WO2023109878A1 - Triazaspiro lpar1 antagonist and use thereof - Google Patents
Triazaspiro lpar1 antagonist and use thereof Download PDFInfo
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- WO2023109878A1 WO2023109878A1 PCT/CN2022/139166 CN2022139166W WO2023109878A1 WO 2023109878 A1 WO2023109878 A1 WO 2023109878A1 CN 2022139166 W CN2022139166 W CN 2022139166W WO 2023109878 A1 WO2023109878 A1 WO 2023109878A1
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- WIPO (PCT)
- Prior art keywords
- methyl
- oxy
- triazol
- cyclopropyl
- cyclohexane
- Prior art date
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- 239000005557 antagonist Substances 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 460
- 150000003839 salts Chemical class 0.000 claims abstract description 23
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 82
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- 238000002360 preparation method Methods 0.000 claims description 62
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- JCWDQBQJDCVUQI-UHFFFAOYSA-N tert-butyl N-(cyclobutylmethyl)-N-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CC1CCC1 JCWDQBQJDCVUQI-UHFFFAOYSA-N 0.000 description 1
- IYIJVINQYQBGFU-UHFFFAOYSA-N tert-butyl n-(cyclobutylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCC1 IYIJVINQYQBGFU-UHFFFAOYSA-N 0.000 description 1
- SJDWKAHMQWSMPV-UHFFFAOYSA-N tert-butyl n-ethenylcarbamate Chemical compound CC(C)(C)OC(=O)NC=C SJDWKAHMQWSMPV-UHFFFAOYSA-N 0.000 description 1
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
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- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 1
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- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
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- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to triazole LPAR1 antagonists. More specifically, the present invention relates to triazole LPR1 antagonists and their use in the preparation of medicines.
- Lysophosphatidic acid is a key endogenous lipid signaling molecule with a molecular weight of 430-480Da, which widely exists in the intracellular and extracellular tissues of the human body, such as various body fluids, saliva, urine, and cerebrospinal fluid , blood, bronchoalveolar lavage fluid (BALF), etc. (Kaffe E et al., Cancers (Basel). 2019; 11(11): 1626.).
- LPA is mainly produced from membrane phospholipids through the following two pathways: (1) phospholipase D (PLD)-phospholipase A2 (PLA2) pathway; (2) PLA2-lysophospholipase D (LysoPLD) pathway.
- the autologous chemoattractant protein (ATX) encoded by the Enpp2 gene is a pyrophosphatase/phosphodiesterase with lysophospholipase D (LysoPLD) activity, which can hydrolyze extracellular lysophosphatidylcholine (LPC) into the corresponding LPA and free choline (Choi JW et al., AnnuRevPharmacolToxicol.2010; 50:157186.), this reaction is the main source of LPA, inhibiting ATX activity can inhibit the production of more than 80% of LPA in the whole body (Kaffe E et al., Cancers ( Basel). 2019;11(11):1626.).
- LPA mediates multiple functions by interacting with G protein-coupled receptors, including cell survival, cell proliferation, cell adhesion, cell migration, cytoskeletal changes, calcium mobilization, increased vascular permeability and angiogenesis, immune function and myeloid sheath formation etc.
- LPA can bind to and function with six lysophosphatidic acid receptors (LPAR), namely: LPAR1-LPAR6.
- LPA regulates various physiological/pathological processes including vascular and neural development, hair follicle development, lymphocyte trafficking, bone development, fibrosis, fat mass regulation, cholestatic pruritus, neuropathic pain, embryo implantation by binding to 6 LPARs , obesity and glucose homeostasis, sperm production, chronic inflammation, cell proliferation, cell chemotaxis, wound healing, tumor progression, fetal hydrocephalus, etc.
- LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41kDa membrane protein consisting of 364 amino acids and widely expressed in various tissues and organs of the human body. The mRNA levels of the brain, heart, colon, small intestine and placenta Higher, while mRNA levels in other organs and tissues were relatively low. LPAR1 activates downstream pathways such as Akt, Rho, mitogen-activated protein kinase, and phospholipase C by coupling with G ⁇ I/o, G ⁇ Q/11, and G ⁇ 12/13, although it has been demonstrated that LPA-LPAR1 signaling has a role in the developmental stages of the nervous system. important role, but no significant toxicity was found in adult individuals with systemic inhibition. However, inhibition of LPAR3 signaling can produce significant reproductive toxicity, so compounds need to avoid inhibition of LPAR3 signaling.
- the diseases that have a significant correlation with LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central nervous system diseases and the like.
- Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorder. The clinical manifestation is common interstitial pneumonia. IPF originates from the repeated injury of alveolar tissue, and this injury will trigger a series of physiological and pathological events, including (I) disrupting homeostasis; (II) causing inflammatory response; (III) cell proliferation, migration and differentiation; ( IV) Matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors in and around the injury site, in which LPA plays an important role.
- LPA extracellular matrix
- LPA induces endothelial cell barrier dysfunction and vascular leakage, and increases vascular permeability in the early stages of tissue injury repair, which can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibroblasts development.
- bleomycin treatment resulted in a significant increase in LPA levels in bronchoalveolar lavage fluid after lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 -/- mice; the LPAR1 antagonist AM966 reduced total protein content and LDH activity in alveolar lavage fluid in the bleomycin model, suggesting that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in acute lung disease.
- LPAR1 is a promising target for the treatment of IPF, and in a randomized, double-blind, placebo-controlled clinical trial, administration of the LPAR1 antagonist BMS-986020 significantly slowed the decline in lung capacity in patients with idiopathic pulmonary fibrosis , and relieved clinical symptoms, and its second-generation compound BMS-986278 is conducting phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol.2010; 160(7):1699-1713.).
- LPAR1/LPAR3 antagonist VPC12249 inhibited the expression of the pro-fibroblast cytokines transforming growth factor ⁇ 1 and connective tissue growth factor in vivo, resulting in decreased proliferation of fibroblasts in mice and slower progression of radiation-induced lung fibrosis, suggesting that LPAR1 antagonists are also therapeutically Potential for radiation-induced pulmonary fibrosis (Xiang H et al., J Cancer. 2020; 11(12):3519-3535.).
- LPAR1 is closely related to the occurrence of liver fibrosis. Studies have shown that the ATX-LPA signaling axis activates PI3K and stabilizes the mRNA of hypoxia-inducible factor HIF-1, thereby promoting the replication of hepatitis C virus, and inhibiting ATX-LPA signaling reduces the replication of hepatitis C virus.
- This process may be related to LPAR1 and LPAR3 are related, and hepatitis is a key factor in the occurrence of liver fibrosis, which suggests that antagonizing LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol.2017; 66(5):919-929.);
- down-regulation of LPAR1 signaling decreased the expression of ⁇ -SMA, CTGF and TGF- ⁇ 1, thereby significantly improving thioacetamide-induced liver fibrosis, which further proves that LPAR1 antagonists can be used to treat liver fibrosis change.
- LPA promotes the progression of renal fibrosis through LPAR1.
- UUO unilateral ureteral obstruction
- TIF renal interstitial fibrosis mice
- ATX and LPA concentrations were elevated, LPAR1 was significantly upregulated, and LPAR3 was significantly downregulated (Sakai N et al., FASEB J. 2013; 27( 5): 1830-1846.).
- ATX-LPA-LPAR1 signaling can stimulate fibroblast migration and proliferation
- UUO-induced renal fibrosis was significantly attenuated in LPAR1 -/- mice or after pretreatment with the LPAR1/3 antagonist Ki16425, and when LPAR1 signaling was blocked
- the expression of pro-fibrotic cytokines was also significantly downregulated when it was disconnected. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.
- Fetal hydrocephalus is a common neurological disease in newborns, and its occurrence is closely related to LPAR1 signaling.
- NPC neural progenitor cell
- LPAR1 neural progenitor cell
- LPA-LPAR1 signaling has a prominent tumor-promoting effect.
- LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and metal matrix protease in vitro, and promotes tumor cell resistance to cisplatin.
- LPA-LPAR1 signaling down-regulates the expression of tumor suppressor p53 in liver cancer cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1, and promotes the expression of MMP-9 and the invasion of HCC; LPA-LPAR1 can also pass GTPase RhoA and Rho-related protein kinase (ROCK) Promotes invasiveness; it also induces protein kinase C (PKC) and nuclear factor kappa B (NF-kB) to promote epithelial to mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis can also promote cancer development , because neovascularization is essential for the development of solid tumors.
- neuropathic pain a pain state
- Symptoms include persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia.
- LPAR1 signaling has been implicated in the development of neuropathic pain. Damage to the nervous system leads to serum leakage at the injury site, exposing a large number of nerve cells to LPA, which may be one of the etiologies of neuropathic pain.
- LPA Low-power neuropeptidetyline
- Makoto Inoue et al. have shown that animal models of behavioral abnormalities and pain sensitivity caused by nerve injury can be eliminated by pretreatment of LPAR1 antagonists or targeted deletion of LPAR1, and can be simulated by intrathecal injection of LPA.
- LPA can induce neuropathic pain by activating LPAR1 and releasing nociceptive factor P, and LPAR1 -/- mice are resistant to neuropathic pain caused by partial sciatic nerve ligation.
- LPA-LPAR1 signaling plays a key role in the initiation of neuropathic pain and that LPAR1 antagonists may hold promise as analgesics for the treatment of neuropathic pain (Inoue M et al., ERRATUM: Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J].2004,10(7):755-755.).
- Rheumatoid arthritis is a chronic autoimmune disease
- LPAR1 signaling is related to the occurrence of RA.
- LPAR1 and/or LPAR2 in the synovium of patients with rheumatoid arthritis are increased.
- Preclinical studies have shown that gene knockout of LPAR1 completely eliminates RA symptoms, and pharmacological antagonism of LPAR1 reduces the severity of the disease. Severity, reduced inflammation and bone erosion (Kaffe E et al., Cancers (Basel). 2019; 11(11): 1626. Published 2019 Oct 23. doi: 10.3390/cancers11111626).
- Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).
- the present invention aims at solving one of the above technical problems at least to a certain extent or at least providing a useful commercial choice.
- the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
- R 1 is selected from unsubstituted or substituted by R 1a C 3-6 cycloalkyl, unsubstituted or substituted by R 1a 3-6 membered heterocyclic group;
- the R 1a is selected from -CN, halogen
- X 1 and X 2 are each independently selected from C(R 1b ) and N, and X 1 and X 2 are not N at the same time, said R 1b is selected from -H, -CN, halogen, -OH, optionally substituted C 1-6 alkyl;
- R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;
- R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
- R 5 is selected from -H, -F, methyl.
- the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
- R 1 is selected from -H, unsubstituted or substituted by R 1a C 3-6 cycloalkyl, unsubstituted or substituted by R 1a C 3-6 heterocycloalkyl; said R 1a is selected from -CN, halogen ;
- X 1 and X 2 are each independently selected from C(R 1 ) and N, and X 1 and X 2 are not N at the same time;
- R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 yuan heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen substituted
- L 1 is absent, or selected from -N(R 4 )- and -N(R 4 )-CO-O-;
- R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
- R is selected from -F, methyl
- the halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine, chlorine, and bromine;
- the alkyl group includes linear alkyl group and branched chain alkyl group.
- R 1 when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the number of R 1a is one or more When there are multiple R 1a , the R 1a is the same or different.
- R 1 when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the R 1a is selected from -CN, fluorine, Chlorine, Bromine, Iodine.
- the C 3-6 cycloalkyl group is selected from Cyclopropyl, cyclobutyl, cyclopentyl.
- R 1 is C 3-6 heterocycloalkyl unsubstituted or substituted by R c
- the C 3-6 heterocycloalkyl The heteroatoms in are selected from O, N, S.
- R 1 is cyclopropyl unsubstituted or substituted by R 1a , and R 1a is selected from -CN, fluorine, chlorine.
- R 1 is cyclopropyl
- R 2 when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more , when there are multiple R 2a , the R 2a are the same or different.
- R 2 when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more , when there are multiple R 2a , said R 2a is selected from -CN, fluorine, chlorine.
- the C 1-6 alkyl group is selected from methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
- R 2 is methyl that is unsubstituted or substituted by R 2a , and the R 2a is selected from -CN, fluorine, and chlorine.
- R 2 is methyl
- R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4
- R 3a When ⁇ 8-membered heterocyclic group, phenyl, C 3-8 bridged cycloalkyl, 5-8-membered heteroaryl group, the number of R 3a is one or more, when there are multiple R 3a , all The above R 3a are the same or different.
- R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4 ⁇ 8-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group, the number of R 3a is one or more, when there are multiple R 3a , the R 3a is the same or different.
- R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4
- R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, Isopropyl, n-butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.
- R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4
- R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n- Butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.
- the C 1-6 alkyl is methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
- the C 3-8 cycloalkyl group is Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
- R 3 is a 4-8 membered heterocyclic group unsubstituted or substituted by R 3a
- the heteroatom is selected from N, O and S
- the number of heteroatoms is 1-2.
- the 5-8 membered heteroaryl group is selected from Thiophene, furan, oxazole, thiazole, triazole, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl.
- R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Phenyl, -CH 2 F, -CHF 2 , -CF 3 , -CHF-CH 3 , -CF 2 -CH 3 .
- R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Phenyl, -CH 2 F, -CHF 2 , -CF 3 , -CHF-CH 3 , -CF 2 -CH 3 .
- R 4 when R 4 is a C 1-3 alkyl group or a C 1-3 alkyl group substituted by halogen, the C 1-3 alkyl group is Methyl, ethyl, n-propyl, isopropyl.
- L 2 does not exist, or is selected from
- the compound represented by the formula (I) is a compound represented by the formula (I-A):
- R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;
- R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
- R 5 is selected from -H, -F, methyl.
- the compound represented by the formula (I) is a compound represented by the formula (I-A):
- R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl;
- the R 3a is selected from halogen, C 3-6 cycloalkyl;
- L 1 is absent, or selected from -N(R 4 )- or -N(R 4 )-CO-O-;
- R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
- R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;
- R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, phenyl, pyridyl, cyclopropyl, cyclo butyl,
- L 1 is absent, or selected from -NH-, -N(CH 3 )-, -O-, -NH-CO-O-, -N(CH 3 )-CO-O-, -O-CO-N (CH 3 )-, -O-CO-NH-;
- L2 is absent, or selected from
- R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;
- R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, phenyl, pyridyl, cyclopropyl, cyclobutyl,
- L 1 does not exist, or is selected from -NH-, -N(CH 3 )-, -NH-CO-O-, -N(CH 3 )-CO-O-;
- L2 is absent, or selected from
- -L 1 -L 2 -R 3 is selected from Undefined groups are as described in any previous scheme.
- -L 1 -L 2 -R 3 is selected from Undefined groups are as described in any previous scheme.
- the compound represented by the formula (I) is a compound represented by the formula (I-B):
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
- the compound represented by the formula (I) is a compound represented by the formula (I-B):
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl;
- the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen substituted C 1-6 alkyl;
- L 2 is absent, or selected from C 1-3 alkylene unsubstituted or substituted by C 1-3 alkyl.
- R 3 is selected from -H, -CN, -F, -Cl, the following groups that are unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, phenyl, pyridyl, undefined groups are as described in any previous scheme.
- R 3 is selected from -H, -CN, -F, -Cl, the following groups that are unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, pyridyl, undefined groups are as described in any previous scheme.
- -L 2 -R 3 is selected from n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl , fluoro-n-butyl, Undefined groups are as described in any previous scheme.
- -L 2 -R 3 is selected from n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl , fluoro-n-butyl, Undefined groups are as described in any previous scheme.
- the compound represented by the formula (I) is a compound represented by the formula (I-C):
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
- the compound represented by the formula (I) is a compound represented by the formula (I-D):
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
- the compound represented by the formula (I) is a compound represented by the formula (I-E):
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
- the compound represented by the formula (I) is a compound represented by the formula (I-F):
- R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
- L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
- the compound represented by the formula (I) can be any of the following compounds:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), or a stereoisomer, hydrate, or solvate of the compound represented by formula (I) , a pharmaceutically acceptable salt or prodrug.
- the compound represented by the formula (I), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) may be in a therapeutically effective dose.
- the present invention also provides a compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable compound of the compound represented by formula (I) Use of salt or prodrug in preparation of medicine for treating diseases related to LPAR.
- a method for treating LPAR-related diseases comprising the step of: administering an effective amount of the compound represented by the formula (I) described in the first aspect of the present invention, or the compound represented by the formula (I) to the subject in need Stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds shown, or pharmaceutical compositions as described in the second aspect.
- the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- the compound represented by formula (I) described in the first aspect of the present invention or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt of the compound represented by formula (I) Or a prodrug, or a pharmaceutical composition as described in the second aspect, for treating diseases related to LPAR.
- the pharmaceutical composition is used for treating LPAR-related diseases, and the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- the pharmaceutical composition is used for treating LPAR-related diseases, and the LPAR-related diseases are selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid Arthritis, fetal hydrocephalus.
- groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
- substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
- a number from 1 to 10 should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
- salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
- stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
- Stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994 to define.
- the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
- the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
- Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
- Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid.
- Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereomerically pure form (e.g., S and R forms or in diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
- Resolution of racemic mixtures can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
- any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
- tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
- the compounds of the present invention may exhibit tautomerism.
- Tautomeric compounds can exist in two or more interconvertible species.
- Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
- Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
- the keto form predominates
- the enol form predominates.
- the present invention encompasses all tautomeric forms of the compounds.
- composition means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients.
- the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
- the term "effective dose”, “effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
- the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
- the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
- active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
- solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
- prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
- the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
- Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- excipient refers to a pharmaceutically acceptable inert ingredient.
- examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
- C 1-6 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
- the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-d
- C 3-8 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- 3-6 membered heterocyclyl is understood to mean a saturated, unsaturated or partially saturated monocyclic or bicyclic ring having 3 to 6 atoms, wherein 1, 2, or 3 ring atoms are selected from N, O and S.
- 4-8 membered heterocyclyl is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 rings The atoms are selected from N, O and S.
- the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form N-oxide or S-oxide or ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted by acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted by One or more halogen substitutions. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other.
- heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is monocyclic, it must not be aromatic.
- heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.
- 5-8 membered heteroaryl is understood as having 5-8 ring atoms - especially 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S
- a monovalent monocyclic, bicyclic or tricyclic aromatic ring group Preferably 1 to 3 - monovalent monocyclic, bicyclic or tricyclic aromatic ring radicals of heteroatoms independently selected from N, O and S, and, additionally, in each case may be benzofused .
- heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridyl, pteridine carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
- bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.
- Non-limiting examples include:
- C 4-8 bridged cycloalkyl refers to a bridged ring with 4-8 carbon atoms, and the definition of the bridged ring is as described above.
- halo or halogen refers to fluoro, chloro, bromo and iodo.
- haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
- the compound represented by formula (I) of the present invention has a good antagonistic effect on LPAR1.
- the compound of the present invention has a good antagonistic effect on LPAR1 and a weak antagonistic effect on LPAR3, that is, the compound of the present invention shows excellent selectivity; the compound of the present invention has better safety and no cholestatic toxicity Risk; the compound of the present invention has excellent pharmacokinetic properties and good druggability; the compound of the present invention can significantly inhibit the release of histamine induced by LPA by antagonizing LPAR1, and at the same time significantly improve the symptoms of pulmonary fibrosis induced by bleomycin in mice and rats .
- the embodiment of the present invention provides the compound shown in formula (I), its pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, co-crystal or prodrug, preparation formula (I) ) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs and intermediates, pharmaceutical compositions, and compounds of the present invention and the use of the pharmaceutical composition in the preparation of medicaments.
- reaction solvent used in each reaction step of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention.
- many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are considered to be within the scope of the present invention.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- Liquid-mass spectrometry was determined by Waters Acquity H-class Uplc-QDA mass spectrometer and monitored by ACQUITY UPLC BEH C18, 2.1*50mm, 1.7 ⁇ m chromatographic column. Gradient elution conditions: at a flow rate of 1.0mL/min, 95-5% solvent A1 and 5-95% solvent B1, then 95% B1 and 5% A1 for 0.5min, the percentage is the volume percentage of a certain solvent in the total solvent volume . Wherein solvent A1: 0.1% formic acid in water; solvent B1: 0.1% formic acid in acetonitrile. The percentage is the volume percentage of the solute in the solution.
- IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
- n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
- DIPEA It can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
- PE petroleum ether
- Comparative Example 1 Comparative Compound 1 and its preparation
- Reference compound 1 was synthesized with reference to patent application WO2017223016A1.
- Comparative Example 2 Comparative Compound 2 and its preparation
- Reference compound 2 was synthesized with reference to patent application WO2017223016A1.
- Embodiment 1 the preparation of target compound I-1
- the synthetic route of target compound 1-1 is as follows:
- the first step the synthesis of (R)-4-nitrophenyl (1-phenylethyl) carbonate (I-1B)
- 2-bromo-6-iodopyridin-3-ol (5g, 16.67mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (2.34g, 16.67mmol), cuprous iodide (317.53mg, 1.67mmol), triethylamine (5.06g, 50.02mmol) and bis(triphenylphosphine)palladium dichloride (1.17g, 1.67mmol) were added to tetrahydrofuran (50mL ), react at room temperature for 1 hour under the protection of nitrogen.
- the seventh step (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-methyl carboxylate (I-1I) synthesis
- Step 10 (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino) Synthesis of methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1L)
- Embodiment 2 the preparation of target compound 1-2
- the pH of the reaction solution was adjusted to 3-4 with 1M hydrochloric acid at 0-10°C, extracted with dichloromethane (15 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
- Embodiment 3 the preparation of target compound 1-3
- the first step the synthesis of (cyclobutylmethyl) tert-butyl carbamate (I-3B)
- the second step the synthesis of (cyclobutylmethyl) (methyl) tert-butyl carbamate (I-3C)
- the third step the synthesis of 1-cyclobutyl-N-methylmethylamine hydrochloride (I-3D)
- Embodiment 4 the preparation of target compound 1-4
- the first step the synthesis of (R)-(1-cyclopropylethyl) tert-butyl carbamate (I-4B)
- the second step the synthesis of (R)-(1-cyclopropylethyl) (methyl) tert-butyl carbamate (I-4C)
- the third step the synthesis of (R)-1-cyclopropyl-N-methylethane-1-amine hydrochloride (I-4D)
- Embodiment 5 the preparation of target compound 1-5
- the synthetic route of target compound 1-5 is as follows:
- Embodiment 6 the preparation of target compound 1-6
- the first step the synthesis of 4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (I-6B)
- the second step the synthesis of tert-butyl (4-fluorobutyl)(methyl)carbamate (I-6C)
- the third step the synthesis of 4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D)
- the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
- Embodiment 7 the preparation of target compound 1-7
- the synthetic route of target compound 1-7 is as follows:
- Embodiment 8 the preparation of target compound 1-8
- the synthetic route of target compound 1-8 is as follows:
- the first step the synthesis of (S)-(2-methylbutyl) tert-butyl carbamate (I-8B)
- the second step the synthesis of (S)-(2-methylbutyl) tert-butyl carbamate (I-8C)
- Embodiment 9 Preparation of target compound 1-9
- the first step the synthesis of (4-nitrophenyl) butyl carbonate (I-9B)
- Embodiment 10 Preparation of target compound I-10
- the synthetic route of target compound 1-10 is as follows:
- the first step the synthesis of 4-fluorobutyl carbonate (4-nitrophenyl) (I-10B)
- Embodiment 11 Preparation of target compound I-11
- Embodiment 12 Preparation of target compound 1-12
- the synthetic route of target compound 1-12 is as follows:
- Embodiment 13 Preparation of target compound 1-13
- the synthetic route of target compound 1-13 is as follows:
- the first step (1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)- 1-Methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-13B) synthesis
- Embodiment 14 Preparation of Target Compound I-14
- the synthetic route of target compound 1-14 is as follows:
- the first step the synthesis of (S)-4-nitrophenyl carbonate pent-2-yl ester (I-14B)
- Embodiment 15 Preparation of target compound I-15
- the synthetic route of target compound 1-15 is as follows:
- the first step 2-cyclobutyl-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-(((trimethylsilyl)methyl Synthesis of -1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15B)
- bromocyclobutane (1.00 g, 7.41 mmol) was added to a solution of elemental magnesium (360 mg, 14.8 mmol) in tetrahydrofuran (15.0 mL), and the reaction was stirred at 60°C for 3 hours.
- the seventh step (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15)
- Embodiment 16 Preparation of Target Compound I-16
- the synthetic route of target compound 1-16 is as follows:
- Embodiment 17 Preparation of Target Compound I-17
- the synthetic route of target compound 1-17 is as follows:
- Embodiment 18 Preparation of target compound I-18
- the synthetic route of target compound 1-18 is as follows:
- Embodiment 19 Preparation of Target Compound I-19
- the synthetic route of target compound 1-19 is as follows:
- Embodiment 20 Preparation of Target Compound I-20
- the synthetic route of target compound 1-20 is as follows:
- the first step 2-(oxyethane-3-yl)-6-(5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilane Base)methyl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-20A) synthesis
- the second step 6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl )-2-(oxyl-3-yl)pyridin-3-ol (I-20B) synthesis
- the seventh step (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)
- Embodiment 21 Preparation of target compound I-21
- the first step the synthesis of N-cyanocyclopropanamide (I-21B)
- the second step the synthesis of 5-cyclopropyl-1,2,4-oxadiazol-3-amine (I-21C)
- Embodiment 22 Preparation of Target Compound I-22
- the first step the synthesis of (E)-4-ethoxy-1,1-difluorobut-3-en-2-one (I-22B)
- Embodiment 23 Preparation of Target Compound I-23
- the target compound I-23 can be synthesized with reference to compound I-18, replacing 3,3,3-trifluoro-N-methylpropan-1-amine with N-isopropylmethylamine.
- Embodiment 24 Preparation of target compound I-24
- the synthetic route of target compound 1-24 is as follows:
- the first step Synthesis of 3-(1,3-dioxylideneisoindolin-2-yl)propionaldehyde (I-24B)
- the second step Synthesis of 2-(3,3-difluoropropyl)isoindoline-1,3-dione (I-24C)
- the third step the synthesis of tert-butyl (3,3-difluoropropyl) aminomethyl ester (I-24D)
- the fourth step the synthesis of tert-butyl (3,3-difluoropropyl) (methyl) aminomethyl ester (I-24E)
- the seventh step (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24)
- Embodiment 25 Preparation of Target Compound I-25
- the synthetic route of target compound 1-25 is as follows:
- Embodiment 26 Preparation of Target Compound I-26
- the first step the synthesis of N-vinyl-N-methylcarbamate tert-butyl ester (I-26B)
- the second step the synthesis of tert-butyl N-(2,2-difluorocyclopropyl)-N-methylcarbamate (I-26D)
- the third step the synthesis of 2,2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E)
- Embodiment 27 Preparation of Target Compound I-27
- the first step the synthesis of N-benzyl-3-fluoro-N-methylpropane-1-amine (compound I-27C)
- Embodiment 28 Preparation of target compound I-28
- the first step the synthesis of 1-(benzyl(methyl)amino)propan-2-ol (I-28B)
- the second step the synthesis of N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C)
- the third step the synthesis of 2-fluoro-N-methylpropane-1-amine hydrochloride (I-28D)
- Embodiment 29 Preparation of Target Compound I-29
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Abstract
A compound effectively antagonizing LPAR1. The compound is a compound represented by the following formula, or is a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug of the compound represented by the following formula.
Description
本发明属于药物化学领域,具体地,本发明涉及三氮唑类LPAR1拮抗剂,更具体地,本发明涉及三氮唑类LPR1拮抗剂及其在制备药物中的用途。The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to triazole LPAR1 antagonists. More specifically, the present invention relates to triazole LPR1 antagonists and their use in the preparation of medicines.
溶血磷脂酸(LPA)是一类分子量为430-480Da的关键内源性脂质信号分子,其广泛存在于人体各组织中的胞内和胞外,如各种体液,唾液、尿液、脑脊液、血液、支气管肺泡灌洗液(BALF)等(Kaffe E等人,Cancers(Basel).2019;11(11):1626.)。LPA主要是以膜磷脂为原料通过以下两条途径产生的:(1)磷脂酶D(PLD)-磷脂酶A2(PLA2)途径;(2)PLA2-溶血磷脂酶D(LysoPLD)途径。Enpp2基因编码的自体趋化蛋白(ATX)是一种焦磷酸酶/磷酸二酯酶,其具有溶血磷脂酶D(LysoPLD)活性,能将胞外溶血磷脂酰胆碱(LPC)水解成相应的LPA和游离胆碱(Choi JW等人,AnnuRevPharmacolToxicol.2010;50:157186.),这一反应是LPA的主要来源,抑制ATX活性能抑制全身80%以上LPA的产生(Kaffe E等人,Cancers(Basel).2019;11(11):1626.)。Lysophosphatidic acid (LPA) is a key endogenous lipid signaling molecule with a molecular weight of 430-480Da, which widely exists in the intracellular and extracellular tissues of the human body, such as various body fluids, saliva, urine, and cerebrospinal fluid , blood, bronchoalveolar lavage fluid (BALF), etc. (Kaffe E et al., Cancers (Basel). 2019; 11(11): 1626.). LPA is mainly produced from membrane phospholipids through the following two pathways: (1) phospholipase D (PLD)-phospholipase A2 (PLA2) pathway; (2) PLA2-lysophospholipase D (LysoPLD) pathway. The autologous chemoattractant protein (ATX) encoded by the Enpp2 gene is a pyrophosphatase/phosphodiesterase with lysophospholipase D (LysoPLD) activity, which can hydrolyze extracellular lysophosphatidylcholine (LPC) into the corresponding LPA and free choline (Choi JW et al., AnnuRevPharmacolToxicol.2010; 50:157186.), this reaction is the main source of LPA, inhibiting ATX activity can inhibit the production of more than 80% of LPA in the whole body (Kaffe E et al., Cancers ( Basel). 2019;11(11):1626.).
LPA通过与G蛋白偶联受体作用介导多种功能,包括细胞存活、细胞增殖、细胞粘附、细胞迁移、细胞骨架改变、钙动员、增加血管通透性和血管形成、免疫功能和髓鞘形成等。LPA可与六种溶血磷脂酸受体(LPAR)结合并发挥功能,分别为:LPAR1-LPAR6。LPA通过与6种LPAR结合调节多种生理/病理过程,包括血管和神经发育、毛囊发育、淋巴细胞转运、骨发育、纤维化、脂肪量调节、胆汁淤积性瘙痒、神经性疼痛、胚胎植入、肥胖和葡萄糖稳态、精子产生、慢性炎症、细胞增殖、细胞趋化、伤口愈合、肿瘤进展、胎儿脑积水等(Fang Yang等人,World journal of gastroenterology,2018,24(36):4132.)。LPA mediates multiple functions by interacting with G protein-coupled receptors, including cell survival, cell proliferation, cell adhesion, cell migration, cytoskeletal changes, calcium mobilization, increased vascular permeability and angiogenesis, immune function and myeloid sheath formation etc. LPA can bind to and function with six lysophosphatidic acid receptors (LPAR), namely: LPAR1-LPAR6. LPA regulates various physiological/pathological processes including vascular and neural development, hair follicle development, lymphocyte trafficking, bone development, fibrosis, fat mass regulation, cholestatic pruritus, neuropathic pain, embryo implantation by binding to 6 LPARs , obesity and glucose homeostasis, sperm production, chronic inflammation, cell proliferation, cell chemotaxis, wound healing, tumor progression, fetal hydrocephalus, etc. (Fang Yang et al., World journal of gastroenterology, 2018,24(36):4132 .).
LPAR1是最早被鉴定和分布最广的LPA受体,其是一个41kDa的膜蛋白,由364个氨基酸组成,在人体各组织器官中广泛表达,其中脑、心、结肠、小肠和胎盘的mRNA水平较高,而在其他器官和组织中的mRNA水平相对较低。LPAR1通过与GαI/o、GαQ/11和Gα12/13偶联,激活Akt、Rho、丝裂原活化蛋白激酶和磷脂酶C等下游通路,虽然已证明LPA-LPAR1信号在神经系统的发育阶段有重要作用,但成年个体的全身抑制未发现明显毒性。但LPAR3信号被抑制会产生显著的生殖毒性,因此化合物需避免对LPAR3信号的抑制。LPAR1 is the earliest identified and most widely distributed LPA receptor. It is a 41kDa membrane protein consisting of 364 amino acids and widely expressed in various tissues and organs of the human body. The mRNA levels of the brain, heart, colon, small intestine and placenta Higher, while mRNA levels in other organs and tissues were relatively low. LPAR1 activates downstream pathways such as Akt, Rho, mitogen-activated protein kinase, and phospholipase C by coupling with GαI/o, GαQ/11, and Gα12/13, although it has been demonstrated that LPA-LPAR1 signaling has a role in the developmental stages of the nervous system. important role, but no significant toxicity was found in adult individuals with systemic inhibition. However, inhibition of LPAR3 signaling can produce significant reproductive toxicity, so compounds need to avoid inhibition of LPAR3 signaling.
与LPAR1具有显著相关性的疾病主要是纤维化疾病、肿瘤、神经性疼痛、RA(类风湿性关节炎)、某些中枢性疾病等。The diseases that have a significant correlation with LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central nervous system diseases and the like.
特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是一种病因不明,以弥漫性肺泡炎和肺泡结构紊乱为特征的慢性、进行性、纤维化性间质性肺炎,在影像学和病理组织学中主要表现为普通型间质性肺炎。IPF起源于肺泡组织的组织的反复损伤,而这种损伤会引发一系列生理病理事件,包括(I)破坏内稳态;(II)引起炎症反应;(III)细胞增殖、迁移和分化;(IV)基质和组织重建;以及(V)伤口挛缩和瘢痕形成,这些事件中的许多是由损伤部位及其周围的生化因子的协调释放控制的,而LPA在其中起重要作用。病理升高的LPA浓度可能会继续激活肺细胞上的LPAR1受体,从而增强组织炎症并刺激过度的细胞外基质(ECM)产生。LPA是受损肺组织BALF中的成纤维细胞迁移的主要介质之一(Tager A M等人,Proceedings of the American Thoracic Society,2008.),IPF患者的BALF(肺泡灌洗液)LPA水平高于正常对照组,抑制LPA信号显著降低成纤维细胞对IPF BALF的趋化反应。Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology characterized by diffuse alveolitis and alveolar structural disorder. The clinical manifestation is common interstitial pneumonia. IPF originates from the repeated injury of alveolar tissue, and this injury will trigger a series of physiological and pathological events, including (I) disrupting homeostasis; (II) causing inflammatory response; (III) cell proliferation, migration and differentiation; ( IV) Matrix and tissue remodeling; and (V) wound contracture and scarring, many of these events are controlled by the coordinated release of biochemical factors in and around the injury site, in which LPA plays an important role. Pathologically elevated LPA concentrations may go on to activate LPAR1 receptors on lung cells, thereby enhancing tissue inflammation and stimulating excessive extracellular matrix (ECM) production. LPA is one of the main mediators of fibroblast migration in the BALF of damaged lung tissue (Tager A M et al., Proceedings of the American Thoracic Society, 2008.), the BALF (alveolar lavage fluid) LPA level of IPF patients is higher than In the normal control group, inhibition of LPA signaling significantly reduced the chemotactic response of fibroblasts to IPF BALF.
在临床前研究中,用博莱霉素处理LPAR1基因缺陷小鼠,结果发现LPAR1基因敲除对小鼠具有明显的保护作用,而且在LPAR1缺陷的小鼠中,博莱霉素处理后的成纤维细胞聚集明显减少。LPA诱导内皮细胞屏障功能障碍和血管渗漏,在组织损伤修复的早期阶段,血管通透性增加,能加快组织修复,但在IPF进程中,LPA-LPAR1介导的血管通透性增加促进纤维化发展。在另一项博来霉素诱导的IPF临床前模型中,博来霉素处理导致肺损伤后支气管 肺泡灌洗液中LPA水平显著升高,并引起肺纤维化、血管渗漏和死亡,这些病理改变在LPAR1
-/-小鼠中明显减轻;LPAR1拮抗剂AM966降低了博来霉素模型中肺泡灌洗液中总蛋白质含量和LDH活性,表明AM966减少了LPA介导的IPF和其他间质性肺疾病中血管渗漏和上皮细胞死亡。这些内容表明LPAR1是治疗IPF有前途的靶点,在一项随机、双盲、安慰剂对照的临床试验中,LPAR1拮抗剂BMS-986020的使用显著减缓了特发性肺纤维化患者肺活量的下降,并减轻了临床症状,其二代化合物BMS-986278正在开展治疗IPF的II期临床试验(Swaney JS等人,Br J Pharmacol.2010;160(7):1699-1713.)。
In preclinical studies, LPAR1 gene-deficient mice were treated with bleomycin, and it was found that LPAR1 gene knockout had a significant protective effect on mice, and in LPAR1-deficient mice, the adult mice treated with bleomycin Fibroblast aggregation was significantly reduced. LPA induces endothelial cell barrier dysfunction and vascular leakage, and increases vascular permeability in the early stages of tissue injury repair, which can accelerate tissue repair, but in the process of IPF, LPA-LPAR1-mediated increased vascular permeability promotes fibroblasts development. In another bleomycin-induced preclinical model of IPF, bleomycin treatment resulted in a significant increase in LPA levels in bronchoalveolar lavage fluid after lung injury and caused pulmonary fibrosis, vascular leakage, and death, which Pathological changes were significantly attenuated in LPAR1 -/- mice; the LPAR1 antagonist AM966 reduced total protein content and LDH activity in alveolar lavage fluid in the bleomycin model, suggesting that AM966 reduces LPA-mediated IPF and other interstitial Vascular leakage and epithelial cell death in acute lung disease. These contents suggest that LPAR1 is a promising target for the treatment of IPF, and in a randomized, double-blind, placebo-controlled clinical trial, administration of the LPAR1 antagonist BMS-986020 significantly slowed the decline in lung capacity in patients with idiopathic pulmonary fibrosis , and relieved clinical symptoms, and its second-generation compound BMS-986278 is conducting phase II clinical trials for the treatment of IPF (Swaney JS et al., Br J Pharmacol.2010; 160(7):1699-1713.).
放射性肺纤维化是肺癌放射治疗常见而严重的并发症。LPAR1/LPAR3拮抗剂VPC12249可在体内抑制促成纤维细胞因子转化生长因子β1和结缔组织生长因子的表达,导致小鼠成纤维细胞增殖减少,减慢放射性肺纤维化进展,这说明LPAR1拮抗剂也有治疗放射性肺纤维化的潜力(Xiang H等人,J Cancer.2020;11(12):3519-3535.)。Radiation pulmonary fibrosis is a common and serious complication of lung cancer radiotherapy. The LPAR1/LPAR3 antagonist VPC12249 inhibited the expression of the pro-fibroblast cytokines transforming growth factor β1 and connective tissue growth factor in vivo, resulting in decreased proliferation of fibroblasts in mice and slower progression of radiation-induced lung fibrosis, suggesting that LPAR1 antagonists are also therapeutically Potential for radiation-induced pulmonary fibrosis (Xiang H et al., J Cancer. 2020; 11(12):3519-3535.).
LPAR1与肝纤维化的发生有密切关联。研究证明ATX-LPA信号轴激活PI3K并稳定缺氧诱导因子HIF-1的mRNA,从而促进丙型肝炎病毒的复制,抑制ATX-LPA信号则减少了丙型肝炎病毒的复制,这一过程可能与LPAR1和LPAR3有关,而肝炎是肝纤维化发生的关键因素,这表明拮抗LPAR1可能具有治疗肝纤维化的潜力(Farquhar MJ等人,J Hepatol.2017;66(5):919-929.);在另一项研究中,下调LPAR1信号,降低了α-SMA、CTGF和TGF-β1表达,从而显著改善硫代乙酰胺诱导的肝纤维化,这更证明了LPAR1拮抗剂可以用于治疗肝纤维化。LPAR1 is closely related to the occurrence of liver fibrosis. Studies have shown that the ATX-LPA signaling axis activates PI3K and stabilizes the mRNA of hypoxia-inducible factor HIF-1, thereby promoting the replication of hepatitis C virus, and inhibiting ATX-LPA signaling reduces the replication of hepatitis C virus. This process may be related to LPAR1 and LPAR3 are related, and hepatitis is a key factor in the occurrence of liver fibrosis, which suggests that antagonizing LPAR1 may have the potential to treat liver fibrosis (Farquhar MJ et al., J Hepatol.2017; 66(5):919-929.); In another study, down-regulation of LPAR1 signaling decreased the expression of α-SMA, CTGF and TGF-β1, thereby significantly improving thioacetamide-induced liver fibrosis, which further proves that LPAR1 antagonists can be used to treat liver fibrosis change.
LPA通过LPAR1促进肾纤维化的进展。在单侧输尿管梗阻(UUO)诱导的肾间质纤维化(TIF)小鼠中,ATX和LPA浓度升高,LPAR1显著上调,而LPAR3显著下调(Sakai N等人,FASEB J.2013;27(5):1830-1846.)。ATX-LPA-LPAR1信号可刺激成纤维细胞迁移和增殖,在LPAR1
-/-小鼠上或使用LPAR1/3拮抗剂Ki16425预处理后,UUO诱导的肾脏纤维化显著减轻,且当LPAR1信号被阻断时,促纤维化细胞因子的表达(结缔组织生长因子和转化生长因子-β)也显著下调。这表明LPAR1拮抗剂可能可以用于肾纤维化的治疗。
LPA promotes the progression of renal fibrosis through LPAR1. In unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis (TIF) mice, ATX and LPA concentrations were elevated, LPAR1 was significantly upregulated, and LPAR3 was significantly downregulated (Sakai N et al., FASEB J. 2013; 27( 5): 1830-1846.). ATX-LPA-LPAR1 signaling can stimulate fibroblast migration and proliferation, UUO-induced renal fibrosis was significantly attenuated in LPAR1 -/- mice or after pretreatment with the LPAR1/3 antagonist Ki16425, and when LPAR1 signaling was blocked The expression of pro-fibrotic cytokines (connective tissue growth factor and transforming growth factor-β) was also significantly downregulated when it was disconnected. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.
胎儿脑积水(FH)是新生儿常见的神经系统疾病,其发生与LPAR1信号密切相关。在临床前的小鼠颅内出血模型中,通过将小鼠胚胎脑暴露在血液或LPA中,神经前体细胞(NPC)表达的LPAR1被过度激活,导致皮层破坏和变薄,最终导致FH。(Yung YC等人,Sci Transl Med.2011;3(99):99ra87.)。在小鼠相关模型使用Ki16425(LPAR1/3拮抗剂)预处理,可降低出血性脑积水(PHH)产生的概率和严重程度,提示LPAR1拮抗剂可能用于治疗胎儿脑积水。Fetal hydrocephalus (FH) is a common neurological disease in newborns, and its occurrence is closely related to LPAR1 signaling. In a preclinical mouse model of intracranial hemorrhage, by exposing mouse embryonic brains to blood or LPA, neural progenitor cell (NPC)-expressed LPAR1 is overactivated, leading to cortical destruction and thinning, ultimately leading to FH. (Yung YC et al., Sci Transl Med. 2011; 3(99):99ra87.). Pretreatment with Ki16425 (LPAR1/3 antagonist) in mouse related models can reduce the probability and severity of hemorrhagic hydrocephalus (PHH), suggesting that LPAR1 antagonists may be used to treat fetal hydrocephalus.
