率:80.6％。
1H NMR(400MHz,MeOD)δ8.08(d,J＝1.1Hz,1H),7.79(dd,J＝0.8Hz,J＝8.3Hz,1H),7.42-7.40(m,1H),7.08(dd,J＝1.4Hz,J＝8.3Hz,1H),6.95-6.88(m,2H),2.58-2.51(m,2H),1.06(t,J＝8.0Hz 3H).
合成中间体7：5-乙基-2-氟-4-(3-碘-1H-吲唑-6-基)苯酚
向体系中加入中间体6(134mg,0.52mmol),2ml DMF,KOH(117mg,2.08mmol)加入完毕后降至0℃。在0℃下滴加I 2(132mg,0.52mmol)的DMF(2ml)溶液,滴加完毕升至室温反应。反应完成后加1M HCl溶液调节pH＝7，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到白色固体150mg，收率:75.5％。
1H NMR(400MHz,CDCl 3)δ7.52(dd,J＝0.8Hz,J＝8.3Hz,1H),7.35(t,J＝1.1Hz,1H),7.15(dd,J＝1.3Hz,J＝8.4Hz,1H),6.98-6.94(m,2H),2.50(q,J＝7.6Hz,2H),1.06(t,J＝7.6Hz,3H).
合成中间体8：6-(2-乙基-5-氟-4–((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-3-碘-1–((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑
向体系中加入中间体7(180mg,0.47mmol),4ml DMF。加入完毕后降至0℃。在0℃下分批加入NaH(37.6mg(60％),0.94mmol),加入完毕后，搅拌1h。然后在0℃下滴加SEMCl(173.4mg,1.04mmol),滴加完毕后升至室温反应。反应完成后加入水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物220mg，收率:72.9％。
1H NMR(400MHz,CDCl 3)δ7.52-7.41(m,2H),7.23-7.12(m,2H),7.02-6.97(m,1H),5.73(s,2H),5.30(s,2H),3.88-3.81(m,2H),3.67-3.55(m,2H),2.56-2.48(m,2H),1.06(t,J＝8.0Hz,3H),1.03-0.96(m,4H),0.03(s,9H),-0.07(s,9H).
合成中间体9：6-(2-乙基-5-氟-4-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-3-(三甲基锡烷基)-1H-吲唑
N 2保护下，向体系中加入中间体8(20mg,0.031mmol),Sn 2Me 6(20.3mg,0.062mmol),Pd(PPh 3) 4(3.6mg,0.0031mmol),5ml干燥甲苯。加入完毕后升至80℃反应。反应完成后加入水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物14.8mg，收率:70.2％。
1H NMR(400MHz,CDCl 3)δ7.72(d,J＝8.0Hz,1H),7.45(s,2H),7.15(d,J＝8.0Hz,1H),7.08(dd,J＝4.0Hz,J＝8.0Hz,1H),6.99(d,J＝12.0Hz,1H),5.77(s,2H),5.31(s,2H),3.88-3.84(m,2H),3.60-3.56(m,2H),2.55(q,J＝8.0Hz,2H),1.07(t,J＝8.0Hz,3H),1.02-0.98(m,2H),0.90-0.85(m,2H),0.48(s,9H),0.03(s,9H),-0.07(s,9H).
合成中间体19：2-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-羧酸甲酯
1.合成中间体18：1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-羧酸甲酯
向体系中加入化合物1H-咪唑-4-羧酸甲酯(1g,7.9mmol),K 2CO 3(2.74g, 19.8mmol),20ml DMF,向体系中滴加SEMCl(1.71g,10.2mmol),滴加完毕后将体系升温至80℃。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到产物750mg，收率:37.1％.
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.58(s,1H),5.26(s,2H),3.84(s,3H),3.48-3.43(m,2H),0.88-0.83(m,2H),-0.05(s,9H).
2.合成中间体19：2-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-羧酸甲酯
向体系中加入中间体18(4g,15.6mmol),NIS(7g,31.1mmol),AIBN(0.26g,1.58mmol),20ml CHCl 3,将体系升温至65℃。反应完成后降至室温，加5％硫代硫酸钠水溶液淬灭反应，加DCM萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到产物3g，收率:50.3％.
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),5.26(s,2H),3.89(s,3H),3.58-3.52(m,2H),0.95-0.85(m,2H),-0.01(s,9H).
合成中间体10：甲基2-(6-(2-乙基-5-氟-4–((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-甲基基)-1–((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-羧酸
N 2保护下，向体系中加入中间体9(40mg,0.059mmol),中间体19(22.4mg,0.059mmol),CuI(2.23mg,0.012mmol),Pd(PPh 3) 4(6.8mg,0.0059mmol),4ml THF。加入完毕后升至65℃反应。反应完成后加入水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物14mg，收率:30.8％。
1H NMR(400MHz,CDCl 3)δ8.57(d,J＝8.0Hz,1H),7.92(s,1H),7.45(s,1H),7.25(dd,J＝1.2Hz,J＝8.4Hz,1H),7.16(d,J＝8.0Hz,1H),7.02(d,J＝12.0Hz,1H),5.96(s,2H),5.76(s,2H),5.31(s,2H),3.96(s,3H),3.88-3.84(m,2H),3.61-3.57(m,4H),2.53(q,J＝8.0Hz,2H),1.05(t,J＝8.0Hz,3H),1.03-0.98(m,2H),0.92-0.87(m,4H),0.03(s,9H),-0.07(s,9H),-0.08(s,9H).
合成中间体11：(2-(6-(2-乙基-5-氟-4-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲 基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲醇
N 2保护下，向体系中加入中间体10(22mg,0.028mmol),4ml THF，降温至-78℃。在-78℃下，向体系中加入DIBAL-H(0.038ml,1.5Mol/L,0.057mmol)。滴加完毕，升至室温反应，反应完成后降温至0℃加水淬灭，过硅藻土，用EA淋洗，滤液加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物17mg，收率:81.8％。
1H NMR(400MHz,CDCl 3)δ8.48(d,J＝8.0Hz,1H),7.46(s,1H),7.23(d,J＝8.0Hz,1H),7.18-7.15(m,2H),7.02(d,J＝12.0Hz,1H),5.92(s,2H),5.76(s,2H),5.32(s,2H),4.75(s,2H),3.88-3.84(m,2H),3.62-3.55(m,4H),2.54(q,J＝8.0Hz,2H),1.06(t,J＝8.0Hz,3H),1.04-0.98(m,2H),0.92-0.86(m,4H),0.04(s,9H),-0.07(s,9H),-0.08(s,9H).
合成中间体12：2-(6-(2-乙基-5-氟-4-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛
向体系中加入中间体11(12mg,0.016mmol),4ml CHCl 3,MnO 2(57.4mg,0.66mmol),升至60℃反应，反应完成后降至室温,过硅藻土，用DCM洗涤，滤液用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物10mg，收率:84.4％。
1H NMR(400MHz,CDCl 3)δ10.04(s,1H),8.59(d,J＝8.0Hz,1H),7.95(s,1H),7.48(s,1H),7.29(dd,J＝4.0Hz,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.02(d,J＝12.0Hz,1H),6.03(s,2H),5.77(s,2H),5.32(s,2H),3.88-3.84(m,2H),3.64-3.59(m,4H),2.55(q,J＝8.0Hz,2H),1.06(t,J＝8.0Hz,3H),1.04-0.99(m,2H),0.93-0.88(m,4H),0.04(s,9H),-0.06(s,9H),-0.07(s,9H).
合成中间体13：2-(6-(2-乙基-5-氟-4-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛肟
向体系中加入中间体12(10mg,0.016mmol),TEA(1.68mg,0.017mmol),2ml DCM,降温至0℃,分批次加入盐酸羟胺(1.15mg,0.017mmol)，加入完毕升至室温反应。反应完成后加水淬灭，加DCM萃取，分液，有机相用 饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩得到无色油状物7mg，直接用于下一步反应，收率:68.4％。
合成中间体14：4-(3-(4-(氨基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚
向体系中加入中间体13(10mg,0.013mmol),Pd/C(2mg),2ml MeOH,催化量的HCl，H 2置换三次，室温反应(H 2压力1atm)。反应完成后体系过硅藻土，滤液浓缩后柱层析得到无色油状物5mg，收率:63.0％。
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝8.0Hz,1H),7.42(s,1H),7.13-7.10(m,2H),6.96-6.91(m,2H,),5.89(s,2H),5.74(s,2H),4.01(s,2H),3.61-3.55(m,4H),2.46(q,J＝8.0Hz,2H),1.00(t,J＝8.0Hz,3H),0.91-0.86(m,4H),-0.08(s,9H),-0.09(s,9H).
合成中间体21：5-(哌啶-1-基)吡嗪-2甲酸
1.合成中间体20：5-(哌啶-1-基)吡嗪-2甲酸甲酯
将5-氯-吡嗪-2-甲酸甲酯(1.72g,10mmol)溶于10ml DMF中，加入N,N-二异丙基乙胺(4.3ml,25.0mmol)和哌啶盐酸盐(1.45g,12.0mmol)，在室温下搅拌过夜，在剧烈搅拌下，加入水，有固体析出，过滤，用水洗滤饼，干燥，得到中间体20，收率80.0％。
2.合成中间体21：5-(哌啶-1-基)吡嗪-2甲酸
将中间体20(430mg,1.95mmol)溶于20ml四氢呋喃和20ml水，加入氢氧化锂(163mg,3.88mmol)，室温反应4小时，减压浓缩掉四氢呋喃,用1N HCl调pH＝4，有固体析出，过滤，用水洗滤饼，干燥得中间体21，收率91.5％。
1H NMR(400MHz,CDCl 3)δ8.84(s,1H),8.02(s,1H),3.76-3.73(m,4H),1.78-1.65(m,6H).