LPA-LPAR1信号具有显著的促肿瘤作用。LPA在体外促进肿瘤细胞存活、增殖、增加迁移和组织侵袭、激活血管内皮生长因子和激活金属基质蛋白酶,促进肿瘤细胞对顺铂耐药。LPAR1信号下调肝癌细胞中肿瘤抑制因子p53的表达;LPA通过LPAR1激活PI3K和P38MPAK信号通路,促进MMP-9的表达和HCC的侵袭;LPA-LPAR1也能通过GTPase RhoA和Rho相关蛋白激酶(ROCK)促进侵袭性;它还诱导蛋白激酶C(PKC)和核因子κB(NF-kB)促进上皮向间充质转化(EMT);另外,LPA-LPAR1对血管生成的积极作用也能促进癌症的发展,因为新生血管对于实体肿瘤的发展是必不可少的。这些研究结果表明LPAR1拮抗剂在相关肿瘤的治疗方面具有巨大潜力(Xiang H等人,J Cancer.2020;11(12):3519-3535.)。LPA-LPAR1 signaling has a prominent tumor-promoting effect. LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion, activates vascular endothelial growth factor and metal matrix protease in vitro, and promotes tumor cell resistance to cisplatin. LPAR1 signaling down-regulates the expression of tumor suppressor p53 in liver cancer cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1, and promotes the expression of MMP-9 and the invasion of HCC; LPA-LPAR1 can also pass GTPase RhoA and Rho-related protein kinase (ROCK) Promotes invasiveness; it also induces protein kinase C (PKC) and nuclear factor kappa B (NF-kB) to promote epithelial to mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis can also promote cancer development , because neovascularization is essential for the development of solid tumors. These findings suggest that LPAR1 antagonists have great potential in the treatment of related tumors (Xiang H et al., J Cancer. 2020; 11(12):3519-3535.).
人类周围神经损伤可导致一种称为神经病理性疼痛的疼痛状态,症状包括持续的烧灼性疼痛和异常感觉,如超敏和痛觉过敏,LPAR1信号与神经性疼痛的发生有关。神经系统受损导致损伤部位血清渗漏,使神经细胞大量暴露在LPA中可能是神经病理性疼痛的病因之一。Makoto Inoue等的研究表明神经损伤引起的行为异常和痛敏动物模型可通过LPAR1的拮抗剂预处理或靶向删除LPAR1来消除痛敏症状,并可通过鞘内注射LPA来模拟。另一项研究表明LPA可通过激活LPAR1,释放伤害性因子P物质而引起神经病理性疼痛,且LPAR1
-/-小鼠对部分坐骨神经结扎引起的神经病理性疼痛具有抵抗力。这些结果表明,LPA-LPAR1信号在神经病理性疼痛的启动中起关键作用,LPAR1拮抗剂可能有希望作为止痛剂用于神经病理性疼痛的治疗(Inoue M等人,ERRATUM:Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J].2004,10(7):755-755.)。
Injury to peripheral nerves in humans can lead to a pain state called neuropathic pain. Symptoms include persistent burning pain and abnormal sensations such as hypersensitivity and hyperalgesia. LPAR1 signaling has been implicated in the development of neuropathic pain. Damage to the nervous system leads to serum leakage at the injury site, exposing a large number of nerve cells to LPA, which may be one of the etiologies of neuropathic pain. Studies by Makoto Inoue et al. have shown that animal models of behavioral abnormalities and pain sensitivity caused by nerve injury can be eliminated by pretreatment of LPAR1 antagonists or targeted deletion of LPAR1, and can be simulated by intrathecal injection of LPA. Another study showed that LPA can induce neuropathic pain by activating LPAR1 and releasing nociceptive factor P, and LPAR1 -/- mice are resistant to neuropathic pain caused by partial sciatic nerve ligation. These results suggest that LPA-LPAR1 signaling plays a key role in the initiation of neuropathic pain and that LPAR1 antagonists may hold promise as analgesics for the treatment of neuropathic pain (Inoue M et al., ERRATUM: Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling[J].2004,10(7):755-755.).
类风湿性关节炎(RA)是一种慢性自身免疫性的疾病,LPAR1信号与RA的发生有关。与骨关节炎患者相比,类风湿性关节炎患者滑膜中LPAR1和/或LPAR2表达水平升高,临床前研究表明LPAR1的基因敲除完全消除了RA症状,LPAR1的药理拮抗降低了疾病的严重程度,减轻了炎症和骨质侵蚀(Kaffe E等人,Cancers(Basel).2019;11(11):1626.Published 2019 Oct 23.doi:10.3390/cancers11111626)。拮抗LPAR1信号还减少RA患者FLS(滑膜成纤维细胞)的增殖,并使其对肿瘤坏死因子(TNF)介导的凋亡敏感,另外LPA还参与了RA FLS中白细胞介素(IL)-6、IL-8和环氧合酶-2(COX-2)的产生。这些结果显示LPAR1是治疗类风湿性关节炎的一个很有前途的靶点(Orosa B等人,Annals of the Rheumatic Diseases,2014,73(1):298-305.)。Rheumatoid arthritis (RA) is a chronic autoimmune disease, and LPAR1 signaling is related to the occurrence of RA. Compared with patients with osteoarthritis, the expression levels of LPAR1 and/or LPAR2 in the synovium of patients with rheumatoid arthritis are increased. Preclinical studies have shown that gene knockout of LPAR1 completely eliminates RA symptoms, and pharmacological antagonism of LPAR1 reduces the severity of the disease. Severity, reduced inflammation and bone erosion (Kaffe E et al., Cancers (Basel). 2019; 11(11): 1626. Published 2019 Oct 23. doi: 10.3390/cancers11111626). Antagonizing LPAR1 signaling also reduces the proliferation of FLS (synovial fibroblasts) in RA patients and sensitizes them to tumor necrosis factor (TNF)-mediated apoptosis, and LPA is also involved in interleukin (IL)- 6. Production of IL-8 and cyclooxygenase-2 (COX-2). These results show that LPAR1 is a promising target for the treatment of rheumatoid arthritis (Orosa B et al., Annals of the Rheumatic Diseases, 2014, 73(1):298-305.).
发明内容Contents of the invention
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选择。The present invention aims at solving one of the above technical problems at least to a certain extent or at least providing a useful commercial choice.
在本发明的第一方面,本发明提供了一种如式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:In the first aspect of the present invention, the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
其中,R
1选自无取代或被R
1a取代的C
3-6环烷基、无取代或被R
1a取代的3-6元杂环基;
Wherein, R 1 is selected from unsubstituted or substituted by R 1a C 3-6 cycloalkyl, unsubstituted or substituted by R 1a 3-6 membered heterocyclic group;
所述R
1a选自-CN、卤素;
The R 1a is selected from -CN, halogen;
X
1和X
2各自独立地选自C(R
1b)和N,且X
1和X
2不同时为N,所述R
1b选自-H、-CN、卤素、-OH、任选取代的C
1-6烷基;
X 1 and X 2 are each independently selected from C(R 1b ) and N, and X 1 and X 2 are not N at the same time, said R 1b is selected from -H, -CN, halogen, -OH, optionally substituted C 1-6 alkyl;
R
2选自-H、-CN、卤素、无取代或被R
2a取代的C
1-6烷基;所述R
2a选自-CN、卤素;
R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
L
1不存在,或选自-N(R
4)-、-O-、-N(R
4)-CO-O-和-O-CO-N(R
4)-;
L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;
R
4选自-H、C
1-3烷基、被卤素取代的C
1-3烷基;
R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基;
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
R
5选自-H、-F、甲基。
R 5 is selected from -H, -F, methyl.
在本发明的另一方面,本发明提供了一种如式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:In another aspect of the present invention, the present invention provides a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
R
1选自-H、无取代或被R
1a取代的C
3-6环烷基、无取代或被R
1a取代的C
3-6杂环烷基;所述R
1a选自-CN,卤素;
R 1 is selected from -H, unsubstituted or substituted by R 1a C 3-6 cycloalkyl, unsubstituted or substituted by R 1a C 3-6 heterocycloalkyl; said R 1a is selected from -CN, halogen ;
X
1和X
2各自独立地选自C(R
1)和N,且X
1和X
2不同时为N;
X 1 and X 2 are each independently selected from C(R 1 ) and N, and X 1 and X 2 are not N at the same time;
R
2选自-H、-CN、卤素、无取代或被R
2a取代的C
1-6烷基;所述R
2a选自-CN、卤素;
R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、卤素取代的
R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 yuan heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen substituted
C
1-6烷基;
C 1-6 alkyl;
L
1不存在,或选自-N(R
4)-和-N(R
4)-CO-O-;
L 1 is absent, or selected from -N(R 4 )- and -N(R 4 )-CO-O-;
R
4选自-H、C
1-3烷基、被卤素取代的C
1-3烷基;
R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基;
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
R
5选自-F、甲基;
R is selected from -F, methyl;
所述卤素选自氟、氯、溴、碘,较佳地,卤素选自氟、氯、溴;The halogen is selected from fluorine, chlorine, bromine, and iodine, preferably, the halogen is selected from fluorine, chlorine, and bromine;
所述烷基包括直链烷基、支链烷基。The alkyl group includes linear alkyl group and branched chain alkyl group.
本领域技术人员可以理解,根据本领域中使用的惯例,在本申请的结构式中,
用于描绘化学键,所述化学键为部分或取代基与核心结构或骨架结构相连的点。
Those skilled in the art can understand that, according to the convention used in this field, in the structural formula of the present application, Used to depict a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure.
根据本发明的某些实施例,式(I)所示化合物中,
选自
According to some embodiments of the present invention, among the compounds represented by formula (I), selected from
根据本发明的某些实施例,式(I)所示化合物中,当R
1为无取代或被R
1a取代的C
3-6环烷基时,所述R
1a的个数为一个或多个,当存在多个R
1a时,所述R
1a相同或不同。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the number of R 1a is one or more When there are multiple R 1a , the R 1a is the same or different.
根据本发明的某些实施例,式(I)所示化合物中,当R
1为无取代或被R
1a取代的C
3-6环烷基时,所述R
1a选自-CN,氟、氯、溴、碘。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the R 1a is selected from -CN, fluorine, Chlorine, Bromine, Iodine.
根据本发明的某些实施例,式(I)所示化合物中,当R
1为无取代或被R
1a取代的C
3-6环烷基时,所述C
3-6环烷基选自环丙基、环丁基、环戊基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the C 3-6 cycloalkyl group is selected from Cyclopropyl, cyclobutyl, cyclopentyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
1为无取代或被R
1a取代的C
3-6杂环烷基时,所述C
3-6杂环烷基中的杂原子个数为1-2个。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 1 is a C 3-6 heterocycloalkyl group unsubstituted or substituted by R 1a , the C 3-6 heterocycloalkyl group The number of heteroatoms in is 1-2.
根据本发明的某些实施例,式(I)所示化合物中,当R
1为无取代或被R
c取代的C
3-6杂环烷基时,所述C
3-6杂环烷基中的杂原子选自O、N、S。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 1 is C 3-6 heterocycloalkyl unsubstituted or substituted by R c , the C 3-6 heterocycloalkyl The heteroatoms in are selected from O, N, S.
根据本发明的某些实施例,式(I)所示化合物中,R
1为无取代或被R
1a取代的环丙基,所述R
1a选自-CN,氟、氯。
According to some embodiments of the present invention, in the compound represented by formula (I), R 1 is cyclopropyl unsubstituted or substituted by R 1a , and R 1a is selected from -CN, fluorine, chlorine.
根据本发明的某些实施例,式(I)所示化合物中,R
1为环丙基。
According to some embodiments of the present invention, in the compound represented by formula (I), R 1 is cyclopropyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
2为无取代或被R
2a取代的C
1-6烷基时,所述R
2a的个数为一个或多个,当存在多个R
2a时,所述R
2a相同或不同。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more , when there are multiple R 2a , the R 2a are the same or different.
根据本发明的某些实施例,式(I)所示化合物中,当R
2为无取代或被R
2a取代的C
1-6烷基时,所述R
2a的个数为一个或多个,当存在多个R
2a时,所述R
2a选自-CN、氟、氯。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more , when there are multiple R 2a , said R 2a is selected from -CN, fluorine, chlorine.
根据本发明的某些实施例,式(I)所示化合物中,当R
2为无取代或被R
2a取代的C
1-6烷基时,所述C
1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、 己基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 2 is a C 1-6 alkyl group unsubstituted or substituted by R 2a , the C 1-6 alkyl group is selected from methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
根据本发明的某些实施例,式(I)所示化合物中,R
2为无取代或被R
2a取代的甲基,所述R
2a选自-CN、氟、氯。
According to some embodiments of the present invention, in the compound represented by formula (I), R 2 is methyl that is unsubstituted or substituted by R 2a , and the R 2a is selected from -CN, fluorine, and chlorine.
根据本发明的某些实施例,式(I)所示化合物中,R
2为甲基。
According to some embodiments of the present invention, in the compound represented by formula (I), R 2 is methyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4~8元杂环基、苯基、C
3-8桥环烷基、5~8元杂芳基时,所述R
3a的个数为一个或多个,当存在多个R
3a时,所述R
3a相同或不同。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4 When ~8-membered heterocyclic group, phenyl, C 3-8 bridged cycloalkyl, 5-8-membered heteroaryl group, the number of R 3a is one or more, when there are multiple R 3a , all The above R 3a are the same or different.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4~8元杂环基、5~8元芳基、5~8元杂芳基时,所述R
3a的个数为一个或多个,当存在多个R
3a时,所述R
3a相同或不同。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4 ~8-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group, the number of R 3a is one or more, when there are multiple R 3a , the R 3a is the same or different.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4~8元杂环基、苯基、C
3-8桥环烷基、5~8元杂芳基时,所述R
3a选自氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、正戊基、二氟甲基、三氟甲基、环丙基、环丁基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4 When ~8-membered heterocyclyl, phenyl, C3-8 bridged cycloalkyl, 5-8-membered heteroaryl, the R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, Isopropyl, n-butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4~8元杂环基、5~8元芳基、5~8元杂芳基时,所述R
3a选自氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、正戊基、二氟甲基、三氟甲基、环丙基、环丁基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is the following group which is unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4 When ~8-membered heterocyclic group, 5-8-membered aryl group, and 5-8-membered heteroaryl group, the R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n- Butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的C
1-6烷基时,所述C
1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is C 1-6 alkyl unsubstituted or substituted by R 3a , the C 1-6 alkyl is methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的C
3-8环烷基时,所述的C
3-8环烷基为环丙基、环丁基、环戊基、环己基、环庚基、环辛基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is a C 3-8 cycloalkyl group that is unsubstituted or substituted by R 3a , the C 3-8 cycloalkyl group is Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的C
3-8桥环烷基时,所述的C
3-8桥环烷基为
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is a C 3-8 bridged cycloalkyl group unsubstituted or substituted by R 3a , the C 3-8 bridged cycloalkane Based on
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的4-8元杂环基时,所述杂原子选自N、O和S,所述杂原子数为1-2个。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is a 4-8 membered heterocyclic group unsubstituted or substituted by R 3a , the heteroatom is selected from N, O and S , the number of heteroatoms is 1-2.
根据本发明的某些实施例,式(I)所示化合物中,当R
3为无取代或被R
3a取代的5-8元杂芳基时,所述5~8元杂芳基选自噻吩、呋喃、噁唑、噻唑、三氮唑、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、吡唑基、咪唑基。
According to some embodiments of the present invention, in the compound represented by formula (I), when R 3 is a 5-8 membered heteroaryl group that is unsubstituted or substituted by R 3a , the 5-8 membered heteroaryl group is selected from Thiophene, furan, oxazole, thiazole, triazole, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl.
根据本发明的某些实施例,式(I)所示化合物中,R
3选自甲基、乙基、丙基、异丙基、环丙基、环丁基、
苯基、-CH
2F、-CHF
2、-CF
3、-CHF-CH
3、-CF
2-CH
3。
According to some embodiments of the present invention, in the compound shown in formula (I), R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Phenyl, -CH 2 F, -CHF 2 , -CF 3 , -CHF-CH 3 , -CF 2 -CH 3 .
根据本发明的某些实施例,式(I)所示化合物中,R
3选自甲基、乙基、丙基、异丙基、环丙基、环丁基、
苯基、-CH
2F、-CHF
2、-CF
3、-CHF-CH
3、-CF
2-CH
3。根据本发明的某些实施例,式(I)所示化合物中,当R
4为C
1-3烷基或被卤素取代的C
1-3烷基时,所述C
1-3烷基为甲基、乙基、正丙基、异丙基。
According to some embodiments of the present invention, in the compound shown in formula (I), R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Phenyl, -CH 2 F, -CHF 2 , -CF 3 , -CHF-CH 3 , -CF 2 -CH 3 . According to some embodiments of the present invention, in the compound represented by formula (I), when R 4 is a C 1-3 alkyl group or a C 1-3 alkyl group substituted by halogen, the C 1-3 alkyl group is Methyl, ethyl, n-propyl, isopropyl.
根据本发明的某些实施例,式(I)所示化合物中,L
2不存在,或选自
According to some embodiments of the present invention, in the compound shown in formula (I), L 2 does not exist, or is selected from
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-A)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-A):
其中:in:
R
2选自-H、-CN、卤素、无取代或被R
2a取代的C
1-6烷基;所述R
2a选自-CN、卤素;
R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
L
1不存在,或选自-N(R
4)-、-O-、-N(R
4)-CO-O-和-O-CO-N(R
4)-;
L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;
R
4选自-H、C
1-3烷基、被卤素取代的C
1-3烷基;
R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基;
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;
R
5选自-H、-F、甲基。
R 5 is selected from -H, -F, methyl.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-A)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-A):
其中:in:
R
2选自-H,-CN,卤素,无取代或被R
2a取代的C
1-6烷基;所述R
2a选自-CN,卤素;
R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;
R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4-8元杂环基、苯基;所述R
3a选自卤素、C
3-6环烷基;
R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl; The R 3a is selected from halogen, C 3-6 cycloalkyl;
L
1不存在,或选自-N(R
4)-或-N(R
4)-CO-O-;
L 1 is absent, or selected from -N(R 4 )- or -N(R 4 )-CO-O-;
R
4选自-H、C
1-3烷基、被卤素取代的C
1-3烷基;
R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基。
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
根据本发明的某些实施例,所述的式(I-A)所示化合物中,R
2选自甲基、乙基、正丙基、异丙基,较佳地,R
2选自甲基;
According to some embodiments of the present invention, in the compound represented by formula (IA), R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;
R
3选自-F、-Cl、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、苯基、 吡啶基、环丙基、环丁基、
R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, phenyl, pyridyl, cyclopropyl, cyclo butyl,
L
1不存在,或选自-NH-、-N(CH
3)-、-O-、-NH-CO-O-、-N(CH
3)-CO-O-、-O-CO-N(CH
3)-、-O-CO-NH-;
L 1 is absent, or selected from -NH-, -N(CH 3 )-, -O-, -NH-CO-O-, -N(CH 3 )-CO-O-, -O-CO-N (CH 3 )-, -O-CO-NH-;
根据本发明的某些实施例,所述的式(I-A)所示化合物中,R
2选自甲基、乙基、正丙基、异丙基,较佳地,R
2选自甲基;
According to some embodiments of the present invention, in the compound represented by formula (IA), R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;
R
3选自-F、-Cl、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、苯基、吡啶基、环丙基、环丁基、
R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, phenyl, pyridyl, cyclopropyl, cyclobutyl,
L
1不存在,或选自-NH-、-N(CH
3)-、-NH-CO-O-、-N(CH
3)-CO-O-;
L 1 does not exist, or is selected from -NH-, -N(CH 3 )-, -NH-CO-O-, -N(CH 3 )-CO-O-;
根据本发明的某些实施例,所述的式(I-A)所示化合物中,-L
1-L
2-R
3选自
未定义的基团如前任一方案所述。
According to some embodiments of the present invention, in the compound represented by formula (IA), -L 1 -L 2 -R 3 is selected from Undefined groups are as described in any previous scheme.
根据本发明的某些实施例,所述的式(I-A)所示化合物中,-L
1-L
2-R
3选自
未定义的基团如前任一方案所述。
According to some embodiments of the present invention, in the compound represented by formula (IA), -L 1 -L 2 -R 3 is selected from Undefined groups are as described in any previous scheme.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-B)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-B):
其中:in:
R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基。
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-B)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-B):
其中:in:
R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、4-8元杂环基、苯基、5-8元杂芳基;
R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl;
所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、卤素取代的C
1-6烷基;
The R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen substituted C 1-6 alkyl;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基。
L 2 is absent, or selected from C 1-3 alkylene unsubstituted or substituted by C 1-3 alkyl.
根据本发明的某些实施例,所述的式(I-B)所示化合物中,R
3选自-H、-CN、-F、-Cl、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、苯基、吡啶基,未定义的基团如前任一方案所述。
According to some embodiments of the present invention, in the compound represented by the formula (IB), R 3 is selected from -H, -CN, -F, -Cl, the following groups that are unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, phenyl, pyridyl, undefined groups are as described in any previous scheme.
根据本发明的某些实施例,所述的式(I-B)所示化合物中,R
3选自-H、-CN、-F、-Cl、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、苯基、吡啶基,未定义的基团如前任一方案所述。
According to some embodiments of the present invention, in the compound represented by the formula (IB), R 3 is selected from -H, -CN, -F, -Cl, the following groups that are unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, pyridyl, undefined groups are as described in any previous scheme.
根据本发明的某些实施例,所述的式(I-B)所示化合物中,-L
2-R
3选自正丙基、异丙基、正丁基、正戊基、氟代正丙基、氟代正丁基、
未定义的基团如前任一方案所述。
According to some embodiments of the present invention, in the compound represented by the formula (IB), -L 2 -R 3 is selected from n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl , fluoro-n-butyl, Undefined groups are as described in any previous scheme.
根据本发明的某些实施例,所述的式(I-B)所示化合物中,-L
2-R
3选自正丙基、异丙基、正丁基、正戊基、氟代正丙基、氟代正丁基、
未定义的基团如前任一方案所述。
According to some embodiments of the present invention, in the compound represented by the formula (IB), -L 2 -R 3 is selected from n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl , fluoro-n-butyl, Undefined groups are as described in any previous scheme.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-C)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-C):
其中,R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
Wherein, R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
R
4选自-H、C
1-3烷基、被卤素取代的C
1-3烷基;
R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基。
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-D)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-D):
其中,R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
Wherein, R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
R
4选自-H、C
1-3烷基、被卤素取代的C
1-3烷基;
R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基。
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-E)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-E):
其中,R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
Wherein, R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基。
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
根据本发明的某些实施例,所述的式(I)所示化合物为式(I-F)所示化合物:According to some embodiments of the present invention, the compound represented by the formula (I) is a compound represented by the formula (I-F):
其中,R
3选自-H、-CN、卤素、无取代或被R
3a取代的以下基团:C
1-6烷基、C
3-8环烷基、C
4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R
3a选自卤素、C
1-6烷基、C
3-6环烷基、4-8元杂环基、卤素取代的C
1-6烷基、卤素取代的C
3-6环烷基;
Wherein, R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-8 membered heteroaryl; the R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic group, Halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;
L
2不存在,或选自无取代或被C
1-3烷基取代的C
1-3亚烷基、苯基、5-8元杂芳基。
L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl.
根据本发明的某些实施例,所述的式(I)所示化合物可为如下任一化合物:According to some embodiments of the present invention, the compound represented by the formula (I) can be any of the following compounds:
在本发明的第二方面,本发明还提供了一种药物组合物,其包含上述的式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。In the second aspect of the present invention, the present invention also provides a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), or a stereoisomer, hydrate, or solvate of the compound represented by formula (I) , a pharmaceutically acceptable salt or prodrug.
在所述的药物组合物中,所述的式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的药物组合物可为治疗有效剂量。In the pharmaceutical composition, the compound represented by the formula (I), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the formula (I) The pharmaceutical composition may be in a therapeutically effective dose.
在本发明的第三方面,本发明还提供了一种上述的式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与LPAR 相关疾病的药物中的用途。In the third aspect of the present invention, the present invention also provides a compound represented by the above formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable compound of the compound represented by formula (I) Use of salt or prodrug in preparation of medicine for treating diseases related to LPAR.
在本发明第四方面,提供了一种治疗LPAR相关疾病的方法,包括步骤:给需要的对象施用有效量的本发明第一方面所述式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或者如第二方面所述药物组合物。In the fourth aspect of the present invention, there is provided a method for treating LPAR-related diseases, comprising the step of: administering an effective amount of the compound represented by the formula (I) described in the first aspect of the present invention, or the compound represented by the formula (I) to the subject in need Stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds shown, or pharmaceutical compositions as described in the second aspect.
所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
在本发明第五方面,提供了本发明第一方面所述式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或者如第二方面所述药物组合物,用于治疗与LPAR相关疾病。In the fifth aspect of the present invention, there is provided the compound represented by formula (I) described in the first aspect of the present invention, or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt of the compound represented by formula (I) Or a prodrug, or a pharmaceutical composition as described in the second aspect, for treating diseases related to LPAR.
本发明第一方面所述式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或者如第二方面所述药物组合物,用于治疗与LPAR相关疾病,所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The compound represented by formula (I) described in the first aspect of the present invention, or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), or as in the second aspect The pharmaceutical composition is used for treating LPAR-related diseases, and the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
本发明第一方面所述式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,或者如第二方面所述药物组合物,用于治疗与LPAR相关疾病,所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The compound represented by formula (I) described in the first aspect of the present invention, or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), or as in the second aspect The pharmaceutical composition is used for treating LPAR-related diseases, and the LPAR-related diseases are selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid Arthritis, fetal hydrocephalus.
术语定义和说明Definitions and Explanations of Terms
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。Unless otherwise stated, the definitions of groups and terms recorded in the specification and claims of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should fall within the scope of the description of the present application.
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there is more than one definition of a term herein, the definition in this chapter shall prevail.
除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,CH
2O等同于OCH
2。
Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/Vis spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be performed using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
本申请说明书和权利要求书记载的数值范围,当该数值范围被理解为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“1~6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如,“1~10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。For the numerical ranges described in the specification and claims of this application, when the numerical range is understood as an "integer", it should be understood as describing the two endpoints of the range and each integer within the range. For example, "an integer of 1 to 6" should be understood as describing every integer of 0, 1, 2, 3, 4, 5, and 6. When this numerical range is understood to be a "number," it should be understood to recite both endpoints of the range as well as each integer within the range and each decimal within the range. For example, "a number from 1 to 10" should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐,包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
除了药学可接受的盐外,本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体、非对应异构体和构象异构体。本发明使用的立体化学定义和惯例大体上按照S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994来定义。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers. Stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994 to define.
依据原料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在,例如作为纯旋光异构体,或作为异构体混合物,如作为外消旋和非对映异构体混合物,这取决于不对称碳原子的数量。当描述具有光学活性的化合物时,使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号,其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言,除了这些立体异构体互为镜像外,这些立体异构体是相同的。具体的立体异构体也可称为对映异构体,并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或方法中没有立体选择性或立体特异性时,可出现所述外消旋混合物或外消旋体。烯烃、C=N双键等的许多几何异构体也可以存在于本文所述的化合物中,且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时,除非另外说明,否则,这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基,环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of starting materials and processes, the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process Spin body. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When compounds described herein contain olefinic double bonds, unless otherwise stated, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.
当将本发明式中与手性碳的键描写直成线时,应当理解为,手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明,用楔形键和虚线键表示一个立体中心的绝对构型。When the bond with the chiral carbon in the formula of the present invention is described as a straight line, it should be understood that the (R) and (S) two configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of the general formula. Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, the absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds.
旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备,或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶,该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸,例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如,S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如,二硝基苯甲酰基苯基甘氨酸)的柱子上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的,还可以使用已知构型的光学纯的起始原料或试剂,通过立体有机合成,获得本发明所描述化合物的任何对映体或非对映体。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β- D and L forms of camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine in stereomerically pure form (e.g., S and R forms or in diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Selection of specific methods, elution conditions, and selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and test results. Furthermore, any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前 体药物与其它化学组分的混合物,其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
针对药物或药理学活性剂而言,术语“有效剂量”、“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。For a drug or a pharmacologically active agent, the term "effective dose", "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the disorder, disease or condition of interest.
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂,当溶剂为水时,则为水合物。The term "solvate" means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备,该修饰可以按常规的操作或者在体内被除去,而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物,当本发明化合物的前药被施予哺乳动物个体时,前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound. Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氘(
2H),氚(
3H),碘-125(
125I)或C-14(
14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of categories of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
术语“C
1-6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C
1-C
3烷基”),例如甲基、乙基、正丙基或异丙基。
The term "C 1-6 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
术语“C
3-8环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~8个碳原子,包括稠合或桥接的多环系统。如环丙基、环丁基、环戊基、环己基。
The term "C 3-8 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“3-6元杂环基”应理解为表示具有3至6个原子的饱和、不饱和或部分饱和的单环或二环,其中1、2、或3个环原子选自N、O和S。术语“4-8元杂环基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的单环、二环或三环,其中1、2、3、4或5个环原子选自N、O和S。除非另有说明,其可通过碳或氮连接,其中-CH
2-基团任选被-C(O)-代替;及其中除非另有相反说明,环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化;其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代;及环任选被一个或多个卤素取代。应该理解的是,当杂环基中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。若所述杂环基为二环或三环,则至少一个环可任选为杂芳族环或芳族环,条件是至少一个环是非杂芳族的。若所述杂环基为单环,则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。
The term "3-6 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic or bicyclic ring having 3 to 6 atoms, wherein 1, 2, or 3 ring atoms are selected from N, O and S. The term "4-8 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 rings The atoms are selected from N, O and S. Unless otherwise stated, it may be attached via carbon or nitrogen, wherein the -CH2- group is optionally replaced by a -C(O)-; and wherein, unless otherwise stated to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form N-oxide or S-oxide or ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted by acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted by One or more halogen substitutions. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is monocyclic, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.
术语“5-8元杂芳基”应理解为具有5-8个环原子——特别是5或6个碳原子——且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,并且,另外在每一种情况 下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "5-8 membered heteroaryl" is understood as having 5-8 ring atoms - especially 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S A monovalent monocyclic, bicyclic or tricyclic aromatic ring group. Preferably 1 to 3 - monovalent monocyclic, bicyclic or tricyclic aromatic ring radicals of heteroatoms independently selected from N, O and S, and, additionally, in each case may be benzofused . In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridyl, pteridine carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
术语“桥环”是指化合物中的任意两个环共用两不直接相连的碳原子的环烃,根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括:The term "bridged ring" refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. Non-limiting examples include:
术语“C
4-8桥环烷基”是指具有4-8个碳原子的桥环,所述桥环的定义如上所述。
The term "C 4-8 bridged cycloalkyl" refers to a bridged ring with 4-8 carbon atoms, and the definition of the bridged ring is as described above.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw,其中v=1至3,w=1至(2v+1))。卤代烷基的实例包括,但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。"Haloalkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups (such as -CvFw, where v=1 to 3, w=1 to (2v+ 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
根据本发明的具体示例,本发明所述式(I)所示化合物,其立体异构体、水合物、溶剂化物、药学上可接受的盐或前药对LPAR1具有良好的拮抗作用。According to a specific example of the present invention, the compound represented by formula (I) of the present invention, its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has a good antagonistic effect on LPAR1.
根据本发明的具体示例,本发明化合物对LPAR1具有良好的拮抗作用,对LPAR3的拮抗作用很弱,亦即本发明化合物显示出优异的选择性;本发明化合物安全性更优,无胆汁淤积毒性风险;本发明化合物药代动力学性质优良,成药性好;本发明化合物能通过拮抗LPAR1显著抑制LPA诱导的组胺释放,同时显著改善博来霉素诱导的小鼠、大鼠肺纤维化症状。According to a specific example of the present invention, the compound of the present invention has a good antagonistic effect on LPAR1 and a weak antagonistic effect on LPAR3, that is, the compound of the present invention shows excellent selectivity; the compound of the present invention has better safety and no cholestatic toxicity Risk; the compound of the present invention has excellent pharmacokinetic properties and good druggability; the compound of the present invention can significantly inhibit the release of histamine induced by LPA by antagonizing LPAR1, and at the same time significantly improve the symptoms of pulmonary fibrosis induced by bleomycin in mice and rats .
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。The solutions of the present invention will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
本发明的实施例提供了式(I)所示化合物,其药学上可接受的盐、互变异构体、立体异构体、水合物、溶剂化物、共晶或前药,制备式(I)所示化合物或其药学上可接受的盐、互变异构体、立体异构体、水合物、溶剂化物、共晶或前药的方法和中间体、药物组合物、以及本发明的化合物和药物组合物在制备药物中的用途。The embodiment of the present invention provides the compound shown in formula (I), its pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, co-crystal or prodrug, preparation formula (I) ) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs and intermediates, pharmaceutical compositions, and compounds of the present invention and the use of the pharmaceutical composition in the preparation of medicaments.
本发明所述的各反应步骤所使用的反应溶剂没有特别限制,任何在一定程度上能溶解起始原料并且不抑制反应的溶剂均包含在本发明中。另外,本领域的许多类似改动,等同替换,或等同于本发明所描述的溶剂,溶剂组合,及溶剂组合的不同比例,均视为本发明的包含范围。The reaction solvent used in each reaction step of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are considered to be within the scope of the present invention.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10
-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等,内标为四甲基硅烷(TMS)。
Compound structures were determined by nuclear magnetic resonance (NMR) and/or mass spectroscopy (MS). The unit of NMR shift is 10 -6 (ppm). The solvents determined by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
液质联用(LC-MS)由Waters Acquity H-class Uplc-QDA质谱仪测定,使用ACQUITY UPLC BEH C18,2.1*50mm,1.7μm色谱柱监测。梯度洗脱条件:以1.0mL/min流速,95—5%溶剂A1和5-95%溶剂B1,然后95%B1和5%A1保持0.5min,百分数为某一溶剂占总溶剂体积的体积百分数。其中溶剂A1:0.1%甲酸的水溶液;溶剂B1:0.1%甲酸的乙腈溶液。百 分数为溶质占溶液的体积百分数。Liquid-mass spectrometry (LC-MS) was determined by Waters Acquity H-class Uplc-QDA mass spectrometer and monitored by ACQUITY UPLC BEH C18, 2.1*50mm, 1.7μm chromatographic column. Gradient elution conditions: at a flow rate of 1.0mL/min, 95-5% solvent A1 and 5-95% solvent B1, then 95% B1 and 5% A1 for 0.5min, the percentage is the volume percentage of a certain solvent in the total solvent volume . Wherein solvent A1: 0.1% formic acid in water; solvent B1: 0.1% formic acid in acetonitrile. The percentage is the volume percentage of the solute in the solution.
本发明的缩写定义如下:The abbreviations of the present invention are defined as follows:
符号或单位:Symbol or unit:
IC
50:半数抑制浓度,指达到最大抑制效果一半时的浓度
IC 50 : half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
M:mol/L,例如正丁基锂(14.56mL,29.1mmol,2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液M: mol/L, such as n-butyllithium (14.56mL, 29.1mmol, 2.5M n-hexane solution) means n-hexane solution of n-butyllithium with a molar concentration of 2.5mol/L
N:当量浓度,例如2N盐酸表示2mol/L盐酸溶液N: Equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
RT:保留时间RT: retention time
试剂:Reagent:
DCM:二氯甲烷DCM: dichloromethane
DIPEA:也可写为DIEA,二异丙基乙胺,亦即N,N-二异丙基乙胺DIPEA: It can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
DMF:N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DMSO:二甲基亚砜DMSO: dimethyl sulfoxide
EA:乙酸乙酯EA: ethyl acetate
Et
3N:三乙胺
Et 3 N: Triethylamine
MeOH:甲醇MeOH: Methanol
PE:石油醚PE: petroleum ether
THF:四氢呋喃THF: Tetrahydrofuran
试验或检测方法:Test or detection method:
HPLC:高效液相色谱HPLC: High Performance Liquid Chromatography
SFC:超临界流体色谱SFC: Supercritical Fluid Chromatography
对照例1:对照化合物1及其制备Comparative Example 1: Comparative Compound 1 and its preparation
对照化合物1参考专利申请WO2017223016A1合成。Reference compound 1 was synthesized with reference to patent application WO2017223016A1.
对照例2:对照化合物2及其制备Comparative Example 2: Comparative Compound 2 and its preparation
对照化合物2参考专利申请WO2017223016A1合成。Reference compound 2 was synthesized with reference to patent application WO2017223016A1.
实施例1:目标化合物I-1的制备Embodiment 1: the preparation of target compound I-1
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-1)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-1)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-1)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-1)
目标化合物I-1的合成路线如下所示:The synthetic route of target compound 1-1 is as follows:
第一步:(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-1B)的合成The first step: the synthesis of (R)-4-nitrophenyl (1-phenylethyl) carbonate (I-1B)
(R)-4-nitrophenyl(1-phenylethyl)carbonate(I-1B)(R)-4-nitrophenyl(1-phenylethyl)carbonate(I-1B)
室温下,往(R)-1-苯基乙-1-醇(0.5g,4.09mmol)的二氯甲烷(10mL)溶液中,缓慢加入4-硝基苯基碳酰氯(0.99g,8.03mmol)和吡啶(0.647g,8.19mmol),室温反应3h,浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)=50:1-20:1)得黄色固体(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-1B)(0.7g,收率59.5%)。At room temperature, to a solution of (R)-1-phenylethan-1-ol (0.5g, 4.09mmol) in dichloromethane (10mL), slowly add 4-nitrophenylcarbonyl chloride (0.99g, 8.03mmol ) and pyridine (0.647g, 8.19mmol), reacted at room temperature for 3h, concentrated, and the residue was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V)=50:1-20:1) to obtain a yellow solid (R )-4-nitrophenyl(1-phenylethyl)carbonate (I-1B) (0.7 g, yield 59.5%).
LC-MS,M/Z(ESI):288.2[M+H]
+
LC-MS, M/Z(ESI):288.2[M+H] +
第二步:2-溴-6-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)吡啶-3-醇(I-1D)的合成The second step: 2-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-ol (I-1D) Synthesis
2-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-ol(I-1D)2-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-ol(I-1D)
在室温下,将2-溴-6-碘吡啶-3-醇(5g,16.67mmol),2-(丙-2-炔-1-基氧基)四氢-2H-吡喃(2.34g,16.67mmol),碘化亚铜(317.53mg,1.67mmol),三乙胺(5.06g,50.02mmol)和二(三苯基磷)二氯化钯(1.17g,1.67mmol)加入到四氢呋喃(50mL)中,氮气保护下室温反应1小时。反应完成后,将反应液中加入20mL饱和的食盐水,用乙酸乙酯(50mL×3)萃取,有机相用饱和的食盐水(10mL)洗涤。无水硫酸钠干燥,过滤浓缩,粗品经柱层析分离(石油醚:乙酸乙酯(V/V)=10:1-3:1)得2-溴-6-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)吡啶-3-醇(3.01g,收率57.83%)。At room temperature, 2-bromo-6-iodopyridin-3-ol (5g, 16.67mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (2.34g, 16.67mmol), cuprous iodide (317.53mg, 1.67mmol), triethylamine (5.06g, 50.02mmol) and bis(triphenylphosphine)palladium dichloride (1.17g, 1.67mmol) were added to tetrahydrofuran (50mL ), react at room temperature for 1 hour under the protection of nitrogen. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution, extracted with ethyl acetate (50 mL×3), and the organic phase was washed with saturated brine (10 mL). Dry over anhydrous sodium sulfate, filter and concentrate, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate (V/V) = 10:1-3:1) to obtain 2-bromo-6-(3-((tetrahydro -2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-ol (3.01 g, yield 57.83%).
LC-MS,M/Z(ESI):312.1,314.1[M+H]
+
LC-MS,M/Z(ESI):312.1,314.1[M+H] +
第三步:(1S,3S)-3-((2-溴-6-(3-(四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)吡啶-3-基)氧)环己烷-1-甲酸甲酯(I-1E)的合成The third step: (1S,3S)-3-((2-bromo-6-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine Synthesis of -3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1E)
methyl(1S,3S)-3-((2-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1E)methyl(1S,3S)-3-((2-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl) oxy)cyclohexane-1-carboxylate (I-1E)
在室温下,将2-溴-6-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)吡啶-3-醇(3.01g,9.61mmol),(1S,3R)-3-羟基环己烷-1-甲酸甲酯(2.28g,14.42mmol)和三苯基膦(5.04g,19.22mmol)加入到30mL的无水四氢呋喃中,氮气保护后用冰水降温,在0~10℃下滴加偶氮二甲酸二异丙酯(3.89g,19.22mmol),加完后25℃反应3小时。将反应液中加入30mL饱和的食盐水,用乙酸乙酯(30mL×3)萃取,有机相用饱和的食盐水(10mL)洗涤。无水硫酸钠干燥,过滤浓缩,粗品经柱层析分离(石油醚:乙酸乙酯(V/V)=10:1-4:1)得(1S,3S)-3-((2-溴-6-(3-(四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)吡啶-3-基)氧)环己烷-1-甲酸甲酯(3.10g,收率71.3%)。At room temperature, 2-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-ol (3.01 g, 9.61mmol), (1S,3R)-3-hydroxycyclohexane-1-carboxylic acid methyl ester (2.28g, 14.42mmol) and triphenylphosphine (5.04g, 19.22mmol) were added in 30mL of anhydrous tetrahydrofuran, After nitrogen protection, cool down with ice water, add diisopropyl azodicarboxylate (3.89 g, 19.22 mmol) dropwise at 0-10°C, and react at 25°C for 3 hours after the addition is complete. 30 mL of saturated brine was added to the reaction solution, extracted with ethyl acetate (30 mL×3), and the organic phase was washed with saturated brine (10 mL). Dry over anhydrous sodium sulfate, filter and concentrate, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate (V/V) = 10:1-4:1) to obtain (1S,3S)-3-((2-bromo -6-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester ( 3.10 g, yield 71.3%).
第四步:(1S,3S)-3-((2-溴-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1F)的合成The fourth step: (1S,3S)-3-((2-bromo-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)methyl)-1H- Synthesis of methyl 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1F)
methyl(1S,3S)-3-((2-bromo-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1F)methyl(1S,3S)-3-((2-bromo-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1F)
在室温下,向(1S,3S)-3-((2-溴-6-(3-(四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)吡啶-3-基)氧)环己烷-1-甲酸甲酯(3g,6.63mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入叠氮化钠(0.69g,10.61mmol),氮气保护下100℃反应24小时。反应完后反应液过滤,滤液直接投下步。At room temperature, to (1S,3S)-3-((2-bromo-6-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl) To a solution of methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate (3g, 6.63mmol) in N,N-dimethylformamide (30mL) was added sodium azide (0.69g, 10.61mmol) , reacted at 100°C for 24 hours under the protection of nitrogen. After the reaction, the reaction solution was filtered, and the filtrate was directly dropped into the next step.
第五步:(1S,3S)-3-((2-溴6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1G)的合成The fifth step: (1S,3S)-3-((2-bromo6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H Synthesis of methyl -1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1G)
methyl(1S,3S)-3-((2-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1G)methyl(1S,3S)-3-((2-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1G)
在室温下,向(1S,3S)-3-((2-溴-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯的N,N-二甲基甲酰胺(30mL)溶液中加入碳酸钾(1.84g,13.28mmol),然后加入碘甲烷(1.41g,9.96mmol),反应液在25℃下反应18小时。将反应液中加入40mL水,用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(10mL)洗涤。无水 硫酸钠干燥,过滤浓缩,粗品经柱层析(石油醚:乙酸乙酯(V/V)=10:1-3:1)分离得到(1S,3S)-3-((2-溴6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(500mg,收率14.6%)。At room temperature, to (1S,3S)-3-((2-bromo-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)methyl)-1H Potassium carbonate (1.84g, 13.28mmol), then iodomethane (1.41g, 9.96mmol) was added, and the reaction solution was reacted at 25°C for 18 hours. 40 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), and the organic phase was washed with saturated brine (10 mL). Dry over anhydrous sodium sulfate, filter and concentrate, the crude product is separated by column chromatography (petroleum ether: ethyl acetate (V/V) = 10:1-3:1) to obtain (1S,3S)-3-((2-bromo 6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine-3 -yl)oxy)cyclohexane-1-carboxylic acid methyl ester (500 mg, yield 14.6%).
第六步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1H)的合成The sixth step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl) Synthesis of )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1H)
methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1H)methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1H)
在室温下,将(1S,3S)-3-((2-溴6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(400mg,785.25μmol),磷酸钾(500.05mg,2.36mmol),1,1-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(32.06mg,39.26μmol)和环丙基硼酸(134.9mg,1.57mmol)加入到1,4-二氧六环(6mL)溶液中,氮气保护下100℃反应16小时。反应完成后,将反应液浓缩得到粗产品。粗品经柱层析分离(石油醚:乙酸乙酯(V/V)=10:1-3:1)得到(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(325mg,收率87.96%)。At room temperature, (1S,3S)-3-((2-bromo6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (400mg, 785.25μmol), potassium phosphate (500.05mg, 2.36mmol), 1,1-Bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (32.06 mg, 39.26 μmol) and cyclopropylboronic acid (134.9 mg, 1.57 mmol) were added to 1,4 - In a dioxane (6 mL) solution, react at 100° C. for 16 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate (V/V)=10:1-3:1) to obtain (1S,3S)-3-((2-cyclopropyl-6-(1-methyl Base-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) Methyl cyclohexane-1-carboxylate (325 mg, yield 87.96%).
LC-MS,M/Z(ESI):471.4[M+H]
+
LC-MS, M/Z(ESI):471.4[M+H] +
第七步:(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1I)的合成The seventh step: (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-methyl carboxylate (I-1I) synthesis
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1I)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylate (I-1I)
在室温下,将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(550mg,1.17mmol)和吡啶对甲苯磺酸盐(146.86mg,584.41μmol)加入到甲醇(70mL)中65℃下反应3小时。反应结束后向反应液中加入碳酸氢钠(1g)淬灭反应,反应液直接浓缩得到粗品。粗品经柱层析(石油醚:乙酸乙酯(V/V)=5:1-3:1)分离得到(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(400mg,收率88.2%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl base)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (550mg, 1.17mmol) and pyridine p-toluenesulfonate ( 146.86mg, 584.41μmol) was added into methanol (70mL) and reacted at 65°C for 3 hours. After the reaction was completed, sodium bicarbonate (1 g) was added to the reaction solution to quench the reaction, and the reaction solution was directly concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate (V/V)=5:1-3:1) to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-( Hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (400mg, yield 88.2% ).
LC-MS,M/Z(ESI):387.3[M+H]
+
LC-MS, M/Z(ESI):387.3[M+H] +
第八步:(1S,3S)-3-((6-(5-(叠氮甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1J)的合成The eighth step: (1S,3S)-3-((6-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ring Synthesis of Methyl Propylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1J)
methyl(1S,3S)-3-((6-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1J)methyl(1S,3S)-3-((6-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane -1-carboxylate (I-1J)
在室温下,将(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(500mg,1.29mmol)和叠氮磷酸二苯酯(712.13mg,2.59mmol)加入到四氢呋喃(8mL)中,反应液用冰浴降温,0~10℃下加入1,8-二氮杂二环十一碳-7-烯(393.94mg,2.59mmol),加完后0~25℃反应6小时。反应完后反应液通过制备板分离(石油醚:乙酸乙酯(V/V)=1:1)得(1S,3S)-3-((6-(5-(叠氮甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(480mg,收率90.2%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4- Base) pyridin-3-yl) oxy) cyclohexane-1-methyl carboxylate (500mg, 1.29mmol) and diphenylphosphoryl azide (712.13mg, 2.59mmol) were added in tetrahydrofuran (8mL), and the reaction solution Cool down with an ice bath, add 1,8-diazabicycloundec-7-ene (393.94 mg, 2.59 mmol) at 0-10°C, and react at 0-25°C for 6 hours after the addition is complete. After the reaction, the reaction solution was separated by a preparation plate (petroleum ether:ethyl acetate (V/V)=1:1) to obtain (1S,3S)-3-((6-(5-(azidomethyl)-1 -Methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (480mg, yield 90.2% ).
第九步:(1S,3S)-3-((6-(5-(氨基甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1K)的合成The ninth step: (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropane Synthesis of methyl pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1K)
methyl(1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1K)methyl(1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane -1-carboxylate (I-1K)
在室温下,将(1S,3S)-3-((6-(5-(叠氮甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(410mg,859.16μmol)加入到四氢呋喃(3mL)和水(1mL)的混合溶液中,向反应液中加入三苯基膦(450.69mg,1.72mmol),25℃下搅拌2小时。反应完后反应液浓缩得(1S,3S)-3-((6-(5-(氨基甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯粗品。At room temperature, (1S,3S)-3-((6-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- Cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (410 mg, 859.16 μmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1 mL), and triphenyl Phosphine (450.69mg, 1.72mmol), stirred at 25°C for 2 hours. After the reaction, the reaction solution was concentrated to obtain (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2 - Crude methyl cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate.
LC-MS,M/Z(ESI):386.3[M+H]
+
LC-MS, M/Z(ESI):386.3[M+H] +
第十步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1L)的合成Step 10: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino) Synthesis of methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1L)
methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1L)methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-1L)
在室温下,将(1S,3S)-3-((6-(5-(氨基甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(331.17mg,859.16μmol)和三乙胺(86.94mg,859.16μmol)加入到四氢呋喃(10mL)中,向反应液中加入(R)-4-硝基苯基(1-苯基乙基)碳酸酯(I-1B)(493.62mg,1.72mmol),加完25℃下搅拌2小时。反应完成后,将反应液浓缩得粗品。粗品经柱层析分 离(石油醚:乙酸乙酯(V/V)=10:1-3:1)得到(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1L)(450mg,两步收率98.1%)。At room temperature, (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclo Propylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (331.17mg, 859.16μmol) and triethylamine (86.94mg, 859.16μmol) were added in tetrahydrofuran (10mL), and added to the reaction solution Add (R)-4-nitrophenyl(1-phenylethyl)carbonate (I-1B) (493.62 mg, 1.72 mmol), and stir at 25°C for 2 hours after the addition is complete. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate (V/V)=10:1-3:1) to obtain (1S,3S)-3-((2-cyclopropyl-6-(1-methyl Base-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy base) methyl cyclohexane-1-carboxylate (I-1L) (450 mg, 98.1% yield in two steps).
LC-MS,M/Z(ESI):534.5[M+H]
+
LC-MS, M/Z(ESI):534.5[M+H] +
第十一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-1)的合成The eleventh step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino) )methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-1)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
在室温下,将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1L)(450mg,843.3μmol)加入到四氢呋喃(6mL)和水(2mL)中,向反应液加入氢氧化锂一水合物(141.55mg,3.37mmol),加完25℃下搅拌3小时。反应完后将用1M盐酸将pH调到3~4,二氯甲烷(20mL×3)萃取,浓缩得粗产品。粗品经制备板(石油醚:乙酸乙酯(V/V)=1:1)分离纯化得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-1-苯基乙氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-1)(389.67mg,收率87.5%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-1-phenylethoxy)carbonyl)amino )methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (1-1L) (450mg, 843.3μmol) was added Add lithium hydroxide monohydrate (141.55 mg, 3.37 mmol) to the reaction solution in tetrahydrofuran (6 mL) and water (2 mL), and stir at 25° C. for 3 hours after the addition is completed. After the reaction, the pH was adjusted to 3-4 with 1M hydrochloric acid, extracted with dichloromethane (20 mL×3), and concentrated to obtain a crude product. The crude product was separated and purified by preparative plate (petroleum ether:ethyl acetate (V/V)=1:1) to obtain (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5- (((((R)-1-phenylethoxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexyl Alkanecarboxylic acid (target compound I-1) (389.67 mg, yield 87.5%).
LC-MS,M/Z(ESI):520.3[M+H]
+
LC-MS, M/Z(ESI):520.3[M+H] +
1H NMR(400MHz,CDCl3)δ7.98-7.96(m,1H),7.33-7.32(m,4H),7.31-7.27(m,1H),7.27-7.25(m,1H),7.24–6.27(t,1H),5.77-5.72(q,1H),4.74(br,1H),4.68-4.56(m,2H),4.14(s,3H),2.94-2.91(m,1H),2.61-2.58(m,1H),2.25-2.15(m,1H),2.01–1.96(m,2H),1.81–1.70(m,2H),1.68-1.66(m,3H),1.52–1.50(m,3H),1.15–0.95(m,4H)。
1 H NMR (400MHz, CDCl3) δ7.98-7.96 (m, 1H), 7.33-7.32 (m, 4H), 7.31-7.27 (m, 1H), 7.27-7.25 (m, 1H), 7.24–6.27 ( t,1H),5.77-5.72(q,1H),4.74(br,1H),4.68-4.56(m,2H),4.14(s,3H),2.94-2.91(m,1H),2.61-2.58( m,1H),2.25-2.15(m,1H),2.01–1.96(m,2H),1.81–1.70(m,2H),1.68-1.66(m,3H),1.52–1.50(m,3H), 1.15–0.95(m,4H).
实施例2:目标化合物I-2的制备Embodiment 2: the preparation of target compound 1-2
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-2)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-2)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)
目标化合物I-2的合成路线如下所示:The synthetic route of target compound 1-2 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)的制备The first step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl) Preparation of -1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A)
(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-2A)(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-2A)
在0℃下,向(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1I)(500mg,1.29mmol)和吡啶(307mg,3.88mmol)的二氯甲烷(5.00mL)溶液中加入(4-硝基苯基)碳酰氯(521mg,2.59mmol),反应液在25℃下搅拌2小时。反应完成后,加水(10.0mL)淬灭反应,混合液用二氯甲烷萃取,有机相用饱和氯化钠水溶液(10.0mL)洗涤,无水硫酸钠干燥,过滤浓缩得到黄色油状粗品化合物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(700mg,粗品),直接用于下一步。At 0°C, to (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4 -yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1I) (500mg, 1.29mmol) and pyridine (307mg, 3.88mmol) in dichloromethane (5.00mL) solution (4-Nitrophenyl)carbonyl chloride (521mg, 2.59mmol) was added, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was complete, water (10.0 mL) was added to quench the reaction, the mixture was extracted with dichloromethane, the organic phase was washed with saturated aqueous sodium chloride (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily crude compound (1S ,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2 ,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (700 mg, crude) was used directly in the next step.
LC-MS,M/Z(ESI):552.2[M+H]
+
LC-MS, M/Z(ESI):552.2[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(丙基)氨甲酰)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2B)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)- Synthesis of 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2B)
methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-2B)methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-2B)
将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(356mg,645.46μmol)和三乙胺(195.9mg,1.94mmol)加入到二氯甲烷(6mL)中,溶解完全后加入N-甲基丙-1-胺(141.62mg,1.94mmol),加完后25℃下搅拌2h。反应完全后向反应液中加入水(10mL)稀释,用二氯甲烷(15mL×3)萃取,合并有机相,无水硫酸钠干燥,浓缩,残余物用硅胶柱分离纯化(石油醚:乙酸乙酯=10:1-4:1)得白色固体化合物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(丙基)氨甲酰)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2B)(280mg,产率89.3%)。(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (356 mg, 645.46 μmol) and triethylamine (195.9 mg, 1.94mmol) was added into dichloromethane (6mL). After the dissolution was complete, N-methylpropan-1-amine (141.62mg, 1.94mmol) was added and stirred at 25°C for 2h after the addition was complete. After the reaction was complete, water (10 mL) was added to the reaction liquid for dilution, extracted with dichloromethane (15 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column (petroleum ether: ethyl acetate Ester=10:1-4:1) to obtain white solid compound (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)amino) Formyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2B) (280mg , yield 89.3%).
LC-MS,M/Z(ESI):486.5[M+H]
+。
LC-MS, M/Z (ESI): 486.5 [M+H] + .
第三步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-2)的合成The third step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)- Synthesis of 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-2)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2)
将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(丙基)氨甲酰)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2B)(275mg,566.3μmol)溶解于四氢呋喃(2mL)和水(0.5mL)中,加入一水合氢氧化锂(118.83mg,2.83mmol),25℃下反应12h。反应完后0~10℃下用1M盐酸将反应液pH调为3~4,二氯甲烷(15mL×3)萃取,合并有机相,无水硫酸钠干燥,浓缩。残余物先用反相高效液相色谱法进行分离(分离方法为:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=40%-70%,10分钟),再用手性色谱法进行分离((色谱柱:DAICEL CHIRALCEL OD(250mm*30mm,10um);流动相:溶剂A=异丙醇+0.1体积%氨水,溶剂B=超临界状态二氧化碳;梯度:B%=40%-40%,循环进样,每2.7min进样一次),得化合物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-2)(68.83mg,收率25.4%)。(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1 , 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2B) (275 mg, 566.3 μmol) was dissolved in tetrahydrofuran (2 mL) and water ( 0.5mL), add lithium hydroxide monohydrate (118.83mg, 2.83mmol), and react at 25°C for 12h. After the reaction, the pH of the reaction solution was adjusted to 3-4 with 1M hydrochloric acid at 0-10°C, extracted with dichloromethane (15 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue is separated by reverse-phase high-performance liquid chromatography (separation method is: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=40%-70%, 10 minutes), then separate by chiral chromatography ((chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: solvent A=isopropanol+0.1 volume % Ammonia, solvent B=carbon dioxide in supercritical state; gradient: B%=40%-40%, cyclic injection, once every 2.7min sample injection), to obtain compound (1S, 3S)-3-((2-cyclopropyl -6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine-3- (yl)oxy)cyclohexane-1-carboxylic acid (target compound I-2) (68.83 mg, yield 25.4%).
1H NMR(400MHz,CDCl
3)δ7.92(d,1H),7.21(d,1H),5.68(s,2H),4.72(s,1H),4.15(s,3H),3.25(t,1H),3.10(t,1H),2.96-2.81(m,4H),2.54-2.49(m,1H),2.22-2.19(m,1H),2.04-1.93(m,3H),1.85-1.78(m,1H),1.71-1.66(m,3H),1.60-1.53(m,1H),1.43-1.37(m,1H),1.12-1.09(m,2H),1.00-0.89(m,4H),0.74(m,1H).
1 H NMR (400MHz, CDCl 3 )δ7.92(d,1H),7.21(d,1H),5.68(s,2H),4.72(s,1H),4.15(s,3H),3.25(t, 1H),3.10(t,1H),2.96-2.81(m,4H),2.54-2.49(m,1H),2.22-2.19(m,1H),2.04-1.93(m,3H),1.85-1.78( m,1H),1.71-1.66(m,3H),1.60-1.53(m,1H),1.43-1.37(m,1H),1.12-1.09(m,2H),1.00-0.89(m,4H), 0.74(m,1H).
LC-MS,M/Z(ESI):472.4[M+H]
+
LC-MS, M/Z(ESI):472.4[M+H] +
实施例3:目标化合物I-3的制备Embodiment 3: the preparation of target compound 1-3
(1S,3S)-3-((6-(5-((((环丁基甲基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-3)(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -Triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-3)(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
目标化合物I-3的合成路线如下所示:The synthetic route of target compound 1-3 is as follows:
第一步:(环丁基甲基)氨基甲酸叔丁酯(I-3B)的合成The first step: the synthesis of (cyclobutylmethyl) tert-butyl carbamate (I-3B)
tert-butyl(cyclobutylmethyl)carbamate(I-3B)tert-butyl(cyclobutylmethyl)carbamate(I-3B)
把环丁基甲胺(500mg,5.87mmol)和三乙胺(1.31g,12.92mmol,1.80mL)溶解在二氯甲烷(5mL)中,在氮气保护下,向反应液中加入二碳酸二叔丁酯(1.28g,5.87mmol,1.35mL),反应液在室温下搅拌过夜。反应完成后,将反应液直接浓缩得到粗品(环丁基甲基)氨基甲酸叔丁酯(I-3B)(780mg,粗品)。Dissolve cyclobutylmethylamine (500mg, 5.87mmol) and triethylamine (1.31g, 12.92mmol, 1.80mL) in dichloromethane (5mL), and add di-tert-butyl dicarbonate to the reaction solution under nitrogen protection (1.28g, 5.87mmol, 1.35mL), the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was directly concentrated to obtain crude tert-butyl (cyclobutylmethyl)carbamate (I-3B) (780 mg, crude product).
第二步:(环丁基甲基)(甲基)氨基甲酸叔丁酯(I-3C)的的合成The second step: the synthesis of (cyclobutylmethyl) (methyl) tert-butyl carbamate (I-3C)
tert-butyl(cyclobutylmethyl)(methyl)carbamate(I-3C)tert-butyl(cyclobutylmethyl)(methyl)carbamate(I-3C)
将钠氢(259.07mg,6.48mmol,60%含量)悬浮在四氢呋喃(8mL)中,然后在氮气保护和0℃下,向其中滴加(环丁基甲基)氨基甲酸叔丁酯(600mg,3.24mmol),之后将反应液在0℃下搅拌1小时,保持在氮气保护和0℃下,向反应液中滴加碘甲烷(689.53mg,4.86mmol,302.4μL),加毕,让反应液在室温下搅拌过夜。反应完成后,向反应液中加入水(10mL)稀释,再用乙酸乙酯(10mL×3)萃取,合并有机层,用饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩得到粗品(环丁基甲基)(甲基)氨基甲酸叔丁酯(I-3C)(645.43mg,粗品)。Sodium hydrogen (259.07mg, 6.48mmol, 60% content) was suspended in tetrahydrofuran (8mL), and then (cyclobutylmethyl)carbamate (600mg, 3.24mmol ), then the reaction solution was stirred at 0° C. for 1 hour, kept under nitrogen protection and 0° C., added dropwise methyl iodide (689.53 mg, 4.86 mmol, 302.4 μ L) to the reaction solution, and the reaction solution was allowed to cool at room temperature Stir overnight. After the reaction is complete, add water (10 mL) to the reaction solution to dilute, then extract with ethyl acetate (10 mL×3), combine the organic layers, wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate to obtain Crude tert-butyl (cyclobutylmethyl)(methyl)carbamate (I-3C) (645.43 mg, crude).
第三步:1-环丁基-N-甲基甲胺盐酸盐(I-3D)的合成The third step: the synthesis of 1-cyclobutyl-N-methylmethylamine hydrochloride (I-3D)
1-cyclobutyl-N-methylmethanamine hydrochloride(I-3D)1-cyclobutyl-N-methylmethanamine hydrochloride (I-3D)
把(环丁基甲基)(甲基)氨基甲酸叔丁酯(I-3C)(645.43mg,3.24mmol)溶解在二氯甲烷(10mL)中,在氮气保护和0℃反应液中滴加氯化氢的1,4-二氧六环溶液(4M,3.24mL),然后在25℃下反应12小时。反应完成后,将反应液直接浓缩得到粗品1-环丁基-N-甲基甲胺盐酸盐(I-3D)(580mg,粗品)。Dissolve (cyclobutylmethyl) (methyl) tert-butyl carbamate (I-3C) (645.43mg, 3.24mmol) in dichloromethane (10mL), add hydrogen chloride dropwise to the reaction solution under nitrogen protection and 0°C 1,4-dioxane solution (4M, 3.24 mL), and reacted at 25° C. for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude 1-cyclobutyl-N-methylmethylamine hydrochloride (I-3D) (580 mg, crude product).
第四步:(1S,3S)-3-((6-(5-((((环丁基甲基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-3E)的合成The fourth step: (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1 , 2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-3E) synthesis
methyl(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-3E)methyl(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl) -2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E)
把(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(1-2A)(400mg,725.23μmol)和1-环丁基-N-甲基甲胺盐酸盐(143.85mg,1.06μmol)溶解在四氢呋喃(3.0mL)中,在氮气保护下,向反应液中滴加N,N-二异丙基乙胺(234.33mg,1.81mmol,315.8μL),然后在25℃下反应2小时。反应完成后,向反应液中加入水(10mL)稀释,再用乙酸乙酯(10mL×3)萃取,合并有机层,用饱和食盐水(30mL)洗涤有机相,硫酸钠干燥,浓缩得粗品(1S,3S)-3-((6-(5-((((环丁基甲基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-3E)(350mg,粗品)。Put (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (1-2A) (400mg, 725.23μmol) and 1-cyclobutyl-N -Methylmethylamine hydrochloride (143.85 mg, 1.06 μmol) was dissolved in tetrahydrofuran (3.0 mL), and N,N-diisopropylethylamine (234.33 mg, 1.81 mmol, 315.8 μL), and then reacted at 25°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to dilute, then extracted with ethyl acetate (10 mL×3), the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product ( 1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- Methyl triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-3E) (350 mg, crude).
LC-MS,M/Z(ESI):512.3[M+H]
+
LC-MS, M/Z(ESI):512.3[M+H] +
第五步:(1S,3S)-3-((6-(5-((((环丁基甲基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-3)的合成The fifth step: (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1 , 2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3) synthesis
(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-3)(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-3)
把(1S,3S)-3-((6-(5-((((环丁基甲基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(223mg,435.88μmol)和一水合氢氧化锂(182.91mg,4.36mmol)溶解在四氢呋喃(3mL)和水(0.6mL)中,在25℃下搅拌反应12小时。反应完成后,将粗品经反相高效液相色谱法进行分离(分离方法为:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225%甲酸,溶剂B=乙腈;梯度:B%:45%-75%,10分钟),得(1S,3S)-3-((6-(5-((((环丁基甲基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-3)(23.86mg,收率10.9%)。Put (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (223 mg, 435.88 μmol) and lithium hydroxide monohydrate (182.91 mg, 4.36 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.6 mL), and the reaction was stirred at 25°C for 12 hours. After the reaction was completed, the crude product was separated by reverse-phase high-performance liquid chromatography (separation method: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225% formic acid, solvent B=acetonitrile; Gradient: B%: 45%-75%, 10 minutes), to get (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy) Methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I -3) (23.86 mg, yield 10.9%).
LC-MS,M/Z(ESI):498.3[M+H]
+
LC-MS, M/Z(ESI):498.3[M+H] +
1H NMR(400MHz,CDCl
3)δ7.93-7.89(m,1H),7.22-7.18(m,1H),5.67(s,2H),4.73(s,1H),4.15(d,3H),3.33(d,1H),3.17(d,1H),2.88-2.79(m,3H),2.55–2.45(m,1H),2.25-2.15(m,1H),2.04-1.95(m,4H),1.88-1.66(m,8H),1.57-1.49(m,3H),1.11(s,2H),0.98(s,2H).
1 H NMR (400MHz, CDCl 3 )δ7.93-7.89(m,1H),7.22-7.18(m,1H),5.67(s,2H),4.73(s,1H),4.15(d,3H), 3.33(d,1H),3.17(d,1H),2.88-2.79(m,3H),2.55–2.45(m,1H),2.25-2.15(m,1H),2.04-1.95(m,4H), 1.88-1.66(m,8H),1.57-1.49(m,3H),1.11(s,2H),0.98(s,2H).
实施例4:目标化合物I-4的制备Embodiment 4: the preparation of target compound 1-4
(1S,3S)-3-((2-环丙基-6-(5-(((((R)-1-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-4)(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-4)(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
目标化合物I-4的合成路线如下所示:The synthetic route of target compound 1-4 is as follows:
第一步:(R)-(1-环丙基乙基)氨基甲酸叔丁酯(I-4B)的合成The first step: the synthesis of (R)-(1-cyclopropylethyl) tert-butyl carbamate (I-4B)
tert-butyl(R)-(1-cyclopropylethyl)carbamate(I-4B)tert-butyl(R)-(1-cyclopropylethyl)carbamate(I-4B)
在室温下,把异丙基环丙烷盐酸盐(500mg,4.11mmol)和三乙胺(915.30mg,9.05mmol,1.26mL)溶解在二氯甲烷(5mL)中,在氮气保护下,向反应液中加入二碳酸二叔丁酯(897.34mg,4.11mmol,944.57μL),反应液在室温下搅拌过夜。反应完成后,将反应液直接浓缩得到粗品(R)-(1-环丙基乙基)氨基甲酸叔丁酯(I-4B)(600mg,粗品)。At room temperature, dissolve isopropylcyclopropane hydrochloride (500mg, 4.11mmol) and triethylamine (915.30mg, 9.05mmol, 1.26mL) in dichloromethane (5mL), under nitrogen protection, to the reaction Di-tert-butyl dicarbonate (897.34 mg, 4.11 mmol, 944.57 μL) was added to the solution, and the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was directly concentrated to obtain crude (R)-(1-cyclopropylethyl)carbamate tert-butyl ester (I-4B) (600 mg, crude product).
第二步:(R)-(1-环丙基乙基)(甲基)氨基甲酸叔丁酯(I-4C)的合成The second step: the synthesis of (R)-(1-cyclopropylethyl) (methyl) tert-butyl carbamate (I-4C)
tert-butyl(R)-(1-cyclopropylethyl)(methyl)carbamate(I-4C)tert-butyl(R)-(1-cyclopropylethyl)(methyl)carbamate(I-4C)
将钠氢(259.07mg,6.48mmol,60%含量)悬浮在四氢呋喃(8mL)中,然后在氮气保护和0℃下,向其中滴加(R)-(1-环丙基乙基)氨基甲酸叔丁酯粗品(600mg,3.24mmol),之后将反应液在0℃下搅拌1个小时,然后在氮气保护和0℃下,向反应液中滴加碘甲烷(689.53mg,4.86mmol,302.4μL)。反应液在室温下搅拌过夜。反应完成后,向反应液中加入水(10mL)稀释,再用乙酸乙酯(10mL×3)萃取,合并有机层,用饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩得粗品(R)-(1-环丙基乙基)(甲基)氨基甲酸叔丁酯(I-4C)(1g,粗品)。Sodium hydrogen (259.07mg, 6.48mmol, 60% content) was suspended in tetrahydrofuran (8mL), and then (R)-(1-cyclopropylethyl) carbamic acid was added dropwise at 0°C under nitrogen protection The crude product of tert-butyl ester (600mg, 3.24mmol), then the reaction solution was stirred at 0°C for 1 hour, then under nitrogen protection and at 0°C, iodomethane (689.53mg, 4.86mmol, 302.4μL ). The reaction was stirred overnight at room temperature. After the reaction was completed, water (10 mL) was added to the reaction solution to dilute, then extracted with ethyl acetate (10 mL×3), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain Crude tert-butyl (R)-(1-cyclopropylethyl)(methyl)carbamate (I-4C) (1 g, crude).
第三步:(R)-1-环丙基-N-甲基乙烷-1-胺盐酸盐(I-4D)的合成The third step: the synthesis of (R)-1-cyclopropyl-N-methylethane-1-amine hydrochloride (I-4D)
(R)-1-cyclopropyl-N-methylethan-1-amine hydrochloride(I-4D)(R)-1-cyclopropyl-N-methylethan-1-amine hydrochloride(I-4D)
把(R)-(1-环丙基乙基)(甲基)氨基甲酸叔丁酯(1g,5.02mmol)溶解在二氯甲烷(10mL)中,在氮气保护和0℃反应液中滴加氯化氢的1,4-二氧六环溶液(4M,5.02mL),然后在25度下反应12小时。反应完成后,将反应液直接浓缩得到粗品(R)-1-环丙基-N-甲基乙烷-1-胺盐酸盐(I-4D)(577mg,粗品)。Dissolve (R)-(1-cyclopropylethyl)(methyl)tert-butyl carbamate (1g, 5.02mmol) in dichloromethane (10mL), and add dropwise to the reaction solution under nitrogen protection and 0°C A solution of hydrogen chloride in 1,4-dioxane (4M, 5.02 mL) was reacted at 25 degrees for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude (R)-1-cyclopropyl-N-methylethane-1-amine hydrochloride (I-4D) (577 mg, crude).
第四步:(1S,3S)-3-((2-环丙基-6-(5-(((((R)-1-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-4E)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy Base) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-4E) synthesis
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4E)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-4E)
把(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(400mg,725.23μmol)和(R)-1-环丙基-N-甲基乙胺盐酸盐(143.85mg,1.45mmol)溶解在四氢呋喃(3.0mL)中,在氮气保护下,向反应液中滴加N,N-二异丙基乙胺(234.33mg,1.81mmol,315.8μL),然后在25℃下反应2小时。反应完成后,向反应液中加入水(10mL)稀释,再用乙酸乙酯(10mL×3)萃取,合并有机相,用饱和食盐水(30mL)洗涤有机相,无水硫酸钠干燥,浓缩得粗品(1S,3S)-3-((2-环丙基-6-(5-(((((R)-1-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-4E)(350mg)。Put (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (400 mg, 725.23 μmol) and (R)-1-cyclo Propyl-N-methylethylamine hydrochloride (143.85mg, 1.45mmol) was dissolved in tetrahydrofuran (3.0mL), and N,N-diisopropylethylamine ( 234.33mg, 1.81mmol, 315.8μL), and then reacted at 25°C for 2 hours. After the reaction was completed, add water (10 mL) to the reaction liquid for dilution, then extract with ethyl acetate (10 mL×3), combine the organic phases, wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate to obtain Crude product (1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methanol yl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-4E) (350 mg).
LC-MS,M/Z(ESI):512.1[M+H]
+
LC-MS, M/Z(ESI):512.1[M+H] +
第五步:(1S,3S)-3-((2-环丙基-6-(5-(((((R)-1-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-4)The fifth step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy Base) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-4)(1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-4)
把(1S,3S)-3-((2-环丙基-6-(5-(((((R)-1-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-4E)(260mg,508.20μmol)和一水合氢氧化锂(213.26mg,5.08mmol)溶解在四氢呋喃(3mL)和水(0.6mL)中,在25℃下搅拌反应12小时。反应完成后,将粗品经反相高效液相色谱法进行分离(分离方法为:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=43%-73%,10分钟),得到(1S,3S)-3-((2-环丙基-6-(5-(((((R)-1-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-4)(19.64mg,收率7.6%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl Base)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-4E) (260mg, 508.20 μmol) and lithium hydroxide monohydrate (213.26mg, 5.08mmol) were dissolved in tetrahydrofuran (3mL) and water (0.6mL), and stirred at 25°C for 12 hours. After the reaction was completed, the crude product was separated by reverse-phase high-performance liquid chromatography (separation method: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile ; Gradient: B%=43%-73%, 10 minutes), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-(((((R)-1-cyclopropane Ethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexyl Alkane-1-carboxylic acid (target compound I-4) (19.64 mg, yield 7.6%).
LC-MS,M/Z(ESI):498.2[M+H]
+
LC-MS, M/Z(ESI):498.2[M+H] +
1H NMR(400MHz,CDCl
3)δ7.91(d,1H),7.20-7.18(m,1H),5.65(d,2H),4.73(s,1H),4.14(s,3H),2.98-2.79(m,4H),2.53-2.49(m,1H),2.22(d,1H),2.02-1.78(m,5H),1.70-1.50(m,4H),1.20-0.96(m,8H),0.58-0.42(m,2H),0.07-0.05(m,1H).
1 H NMR (400MHz, CDCl 3 )δ7.91(d,1H),7.20-7.18(m,1H),5.65(d,2H),4.73(s,1H),4.14(s,3H),2.98- 2.79(m,4H),2.53-2.49(m,1H),2.22(d,1H),2.02-1.78(m,5H),1.70-1.50(m,4H),1.20-0.96(m,8H), 0.58-0.42(m,2H),0.07-0.05(m,1H).
实施例5:目标化合物I-5的制备Embodiment 5: the preparation of target compound 1-5
(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-5)(1S,3S)-3-((6-(5-(((Butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole -4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-5)(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
目标化合物I-5的合成路线如下所示:The synthetic route of target compound 1-5 is as follows:
第一步:(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-5A)的合成The first step: (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of methyl 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5A)
methyl(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5A)methyl(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2 -cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-5A)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(350mg,634μmol)和N-甲基丁-1-胺(110mg,1.27mmol)的四氢呋喃(4.00mL)的混合液中加入二异丙基乙胺(205mg,1.59mmol,276μL),反应液在室温下搅拌2小时。反应完成后,反应液加水(10.0mL)稀释,用乙酸乙酯(10.0mL)萃取,有机相用饱和氯化钠溶液(10.0mL)洗涤,无水硫酸钠干燥,过滤浓缩得粗品(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-5A)(250mg)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (350mg, 634μmol) and N-methyl Diisopropylethylamine (205 mg, 1.59 mmol, 276 μL) was added to a mixture of butan-1-amine (110 mg, 1.27 mmol) in tetrahydrofuran (4.00 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (10.0 mL), extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product (1S, 3S)-3-((6-(5-(((Butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole-4- yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-5A) (250 mg).
LC-MS,M/Z=500.2[M+H]
+
LC-MS, M/Z=500.2[M+H] +
第二步:(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-5)的合成The second step: (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-5)(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5)
向(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(250mg,500μmol)的甲醇(2mL)溶液中加入一水合氢氧化锂(83.9mg,2mmol)的水(0.5mL)溶液,将混合物在25℃下搅拌12小时。反应液使用0.5M盐酸调节至pH为4,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤浓缩得粗产品。粗产物经反相高效液相色谱纯化(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%:43%-73%,15分钟)并通过SFC分离(柱子:DAICEL CHIRALCEL OD(250mm*30mm,10um);流动相:溶剂A=甲醇+0.1%NH
3H
2O;溶剂B=30%-30%二氧化碳,3.7min;40分钟)分离得(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-5)(89.2mg,174μmol,收率34.8%)。
To (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-tri Add lithium hydroxide monohydrate (83.9 mg, 2 mmol) in water (0.5 mL), and the mixture was stirred at 25°C for 12 hours. The reaction solution was adjusted to pH 4 with 0.5M hydrochloric acid, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%: 43%-73 %, 15 minutes) and separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: solvent A=methanol+0.1%NH 3 H 2 O; solvent B=30%-30% carbon dioxide, 3.7 min; 40 minutes) isolated (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1 ,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-5) (89.2mg, 174μmol, yield 34.8 %).
LC-MS,M/Z(ESI):486.4[M+H]
+
LC-MS, M/Z (ESI): 486.4[M+H] +
1H NMR(400MHz,CHLOROFORM-d)δ7.90-7.88(m,1H),7.20(d,1H),5.63(s,2H),4.69(br s,1H),4.14(s,3H),3.27(t,1H),3.12(t,1H),2.94-2.77(m,4H),2.55-2.46(m,1H),2.16(d,1H),2.05-1.87(m,3H),1.86-1.73(m,1H),1.71-1.57(m,3H),1.56-1.46(m,1H),1.39-1.24(m,2H),1.17-1.05(m,3H),1.00-0.92(m,3H),0.91(br s,2H).
1 H NMR (400MHz, CHLOROFORM-d) δ7.90-7.88 (m, 1H), 7.20 (d, 1H), 5.63 (s, 2H), 4.69 (br s, 1H), 4.14 (s, 3H), 3.27(t,1H),3.12(t,1H),2.94-2.77(m,4H),2.55-2.46(m,1H),2.16(d,1H),2.05-1.87(m,3H),1.86- 1.73(m,1H),1.71-1.57(m,3H),1.56-1.46(m,1H),1.39-1.24(m,2H),1.17-1.05(m,3H),1.00-0.92(m,3H ),0.91(br s,2H).
实施例6:目标化合物I-6的制备Embodiment 6: the preparation of target compound 1-6
(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-6)(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl -1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-6)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-6)(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-6)
目标化合物I-6的合成路线如下所示:The synthetic route of target compound 1-6 is as follows:
第一步:4-甲基苯磺酸4-((叔丁氧基羰基)(甲基)氨基)丁酯(I-6B)的合成The first step: the synthesis of 4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (I-6B)
4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate(I-6B)4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate(I-6B)
在室温下,向4-(甲基氨基)-1丁醇(240mg,2.33mmol),三乙胺(941mg,9.31mmol)的二氯甲烷溶液(3mL)加入碳酸二叔丁酯(558mg,2.56mmol),将反应液在25℃下搅拌1小时。将对甲苯磺酰氯(488mg,2.56mmol)加入到反应液中,反应液在25摄氏度下搅拌11小时。向反应液中加入水(5mL)淬灭反应,使用二氯甲烷萃取3次,无水硫酸钠干燥过滤,浓缩得黄色油状液体4-甲基苯磺酸4-((叔丁氧基羰基)(甲基)氨基)丁酯(I-6B)(700mg,783μmol,收率33%)。To 4-(methylamino)-1 butanol (240 mg, 2.33 mmol), triethylamine (941 mg, 9.31 mmol) in dichloromethane (3 mL) was added di-tert-butyl carbonate (558 mg, 2.56 mg) at room temperature. mmol), the reaction solution was stirred at 25°C for 1 hour. p-Toluenesulfonyl chloride (488mg, 2.56mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 11 hours. Add water (5mL) to the reaction solution to quench the reaction, extract 3 times with dichloromethane, dry and filter over anhydrous sodium sulfate, and concentrate to give yellow oily liquid 4-methylbenzenesulfonic acid 4-((tert-butoxycarbonyl) (Methyl)amino)butyl ester (I-6B) (700 mg, 783 μmol, yield 33%).
第二步:(4-氟丁基)(甲基)氨基甲酸叔丁酯(I-6C)的合成The second step: the synthesis of tert-butyl (4-fluorobutyl)(methyl)carbamate (I-6C)
tert-butyl(4-fluorobutyl)(methyl)carbamatetert-butyl(4-fluorobutyl)(methyl)carbamate
向4-甲基苯磺酸4-((叔丁氧基羰基)(甲基)氨基)丁酯(I-6B)(700mg,1.96mmol)的四氢呋喃(2mL)和水(1mL)溶液加入四丁基氟化铵(1M,3.92mL),将反应液在60度下搅拌16小时。将反应液直接浓缩得残余物。残余物经制备板(石油醚:乙酸乙酯=5:1)纯化得黄色油状液体(4-氟丁基)(甲基)氨基甲酸叔丁酯(I-6C)(200mg,974μmol,收率49.8%)。To a solution of 4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (I-6B) (700 mg, 1.96 mmol) in THF (2 mL) and water (1 mL) was added tetrahydrofuran (2 mL) and water (1 mL). Butylammonium fluoride (1M, 3.92mL), and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was directly concentrated to obtain a residue. The residue was purified by preparative plates (petroleum ether: ethyl acetate = 5:1) to obtain yellow oily liquid (4-fluorobutyl) (methyl) tert-butyl carbamate (I-6C) (200 mg, 974 μmol, yield 49.8%).
1H NMR(400MHz,DMSO-d
6)δ4.50(t,1H),4.41-4.36(m,1H),3.18(t,2H),2.76(s,3H),1.65-1.49(m,4H),1.39(s,9H)
1 H NMR (400MHz,DMSO-d 6 )δ4.50(t,1H),4.41-4.36(m,1H),3.18(t,2H),2.76(s,3H),1.65-1.49(m,4H ),1.39(s,9H)
第三步:4-氟-N-甲基丁-1-胺盐酸盐(I-6D)的合成The third step: the synthesis of 4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D)
4-fluoro-N-methylbutan-1-amine hydrochloride(I-6D)4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D)
在0℃下,向N-(4-氟丁基)-N-甲基氨基甲酸叔丁酯(180mg,876μmol)的乙酸乙酯(2mL)溶液中加入盐酸乙酸乙酯溶液(4M,3mL),并在25度下搅拌0.5小时。直接减压浓缩反应液,得黄色的油状液体4-氟-N-甲基丁-1-胺盐酸盐(I-6D)(120mg)。To a solution of tert-butyl N-(4-fluorobutyl)-N-methylcarbamate (180 mg, 876 μmol) in ethyl acetate (2 mL) was added a solution of hydrochloric acid in ethyl acetate (4M, 3 mL) at 0 °C , and stirred at 25 degrees for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain 4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D) (120 mg) as a yellow oily liquid.
第四步:(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-6E)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)- Synthesis of methyl 1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-6E)
(1S,3S)-methyl 3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-6E)(1S,3S)-methyl 3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-6E)
在室温下,向溶有4-氟-N-甲基-丁-1-胺(77.0mg,543.9μmol)和乙基二异丙基(234.3mg,1.81mmol)的四氢呋喃溶液(4mL)加入(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(200mg,362μmol),将反应液在25℃下搅拌0.5小时。减压浓缩反应液得残余物。残余物经制备板(石油醚:乙酸乙酯=1:1),得黄色油状物(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-6E)(105mg,202μmol,收率55.9%)To a solution (4 mL) of 4-fluoro-N-methyl-butan-1-amine (77.0 mg, 543.9 μmol) and ethyldiisopropyl (234.3 mg, 1.81 mmol) in tetrahydrofuran (4 mL) was added at room temperature ( 1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (200mg, 362μmol), the reaction solution was stirred at 25°C for 0.5 hours . The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluoro Butyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane - Methyl 1-carboxylate (I-6E) (105 mg, 202 μmol, yield 55.9%)
LC-MS,M/Z(ESI):518.4[M+H]
+
LC-MS, M/Z(ESI): 518.4[M+H] +
第五步:(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-6)的合成The fifth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)- Synthesis of 1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-6)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-6)(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-6)
向(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(105mg,202μmol)的甲醇(2mL)和水(0.2mL)中的溶液中加入一水合氢氧化锂(42.5mg,1.01mmol),将混合物在25℃下搅拌12小时。用1M盐酸将pH调至3,并用乙酸乙酯(3mL×4)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得粗产物。粗产物经反相高效液相色谱法纯化(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度: B%=8%-68%,15分钟)得(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-6)(48.8mg,94.97μmol,收率46.82%)。To (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (105mg, 202μmol) in methanol (2mL) and water (0.2mL ) was added lithium hydroxide monohydrate (42.5 mg, 1.01 mmol), and the mixture was stirred at 25° C. for 12 hours. The pH was adjusted to 3 with 1M hydrochloric acid, and extracted with ethyl acetate (3 mL×4). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%= 8%-68%, 15 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy Base) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-6) (48.8mg , 94.97 μmol, yield 46.82%).
LC-MS,M/Z(ESI):504.4[M+H]
+
LC-MS, M/Z (ESI): 504.4[M+H] +
1H NMR(400MHz,CHLOROFORM-d)δ7.92(d,1H),7.22(d,1H),5.67(s,2H),4.76-4.69(m,1H),4.57-4.20(m,2H),4.19-4.10(m,3H),3.39-3.28(m,1H),3.19(br s,1H),2.95-2.78(m,4H),2.57-2.47(m,1H),2.26-2.15(m,1H),2.04-1.92(m,3H),1.87-1.79(m,1H),1.68(s,5H),1.55-1.44(m,2H),1.09(d,2H),0.98(d,2H).