合成中间体15：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-5-(哌啶-1-基)吡嗪-2-甲酰胺
向体系中加入中间体21(10.4mg,0.050mmol),HATU(22.9mg, 0.060mmol),DIPEA(12.9mg,0.10mmol),2ml DMF,室温反应1h。将体系降至0℃,滴加化合物14(30mg,0.049mmol)的DMF(0.5ml)溶液,滴加完成后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物27mg，收率:67.2％。
1H NMR(400MHz,CDCl 3)δ8.86(d,J＝1.3Hz,1H),8.50(d,J＝8.0Hz,1H),7.95(d,J＝1.4Hz,1H),7.44(s,1H),7.22-7.20(m,2H),7.00-6.94(m,2H),5.89(s,2H),5.75(s,2H),4.71(d,J＝5.7Hz,2H),3.69-3.66(m,4H),3.61-3.55(m,4H),2.51(q,J＝8.0Hz,2H),1.71-1.65(m,6H),1.04(t,J＝8.0Hz,3H),0.91-0.86(m,4H),-0.08(s,9H),-0.09(s,9H).
合成化合物16(即，MDI-3):N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-5-(哌啶-1-基)吡嗪-2-甲酰胺
向体系中加入化合物15(30mg,0.037mmol),4ml MeOH,2ml浓盐酸，加入完毕后升至60℃反应。反应完成后加入饱和NaHCO 3调节pH＝7，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩薄层析得到白色固体14mg，收率:69.2％.
1H NMR(400MHz,MeOD)δ8.70(d,J＝1.4Hz,1H),8.30(d,J＝8.0Hz,1H),8.21(d,J＝1.4Hz,1H),7.43(s,1H),7.19-7.17(m,2H),6.98-6.90(m,2H),4.67(s,2H),3.78-3.75(m,4H),2.56(q,J＝8.0Hz,2H),1.79-1.67(m,6H),1.08(t,J＝8.0Hz,3H).
实施例2：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)丙酰胺(MDI-301)
Figure PCTCN2020141251-appb-000013
MDI-301的合成路线：
Figure PCTCN2020141251-appb-000014
合成方法：
合成中间体MDI-301-1：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)丙酰胺
向体系中加入中间体14(30mg,0.049mmol),DIPEA(7.6mg,0.059mmol),5ml DCM。将体系降至0℃,滴加丙酰氯(4.5mg,0.049mmol),滴加完成后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物18mg，收率:55.0％
1H NMR(400MHz,CDCl 3)δ8.41(d,J＝8.0Hz,1H),7.45(s,1H),7.21(d,J＝8.0Hz,1H),7.15(s,1H),6.96(t,J＝10.0Hz,2H),5.88(s,2H),5.75(s,2H),4.50(d,J＝8.0Hz,2H),3.62-3.54(m,4H),2.54-2.48(m,2H),2.30-2.20(m,2H),1.20(t,J＝8.0Hz,3H),1.05(t,J＝8.0Hz,3H),0.92-0.86(m,4H),-0.07(s,9H),-0.09(s,9H).
合成化合物MDI-301：N–((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)丙酰胺
向体系中加入中间体MDI-301-1(18mg,0.027mmol),4ml MeOH,2ml浓盐酸，加入完毕后升至50℃反应。反应6小时后降至室温，减压浓缩蒸去反应溶剂，然后加入4ml甲醇，0.5ml氨水，浓缩后残留物薄层析得到白色固体3mg，收率:27.3％.
1H NMR(400MHz,MeOD)δ8.27(d,J＝8.0Hz,1H),7.40(s,1H),7.15(d,J＝8.0Hz,1H),7.10(s,1H),6.91(dd,J＝12.0Hz,J＝20.0Hz,2H),4.44(s,2H),2.53(q,J＝8.0Hz,2H),2.87(q,J＝8.0Hz,2H),1.16(t,J＝8.0Hz,3H),1.06(t,J＝8.0Hz,3H).
实施例3：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)环丙烷甲酰胺(MDI-302)
Figure PCTCN2020141251-appb-000015
MDI-302的合成路线：
Figure PCTCN2020141251-appb-000016
合成方法：
合成中间体MDI-302-1：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)环丙烷甲酰胺
向体系中加入中间体14(30mg,0.049mmol),DIPEA(7.6mg,0.059mmol),5ml DCM。将体系降至0℃,滴加环丙基甲酰氯(5.1mg,0.049mmol),滴加完成后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物22mg，收率:66.1％。
1H NMR(400MHz,CDCl 3)δ8.42(d,J＝8.0Hz,1H),7.44(s,1H),7.20(d,,J＝8.0Hz,1H),7.15(s,1H),6.9(t,J＝12.0Hz,2H),5.88(s,2H),5.75(s,2H),4.52(d,J＝8.0Hz,2H),3.62-3.54(m,4H),2.53-2.47(m,2H),1.75-1.68(m,1H),1.06(t,J＝8.0Hz,3H),1.02-1.00(m,2H),0.91-0.87(m,4H),0.76-0.72(m,2H),-0.07(s,9H),-0.09(s,9H).
合成化合物MDI-302：N–((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丙烷甲酰胺
向体系中加入中间体MDI-302-1(20mg,0.029mmol),4ml MeOH,2ml浓盐酸，加入完毕后升至50℃反应。反应6小时后降至室温，减压浓缩蒸去反应溶剂，然后加入4ml甲醇，0.5ml氨水，浓缩后残留物薄层析得到白色固体8.5mg，收率:69.9％.
1H NMR(400MHz,MeOD)δ8.28(d,J＝8.0Hz 1H),7.40(s,1H),7.15(d,J＝8.0Hz,1H),7.10(s,1H),6.91(dd,J＝12.0Hz,J＝20.0Hz,2H),4.45(s,2H),2.54(q,J＝8.0Hz,2H),1.67-1.61(m,1H),1.06(t,J＝8.0Hz,3H),0.92-0.85(m,2H),0.79-0.75(m,2H).
实施例4：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)异丁酰胺(MDI-303)
Figure PCTCN2020141251-appb-000017
MDI-303的合成路线：
Figure PCTCN2020141251-appb-000018
合成方法：
合成中间体MDI-303-1：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)异丁酰胺
向体系中加入中间体14(20mg,0.033mmol),DIPEA(5.1mg,0.039),5ml DCM。将体系降至0℃,滴加异丁酰氯(3.48mg,0.033mmol),滴加完成后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物14mg，收率:62.3％。
1H NMR(400MHz,CDCl 3)δ8.38(d,J＝8.0Hz,1H),7.44(s,1H),7.18(d,J＝8.0Hz,1H),7.15(s,1H),6.96-6.92(m,2H),5.87(s,2H),5.75(s,2H),4.50(d,J＝8.0Hz,2H),3.62-3.54(m,4H),2.52-2.46(m,2H),2.44-2.39(m,1H),1.19(d,J＝4.0Hz,6H),1.03(t,J＝8.0Hz,3H),0.92-0.86(m,4.0H),-0.07(s,9H),-0.09(s,9H).
合成化合物MDI-303：N–((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)异丁酰胺
向体系中加入中间体MDI-303-1(14mg,0.021mmol),4ml MeOH,2ml浓盐酸，溶液加入完毕后升至50℃反应。反应6小时后降至室温，减压浓缩蒸去反应溶剂，然后加入4ml甲醇，0.5ml氨水，浓缩后残留物薄层析得到白色固体4.9mg，收率:56.6％.
1H NMR(400MHz,MeOD)δ8.29(d,J＝8.0Hz,1H),7.43(s,1H,),7.17(dd,J＝4.0Hz,J＝8.0Hz,1H),7.11(s,1H),6.93(dd,J＝12.0Hz,J＝20.0Hz,2H),4.46(s,2H),2.68-2.50(m,3H),1.17(d,J＝4.0Hz,6H),1.08(t,J＝8.0Hz, 3H).
实施例5：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)甲磺酰胺(MDI-304)
Figure PCTCN2020141251-appb-000019
MDI-304的合成路线：
Figure PCTCN2020141251-appb-000020
合成方法：
合成中间体MDI-304-1：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)甲磺酰胺
向体系中加入中间体14(30mg,0.049mmol),DIPEA(7.6mg,0.059mmol),5ml DCM。将体系降至0℃,滴加甲磺酰氯(5.61mg,0.049mmol),滴加完成后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物12mg，收率:35.5％。
1H NMR(400MHz,CDCl 3)δ8.40(d,J＝8.0Hz,1H),7.46(s,1H),7.23(d,J＝8.0Hz,1H),7.19(s,1H),7.00-6.95(m,2H),5.91(s,2H),5.75(s,2H),4.41(d,J＝4.0Hz,2H),2.97(s,3H),2.55-2.49(m,2H),1.06(t,J＝8.0Hz,3H),0.92-0.86(m,4H),-0.07(s,9H),-0.09(s,9H).
合成化合物MDI-304：N–((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)- 1H-咪唑-4-基)甲基)甲磺酰胺
向体系中加入中间体MDI-304-1(12mg,0.017mmol),4ml MeOH,2ml浓盐酸，溶液加入完毕后升至50℃反应。反应6小时后降至室温，减压浓缩蒸去反应溶剂，然后加入4ml甲醇，0.5ml氨水，浓缩后残留物薄层析得到白色固体3.0mg，收率:40.2％.
1H NMR(400MHz,MeOD)δ8.21(d,J＝8.0Hz,1H),7.43(s,1H,),7.21-7.17(m,2H),6.93(dd,J＝12.0Hz,J＝20.0Hz,2H),4.37(s,2H),2.97(s,3H),2.56(q,J＝8.0Hz,2H),1.08(t,J＝8.0Hz,3H).