1 H NMR(400MHz,CHLOROFORM-d)δ7.92(d,1H),7.22(d,1H),5.67(s,2H),4.76-4.69(m,1H),4.57-4.20(m,2H) ,4.19-4.10(m,3H),3.39-3.28(m,1H),3.19(br s,1H),2.95-2.78(m,4H),2.57-2.47(m,1H),2.26-2.15(m ,1H),2.04-1.92(m,3H),1.87-1.79(m,1H),1.68(s,5H),1.55-1.44(m,2H),1.09(d,2H),0.98(d,2H ).
实施例7:目标化合物I-7的制备Embodiment 7: the preparation of target compound 1-7
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(戊基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-7)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-7)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-7)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-7)
目标化合物I-7的合成路线如下所示:The synthetic route of target compound 1-7 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(戊基)氨基甲酰基)氧基)甲基)))-1H-1,2,3-三唑-4-吡啶基-3-基)氧基)环己烷甲酸甲酯(I-7B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)) Synthesis of )-1H-1,2,3-triazol-4-pyridyl-3-yl)oxy)methylcyclohexanecarboxylate (I-7B)
(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-7B)(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexanecarboxylate (I-7B)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(150mg,271.96μmol)和N-甲基戊-1-胺(55.04mg,543.92μmol)的四氢呋喃(2.00mL)溶液中加入二异丙基乙胺(87.87 mg,679.90μmol,118.43μL),混合液在室温下搅拌2小时。反应完成后,加水(5.00mL)稀释,用乙酸乙酯(5.00mL)萃取,有机相用饱和食盐水在(5.00mL)洗涤,无水硫酸钠干燥,过滤浓缩得粗品(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(戊基)氨基甲酰基)氧基)甲基)))-1H-1,2,3-三唑-4-吡啶基-3-基)氧基)环己烷甲酸甲酯(I-7B)(90.0mg)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (150mg, 271.96μmol) and N-methyl Diisopropylethylamine (87.87 mg, 679.90 μmol, 118.43 μL) was added to a solution of pentylpentan-1-amine (55.04 mg, 543.92 μmol) in tetrahydrofuran (2.00 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with water (5.00mL), extracted with ethyl acetate (5.00mL), the organic phase was washed with saturated brine (5.00mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product (1S, 3S)- 3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl))-1H-1,2,3- Methyl triazol-4-pyridinyl-3-yl)oxy)cyclohexanecarboxylate (I-7B) (90.0 mg).
LC-MS,M/Z(ESI)=514.3[M+H]
+
LC-MS, M/Z(ESI)=514.3[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(戊基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-7)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)- Synthesis of 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-7)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-7)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-7)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(戊基)氨基甲酰基)氧基)甲基)))-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-7B)(90.0mg,175.22μmol)的四氢呋喃(2.00mL)和水(0.50mL)溶液中加入一水合氢氧化锂(73.53mg,1.75mmol),室温下搅拌过夜。反应完成后,将反应液浓缩得粗品,粗品经反相高效液相色谱法分离纯化(分离方法:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=43%-76%,20分钟)得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(戊基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-7)(24.29mg,收率26.94%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl) ))-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-7B) (90.0 mg, 175.22 μmol) in tetrahydrofuran Lithium hydroxide monohydrate (73.53 mg, 1.75 mmol) was added to a solution of (2.00 mL) and water (0.50 mL), and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by reverse-phase high-performance liquid chromatography (separation method: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid , solvent B=acetonitrile; gradient: B%=43%-76%, 20 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((( Methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I -7) (24.29 mg, yield 26.94%).
LC-MS,M/Z(ESI)=500.2[M+H]
+
LC-MS, M/Z(ESI)=500.2[M+H] +
1H NMR(400MHz,CHLOROFORM-d)δ7.92(d,J=8.6Hz,1H),7.21(d,J=8.6Hz,1H),5.67(s,2H),4.72(br s,1H),4.15(s,3H),3.27(t,1H),3.12(t,1H),2.94-2.90(m,4H),2.53-2.50(m,1H),2.19(d,1H),2.00-1.96(m,3H),1.89-1.75(m,1H),1.68-1.67(m,1H),1.59-1.47(m,1H),1.35–0.99(m,8H),0.98-0.78(m,6H).
1 H NMR (400MHz, CHLOROFORM-d) δ7.92(d, J=8.6Hz, 1H), 7.21(d, J=8.6Hz, 1H), 5.67(s, 2H), 4.72(br s, 1H) ,4.15(s,3H),3.27(t,1H),3.12(t,1H),2.94-2.90(m,4H),2.53-2.50(m,1H),2.19(d,1H),2.00-1.96 (m,3H),1.89-1.75(m,1H),1.68-1.67(m,1H),1.59-1.47(m,1H),1.35–0.99(m,8H),0.98-0.78(m,6H) .
实施例8:目标化合物I-8的制备Embodiment 8: the preparation of target compound 1-8
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基((S)-2-甲基丁基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-8)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-8)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-8)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-8)
目标化合物I-8的合成路线如下所示:The synthetic route of target compound 1-8 is as follows:
第一步:(S)-(2-甲基丁基)氨基甲酸叔丁酯(I-8B)的合成The first step: the synthesis of (S)-(2-methylbutyl) tert-butyl carbamate (I-8B)
(S)-tert-butyl(2-methylbutyl)carbamate(I-8B)(S)-tert-butyl(2-methylbutyl)carbamate(I-8B)
把环丁基甲胺(360mg,4.13mmol)和三乙胺(501.52mg,4.96mmol,689.84μL)溶解在二氯甲烷(5mL)中,在氮气保护下,向反应液中加入二碳酸二叔丁酯(901.40mg,4.13mmol,948.85μL),反应液在室温下搅拌过夜。反应完成后,将反应液直接浓缩得到粗品(S)-(2-甲基丁基)氨基甲酸叔丁酯(I-8B)(773.5mg)。Dissolve cyclobutylmethylamine (360mg, 4.13mmol) and triethylamine (501.52mg, 4.96mmol, 689.84μL) in dichloromethane (5mL), and add di-tert-butyl dicarbonate to the reaction solution under nitrogen protection (901.40 mg, 4.13 mmol, 948.85 μL), and the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was directly concentrated to obtain crude (S)-(2-methylbutyl)carbamate tert-butyl ester (I-8B) (773.5 mg).
第二步:(S)-(2-甲基丁基)氨基甲酸叔丁酯(I-8C)的合成The second step: the synthesis of (S)-(2-methylbutyl) tert-butyl carbamate (I-8C)
(S)-tert-butyl methyl(2-methylbutyl)carbamate(I-8C)(S)-tert-butyl methyl(2-methylbutyl)carbamate(I-8C)
将钠氢(330.39mg,8.26mmol,60%纯度)悬浮液四氢呋喃(8mL)中,然后在氮气保护和零度下,向其中滴加(S)-(2-甲基丁基)氨基甲酸叔丁酯(I-8B)(773.50mg,4.13mmol),之后将反应液在0℃下搅拌1个小时,然后在氮气保护和零度下,向反应液中滴加碘甲烷(879.35mg,6.20mmol,385.68μL),反应液在室温下搅拌过夜。反应完成后,向反应液中加入水(10mL)稀释,再用乙酸乙酯(10mL×3)萃取,合并有机层,用饱和食盐水(30mL)洗涤有机相,硫酸钠干燥,浓缩得粗品(S)-(2-甲基丁基)氨基甲酸叔丁酯(I-8C)(831.43mg)。Sodium hydrogen (330.39 mg, 8.26 mmol, 60% purity) was suspended in tetrahydrofuran (8 mL), and then (S)-(2-methylbutyl) tert-butyl carbamate was added dropwise at zero temperature under nitrogen protection. Ester (I-8B) (773.50mg, 4.13mmol), then the reaction solution was stirred at 0°C for 1 hour, and then methyl iodide (879.35mg, 6.20mmol, 385.68 μL), and the reaction solution was stirred overnight at room temperature. After the reaction was completed, water (10 mL) was added to the reaction solution to dilute, then extracted with ethyl acetate (10 mL×3), the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product ( S)-tert-Butyl(2-methylbutyl)carbamate (I-8C) (831.43 mg).
第三步:(S)-N,2-二甲基丁-1-胺盐酸盐(I-8D)的合成The third step: the synthesis of (S)-N,2-dimethylbutan-1-amine hydrochloride (I-8D)
(S)-N,2-dimethylbutan-1-amine hydrochloride(I-8D)(S)-N,2-dimethylbutan-1-amine hydrochloride(I-8D)
把(S)-(2-甲基丁基)氨基甲酸叔丁酯(831.43mg,4.13mmol)溶解在二氯甲烷(10mL)中,在氮气保护和0℃反应液中滴加盐酸二氧六环(4M,4.13mL),然后在25℃下反应12小时。反应完成后,将反应液直接浓缩得粗品(S)-N,2-二甲基丁-1-胺盐酸盐(I-8D)(417.93mg)。Dissolve (S)-(2-methylbutyl) tert-butyl carbamate (831.43mg, 4.13mmol) in dichloromethane (10mL), add dioxane hydrochloride dropwise to the reaction solution under nitrogen protection and 0°C ring (4M, 4.13 mL), then reacted at 25°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain crude (S)-N,2-dimethylbutan-1-amine hydrochloride (I-8D) (417.93 mg).
第四步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基((S)-2-甲基丁基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-8E)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl) )oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-8E)
methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-8E)methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-8E)
将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-2A)(150mg,271.96μmol)和(S)-N,2-二甲基丁-1-胺盐酸盐(93.59mg,679.91μmol)溶解在四氢呋喃(0.5mL)中,在氮气保护下,向反应液中滴加N,N-二异丙基乙胺(123.02mg,951.87μmol,165.80μL),然后在25度下反应2小时。反应完成后,反应液经制备板(石油醚:乙酸乙酯=1:1)分离纯化得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基((S)-2-甲基丁基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-8E)(77mg,收率55.1%)。(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-Triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid methyl ester (I-2A) (150 mg, 271.96 μmol) and (S)-N,2-dimethyl Butan-1-amine hydrochloride (93.59 mg, 679.91 μmol) was dissolved in tetrahydrofuran (0.5 mL), and N,N-diisopropylethylamine (123.02 mg, 951.87 μmol, 165.80 μL), and then reacted at 25 degrees for 2 hours. After the reaction was completed, the reaction solution was separated and purified by a preparation plate (petroleum ether: ethyl acetate = 1:1) to obtain (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5- (((Methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy base) cyclohexane-1-carboxylic acid methyl ester (I-8E) (77 mg, yield 55.1%).
LC-MS,M/Z(ESI):514.3[M+H]
+
LC-MS, M/Z(ESI):514.3[M+H] +
第五步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基((S)-2-甲基丁基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-8)的合成The fifth step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl) )oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-8)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-8)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-8)
把(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基((S)-2-甲基丁基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(77mg,149.91μmol)和一水合氢氧化锂(62.91mg,1.50mmol)溶解在四氢呋喃(1mL)和水(0.2mL)中,在25℃下搅拌反应12小时。反应完成后,将粗品经反相高效液相色谱法进行分离(分离方法:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225%甲酸(体积),溶剂B=乙腈;梯度:B%=47%-77%,15分钟)得((1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基((S)-2-甲基丁基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-8)(24.95mg,收率33.31%)。Put (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl((S)-2-methylbutyl)carbamoyl)oxy )methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (77 mg, 149.91 μmol) and lithium hydroxide monohydrate (62.91 mg, 1.50 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL), and the reaction was stirred at 25°C for 12 hours. After the reaction was completed, the crude product was separated by reverse-phase high-performance liquid chromatography (separation method: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225% formic acid (volume), solvent B= Acetonitrile; gradient: B%=47%-77%, 15 minutes) to get ((1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl( (S)-2-methylbutyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane- 1-Formic acid (I-8) (24.95 mg, yield 33.31%).
LC-MS,M/Z(ESI):500.4[M+H]
+
LC-MS, M/Z(ESI):500.4[M+H] +
1H NMR(400MHz,CDCl
3)δ7.93-7.90(m,1H),7.22-7.20(m,1H),5.68-5.67(m,2H),4.72(s,1H),4.15-4.14(m,3H),3.16-3.13(m,1H),2.98-2.93(m,1H),2.92-2.80(m,3H),2.55-2.51(m,1H),2.22-2.20(m,1H),1.99-1.96(m,4H),1.70-1.66(m,6H),1.10(s,2H),0.98(br dd,6H),0.74-0.68(m,3H).
1 H NMR (400MHz, CDCl 3 )δ7.93-7.90(m,1H),7.22-7.20(m,1H),5.68-5.67(m,2H),4.72(s,1H),4.15-4.14(m ,3H),3.16-3.13(m,1H),2.98-2.93(m,1H),2.92-2.80(m,3H),2.55-2.51(m,1H),2.22-2.20(m,1H),1.99 -1.96(m,4H),1.70-1.66(m,6H),1.10(s,2H),0.98(br dd,6H),0.74-0.68(m,3H).
实施例9:目标化合物I-9制备Embodiment 9: Preparation of target compound 1-9
(1S,3S)-3-((6-(5-(((丁氧基羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-9)(1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazole-4 -yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-9)
(1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-9)(1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin -3-yl)oxy)cyclohexanecarboxylic acid (target compound I-9)
目标化合物I-9的合成路线如下所示:The synthetic route of target compound 1-9 is as follows:
第一步:碳酸(4-硝基苯基)丁酯(I-9B)的合成The first step: the synthesis of (4-nitrophenyl) butyl carbonate (I-9B)
butyl(4-nitrophenyl)carbonate(I-9B)butyl(4-nitrophenyl)carbonate(I-9B)
在0℃下,向正丁醇(500mg,6.75mmol,617.28μL)和吡啶(1.60g,20.24mmol,1.63mL)的二氯甲烷(5.00mL)溶液中加入4-硝基苯基碳酰氯(2.72g,13.49mmol),反应液在室温下搅拌2小时。反应完成后,反应液用水(5.00mL)和饱和氯化钠水溶液(5.00mL)洗涤,有机相用无水硫酸钠干燥,过滤浓缩得粗品碳酸(4-硝基苯基)丁酯(I-9B)(500mg)。4-Nitrophenylcarbonyl chloride ( 2.72g, 13.49mmol), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was washed with water (5.00mL) and saturated aqueous sodium chloride solution (5.00mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product (4-nitrophenyl) butyl carbonate (I- 9B) (500 mg).
第二步:(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-9C)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridine- Synthesis of Methyl 3-yl)oxy)cyclohexanecarboxylate (I-9C)
(1S,3S)-methyl3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-9C)(1S,3S)-methyl3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I -9C)
在0℃下,向(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1I)(300mg,776μmol)的二氯甲烷(5.00mL)溶液缓慢分批加入戴斯马丁氧化剂(658mg,1.55mmol),反应液在25℃下搅拌2小时。反应完成后,将反应液过滤浓缩得到粗品,粗品通过层析硅胶板(二氧化硅,石油醚:乙酸乙酯=1:1)制备得到白色固体化合物(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9C)(150mg,383μmol,收率49.4%,纯度98.3%)。At 0°C, to (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4 -yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1I) (300 mg, 776 μmol) in dichloromethane (5.00 mL) was slowly added in portions to Dess Martin oxidant (658 mg , 1.55mmol), and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product, which was prepared by chromatography on a silica gel plate (silica, petroleum ether: ethyl acetate = 1:1) to obtain a white solid compound (1S,3S)-3-((2 -Cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl Ester (I-9C) (150 mg, 383 μmol, yield 49.4%, purity 98.3%).
LC-MS,M/Z(ESI):385.1[M+H]
+
LC-MS, M/Z(ESI):385.1[M+H] +
第三步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((甲基氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9D)的合成The third step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazole Synthesis of -4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-9D)
(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-9D)(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl) oxy)cyclohexanecarboxylate (I-9D)
在0℃下,向(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-9C)(180mg,468.23μmol)和甲胺盐酸盐(66.56mg,936.46μmol)的甲醇(3.00mL)溶液中加入醋酸硼氢化钠(248.09mg,1.17mmol),反应液在室温下搅拌过夜。反应完成后,将反应液浓缩得粗品,粗品用制备板分离纯化(纯化方法:石油醚:乙酸乙酯=1:1)得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((甲基氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9D)(180mg,352.35μmol,收率75.25%)。At 0°C, to (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl) To a solution of methylpyridin-3-yl)oxy)cyclohexanecarboxylate (I-9C) (180 mg, 468.23 μmol) and methylamine hydrochloride (66.56 mg, 936.46 μmol) in methanol (3.00 mL) was added boron acetate Sodium hydride (248.09mg, 1.17mmol), the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by a preparative plate (purification method: petroleum ether: ethyl acetate = 1:1) to obtain (1S,3S)-3-((2-cyclopropyl-6 -(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid Methyl ester (I-9D) (180 mg, 352.35 μmol, yield 75.25%).
LC-MS,M/Z(ESI)=400.2[M+H]
+
LC-MS, M/Z(ESI)=400.2[M+H] +
第四步:(1S,3S)-3-((6-(5-(((丁氧基羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9E)的合成The fourth step: (1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3- Synthesis of methyl triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-9E)
(1S,3S)-methyl3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-9E)(1S,3S)-methyl3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin -3-yl)oxy)cyclohexanecarboxylate (I-9E)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((甲基氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(90.0mg,225.29μmol)和碳酸(4-硝基苯基)丁酯(107.79mg,450.58μmol)的四氢呋喃(1.00mL)溶液中加入二异丙基乙胺(72.79mg,563.22μmol,98.10μL),反应液在室温下搅拌2小时。反应完成后,将反应液浓缩得粗品,粗品用制备板分离纯化(纯化方法:石油醚:乙酸乙酯=1:1)得(1S,3S)-3-((6-(5-(((丁氧基羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9E)(80.0mg,160.13μmol,收率71.08%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-tri Azol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (90.0 mg, 225.29 μmol) and (4-nitrophenyl)butyl carbonate (107.79 mg, 450.58 μmol) Diisopropylethylamine (72.79 mg, 563.22 μmol, 98.10 μL) was added to a solution of tetrahydrofuran (1.00 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified on a preparative plate (purification method: petroleum ether: ethyl acetate = 1:1) to obtain (1S,3S)-3-((6-(5-(( (Butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy ) methyl cyclohexane-1-carboxylate (I-9E) (80.0 mg, 160.13 μmol, yield 71.08%).
LC-MS,M/Z(ESI)=500.2[M+H]
+
LC-MS, M/Z(ESI)=500.2[M+H] +
第五步:(1S,3S)-3-((6-(5-(((丁氧基羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-9)的合成The fifth step: (1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3- Synthesis of triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-9)
(1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-9)(1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin -3-yl)oxy)cyclohexanecarboxylic acid (target compound I-9)
在室温下,向(1S,3S)-3-((6-(5-(((丁氧基羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9E)(80.0mg,160.13μmol)的四氢呋喃(1.50mL)和水(0.40mL)溶液中加入一水合氢氧化锂(67.20mg,1.60mmol),反应液在室温下搅拌过夜。反应完成后,将反应液浓缩的到粗品,粗品经高效液相色谱法分离纯化(分离方法:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225%甲酸(体积),溶剂B=乙腈;梯度:B%=43%-76%,15min)得(1S,3S)-3-((6-(5-(((丁氧基羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷甲酸(I-9)(29.6mg,59.77μmol,收率37.7%)。At room temperature, to (1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3 -Triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-9E) (80.0 mg, 160.13 μmol) in tetrahydrofuran (1.50 mL) Lithium hydroxide monohydrate (67.20 mg, 1.60 mmol) was added to the solution with water (0.40 mL), and the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to the crude product, which was separated and purified by high performance liquid chromatography (separation method: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225% formic acid (volume ), solvent B=acetonitrile; gradient: B%=43%-76%, 15min) to get (1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino) Methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (I-9) (29.6 mg, 59.77 μmol, yield 37.7%).
LC-MS,M/Z(ESI)=486.3[M+H]
+
LC-MS, M/Z(ESI)=486.3[M+H] +
1H NMR(400MHz,CHLOROFORM-d)δ7.95(d,J=8.5Hz,1H),7.23(d,1H),5.26(s,2H),4.73(s,1H),4.16(s,2H),4.04(s,3H),2.93(t,1H),2.74(s,3H),2.59-2.51(m,1H),2.21(d,1H),2.08-1.91(m,4H),1.88-1.76(m,2H),1.74-1.67(m,3H),1.48-1.36(m,2H),1.04-0.94(m,7H).
1 H NMR (400MHz, CHLOROFORM-d) δ7.95(d, J=8.5Hz, 1H), 7.23(d, 1H), 5.26(s, 2H), 4.73(s, 1H), 4.16(s, 2H ),4.04(s,3H),2.93(t,1H),2.74(s,3H),2.59-2.51(m,1H),2.21(d,1H),2.08-1.91(m,4H),1.88- 1.76(m,2H),1.74-1.67(m,3H),1.48-1.36(m,2H),1.04-0.94(m,7H).
实施例10:目标化合物I-10制备Embodiment 10: Preparation of target compound I-10
(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁氧基)羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-10)(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H -1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-10)(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-10)
目标化合物I-10的合成路线如下所示:The synthetic route of target compound 1-10 is as follows:
第一步:碳酸4-氟丁酯(4-硝基苯基)(I-10B)的合成The first step: the synthesis of 4-fluorobutyl carbonate (4-nitrophenyl) (I-10B)
4-fluorobutyl(4-nitrophenyl)carbonate(I-10B)4-fluorobutyl(4-nitrophenyl)carbonate(I-10B)
在0℃下,向4-氟丁-1-醇(200mg,2.17mmol,617.28μL)和吡啶(429.37mg,5.43mmol,438.13μL)的二氯甲烷(5.00mL)溶液中加入4-硝基苯基碳酰氯(656.48mg,3.26mmol),反应液在室温下搅拌2小时。反应完成后,反应液用水(5.00mL)和饱和氯化钠水溶液(5.00mL)洗涤,有机相用无水硫酸钠干燥,过滤浓缩的到粗品碳酸4-氟丁酯(4-硝基苯基)(I-10B)(350mg)。4-Nitro Phenylcarbonyl chloride (656.48mg, 3.26mmol), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with water (5.00mL) and saturated aqueous sodium chloride solution (5.00mL), the organic phase was dried over anhydrous sodium sulfate, and the crude product 4-fluorobutyl carbonate (4-nitrophenyl ) (I-10B) (350 mg).
第二步:(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁氧基)羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-10C)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1- Synthesis of Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-10C)
(1S,3S)-methyl3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-10C)(1S,3S)-methyl3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-10C)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((甲基氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9D)(100mg,250.32μmol)和碳酸4-氟丁酯(4-硝基苯基)(I-10B)(128.77mg,500.64μmol)的四氢呋喃(1.00mL)溶液中加入二异丙基乙胺(80.88mg, 625.80μmol,109.00μL),反应液在室温下搅拌2小时。反应完成后,将反应液浓缩得粗品,粗品用制备板分离纯化(纯化方法:石油醚:乙酸乙酯=1:1)得(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁氧基)羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-10C)(80.0mg,154.56μmol,收率61.75%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-tri Azol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-9D) (100 mg, 250.32 μmol) and 4-fluorobutyl carbonate (4-nitrophenyl) Diisopropylethylamine (80.88 mg, 625.80 μmol, 109.00 μL) was added to a solution of (I-10B) (128.77 mg, 500.64 μmol) in tetrahydrofuran (1.00 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by a preparative plate (purification method: petroleum ether: ethyl acetate = 1:1) to obtain (1S,3S)-3-((2-cyclopropyl-6 -(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine-3 -yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-10C) (80.0 mg, 154.56 μmol, yield 61.75%).
LC-MS,M/Z(ESI)=518.3[M+H]
+
LC-MS, M/Z(ESI)=518.3[M+H] +
第四步:(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁氧基)羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-10)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1- Synthesis of methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-10)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-10)(1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-10)
在室温下,向(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁氧基)羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-10C)(80.0mg,154.56μmol)的四氢呋喃(1.50mL)和水(0.40mL)溶液中加入一水合氢氧化锂(64.86mg,1.55mmol),反应液在室温下搅拌过夜。反应完成后,将反应液浓缩得粗品,粗品经反相液相高效色谱法分离纯化(分离方法:色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225%甲酸,溶剂B=乙腈;梯度:B%=41%-71%,20min)得到(1S,3S)-3-((2-环丙基-6-(5-((((4-氟丁氧基)羰基)(甲基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-10)(23.34mg,46.16μmol,收率29.87%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy)carbonyl)(methyl)amino)methyl)-1 -Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-10C) (80.0mg, 154.56μmol) Lithium hydroxide monohydrate (64.86 mg, 1.55 mmol) was added to a solution of tetrahydrofuran (1.50 mL) and water (0.40 mL), and the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by reverse-phase liquid phase high-performance chromatography (separation method: chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225% formic acid, Solvent B = acetonitrile; Gradient: B% = 41%-71%, 20min) to give (1S,3S)-3-((2-cyclopropyl-6-(5-((((4-fluorobutoxy )carbonyl)(methyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid ( I-10) (23.34 mg, 46.16 μmol, yield 29.87%).
LC-MS,M/Z(ESI)=504.2[M+H]
+
LC-MS, M/Z(ESI)=504.2[M+H] +
1H NMR(400MHz,CHLOROFORM-d)δ7.95(d,1H),7.23(d,1H),5.26(s,2H),4.73(s,1H),4.56(t,1H),4.44(t,1H),4.21(s,2H),4.04(s,3H),3.00-2.87(m,1H),2.75(s,3H),2.55-2.53(m,1H),2.21(d,1H),2.12-1.77(m,11H),1.01(d,4H).
1 H NMR (400MHz, CHLOROFORM-d) δ7.95(d,1H),7.23(d,1H),5.26(s,2H),4.73(s,1H),4.56(t,1H),4.44(t ,1H),4.21(s,2H),4.04(s,3H),3.00-2.87(m,1H),2.75(s,3H),2.55-2.53(m,1H),2.21(d,1H), 2.12-1.77(m,11H),1.01(d,4H).
实施例11:目标化合物I-11的制备Embodiment 11: Preparation of target compound I-11
(1S,3S)-3-((2-环丙基-6-(5-(((4-异丙基嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-11)(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-11)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-11)(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4 -yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-11)
目标化合物I-11的合成路线如下所示:The synthetic route of target compound I-11 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(5-(((4-异丙基嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-11B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl- Synthesis of methyl 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-11B)
(1S,3S)-methyl3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-11B)(1S,3S)-methyl3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4 -yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-11B)
在室温下,向(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9C)(70.0mg,182μmol)和4-异丙基嘧啶-2-胺(37.4mg,273μmol)的甲醇(1.00mL)溶液中滴加冰醋酸(21.8mg,364μmol),反应液在60度下搅拌6小时后降温至25℃,向反应液中加入氰基硼氢化钠(22.8mg,364μmol),反应液继续在25℃下搅拌12小时。反应完成后,加水(5.0mL)淬灭,乙酸乙酯(5.00mL)萃取,有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩得黄色油状物(1S,3S)-3-((2-环丙基-6-(5-(((4-异丙基嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-11B)(120mg,粗品),直接用于下一步。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridine -3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-9C) (70.0 mg, 182 μmol) and 4-isopropylpyrimidin-2-amine (37.4 mg, 273 μmol) in methanol (1.00 mL ) solution was added dropwise glacial acetic acid (21.8mg, 364μmol), and the reaction solution was stirred at 60°C for 6 hours and then cooled to 25°C. Sodium cyanoborohydride (22.8mg, 364μmol) was added to the reaction solution, and the reaction solution continued to Stir at 25°C for 12 hours. After the reaction was completed, it was quenched with water (5.0 mL), extracted with ethyl acetate (5.00 mL), the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give yellow oil (1S,3S)-3 -((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazole- 4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-11B) (120 mg, crude), used directly in the next step.
LC-MS,M/Z(ESI):506.3[M+H]
+
LC-MS, M/Z(ESI):506.3[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(5-(((4-异丙基嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-11)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl- Synthesis of 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-11)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-11)(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4 -yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-11)
在室温下,将(1S,3S)-3-((2-环丙基-6-(5-(((4-异丙基嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-11B)(115mg,227.45μmol)溶解在四氢呋喃(2.0mL)中,然后向其中加入水(0.5mL)和一水合氢氧化锂(57.27mg,1.36mmol),然后将混合物在25℃下搅拌12个小时。反应完成后,0~10℃下用1M盐酸将反应液pH调到3~4,然后二氯甲烷萃取,浓缩有机相得到粗品,粗品先经反相高效液相色谱纯化(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B= 乙腈;梯度:B%=39%-72%,11分钟),然后经手性柱拆分(色谱柱:AICEL CHIRALCEL OD(250mm*30mm,10um),流动相:溶剂A=0.1%的氨水+异丙醇,溶剂B=超临界二氧化碳,梯度:B%=40%-40%,连续进样,每3.8分钟进样一次)得(1S,3S)-3-((2-环丙基-6-(5-(((4-异丙基嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-11)(46.5mg,收率41.6%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl -1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-11B) (115 mg, 227.45 μmol) was dissolved in tetrahydrofuran (2.0 mL), then water (0.5 mL) and lithium hydroxide monohydrate (57.27 mg, 1.36 mmol) were added thereto, and the mixture was stirred at 25° C. for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with 1M hydrochloric acid at 0-10°C, then extracted with dichloromethane, and the organic phase was concentrated to obtain the crude product, which was first purified by reverse-phase high-performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=39%-72%, 11 minutes), then split through chiral column (chromatographic column: AICEL CHIRALCEL OD (250mm*30mm, 10um), mobile phase: solvent A = 0.1% ammonia + isopropanol, solvent B = supercritical carbon dioxide, gradient: B% = 40% -40%, continuous injection, every 3.8 (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-isopropylpyrimidin-2-yl)amino)methyl)-1-methyl yl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-11) (46.5 mg, yield 41.6%).
LC-MS,M/Z(ESI):492.5[M+H]
+
LC-MS, M/Z(ESI):492.5[M+H] +
1H NMR(400MHz,CDCl
3)δ8.11(br s,1H),7.90-7.86(m,1H),7.14-7.12(d,1H),6.46-6.45(d,1H),5.07(s,2H),4.61(s,1H),4.17(s,3H),2.83-2.78(m,2H),2.52-2.50(m,1H),2.27-2.03(m,1H),1.90-1.89(m,2H),1.84-1.76(m,1H),1.75-1.72(m,1H),1.60-1.55(m,4H),1.17-1.15(d,6H),1.10-1.06(m,2H),0.97-0.92(m,2H).
1 H NMR (400MHz, CDCl 3 )δ8.11(br s,1H),7.90-7.86(m,1H),7.14-7.12(d,1H),6.46-6.45(d,1H),5.07(s, 2H),4.61(s,1H),4.17(s,3H),2.83-2.78(m,2H),2.52-2.50(m,1H),2.27-2.03(m,1H),1.90-1.89(m, 2H),1.84-1.76(m,1H),1.75-1.72(m,1H),1.60-1.55(m,4H),1.17-1.15(d,6H),1.10-1.06(m,2H),0.97- 0.92(m,2H).
实施例12:目标化合物I-12的制备Embodiment 12: Preparation of target compound 1-12
(1S,3S)-3-((2-环丙基-6-(5-((4-(环丙基甲基)-1H-1,2,3-三唑-1-基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-12)(1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
(1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-12)(1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
目标化合物I-12的合成路线如下所示:The synthetic route of target compound 1-12 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(5-((4-(环丙基甲基)-1H-1,2,3-三唑-1-基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基氧基)环己烷-1-甲酸甲酯(I-12B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazole-1- Synthesis of methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yloxy)cyclohexane-1-carboxylate (I-12B)
(1S,3S)-methyl3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-12B)(1S,3S)-methyl3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-12B)
在室温下,将(1S,3S)-3-((6-(5-(叠氮甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基) 氧基)环己烷-1-甲酸甲酯(I-1J)(210mg,510μmol),(3-环丙基丙-1-炔-1-基)三甲基硅烷(388.68mg,2.55mmol),硫酸铜(81.46mg,510.38μmol)和L-抗坏血酸钠(101.11mg,510.38μmol)加入到四氢呋喃(3.0mL)和水(1.0mL)中,在室温搅拌12小时。反应完成后,向反应液中加水(15.0mL)淬灭,二氯甲烷萃取,有机相用饱和食盐水洗涤后再用无水硫酸钠干燥,过滤并减压浓缩得粗品,粗品经硅胶层析柱纯化(石油醚:乙酸乙酯=5:1至2:1)得白色固体化合物(1S,3S)-3-((2-环丙基-6-(5-((4-(环丙基甲基)-1H-1,2,3-三唑-1-基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-12B)(220mg,收率87.7%)。At room temperature, (1S,3S)-3-((6-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- Cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1J) (210mg, 510μmol), (3-cyclopropylprop-1-yn-1-yl)trimethyl Silane (388.68mg, 2.55mmol), copper sulfate (81.46mg, 510.38μmol) and sodium L-ascorbate (101.11mg, 510.38μmol) were added to tetrahydrofuran (3.0mL) and water (1.0mL), stirred at room temperature for 12 Hour. After the reaction was completed, water (15.0 mL) was added to the reaction liquid to quench, dichloromethane extracted, the organic phase was washed with saturated brine and then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Column purification (petroleum ether: ethyl acetate = 5:1 to 2:1) gave white solid compound (1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropyl Methyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl) Oxy)methyl cyclohexane-1-carboxylate (I-12B) (220 mg, yield 87.7%).
LC-MS,M/Z(ESI):492.5[M+H]
+
LC-MS, M/Z(ESI):492.5[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(5-((4-(环丙基甲基)-1H-1,2,3-三唑-1-基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-12)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazole-1- Base) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-12) synthesis
(1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-12)(1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-12)
在室温下,将(1S,3S)-3-((2-环丙基-6-(5-((4-(环丙基甲基)-1H-1,2,3-三唑-1-基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-12B)(210mg,427.19μmol)溶解在四氢呋喃(3.0mL)和水(1.0mL)中,然后向其中加入一水合氢氧化锂(107.55mg,2.56mmol),混合物在25℃下搅拌10个小时。反应完成后,0~10℃下用1N的盐酸将反应液的pH调到3~4,用二氯甲烷萃取,浓缩有机相得到粗品。粗品先经反相高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=38%-68%,10min)纯化然后经手性拆分(色谱柱:AICEL CHIRALCEL OD(250mm*30mm,10um),流动相:溶剂A=0.1%的氨水+异丙醇,溶剂B=超临界二氧化碳,梯度:B%=35%-35%,连续进样,每4.0分钟进样一次)得(1S,3S)-3-((2-环丙基-6-(5-((4-(环丙基甲基)-1H-1,2,3-三唑-1-基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-12)(70.3mg,33.5%收率)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl)-1H-1,2,3-triazole-1 -yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-12B) (210 mg, 427.19 μmol) was dissolved in tetrahydrofuran (3.0 mL) and water (1.0 mL), then lithium hydroxide monohydrate (107.55 mg, 2.56 mmol) was added thereto, and the mixture was stirred at 25° C. for 10 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid at 0-10° C., extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product. The crude product is first subjected to reverse-phase high-performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=38%-68% , 10min) purification and then chiral resolution (column: AICEL CHIRALCEL OD (250mm*30mm, 10um), mobile phase: solvent A = 0.1% ammonia + isopropanol, solvent B = supercritical carbon dioxide, gradient: B% =35%-35%, continuous sampling, sampling once every 4.0 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(5-((4-(cyclopropylmethyl )-1H-1,2,3-triazol-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) Cyclohexane-1-carboxylic acid (I-12) (70.3 mg, 33.5% yield).
LC-MS,M/Z(ESI):478.1[M+H]
+
LC-MS, M/Z(ESI):478.1[M+H] +
1H NMR(400MHz,CDCl
3)δ8.03-8.00(d,1H),7.50(s,1H),7.30-7.28(d,1H),6.19(s,2H),4.76(br s,1H),4.08(s,3H),2.97-2.90(m,1H),2.61-2.54(m,3H),2.23-2.19(m,1H),2.02-1.97(m,3H),1.85-1.79(m,1H),1.74-1.67(m,3H),1.02-0.92(m,5H),0.51-0.46(m,2H),0.18-0.14(m,2H).
1 H NMR (400MHz, CDCl 3 )δ8.03-8.00(d,1H),7.50(s,1H),7.30-7.28(d,1H),6.19(s,2H),4.76(br s,1H) ,4.08(s,3H),2.97-2.90(m,1H),2.61-2.54(m,3H),2.23-2.19(m,1H),2.02-1.97(m,3H),1.85-1.79(m, 1H),1.74-1.67(m,3H),1.02-0.92(m,5H),0.51-0.46(m,2H),0.18-0.14(m,2H).
实施例13:目标化合物I-13的制备Embodiment 13: Preparation of target compound 1-13
(1S,3S)-3-((6-(5-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷甲酸(目标化合物I-13)(1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl -1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-13)
(1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-13)(1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-13)
目标化合物I-13的合成路线如下所示:The synthetic route of target compound 1-13 is as follows:
第一步:(1S,3S)-3-((6-(5-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-13B)的合成The first step: (1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)- 1-Methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-13B) synthesis
(1S,3S)-methyl3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylate(I-13B)(1S,3S)-methyl3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylate (I-13B)
在室温下,向(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9C)(130mg,338μmol)和5-(环丁基甲基)-1,2,4-恶二唑-3-胺(77.7mg,507μmol)的甲醇(1.50mL)溶液中滴加冰醋酸(40.6mg,676μmol),反应液在60℃下搅拌12小时后降温至25℃,加入氰基硼氢化钠(42.5mg,676μmol),反应液继续在25℃下搅拌12小时。反应完成后,加水(5.00mL)淬灭反应,用乙酸乙酯萃取(5.00mL),有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤浓缩得粗品化合物(1S,3S)-3-((6-(5-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-13B)(140mg,粗品),直接用于下一步。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridine -3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-9C) (130 mg, 338 μmol) and 5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-amine ( 77.7mg, 507μmol) in methanol (1.50mL) was added dropwise glacial acetic acid (40.6mg, 676μmol), the reaction solution was stirred at 60°C for 12 hours and then cooled to 25°C, sodium cyanoborohydride (42.5mg, 676μmol ), and the reaction solution continued to stir at 25°C for 12 hours. After the reaction was complete, add water (5.00mL) to quench the reaction, extract with ethyl acetate (5.00mL), wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter and concentrate to obtain crude compound (1S, 3S)- 3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-13B) (140 mg, crude product) was directly used in the next step .
LC-MS,M/Z(ESI):522.2[M+H]
+
LC-MS, M/Z(ESI):522.2[M+H] +
第二步:(1S,3S)-3-((6-(5-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-13)的合成The second step: (1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)- 1-Methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-13) synthesis
(1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-13)(1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-13)
在室温下,将(1S,3S)-3-((6-(5-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-13B)(115mg,220.47μmol)溶解在四氢呋喃(3.0mL)中,然后向其中加入水(1.0mL)和一水合氢氧化锂(5.51mg,1.32mmol),然后将混合物在25℃下搅拌12个小时。反应完成后,0~10℃下用1N的盐酸将反应液的pH调到3~4,然后二氯甲烷萃取,浓缩有机相得粗品。然后粗品先经反相高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=46%-76%,11分钟)纯化,然后经手性拆分(色谱柱:AICEL CHIRALCEL OD(250mm*30mm,10um),流动相:溶剂A=0.1%的氨水+异丙醇,溶剂B=超临界二氧化碳,梯度:B%=39%-72%,连续进样,每3.8分钟进样一次)得(1S,3S)-3-((6-(5-(((5-(环丁基甲基)-1,2,4-恶二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(38.2mg,收率34.2%)。At room temperature, (1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1,2,4-oxadiazol-3-yl)amino)methyl) -1-Methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-13B) (115 mg, 220.47 μmol) was dissolved in tetrahydrofuran (3.0 mL), then water (1.0 mL) and lithium hydroxide monohydrate (5.51 mg, 1.32 mmol) were added thereto, and the mixture was then stirred at 25° C. for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid at 0-10°C, then extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product. Then the crude product is first through reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=46%-76 %, 11 minutes) purification, and then chiral resolution (column: AICEL CHIRALCEL OD (250mm*30mm, 10um), mobile phase: solvent A = 0.1% ammonia + isopropanol, solvent B = supercritical carbon dioxide, gradient : B%=39%-72%, continuous sampling, sampling once every 3.8 minutes) to get (1S,3S)-3-((6-(5-(((5-(cyclobutylmethyl)-1, 2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl) Oxy)cyclohexane-1-carboxylic acid (38.2 mg, yield 34.2%).
LC-MS,M/Z(ESI):508.5[M+H]
+
LC-MS, M/Z(ESI):508.5[M+H] +
1H NMR(400MHz,CDCl
3)δ8.00-7.98(d,1H),7.29(s,1H),4.74-4.68(m,3H),4.24(s,3H),2.93-2.92(m,1H),2.81-2.79(d,2H),2.77-2.68(m,1H),2.61-2.59(m,1H),2.19-2.08(m,3H),2.01-1.68(m,12H),1.10-1.06(m,4H).
1 H NMR (400MHz, CDCl 3 )δ8.00-7.98(d,1H),7.29(s,1H),4.74-4.68(m,3H),4.24(s,3H),2.93-2.92(m,1H ),2.81-2.79(d,2H),2.77-2.68(m,1H),2.61-2.59(m,1H),2.19-2.08(m,3H),2.01-1.68(m,12H),1.10-1.06 (m,4H).
实施例14:目标化合物I-14的制备Embodiment 14: Preparation of Target Compound I-14
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-戊烷-2-基氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-14)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl) -1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-14)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl)-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14)
目标化合物I-14的合成路线如下所示:The synthetic route of target compound 1-14 is as follows:
第一步:(S)-4-硝基苯基碳酸戊-2-基酯(I-14B)的合成The first step: the synthesis of (S)-4-nitrophenyl carbonate pent-2-yl ester (I-14B)
(S)-4-nitrophenyl pentan-2-yl carbonate(I-14B)(S)-4-nitrophenyl pentan-2-yl carbonate(I-14B)
在室温下,将(R)-戊烷-2-醇(300mg,3.40mmol)和吡啶(807mg,10.2mmol)加入到二氯甲烷(5.00mL)中,然后再0~10℃下缓慢加入4-硝基苯基碳酰氯(685mg,3.40mmol),加完后室温搅拌2.0小时,将反应混合物经柱层析(石油醚:乙酸乙酯(V/V)=50:1到20:1)制备得到黄色油状物(S)-4-硝基苯基碳酸戊-2-基酯(I-14B)(600mg,收率69.6%)。At room temperature, (R)-pentan-2-ol (300mg, 3.40mmol) and pyridine (807mg, 10.2mmol) were added to dichloromethane (5.00mL), and then slowly added 4 -Nitrophenylcarbonyl chloride (685mg, 3.40mmol), stirred at room temperature for 2.0 hours after the addition, and the reaction mixture was subjected to column chromatography (petroleum ether: ethyl acetate (V/V) = 50:1 to 20:1) (S)-pent-2-yl 4-nitrophenylcarbonate (I-14B) (600 mg, yield 69.6%) was prepared as a yellow oil.
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烯-1-甲酸甲酯(I-14C)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentane-2-yl)oxy)carbonyl) Synthesis of amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexene-1-carboxylic acid methyl ester (I-14C)
(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-14C)(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl)-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-14C)
在室温下,将(1S,3S)-3-((6-(5-(氨基甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1K)(161mg,417μmol)和三乙胺(126mg,1.25mmol)加入到四氢呋喃(5.00mL)中,然后加入(S)-4-硝基苯基碳酸戊-2-基酯(I-14B)(158mg,626μmol),反应液在室温搅拌12小时。反应完成后,将反应浓缩得粗品,粗品经柱层析(石油醚:乙酸乙酯=10:1-3:1)制备得到黄色油状物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烯-1-甲酸甲酯(I-14C)(200mg,收率95.8%)。At room temperature, (1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclo Propylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1K) (161 mg, 417 μmol) and triethylamine (126 mg, 1.25 mmol) were added to tetrahydrofuran (5.00 mL), then (S)-4-Nitrophenyl pent-2-yl carbonate (I-14B) (158 mg, 626 μmol) was added, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction was concentrated to obtain a crude product, which was prepared by column chromatography (petroleum ether: ethyl acetate = 10:1-3:1) to obtain (1S,3S)-3-((2-cyclopropane Base-6-(1-methyl-5-(((((R)-pentane-2-yl)oxy)carbonyl)amino)methyl)-1H-1,2,3-triazole-4 -yl)pyridin-3-yl)oxy)cyclohexene-1-carboxylic acid methyl ester (I-14C) (200 mg, yield 95.8%).
LC-MS,M/Z(ESI):500.2[M+H]
+
LC-MS, M/Z(ESI):500.2[M+H] +
第三步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-戊烷-2-基氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-14)The third step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentane-2-yloxy)carbonyl)amino )methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-14)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-14)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methyl)-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-14)
在室温下,将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-戊烷-2-基)氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烯-1-甲酸甲酯(I-14C)(200mg,400μmol)溶解在四氢呋喃(4.00mL)中,然后向其中加入水(0.800mL)和一水合氢氧化锂(100mg,2.40mmol),然后将混合物在室温下搅拌12个小时。反应完成后,用1N的盐酸将反应液的pH调到3~4,然后用二氯甲烷萃取,浓缩有机相得到粗品。然后粗品先经反相高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=45%-75%,7分钟)纯化,然后再经手性拆分(色谱柱:AICEL CHIRALCEL OD(250mm*30mm,10um),流动相:溶剂A=0.1%的氨水+异丙醇,溶剂B=超临界二氧化碳,梯度:B%=40%-40%,连续进样,每3.8分钟进样一次)得到(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((((R)-戊烷-2-基氧基)羰基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-14)(130mg,收率67.5%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentane-2-yl)oxy)carbonyl )amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexene-1-carboxylic acid methyl ester (I-14C) (200mg, 400μmol) It was dissolved in tetrahydrofuran (4.00 mL), then water (0.800 mL) and lithium hydroxide monohydrate (100 mg, 2.40 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid, then extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product. Then the crude product is first through reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=45%-75 %, 7 minutes) purification, and then through chiral resolution (chromatographic column: AICEL CHIRALCEL OD (250mm*30mm, 10um), mobile phase: solvent A=0.1% ammonia+isopropanol, solvent B=supercritical carbon dioxide, Gradient: B%=40%-40%, continuous sample injection, sample injection once every 3.8 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-( ((((R)-pentane-2-yloxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexyl Alkane-1-carboxylic acid (I-14) (130 mg, yield 67.5%).
LC-MS,M/Z(ESI):486.4[M+H]
+
LC-MS, M/Z(ESI):486.4[M+H] +
1H NMR(400MHz,CDCl
3)δ7.99-7.92(d,1H),7.28(s,1H),6.07(s,1H),4.79-4.74(m,2H),4.67-4.59(m,2H),4.19(s,3H),2.96-2.92(m,1H),2.60-2.57(m,1H),2.20-2.17(m,1H),2.02-1.96(m,3H),1.84-1.81(m,1H),1.73-1.61(m,3H),1.58-1.50(m,1H),1.45-1.35(m,1H),1.34-1.26(m,2H),1.20-1.18(d,3H),1.06-1.04(m,4H),0.91-0.87(t,3H).
1 H NMR (400MHz, CDCl 3 )δ7.99-7.92(d,1H),7.28(s,1H),6.07(s,1H),4.79-4.74(m,2H),4.67-4.59(m,2H ),4.19(s,3H),2.96-2.92(m,1H),2.60-2.57(m,1H),2.20-2.17(m,1H),2.02-1.96(m,3H),1.84-1.81(m ,1H),1.73-1.61(m,3H),1.58-1.50(m,1H),1.45-1.35(m,1H),1.34-1.26(m,2H),1.20-1.18(d,3H),1.06 -1.04(m,4H),0.91-0.87(t,3H).
实施例15:目标化合物I-15的制备Embodiment 15: Preparation of target compound I-15
(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丁基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-15)(1S,3S)-3-((6-(5-(((Butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole -4-yl)-2-cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15)
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclobutylpy din-3-yl)oxy)cyclohexanecarboxylicacid(目标化合物I-15)(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- cyclobutylpy din-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-15)
目标化合物I-15的合成路线如下所示:The synthetic route of target compound 1-15 is as follows:
第一步:2-环丁基-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-(((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡啶(I-15B)的合成The first step: 2-cyclobutyl-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-(((trimethylsilyl)methyl Synthesis of -1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15B)
2-cyclobutyl-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine(I-15B)2-cyclobutyl-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl) -3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15B)
在60℃下,向单质镁(360mg,14.8mmol)的四氢呋喃(15.0mL)溶液中加入溴环丁烷(1.00g,7.41mmol),并在60℃下搅拌反应3小时。在氮气氛围下将2-溴-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡啶(1.06g,1.85mmol)和四三苯基膦钯(321mg,277μmol)加入反应混合物中并将反应混合物在60℃下搅拌2小时。反应完成后,加水和乙酸乙酯萃取,有机相浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=3:1)制备得到黄色油状物2-环丁基-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-(((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡啶(I-15B)(650mg,收率64.1%)。At 60°C, bromocyclobutane (1.00 g, 7.41 mmol) was added to a solution of elemental magnesium (360 mg, 14.8 mmol) in tetrahydrofuran (15.0 mL), and the reaction was stirred at 60°C for 3 hours. Under nitrogen atmosphere, 2-bromo-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl) -1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (1.06g, 1.85mmol) and tetrathree Phenylphosphine palladium (321 mg, 277 μmol) was added to the reaction mixture and the reaction mixture was stirred at 60° C. for 2 hours. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phase was concentrated to obtain a crude product. The crude product was prepared through a preparation plate (petroleum ether: ethyl acetate = 3:1) to obtain a yellow oil 2-cyclobutyl-6-(5-( ((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-(((trimethylsilyl)methyl)-1H-1,2,3-triazole-4- yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15B) (650 mg, yield 64.1%).
LC-MS,M/Z(ESI):547.4[M+H]
+
LC-MS, M/Z(ESI):547.4[M+H] +
第二步:2-环丁基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-醇(I-15C)的合成The second step: 2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3- Synthesis of Triazol-4-yl)pyridin-3-ol (I-15C)
2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol(I-15C)2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol (I-15C)
在室温下,向2-环丁基-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡啶(I-15B)(530mg,969μmol)的四氢呋喃(2mL)溶液中加入四丁基氟化铵的四氢呋喃溶液(1M,3.88mL),将反应液在60℃下搅拌12小时。反应完成后直接浓缩,将反应混合物经制备板(石油醚:乙酸乙酯=2:1)分离纯化得黄色油状液体2-环丁基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-醇(I-15C)(230mg,收率68.9%)。At room temperature, to 2-cyclobutyl-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl yl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15B) (530mg, 969 μmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride in tetrahydrofuran (1M, 3.88 mL), and the reaction solution was stirred at 60° C. for 12 hours. After the reaction was completed, it was directly concentrated, and the reaction mixture was separated and purified by a preparation plate (petroleum ether: ethyl acetate = 2:1) to obtain a yellow oily liquid 2-cyclobutyl-6-(1-methyl-5-((( Hydrogen-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol (I-15C) (230mg, yield 68.9% ).
LC-MS,M/Z(ESI):345.2[M+H]
+
LC-MS, M/Z(ESI):345.2[M+H] +
第三步:(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1)-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15D)的合成The third step: (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl Synthesis of )-1)-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15D)
(1S,3S)-methyl3-((2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-15D)(1S,3S)-methyl3-((2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-15D)
在0℃下,向2-环丁基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-醇(I-15C)(211mg,1.34mmol)三苯基膦(350mg,1.34mmol)的甲苯溶液(3mL)加入偶氮二甲酸二异丙酯(270mg,1.34mmol,259μL),将混合物在25℃下搅拌12小时。将反应混合物经制备板(石油醚:乙酸乙酯=1:1)制备得黄色油状化合物(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1)-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15D)(200mg,收率61.8%)。At 0°C, to 2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2, 3-Triazol-4-yl)pyridin-3-ol (I-15C) (211 mg, 1.34 mmol) triphenylphosphine (350 mg, 1.34 mmol) in toluene (3 mL) was added diisopropyl azodicarboxylate (270 mg, 1.34 mmol, 259 μL), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was prepared through a preparative plate (petroleum ether: ethyl acetate = 1:1) to prepare yellow oily compound (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-( ((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1)-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane- Methyl 1-carboxylate (I-15D) (200 mg, yield 61.8%).
LC-MS,M/Z(ESI):485.3[M+H]
+
LC-MS, M/Z(ESI):485.3[M+H] +
第四步:(1S,3S)-3-((2-环丁基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15E)的合成The fourth step: (1S,3S)-3-((2-cyclobutyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15E) synthesis
(1S,3S)-methyl 3-((2-cyclobutyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-15E)(1S,3S)-methyl 3-((2-cyclobutyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylate (I-15E)
在室温下,向(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1)-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15D)(200mg,412.72μmol)的甲醇溶液(3 mL)中加入吡啶对甲苯磺酸盐(20.7mg,82.5μmol),将混合物在60℃下搅拌12小时。将反应混合物经制备板(石油醚:乙酸乙酯=1:2)制备得黄色油状化合物(1S,3S)-3-((2-环丁基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15E)(220mg)。At room temperature, to (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl Base)-1)-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15D) (200 mg, 412.72 μmol) in methanol To the solution (3 mL) was added pyridine p-toluenesulfonate (20.7 mg, 82.5 μmol), and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was prepared through a preparative plate (petroleum ether: ethyl acetate = 1:2) to prepare a yellow oily compound (1S,3S)-3-((2-cyclobutyl-6-(5-(hydroxymethyl)- Methyl 1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-15E) (220 mg).
LC-MS,M/Z(ESI):410.0[M+H]
+
LC-MS, M/Z(ESI):410.0[M+H] +
第五步:(1S,3S)-3-((2-环丁基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H)1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15F)的合成The fifth step: (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl) -1H) Synthesis of 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15F)
(1S,3S)-methyl 3-((2-cyclobutyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-15F)(1S,3S)-methyl 3-((2-cyclobutyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4 -yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-15F)
在0℃下,向(1S,3S)-3-((2-环丁基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15E)(220mg,549μmol,)和吡啶(130mg,1.65mmol)的二氯甲烷(3mL)溶液中加入(4-硝基苯基)氯甲酸苯酯(166mg,824μmol),反应液在25℃搅拌12小时。反应完成后,将反应浓缩得到黄色油状(1S,3S)-3-((2-环丁基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H)1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15F)(300mg)。At 0°C, to (1S,3S)-3-((2-cyclobutyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4 -yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15E) (220 mg, 549 μmol,) and pyridine (130 mg, 1.65 mmol) in dichloromethane (3 mL) were added (4-Nitrophenyl)phenyl chloroformate (166mg, 824μmol), and the reaction solution was stirred at 25°C for 12 hours. After completion of the reaction, the reaction was concentrated to give (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl) as a yellow oil Oxy)methyl)-1H)1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15F) (300 mg).
LC-MS,M/Z(ESI):566.2[M+H]
+
LC-MS, M/Z(ESI):566.2[M+H] +
第六步:(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丁基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15G)的合成The sixth step: (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-cyclobutyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15G)
(1S,3S)-methyl 3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-15G)(1S,3S)-methyl 3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2 -cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-15G)
在室温下,向(1S,3S)-3-((2-环丁基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H)1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15F)(300mg,530μmol)和二异丙基乙胺(205mg,1.59mmol)的四氢呋喃溶液(3mL)中加入N-甲基丁烷-1-胺(92.4mg,1.06mmol),将混合物在25℃下搅拌0.5小时。将反应混合物经制备板(石油醚:乙酸乙酯=2:1)制备得黄色油状物(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丁基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15G)(150mg,收率55.2%)。At room temperature, to (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H) 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15F) (300mg, 530μmol) and diisopropyl To a tetrahydrofuran solution (3 mL) of ethylamine (205 mg, 1.59 mmol) was added N-methylbutan-1-amine (92.4 mg, 1.06 mmol), and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was prepared through a preparative plate (petroleum ether: ethyl acetate = 2:1) to prepare a yellow oil (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl )oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclobutyl)pyridin-3-yl)oxy)cyclohexane-1- Methyl formate (I-15G) (150 mg, yield 55.2%).
LC-MS,M/Z(ESI):514.2[M+H]
+
LC-MS, M/Z(ESI):514.2[M+H] +
第七步:(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丁基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-15)的合成The seventh step: (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15)
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclobutylpy din-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-15)(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- cyclobutylpy din-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-15)
在室温下,向(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丁基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15G)(150mg,292μmol)的甲醇(3mL)和水(0.3mL)溶液中加入一水和氢氧化锂(61.2mg,1.46mmol),将混合物在25℃下搅拌12小时。反应完成后,反应液用1M盐酸调节至pH为4,乙酸乙酯萃取,浓缩得到粗品。然后粗品经反相高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=54%-84%,11分钟)得(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丁基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-15)(44.5mg,收率29.2%)。At room temperature, to (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclobutyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (1-15G) (150 mg, 292 μmol) in methanol (3 mL) To a solution with water (0.3 mL) were added monowater and lithium hydroxide (61.2 mg, 1.46 mmol), and the mixture was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction solution was adjusted to pH 4 with 1M hydrochloric acid, extracted with ethyl acetate, and concentrated to obtain a crude product. Then the crude product is through reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; Mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; Gradient: B%=54%-84% , 11 minutes) to (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclobutylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-15) (44.5 mg, yield 29.2%).
LC-MS,M/Z(ESI):500.4[M+H]
+
LC-MS, M/Z(ESI):500.4[M+H] +
1H NMR(400MHz,CHLOROFORM-d)δ=8.04-7.94(d,1H),7.18-7.16(d,1H),5.83(s,2H),4.74-4.61(s,1H),4.16(s,3H),4.00-3.89(m,1H),3.31-3.21(m,1H),3.19-3.09(m,1H),2.92-2.85(m,2H),2.84-2.78(m,2H),2.47-2.37(m,2H),2.31-2.26(m,2H),2.17-1.97(m,3H),1.96-1.84(m,3H),1.78-1.70(m,1H),1.68-1.56(m,3H),1.50(m,1H),1.40-1.28(m,2H),1.16-1.06(m,1H),0.76(m,3H).
1 H NMR (400MHz, CHLOROFORM-d) δ=8.04-7.94(d,1H),7.18-7.16(d,1H),5.83(s,2H),4.74-4.61(s,1H),4.16(s, 3H),4.00-3.89(m,1H),3.31-3.21(m,1H),3.19-3.09(m,1H),2.92-2.85(m,2H),2.84-2.78(m,2H),2.47- 2.37(m,2H),2.31-2.26(m,2H),2.17-1.97(m,3H),1.96-1.84(m,3H),1.78-1.70(m,1H),1.68-1.56(m,3H ),1.50(m,1H),1.40-1.28(m,2H),1.16-1.06(m,1H),0.76(m,3H).
实施例16:目标化合物I-16的制备Embodiment 16: Preparation of Target Compound I-16
(1S,3S)-3-((2-环丙基-6-(5-((((2-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-16)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1- Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-16)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-16)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-16)
目标化合物I-16的合成路线如下所示:The synthetic route of target compound 1-16 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(5-((((2-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-16A)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)methylcyclohexanecarboxylate (I-16A)
(1S,3S)-methyl3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-16A)(1S,3S)-methyl3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-16A)
在室温下,将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(120mg,217.57μmol)和2-环丙基-N-甲基乙胺盐酸盐(3.78mg,543.92μmol)加入到四氢呋喃(1.5mL)中,然后再滴加N,N-二异丙基乙胺(98.42mg,761.49μmol),反应液在室温搅拌0.5小时。反应完成后,将反应液浓缩得粗品,粗品用制备板(石油醚:乙酸乙酯=2:1)制备得黄色油状化合物(1S,3S)-3-((2-环丙基-6-(5-((((2-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-16A)(100mg,收率89.8%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (120mg, 217.57μmol) and 2-ring Propyl-N-methylethylamine hydrochloride (3.78mg, 543.92μmol) was added to tetrahydrofuran (1.5mL), and then N,N-diisopropylethylamine (98.42mg, 761.49μmol) was added dropwise, The reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was prepared in a preparation plate (petroleum ether: ethyl acetate = 2:1) to obtain a yellow oily compound (1S,3S)-3-((2-cyclopropyl-6- (5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl) Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-16A) (100 mg, yield 89.8%).
LC-MS,M/Z(ESI):512.7[M+H]
+
LC-MS, M/Z(ESI):512.7[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(5-((((2-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-16)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-16)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-16)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-16)
在室温下,将(1S,3S)-3-((2-环丙基-6-(5-((((2-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-16A)(100mg,195μmol)溶解在四氢呋喃(1.00mL)中,然后向其中加入水(0.20mL)和一水合氢氧化锂(82.0mg,1.95mmol),然后将混合物在室温下搅拌12个小时。反应完成后,用1M盐酸将反应液的pH调到4~5,然后用乙酸乙酯萃取,浓缩有机相得粗品。粗品经反相高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=56%-89%,11min)分离得到(1S,3S)-3-((2-环丙基-6-(5-((((2-环丙基乙基)(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-16)(15.6mg,收率16.0%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methanol yl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)methylcyclohexanecarboxylate (I-16A) (100mg, 195μmol) was dissolved in In tetrahydrofuran (1.00 mL), water (0.20 mL) and lithium hydroxide monohydrate (82.0 mg, 1.95 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1M hydrochloric acid, then extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was subjected to reverse-phase high-performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=56%-89%, 11min) to separate (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-16) (15.6mg, yield 16.0 %).
LC-MS,M/Z(ESI):498.3[M+H]
+
LC-MS, M/Z(ESI):498.3[M+H] +
1H NMR(400MHz,CDCl
3)δ7.90(d,1H),7.21(d,1H),5.67(s,2H),4.72(s,1H),4.15(d,3H),3.36(t,1H),3.21(t,1H),2.9-3.0(m,1H),2.8-3.0(m,4H),2.51(dd,1H),1.9-2.0(m,4H),1.67(d,4H),1.2-1.3(m,2H),1.09(d,2H),0.97(s,2H),0.3-0.4(m,2H),-0.2-0.1(m,2H)
1 H NMR (400MHz, CDCl 3 )δ7.90(d,1H),7.21(d,1H),5.67(s,2H),4.72(s,1H),4.15(d,3H),3.36(t, 1H),3.21(t,1H),2.9-3.0(m,1H),2.8-3.0(m,4H),2.51(dd,1H),1.9-2.0(m,4H),1.67(d,4H) ,1.2-1.3(m,2H),1.09(d,2H),0.97(s,2H),0.3-0.4(m,2H),-0.2-0.1(m,2H)
实施例17:目标化合物I-17的制备Embodiment 17: Preparation of Target Compound I-17
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((5-丙基-1,2,4-恶二唑-3-基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-17)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino) Methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-17)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-17)
目标化合物I-17的合成路线如下所示:The synthetic route of target compound 1-17 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((5-丙基-1,2,4-恶二唑-3-基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-17B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazole-3- Synthesis of methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-17B)
(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
在室温下,向(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-9C)(100mg,260μmol)和5-丙基-1,2,4-恶二唑-3-胺(82.6mg,650μmol)的甲醇(2.00mL)溶液滴加冰醋酸(5.62mg,260μmol),反应液在60℃下搅拌12小时后降至室温,加入氰基硼氢化钠(24.5mg,390μmol),反应液继续在室温下搅拌0.5小时。反应完成后,将反应液浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=1:1)制备得到黄色油状物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((5-丙基-1,2,4-恶二唑-3-基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-17B)(52.0mg,104μmol,收率40.3%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridine -3-yl)oxy)methylcyclohexanecarboxylate (I-9C) (100mg, 260μmol) and 5-propyl-1,2,4-oxadiazol-3-amine (82.6mg, 650μmol) Methanol (2.00mL) solution was added dropwise with glacial acetic acid (5.62mg, 260μmol), the reaction solution was stirred at 60°C for 12 hours and then cooled to room temperature, sodium cyanoborohydride (24.5mg, 390μmol) was added, and the reaction solution continued to Stir for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (1S,3S)-3-((2-cyclopropyl-6- (1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-17B) (52.0 mg, 104 μmol, yield 40.3%).
LC-MS,M/Z(ESI):505.2[M+H]
+
LC-MS, M/Z(ESI):505.2[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((5-丙基-1,2,4-恶二唑-3-基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-17)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazole-3- Synthesis of (yl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-17)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1H-1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)
在室温下,将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((5-丙基-1,2,4-恶二唑-3-基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-17B)(50.0mg,100μmol)溶解在四氢呋喃(1.00mL)中,然后向其中加入水(0.250mL)和一水合氢氧化锂(42.3mg,1.01mmol),混合物在室温下搅拌12小时。反应完成后,用1N的盐酸水溶液将反应液的pH调到4~5,然后用乙酸乙酯萃取,浓缩有机相得粗品。然后粗品经反相高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=40%-70%,10分钟)得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((5-丙基-1,2,4-恶二唑-3-基)氨基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-17)(1.70mg,3.51μmol,收率3.48%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazole-3 -yl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-17B) (50.0mg , 100 μmol) was dissolved in tetrahydrofuran (1.00 mL), then water (0.250 mL) and lithium hydroxide monohydrate (42.3 mg, 1.01 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1N hydrochloric acid aqueous solution, then extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. Then the crude product is separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=40%- 70%, 10 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazole -3-yl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-17)( 1.70 mg, 3.51 μmol, yield 3.48%).
LC-MS,M/Z(ESI):482.5[M+H]
+
LC-MS, M/Z(ESI):482.5[M+H] +
1H NMR(400MHz,DMSO-d
6)δ7.76(d,1H),7.47(d,1H),7.03(t,1H),4.78(d,3H),4.04(s,3H),2.72-2.68(m,2H),1.88-1.52(m,12H),0.94-0.89(m,7H)
1 H NMR (400MHz,DMSO-d 6 )δ7.76(d,1H),7.47(d,1H),7.03(t,1H),4.78(d,3H),4.04(s,3H),2.72- 2.68(m,2H),1.88-1.52(m,12H),0.94-0.89(m,7H)
实施例18:目标化合物I-18的制备Embodiment 18: Preparation of target compound I-18
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基氧基)环己烷-1-甲酸(目标化合物I-18)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yloxy)cyclohexane-1-carboxylic acid (target compound I-18)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-18)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-18)
目标化合物I-18的合成路线如下所示:The synthetic route of target compound 1-18 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-18B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl )oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-18B)
methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-18B)methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-18B)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(300mg,543μmol)和3,3,3-三氟-N-甲基丙烷-1-胺(177mg,1.09mmol)的四氢呋喃(3.00mL)溶液加入N,N-二异丙基乙胺(210mg,1.63mmol),反应液在25℃下搅拌0.5小时。反应完成后,将反应液浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=1:1)制备得黄色油状物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-18B)(100mg,173μmol,收率31.8%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (300mg, 543μmol) and 3,3, Add N,N-diisopropylethylamine (210mg, 1.63mmol) to a solution of 3-trifluoro-N-methylpropane-1-amine (177mg, 1.09mmol) in tetrahydrofuran (3.00mL), and the reaction solution was heated at 25°C Stirring was continued for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (1S,3S)-3-((2-cyclopropyl-6- (1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-18B) (100 mg, 173 μmol, yield 31.8%).
LC-MS,M/Z(ESI):540.2[M+H]
+
LC-MS, M/Z(ESI):540.2[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基氧基)环己烷-1-甲酸(目标化合物I-18)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl) )oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yloxy)cyclohexane-1-carboxylic acid (target compound I-18)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-18)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-18)
在室温下,将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-18B)(100mg,185μmol)溶解在四氢呋喃(0.750mL)中,然后向其中加入水(0.250mL)和一水合氢氧化锂(77.7mg,1.85mmol),混合物在室温下搅拌12个小时。反应完成后,用1N盐酸将反应液的pH调到4~5,然后用乙酸乙酯萃取,浓缩有机相得粗品。然后粗品经反相高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=43%-73%,10分钟)得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基甲酰基)氧基)甲基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基氧基)环己烷-1-甲酸(目标化合物I-18)(58.2mg,109μmol,收率59.1%)。At room temperature, (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminomethyl) Acyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-18B) (100mg, 185 μmol) was dissolved in tetrahydrofuran (0.750 mL), then water (0.250 mL) and lithium hydroxide monohydrate (77.7 mg, 1.85 mmol) were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1N hydrochloric acid, then extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. Then the crude product is separated and purified by reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; gradient: B%=43%- 73%, 10 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl) Carbamoyl) oxy)methyl) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yloxy)cyclohexane-1-carboxylic acid (target compound I-18 ) (58.2 mg, 109 μmol, yield 59.1%).
LC-MS,M/Z(ESI):526.3[M+H]
+
LC-MS, M/Z(ESI):526.3[M+H] +
1H NMR(400MHz,CDCl
3)δ7.92(d,1H),7.21(d,1H),5.69(s,2H),4.77-4.67(m,1H),4.15(d,3H),3.58-3.47(m,1H),3.45-3.31(m,1H),3.01-2.79(m,4H),2.58-2.48(m,1H),2.47-2.35(m,1H),2.28-1.90(m,5H),1.89-1.75(m,1H),1.74-1.59(m,3H),1.13-0.91(m,4H).
1 H NMR (400MHz, CDCl 3 )δ7.92(d,1H),7.21(d,1H),5.69(s,2H),4.77-4.67(m,1H),4.15(d,3H),3.58- 3.47(m,1H),3.45-3.31(m,1H),3.01-2.79(m,4H),2.58-2.48(m,1H),2.47-2.35(m,1H),2.28-1.90(m,5H ),1.89-1.75(m,1H),1.74-1.59(m,3H),1.13-0.91(m,4H).
实施例19:目标化合物I-19的制备Embodiment 19: Preparation of Target Compound I-19
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(氧杂环丁-3-基甲基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-19)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-19)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)
目标化合物I-19的合成路线如下所示:The synthetic route of target compound 1-19 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(氧杂环丁-3-基甲基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸甲酯(I-19B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl )oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid methyl ester (I-19B)
(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-19B)(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-19B)
在室温下,向(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(300mg,543μmol)和N-甲基-1-(氧杂环丁-3-基)甲胺(110mg,1.09mmol)的四氢呋喃(3.00mL)溶液加入N,N-二异丙基乙胺(210mg,1.63mmol),反应液在25℃下搅拌0.5小时。反应完成后,将反应液浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=0:1)制备得到黄色油状物(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(氧杂环丁-3-基甲基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-19B)(100mg,169μmol,收率31.2%)。At room temperature, to (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (300mg, 543μmol) and N-methyl-1-(oxygen Heterobutan-3-yl)methanamine (110mg, 1.09mmol) in tetrahydrofuran (3.00mL) was added to N,N-diisopropylethylamine (210mg, 1.63mmol), and the reaction solution was stirred at 25°C for 0.5 hours . After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 0:1) to obtain (1S,3S)-3-((2-cyclopropyl-6- (1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-19B) (100 mg, 169 μmol, yield 31.2%).
LC-MS,M/Z(ESI):514.2[M+H]
+
LC-MS, M/Z(ESI):514.2[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(氧杂环丁-3-基甲基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-19)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl )oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-19)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-19)
在室温下,将(1S,3S)-3-(((2-环丙基-6-(1-甲基-5-((((甲基(氧杂环丁-3-基甲基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(100mg,194μmol)溶解在四氢呋喃(0.750mL)中,然后向其中加入水(0.250mL)和一水合氢氧化锂(81.7mg,1.95mmol),混合物在室温下搅拌12个小时。反应完成后,用1N的盐酸水溶液将反应液的pH调到4~5,然后用乙酸乙酯萃取,浓缩有机相得粗品。然后粗品经反相高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150*25mm*10um;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=30%-60%,10分钟)得(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(氧杂环丁-3-基甲基)氨基甲酰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷甲酸(目标化合物I-19)(42.3mg,82.4μmol,收率42.3%)。At room temperature, (1S,3S)-3-(((2-cyclopropyl-6-(1-methyl-5-((((methyl(oxetan-3-ylmethyl) Carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (100 mg, 194 μmol) dissolved In tetrahydrofuran (0.750mL), water (0.250mL) and lithium hydroxide monohydrate (81.7mg, 1.95mmol) were then added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solution was dissolved with 1N aqueous hydrochloric acid solution The pH of the reaction solution was adjusted to 4-5, then extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product. Then the crude product was separated and purified by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: Solvent A=water+0.225vol% formic acid, solvent B=acetonitrile; gradient: B%=30%-60%, 10 minutes) to get (1S,3S)-3-((2-cyclopropyl-6-(1 -Methyl-5-(((methyl(oxetan-3-ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine -3-yl)oxy)cyclohexanecarboxylic acid (target compound I-19) (42.3 mg, 82.4 μmol, yield 42.3%).
LC-MS,M/Z(ESI):500.3[M+H]
+
LC-MS, M/Z(ESI):500.3[M+H] +
1H NMR(400MHz,CDCl3)δ7.92(d,1H),7.22(d,1H),5.66(s,2H),4.86-4.67(m,2H),4.64-4.43(m,2H),4.31-4.22(m,1H),4.15(d,3H),3.63(d,1H),3.56-3.44(m,1H),3.35-2.98(m,1H),2.94-2.78(m,4H),2.53(br s,1H),2.29-2.13(m,1H),2.08-1.90(m,3H),1.88-1.76(m,1H),1.74-1.60(m,3H),1.10-0.94(m,4H).
1 H NMR (400MHz, CDCl3) δ7.92(d,1H),7.22(d,1H),5.66(s,2H),4.86-4.67(m,2H),4.64-4.43(m,2H),4.31 -4.22(m,1H),4.15(d,3H),3.63(d,1H),3.56-3.44(m,1H),3.35-2.98(m,1H),2.94-2.78(m,4H),2.53 (br s,1H),2.29-2.13(m,1H),2.08-1.90(m,3H),1.88-1.76(m,1H),1.74-1.60(m,3H),1.10-0.94(m,4H ).
实施例20:目标化合物I-20的制备Embodiment 20: Preparation of Target Compound I-20
(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-20)(1S,3S)-3-((6-(5-(((Butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole -4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid(目标化合物I-20)(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- (oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)
目标化合物I-20的合成路线如下所示:The synthetic route of target compound 1-20 is as follows:
第一步:2-(氧乙烷-3-基)-6-(5-((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基硅烷基)乙氧基)甲氧基)吡啶(I-20A)的合成The first step: 2-(oxyethane-3-yl)-6-(5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilane Base)methyl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-20A) synthesis
2-(oxetan-3-yl)-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine(I-20A)2-(oxetan-3-yl)-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3- triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-20A)
在室温下,将2-溴-6-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡啶(I-15A)(2.00g,3.50mmol),3-溴氧杂环丁烷(958mg,7.00mmol),锌(457mg,7.00mmol),碘化钠(524mg,3.50mmol)和1,2-二甲氧基乙烷氯化镍(76.8mg,349μmol)三氟乙酸(39.8mg,349umol)吡啶-2-甲脒盐酸盐(55.1mg,349μmol)的N,N二甲基乙酰胺(30mL)混合,然后将混合物在氮气气氛下在60℃搅拌12小时。反应完成后加水,乙酸乙酯萃取浓缩,将反应混合物经柱层析分离(石油醚:乙酸乙酯=20:1到5:1)得黄色油状化合物2-(氧乙烷-3-基)-6-(5-((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基硅烷基)乙氧基)甲氧基)吡啶(I-20A)(600mg,收率31.2%)。At room temperature, 2-bromo-6-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl) -1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-15A) (2.00g, 3.50 mmol), 3-bromooxetane (958mg, 7.00mmol), zinc (457mg, 7.00mmol), sodium iodide (524mg, 3.50mmol) and 1,2-dimethoxyethane nickel chloride ( 76.8 mg, 349 μmol) of trifluoroacetic acid (39.8 mg, 349 μmol) of pyridine-2-carboxamidine hydrochloride (55.1 mg, 349 μmol) in N,N dimethylacetamide (30 mL) were mixed, and the mixture was then placed under a nitrogen atmosphere Stir at 60°C for 12 hours. After the reaction was completed, water was added, ethyl acetate was extracted and concentrated, and the reaction mixture was separated by column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain yellow oily compound 2-(oxyethane-3-yl) -6-(5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-tri Azol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (I-20A) (600 mg, yield 31.2%).
LC-MS,M/Z(ESI):549.4[M+H]
+
LC-MS, M/Z(ESI):549.4[M+H] +
第二步:6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧基-3-基)吡啶-3-醇(I-20B)的合成The second step: 6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl )-2-(oxyl-3-yl)pyridin-3-ol (I-20B) synthesis
6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-ol(I-20B)6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl )pyridin-3-ol (I-20B)
在室温下,向2-(氧乙烷-3-基)-6-(5-((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑-4-基)-3-((2-(三甲基硅烷基)乙氧基)甲氧基)吡啶(800mg,1.46mmol)的四氢呋喃(8.00mL)溶液中加入四丁基氟化铵溶液(1M,2.92mL),将反应混合物在60℃下搅拌12小时。反应完成后,将反应浓缩得到粗品,粗品经制备板(石油醚:乙酸乙酯=1:1)制备得黄色固体6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧基-3-基)吡啶-3-醇(I-20B)(440mg,收率87.1%)。At room temperature, to 2-(oxyethane-3-yl)-6-(5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethyl Silyl)methyl)-1H-1,2,3-triazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (800mg, 1.46mmol ) in tetrahydrofuran (8.00 mL) was added tetrabutylammonium fluoride solution (1M, 2.92 mL), and the reaction mixture was stirred at 60° C. for 12 hours. After the reaction was completed, the reaction was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid 6-(1-methyl-5-(((tetrahydro-2H-pyran -2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxyl-3-yl)pyridin-3-alcohol (I-20B) (440mg , yield 87.1%).
LC-MS,M/Z(ESI):349.2[M+H]
+
LC-MS, M/Z(ESI):349.2[M+H] +
第三步:(1S,3S)-3-((6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20C)的合成The third step: (1S,3S)-3-((6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1, Synthesis of methyl 2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20C)
(1S,3S)-methyl 3-((6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-20C)(1S,3S)-methyl 3-((6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4- yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate (I-20C)
在0℃下,向6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧基-3-基)吡啶-3-醇(383mg,2.43mmol)和三苯基膦(636mg,2.43mmol)的甲苯溶液中(10.0mL)加入偶氮二甲酸二异丙酯(490mg,2.43mmol),混合物在25℃下搅拌12小时。反应完成后,将反应浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=1:2)制备得到黄色油状物(1S,3S)-3-((6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20C)(550mg,收率46.1%)。At 0°C, to 6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4 -yl)-2-(oxyl-3-yl)pyridin-3-ol (383mg, 2.43mmol) and triphenylphosphine (636mg, 2.43mmol) in toluene (10.0mL) was added Isopropyl ester (490mg, 2.43mmol), the mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 1:2) to obtain a yellow oil (1S,3S)-3-((6-(1-methyl-5 -(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20C) (550 mg, yield 46.1%).
LC-MS,M/Z(ESI):487.3[M+H]
+
LC-MS, M/Z(ESI):487.3[M+H] +
第四步:(1S,3S)-3-((6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-甲酸甲酯(I-20D)的合成The fourth step: (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxygen Synthesis of Heterobutan-3-yl)pyridin-3-yl)oxy)cyclohexane-methyl carboxylate (I-20D)
methyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-20D)methyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin- 3-yl)oxy)cyclohexane-1-carboxylate (I-20D)
在室温下,向(1S,3S)-3-((6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20C)(550mg,1.13mmol)的甲醇溶液(10mL)中加入吡啶对甲苯磺酸盐(28.4mg,113μmol),混合物在60℃下搅拌12小时。反应完成后,将反应浓缩得到粗品,粗品经制备板(石油醚:乙酸乙酯=1:2)制备黄色油状物(1S,3S)-3-((6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20D)的合成(200mg,收率43.9%)。At room temperature, to (1S,3S)-3-((6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1 , 2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20C) (550mg , 1.13 mmol) in methanol (10 mL) was added pyridine p-toluenesulfonate (28.4 mg, 113 μmol), and the mixture was stirred at 60° C. for 12 hours. After the reaction was completed, the reaction was concentrated to obtain the crude product, which was prepared through a preparative plate (petroleum ether: ethyl acetate = 1:2) to prepare a yellow oil (1S,3S)-3-((6-(5-(hydroxymethyl) -1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid Synthesis of methyl ester (I-20D) (200 mg, yield 43.9%).
LC-MS,M/Z(ESI):412.0[M+H]+LC-MS, M/Z(ESI):412.0[M+H]+
第五步:(1S,3S)-3-((6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20E)的合成The fifth step: (1S,3S)-3-((6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2 , Synthesis of 3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20E)
methyl(1S,3S)-3-((6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-20E)methyl(1S,3S)-3-((6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)- 2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20E)
在零℃下,向(1S,3S)-3-((6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(200mg,496μmol)和吡啶(117mg,1.49mmol)的二氯甲烷溶液(10.0mL)中加入4-硝基苯基碳酰氯(120mg,596umol),反应液在25℃下搅拌2小时。反应完成后,将反应浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=1:1)制备得黄色油状物(1S,3S)-3-((6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20E)(180mg,收率70.9%)。At zero ℃, to (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- (Oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (200 mg, 496 μmol) and pyridine (117 mg, 1.49 mmol) in dichloromethane (10.0 mL) 4-Nitrophenylcarbonyl chloride (120mg, 596umol) was added to the mixture, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (1S,3S)-3-((6-(1-methyl-5 -((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl) Pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20E) (180 mg, yield 70.9%).
第六步:(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20F)的合成The sixth step: (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of methyl 3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20F)
methyl(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-20F)methyl(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2 -(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-20F)
在室温下,向(1S,3S)-3-((6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20E)(180mg,317μmol)和二异丙基乙胺(122mg,951μmol)的四氢呋喃(2.00mL)溶液中加入N-甲基丁烷-1-胺(55.2mg,634μmol),反应混合物在25℃搅拌0.5小时。反应完成后,将反应浓缩得粗品,粗品经制备板(石油醚:乙酸乙酯=2:1)制备得黄色油状物(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20F)(120mg,收率73.3%)。At room temperature, to (1S,3S)-3-((6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1, 2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20E) (180 mg, 317 μmol) and diisopropylethylamine (122 mg, 951 μmol) in tetrahydrofuran (2.00 mL) were added N-methylbutane-1-amine (55.2 mg, 634 μmol), and the reaction mixture was stirred at 25° C. for 0.5 hours. After the reaction was completed, the reaction was concentrated to obtain a crude product, which was prepared through a preparation plate (petroleum ether: ethyl acetate = 2:1) to obtain a yellow oil (1S,3S)-3-((6-(5-(((butan Base (methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridine -3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20F) (120 mg, yield 73.3%).
LC-MS,M/Z(ESI):516.4[M+H]
+
LC-MS, M/Z(ESI):516.4[M+H] +
第七步:(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基) -2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-20)的合成The seventh step: (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)
(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid(目标化合物I-20)(1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- (oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20)
在室温下,向(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-20F)(120mg,232μmol)的甲醇(2.00mL)和水(0.40mL)溶液中加入一水合氢氧化锂(39.0mg,930μmol),混合物在25℃下搅拌12小时。反应完成后,反应液用1M盐酸调节pH为4,乙酸乙酯萃取,浓缩得粗品。然后粗品经反相高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25mm*10μm;流动相:溶剂A=水+0.225体积%甲酸,溶剂B=乙腈;梯度:B%=38%-68%,11分钟)得(1S,3S)-3-((6-(5-(((丁基(甲基)氨基甲酰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(氧杂环丁-3-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-20)(55.7mg,收率47.2%)。At room temperature, to (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-20F) (120 mg, 232 μmol ) in methanol (2.00 mL) and water (0.40 mL) was added lithium hydroxide monohydrate (39.0 mg, 930 μmol), and the mixture was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction solution was adjusted to pH 4 with 1M hydrochloric acid, extracted with ethyl acetate, and concentrated to obtain a crude product. Then the crude product is through reverse phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10 μm; Mobile phase: solvent A=water+0.225 volume % formic acid, solvent B=acetonitrile; Gradient: B%=38%-68% , 11 minutes) to (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-(oxetan-3-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-20) (55.7mg, Yield 47.2%).
LC-MS,M/Z(ESI):502.3[M+H]+LC-MS, M/Z(ESI):502.3[M+H]+
1H NMR(400MHz,CHLOROFORM-d)δ8.15-8.08(d,1H),7.29(d,1H),5.81-5.74(m,2H),5.17-5.09(s,2H),5.07-4.99(m,2H),4.72-4.60(m,2H),4.22-4.16(s,3H),3.30-3.21(m,1H),3.19-3.09(m,1H),2.92-2.79(m,4H),2.08-1.91(m,3H),1.90-1.80(m,1H),1.75-1.59(m,4H),1.54-1.47(m,1H),1.36-1.32(m,2H),1.17-1.05(m,1H),0.95-0.74(m,3H).1H NMR(400MHz,CHLOROFORM-d)δ8.15-8.08(d,1H),7.29(d,1H),5.81-5.74(m,2H),5.17-5.09(s,2H),5.07-4.99(m ,2H),4.72-4.60(m,2H),4.22-4.16(s,3H),3.30-3.21(m,1H),3.19-3.09(m,1H),2.92-2.79(m,4H),2.08 -1.91(m,3H),1.90-1.80(m,1H),1.75-1.59(m,4H),1.54-1.47(m,1H),1.36-1.32(m,2H),1.17-1.05(m, 1H),0.95-0.74(m,3H).
实施例21:目标化合物I-21的制备Embodiment 21: Preparation of target compound I-21
(1S,3S)-3-((2-环丙基-6-(5-(((5-环丙基-1,2,4-噁二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-21)(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-21)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-21)(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-21)
目标化合物I-21的合成路线如下所示:The synthetic route of target compound I-21 is as follows:
第一步:N-氰基环丙甲酰胺(I-21B)的合成The first step: the synthesis of N-cyanocyclopropanamide (I-21B)
N-cyanocyclopropanecarboxamideN-cyanocyclopropanecarboxamide
在室温下,将氰基酰胺(1.21g,28.7mmol)溶解在二氯甲烷(10.0mL),加入氯化环丙羰基(1.00g,9.57mmol),置换氮气,充分搅拌,在25℃反应12小时。反应结束后,直接浓缩得到N-氰基环丙甲酰胺(I-21B)(1.00g,粗品),直接用于下一步。At room temperature, dissolve cyanoamide (1.21g, 28.7mmol) in dichloromethane (10.0mL), add cyclopropylcarbonyl chloride (1.00g, 9.57mmol), replace nitrogen, stir well, and react at 25°C for 12 Hour. After the reaction was completed, it was directly concentrated to obtain N-cyanocyclopropylcarboxamide (I-21B) (1.00 g, crude product), which was directly used in the next step.