实施例6：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-5-吗啉并吡嗪-2-甲酰胺(MDI-305)
Figure PCTCN2020141251-appb-000021
MDI-305的合成路线：
Figure PCTCN2020141251-appb-000022
合成方法：
合成中间体MDI-305-1：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-5-吗啉并吡嗪-2-甲酰胺
向体系中加入化合物5-(4-吗啉基)-2-吡嗪甲酸(6.84mg,0.033mmol),HATU(13.05mg,0.034mmol),DIPEA(5.06mg,0.039mmol),5ml DMF,室温反应1h。将体系降至0℃,滴加化合物14(20mg,0.033mmol)的DMF(2.0ml)溶液,滴加完成后升至室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物14mg，收率:52.9％。
1H NMR(400MHz,CDCl 3)δ8.91(s,1H),8.50(d,J＝8.0Hz,1H),7.95(s,1H),7.44(s,1H),7.22-7.20(m,2H),7.00-6.95(m,2H),5.90(s,2H),5.75(s,2H),4.71(d,J＝8.0Hz,2H),3.83-3.81(m,4H),3.68-3.66(m,4H),3.62-3.55(m,4H),2.51(q,J＝8.0Hz,2H),1.05(t,J＝8.0Hz,3H),0.91-0.86(m,4H),-0.07(s,9H),-0.09(s,9H).
合成化合物MDI-305：N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-5-吗啉并吡嗪-2-甲酰胺
向体系中加入中间体MDI-305-1(14mg,0.017mmol),4ml MeOH,2ml浓盐酸，溶液加入完毕后升至50℃反应。反应6小时后降至室温，减压浓缩蒸去反应溶剂，然后加入4ml甲醇，0.5ml氨水，浓缩后残留物薄层析得到白色固体3.9mg，收率:41.2％.
1H NMR(400MHz,MeOD)δ8.73(s,1H),8.28(d,J＝8.0Hz,1H),8.20(s, 1H),7.40(s,1H),7.17-7.14(m,2H),6.95-6.87(m,2H),4.65(s,2H),3.80-3.77(m,4H),3.73-3.70(m,4H),2.53(q,J＝8.0Hz,2H),1.06(t,J＝8.0Hz,3H).
实施例7：(S)-1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4- 基)甲基)吡咯烷-3-醇(MDI-306)
Figure PCTCN2020141251-appb-000023
MDI-306的合成路线：
Figure PCTCN2020141251-appb-000024
合成方法：
合成中间体MDI-306-1：(S)-1-((2-(6-(2-乙基-5-氟-4-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)吡咯烷-3-醇
向体系中加入(s)-1-N-叔丁氧羰基-3-羟基吡咯烷(9.1mg,0.049mmol)，2ml DCM，2ml三氟乙酸，加入完毕后室温搅拌30min，反应完成后将体系浓缩，浓缩后加入5ml 1,2-二氯乙烷，中间体12(30mg,0.041mmol)，加入完毕后室温搅拌30min，然后加入三乙酰基硼氢化钠(17.08mg,0.081mmol)，室温反应。反应结束后加水淬灭，加DCM萃取，有机相用饱和氯化钠洗涤，硫酸钠干燥，浓缩薄层析分离，得到产品20mg，收率：60.8％
1H NMR(400MHz,CDCl 3)δ8.44(d,J＝8.0Hz,1H),7.45(s,1H),7.24-7.21(m,2H),7.15(d,J＝8.0Hz,1H),7.0(d,J＝12.0Hz,1H),5.91(s,2H),5.75(s,2H)，5.32(s,2H)，4.44-4.39(m,1H),3.92-3.84(m,4H),3.64-3.55(m,4H),3.29-3.19(m,1H),3.12-3.07(m,1H),2.96-2.88(m,1H),2.78-2.66(m,1H),2.57-2.51(m,2H),2.24-2.20(m,1H),1.91-1.87(m,1H),1.05(t,J＝8.0Hz,3H),,1.03-0.98(m,2H),0.92-0.86(m,4H),0.03(s,9H),-0.07(s,9H),-0.09(s,9H).
合成化合物MDI-306：(S)-1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吡咯烷-3-醇
向体系中加入中间体MDI-306-1(20mg,0.025mmol),4ml MeOH,2ml浓盐酸，溶液加入完毕后升至50℃反应。反应6小时后降至室温，减压浓缩蒸去反应溶剂，然后加入4ml甲醇，0.5ml氨水，浓缩后残留物薄层析得到白色固体6.2mg，收率:59.7％.
1H NMR(400MHz,MeOD)δ8.31(d,J＝8.0Hz,1H),7.43(s,1H,),7.18-7.16(m,2H),6.97-6.89(m,2H),4.44-4.39(m,1H),3.90-3.82(m,2H),3.01-2.95(m,2H),2.77-2.74(m,2H),2.58-2.53(m,2H),2.25-2.16(m,1H),1.84-1.78(m,1H),1.08(t,J＝8.0Hz,3H).
实施例9:1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)哌啶-4-醇(Ex-9)
Figure PCTCN2020141251-appb-000025
化合物Ex-9的合成路线：
Figure PCTCN2020141251-appb-000026
合成方法：
合成化合物Ex-9:1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)哌啶-4-醇
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30mg,0.04mmol)溶于DCM中，向溶液中加入哌啶-4-醇(4.9mg,0.05mmol)，室温反应0.5小时，向反应液中加入三乙酰基硼 氢化钠(17.2mg,0.08mmol)，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶板纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物6mg,收率32.8％。
1H NMR(400MHz,MeOD)δ8.33(d,J＝12.0Hz,1H),7.44(s,1H),7.32(s,1H),7.18(d,J＝8.0Hz,1H),6.90-6.97(m,2H),4.01-4.08(m,2H),3.81-3.86(m,1H),3.23-3.30(m,2H),2.78-2.92(m,2H),2.53-2.59(m,2H),1.98-2.04(m,2H),1.72-1.80(m,2H),1.08(t,J＝8.0Hz,3H).
实施例10:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-N-甲基环丙烷甲酰胺(Ex-10)
Figure PCTCN2020141251-appb-000027
化合物Ex-10的合成路线：
Figure PCTCN2020141251-appb-000028
合成方法：
合成化合物Ex-10:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-N-甲基环丙烷甲酰胺
将1-(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)-N-甲基甲胺(20mg,0.03mmol)溶于DCM中，加入三乙胺(5.3mg,0.05mmol)，降到零度，滴加环丙烷甲酰氯(3.3mg,0.03mmol)，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶板纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物4mg,收率34.9％。
1H NMR(400MHz,DMSO)δ13.29(s,1H),12.62(s,1H),9.86(s,1H),8.34(d,J＝8.0Hz,1H),7.40(s,1H),7.13(d,J＝8.0Hz,2H),7.04(d,J＝12.0Hz,1H),6.92(d,J＝8.0Hz,1H),4.51-4.67(m,2H),3.17-3.23(s,3H),2.46-2.48(m,2H),1.99-2.01(m,1H),1.02(t,J＝8.0Hz,3H),0.76-0.87(m,4H).LC-MS m/z(ESI)[M+H] +针对C 24H 25FN 5O 2的计算值为:434.2；测量值为:434.2
实施例11:1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)哌啶-4-腈(Ex-11)
Figure PCTCN2020141251-appb-000029
化合物Ex-11的合成路线：
Figure PCTCN2020141251-appb-000030
合成方法：
合成中间体11-1:1-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)哌啶-4-腈
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(25.0mg,0.03mmol)溶于5ml干燥二氯甲烷中，加入4-氰基哌啶(5.6mg,0.05mmol)，室温反应30分钟，加入三乙酰基硼氢化钠(10.7mg,0.05mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体11-1 24.2mg，收率86.0％。
合成化合物Ex-11:1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)哌啶-4-腈
将11-1(24.2mg,0.03mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物3.4mg,收率26.4％。
1H NMR(400MHz,MeOD)δ8.30(dd,J＝4.0Hz,J＝8.0Hz,1H),7.43(d,J＝4.0Hz,1H),7.19-7.16(m,2H),6.95(dd,J＝8.0Hz,J＝20.0Hz,2H),3.75(s,2H),2.89-2.86(m,3H),2.59-2.53(m,4H),2.06-2.03(m,2H),1.97-1.86(m,2H),1.08(t,J＝8.0Hz,3H).
实施例12:1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)吡咯烷-3-甲腈(Ex-12)
Figure PCTCN2020141251-appb-000031
化合物Ex-12的合成路线：
Figure PCTCN2020141251-appb-000032
合成方法：
合成中间体12-1:1-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)吡咯烷-3-甲腈
将中间体2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30.0mg,0.04mmol)溶于5ml二氯甲烷中，加入吡咯烷-3-腈(5.1mg,0.05mmol)，室温搅拌0.5小时后，再向反应液中加入三乙酰基硼氢化钠(17.0mg,0.08mmol)，继续在室温下搅拌反应2h。向反应液中加少量水淬灭，用真空泵抽干溶剂，制备硅胶板进行纯化，得到12-1中间体21mg，收率56.9％。
合成化合物Ex-12:1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吡咯烷-3-甲腈
将12-1(20.0mg,0.02mmol)溶于2ml甲醇溶液中，加入1ml浓盐酸，50度反应6h。将反应溶液浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化得终产物3mg，收率为28.6％。
1H NMR(400MHz,DMSO)δ13.27(s,1H),12.58(s,1H),9.87(s,1H),8.34(d,J＝8.4Hz,1H),7.39(s,1H),7.13(d,J＝7.5Hz,2H),7.04(d,J＝11.9Hz,1H),6.92(d,J＝9.1Hz,1H),3.61(s,2H),3.17-3.18(m,1H),2.98-3.11(m,1H),2.75-2.82(m,1H),2.62-2.72(m,1H),2.55-2.61(m,1H),2.43-2.49(m,2H),1.96-2.04(m,2H),1.02(t,J＝7.5Hz,3H).
实施例13:5-乙基-2-氟-4-(3-(4-(吗啉代甲基)-1H-咪唑-2-基)-1H-吲唑-6-基) 苯酚(Ex-13)
Figure PCTCN2020141251-appb-000033
化合物Ex-13的合成路线：
Figure PCTCN2020141251-appb-000034
合成方法：
合成化合物Ex-13:5-乙基-2-氟-4-(3-(4-(吗啉代甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30.0mg,0.04mmol)溶于DCM中，加入吗啉(4.4mg,0.05mmol)，室温反应0.5小时，向反应液中加入三乙酰基硼氢化钠(17.2mg,0.08mmol)，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物8mg,收率46.9％。
1H NMR(400MHz,DMSO)δ13.23(s,1H),12.55(d,J＝20.0Hz,1H),9.85(s,1H),8.34(d,J＝8.0Hz,1H),7.39(s,1H),7.10-7.14(m,1H),6.95-7.05(m,2H),6.92(t,J＝8.0Hz,1H),3.59(t,J＝4Hz,4H),3.49-3.55(m,2H),2.49-2.50(m,2H),2.42-2.48(m,4H),1.02(t,J＝8Hz,3H).
实施例14:5-乙基-2-氟-4-(3-(4-((吡啶-3-基氨基)甲基)-1H-咪唑-2-基)-1H-吲 唑-6-基)苯酚(Ex-14)
Figure PCTCN2020141251-appb-000035
化合物Ex-14的合成路线：
Figure PCTCN2020141251-appb-000036
合成方法：
合成中间体14-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)吡啶-3-胺
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30.0mg,0.04mmol)溶于5ml甲苯中，加入3-氨基吡啶(5.6mg,0.06mmol)和1滴冰醋酸，加热到90度反应24小时，冷却到室温，加入三乙酰基硼氢化钠(12.7mg,0.06mmol)，室温反应1小时。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体14-1 23mg，收率69.3％。
合成化合物Ex-14:5-乙基-2-氟-4-(3-(4-((吡啶-3-基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将14-1(23.0mg,0.03mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物7.1mg,收率59.0％。
1H NMR(400MHz,MeOD)δ8.29(dd,J＝4.0Hz,J＝12.0Hz,1H),8.05(d,J＝4.0Hz,1H),7.80(d,J＝4.0Hz,1H),7.42(d,J＝4.0Hz,1H),7.20-7.14(m,4H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.44(s,2H),2.59-2.53(m,2H),1.08(t,J＝8.0Hz,3H).
实施例15:5-乙基-2-氟-4-(3-(4-(((1-甲基-1H-吡唑-4-基)氨基)甲基)-1H-咪唑 -2-基)-1H-吲唑-6-基)苯酚(Ex-15)
Figure PCTCN2020141251-appb-000037
化合物Ex-15的合成路线：
Figure PCTCN2020141251-appb-000038
合成方法：
合成中间体15-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-1-甲基-1H-吡唑-4-胺
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30.0mg,0.04mmol)溶于5ml甲苯中，加入1-甲基-1H-吡唑-4-胺(5.9mg,0.06mmol)和1滴冰醋酸，加热到90度反应24小时，冷却到室温，加入三乙酰基硼氢化钠(12.7mg,0.06mmol)，室温反应1小时。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体15-1 22.9mg，收率68.8％。
合成化合物Ex-15:5-乙基-2-氟-4-(3-(4-(((1-甲基-1H-吡唑-4-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将15-1(22.9mg,0.03mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物5.4mg,收率45.0％。
1H NMR(400MHz,MeOD)δ8.29(dd,J＝4.0Hz,J＝12.0Hz,1H),7.42(d,J＝4.0Hz,1H),7.25(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.17(dd,J＝4.0Hz,J＝8.0Hz,1H),7.13(s,1H),6.94(dd,J＝12.0Hz,J＝20.0Hz,2H),4.21(s,2H),3.80(s,3H),2.59-2.53(m,2H),1.08(t,J＝8.0Hz,3H).
实施例16:3-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-1-(2-羟基乙基)-1-甲基脲(Ex-16)
Figure PCTCN2020141251-appb-000039
化合物Ex-16的合成路线：
Figure PCTCN2020141251-appb-000040
合成化合物Ex-16:3-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-(2-羟基乙基)-1-甲基脲
将三光气(11.1mg,0.04mmol)溶于DCM中，降温至零度，向溶液中滴加(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(25.0mg,0.03mmol)的DCM溶液，反应5分钟，缓慢滴加三乙胺(10.2mg,0.10mmol)，零度反应0.5小时，向反应液中加入2-(甲基氨基)乙烷-1-醇(3.8mg,0.05mmol)，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物7mg,收率45.9％。
1H NMR(400MHz,MeOD)δ8.28(d,J＝8.0Hz,1H),7.42(s,1H),7.17(d,J＝8.0Hz,1H),7.10(s,1H),6.89-6.97(m,2H),4.44(s,2H),3.71(t,J＝6.0Hz,2H),3.45(t,J＝6.0Hz,2H),3.01(s,3H),2.53-2.59(m,2H),1.08(t,J＝8.0Hz,3H).
实施例17:4-(3-(4-(((环丙基甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)- 5-乙基-2-氟苯酚(Ex-17)
Figure PCTCN2020141251-appb-000041
化合物Ex-17的合成路线：
Figure PCTCN2020141251-appb-000042
合成方法：
合成化合物Ex-17:4-(3-(4-(((环丙基甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30.0mg,0.04mmol)和环丙基甲胺(4.2mg,0.06mmol)溶于DCM中，室温反应0.5小时，向反应液中加三乙酰基硼氢化钠(16.4mg,0.06mmol)，室温反应1.5小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，纯化，将产物溶于2ml甲醇中，加入1ml的浓盐酸，50度反应6小时，浓缩，溶于3ml的甲醇中，加入0.5ml的氨水，浓缩，制备硅胶板进行纯化，得到终产物6.4mg，收率39.0％。
1H NMR(400MHz,MeOD)δ8.35(d,J＝8Hz,1H),7.45(s,1H),7.33(s,1H),7.22-7.17(m,1H),6.99-6.88(m,2H),4.19(s,2H),2.91(d,J＝8Hz,2H),2.62-2.51(m,2H),1.18-1.11(m,1H),1.08(t,J＝8Hz,3H),0.74-0.67(m,2H),0.42-0.35(m,2H).
实施例18:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)环丙烷磺酰胺(Ex-18)
Figure PCTCN2020141251-appb-000043
化合物Ex-18的合成路线：
Figure PCTCN2020141251-appb-000044
合成方法：
合成中间体18-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)环丙烷磺酰胺
向体系中加入(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(30.0mg,0.04mmol)，TEA(13.1mg，0.12mmol)，5ml DCM。将体系降至0℃，滴加环丙烷磺酰氯(7.4mg，0.05mmol)，滴加完室温反应1小时。反应完成后加水淬灭，加DCM萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩纯化得到无色油状物24mg，收率:70.0％。
合成化合物Ex-18:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丙烷磺酰胺
向体系中加入中间体18-1(24mg,0.03mmol),4ml甲醇,2ml浓盐酸，加热至50℃反应。反应6小时，浓缩，然后加入4ml甲醇，0.5ml氨水， 浓缩，制备硅胶板进行纯化得到白色固体8mg，收率:61.3％。LC-MS m/z(ESI)[M+H] +针对C 22H 23FN 5O 3S的计算值为:456.1；测量值为:456.1。
实施例19:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)乙磺酰胺(Ex-19)
Figure PCTCN2020141251-appb-000045
化合物Ex-19合成路线:
Figure PCTCN2020141251-appb-000046
合成方法：
合成中间体19-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)乙磺酰胺
向体系中加入(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(30.0mg，0.04mmol),TEA(12.3mg,0.12mmol)，5ml DCM。将体系降至0℃，滴加乙基磺酰氯(7.8mg,0.06mmol)，滴加完室温反应1小时。反应完成后加水淬灭，加DCM萃取，分 液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物22mg，收率:65.16％。
合成化合物Ex-19:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)乙磺酰胺
向体系中加入中间体19-1(22mg,0.03mmol),4ml MeOH,2ml浓盐酸，加热至50℃反应6小时，浓缩，加入4ml甲醇，0.5ml氨水，浓缩，制备硅胶板进行纯化得到白色固体3mg，收率:25.7％.LC-MS m/z(ESI)[M+H] +针对C 21H 23FN 5O 3S的计算值为:444.1；测量值为:444.1.
实施例20:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-4-羟基哌啶-1-甲酰胺(Ex-20)
Figure PCTCN2020141251-appb-000047
化合物Ex-20的合成路线：
Figure PCTCN2020141251-appb-000048
合成方法：
合成中间体20-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-4-羟基哌啶-1-甲酰胺
将(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(25.0mg,0.03mmol)溶于5ml干燥的二氯甲烷中，冷却到0度，加入三光气(10.0mg,0.03mmol)反应5分钟，缓慢加入三乙胺(34.1mg,0.34mmol)，反应30分钟，加入4-羟基哌啶(4.1mg,0.04mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体20-1 19.1mg，收率65.2％。
合成化合物Ex-20:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-4-羟基哌啶-1-甲酰胺
将20-1(19.1mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物3.6mg,收率34.2％。
1H NMR(400MHz,MeOD)δ8.29(d,J＝8.0Hz,1H),7.43(d,J＝4.0Hz,1H),7.19(dd,J＝4.0Hz,J＝8.0Hz,1H),7.09(s,1H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.44(s,2H),3.90-3.78(m,3H),3.13-3.06(m,2H),2.59-2.53(m,2H),1.90-1.85(m,2H),1.48-1.45(m,2H),1.08(t,J＝8.0Hz,3H).