1H NMR(400MHz,DMSO-d6)δ6.19(s,1H),1.64-1.57(m,1H),0.91-0.78(m,4H)
1 H NMR(400MHz,DMSO-d6)δ6.19(s,1H),1.64-1.57(m,1H),0.91-0.78(m,4H)
第二步:5-环丙基-1,2,4-噁二唑-3-胺(I-21C)的合成The second step: the synthesis of 5-cyclopropyl-1,2,4-oxadiazol-3-amine (I-21C)
5-cyclopropyl-1,2,4-oxadiazol-3-amine(I-21C)5-cyclopropyl-1,2,4-oxadiazol-3-amine (I-21C)
把N-氰基环丙甲酰胺(I-21B)(1.00g,9.08mmol)溶解于乙醇(10.0mL)中,加入盐酸羟胺(946mg,13.6mmol),碳酸钾(1.88g,13.6mmol),置换氮气,在70℃搅拌2小时。反应结束后,浓缩,粗产品制备液相色谱纯化(色谱柱:120g Flash Column Welch Ultimate XB_C18 20-40μm;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:0%-10%,10min),得到5-环丙基-1,2,4-噁二唑-3-胺(I-21C)(160mg,产率14.0%)。Dissolve N-cyanocyclopropylcarboxamide (I-21B) (1.00g, 9.08mmol) in ethanol (10.0mL), add hydroxylamine hydrochloride (946mg, 13.6mmol), potassium carbonate (1.88g, 13.6mmol), Nitrogen was replaced, and the mixture was stirred at 70°C for 2 hours. After the reaction was finished, it was concentrated, and the crude product was purified by preparative liquid chromatography (chromatographic column: 120g Flash Column Welch Ultimate XB_C18 20-40μm; solvent: A=water+0.225vol% ammonia water (99%), B=acetonitrile; gradient: 0% -10%, 10 min), to obtain 5-cyclopropyl-1,2,4-oxadiazol-3-amine (I-21C) (160 mg, yield 14.0%).
LC-MS,M/Z(ESI):126.1[M+H]
+
LC-MS, M/Z(ESI):126.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ6.09(s,2H),2.13-1.99(m,1H),1.18-1.07(m,2H),1.03-0.90(m,2H)
1 H NMR(400MHz,DMSO-d6)δ6.09(s,2H),2.13-1.99(m,1H),1.18-1.07(m,2H),1.03-0.90(m,2H)
第三步:(1S,3S)-3-((2-环丙基-6-(5-(((5-环丙基-1,2,4-噁二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧代)环己烷-1-甲酸甲酯(I-21D)的合成The third step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino) Synthesis of methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxo)cyclohexane-1-carboxylate (I-21D)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-21D)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-21D)
把(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9C)(50.0mg,130μmol)和5-环丙基-1,2,4-噁二唑-3-胺(I-21C)(24.4mg,195μmol)溶解于二氯甲烷(1.00mL)中,加入氯(三异丙氧基)钛(101mg,390μmol),置换氮气,在25℃搅拌2小时,再加入氰基硼氢化钠(16.3mg,260μmol),在25℃下反应2小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,然后用饱和食盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=2:1得到(1S,3S)-3-((2-环丙基-6-(5-(((5-环丙基-1,2,4-噁二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-21D)(40.0mg,产率62.3%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl )Oxy)cyclohexane-1-methyl carboxylate (I-9C) (50.0 mg, 130 μmol) and 5-cyclopropyl-1,2,4-oxadiazol-3-amine (I-21C) ( 24.4mg, 195μmol) was dissolved in dichloromethane (1.00mL), added chloro(triisopropoxy)titanium (101mg, 390μmol), replaced nitrogen, stirred at 25°C for 2 hours, then added sodium cyanoborohydride ( 16.3mg, 260μmol), react at 25°C for 2 hours. After the reaction was completed, add water (10mL) to quench, extract with ethyl acetate (15mL), then wash with saturated brine (15mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified on a silica gel plate (petroleum ether: Ethyl acetate (V/V)=2:1 to get (1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxa Oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid Ester (I-21D) (40.0 mg, 62.3% yield).
LC-MS,M/Z(ESI):494.2[M+H]
+
LC-MS, M/Z(ESI):494.2[M+H] +
第四步:(1S,3S)-3-((2-环丙基-6-(5-(((5-环丙基-1,2,4-噁二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-21)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino) Synthesis of methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-21)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-21)(1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-21)
把(1S,3S)-3-((2-环丙基-6-(5-(((5-环丙基-1,2,4-噁二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-21D)(40.0mg,81.0μmol)溶解于四氢呋喃(1.00mL)中,加一水合氢氧化锂(17.0mg,405μmol)的水溶液(0.20mL),加热到25℃,搅拌12小时,加入稀盐酸水溶液调节pH=1,用乙酸乙酯(10mL)萃取,然后用饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩得到粗品,用制备高效液相色谱纯化(色谱柱:Waters Xbridge 150*25mm*5μm;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:37%-67%,7min),得到(1S,3S)-3-((2-环丙基-6-(5-(((5-环丙基-1,2,4-噁二唑-3-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-21)(20.0mg,产率50.5%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl) -1-Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-21D) (40.0mg, 81.0μmol ) was dissolved in tetrahydrofuran (1.00mL), and an aqueous solution (0.20mL) of lithium hydroxide monohydrate (17.0mg, 405μmol) was added, heated to 25°C, stirred for 12 hours, and diluted aqueous hydrochloric acid was added to adjust the pH to 1. Ester (10mL) was extracted, then washed with saturated brine (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5μm; Solvent: A=water+0.225vol% ammonia water (99%), B=acetonitrile; gradient: 37%-67%, 7min), to obtain (1S,3S)-3-((2-cyclopropyl-6-( 5-(((5-cyclopropyl-1,2,4-oxadiazol-3-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-21) (20.0 mg, yield 50.5%).
LC-MS,M/Z(ESI):480.3[M+H]
+
LC-MS, M/Z(ESI):480.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.46(d,1H),4.81-4.73(m,3H),4.03(s,3H),2.69-2.64(m,1H),2.51(d,1H),2.13-2.06(m,1H),2.05-1.98(m,1H),1.89-1.76(m,3H),1.71-1.60(m,2H),1.58-1.46(m,2H),1.14-1.08(m,2H),0.97-0.89(m,6H),0.86-0.78(m,1H)
1 H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.46(d,1H),4.81-4.73(m,3H),4.03(s,3H),2.69-2.64(m,1H) ,2.51(d,1H),2.13-2.06(m,1H),2.05-1.98(m,1H),1.89-1.76(m,3H),1.71-1.60(m,2H),1.58-1.46(m, 2H),1.14-1.08(m,2H),0.97-0.89(m,6H),0.86-0.78(m,1H)
实施例22:目标化合物I-22的制备Embodiment 22: Preparation of Target Compound I-22
(1S,3S)-3-((2-环丙基-6-(5-(((4-(二氟甲基)嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-22)(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H -1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-22)(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22)
目标化合物I-22的合成路线如下所示:The synthetic route of target compound I-22 is as follows:
第一步:(E)-4-乙氧基-1,1-二氟丁-3-烯-2-酮(I-22B)的合成The first step: the synthesis of (E)-4-ethoxy-1,1-difluorobut-3-en-2-one (I-22B)
(E)-4-ethoxy-1,1-difluorobut-3-en-2-one(I-22B)(E)-4-ethoxy-1,1-difluorobut-3-en-2-one (I-22B)
在室温下,将吡啶(545mg,6.89mmol)溶解在二氯甲烷(12.0mL),在-70℃加入乙烯基氧代乙烷(414mg,5.75mmol),二氟乙酸酐(1.20g,6.89mmol),滴加完毕后,缓慢升至25℃搅拌12小时。反应结束后,减压浓缩得到粗品(E)-4-乙氧基-1,1-二氟丁-3-烯-2-酮(I-22B)(1.00g,粗品),直接用于下一步。Dissolve pyridine (545mg, 6.89mmol) in dichloromethane (12.0mL) at room temperature, add vinyloxyethane (414mg, 5.75mmol) at -70°C, difluoroacetic anhydride (1.20g, 6.89mmol ), after the dropwise addition was completed, slowly rise to 25°C and stir for 12 hours. After the reaction, concentrated under reduced pressure to obtain the crude product (E)-4-ethoxy-1,1-difluorobut-3-en-2-one (I-22B) (1.00g, crude product), which was directly used in the following step.
第二步:4-(二氟甲基)嘧啶-2-胺(I-22C)的合成The second step: the synthesis of 4-(difluoromethyl)pyrimidin-2-amine (I-22C)
4-(difluoromethyl)pyrimidin-2-amine(I-22C)4-(difluoromethyl)pyrimidin-2-amine(I-22C)
把氢氧化钠((255mg,6.39mmol)加到盐酸胍(509mg,5.33mmol)的乙醇溶液(5.00mL)中,并将其滴加到(E)-4-乙氧基-1,1-二氟丁-3-烯-2-酮(I-22B)(800mg,5.33mmol)的二氯甲烷(10.0mL)溶液中,反应液在氮气保护下于25℃搅拌2小时。反应结束后,减压浓缩,粗品打浆纯化得到4-(二氟甲基)嘧啶-2-胺(I-22C)(400mg,产率51.7%)。Add sodium hydroxide ((255mg, 6.39mmol) to a solution of guanidine hydrochloride (509mg, 5.33mmol) in ethanol (5.00mL), and add it dropwise to (E)-4-ethoxy-1,1- In a solution of difluorobut-3-en-2-one (I-22B) (800mg, 5.33mmol) in dichloromethane (10.0mL), the reaction solution was stirred at 25°C for 2 hours under nitrogen protection. After the reaction, Concentrated under reduced pressure, and the crude product was purified by pulping to obtain 4-(difluoromethyl)pyrimidin-2-amine (I-22C) (400 mg, yield 51.7%).
1H NMR(400MHz,DMSO-d6)δ8.42(d,1H),7.00(s,2H),6.80-6.53(m,1H),6.77(s,1H)
1 H NMR(400MHz,DMSO-d6)δ8.42(d,1H),7.00(s,2H),6.80-6.53(m,1H),6.77(s,1H)
第三步:(1S,3S)-3-((2-环丙基-6-(5-(((4-(二氟甲基)嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-22D)的合成The third step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1- Synthesis of methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-22D)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-22D)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-22D)
把(1S,3S)-3-((2-环丙基-6-(5-甲酰基-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-9C)(50.0mg,130μmol)和4-(二氟甲基)嘧啶-2-胺(I-22C)(28.3mg,195μmol)溶解于二氯甲烷(1.00mL)中,加入氯(三异丙氧基)钛(101mg,390μmol),置换氮气,在25℃搅拌2小时,再加入氰基硼氢化钠(16.3mg,260μmol),在25℃下继续搅拌2小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,有机相用饱和食盐水(15mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=2:1),得到(1S,3S)-3-((2-环丙基-6-(5-(((4-(二氟甲基)嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-22D)(50.0mg,产率74.8%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl )oxy)methyl cyclohexane-1-carboxylate (I-9C) (50.0 mg, 130 μmol) and 4-(difluoromethyl)pyrimidin-2-amine (I-22C) (28.3 mg, 195 μmol) were dissolved In dichloromethane (1.00 mL), add (triisopropoxy)titanium chloride (101 mg, 390 μmol), replace nitrogen, stir at 25° C. for 2 hours, then add sodium cyanoborohydride (16.3 mg, 260 μmol), Stirring was continued for 2 hours at 25°C. After the reaction was completed, quenched with water (10 mL), extracted with ethyl acetate (15 mL), washed the organic phase with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was separated and purified on a silica gel plate ( Petroleum ether: ethyl acetate (V/V)=2:1), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl) Pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-22D) (50.0 mg, 74.8% yield).
LC-MS,M/Z(ESI):514.1[M+H]
+
LC-MS, M/Z(ESI):514.1[M+H] +
第四步:(1S,3S)-3-((2-环丙基-6-(5-(((4-(二氟甲基)嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-22)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1- Synthesis of methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-22)(1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-22)
把(1S,3S)-3-((2-环丙基-6-(5-(((4-(二氟甲基)嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-22D)(50.0mg,97.3μmol)溶解于四氢呋喃(1.00mL)中,加入一水合氢氧化锂(20.4mg,486μmol)的水溶液(0.20mL),反应液于25℃下搅拌12小时,加入稀盐酸水溶液调节反应液pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备液相色谱(色谱柱:Waters Xbridge 150*25mm*5μm;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:40%-70%,7min)纯化,得(1S,3S)-3-((2-环丙基-6-(5-(((4-(二氟甲基)嘧啶-2-基)氨基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-22)(10.0mg,产率20.0%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(((4-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-22D) (50.0mg, 97.3μmol) was dissolved in tetrahydrofuran (1.00 mL), add an aqueous solution (0.20 mL) of lithium hydroxide monohydrate (20.4 mg, 486 μmol), and stir the reaction solution at 25°C for 12 hours, add dilute aqueous hydrochloric acid to adjust the pH of the reaction solution to 1, and use ethyl acetate (10.0 mL) extraction, the organic phase was washed with saturated brine (10mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product by preparative liquid chromatography (column: Waters Xbridge 150*25mm*5 μm; solvent: A= Water+0.225vol% ammonia water (99%), B=acetonitrile; Gradient: 40%-70%, 7min) purified to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-( ((4-(Difluoromethyl)pyrimidin-2-yl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy ) cyclohexane-1-carboxylic acid (I-22) (10.0 mg, yield 20.0%).
LC-MS,M/Z(ESI):500.1[M+H]
+
LC-MS, M/Z(ESI):500.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.51(d,1H),7.76(d,1H),7.74-7.69(m,1H),7.48(d,1H),6.87(d,1H),6.62-6.50(m,1H),4.97(s,2H),4.79(s,1H),4.07(s,3H),2.66-2.60(m,1H),2.45(br s,1H),2.08-1.99(m,1H),1.90-1.75(m,3H),1.69-1.46(m,4H),0.94-0.83(m,4H)
1 H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.51(d,1H),7.76(d,1H),7.74-7.69(m,1H),7.48(d,1H),6.87 (d,1H),6.62-6.50(m,1H),4.97(s,2H),4.79(s,1H),4.07(s,3H),2.66-2.60(m,1H),2.45(br s, 1H),2.08-1.99(m,1H),1.90-1.75(m,3H),1.69-1.46(m,4H),0.94-0.83(m,4H)
实施例23:目标化合物I-23的制备Embodiment 23: Preparation of Target Compound I-23
(1S,3S)-3-((2-环丙基-6-(5-(((异丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-23)(1S,3S)-3-((2-cyclopropyl-6-(5-(((isopropyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((isopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-23)(1S,3S)-3-((2-cyclopropyl-6-(5-(((isopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-23)
目标化合物I-23可参考化合物I-18合成,将3,3,3-三氟-N-甲基丙烷-1-胺替换为N-异丙基甲胺。The target compound I-23 can be synthesized with reference to compound I-18, replacing 3,3,3-trifluoro-N-methylpropan-1-amine with N-isopropylmethylamine.
LC-MS,M/Z(ESI):472.2[M+H]LC-MS, M/Z(ESI):472.2[M+H]
实施例24:目标化合物I-24的制备Embodiment 24: Preparation of target compound I-24
(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-24)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1- Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic(目标化合物I-24)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic (target compound I-24)
目标化合物I-24的合成路线如下所示:The synthetic route of target compound 1-24 is as follows:
第一步:3-(1,3-二氧亚基异二氢吲哚-2-基)丙醛(I-24B)的合成The first step: Synthesis of 3-(1,3-dioxylideneisoindolin-2-yl)propionaldehyde (I-24B)
3-(1,3-dioxoisoindolin-2-yl)propanal(I-24B)3-(1,3-dioxoisoindolin-2-yl) propanal (I-24B)
把2-(3-羟基丙基)异二氢吲哚-1,3-二酮(5.00g,24.3mmol)溶解于二氯甲烷(50.0mL)中,在0℃加入戴斯-马丁氧化剂(12.90g,30.4mmol),置换氮气,在25℃搅拌2小时。反应结束后用饱和亚硫酸钠水溶液(50mL)淬灭,用乙酸乙酯(90mL)萃取,有机相用饱和食盐水(90mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到的粗品用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=10:1至3:1)得到3-(1,3-二氧亚基异二氢吲哚-2-基)丙醛(I-24B)(1.80g,产率34.3%)。Dissolve 2-(3-hydroxypropyl)isoindoline-1,3-dione (5.00g, 24.3mmol) in dichloromethane (50.0mL), add Dess-Martin oxidant ( 12.90g, 30.4mmol), replaced with nitrogen, and stirred at 25°C for 2 hours. After the reaction was completed, it was quenched with saturated aqueous sodium sulfite (50 mL), extracted with ethyl acetate (90 mL), and the organic phase was washed with saturated brine (90 mL), then dried with anhydrous sodium sulfate, filtered, and concentrated. Chromatographic separation and purification (petroleum ether: ethyl acetate (V/V) = 10:1 to 3:1) to obtain 3-(1,3-dioxylidene isoindolin-2-yl) propanal ( I-24B) (1.80 g, 34.3% yield).
1H NMR(400MHz,DMSO-d6)δ9.67(m,1H),7.98(dd,1H),7.71(dd,1H),7.48(m,1H),7.23(m,1H),3.93-3.90(m,1H),3.85(m,2H),2.81(m,2H)
1 H NMR(400MHz,DMSO-d6)δ9.67(m,1H),7.98(dd,1H),7.71(dd,1H),7.48(m,1H),7.23(m,1H),3.93-3.90 (m,1H),3.85(m,2H),2.81(m,2H)
第二步:2-(3,3-二氟丙基)异二氢吲哚-1,3-二酮(I-24C)的合成The second step: Synthesis of 2-(3,3-difluoropropyl)isoindoline-1,3-dione (I-24C)
2-(3,3-difluoropropyl)isoindoline-1,3-dione(I-24C)2-(3,3-difluoropropyl)isoindoline-1,3-dione (I-24C)
把3-(1,3-二氧亚基异二氢吲哚-2-基)丙醛(I-24B)(1.80g,8.86mmol)溶解于四氢呋喃(18.0mL)中,在0℃下加入双(2-甲氧基乙基)氨基三氟化硫(5.88g,26.5mmol),加热到25℃,搅拌12小时,滴加入冰水溶液,用乙酸乙酯(60mL)萃取,有机相用饱和食盐水(60mL) 洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到的粗品用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=10:1至5:1),得到2-(3,3-二氟丙基)异二氢吲哚-1,3-二酮(I-24C)(510mg,产率25.5%)。Dissolve 3-(1,3-dioxylideneisoindolin-2-yl)propanal (I-24B) (1.80g, 8.86mmol) in tetrahydrofuran (18.0mL), and add Bis(2-methoxyethyl)aminosulfur trifluoride (5.88g, 26.5mmol), heated to 25°C, stirred for 12 hours, added dropwise to ice-water solution, extracted with ethyl acetate (60mL), and the organic phase was washed with saturated Washed with brine (60mL), then dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate (V/V)=10:1 to 5:1), 2-(3,3-Difluoropropyl)isoindoline-1,3-dione (I-24C) (510 mg, yield 25.5%) was obtained.
LC-MS,M/Z(ESI):226.1[M+H]
+
LC-MS, M/Z(ESI):226.1[M+H] +
第三步:叔-丁基(3,3-二氟丙基)氨基甲酯(I-24D)的合成The third step: the synthesis of tert-butyl (3,3-difluoropropyl) aminomethyl ester (I-24D)
tert-butyl(3,3-difluoropropyl)carbamate(I-24D)tert-butyl (3,3-difluoropropyl) carbamate (I-24D)
把2-(3,3-二氟丙基)异二氢吲哚-1,3-二酮(I-24C)(300mg,1.33mmol)溶解于乙醇(10.0mL)中,在氮气保护下加入水合肼(100mg,2.66mmol),置换氮气,加热到70℃下搅拌2小时。反应液冷却至室温,过滤,往滤液中加入氯化氢的乙酸乙酯溶液(4M,10.0mL)并在室温下搅拌10分钟。上述溶液直接浓缩,往残留物中依次加入乙酸乙酯(10mL),三乙胺(383mg,3.79mmol)和二碳酸二叔丁酯(275mg,1.26mmol),反应液在25℃搅拌12小时,用水淬灭,然后用乙酸乙酯(20.0mL)萃取,有机相用饱和食盐水(20.0mL)洗涤,再用无水硫酸钠干燥,过滤,浓缩得到粗品叔-丁基(3,3-二氟丙基)氨基甲酯(I-24D)(220mg,粗品)。Dissolve 2-(3,3-difluoropropyl)isoindoline-1,3-dione (I-24C) (300mg, 1.33mmol) in ethanol (10.0mL), and add Hydrazine hydrate (100mg, 2.66mmol) was replaced with nitrogen, heated to 70°C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, hydrogen chloride in ethyl acetate solution (4M, 10.0 mL) was added to the filtrate and stirred at room temperature for 10 minutes. The above solution was directly concentrated, and ethyl acetate (10 mL), triethylamine (383 mg, 3.79 mmol) and di-tert-butyl dicarbonate (275 mg, 1.26 mmol) were successively added to the residue, and the reaction solution was stirred at 25°C for 12 hours. Quenched with water, then extracted with ethyl acetate (20.0 mL), the organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude tert-butyl(3,3-di Fluoropropyl)aminomethyl ester (I-24D) (220 mg, crude).
1H NMR(400MHz,DMSO-d6)δ6.30-5.87(m,1H),3.32-3.28(m,2H),2.05-2.00(m,2H),1.44(d,9H)
1 H NMR(400MHz,DMSO-d6)δ6.30-5.87(m,1H),3.32-3.28(m,2H),2.05-2.00(m,2H),1.44(d,9H)
第四步:叔-丁基(3,3-二氟丙基)(甲基)氨基甲酯(I-24E)的合成The fourth step: the synthesis of tert-butyl (3,3-difluoropropyl) (methyl) aminomethyl ester (I-24E)
tert-butyl(3,3-difluoropropyl)(methyl)carbamate(I-24E)tert-butyl(3,3-difluoropropyl)(methyl)carbamate(I-24E)
把叔-丁基(3,3-二氟丙基)氨基甲酯(I-24D)(200mg,1.02mmol)溶解于四氢呋喃(5.00mL)中,在0℃下加入钠氢(81.9mg,2.04mmol),搅拌15分钟,0℃滴加碘甲烷(270mg,2.04mmol),反应液升温至25℃搅拌30分钟,将反应液滴加到饱和的氯化铵冰水溶液中,用乙酸乙酯(15mL)萃取,然后用饱和食盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,得到粗品用柱层析板分离纯化(石油醚:乙酸乙酯(V/V)=5:1),得到叔-丁基(3,3-二氟丙基)(甲基)氨基甲酯(I-24E)(110mg,产率46.6%)。Dissolve tert-butyl (3,3-difluoropropyl)aminomethyl ester (I-24D) (200mg, 1.02mmol) in tetrahydrofuran (5.00mL), add sodium hydrogen (81.9mg, 2.04 mmol), stirred for 15 minutes, iodomethane (270mg, 2.04mmol) was added dropwise at 0°C, the reaction solution was warmed up to 25°C and stirred for 30 minutes, the reaction solution was added dropwise to saturated ammonium chloride ice solution, and ethyl acetate ( 15mL), then washed with saturated brine (15mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was separated and purified by column chromatography (petroleum ether: ethyl acetate (V/V)=5 :1) to obtain tert-butyl(3,3-difluoropropyl)(methyl)aminomethyl ester (I-24E) (110 mg, yield 46.6%).
1H NMR(400MHz,CDCl3)δ6.04-5.60(m,1H),3.33(t,2H),2.81(s,3H),2.00-1.97(m,2H),1.38(s,9H)
1 H NMR (400MHz, CDCl3) δ6.04-5.60(m,1H),3.33(t,2H),2.81(s,3H),2.00-1.97(m,2H),1.38(s,9H)
第五步:3,3-二氟-N-甲基丙烷-1-胺盐酸盐(I-24F)的合成Step 5: Synthesis of 3,3-difluoro-N-methylpropane-1-amine hydrochloride (I-24F)
3,3-difluoro-N-methylpropan-1-amine hydrochloride(I-24F)3,3-difluoro-N-methylpropan-1-amine hydrochloride(I-24F)
把叔-丁基(3,3-二氟丙基)(甲基)氨基甲酯(I-24E)(110mg,476μmol)溶解于乙酸乙酯(1.00mL)中,在氮气保护下加入盐酸/乙酸乙酯(4.00M,1.00mL),置换氮气,25℃下搅拌0.5小时,浓缩得到3,3-二氟-N-甲基丙烷-1-胺盐酸盐(I-24F)(65.2mg,粗品)。Dissolve tert-butyl (3,3-difluoropropyl) (methyl) aminomethyl ester (I-24E) (110 mg, 476 μmol) in ethyl acetate (1.00 mL), add hydrochloric acid/ Ethyl acetate (4.00M, 1.00mL), replaced with nitrogen, stirred at 25°C for 0.5 hours, concentrated to give 3,3-difluoro-N-methylpropane-1-amine hydrochloride (I-24F) (65.2mg ,Crude).
第六步:(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基 -1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-24G)的合成The sixth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-24G)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-24G)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-24G)
把3,3-二氟-N-甲基丙烷-1-胺盐酸盐(I-24F)(65.2mg,598μmol)溶解于四氢呋喃(2.00mL)中,加入N,N-二异丙基乙胺(231mg,1.79mmol),(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(330mg,598μmol),置换氮气,在25℃搅拌0.5小时。反应结束后加水(10.0mL)淬灭,用乙酸乙酯(15.0mL)萃取,有机相用饱和食盐水(15.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-24G)(58.0mg,产率18.5%)。Dissolve 3,3-difluoro-N-methylpropane-1-amine hydrochloride (I-24F) (65.2mg, 598μmol) in tetrahydrofuran (2.00mL), add N,N-diisopropylethyl Amine (231mg, 1.79mmol), (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy) )methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-methyl carboxylate (I-2A) (330mg, 598μmol), displacement Nitrogen, stirred at 25°C for 0.5 hours. After the reaction was completed, add water (10.0 mL) to quench, extract with ethyl acetate (15.0 mL), wash the organic phase with saturated brine (15.0 mL), then dry over anhydrous sodium sulfate, filter, concentrate, and the residue was cleaned on a silica gel plate Separation and purification (petroleum ether: ethyl acetate (V/V) = 1:1), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3- Difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexyl Methyl alkane-1-carboxylate (I-24G) (58.0 mg, 18.5% yield).
LC-MS,M/Z(ESI):522.1[M+H]
+
LC-MS, M/Z(ESI):522.1[M+H] +
第七步:(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-24)的合成The seventh step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic(目标化合物I-24)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic (target compound I-24)
把(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-24G)(58.0mg,111μmol)溶解于四氢呋喃(2.00mL)中,加一水合氢氧化锂(46.6mg,1.11mmol)的水溶液(0.50mL),加热到25℃,搅拌12小时,加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备液相色谱(色谱柱:Phenomenex Luna C18 150*25mm*10μm;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:36%-66%,10min)纯化,得到(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-24)(20.0mg,产率35.4%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1 -Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-24G) (58.0mg, 111μmol) dissolved in Add an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (46.6 mg, 1.11 mmol) to tetrahydrofuran (2.00 mL), heat to 25 ° C, stir for 12 hours, add dilute hydrochloric acid aqueous solution to adjust the pH to 1, and use ethyl acetate ( 10.0mL), the organic phase was washed with saturated brine (10.0mL), then dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product by preparative liquid chromatography (chromatographic column: Phenomenex Luna C18 150*25mm*10μm; solvent : A=water+0.225vol% ammonia water (99%), B=acetonitrile; Gradient: 36%-66%, 10min) purification to obtain (1S,3S)-3-((2-cyclopropyl-6-( 5-((((3,3-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-24) (20.0 mg, yield 35.4%).
LC-MS,M/Z(ESI):508.0[M+H]
+
LC-MS, M/Z(ESI):508.0[M+H] +
1H NMR(400MHz,CDCl
3)δ7.93(d,1H),7.22(d,1H),6.13-5.70(m,1H),5.68(s,2H),4.73(s,1H),4.15(d,3H),3.48(t,1H),3.38-3.28(m,1H),2.93-2.83(m,4H),2.59-2.48(m,1H),2.26-1.91(m,5H),1.90-1.77(m,2H),1.68(br s,3H),1.08(s,2H),1.03-0.95(m,2H)
1 H NMR (400MHz, CDCl 3 )δ7.93(d,1H),7.22(d,1H),6.13-5.70(m,1H),5.68(s,2H),4.73(s,1H),4.15( d,3H),3.48(t,1H),3.38-3.28(m,1H),2.93-2.83(m,4H),2.59-2.48(m,1H),2.26-1.91(m,5H),1.90- 1.77(m,2H),1.68(br s,3H),1.08(s,2H),1.03-0.95(m,2H)
实施例25:目标化合物I-25的制备Embodiment 25: Preparation of Target Compound I-25
(1S,3S)-3-((6-(5-(((环丁基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-25)(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazole -4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-25)
(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-25)(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-25)
目标化合物I-25的合成路线如下所示:The synthetic route of target compound 1-25 is as follows:
第一步:(1S,3S)-3-((6-(5-(((环丁基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-25B)的合成The first step: (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of methyl 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-25B)
methyl(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(目标化合物I-25)methyl(1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2 -cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (target compound I-25)
把N-甲基环丁胺(20.0mg,164μmol)溶解于四氢呋喃(0.50mL)中,加入N,N-二异丙基乙胺(49.2mg,380μmol),(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(70.0mg,126μmol),置换氮气,在25℃搅拌0.5小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,然后用饱和食盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,得到粗品用柱层析板分离纯化(石油醚:乙酸乙酯(V/V)=2:1),得到(1S,3S)-3-((6-(5-(((环丁基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-25B)(50.0mg,产率79.1%)。Dissolve N-methylcyclobutylamine (20.0 mg, 164 μmol) in tetrahydrofuran (0.50 mL), add N,N-diisopropylethylamine (49.2 mg, 380 μmol), (1S, 3S)-3-( (2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazole-4 -yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (70.0mg, 126μmol), nitrogen replacement, stirred at 25°C for 0.5 hours. After the reaction was completed, add water (10mL) to quench, extract with ethyl acetate (15mL), then wash with saturated brine (15mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which was separated by column chromatography Purification (petroleum ether:ethyl acetate (V/V)=2:1) gave (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)aminocarbonyl)oxy )methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester ( I-25B) (50.0 mg, 79.1% yield).
LC-MS,M/Z(ESI):498.2[M+H]
+
LC-MS, M/Z(ESI):498.2[M+H] +
第二步:(1S,3S)-3-((6-(5-(((环丁基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-25)的合成The second step: (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2, Synthesis of 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-25)
把(1S,3S)-3-((6-(5-(((环丁基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-25B)(50.0mg,100μmol)溶解于四氢呋喃(1.00mL)中,加一水合氢氧化锂(21.0mg,502μmol)的水溶液(0.20mL),加热到25℃,搅拌12小时,加入稀盐酸溶液调节pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备液相色谱(柱子:Waters Xbridge 150*25mm*5μm;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:42%-72%,7min)纯化,得到(1S,3S)-3-((6-(5-(((环丁基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(I-25)(5.10mg,产率21.9%)。Put (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-tri Azol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-25B) (50.0 mg, 100 μmol) was dissolved in tetrahydrofuran (1.00 mL), Add an aqueous solution (0.20 mL) of lithium hydroxide monohydrate (21.0 mg, 502 μmol), heat to 25 ° C, stir for 12 hours, add dilute hydrochloric acid solution to adjust the pH to 1, extract with ethyl acetate (10.0 mL), and use Wash with saturated brine (10.0 mL), then dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product by preparative liquid chromatography (column: Waters Xbridge 150*25mm*5 μm; solvent: A=water+0.225% by volume ammonia ( 99%), B = acetonitrile; gradient: 42%-72%, 7min) purification to obtain (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)aminocarbonyl)oxy Base) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I -25) (5.10 mg, yield 21.9%).
LC-MS,M/Z(ESI):484.2[M+H]
+
LC-MS, M/Z(ESI):484.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ=7.75(d,1H),7.47(d,1H),5.54(s,2H),4.79(s,1H),4.08(s,3H),2.74(s,3H),2.67(m,1H),2.17-1.95(m,4H),1.94-1.74(m,5H),1.73-1.33(m,7H),1.00-0.91(m,4H)
1 H NMR (400MHz, DMSO-d6) δ=7.75(d,1H),7.47(d,1H),5.54(s,2H),4.79(s,1H),4.08(s,3H),2.74(s ,3H),2.67(m,1H),2.17-1.95(m,4H),1.94-1.74(m,5H),1.73-1.33(m,7H),1.00-0.91(m,4H)
实施例26:目标化合物I-26的制备Embodiment 26: Preparation of Target Compound I-26
(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟环丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基]吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-26)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)aminocarbonyl)oxy)methyl)-1 -Methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-26)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)
目标化合物I-26的合成路线如下所示:The synthetic route of target compound 1-26 is as follows:
第一步:N-乙烯基-N-甲基氨基甲酸叔丁酯(I-26B)的合成The first step: the synthesis of N-vinyl-N-methylcarbamate tert-butyl ester (I-26B)
tert-butyl N-ethenyl-N-methylcarbamate(I-26B)tert-butyl N-ethenyl-N-methylcarbamate (I-26B)
在氮气保护和冰浴条件下,将钠氢(2.10g,52.3mmol,60%)加入四氢呋喃(20.0mL)中,再缓慢加入N-乙烯基氨基甲酸叔丁酯(5.00g,34.9mmol),搅拌0.5小时后,加入碘甲烷(7.43g,52.3mmol,3.26mL),随后反应液升至25℃搅拌16小时。反应结束后缓慢加水(10.0mL)淬灭,用乙酸乙酯(30.0mL)萃取,有机相用饱和食盐水(15.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=10:1),得到化合物N-乙烯基-N-甲基氨基甲酸叔丁酯(I-26B)(3.50g,产率63.7%)。Under nitrogen protection and ice bath conditions, sodium hydrogen (2.10g, 52.3mmol, 60%) was added into tetrahydrofuran (20.0mL), and N-vinylcarbamate tert-butyl ester (5.00g, 34.9mmol) was added slowly, After stirring for 0.5 hour, iodomethane (7.43 g, 52.3 mmol, 3.26 mL) was added, and then the reaction solution was raised to 25° C. and stirred for 16 hours. After the reaction was completed, water (10.0 mL) was slowly added to quench, extracted with ethyl acetate (30.0 mL), the organic phase was washed with saturated brine (15.0 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Chromatographic separation and purification (petroleum ether:ethyl acetate (V/V)=10:1), the compound N-vinyl-N-methylcarbamate tert-butyl ester (I-26B) (3.50g, yield 63.7 %).
1H NMR(400MHz,CDCl
3)δ7.25-7.00(m,1H),4.31-4.13(m,2H),3.01(s,3H),1.50(s,9H),1.49-1.43(m,5H)。
1 H NMR (400MHz, CDCl 3 )δ7.25-7.00(m,1H),4.31-4.13(m,2H),3.01(s,3H),1.50(s,9H),1.49-1.43(m,5H ).
第二步:N-(2,2-二氟环丙基)-N-甲基氨基甲酸叔丁酯(I-26D)的合成The second step: the synthesis of tert-butyl N-(2,2-difluorocyclopropyl)-N-methylcarbamate (I-26D)
tert-butyl N-(2,2-difluorocyclopropyl)-N-methylcarbamate(I-26D)tert-butyl N-(2,2-difluorocyclopropyl)-N-methylcarbamate(I-26D)
把N-乙烯基-N-甲基氨基甲酸叔丁酯(500mg,3.18mmol)溶解于四氢呋喃(10.0mL)中,加入三甲基(三氟甲基)硅烷(1.13g,7.95mmol)和碘化钠(1.00g,6.68mmol),反应液加热至66℃搅拌4小时。反应结束后,过滤,滤液浓缩,粗品用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=20:1),得到化合物N-(2,2-二氟环丙基)-N-甲基氨基甲酸叔丁酯(I-26D)(500mg,产率75.87%)。Dissolve tert-butyl N-vinyl-N-methylcarbamate (500mg, 3.18mmol) in tetrahydrofuran (10.0mL), add trimethyl(trifluoromethyl)silane (1.13g, 7.95mmol) and iodine Sodium chloride (1.00g, 6.68mmol), the reaction solution was heated to 66°C and stirred for 4 hours. After the reaction, filter, concentrate the filtrate, and separate and purify the crude product by column chromatography (petroleum ether: ethyl acetate (V/V) = 20:1) to obtain the compound N-(2,2-difluorocyclopropyl)- tert-Butyl N-methylcarbamate (I-26D) (500 mg, yield 75.87%).
1H NMR(400MHz,CDCl3)δ3.14-3.00(m,1H),2.86(s,3H),1.73-1.56(m,1H),1.48(s,9H),1.44-1.34(m,1H)
1 H NMR (400MHz, CDCl3) δ3.14-3.00(m,1H),2.86(s,3H),1.73-1.56(m,1H),1.48(s,9H),1.44-1.34(m,1H)
第三步:2,2-二氟-N-甲基环丙烷-1-胺盐酸(I-26E)的合成The third step: the synthesis of 2,2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E)
2,2-difluoro-N-methylcyclopropan-1-amine hydrochloride(I-26E)2,2-difluoro-N-methylcyclopropan-1-amine hydrochloride (I-26E)
把N-(2,2-二氟环丙基)-N-甲基氨基甲酸叔丁酯(500mg,2.41mmol)溶解于乙酸乙酯(30.0mL)中,加入氯化氢的乙酸乙酯溶液(4M,3.02mL),反应液于25℃下搅拌4小时。反应结束后直接过滤,浓缩,得到化合物2,2-二氟-N-甲基环丙烷-1-胺盐酸(I-26E)(302mg,产率87.1%)。Dissolve tert-butyl N-(2,2-difluorocyclopropyl)-N-methylcarbamate (500mg, 2.41mmol) in ethyl acetate (30.0mL), add hydrogen chloride in ethyl acetate solution (4M , 3.02mL), the reaction solution was stirred at 25°C for 4 hours. After the reaction was completed, it was directly filtered and concentrated to obtain compound 2,2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E) (302 mg, yield 87.1%).
第四步:N-(2,2-二氟环丙基)-N-甲基-1H-咪唑-1-甲酰胺(I-26F)的合成Step 4: Synthesis of N-(2,2-difluorocyclopropyl)-N-methyl-1H-imidazole-1-carboxamide (I-26F)
N-(2,2-difluorocyclopropyl)-N-methyl-1H-imidazole-1-carboxamide(I-26F)N-(2,2-difluorocyclopropyl)-N-methyl-1H-imidazole-1-carboxamide (I-26F)
把2,2-二氟-N-甲基环丙烷-1-胺盐酸(I-26E)(200mg,1.39mmol)溶解于二氯甲烷(5.00mL)中,加入N,N-二异丙基乙胺(180mg,1.39mmol),反应液在25℃搅拌12小时。反应结束后加水(10.0mL)淬灭,用乙酸乙酯(15.0mL)萃取,有机相用饱和食盐水(15.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩得到化合物N-(2,2-二氟环丙基)-N-甲基-1H-咪唑-1-甲酰胺(I-26F)(280mg,粗品)。Dissolve 2,2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E) (200mg, 1.39mmol) in dichloromethane (5.00mL), add N,N-diisopropyl Ethylamine (180mg, 1.39mmol), the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, water (10.0 mL) was added to quench, extracted with ethyl acetate (15.0 mL), the organic phase was washed with saturated brine (15.0 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound N-(2 ,2-Difluorocyclopropyl)-N-methyl-1H-imidazole-1-carboxamide (I-26F) (280 mg, crude).
第五步:(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-26G)的合成The fifth step: (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-26G) synthesis
(1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-26G)(1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane -1-carboxylic acid (I-26G)
把(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1I)(200mg,517μmol)溶解于四氢呋喃(5.00mL)中,加一水合氢氧化锂(217mg,5.18mmol)和水(2.0mL),反应液在室温下搅拌12小时。反应完全后,加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,减压浓缩得到化合物(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-26G)(192mg,粗品)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine- 3-yl)oxy)methyl cyclohexane-1-carboxylate (I-1I) (200 mg, 517 μmol) was dissolved in tetrahydrofuran (5.00 mL), and lithium hydroxide monohydrate (217 mg, 5.18 mmol) and water ( 2.0 mL), the reaction solution was stirred at room temperature for 12 hours. After the reaction was complete, dilute aqueous hydrochloric acid was added to adjust the pH to 1, extracted with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound (1S ,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl )oxy)cyclohexane-1-carboxylic acid (I-26G) (192 mg, crude).
LC-MS,M/Z(ESI):373.2[M+H]
+
LC-MS, M/Z(ESI):373.2[M+H] +
第六步:(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟环丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基]吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-26)的合成The sixth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of -1-methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)carbamoyl)oxy)methyl)-1 -methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-26)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-26)
把(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-26G)(100mg,268μmol)溶解于叔戊醇(3.0mL)中,反应液在氮气保护下缓慢加入N-(2,2-二氟环丙基)-N-甲基-1H-咪唑-1-甲酰胺(108mg,537μmol),加完后,加热到60℃,再滴加叔丁醇钾(1M,671μL),继续搅拌2小时。反应液冷至室温,加入稀盐酸调节水溶液pH至1,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备高效液相色谱纯化(色谱柱:3_Phenomenex Luna C18 75*30mm*3um;溶剂:A=水(HCl),B=乙腈;梯度:40%-60%,8min),得到化合物(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟环丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基]吡啶-3-基)氧基)环己烷-1-甲酸(I-26)(15.0mg,产率10.9%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine- 3-yl)oxy)cyclohexane-1-carboxylic acid (I-26G) (100 mg, 268 μmol) was dissolved in tert-amyl alcohol (3.0 mL), and the reaction solution was slowly added to N-(2,2- Difluorocyclopropyl)-N-methyl-1H-imidazole-1-carboxamide (108mg, 537μmol), after the addition, heated to 60°C, then added dropwise potassium tert-butoxide (1M, 671μL), and continued to stir 2 hours. The reaction solution was cooled to room temperature, dilute hydrochloric acid was added to adjust the pH of the aqueous solution to 1, extracted with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product Preparative HPLC purification (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water (HCl), B=acetonitrile; gradient: 40%-60%, 8min) to obtain compound (1S, 3S) -3-((2-cyclopropyl-6-(5-((((2,2-difluorocyclopropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H -1,2,3-Triazol-4-yl]pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-26) (15.0 mg, yield 10.9%).