实施例21:(R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑- 4-基)甲基)-3-羟基-N-甲基吡咯烷-1-甲酰胺(Ex-21)
Figure PCTCN2020141251-appb-000049
化合物Ex-21的合成路线：
Figure PCTCN2020141251-appb-000050
合成方法：
合成中间体21-1:1-(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)-N-甲基甲胺
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(50mg,0.07mmol)和甲氨盐酸盐(5.3mg,0.08mmol)溶于DCM中，向溶液中加入三乙胺(9.8mg,0.10mmol),室温反应0.5小时，向反应液中加三乙酰基硼氢化钠(28.6mg,0.13mmol)，室温反应1.5小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶板纯化，得中间体21-1 37mg，收率72.5％。
1H NMR(400MHz,CDCl 3)δ8.48(d,J＝8.0Hz,1H),7.44(d,J＝12.0Hz,2H),7.24(d,J＝8.0Hz,1H),7.15(d,J＝8.0Hz,1H),6.99(d,J＝12.0Hz,1H),5.91(s,2H),5.75(s,2H),5.32(s,2H),4.14(s,2H),3.86(t,J＝10.0Hz,2H), 3.56-3.62(m,4H),2.71(s,3H),2.51-2.57(m,2H),1.05(t,J＝8.0Hz,3H),0.86-0.91(m,6H),0.02-0.04(m,9H),-0.10--0.07(m,18H).
合成化合物Ex-21:(R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基-N-甲基吡咯烷-1-甲酰胺
将三光气(14.5mg,0.05mmol)溶于DCM中，降到零度，滴加中间体21-1(37mg,0.05mmol)的DCM溶液，反应5分钟，缓慢加入三乙胺(14.8mg,0.15mmol)，零度反应半小时，向反应液中滴加(R)-吡咯烷丁-3-醇(6.4mg,0.07mmol)的DCM溶液，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物11mg,收率47.0％。
1H NMR(400MHz,MeOD)δ8.28(d,J＝8.0Hz,1H),7.43(s,1H),7.17-7.19(m,2H),6.90-6.97(m,2H),4.47(s,2H),4.40-4.42(m,1H),3.62-3.75(m,2H),3.49-3.54(m,1H),3.37-3.38(m,1H),2.94(s,3H),2.53-2.58(m,2H),1.90-2.01(m,2H),1.08(t,J＝8.0Hz,3H).
实施例22:(R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑- 4-基)甲基)-3-羟基吡咯烷-1-甲酰胺(Ex-22)
Figure PCTCN2020141251-appb-000051
化合物Ex-22的合成路线：
Figure PCTCN2020141251-appb-000052
合成方法：
合成中间体22-1:(R)-N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺
将(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(25.0mg,0.03mmol)溶于5ml干燥的二氯甲烷中，冷却到0度，加入三光气(10.0mg,0.03mmol)反应5分钟，缓慢加入三乙胺(34.1mg,0.34mmol)，反应30分钟，加入(R)-吡咯烷-3-醇(3.5mg,0.04mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体22-1 21.0mg，收率72.9％。
合成化合物Ex-22:(R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺
将22-1(21.0mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物6.7mg,收率58.6％。
1H NMR(400MHz,MeOD)δ8.29(d,J＝8.0Hz,1H),7.43(d,J＝4.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.11(s,1H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.45-4.43(m,3H),3.54-3.49(m,3H),3.40-3.37(m,1H),2.59-2.53(m,2H),2.08-2.02(m,2H),1.08(t,J＝8.0Hz,3H).
实施例23:(S)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑- 4-基)甲基)-3-羟基吡咯烷-1-甲酰胺(Ex-23)
Figure PCTCN2020141251-appb-000053
化合物Ex-23的合成路线：
Figure PCTCN2020141251-appb-000054
合成方法：
合成中间体23-1:(S)-N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺
将(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(25.0mg,0.03mmol)溶于5ml干燥的二氯甲烷中，冷却到0度，加入三光气(10.0mg,0.03mmol)反应5分钟，缓慢加入三乙胺(34.1mg,0.34mmol)，反应30分钟，加入(S)-吡咯烷-3-醇(3.5mg,0.04mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有 机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体22-1 17.8mg，收率61.6％。
合成化合物Ex-23:(S)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺
将23-1(17.8mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物4.2mg,收率43.5％。
1H NMR(400MHz,MeOD)δ8.29(d,J＝8.0Hz,1H),7.43(d,J＝4.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.10(s,1H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.45-4.43(m,3H),3.53-3.49(m,3H),3.40-3.37(m,1H),2.59-2.53(m,2H),2.07-2.03(m,2H),1.08(t,J＝8.0Hz,3H).
实施例24:5-乙基-2-氟-4-(3-(4-(((2-羟乙基)(甲基)氨基)甲基)-1H-咪唑-2- 基)-1H-吲唑-6-基)苯酚(Ex-24)
Figure PCTCN2020141251-appb-000055
化合物Ex-24的合成路线：
Figure PCTCN2020141251-appb-000056
合成方法：
合成化合物Ex-24:5-乙基-2-氟-4-(3-(4-(((2-羟乙基)(甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(20mg,0.03mmol)和2-(甲基氨基)乙烷-1-醇(3mg,0.04mmol)溶于DCM中，室温反应0.5小时，向反应液中加三乙酰基硼氢化钠(8.2mg,0.04mmol)，室温反应1.5小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶板纯化，将纯化后的浓缩物溶于2ml甲醇中，加入1ml的浓盐酸，50度反应6小时，浓缩，溶于3ml的甲醇中，加入0.5ml的氨水，浓缩，硅胶板纯化，得到终产物4.8mg，收率43.4％。
1H NMR(400MHz,MeOD)δ8.34(d,J＝8.0Hz,1H),7.51(s,1H),7.45(s,1H),7.22-7.17(m,1H),7.00-6.89(m,2H),4.47(s,2H),3.98(t,J＝4.0Hz,2H),3.43-3.37(m,2H),3.00(s,3H),2.60-2.51(m,2H),1.08(t,J＝8.0Hz,3H).
实施例25:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)丙烷-2-磺酰胺(Ex-25)
Figure PCTCN2020141251-appb-000057
化合物Ex-25的合成路线：
Figure PCTCN2020141251-appb-000058
合成方法：
合成中间体25-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)丙烷-2-磺酰胺
向体系中加入(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(17.0mg,0.02mmol),TEA(7.0mg，0.07mmol)，5ml DCM。将体系降至0℃，滴加丙烷2-磺酰氯(7.4mg，0.05mmol)，滴加完室温反应1小时。反应完成后加水淬灭，加DCM萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩纯化得到无色油状物11mg，收率:56.6％。
合成化合物Ex-25:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)丙烷-2-磺酰胺
向体系中加入中间体25-1(11mg,0.01mmol),4ml MeOH,2ml浓盐酸，加热至50℃反应6小时，浓缩，然后加入4ml甲醇，0.5ml氨水，浓缩，制备硅胶板进行纯化得到白色固体3mg，收率:50.5％.LC-MS m/z(ESI)[M+H] +针对C 22H 25FN 5O 3S的计算值为:458.1；测量值为:458.1.
实施例26:((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲 基)氨基甲酸甲酯(Ex-26)
Figure PCTCN2020141251-appb-000059
化合物Ex-26的合成路线：
Figure PCTCN2020141251-appb-000060
合成方法：
合成中间体26-1:((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)氨基甲酸甲酯
将(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(30.0mg,0.04mmol)溶于5ml干燥的二氯甲烷中，冷却到0度，加入三光气(11.9mg,0.04mmol)反应5分钟，缓慢加入三乙胺(40.4mg,0.40mmol)，反应30分钟，浓缩，加入2ml甲醇溶解，加入DMAP(4.9mg,0.04mmol),加热到70度反应4小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体26-1 17.9mg，收率55.3％。
合成化合物Ex-26:((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)氨基甲酸甲酯
将26-1(17.9mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物3.9mg,收率42.5％。
1H NMR(400MHz,MeOD)δ8.29(dd,J＝4.0Hz,J＝8.0Hz,1H),7.42(s,1H),7.17(dd,J＝4.0Hz,J＝8.0Hz,1H),7.10(s,1H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.39(s,2H),3.70(s,3H),2.58-2.53(m,2H),1.08(t,J＝8.0Hz,3H).
实施例27:2-氰基乙基((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H- 咪唑-4-基)甲基)氨基甲酸酯(Ex-27)
Figure PCTCN2020141251-appb-000061
化合物Ex-27的合成路线：
Figure PCTCN2020141251-appb-000062
合成方法：
合成中间体27-1:3-氰基乙基((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)氨基甲酸酯
向体系中加入3-羟基丙腈(10.1mg，0.14mmol)，5ml DMF，0.2ml三乙胺，CDI(10.0mg，0.06mmol)，反应10min后加入(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(30.0mg，0.04mmol),DMAP(0.6mg,0.005ml)。室温反应17h。反应完成后加水淬灭，加EA萃取，用氯化铵水溶液洗有机相两次，用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物19mg，收率:57％。
合成化合物Ex-27:2-氰基乙基((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)氨基甲酸酯
向体系中加入中间体27-1(19mg,0.02mmol),4ml 1,4-二氧六环,2ml浓盐酸，加热至50℃反应4小时，浓缩，加入4ml 1,4-二氧六环，0.5ml氨水，浓缩，制备硅胶板进行纯化得到白色固体2mg，收率:20.0％.LC-MS m/z(ESI)[M+H] +针对C 23H 22FN 6O 3的计算值为:449.2；测量值为:449.2.
实施例28:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)环丁烷甲酰胺(Ex-28)
Figure PCTCN2020141251-appb-000063
化合物Ex-28的合成路线：
Figure PCTCN2020141251-appb-000064
合成方法：
合成化合物Ex-28:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丁烷甲酰胺
将(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(30.0mg,0.04mmol)溶于5ml干燥的二氯甲烷中，加入三乙胺(4.9mg,0.05mmol)，加入环丁基甲酰氯(7.2mg,0.06mmol)，室温反应1小时，加水淬灭，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品用4ml甲醇溶解，然后加入2ml浓盐酸，加热至50℃反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物7.0mg,收率39.9％。
1H NMR(400MHz,MeOD)δ8.28(d,J＝8.4Hz,1H),7.42(s,1H),7.17(dd,J＝1.4Hz,J＝8.4Hz,1H),7.10(s,1H),6.93(dd,J＝11.8Hz,J＝21.8Hz,2H),4.45(s,2H),3.22-3.14(m,1H),2.55(q,J＝7.6Hz,2H),2.37-2.27(m,2H),2.23-2.13(m,2H),2.07-1.96(m,2H),1.08(t,J＝7.6Hz,3H).
实施例29:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-1-甲基吡咯烷-3-甲酰胺(Ex-29)
Figure PCTCN2020141251-appb-000065
化合物Ex-29合成路线：
Figure PCTCN2020141251-appb-000066
合成方法：
合成中间体29-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-1-甲基吡咯烷-3-甲酰胺
向体系中加入(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(50.0mg，0.07mmol),1-甲基吡咯烷-3-羧酸(28.0mg,0.16mmol)，HATU(46.8mg，0.12mmol)，10ml DMF,0.4ml DIEA，室温下搅拌2h。反应完成后加水淬灭，加EA萃取，分液，无水硫酸钠干燥。浓缩柱层析得到无色油状物28mg，收率:40.0％。
合成化合物Ex-29:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-甲基吡咯烷-3-甲酰胺
向体系中加入中间体29-1(28.0mg,0.03mmol),6ml MeOH,3ml浓盐酸，加热至50℃反应6小时，浓缩，然后加入4ml甲醇，0.5ml氨水，浓缩，制备硅胶板进行纯化得到白色固体2mg，收率:13.1％.LC-MS m/z(ESI)[M+H] +针对C 25H 28FN 6O 2的计算值为:463.2；测量值为:463.2.
实施例30:4-(3-(4-((2-氮杂双环[2.2.2]辛烷-2-基)甲基)-1H-咪唑-2-基)-1H-吲 唑-6-基)-5-乙基-2-氟苯酚(Ex-30)
Figure PCTCN2020141251-appb-000067
化合物Ex-30合成路线：
Figure PCTCN2020141251-appb-000068
合成方法：
合成中间体30-1:2-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-2-氮杂双环[2.2.2]辛烷
向体系中加入2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(55.0mg，0.08mmol),2-氮杂双环[2.2.2]辛烷(45.1mg，0.40mmol)，10ml 1,2-二氯乙烷，室温下搅拌2h，然后加入三乙酰基硼氢化钠(53.6mg，0.24mmol)，室温反应。反应完成后加水淬灭，加EA萃取，分液，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物36mg，收率:49.3％。
合成化合物Ex-30:4-(3-(4-((2-氮杂双环[2.2.2]辛烷-2-基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚
向体系中加入中间体30-1(36mg,0.04mmol),6ml MeOH,3ml浓盐酸，加热至50℃反应6小时，浓缩，然后加入4ml甲醇，0.5ml氨水，浓缩，制备硅胶板进行纯化得到白色固体12mg，收率:62.6％.LC-MS m/z(ESI)[M+H] +针对C 26H 29FN 5O的计算值为:446.2；测量值为:446.2.
实施例31:4-(3-(4-((环丁基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基 -2-氟苯酚(Ex-31)
Figure PCTCN2020141251-appb-000069
化合物Ex-31的合成路线：
Figure PCTCN2020141251-appb-000070
合成方法：
合成化合物Ex-31:4-(3-(4-((环丁基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(20.0mg,0.03mmol)和环丁胺(3.1mg,0.04mmol)溶于DCM中，室温反应0.5小时，向反应液中加三乙酰基硼氢化钠(8.2mg,0.04mmol)，室温反应1.5小时，向反应液中加水，用DCM萃取2次，合并有 机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，纯化，溶于2ml甲醇中，加入1ml的浓盐酸，50度反应6小时，浓缩，溶于3ml的甲醇中，加入0.5ml的氨水，浓缩，制备硅胶板进行纯化，得到终产物5.2mg，收率49.0％。
1H NMR(400MHz,MeOD)δ8.39(d,J＝8.0Hz,1H),7.45(s,1H),7.40(s,1H),7.22-7.17(m,1H),7.00-6.89(m,2H),4.19(s,2H),3.97-3.87(m,1H),2.62-2.51(m,2H),2.46-2.36(m,2H),2.3-2.22(m,2H),2.02-1.93(m,2H),1.08(t,J＝8.0Hz,3H).
实施例32:5-乙基-2-氟-4-(3-(4-(((四氢呋喃-3-基)氨基)甲基)-1H-咪唑-2-基) -1H-吲唑-6-基)苯酚(Ex-32)
Figure PCTCN2020141251-appb-000071
化合物Ex-32的合成路线：
Figure PCTCN2020141251-appb-000072
合成方法：
合成中间体32-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)四氢呋喃-3-胺
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(20.0mg,0.03mmol)溶于5ml干燥二氯甲烷中，加入四氢呋喃-3-胺(3.5mg,0.04mmol)，室温反应30分钟，加入三乙酰基硼氢化钠(8.6mg,0.04mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体32-1 15.0mg，收率68.4％。
合成化合物Ex-32:5-乙基-2-氟-4-(3-(4-(((四氢呋喃-3-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将32-1(15.0mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物4.3mg,收率55.1％。
1H NMR(400MHz,MeOD)δ8.32(dd,J＝4.0Hz,J＝8.0Hz,1H),7.43(s,1H),7.20-7.17(m,2H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.01-3.96(m,1H),3.92(d,J＝4.0Hz,2H),3.90-3.87(m,1H),3.82-3.77(m,1H),3.72-3.69(m,1H),3.59-3.56(m,1H),2.59-2.53(m,2H),2.24-2.17(m,1H),1.92-1.87(m,1H),1.08(t,J＝8.0Hz,3H).
实施例33:5-乙基-2-氟-4-(3-(4-((吡啶-2-基氨基)甲基)-1H-咪唑-2-基)-1H-吲 唑-6-基)苯酚(Ex-33)
Figure PCTCN2020141251-appb-000073
化合物Ex-33的合成路线：
Figure PCTCN2020141251-appb-000074
合成中间体33-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)吡啶-2-胺
将中间体2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲哚-3-基)-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(30.0mg,0.04mmol)和吡啶-2-胺(7.6mg,0.08mmol)溶于3ml甲苯中，100度温度条件下加热搅拌20h，向反应液中加入三乙酰基硼氢化钠(17.0mg,0.08mmol)，室温反应1小时。向反应液中加水淬灭，用DCM萃取2次，合并有机相，无水硫酸钠干燥，浓缩，硅胶柱纯化，得33-1中间体20.0mg，收率60.3％。
合成化合物Ex-33:5-乙基-2-氟-4-(3-(4-((吡啶-2-基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将33-1(18.0mg,0.02mmol)溶于2ml甲醇溶液中，加入1ml浓盐酸，50度反应6h。将反应溶液进行真空浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行分离得到化合物7mg，收率为74.3％。
1H NMR(400MHz,MeOD)δ8.30(d,J＝8.4Hz,1H),8.07-7.91(m,1H),7.50(ddd,J＝8.7Hz,J＝7.1Hz,J＝1.9Hz,1H),7.42(s,1H),7.24-7.10(m,2H),7.01-6.85(m,2H),6.74-6.55(m,2H),4.57(s,2H),2.55(q,J＝7.5Hz,2H),1.07(t,J＝7.5Hz,3H).
实施例34:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-1-甲基-1H-吡唑-4-甲酰胺(Ex-34)
Figure PCTCN2020141251-appb-000075
化合物Ex-34的合成路线：
Figure PCTCN2020141251-appb-000076
合成方法：
合成化合物Ex-34:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-甲基-1H-吡唑-4-甲酰胺
将1-甲基吡唑-4-甲酸(7.4mg,0.06mmol)溶于10ml DMF中，加入HATU(22.4mg,0.06mmol),DIEA(12.7mg,0.10mmol)，室温下搅拌30分钟，加入(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(30.0mg,0.04mmol)，室温反应2小时。加水淬灭，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品用4ml甲醇溶解，然后加入2ml浓盐酸，加热至50℃反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物8.0mg,收率43.1％。
1H NMR(400MHz,MeOD)δ8.29(d,J＝8.3Hz,1H),8.10(s,1H),7.94(s,1H),7.42(s,1H),7.17(dd,J＝1.4Hz,J＝8.3Hz,1H),7.16(s,1H),6.93(dd,J＝11.7Hz,J＝21.7Hz,2H),4.61(s,2H),3.94(s,3H),2.55(q,J＝7.6Hz,2H),1.08(t,J＝7.6Hz,3H).