LC-MS,M/Z(ESI):506.2[M+H]
+
LC-MS, M/Z(ESI):506.2[M+H] +
1H NMR(400MHz,CDCl
3)δ7.92(d,1H),7.21(d,1H),6.07-5.49(m,2H),4.73(br s,1H),4.15(s,3H),3.21-3.00(m,1H),2.92(br s,3H),2.59-2.50(m,1H),2.25-2.18(m,1H),2.08-1.91(m,4H),1.88-1.77(m,2H),1.73-1.62(m,4H),1.14-1.05(m,2H),1.02-0.95(m,2H)
1 H NMR (400MHz, CDCl 3 )δ7.92(d,1H),7.21(d,1H),6.07-5.49(m,2H),4.73(br s,1H),4.15(s,3H),3.21 -3.00(m,1H),2.92(br s,3H),2.59-2.50(m,1H),2.25-2.18(m,1H),2.08-1.91(m,4H),1.88-1.77(m,2H ),1.73-1.62(m,4H),1.14-1.05(m,2H),1.02-0.95(m,2H)
实施例27:目标化合物I-27的制备Embodiment 27: Preparation of Target Compound I-27
(1S,3S)-3-((2-环丙基-6-(5-((((3-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-27)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-27)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27)
目标化合物I-27的合成路线如下所示:The synthetic route of target compound 1-27 is as follows:
第一步:N-苯甲基-3-氟-N-甲基丙烷-1-胺(化合物I-27C)的合成The first step: the synthesis of N-benzyl-3-fluoro-N-methylpropane-1-amine (compound I-27C)
N-benzyl-3-fluoro-N-methylpropan-1-amine(化合物I-27C)N-benzyl-3-fluoro-N-methylpropan-1-amine (Compound I-27C)
向乙腈(140mL)中加入1-溴-3-氟丙烷(I-27A)(5.00g,35.4mmol),N-甲基苄胺(I-27B)(4.17g,34.4mmol)和碳酸钾(11.7g,85.1mmol),反应液于60℃搅拌12小时。反应结束后,直接减压浓缩,粗产物经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到N-苯甲基-3-氟-N-甲基丙烷-1-胺(I-27C)。To acetonitrile (140 mL) was added 1-bromo-3-fluoropropane (I-27A) (5.00 g, 35.4 mmol), N-methylbenzylamine (I-27B) (4.17 g, 34.4 mmol) and potassium carbonate ( 11.7g, 85.1mmol), and the reaction solution was stirred at 60°C for 12 hours. After the reaction was completed, it was directly concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain N-benzyl-3-fluoro-N-methylpropane -1-amine (I-27C).
1H NMR(400MHz,CDCl
3)δ7.34-7.23(s,5H),4.61-4.58(m,1H),4.49-4.46(m,1H),3.51(s,2H),2.54-2.51(m,2H),2.21(s,3H),2.00-1.83(m,2H)
1 H NMR (400MHz, CDCl 3 )δ7.34-7.23(s,5H),4.61-4.58(m,1H),4.49-4.46(m,1H),3.51(s,2H),2.54-2.51(m ,2H),2.21(s,3H),2.00-1.83(m,2H)
第二步:3-氟-N-甲基丙烷-1-胺盐酸(化合物I-27D)的合成The second step: the synthesis of 3-fluoro-N-methylpropane-1-amine hydrochloric acid (compound I-27D)
3-fluoro-N-methylpropan-1-amine hydrochloride(化合物I-27D)3-fluoro-N-methylpropan-1-amine hydrochloride (compound I-27D)
将N-苯甲基-3-氟-N-甲基丙烷-1-胺(I-27C)(2.00g,11.0mmol)溶于盐酸/甲醇(20.0mL)中,氮气保护下加入氢氧化钯/碳(774mg,10%),反应体系用氢气置换并在氢气(50Psi)氛围下于40℃搅拌24小时。反应结束后,过滤,滤液减压浓缩得到化合物3-氟-N-甲基丙烷-1-胺盐酸(1.2g,产率85.2%)。Dissolve N-benzyl-3-fluoro-N-methylpropane-1-amine (I-27C) (2.00g, 11.0mmol) in hydrochloric acid/methanol (20.0mL), and add palladium hydroxide under nitrogen protection / carbon (774 mg, 10%), the reaction system was replaced with hydrogen and stirred at 40° C. for 24 hours under a hydrogen (50 Psi) atmosphere. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the compound 3-fluoro-N-methylpropane-1-amine hydrochloride (1.2 g, yield 85.2%).
第三步:(1S,3S)-3-((2-环丙基-6-(5-((((3-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(化合物I-27E)的合成The third step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1 Synthesis of methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (compound I-27E)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylatemethyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate
将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(400mg,725μmol),3-氟-N-甲基丙烷-1-胺盐酸(I-27D)(101mg,797μmol)溶于四氢呋喃(5.00mL)中,反应液冷至0℃,滴加二异丙基乙胺(187mg,1.45mmol),随后升温至25℃搅拌0.5小时。反应完毕后,向反应液中加水(10mL),并用乙酸乙酯萃取(15mL*3),合并有机相并用无水硫酸钠干燥,过滤浓缩,得到粗品用薄层硅胶板纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((2-环丙基-6-(5-((((3-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-27E)(302mg,产率82.6%)。(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (400mg, 725μmol), 3-fluoro-N-methyl Propan-1-amine hydrochloride (I-27D) (101mg, 797μmol) was dissolved in tetrahydrofuran (5.00mL), the reaction solution was cooled to 0°C, diisopropylethylamine (187mg, 1.45mmol) was added dropwise, and then heated to Stir at 25°C for 0.5 hours. After the reaction was completed, water (10 mL) was added to the reaction liquid, and extracted with ethyl acetate (15 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by a thin-layer silica gel plate (petroleum ether: acetic acid Ethyl ester (V/V)=1:1), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)amino Carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I- 27E) (302 mg, 82.6% yield).
LC-MS,M/Z(ESI):504.3[M+H]
+
LC-MS, M/Z(ESI):504.3[M+H] +
第四步:(1S,3S)-3-((2-环丙基-6-(5-((((3-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-27)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1 Synthesis of -methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-27)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-27)
将(1S,3S)-3-((2-环丙基-6-(5-((((3-氟丙基)(甲基)氨基羰基)氧代)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(300mg,595μmol)溶于四氢呋喃(9.00mL)和水(3.00mL)中,再加入一水氢氧化锂(250mg,5.96mmol),反应液于25℃搅拌12小时。反应完毕后,用稀盐酸(1mol/L)调节反应液pH至2,并用乙酸乙酯萃取(15mL*3),合并有机相,用无水硫酸钠干燥,过滤浓缩,得到的粗品通过制备高效液相色谱仪进行分离(色谱柱:3_Phenomenex Luna C18 75*30mm*3um;溶剂:A=水+0.01%HCl,B=乙腈;梯度:34%-54%,8分钟),得到(1S,3S)-3-((2-环丙基-6-(5-((((3-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-27)(180mg,产率61.1%)。(1S,3S)-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)aminocarbonyl)oxo)methyl)-1-methyl -1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (300mg, 595μmol) was dissolved in tetrahydrofuran (9.00mL) and water (3.00 mL), lithium hydroxide monohydrate (250mg, 5.96mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 2 with dilute hydrochloric acid (1mol/L), and extracted with ethyl acetate (15mL*3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was prepared by preparing high-efficiency Liquid chromatography is separated (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3um; Solvent: A=water+0.01%HCl, B=acetonitrile; Gradient: 34%-54%, 8 minutes), obtain (1S, 3S )-3-((2-cyclopropyl-6-(5-((((3-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-27) (180 mg, yield 61.1%).
LC-MS,M/Z(ESI):490.2[M+H]
+
LC-MS, M/Z(ESI):490.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.2(s,1H),7.76-7.47(m,1H),7.46-7.45(m,1H),5.56(s,2H),4.79(br s,1H),4.56-4.18(m,2H),4.09(s,3H),3.31(m,2H),3.21-3.16(m,1H),2.81-2.77(m,3H),2.69-2.64(m,1H),2.09-1.97(m,1H),1.93-1.76(m,4H),1.75-1.45(m,5H),1.05-0.90(m,4H)
1 H NMR (400MHz,DMSO-d6)δ12.2(s,1H),7.76-7.47(m,1H),7.46-7.45(m,1H),5.56(s,2H),4.79(br s,1H ),4.56-4.18(m,2H),4.09(s,3H),3.31(m,2H),3.21-3.16(m,1H),2.81-2.77(m,3H),2.69-2.64(m,1H ),2.09-1.97(m,1H),1.93-1.76(m,4H),1.75-1.45(m,5H),1.05-0.90(m,4H)
实施例28:目标化合物I-28的制备Embodiment 28: Preparation of target compound I-28
(1S,3S)-3-((2-环丙基-6-(5-((((2-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-28)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-28)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-28)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol -4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-28)
目标化合物I-28的合成路线如下所示:The synthetic route of target compound I-28 is as follows:
第一步:1-(苯甲基(甲基)氨基)丙烷-2-醇(I-28B)的合成The first step: the synthesis of 1-(benzyl(methyl)amino)propan-2-ol (I-28B)
1-(benzyl(methyl)amino)propan-2-ol(I-28B)1-(benzyl(methyl)amino)propan-2-ol(I-28B)
把N-甲基-1-苯基甲胺(4.17g,34.4mmol)溶解于乙醇(50.0mL)中,加入2-甲基噁丙环(6.00g,103mmol),置换氮气,反应液在60℃搅拌12小时。反应结束后浓缩除去溶剂,残留物用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=10:1至5:1),得到1-(苯甲基(甲基)氨基)丙烷-2-醇(I-28B)(2.60g,产率42.1%)。Dissolve N-methyl-1-phenylmethanamine (4.17g, 34.4mmol) in ethanol (50.0mL), add 2-methyloxapropane (6.00g, 103mmol), replace nitrogen, and the reaction solution is at 60 °C and stirred for 12 hours. After the reaction was completed, the solvent was concentrated and removed, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate (V/V)=10:1 to 5:1) to obtain 1-(benzyl (methyl)amino) Propan-2-ol (I-28B) (2.60 g, 42.1% yield).
1H NMR(400MHz,CDCl
3)δ7.27(s,5H),3.88-3.79(m,1H),3.64(d,1H),3.43(d,1H),2.38-2.25(m,2H),2.20(s,3H),1.10(d,3H)
1 H NMR (400MHz, CDCl 3 )δ7.27(s,5H),3.88-3.79(m,1H),3.64(d,1H),3.43(d,1H),2.38-2.25(m,2H), 2.20(s,3H),1.10(d,3H)
第二步:N-苯甲基-2-氟-N-甲基丙烷-1-胺(I-28C)的合成The second step: the synthesis of N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C)
N-benzyl-2-fluoro-N-methylpropan-1-amine(I-28C)N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C)
把1-(苯甲基(甲基)氨基)丙烷-2-醇(I-28B)(500mg,2.79mmol)溶解于二氯甲烷(5mL)中,在0℃下加入氟化铯(127mg,836μmol),二乙氨基三氟化硫(1.35g,8.37mmol)和三氟乙酸(3.18mg,27.8μmol),加热到25℃,搅拌12小时,加入饱和碳酸氢钠水溶液,用乙酸乙酯(10mL)萃取,然后用饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩直接浓缩得到粗品,用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=2:1),得到N-苯甲基-2-氟-N-甲基丙烷-1-胺(I-28C)(200mg,产率39.5%)。Dissolve 1-(benzyl(methyl)amino)propan-2-ol (I-28B) (500mg, 2.79mmol) in dichloromethane (5mL), add cesium fluoride (127mg, 836μmol), diethylaminosulfur trifluoride (1.35g, 8.37mmol) and trifluoroacetic acid (3.18mg, 27.8μmol), heated to 25°C, stirred for 12 hours, added saturated aqueous sodium bicarbonate solution, washed with ethyl acetate ( 10 mL), then washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and directly concentrated to obtain the crude product, which was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V/V)=2 :1), N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C) (200 mg, yield 39.5%) was obtained.
LC-MS,M/Z(ESI):182.1[M+H]
+
LC-MS, M/Z(ESI):182.1[M+H] +
1H NMR(400MHz,CDCl
3)δ7.35-7.28(m,5H),4.95-4.79(m,1H),3.61(s,2H),2.69-2.62(m,1H),2.59-2.44(m,1H),2.33(s,3H),1.37(d,1H),1.31(d,1H),1.12(dd,1H)
1 H NMR (400MHz, CDCl 3 )δ7.35-7.28(m,5H),4.95-4.79(m,1H),3.61(s,2H),2.69-2.62(m,1H),2.59-2.44(m ,1H),2.33(s,3H),1.37(d,1H),1.31(d,1H),1.12(dd,1H)
第三步:2-氟-N-甲基丙烷-1-胺盐酸盐(I-28D)的合成The third step: the synthesis of 2-fluoro-N-methylpropane-1-amine hydrochloride (I-28D)
2-fluoro-N-methylpropan-1-amine hydrochloride(I-28D)2-fluoro-N-methylpropan-1-amine hydrochloride (I-28D)
把N-苯甲基-2-氟-N-甲基丙烷-1-胺(I-28C)(200mg,1.10mmol)溶解于甲醇(10.0mL)中,在氮气保护下加入钯碳(10%,0.02g),反应体系置换氢气,反应液加热到25℃搅拌12小时,用硅藻土过滤,滤液中加入盐酸乙酸乙酯(4.00M,5.00mL),室温搅拌10分钟,直接浓缩得到粗品2-氟-N-甲基丙烷-1-胺盐酸盐(I-28D)(52.0mg,粗品)。Dissolve N-benzyl-2-fluoro-N-methylpropane-1-amine (I-28C) (200mg, 1.10mmol) in methanol (10.0mL), add palladium on carbon (10% , 0.02g), the reaction system was replaced with hydrogen, the reaction solution was heated to 25°C and stirred for 12 hours, filtered with diatomaceous earth, ethyl acetate hydrochloride (4.00M, 5.00mL) was added to the filtrate, stirred at room temperature for 10 minutes, and concentrated directly to obtain the crude product 2-Fluoro-N-methylpropan-1-amine hydrochloride (I-28D) (52.0 mg, crude).
1H NMR(400MHz,CDCl
3)δ5.43-5.26(m,1H),4.84-4.66(m,1H),2.80(s,3H),2.77(s,1H),1.48(d,2H),1.42(d,1H)
1 H NMR (400MHz, CDCl 3 )δ5.43-5.26(m,1H),4.84-4.66(m,1H),2.80(s,3H),2.77(s,1H),1.48(d,2H), 1.42(d,1H)
第四步:(1S,3S)-3-((2-环丙基-6-(5-((((2-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-28E)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1 Synthesis of methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-28E)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-28E)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-28E)
把2-氟-N-甲基丙烷-1-胺盐酸盐(I-28D)(23.1mg,253μmol)溶解于四氢呋喃(2.00mL)中,加入N,N-二异丙基乙胺(98.4mg,761μmol),(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(140mg,253μmol),反应液在氮气保护下于25℃搅拌12小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,有机相用饱和食盐水(15mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((2-环丙基-6-(5-((((2-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-28E)(80.0mg,产率62.5%)。Dissolve 2-fluoro-N-methylpropane-1-amine hydrochloride (I-28D) (23.1mg, 253μmol) in tetrahydrofuran (2.00mL), add N,N-diisopropylethylamine (98.4 mg,761μmol), (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl )-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxyl)cyclohexane-1-carboxylic acid methyl ester (I-2A) (140mg, 253μmol), the reaction solution in nitrogen Stir at 25°C for 12 hours under protection. After the reaction was completed, quenched with water (10 mL), extracted with ethyl acetate (15 mL), washed the organic phase with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was separated and purified on a silica gel plate ( Petroleum ether: ethyl acetate (V/V)=1:1), obtain (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)( Methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid Ester (I-28E) (80.0 mg, 62.5% yield).
LC-MS,M/Z(ESI):504.1[M+H]
+
LC-MS, M/Z(ESI):504.1[M+H] +
第五步:(1S,3S)-3-((2-环丙基-6-(5-((((2-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-28)的合成The fifth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1 Synthesis of -methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-28)
把(1S,3S)-3-((2-环丙基-6-(5-((((2-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(80.0mg,158μmol)溶解于四氢呋喃(2.00mL)中,加入一水合氢氧化锂(66.6mg,1.59mmol)的水溶液(0.50mL),反应液于25℃搅拌12小时。反应完后反应液中加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备液相色谱(柱子:Phenomenex Luna C18 150*25mm*10um;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:40%-70%,10min)纯化,得到(1S,3S)-3-((2-环丙基-6-(5-((((2-氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-28)(11.0mg,产率14.0%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl -1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (80.0mg, 158μmol) was dissolved in tetrahydrofuran (2.00mL), added An aqueous solution (0.50 mL) of lithium hydroxide monohydrate (66.6 mg, 1.59 mmol) was stirred at 25°C for 12 hours. After the reaction, dilute hydrochloric acid aqueous solution was added to the reaction solution to adjust the pH to 1, extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (10.0 mL), then dried with anhydrous sodium sulfate, filtered, and concentrated to obtain The crude product was purified by preparative liquid chromatography (column: Phenomenex Luna C18 150*25mm*10um; solvent: A=water+0.225% by volume ammonia (99%), B=acetonitrile; gradient: 40%-70%, 10min) to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-((((2-fluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-28) (11.0 mg, yield 14.0%).
LC-MS,M/Z(ESI):490.2[M+H]
+
LC-MS, M/Z(ESI):490.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.76(dd,1H),7.47(dd,1H),5.58(d,2H),4.89-4.48(m,2H),4.09(s,3H),3.41(s,1H),2.84(d,3H),2.57-2.55(m,1H),2.10-1.98(m,1H),1.98-1.98(m,1H),1.82(m,3H),1.68-1.48(m,4H),1.31-1.12(m,2H),1.10-0.92(m,6H)
1 H NMR(400MHz,DMSO-d6)δ7.76(dd,1H),7.47(dd,1H),5.58(d,2H),4.89-4.48(m,2H),4.09(s,3H),3.41 (s,1H),2.84(d,3H),2.57-2.55(m,1H),2.10-1.98(m,1H),1.98-1.98(m,1H),1.82(m,3H),1.68-1.48 (m,4H),1.31-1.12(m,2H),1.10-0.92(m,6H)
实施例29:目标化合物I-29的制备Embodiment 29: Preparation of Target Compound I-29
(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-29)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1- Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-29)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid(目标化合物I-29)(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid (target compound I-29)
目标化合物I-29的合成路线如下所示:The synthetic route of target compound 1-29 is as follows:
第一步:1-(苯甲基(甲基)氨基)丙烷-2-酮(I-29C)的合成The first step: the synthesis of 1-(benzyl(methyl)amino)propan-2-one (I-29C)
1-(benzyl(methyl)amino)propan-2-one1-(benzyl(methyl)amino)propan-2-one
将N-甲基苄胺(5.00g,41.2mmol)和二异丙基乙胺(5.44g,42.0mmol)溶于乙腈(13.0mL)中,并氮气置换三次,反应液于15℃下缓慢滴加一氯丙酮(4.08g,44.15mmol),随后升温至25℃搅拌12小时。反应结束后,将反应液加入到饱和的碳酸氢钠水溶液中,并用二氯甲烷(15mL×3)萃取,有机相用无水硫酸钠干燥,过滤浓缩,得到1-(苯甲基(甲基)氨基)丙烷-2-酮(I-29C)(6.40g,产率87.5%)。Dissolve N-methylbenzylamine (5.00g, 41.2mmol) and diisopropylethylamine (5.44g, 42.0mmol) in acetonitrile (13.0mL), replace with nitrogen three times, and slowly drop the reaction solution at 15°C Add monochloroacetone (4.08g, 44.15mmol), then raise the temperature to 25°C and stir for 12 hours. After the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (15mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1-(benzyl(methyl )amino)propan-2-one (I-29C) (6.40 g, 87.5% yield).
1H NMR(400MHz,CDCl
3)δ7.48-7.16(m,5H),3.59(s,2H),3.16(s,2H),2.31(s,3H),2.16(s,3H)
1 H NMR (400MHz, CDCl 3 )δ7.48-7.16(m,5H),3.59(s,2H),3.16(s,2H),2.31(s,3H),2.16(s,3H)
第二步:N-苯甲基-2,2-二氟-N-甲基丙烷-1-胺(I-29D)的合成The second step: the synthesis of N-benzyl-2,2-difluoro-N-methylpropane-1-amine (I-29D)
N-benzyl-2,2-difluoro-N-methylpropan-1-amineN-benzyl-2,2-difluoro-N-methylpropan-1-amine
在氮气保护下,向100mL的三口瓶中加入1-(苯甲基(甲基)氨基)丙烷-2-酮(I-29C)(2.00g,11.2mmol),氟化铯(257mg,1.69mmol)和二氯甲烷(20.0mL),反应液冷至10℃,缓慢滴加三氟化二乙氨基硫(5.46g,33.8mmol)和三氟乙酸(12.8mg,112μmol),随后升温至25℃搅拌12小时。反应结束后,将反应液加入到饱和的碳酸氢钠水溶液中,并用二氯甲烷(15.0mL×3)萃取,有机相用无水硫酸钠干燥,过滤浓缩,粗品用柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到N-苯甲基-2,2-二氟-N-甲基丙烷-1-胺(I-29D)(950mg,4.77mmol,产率42.2%)。Under the protection of nitrogen, add 1-(benzyl(methyl)amino)propan-2-one (I-29C) (2.00g, 11.2mmol), cesium fluoride (257mg, 1.69mmol) into a 100mL three-necked flask ) and dichloromethane (20.0mL), the reaction solution was cooled to 10°C, diethylaminosulfur trifluoride (5.46g, 33.8mmol) and trifluoroacetic acid (12.8mg, 112μmol) were slowly added dropwise, then the temperature was raised to 25°C Stir for 12 hours. After the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (15.0mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether : Ethyl acetate (V/V)=1:1), N-benzyl-2,2-difluoro-N-methylpropane-1-amine (I-29D) (950mg, 4.77mmol, produced rate 42.2%).
1H NMR(400MHz,CDCl
3)δ7.38-7.27(m,5H),3.63(s,2H),2.72(m,2H),2.36(s,3H),1.62(m,3H)
1 H NMR (400MHz, CDCl 3 )δ7.38-7.27(m,5H),3.63(s,2H),2.72(m,2H),2.36(s,3H),1.62(m,3H)
第三步:2,2-二氟-N-甲基丙烷-1-胺盐酸(I-29E)的合成The third step: the synthesis of 2,2-difluoro-N-methylpropane-1-amine hydrochloride (I-29E)
2,2-difluoro-N-methylpropan-1-amine hydrochloride(I-29E)2,2-difluoro-N-methylpropan-1-amine hydrochloride (I-29E)
将N-苯甲基-2,2-二氟-N-甲基丙烷-1-胺(I-29D)(850mg,4.27mmol)溶于盐酸/甲醇(10.0mL)中,加入氢氧化钯(29.9mg,213μmol),反应液至于氢气氛围(50Psi)下,升温至40℃搅拌24小时。反应结束后,过滤收集滤液,减压浓缩得到2,2-二氟-N-甲基丙烷-1-胺盐酸(I-29E)(250mg,粗品)。Dissolve N-benzyl-2,2-difluoro-N-methylpropane-1-amine (I-29D) (850 mg, 4.27 mmol) in hydrochloric acid/methanol (10.0 mL), add palladium hydroxide ( 29.9mg, 213μmol), and the reaction solution was placed in a hydrogen atmosphere (50Psi), heated to 40°C and stirred for 24 hours. After the reaction, the filtrate was collected by filtration and concentrated under reduced pressure to obtain 2,2-difluoro-N-methylpropane-1-amine hydrochloride (I-29E) (250 mg, crude product).
第四步:(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-29F)的合成The fourth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-29F)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-29F)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-29F)
将(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(280mg,507μmol),2,2-二氟-N-甲基丙烷-1-胺盐酸(I-29E)(110.79mg,1.02mmol)溶于四氢呋喃(5.00mL)中,反应液冷至0℃,滴加二异丙基乙胺(196mg,1.52mmol),随后升温至25℃搅拌2小时。反应完毕后,向反应液中加水(10mL),并用乙酸乙酯萃取(15mL×3),有机相用无水硫酸钠干燥,过滤浓缩,得到粗品用薄层硅胶板纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-29F)(105mg,产率39.6%)。(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (280mg, 507μmol), 2,2-difluoro-N -Methylpropane-1-amine hydrochloride (I-29E) (110.79mg, 1.02mmol) was dissolved in tetrahydrofuran (5.00mL), the reaction solution was cooled to 0°C, diisopropylethylamine (196mg, 1.52mmol) was added dropwise ), followed by heating to 25°C and stirring for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and extracted with ethyl acetate (15 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified with a thin-layer silica gel plate (petroleum ether: ethyl acetate Ester (V/V)=1:1), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl )aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester ( I-29F) (105 mg, 39.6% yield).
LC-MS,M/Z(ESI):522.2[M+H]
+
LC-MS, M/Z(ESI):522.2[M+H] +
第五步:(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-29)的合成The fifth step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-29)
将(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-29F)(100mg,191μmol)溶于四氢呋喃(6.00mL)和水(2.00mL)中,再加入一水氢氧化锂(80.4mg,1.92mmol),反应液置于25℃搅拌12小时。反应完毕后,用稀盐酸(1mol/L)调节反应液pH至2,并用乙酸乙酯(15mL×3)萃取,有机相用无水硫酸钠干燥,过滤浓缩,将得到的粗品通过制备高效液相色谱纯化(柱子:3_Phenomenex Luna C18 75*30mm*3um;溶剂:A=水+0.01%HCl,B=乙腈;梯度:35%-55%,8分钟),得到(1S,3S)-3-((2-环丙基-6-(5-((((2,2-二氟丙基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-29)(48mg,产率48.78%)。(1S,3S)-3-((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1 -Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-29F) (100 mg, 191 μmol) dissolved in THF (6.00mL) and water (2.00mL), and lithium hydroxide monohydrate (80.4mg, 1.92mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 2 with dilute hydrochloric acid (1mol/L), and extracted with ethyl acetate (15mL×3). Purification by phase chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 35%-55%, 8 minutes) to obtain (1S,3S)-3- ((2-cyclopropyl-6-(5-((((2,2-difluoropropyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-29) (48 mg, yield 48.78%).
LC-MS,M/Z(ESI):508.2[M+H]
+
LC-MS, M/Z(ESI):508.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.4-11.8(m,1H),7.84-7.70(m,1H),7.48-7.46(m,1H),5.62–5.60(m,2H),4.79(s,1H),4.09(s,3H),3.78-3.53(m,2H),2.88–2.85(m,3H),2.65-2.61(m,1H),2.09-1.99(m,1H),1.91-1.77(m,3H),1.71-1.31(m,8H),1.04-0.93(m,4H)
1 H NMR (400MHz, DMSO-d6) δ12.4-11.8 (m, 1H), 7.84-7.70 (m, 1H), 7.48-7.46 (m, 1H), 5.62–5.60 (m, 2H), 4.79 ( s,1H),4.09(s,3H),3.78-3.53(m,2H),2.88–2.85(m,3H),2.65-2.61(m,1H),2.09-1.99(m,1H),1.91- 1.77(m,3H),1.71-1.31(m,8H),1.04-0.93(m,4H)
实施例30:目标化合物I-30的制备Embodiment 30: Preparation of target compound I-30
(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-30)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)aminocarbonyl)oxy)methyl Base)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30)
(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-30)(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30)
目标化合物I-30的合成路线如下所示:The synthetic route of target compound 1-30 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-30B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)aminocarbonyl) Synthesis of oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-30B)
methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-30B)methyl(1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-30B)
把2,2,2-三氟-N-甲基-乙胺盐酸盐(97.6mg,652μmol)溶解于四氢呋喃(1.00mL)中,加入N,N-二异丙基乙胺(246mg,1.90mmol),(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(300mg,543μmol),反应液在氮气下于25℃搅拌12小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,然后用饱和食盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,得到粗产品用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-30B)(240mg,产率83.9%)。Dissolve 2,2,2-trifluoro-N-methyl-ethylamine hydrochloride (97.6mg, 652μmol) in tetrahydrofuran (1.00mL), add N,N-diisopropylethylamine (246mg, 1.90 mmol), (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (300mg, 543μmol), the reaction solution was placed under nitrogen in Stir at 25°C for 12 hours. After the reaction was completed, add water (10 mL) to quench, extract with ethyl acetate (15 mL), and then wash with saturated brine (15 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V/V)=1:1), obtain (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl (2,2,2-trifluoroethyl)aminocarbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane- 1-Methyl carboxylate (I-30B) (240 mg, 83.9% yield).
LC-MS,M/Z(ESI):526.1[M+H]
+
LC-MS, M/Z(ESI):526.1[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-30)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)aminocarbonyl) Synthesis of oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30)
把(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-30B)(250mg,475μmol)溶解于四氢呋喃(2.00mL)中,加入一水合氢氧化锂(199.63mg,4.76mmol)的水溶液(0.50mL),反应液于25℃搅拌12小时。反应完后往反应液中加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备高效液相色谱纯化(柱子Phenomenex Luna C18 150*25mm*10um;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:40%-70%,10min),得到(1S,3S)-3-((2-环丙基-6-(1-甲基-5-(((甲基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-30)(34.0mg,产率14.0%)。Put (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)aminocarbonyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-30B) (250 mg, 475 μmol) dissolved in THF (2.00 mL), an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (199.63 mg, 4.76 mmol) was added, and the reaction solution was stirred at 25° C. for 12 hours. After the reaction was completed, dilute hydrochloric acid aqueous solution was added to the reaction solution to adjust the pH to 1, extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (10.0 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (column Phenomenex Luna C18 150*25mm*10um; solvent: A=water+0.225% by volume ammonia (99%), B=acetonitrile; gradient: 40%-70%, 10min), This gives (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-(((methyl(2,2,2-trifluoroethyl)aminocarbonyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-30) (34.0mg, yield 14.0% ).
LC-MS,M/Z(ESI):512.4[M+H]
+
LC-MS, M/Z(ESI):512.4[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.47-11.88(m,1H),7.77(d,1H),7.47(d,1H),5.64(s,2H),4.79(s,1H),4.08(d,3H),4.04–4.00(m,1H),3.30(s,3H),2.90(d,2H),2.06-2.00(m,1H),1.90-1.75(m,4H),1.68-1.60(m,2H),1.56-1.48(m,2H),0.99-0.92(m,4H)
1 H NMR(400MHz,DMSO-d6)δ12.47-11.88(m,1H),7.77(d,1H),7.47(d,1H),5.64(s,2H),4.79(s,1H),4.08 (d,3H),4.04–4.00(m,1H),3.30(s,3H),2.90(d,2H),2.06-2.00(m,1H),1.90-1.75(m,4H),1.68-1.60 (m,2H),1.56-1.48(m,2H),0.99-0.92(m,4H)
实施例31:目标化合物I-31的制备Example 31: Preparation of target compound I-31
(1S,3S)-3-((2-环丙基-6-(5-(((环丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-31)(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-31)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-31)(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-31)
目标化合物I-31的合成路线如下所示:The synthetic route of target compound I-31 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(5-(((环丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-The first step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl- 1H-1,2,3-
三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-31B)的合成Synthesis of methyl triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-31B)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-31B)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-31B)
把N-甲基环丙胺(44.1mg,620μmol)溶解于四氢呋喃(1.00mL)中,加入(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(285mg,516μmol),N,N-二异丙基乙胺(200mg,1.55mmol),反应液在25℃搅拌0.5小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,然后用饱和食盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,得到粗品硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((2-环丙基-6-(5-(((环丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-31B)(210mg,产率84.0%)。Dissolve N-methylcyclopropylamine (44.1 mg, 620 μmol) in tetrahydrofuran (1.00 mL), add (1S, 3S)-3-((2-cyclopropyl-6-(1-methyl-5-( (((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- Methyl formate (I-2A) (285mg, 516μmol), N,N-diisopropylethylamine (200mg, 1.55mmol), and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was completed, add water (10mL) to quench, extract with ethyl acetate (15mL), then wash with saturated brine (15mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified on a silica gel plate (petroleum Ether: ethyl acetate (V/V) = 1:1), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)aminocarbonyl )oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-31B ) (210 mg, 84.0% yield).
LC-MS,M/Z(ESI):483.4[M+H]
+
LC-MS, M/Z(ESI):483.4[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(5-(((环丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-31)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl- Synthesis of 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-31)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid
把(1S,3S)-3-((2-环丙基-6-(5-(((环丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-31B)(210mg,434μmol)溶解于四氢呋喃(2.00mL)中,加入一水合氢氧化锂(182mg,4.34mmol)的水溶液(0.50mL),反应液在25℃下搅拌12小时,加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用SFC(柱子DAICEL CHIRALCEL OJ(250mm*30mm,10um);溶剂:A=甲醇+0.1体积%氨水(99%),B=乙腈;梯度:30%-30%,4.6min)纯化,得到(1S,3S)-3-((2-环丙基-6-(5-(((环丙基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-31)(53.7mg,产率26.2%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1 , 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-31B) (210 mg, 434 μmol) was dissolved in tetrahydrofuran (2.00 mL), added Lithium hydroxide monohydrate (182mg, 4.34mmol) in aqueous solution (0.50mL), the reaction solution was stirred at 25°C for 12 hours, added dilute hydrochloric acid aqueous solution to adjust the pH to 1, extracted with ethyl acetate (10mL), and the organic phase was washed with saturated Wash with brine (10mL), then dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Use SFC (column DAICEL CHIRALCEL OJ (250mm*30mm, 10um); solvent: A=methanol+0.1vol% ammonia water (99%) , B = acetonitrile; Gradient: 30%-30%, 4.6min) purification to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-(((cyclopropyl(methyl) Aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-31 ) (53.7 mg, 26.2% yield).
LC-MS,M/Z(ESI):469.5[M+H]
+
LC-MS, M/Z(ESI):469.5[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.47(d,1H),5.58(s,2H),4.79(s,1H),4.10(s,3H),2.75(s,3H),2.66(t,1H),2,54-2.51(m,1H),2.46(s,1H),2.08-1.97(m,1H),1.91-1.75(m,3H),1.71-1.46(m,4H),1.05-0.90(m,4H),0.66-0.40(m,4H)
1 H NMR (400MHz,DMSO-d6)δ7.75(d,1H),7.47(d,1H),5.58(s,2H),4.79(s,1H),4.10(s,3H),2.75(s ,3H),2.66(t,1H),2,54-2.51(m,1H),2.46(s,1H),2.08-1.97(m,1H),1.91-1.75(m,3H),1.71-1.46 (m,4H),1.05-0.90(m,4H),0.66-0.40(m,4H)
实施例32:目标化合物I-32的制备Example 32: Preparation of target compound I-32
(1S,3S)-3-((6-(5-(((4-环丁基嘧啶-2-基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-32)(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-tri Azol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-32)
(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-32)(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-32)
目标化合物I-32的合成路线如下所示:The synthetic route of target compound I-32 is as follows:
第一步:2-氯-4-环丁基嘧啶(I-32B)的合成The first step: the synthesis of 2-chloro-4-cyclobutylpyrimidine (I-32B)
2-chloro-4-cyclobutylpyrimidine(I-32B)2-chloro-4-cyclobutylpyrimidine (I-32B)
把2-氯嘧啶(3.00g,26.1mmol)溶解于二氯甲烷(15.0mL)中,向其中加入环丁甲酸(2.36g,23.5mmol)的水溶液(15.0ml),硝酸银(889mg,5.24mmol)和过硫酸铵(5.98g,26.1mmol),反应液于25℃下搅拌16小时。反应结束后加水(30.0mL)稀释,用二氯甲烷(75.0mL)萃取,有机相用饱和食盐水(60.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化(石油醚:乙酸乙酯(V/V)=5:1),得到2-氯-4-环丁基嘧啶(I-32B)(2.25g,产率78.5%)。2-Chloropyrimidine (3.00g, 26.1mmol) was dissolved in dichloromethane (15.0mL), an aqueous solution (15.0ml) of cyclobutanic acid (2.36g, 23.5mmol), silver nitrate (889mg, 5.24mmol) were added ) and ammonium persulfate (5.98g, 26.1mmol), the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, it was diluted with water (30.0 mL), extracted with dichloromethane (75.0 mL), and the organic phase was washed with saturated brine (60.0 mL), then dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography ( Petroleum ether:ethyl acetate (V/V)=5:1) to obtain 2-chloro-4-cyclobutylpyrimidine (I-32B) (2.25g, yield 78.5%).
LC-MS,M/Z(ESI):168.1[M+H]
+
LC-MS, M/Z(ESI):168.1[M+H] +
1H NMR(400MHz,CDCl3)δ8.45(m,1H),7.09(d,1H),3.64-3.54(m,1H),2.41-2.27(m,4H),2.07–2.06(m,1H),2.04-1.91(m,1H)
1 H NMR (400MHz, CDCl3) δ8.45 (m, 1H), 7.09 (d, 1H), 3.64-3.54 (m, 1H), 2.41-2.27 (m, 4H), 2.07–2.06 (m, 1H) ,2.04-1.91(m,1H)
第二步:(1S,3S)-3-((6-(5-(((4-环丁基嘧啶-2-基)氧代)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧代)环己烷-1-甲酸甲酯(I-32C)的合成The second step: (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxo)methyl)-1-methyl-1H-1,2 , Synthesis of 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxo)cyclohexane-1-carboxylic acid methyl ester (I-32C)
Methyl(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-32C)Methyl(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl) -2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-32C)
把2-氯嘧啶(109mg,646μmol)溶解于四氢呋喃(2.00mL)中,向其中加入(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1I)(200mg,517μmol),反应液在0℃滴加叔丁醇钾(1.00M,646μL),滴加完毕后逐渐升温至25℃搅拌16小时。反应结束后加冰水(10.0mL)淬灭,用乙酸乙酯(15.0mL)萃取,然后用饱和食盐水(15.0mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,得到的村产品用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((6-(5-(((4-环丁基嘧啶-2-基)氧代)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧代)环己烷-1-甲酸甲酯(I-32C)(210mg,产率78.2%)。Dissolve 2-chloropyrimidine (109 mg, 646 μmol) in tetrahydrofuran (2.00 mL), add (1S, 3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1 -Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-1I) (200mg, 517μmol), reaction solution Potassium tert-butoxide (1.00M, 646 μL) was added dropwise at 0°C, and after the dropwise addition was completed, the temperature was gradually raised to 25°C and stirred for 16 hours. After the reaction was completed, it was quenched with ice water (10.0 mL), extracted with ethyl acetate (15.0 mL), washed with saturated brine (15.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the village The product was separated and purified on a silica gel plate (petroleum ether:ethyl acetate (V/V)=1:1) to obtain (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidine- 2-yl)oxo)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxo)cyclohexane- Methyl 1-carboxylate (I-32C) (210 mg, 78.2% yield).
LC-MS,M/Z(ESI):518.2[M+H]
+
LC-MS, M/Z(ESI):518.2[M+H] +
第三步:(1S,3S)-3-((6-(5-(((4-环丁基嘧啶-2-基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(I-32)的合成The third step: (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-32) synthesis
(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-32)(1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-32)
把(1S,3S)-3-((6-(5-(((4-环丁基嘧啶-2-基)氧代)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧代)环己烷-1-甲酸甲酯(I-32C)(190mg,366μmol)溶解于四氢呋喃(2.00mL)中,向其中加入一水合氢氧化锂(76.8mg,1.83mmol)的水溶液(0.50mL),反应液于25℃搅拌12小时,加入稀盐酸溶液调节pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备液相色谱(柱子Phenomenex Luna C18 75*30mm*3um;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:42%-72%,7min)进行纯化得到(1S,3S)-3-((6-(5-(((4-环丁基嘧啶-2-基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(I-32)(33.4mg,产率18%)。Put (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidin-2-yl)oxo)methyl)-1-methyl-1H-1,2,3- Triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxo)cyclohexane-1-carboxylic acid methyl ester (I-32C) (190 mg, 366 μmol) was dissolved in tetrahydrofuran (2.00 mL), An aqueous solution (0.50 mL) of lithium hydroxide monohydrate (76.8 mg, 1.83 mmol) was added thereto, and the reaction solution was stirred at 25° C. for 12 hours. Dilute hydrochloric acid solution was added to adjust the pH to 1, and extracted with ethyl acetate (10.0 mL). The organic phase was washed with saturated brine (10.0mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product by preparative liquid chromatography (column Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.225 volume % ammonia (99%), B=acetonitrile; gradient: 42%-72%, 7min) was purified to obtain (1S,3S)-3-((6-(5-(((4-cyclobutylpyrimidine-2 -yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1 - Formic acid (I-32) (33.4 mg, 18% yield).
LC-MS,M/Z(ESI):504.2[M+H]
+
LC-MS, M/Z(ESI):504.2[M+H] +
1H NMR(400MHz,CD3SOCD3)δ12.96-11.51(m,1H),8.50(d,1H),7.80(d,1H),7.47(d,1H),7.04(d,1H),5.91(s,2H),4.78(s,1H),4.13(s,3H),3.58-3.50(m,1H),2.68-2.60(m,1H),2.43-2.40(m,1H),2.24-2.16(m,4H),2.04-1.92(m,2H),1.86-1.73(m,4H),1.67-1.51(m, 4H),0.81-0.74(m,4H)
1 H NMR(400MHz,CD3SOCD3)δ12.96-11.51(m,1H),8.50(d,1H),7.80(d,1H),7.47(d,1H),7.04(d,1H),5.91(s ,2H),4.78(s,1H),4.13(s,3H),3.58-3.50(m,1H),2.68-2.60(m,1H),2.43-2.40(m,1H),2.24-2.16(m ,4H),2.04-1.92(m,2H),1.86-1.73(m,4H),1.67-1.51(m, 4H),0.81-0.74(m,4H)
实施例33:目标化合物I-33的制备Example 33: Preparation of target compound I-33
(1S,3S)-3-((2-环丙基-6-(5-(((((3,3-二氟环丁基)甲基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-33)(1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)aminocarbonyl)oxy)methyl Base)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-33)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-33)(1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1, 2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-33)
目标化合物I-33的合成路线如下所示:The synthetic route of target compound I-33 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(5-(((((3,3-二氟环丁基)甲基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-33B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)aminocarbonyl) Oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-33B) Synthesis
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-33B)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1 ,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-33B)
把1-(3,3-二氟环丁基)-N-甲基-甲胺(73.5mg,543μmol)溶解于四氢呋喃(1.00mL)中,依次加入N,N-二异丙基乙胺(246mg,1.90mmol)和(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(300mg,543μmol),反应液在25℃搅拌1小时。反应结束后加水(10mL)淬灭,用乙酸乙酯(15mL)萃取,有机相用饱和食盐水(15mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用硅胶板分离纯化(乙酸乙酯),得到(1S,3S)-3-((2-环丙基-6-(5-(((((3,3-二氟环丁基)甲基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1- 甲酸甲酯(I-33B)(146mg,产率49.0%)。Dissolve 1-(3,3-difluorocyclobutyl)-N-methyl-methylamine (73.5 mg, 543 μmol) in tetrahydrofuran (1.00 mL), and add N,N-diisopropylethylamine ( 246mg, 1.90mmol) and (1S,3S)-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methanol Base)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-methyl carboxylate (I-2A) (300mg, 543μmol), the reaction solution in Stir at 25°C for 1 hour. After the reaction was completed, quenched with water (10 mL), extracted with ethyl acetate (15 mL), washed the organic phase with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was separated and purified on a silica gel plate ( ethyl acetate) to give (1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)amino Carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I- 33B) (146 mg, 49.0% yield).