实施例35:5-乙基-2-氟-4-(3-(4-(((1-甲基吡咯烷-3-基)氨基)甲基)-1H-咪唑-2- 基)-1H-吲唑-6-基)苯酚(Ex-35)
Figure PCTCN2020141251-appb-000077
化合物Ex-35的合成路线：
Figure PCTCN2020141251-appb-000078
合成方法：
合成中间体35-1:N-((2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲基)-1-甲基吡咯烷-3-胺
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(25.0mg,0.03mmol)溶于5ml干燥二氯甲烷中，加入 1-甲基吡咯烷-3-胺(5.1mg,0.05mmol)，室温反应30分钟，加入三乙酰基硼氢化钠(10.7mg,0.05mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体35-1 17.2mg，收率61.8％。
合成化合物Ex-35:5-乙基-2-氟-4-(3-(4-(((1-甲基吡咯烷-3-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚
将35-1(17.2mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物3.4mg,收率37.6％。
1H NMR(400MHz,MeOD)δ8.36(d,J＝8.0Hz,1H),7.46(dd,J＝4.0Hz,J＝8.0Hz,2H),7.22-7.20(m,1H),6.95(dd,J＝12.0Hz,J＝20.0Hz,2H),4.22(s,2H),4.10-4.04(m,1H),3.67-3.54(m,3H),3.37-3.33(m,1H),2.96(s,3H),2.61-2.52(m,3H),2.32-2.21(m,1H),1.08(t,J＝8.0Hz,3H).
实施例36:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)吗啉-4-甲酰胺(Ex-36)
Figure PCTCN2020141251-appb-000079
化合物Ex-36的合成路线：
Figure PCTCN2020141251-appb-000080
合成方法：
合成化合物Ex-36:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吗啉-4-甲酰胺
将三光气(11mg,0.04mmol)溶于DCM中，降至零度，向溶液中滴加(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(25.0mg,0.03mmol)的DCM溶液，反应5分钟，缓慢滴加三乙胺(10.2mg,0.10mmol)，零度反应0.5小时，向反应液中加入吗啉(4.4mg,0.05mmol)，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶板纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶于3ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物5mg,收率32.0％。
1H NMR(400MHz,MeOD)δ8.28(d,J＝8.0Hz,1H),7.43(s,1H),7.18(d,J＝8.0Hz,1H),7.10(s,1H),6.90-6.97(m,2H),4.45(s,2H),3.68(t,J＝4.0Hz,4H),3.43(t,J＝4.0Hz,4H),2.53-2.58(m,2H),1.08(t,J＝8.0Hz,3H).
实施例37:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基) 甲基)-4-甲基哌嗪-1-甲酰胺(Ex-37)
Figure PCTCN2020141251-appb-000081
化合物Ex-37的合成路线：
Figure PCTCN2020141251-appb-000082
合成方法：
合成化合物Ex-37:N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-4-甲基哌嗪-1-甲酰胺
将三光气(11mg,0.04mmol)溶于DCM中，降至零度，向溶液中滴加(2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-基)甲胺(25mg,0.03mmol)的DCM溶液,反应5分钟，缓慢滴加三乙胺(10.2mg,0.10mmol)，零度反应0.5小时，向反应液中加入1-甲基哌嗪(5.1mg,0.05mmol)，室温反应1小时，向反应液中加水，用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，纯化，得到的产物溶于2ml甲醇和1ml浓盐酸中，50度反应6小时，浓缩，溶 于3ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物6mg,收率37.3％。
1H NMR(400MHz,MeOD)δ8.27(d,J＝8.0Hz,1H),7.45(s,1H),7.19(d,J＝8.0Hz,1H),7.16(s,1H),6.90-6.97(m,2H),4.46(s,2H),3.67-3.74(m,4H),3.10-3.15(m,4H),2.80(s,3H),2.53-2.58(m,2H),1.08(t,J＝8.0Hz,3H).
实施例38:5-乙基-4-(3-(4-((4-乙基哌嗪-1-基)甲基)-1H-咪唑-2-基)-1H-吲唑 -6-基)-2-氟苯酚(Ex-38)
Figure PCTCN2020141251-appb-000083
化合物Ex-38的合成路线：
Figure PCTCN2020141251-appb-000084
合成方法：
合成中间体38-1:(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-3-(4-((4-乙基哌嗪-1-基)甲基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-2-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑
将2-(6-(2-乙基-5-氟-4-((2-(三甲基硅烷基)乙氧基)甲氧基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-4-甲醛(25.0mg,0.03mmol)溶于5ml干燥二氯甲烷中，加入 1-乙基哌嗪(5.8mg,0.05mmol)，室温反应30分钟，加入三乙酰基硼氢化钠(10.7mg,0.05mmol)，室温反应1小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得中间体32-1 23.0mg，收率81.3％。
合成化合物Ex-38:5-乙基-4-(3-(4-((4-乙基哌嗪-1-基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-2-氟苯酚
将38-1(23.0mg,0.02mmol)溶于2ml甲醇中，加入1ml浓盐酸，50度反应6小时，浓缩，溶于2ml甲醇，加0.5ml氨水，浓缩，制备硅胶板进行纯化，得到终产物6.7mg,收率54.5％。LC-MS m/z(ESI)[M+H] +针对C 25H 30FN 6O的计算值为:449.2；测量值为:449.2。
实验：药理学活性评价
1.实验原理
通过基于JAK1、JAK2、JAK3、TYK2激酶的药物筛选体系来检测小分子化合物分别对于激酶活性的抑制能力。激酶与其底物IRS1,IGF1Rtide,Poly(4:1Glu,Tyr)进行酶学反应，消耗ATP产生ADP,利用ADP-Glo试剂和发光的方法检测产物的量用以反映激酶的活性。
2.实验方案
2.1实验材料和仪器
序号 名称 来源 货号
1 HEPES Life Technologies 15630-080
2 BRIJ 35 detergent(10％) Sigma 1018940100
3 MgCl2 Sigma M1028
4 EGTA Sigma E3889
5 ADP-Glo Kinase Assay Promega V9101
6 JAK1 Carna 08-144
7 JAK2 Carna 08-045
8 JAK3 Carna 08-046
9 TYK2 Carna 08-147
10 ATP Promega V915B
11 IRS1 Signalchem I40-58-1000
12 IGF1Rtide Signalchem I15-58
13 Poly(4:1Glu,Tyr) Sigma P0275
15 384 polystyrene shallow flat white Greiner 784075
16 384-Well Polypropylene microplate labcyte PP-0200
17 Biotek酶标仪 Biotek Synergy 4
18 微孔板低速离心机 湘智 TD5B
2.2实验方法
2.2.1激酶反应试剂配方
2.2.1.1 1X激酶反应缓冲液(400mL)
名称 储液浓度 体积 终浓度
HEPES 1M(20X) 20mL 50mM
MgCl 2 1M(100X) 4mL 10mM
BRIJ-35 10％(1000X) 400μL 0.01％
EGTA 粉末 152mg 1mM
ddH2O   375.6mL  
2mM DTT,现用现配
2.2.1.2 2X激酶配方
Figure PCTCN2020141251-appb-000085
Figure PCTCN2020141251-appb-000086
Figure PCTCN2020141251-appb-000087
Figure PCTCN2020141251-appb-000088
Figure PCTCN2020141251-appb-000089
2.2.1.3 4X底物混合物配方
Figure PCTCN2020141251-appb-000090
Figure PCTCN2020141251-appb-000091
Figure PCTCN2020141251-appb-000092
Figure PCTCN2020141251-appb-000093
2.2.2激酶反应实验步骤
a)用100％DMSO将Filgotinib(10mM储液)原倍，待测化合物稀释5倍， 在96孔稀释板中进行4倍等比稀释,取1μL的化合物加入49μL的激酶反应缓冲液中，在微孔板振荡器上震荡20min。
b)转移2μL的激酶(2.2.1.2步骤中制备)到384反应板中,加入1μL的待测化合物(a步骤中准备)到384反应板中(Greiner,784075)，1000rpm/min，离心1min,25℃孵育10min。
c)转移1μL底物混合物(2.2.1.3步骤中制备)到384反应板中，1000rpm/min，离心1min，25℃孵育60min。在反应体系中，Filgotinib终浓度50,12.5,3.125,0.7812,0.1953,0.0488,0.0122,0.003,0.00076,0.00019,0.000047μM。待测化合物终浓度:10,2.5,0.625,0.15625,0.039,0.0097,0.0024,0.0006，0.0015,0.000038,0.0000095μM。DMSO终浓度均为0.5％。
d)转移4μL ADP-Glo到384反应板中1000rpm/min,离心1min，25℃孵育40min。
e)转移8μL Detection溶液到384反应板中1000rpm/min,离心1min，25℃孵育40min。
f)使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。
2.2.3实验数据处理方法
化合物抑制率(％inh)＝(阴性对照-化合物)/(阴性对照-阳性对照)*100％
阴性对照：DMSO
阳性对照：10uM/50uM Filgotinib
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值
Y:化合物抑制率(％inh)
Z’因子计算方程：
Z’＝1-3(SDmin+SDmax)/(AVEmax-AVEmin)
其中：
Min为阳性对照10uM/50uM Filgotinib RLU值，Max为阴性对照DMSO RLU值。
SD为标准误差，AVE为RLU平均值。
3.结果
3.1化合物检测质控结果
3.1.1 JAK1结合实验质控结果
Z’＝0.79CV％(min)＝4％CV％(max)＝5％
3.1.2 JAK2结合实验质控结果
Z’＝0.74CV％(min)＝9％CV％(max)＝8％
3.1.3 JAK3结合实验质控结果
Z’＝0.76CV％(min)＝15％CV％(max)＝6％
3.1.4 TYK2结合实验质控结果
Z’＝0.84CV％(min)＝8％CV％(max)＝4％
3.2化合物检测结果总结
Figure PCTCN2020141251-appb-000094
Figure PCTCN2020141251-appb-000095
以上实验结果表明：实验中所检测的本申请化合物在极低的浓度下均能够抑制JAK1、JAK2、JAK3、TYK2，这些实施例化合物的抑制活性远远高于Filgotinib。
虽然已经阐明并描述了本申请的特定实施方式，但并不意味着这些实施方式阐明了并描述了本申请的所有可能形式。更确切地，用在本说明书中的文字仅仅是描述性的文字并非限制性的。对于本领域技术人员明显的是，在不脱离本公开的一般范围的情况下，可以进行各种其他改变和修改。因此，在所附权利要求中，旨在包括在本申请范围内的所有这些改变和修改。

Claims (32)

  1. 一种式(I)的化合物：
    Figure PCTCN2020141251-appb-100001
    或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中：
    L为C＝O、O＝S＝O、CH 2或连接键；且
    X 1为N或CR 14；且
    X 2为N或CR 15；且
    X 3为N或CR 16；且
    R 13为H、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基、C 5-11双环烷基、5-11元双环杂烷基，且R 13被0、1、2、3或4个R 1取代；且
    R 17选自以下群组：H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-S(＝O) 2-N(R 9)(R 10)，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；或者
    R 13和R 17以及与它们相连的L和N原子共同形成4-10元杂环烷基,并且所述4-10元杂环烷基任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
    R 18、R 19各自独立地选自以下群组：H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6- 10芳基)-C 1-4烷基-、(5-10元杂芳基)-C 1-4烷基-，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；或者
    R 18和R 19以及与它们相连的碳原子共同形成C 3-10环烷基、4-10元杂环烷基，并且所述C 3-10环烷基、4-10元杂环烷基任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基；且
    R 2的个数为0、1、2、3或4个，并且各个R 2独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、- OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 3-7环烷基、4-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、以及7-11元双环杂芳基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CN、-OH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-OR 12、-C(＝O)H、-C(＝O)R 12、-C(＝O)-N(R 9)(R 10)、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12；且
    各个R 1独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基、C 5-11双环烷基、5-11元双环杂烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基任选地被1个、2个、3个或4个R 3取代，并且其中所述C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基任选地被1个、2个、3个或4个R 4取代；且
    R 14、R 15、R 16各自独立地选自H、-OH、-SH、-CN、卤素、-NO 2、-SF 5、-S-C 1-4烷基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-N(R 9)(R 10)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、3-7元杂环烷基任选地被1个、2个或3个选自卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基的取代基取代；且
    R 3、R 4各自独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-N(R 5)(R 6)、-N(R 11)(C(＝O)R 12)、-CON(R 7)(R 8)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12，其中所述C 1-6烷基、C 3-7环烷基、3-10元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、以及7-11元双环杂芳基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CN、-OH、C 1-4烷基、C 1-6烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 3-6环烷基、-N(R 9)(R 10)、-N(R 11)(C(＝O)R 12)、-C(＝O)-OR 12、-C(＝O)H、-C(＝O)R 12、-C(＝O)-N(R 9)(R 10)、-N(R 11)(S(＝O) 2R 12)、-S(＝O) 2-N(R 9)(R 10)、-SR 12及-OR 12；且
    R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立地是H或选自以下群组：C 1-6烷基、C 1-4卤代烷基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基、5-10元杂芳基、(C 3-7环烷基)-C 1-4烷基-、(4-10元杂环烷基)-C 1-4烷基-、(C 6-10芳基)-C 1-4烷基-以及(5-10元杂芳基)-C 1-4烷基-，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  2. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其是式(I)的化合物的同位素标记化合物，其中所有H各自独立地任选地被D代替。
  3. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 1为N。
  4. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 2为N。
  5. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 3为N。
  6. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 1为CR 14、X 2为CR 15、X 3为CR 16。
  7. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 1、X 2、X 3是相同的。
  8. 根据权利要求2所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 1、X 2、X 3是相同的。
  9. 根据权利要求7所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 1、X 2、X 3均为CH。
  10. 根据权利要求8所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中X 1、X 2、X 3均为CH。
  11. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中L为C＝O、O＝S＝O或CH 2。
  12. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 13为H、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、11-15元三环基，并任选地被1、2、3或4个R 1取代。
  13. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 13为H、C 1-6烷基或者C 3-7环烷基、3-7元杂环烷基、C 5-7芳基、5-7元杂芳基，并任选地被1、2、3或4个R 1取代。
  14. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 13为C 1-6烷基或者C 3-7环烷基、4-6元杂环烷基、苯基、5-6元杂芳基，并任选地被1、2、3或4个R 1取代。
  15. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 17为H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基或者5-10元杂芳基，并任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  16. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 17为H、C 1-6烷基、C 3-7环烷基、4-6元杂环烷基、苯基或者5-6元杂芳基，并任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1- 4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  17. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 13和R 17以及与它们相连的L和N原子共同形成4-6元杂环烷基,并且所述4-6元杂环烷基任选地被1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  18. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 18、R 19各自独立地选自以下群组：H、C 1-6烷基、C 1-4卤代烷基、C 2-8烯基、C 2-8炔基、C 1-6烷氧基、C 3-7环烷基、4-14元杂环烷基、C 6-10芳基以及5-10元杂芳基，其中该群组内的各个选项任选地被1、2、3或4个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、-N(C 1-4烷基)(C(＝O)C 1-4烷基)、C 1-4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  19. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 18为H。
  20. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 19为H。
  21. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 18和R 19均为H。
  22. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 18和R 19以及与它们相连的碳原子共同形成C 3-6环烷基、4-6元杂环烷基，并且所述C 3-6环烷基、4-6元杂环烷基任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-CF 3、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、氧代、C 1-4烷基。
  23. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中存在1个、2个或3个R 2，并且各个R 2独立地选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-10元杂环烷基，其中所述-S-C 1-4烷基、C 1-6烷基、C 3-7环烷基、4-10元杂环烷基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 1- 4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  24. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中存在1个、2个或3个R 2，并且各个R 2独立地选自卤素、C 1-6烷基以及C 3-6环烷基，其中所述C 1-6烷基及C 3-6环烷基各自任选地被1、2或3个各自独立地选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、C 1-4烷基、C 1- 4卤代烷基、C 1-4烷氧基以及C 1-4卤代烷氧基。
  25. 根据权利要求14所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中存在1个或2个R 2，并且各个R 2独立地选自卤素、C 1-6烷基。
  26. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中R 13被0个或1个R 1取代， 并且R 1选自卤素、-OH、C 1-6烷基、5-7元杂环烷基、C 3-7环烷基，其中所述C 1-6烷基任选地被1个、2个或3个R 3取代，并且其中所述5-7元杂环烷基、C 3-7环烷基任选地被1个、2个、3个或4个C 1-3烷基取代。
  27. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，其中所述化合物选自：
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-5-(哌啶-1-基)吡嗪-2-甲酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)丙酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丙烷甲酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)异丁酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)甲磺酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-5-吗啉并吡嗪-2-甲酰胺；
    (S)-1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吡咯烷-3-醇；
    1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)哌啶-4-醇；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-N-甲基环丙烷甲酰胺(Ex-10)
    1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)哌啶-4-腈；
    1-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吡咯烷-3-甲腈；
    5-乙基-2-氟-4-(3-(4-(吗啉代甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    5-乙基-2-氟-4-(3-(4-((吡啶-3-基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    5-乙基-2-氟-4-(3-(4-(((1-甲基-1H-吡唑-4-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    3-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-(2-羟基乙基)-1-甲基脲；
    4-(3-(4-(((环丙基甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丙烷磺酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)乙磺酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-4-羟基哌啶-1-甲酰胺；
    (R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基-N-甲基吡咯烷-1-甲酰胺；
    (R)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺；
    (S)-N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-3-羟基吡咯烷-1-甲酰胺；
    5-乙基-2-氟-4-(3-(4-(((2-羟乙基)(甲基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)丙烷-2-磺酰胺；
    ((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)氨基甲酸甲酯；
    2-氰基乙基((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)氨基甲酸酯；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)环丁烷甲酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-甲基吡咯烷-3-甲酰胺；
    4-(3-(4-((2-氮杂双环[2.2.2]辛烷-2-基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚；
    4-(3-(4-((环丁基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-5-乙基-2-氟苯酚；
    5-乙基-2-氟-4-(3-(4-(((四氢呋喃-3-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    5-乙基-2-氟-4-(3-(4-((吡啶-2-基氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-1-甲基-1H-吡唑-4-甲酰胺；
    5-乙基-2-氟-4-(3-(4-(((1-甲基吡咯烷-3-基)氨基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)苯酚；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)吗啉-4-甲酰胺；
    N-((2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-1H-咪唑-4-基)甲基)-4-甲基哌嗪-1-甲酰胺；
    5-乙基-4-(3-(4-((4-乙基哌嗪-1-基)甲基)-1H-咪唑-2-基)-1H-吲唑-6-基)-2-氟苯酚。
  28. 一种药物组合物，其包含如权利要求1-27中任意一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物，以及一种或多种药学上可接受的载体、佐剂或赋形剂。
  29. 根据权利要求1-27中任意一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药 学上可接受的盐、或其前体药、或其代谢物或者根据权利要求28所述的组合物在制备用于治疗和/或预防与JAK相关的疾病或病症的药物中的用途。
  30. 根据权利要求29所述的用途，其中所述与JAK相关的疾病或病症选自关节炎，自身免疫疾病或病症，癌症或肿瘤，糖尿病，眼疾病、病症或病况，肠炎症、变态反应或病况，神经变性疾病，皮肤疾病、病况或病症，变态反应，哮喘和其它阻塞性气道疾病，移植排斥。
  31. 一种治疗与JAK相关的疾病或病症的方法，包括将治疗有效量的根据权利要求1-27中任意一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物或者根据权利要求28所述的组合物给予有需要的患者，优选人类患者。
  32. 根据权利要求31所述的方法，其中所述与JAK相关的疾病或病症选自关节炎，自身免疫疾病或病症，癌症或肿瘤，糖尿病，眼疾病、病症或病况，肠炎症、变态反应或病况，神经变性疾病，皮肤疾病、病况或病症，变态反应，哮喘和其它阻塞性气道疾病，移植排斥。
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