LC-MS,M/Z(ESI):548.3[M+H]
+
LC-MS, M/Z(ESI):548.3[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(5-(((((3,3-二氟环丁基)甲基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-33)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)aminocarbonyl) Oxygen)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-33) Synthesis
把(1S,3S)-3-((2-环丙基-6-(5-(((((3,3-二氟环丁基)甲基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-33B)(136mg,248μmol)溶解于四氢呋喃(1.00mL)中,加入一水合氢氧化锂(104mg,2.48mmol)的水溶液(0.20mL),反应液于25℃搅拌12小时,随后加入稀盐酸水溶液调节pH至2~3,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备液相色谱(柱子Phenomenex Luna C18 150*25mm*10um;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:42%-72%,10min)纯化,得(1S,3S)-3-((2-环丙基-6-(5-(((((3,3-二氟环丁基)甲基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-33)(16.0mg,产率12.0%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)aminocarbonyl)oxy) Methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-33B) (136mg, 248 μmol) was dissolved in tetrahydrofuran (1.00mL), and an aqueous solution (0.20mL) of lithium hydroxide monohydrate (104mg, 2.48mmol) was added, and the reaction solution was stirred at 25°C for 12 hours, then dilute aqueous hydrochloric acid was added to adjust the pH to 2-3 , extracted with ethyl acetate (10.0mL), the organic phase was washed with saturated brine (10.0mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product by preparative liquid chromatography (column Phenomenex Luna C18 150*25mm *10um; Solvent: A=water+0.225% by volume ammonia water (99%), B=acetonitrile; Gradient: 42%-72%, 10min) purification, get (1S,3S)-3-((2-cyclopropyl -6-(5-(((((3,3-difluorocyclobutyl)methyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-33) (16.0 mg, yield 12.0%).
LC-MS,M/Z(ESI):534.2[M+H]
+
LC-MS, M/Z(ESI):534.2[M+H] +
1H NMR(400MHz,DMSO-d6,)δ7.76(d,1H),7.51-7.43(m,1H),5.56(s,2H),4.78(s,1H),4.09(s,3H),3.31(s,5H),3.23(d,1H),2.78(d,3H),2.55-2.54(m,1H),2.18-2.00(m,3H),1.88-1.76(m,3H),1.66-1.48(m,4H),0.98-0.90(m,4H)
1 H NMR (400MHz,DMSO-d6,)δ7.76(d,1H),7.51-7.43(m,1H),5.56(s,2H),4.78(s,1H),4.09(s,3H), 3.31(s,5H),3.23(d,1H),2.78(d,3H),2.55-2.54(m,1H),2.18-2.00(m,3H),1.88-1.76(m,3H),1.66- 1.48(m,4H),0.98-0.90(m,4H)
实施例34:目标化合物I-34的制备Example 34: Preparation of target compound I-34
(1S,3S)-3-((2-环丙基-6-(5-(((乙基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-34)(1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)aminocarbonyl)oxy)methyl)-1- Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-34)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-34)(1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-34)
目标化合物I-34的合成路线如下所示:The synthetic route of target compound I-34 is as follows:
第一步:N-乙基-N-(2,2,2-三氟乙基)-1H-咪唑-1-甲酰胺(I-34B)的合成Step 1: Synthesis of N-ethyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (I-34B)
N-ethyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide(I-34B)N-ethyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (I-34B)
把N-乙基-2,2,2-三氟-乙胺盐酸盐(100mg,786μmol),三乙胺(95.5mg,944μmol)溶解于二氯甲烷(1.00mL)中,在0℃加入羰基二咪唑(153mg,944μmol),反应液在25℃搅拌2小时。反应结束后加水(10.0mL)淬灭,用乙酸乙酯(15.0mL)萃取,然后用饱和食盐水(15.0mL)洗涤,有机相用无水硫酸钠干燥,过滤浓缩,粗产品用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物N-乙基-N-(2,2,2-三氟乙基)-1H-咪唑-1-甲酰胺(I-34B)(82.0mg,产率47.1%)。Dissolve N-ethyl-2,2,2-trifluoro-ethylamine hydrochloride (100mg, 786μmol) and triethylamine (95.5mg, 944μmol) in dichloromethane (1.00mL), and add Carbonyldiimidazole (153mg, 944μmol), the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, add water (10.0 mL) to quench, extract with ethyl acetate (15.0 mL), and then wash with saturated brine (15.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated on a silica gel plate Purify (petroleum ether: ethyl acetate (V/V)=1:1), obtain compound N-ethyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide ( I-34B) (82.0 mg, 47.1% yield).
LC-MS,M/Z(ESI):222.2[M+H]
+
LC-MS, M/Z(ESI):222.2[M+H] +
1H NMR(400MHz,CDCl
3)δ7.94(s,1H),7.25(s,1H),7.15(s,1H),4.10(q,2H),3.61(q,2H),1.26(t,3H)
1 H NMR (400MHz, CDCl 3 )δ7.94(s,1H),7.25(s,1H),7.15(s,1H),4.10(q,2H),3.61(q,2H),1.26(t, 3H)
第二步:(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-34C)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-34C) synthesis
(1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(I-34C)(1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane -1-carboxylic acid (I-34C)
把(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-1I)(150mg,388μmol)溶解于四氢呋喃(2.00mL)中,加入一水合氢氧化锂(162mg,3.88mmol)的水溶液(0.50mL),反应液置于25℃搅拌12小时,加入稀盐酸水溶液(1mol/L)调节pH至1,用乙酸乙酯(10.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤浓缩,得到(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-34C)(100mg,粗品)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine- 3-yl)oxy)methyl cyclohexane-1-carboxylate (I-1I) (150 mg, 388 μmol) was dissolved in tetrahydrofuran (2.00 mL), and an aqueous solution of lithium hydroxide monohydrate (162 mg, 3.88 mmol) was added ( 0.50mL), the reaction solution was placed at 25°C and stirred for 12 hours, added dilute hydrochloric acid aqueous solution (1mol/L) to adjust the pH to 1, extracted with ethyl acetate (10.0mL), and the organic phase was washed with saturated brine (10.0mL), It was then dried over anhydrous sodium sulfate, filtered and concentrated to give (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (I-34C) (100 mg, crude).
LC-MS,M/Z(ESI):373.4[M+H]
+
LC-MS, M/Z(ESI):373.4[M+H] +
第三步:(1S,3S)-3-((2-环丙基-6-(5-(((乙基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-34)的合成The third step: (1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)aminocarbonyl)oxy)methyl Synthesis of )-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-34)
(1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-34)(1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-34)
把N-乙基-N-(2,2,2-三氟乙基)-1H-咪唑-1-甲酰胺(I-34B)(64.1mg,290μmol)溶解于叔戊醇(1.00mL)中,加入(1S,3S)-3-((2-环丙基-6-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(I-34C)(60mg,161μmol),反应液升温至60℃,缓慢滴加叔丁醇钾四氢呋喃溶液(1.00M,966μL),继续于60℃搅拌2小时。反应结束后加水(2mL)淬灭,加入6M盐酸水溶液调节pH至4,用乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(15mL)洗涤,然后用无水硫酸钠干燥,过滤浓缩,粗品用制备高效液相色谱纯化(色谱柱:Phenomenex Luna C18 150*25mm*10um;溶剂:A=水+0.225体积%三氟乙酸(99%),B=乙腈;梯度:44%-74%,10min),得到(1S,3S)-3-((2-环丙基-6-(5-(((乙基(2,2,2-三氟乙基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-34)(10.0mg,产率11.5%)。Dissolve N-ethyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (I-34B) (64.1 mg, 290 μmol) in tert-amyl alcohol (1.00 mL) , adding (1S,3S)-3-((2-cyclopropyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine -3-yl)oxy)cyclohexane-1-carboxylic acid (I-34C) (60 mg, 161 μmol), the temperature of the reaction solution was raised to 60° C., potassium tert-butoxide tetrahydrofuran solution (1.00 M, 966 μL) was slowly added dropwise, and continued Stir at 60°C for 2 hours. Add water (2mL) to quench after the reaction, add 6M hydrochloric acid aqueous solution to adjust the pH to 4, extract with ethyl acetate (15mL×3), wash the organic phase with saturated brine (15mL), then dry with anhydrous sodium sulfate, filter Concentrated, the crude product was purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150*25mm*10um; solvent: A=water+0.225 volume% trifluoroacetic acid (99%), B=acetonitrile; gradient: 44%-74 %, 10min), to obtain (1S,3S)-3-((2-cyclopropyl-6-(5-(((ethyl(2,2,2-trifluoroethyl)aminocarbonyl)oxy) Methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-34) (10.0mg , yield 11.5%).
LC-MS,M/Z(ESI):526.2[M+H]
+
LC-MS, M/Z(ESI):526.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.76(d,1H),7.48(d,1H),5.62(s,2H),4.78(br s,1H),4.13-3.98(m,5H),3.22(d,2H),2.64-2.60(m,1H),2.04-1.97(m,1H),1.82(s,3H),1.69-1.47(m,5H),1.07(d,1H),0.99-0.87(m,6H)
1 H NMR (400MHz,DMSO-d6)δ7.76(d,1H),7.48(d,1H),5.62(s,2H),4.78(br s,1H),4.13-3.98(m,5H), 3.22(d,2H),2.64-2.60(m,1H),2.04-1.97(m,1H),1.82(s,3H),1.69-1.47(m,5H),1.07(d,1H),0.99- 0.87(m,6H)
实施例35:目标化合物I-35的制备Example 35: Preparation of target compound I-35
(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟环丁基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-35)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)aminocarbonyl)oxy)methyl)-1 -Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-35)
(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-35)(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-35)
目标化合物I-35的合成路线如下所示:The synthetic route of target compound I-35 is as follows:
第一步:(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟环丁基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-35B)的合成The first step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-35B)
methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-35B)methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-35B)
把3,3-二氟-N-甲基-环丁胺盐酸盐(1a)(314mg,1.99mmol)、N,N-二异丙基乙胺(702mg,5.44mmol)和(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(1.00g,1.81mmol)依次加入四氢呋喃(2.00mL)中,反应液在25℃下搅拌0.5小时。反应结束后加水(20.0mL)淬灭,用乙酸乙酯(15mL×3)萃取,合并有机相,依次用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤浓缩,得到粗品用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟环丁基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-35B)(200mg,产率20.6%)。3,3-difluoro-N-methyl-cyclobutylamine hydrochloride (1a) (314mg, 1.99mmol), N,N-diisopropylethylamine (702mg, 5.44mmol) and (1S,3S )-3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3 -Triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-2A) (1.00g, 1.81mmol) was added in tetrahydrofuran (2.00mL) successively, and the reaction solution was Stir at 25°C for 0.5 hours. After the reaction was completed, add water (20.0 mL) to quench, extract with ethyl acetate (15 mL×3), combine the organic phases, wash with saturated brine (30 mL) successively, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude Analysis, separation and purification (petroleum ether: ethyl acetate (V/V)=1:1), to obtain compound (1S,3S)-3-((2-cyclopropyl-6-(5-((((3, 3-Difluorocyclobutyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy ) methyl cyclohexane-1-carboxylate (I-35B) (200 mg, yield 20.6%).
LC-MS,M/Z(ESI):534.6[M+H]
+
LC-MS, M/Z(ESI):534.6[M+H] +
第二步:(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟环丁基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-35)的合成The second step: (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)aminocarbonyl)oxy)methyl Synthesis of -1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-35)
把(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟环丁基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-35B)(200mg,374μmol)溶解于四氢呋喃(4.00mL)中,加入一水合氢氧化锂(157mg,3.75mmol)的水溶液(1.00mL),反应液置于25℃搅拌12小时。反应完加入稀盐酸水溶液调节pH至1,用乙酸乙酯(15.0mL)萃取,有机相用饱和食盐水(10.0mL)洗涤,然后用无水硫酸钠干燥,过滤浓缩,得到粗品用制备高效液相色谱纯化(柱子:Phenomenex Luna C18 150*25mm*10um;溶剂:A=水+0.225体积%氨水(99%),B=乙腈;梯度:36%-66%,10min),得到(1S,3S)-3-((2-环丙基-6-(5-((((3,3-二氟环丁基)(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-35)(75.0mg,产率38.4%)。Put (1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)aminocarbonyl)oxy)methyl)- 1-Methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-35B) (200mg, 374μmol) dissolved in To tetrahydrofuran (4.00 mL), an aqueous solution (1.00 mL) of lithium hydroxide monohydrate (157 mg, 3.75 mmol) was added, and the reaction solution was stirred at 25° C. for 12 hours. After the reaction, add dilute hydrochloric acid aqueous solution to adjust the pH to 1, extract with ethyl acetate (15.0 mL), wash the organic phase with saturated brine (10.0 mL), then dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Phase chromatography purification (column: Phenomenex Luna C18 150*25mm*10um; Solvent: A=water+0.225 volume % ammonia water (99%), B=acetonitrile; Gradient: 36%-66%, 10min), obtain (1S,3S )-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)aminocarbonyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-35) (75.0 mg, yield 38.4%).
LC-MS,M/Z(ESI):520.3[M+H]
+
LC-MS, M/Z(ESI):520.3[M+H] +
1H NMR(400MHz,CDCl
3)δ7.93(d,1H),7.22(d,1H),5.68(s,2H),4.73(s,1H),4.62-4.28(m,1H),4.15(s,3H),2.99-2.88(m,2H),2.84(s,3H),2.78-2.62(m,3H),2.56-2.50(m,1H),2.21(d,1H),2.06-1.93(m,3H),1.86-1.76(m,1H),1.71-1.63(m,3H),1.06(d,2H),1.01-0.95(m,2H)
1 H NMR (400MHz, CDCl 3 )δ7.93(d,1H),7.22(d,1H),5.68(s,2H),4.73(s,1H),4.62-4.28(m,1H),4.15( s,3H),2.99-2.88(m,2H),2.84(s,3H),2.78-2.62(m,3H),2.56-2.50(m,1H),2.21(d,1H),2.06-1.93( m,3H),1.86-1.76(m,1H),1.71-1.63(m,3H),1.06(d,2H),1.01-0.95(m,2H)
实施例36:目标化合物I-36的制备Embodiment 36: Preparation of target compound I-36
(1S,3S)-3-((6-(5-(((二环[1.1.1]戊烷-1-基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-36)的合成(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentane-1-yl(methyl)aminocarbonyl)oxy)methyl)-1-methyl- Synthesis of 1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-36)
(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-36)(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3 -triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-36)
目标化合物I-36的合成路线如下所示:The synthetic route of target compound I-36 is as follows:
第一步:(1S,3S)-3-((6-(5-(((二环[1.1.1]戊烷-1-基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-36B)的合成The first step: (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentane-1-yl(methyl)aminocarbonyl)oxy)methyl)-1 Synthesis of methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-36B)
methyl(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylatemethyl(1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2, 3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate
把N-甲基二环[1.1.1]戊烷-1-胺盐酸(31.9mg,239μmol)和(1S,3S)-3-((2-环丙基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-2A)(120mg,217μmol)溶于四氢呋喃(2mL)中,在25℃下滴加N,N-二异丙基乙胺(84.3mg,652μmol),并搅拌12小时。反应结束后加水(10.0mL)淬灭,用乙酸乙酯(15mL)萃取,有机相用饱和食盐水(15mL)洗涤,然后用无水硫酸钠干燥,过滤浓缩,粗品用硅胶板分离纯化(石油醚:乙酸乙酯(V/V)=1:1),得到(1S,3S)-3-((6-(5-(((二环[1.1.1]戊烷-1-基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-36B)(80mg,产率64.22%).Mix N-methylbicyclo[1.1.1]pentane-1-amine hydrochloride (31.9 mg, 239 μmol) and (1S,3S)-3-((2-cyclopropyl-6-(1-methyl- 5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane - Methyl 1-carboxylate (I-2A) (120mg, 217μmol) was dissolved in tetrahydrofuran (2mL), and N,N-diisopropylethylamine (84.3mg, 652μmol) was added dropwise at 25°C, and stirred for 12 Hour. After the reaction was completed, add water (10.0 mL) to quench, extract with ethyl acetate (15 mL), wash the organic phase with saturated brine (15 mL), then dry over anhydrous sodium sulfate, filter and concentrate, and the crude product was separated and purified on a silica gel plate (petroleum Ether: ethyl acetate (V/V)=1:1), obtain (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl Base)aminocarbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane - Methyl 1-carboxylate (I-36B) (80mg, yield 64.22%).
LC-MS,M/Z(ESI):510.4[M+H]
+
LC-MS, M/Z(ESI):510.4[M+H] +
第二步:(1S,3S)-3-((6-(5-(((二环[1.1.1]戊烷-1-基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-36)的合成The second step: (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentane-1-yl(methyl)aminocarbonyl)oxy)methyl)-1 Synthesis of -methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-36)
把(1S,3S)-3-((6-(5-(((二环[1.1.1]戊烷-1-基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-36B)(80.0mg,156μmol)溶解于四氢 呋喃(2mL)中,加入一水合氢氧化锂(32.9mg,784μmol)的水溶液(0.50mL),反应液于25℃搅拌12小时。反应完全后,加入稀盐酸水溶液(1mol/L)调节pH至1,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤浓缩,得到粗品用制备液相色谱纯化,得到(1S,3S)-3-((6-(5-(((二环[1.1.1]戊烷-1-基(甲基)氨基羰基)氧基)甲基)-1-甲基-1H-1,2,3-三唑-4-基)-2-环丙基吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-36)((22.8mg,产率27.8%)。Put (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentane-1-yl(methyl)aminocarbonyl)oxy)methyl)-1-methyl -1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-36B) (80.0mg, 156μmol ) was dissolved in tetrahydrofuran (2 mL), and an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (32.9 mg, 784 μmol) was added, and the reaction solution was stirred at 25° C. for 12 hours. After the reaction was complete, dilute hydrochloric acid aqueous solution (1mol/L) was added to adjust the pH to 1, extracted with ethyl acetate (10mL), the organic phase was washed with saturated brine (10mL), then dried over anhydrous sodium sulfate, filtered and concentrated to obtain The crude product was purified by preparative liquid chromatography to give (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)aminocarbonyl)oxy) Methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I -36)((22.8 mg, yield 27.8%).
LC-MS,M/Z(ESI):496.3[M+H]+LC-MS, M/Z(ESI):496.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.46(d,1H),5.53(s,2H),4.75-4.81(m,1H),4.08(s,3H),2.72(s,3H),2.65-2.62(m,2H),2.10-1.94(m,4H),1.91-1.86(m,6H),1.78-1.60(m,2H),1.58-1.46(m,3H),0.96-0.94(m,4H).
1 H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.46(d,1H),5.53(s,2H),4.75-4.81(m,1H),4.08(s,3H),2.72 (s,3H),2.65-2.62(m,2H),2.10-1.94(m,4H),1.91-1.86(m,6H),1.78-1.60(m,2H),1.58-1.46(m,3H) ,0.96-0.94(m,4H).
实施例37:目标化合物I-37的制备Example 37: Preparation of target compound I-37
(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((甲基(丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-37)的合成(1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)aminocarbonyl)oxy)methyl)-1H-1,2 , 3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-37) synthesis
(1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-37)(1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl )pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-37)
目标化合物I-37的合成路线如下所示:The synthetic route of target compound I-37 is as follows:
第一步:(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((甲基(丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-37B)的合成The first step: (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)aminocarbonyl)oxy)methyl)-1H Synthesis of methyl -1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-37B)
methyl(1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-37B)methyl(1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (I-37B)
将(1S,3S)-3-((2-环丁基-6-(1-甲基-5-((((4-硝基苯氧基)羰基)氧基)甲基)-1H)1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-15F)(300mg,530μmol)溶于四氢呋喃(5.00mL)中,氮气置换三次,于0℃下缓慢加入甲基(丙基)胺(97mg,1.33mmol),滴加完毕后,反应液于25℃搅拌0.5小时。反应完后,向反应液中加水(10mL),并用乙酸乙酯(15mL×3)萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品用薄层硅胶板纯化(石油醚:乙酸乙酯(V/V=1:1)),得到化合物(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((甲基(丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-37B)(200mg,产率75.4%)。(1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H) 1,2,3-Triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-15F) (300 mg, 530 μmol) was dissolved in tetrahydrofuran (5.00 mL), Nitrogen was replaced three times, and methyl (propyl)amine (97 mg, 1.33 mmol) was slowly added at 0°C. After the dropwise addition, the reaction solution was stirred at 25°C for 0.5 hours. After the reaction, add water (10mL) to the reaction solution, and extract with ethyl acetate (15mL×3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product, which is purified with a thin-layer silica gel plate (petroleum Ether: ethyl acetate (V/V=1:1)), to obtain compound (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl( Propyl)aminocarbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-37B ) (200mg, yield 75.4%).
LC-MS,M/Z(ESI):500.3[M+H]
+
LC-MS, M/Z(ESI):500.3[M+H] +
第二步:(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((甲基(丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-37)的合成The second step: (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)aminocarbonyl)oxy)methyl)-1H Synthesis of -1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-37)
把(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((甲基(丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸甲酯(I-37B)(200mg,400μmol)溶解于四氢呋喃(5mL)中,加一水合氢氧化锂(167mg,4.00mmol)的水溶液(1mL),反应液置于25℃搅拌12小时。反应完后,加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,减压浓缩,得到粗品用制备液相色谱纯化(色谱柱:3_Phenomenex Luna C18 75*30mm*3um;溶剂:A=水+0.01%HCl,B=乙腈;梯度:40%-60%,8min),得到化合物(1S,3S)-3-((2-环丁基-6-(1-甲基-5-(((甲基(丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡啶-3-基)氧基)环己烷-1-甲酸(目标化合物I-37)(74.1mg,产率38.1%)。Put (1S,3S)-3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)aminocarbonyl)oxy)methyl)-1H-1, 2,3-Triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-37B) (200 mg, 400 μmol) was dissolved in tetrahydrofuran (5 mL) and added monohydrate Lithium hydroxide (167mg, 4.00mmol) in aqueous solution (1mL), and the reaction solution was stirred at 25°C for 12 hours. After the reaction, dilute hydrochloric acid aqueous solution was added to adjust the pH to 1, extracted with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product Purification by preparative liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 40%-60%, 8min) to obtain compound (1S, 3S) -3-((2-cyclobutyl-6-(1-methyl-5-(((methyl(propyl)aminocarbonyl)oxy)methyl)-1H-1,2,3-triazole -4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-37) (74.1 mg, yield 38.1%).
LC-MS,M/Z(ESI):486.2[M+H]
+
LC-MS, M/Z(ESI):486.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.06-8.04(m,1H),7.75-7.51(m,1H),5.78–5.75(m,1H)5.64–5.61(m,1H),4.85(s,1H),4.27(s,1H),4.21(s,3H),3.17–3.13(m,2H),2.85(s,4H),2.70–2.60(m,2H),2.47-2.45(m,2H),2.15-1.79(m,10H),1.49-1.46(m,2H),0.83-0.81(m,3H).
1 H NMR (400MHz,DMSO-d6)δ8.06-8.04(m,1H),7.75-7.51(m,1H),5.78–5.75(m,1H),5.64–5.61(m,1H),4.85(s ,1H),4.27(s,1H),4.21(s,3H),3.17–3.13(m,2H),2.85(s,4H),2.70–2.60(m,2H),2.47-2.45(m,2H ),2.15-1.79(m,10H),1.49-1.46(m,2H),0.83-0.81(m,3H).
实施例38:目标化合物I-38的制备Example 38: Preparation of target compound I-38
(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸(目标化合物I-38)(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy)methyl Base)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-38)
(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-38)(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-38)
目标化合物I-38的合成路线如下所示:The synthetic route of target compound I-38 is as follows:
第一步:2-氯-4-环丙基-5-甲氧基嘧啶(I-38B)的合成The first step: the synthesis of 2-chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B)
2-chloro-4-cyclopropyl-5-methoxypyrimidine(I-38B)2-chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B)
在氮气保护,把2,4-二氯-5-甲氧基-嘧啶(10.0g,55.8mmol),环丙基硼酸(4.80g,55.8mmol)溶解于四氢呋喃(100mL)中,再加入磷酸钾(23.7g,111mmol),三苯基膦二氯化钯(1.22g,2.79mmol)和水(6.04g,335mmol),并于60℃下搅拌16小时。反应结束后,加水(20.0mL),并用乙酸乙酯(150mL)萃取,然后用饱和食盐水(50mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,粗品用柱层析分离纯化(石油醚:乙酸乙酯(V/V)=10:1),得到化合物2-氯-4-环丙基-5-甲氧基嘧啶(I-38B)(9.10g,产率88.2%)。Under nitrogen protection, dissolve 2,4-dichloro-5-methoxy-pyrimidine (10.0g, 55.8mmol), cyclopropylboronic acid (4.80g, 55.8mmol) in tetrahydrofuran (100mL), and then add potassium phosphate (23.7g, 111mmol), triphenylphosphinepalladium dichloride (1.22g, 2.79mmol) and water (6.04g, 335mmol), and stirred at 60°C for 16 hours. After the reaction, add water (20.0mL), and extract with ethyl acetate (150mL), then wash with saturated brine (50mL), the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product is separated and purified by column chromatography ( Petroleum ether: ethyl acetate (V/V)=10:1) to obtain compound 2-chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B) (9.10 g, yield 88.2%).
1H NMR(400MHz,CDCl
3)δ7.98(s,1H),3.94(s,3H),2.50-2.34(m,1H),1.26-1.20(m,2H),1.17-1.08(m,2H)
1 H NMR (400MHz, CDCl 3 )δ7.98(s,1H),3.94(s,3H),2.50-2.34(m,1H),1.26-1.20(m,2H),1.17-1.08(m,2H )
第二步:4-环丙基-5-甲氧基-2-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶(I-38C) 的合成The second step: 4-cyclopropyl-5-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine ( Synthesis of I-38C)
4-cyclopropyl-5-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine4-cyclopropyl-5-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine
把2-氯-4-环丙基-5-甲氧基嘧啶(I-38B)(8.50g,46.0mmol),2-(丙-2-炔-1-氧基)噁烷(9.60g,69.0mmol)溶于乙腈(100mL)中,加入碳酸铯(30.0g,92.0mmol)和二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(1.63g,2.30mmol),反应液在氮气保护下置于90℃搅拌12小时。反应结束后加水(50.0mL)淬灭,用乙酸乙酯(150mL)萃取,然后用饱和食盐水(50mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩得到棕色油状物,经柱层析纯化(石油醚:乙酸乙酯(V/V)=2:1)得到化合物4-环丙基-5-甲氧基-2-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶(I-38C)(5.20g,产率39.1%)。2-Chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B) (8.50g, 46.0mmol), 2-(prop-2-yn-1-oxyl)oxane (9.60g, 69.0mmol) was dissolved in acetonitrile (100mL), cesium carbonate (30.0g, 92.0mmol) and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (1.63g , 2.30 mmol), and the reaction solution was stirred at 90° C. for 12 hours under the protection of nitrogen. After the reaction was completed, add water (50.0 mL) to quench, extract with ethyl acetate (150 mL), and then wash with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oil, which was passed through the column layer Analysis and purification (petroleum ether: ethyl acetate (V/V) = 2:1) to obtain compound 4-cyclopropyl-5-methoxy-2-(3-((tetrahydro-2H-pyran-2- yl)oxy)prop-1-yn-1-yl)pyrimidine (I-38C) (5.20 g, 39.1% yield).
LC-MS,M/Z(ESI):289.1[M+H]
+
LC-MS, M/Z(ESI):289.1[M+H] +
1H NMR(400MHz,CDCl
3)δ8.09(s,1H),4.92(t,J=3.1Hz,1H),4.60-4.42(m,2H),3.97(s,3H),3.93-3.83(m,1H),3.62-3.51(m,1H),2.51-2.38(m,1H),1.94-1.73(m,2H),1.71-1.56(m,4H),1.31-1.17(m,2H),1.14-1.03(m,2H)
1 H NMR (400MHz, CDCl 3 ) δ8.09(s, 1H), 4.92(t, J=3.1Hz, 1H), 4.60-4.42(m, 2H), 3.97(s, 3H), 3.93-3.83( m,1H),3.62-3.51(m,1H),2.51-2.38(m,1H),1.94-1.73(m,2H),1.71-1.56(m,4H),1.31-1.17(m,2H), 1.14-1.03(m,2H)
第三步:4-环丙基-5-甲氧基-2-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)嘧啶(I-38D)的合成The third step: 4-cyclopropyl-5-methoxy-2-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethyl Synthesis of silyl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine (I-38D)
4-cyclopropyl-5-methoxy-2-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine(I-38D)4-cyclopropyl-5-methoxy-2-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol- 4-yl)pyrimidine (I-38D)
把4-环丙基-5-甲氧基-2-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶(I-38C)(4.50g,15.6mmol),叠氮甲基(三甲基)硅烷(2.52g,19.5mmol)溶解于四氢呋喃(50.0mL)中,氮气置换三次,加入五甲基环戊二烯基双(三苯基膦)氯化钌(II)(621.39mg,780.33μmol)和碘化亚铜(297.23mg,1.56mmol),反应液于55℃搅拌12小时。反应结束后直接过滤,滤液减压浓缩,得到粗品经柱层析纯化(石油醚:乙酸乙酯(V/V)=2:1)得到化合物4-环丙基-5-甲氧基-2-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)嘧啶(I-38D)(3.10g,产率47.5%)。4-cyclopropyl-5-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine (I-38C ) (4.50g, 15.6mmol), azidomethyl (trimethyl) silane (2.52g, 19.5mmol) was dissolved in tetrahydrofuran (50.0mL), replaced with nitrogen three times, added pentamethylcyclopentadienylbis( Triphenylphosphine) ruthenium (II) chloride (621.39 mg, 780.33 μmol) and cuprous iodide (297.23 mg, 1.56 mmol), and the reaction solution was stirred at 55° C. for 12 hours. After the reaction was completed, it was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) = 2:1) to obtain the compound 4-cyclopropyl-5-methoxy-2 -(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-tri Azol-4-yl)pyrimidine (I-38D) (3.10 g, 47.5% yield).
LC-MS,M/Z(ESI):418.2[M+H]
+
LC-MS, M/Z(ESI):418.2[M+H] +
1H NMR(400MHz,CDCl
3)δ8.24(s,1H),5.15(d,1H),4.93(d,1H),4.83(t,1H),4.49(d,1H),4.41(d,2H),4.01(s,3H),3.93-3.89(m,1H),3.53-3.47(m,1H),2.56-2.48(m,1H),1.89-1.75(m,2H),1.52-1.43(m,2H),1.31-1.20(m,4H),1.11-1.03(m,1H),0.07(s,9H)
1 H NMR (400MHz, CDCl 3 )δ8.24(s,1H),5.15(d,1H),4.93(d,1H),4.83(t,1H),4.49(d,1H),4.41(d, 2H),4.01(s,3H),3.93-3.89(m,1H),3.53-3.47(m,1H),2.56-2.48(m,1H),1.89-1.75(m,2H),1.52-1.43( m,2H),1.31-1.20(m,4H),1.11-1.03(m,1H),0.07(s,9H)
第四步:4-环丙基-5-甲氧基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑 -4-基)嘧啶(I-38E)的合成The fourth step: 4-cyclopropyl-5-methoxy-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H- Synthesis of 1,2,3-triazol-4-yl)pyrimidine (I-38E)
4-cyclopropyl-5-methoxy-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine(I-38E)4-cyclopropyl-5-methoxy-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine (I-38E)
把4-环丙基-5-甲氧基-2-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)嘧啶(2.50g,7.24mmol)(I-38D)溶解于N,N-二甲基甲酰胺(10.0mL)中,加入四丁基氟化氨(2.08g,7.96mmol),反应液在25℃搅拌0.5小时。反应结束后加水(10.0mL)淬灭,用乙酸乙酯(15.0mL)萃取,然后用饱和食盐水(15.0mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩得到化合物4-环丙基-5-甲氧基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶(I-38E)(1.20g,产率为48.0%)。4-cyclopropyl-5-methoxy-2-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl )methyl)-1H-1,2,3-triazol-4-yl)pyrimidine (2.50 g, 7.24 mmol) (1-38D) was dissolved in N,N-dimethylformamide (10.0 mL), Tetrabutylammonium fluoride (2.08g, 7.96mmol) was added, and the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was completed, add water (10.0 mL) to quench, extract with ethyl acetate (15.0 mL), then wash with saturated brine (15.0 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain compound 4-cyclopropane Base-5-methoxy-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole -4-yl)pyrimidine (I-38E) (1.20 g, 48.0% yield).
第五步:4-环丙基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-酚(I-38F)的合成The fifth step: 4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3- Synthesis of Triazol-4-yl)pyrimidin-5-ol (I-38F)
4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-ol(I-38F)4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-ol (I-38F)
把4-环丙基-5-甲氧基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶(I-38E)(1.10g,3.18mmol)溶解于N,N-二甲基甲酰胺(10.0mL)中,并向其中加入甲硫醇钠(892mg,12.7mmol),反应液在氮气保护下置于120℃搅拌2小时。反应完后,加入水(20mL),用乙酸乙酯(30mL)萃取,然后用饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩得到化合物4-环丙基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-酚(I-38F)(1.05g,产率94.7%)。4-cyclopropyl-5-methoxy-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2 ,3-triazol-4-yl)pyrimidine (I-38E) (1.10 g, 3.18 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and sodium methylthiolate (892 mg , 12.7mmol), and the reaction solution was stirred at 120°C for 2 hours under the protection of nitrogen. After the reaction, add water (20mL), extract with ethyl acetate (30mL), then wash with saturated brine (10mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain compound 4-cyclopropyl-2 -(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine-5- Phenol (I-38F) (1.05 g, 94.7% yield).
LC-MS,M/Z(ESI):332.2[M+H]
+
LC-MS, M/Z(ESI):332.2[M+H] +
第六步:(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧代)环己烷-1-甲酸甲酯(I-38G)的合成The sixth step: (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl Synthesis of )-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxo)cyclohexane-1-carboxylic acid methyl ester (I-38G)
(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-38G)(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol -4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-38G)
把4-环丙基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-酚(I-38F)(1.00g,3.02mmol),(1S,3R)-3-羟基环己甲酸甲酯(620.62mg,3.92mmol)和三苯基膦(1.58g,6.04mmol)溶解于甲苯(10.0mL)中,氮气置换三次,并于10℃滴加偶氮二甲酸二异丙酯(1.22g,6.04mmol),反应液在室温下搅拌12小时。反应完全后,加入水(10mL)淬灭。用乙酸乙酯(20mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,直接浓缩得到粗品,经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1)得到化合物(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧代)环己烷-1-甲酸甲酯(I-38G)(1.01g,产率70.9%)。4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole- 4-yl)pyrimidin-5-ol (I-38F) (1.00g, 3.02mmol), methyl (1S,3R)-3-hydroxycyclohexanecarboxylate (620.62mg, 3.92mmol) and triphenylphosphine (1.58 g, 6.04mmol) was dissolved in toluene (10.0mL), replaced with nitrogen three times, and diisopropyl azodicarboxylate (1.22g, 6.04mmol) was added dropwise at 10°C, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was complete, water (10 mL) was added to quench. Extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and directly concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate (V/ V)=1:1) to obtain compound (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl) Oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxo)cyclohexane-1-carboxylic acid methyl ester (I-38G) (1.01g, yield rate of 70.9%).
LC-MS,M/Z(ESI):472.4[M+H]
+
LC-MS, M/Z(ESI):472.4[M+H] +
第七步:(1S,3S)-3-((4-环丙基-2-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-38H)的合成The seventh step: (1S,3S)-3-((4-cyclopropyl-2-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyrimidin-5-yl)oxy)cyclohexane-1-methyl carboxylate (I-38H) synthesis
Methyl(1S,3S)-3-((4-cyclopropyl-2-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-38H)Methyl(1S,3S)-3-((4-cyclopropyl-2-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy) cyclohexane-1-carboxylate (I-38H)
把(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧代)环己烷-1-甲酸甲酯(I-38G)(500mg,1.06mmol)和对甲苯磺酸(53.2mg,212μmol)溶解于乙醇(5mL)中,反应液在氮气保护下于60度搅拌12小时,反应完全后,直接浓缩得到棕色的固体,经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1)得到化合物(1S,3S)-3-((4-环丙基-2-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-38H)(205mg,产率60.6%)。Put (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H -1,2,3-triazol-4-yl)pyrimidin-5-yl)oxo)cyclohexane-1-carboxylic acid methyl ester (I-38G) (500mg, 1.06mmol) and p-toluenesulfonic acid (53.2 mg, 212 μmol) was dissolved in ethanol (5mL), and the reaction solution was stirred at 60°C for 12 hours under nitrogen protection. After the reaction was complete, it was concentrated directly to obtain a brown solid, which was purified by column chromatography (petroleum ether: ethyl acetate (V /V)=1:1) to obtain compound (1S,3S)-3-((4-cyclopropyl-2-(5-(hydroxymethyl)-1-methyl-1H-1,2,3- Triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-38H) (205 mg, 60.6% yield).
LC-MS,M/Z(ESI):388.3[M+H]
+
LC-MS, M/Z(ESI):388.3[M+H] +
第八步:(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-38I)的合成The eighth step: (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl) Synthesis of oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-38I)
methyl(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-38I)methyl(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2, 3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate (I-38I)
把(1S,3S)-3-((4-环丙基-2-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-38H)(105mg,271.02μmol)和吡啶(64.31mg,813.05μmol)溶解于二氯甲烷(5.00mL)中,冰浴条件下加入对硝基氯甲酸苯酯(109.25mg,542.03μmol),反应液搅拌0.5小时后,加入甲基(3,3,3-三氟丙基)胺盐酸盐(85.85mg,524.85μmol),随后升至室温搅拌0.5小时。反应完全后,加入水(5.00mL)淬灭,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,减压浓缩,得到粗品经柱层析纯化(石油醚:乙酸乙酯(V/V)=3:1)得到化合物(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-38I)(52.0mg,产率36.6%)。Put (1S,3S)-3-((4-cyclopropyl-2-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrimidine- 5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-38H) (105mg, 271.02μmol) and pyridine (64.31mg, 813.05μmol) were dissolved in dichloromethane (5.00mL), ice bath condition Phenyl p-nitrochloroformate (109.25 mg, 542.03 μmol) was added at the same time, and after the reaction solution was stirred for 0.5 hours, methyl (3,3,3-trifluoropropyl)amine hydrochloride (85.85 mg, 524.85 μmol) was added , followed by warming to room temperature and stirring for 0.5 hours. After the reaction was complete, it was quenched by adding water (5.00 mL), extracted with ethyl acetate (10 mL), and the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product Purified by column chromatography (petroleum ether: ethyl acetate (V/V) = 3:1) to obtain compound (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-( ((Methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy) Methyl cyclohexane-1-carboxylate (I-38I) (52.0 mg, 36.6% yield).
LC-MS,M/Z(ESI):541.4[M+H]
+
LC-MS, M/Z(ESI):541.4[M+H] +
第九步:(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸(目标化合物I-38)The ninth step: (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl) Oxygen)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-38)
(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-38)(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-38)
把(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸甲酯(I-38I)(52.0mg,96.2μmol)溶解于四氢呋喃(2.50mL)中,加入一水合氢氧化锂(40.3mg,962μmol)和水(2.00mL),室温下搅拌12小时。反应完全后,加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10mL)萃取,然后用饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,得到粗品用制备高效液相色谱纯化(色谱柱:3_Phenomenex Luna C18 75*30mm*3um;溶剂:A=水+0.01%HCl,B=乙腈;梯度:37%-57%,8min),得到化合物(1S,3S)-3-((4-环丙基-2-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-5-基)氧基)环己烷-1-甲酸(目标化合物I-38)(3.00mg,产率5.87%)。Put (1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-38I) (52.0mg, 96.2μmol) dissolved Lithium hydroxide monohydrate (40.3 mg, 962 μmol) and water (2.00 mL) were added to tetrahydrofuran (2.50 mL), and stirred at room temperature for 12 hours. After the reaction is complete, dilute hydrochloric acid aqueous solution is added to adjust the pH to 1, extracted with ethyl acetate (10 mL), then washed with saturated brine (10 mL), the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 37%-57%, 8min) to obtain compound (1S, 3S)- 3-((4-cyclopropyl-2-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy)methyl)-1H-1 ,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-38) (3.00 mg, yield 5.87%).
LC-MS,M/Z(ESI):527.2[M+H]
+
LC-MS, M/Z(ESI):527.2[M+H] +
1H NMR(400MHz,CDCl
3)δ8.28(br s,1H),5.55(d,2H),4.82(br s,1H),4.38(s,3H),3.57-3.34(m,2H),3.00-2.84(m,4H),2.56-2.48(m,1H),2.46-2.34(m,1H),2.29-2.15(m,2H),2.11-1.96(m,3H),1.83-1.68(m,4H),1.23-1.14(m,4H)
1 H NMR (400MHz, CDCl 3 )δ8.28(br s,1H),5.55(d,2H),4.82(br s,1H),4.38(s,3H),3.57-3.34(m,2H), 3.00-2.84(m,4H),2.56-2.48(m,1H),2.46-2.34(m,1H),2.29-2.15(m,2H),2.11-1.96(m,3H),1.83-1.68(m ,4H),1.23-1.14(m,4H)
实施例39:目标化合物I-39的制备Embodiment 39: Preparation of target compound I-39
(1S,3S)-3-((3-环丙基-5-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸(目标化合物I-39)(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy)methyl Base)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-39)
(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-39)(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-39)
目标化合物I-39的合成路线如下所示:The synthetic route of target compound I-39 is as follows:
第一步:3-溴-5-碘吡嗪-2-胺(I-39B)的合成The first step: the synthesis of 3-bromo-5-iodopyrazin-2-amine (I-39B)
3-bromo-5-iodopyrazin-2-amine(I-39B)3-bromo-5-iodopyrazin-2-amine (I-39B)
在氮气保护下,将5-碘吡嗪-2-胺(I-39A)(25g,113.12mmol)溶解于N,N-二甲基甲酰胺(250mL)中,冰浴下缓慢加入N-溴代丁二酰亚胺(22.15g,124.44mmol),加完后,反应液于20℃搅拌12小时。反应结束后缓慢加水(500mL)淬灭,用乙酸乙酯(500mL×3)萃取,有机相用饱和食盐水(150mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩得到化合物3-溴-5-碘吡嗪-2-胺(I-39B)(25.0g,产率73.6%).Under nitrogen protection, 5-iodopyrazin-2-amine (I-39A) (25g, 113.12mmol) was dissolved in N,N-dimethylformamide (250mL), and N-bromo Subsuccinimide (22.15g, 124.44mmol), after the addition was complete, the reaction solution was stirred at 20°C for 12 hours. After the reaction was completed, water (500 mL) was slowly added to quench, extracted with ethyl acetate (500 mL×3), the organic phase was washed with saturated brine (150 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-bromo- 5-iodopyrazin-2-amine (I-39B) (25.0g, yield 73.6%).
LC-MS,M/Z(ESI):299.9[M+H]
+
LC-MS, M/Z(ESI):299.9[M+H] +
1H NMR(400MHz,CDCl
3)δ8.26-8.00(m,1H),5.05(br s,2H)
1 H NMR (400MHz, CDCl 3 ) δ8.26-8.00 (m, 1H), 5.05 (br s, 2H)
第二步:3-溴-5-碘吡嗪-2-醇(I-39C)的合成The second step: the synthesis of 3-bromo-5-iodopyrazin-2-ol (I-39C)
3-bromo-5-iodopyrazin-2-ol(I-39C)3-bromo-5-iodopyrazin-2-ol (I-39C)
把3-溴-5-碘吡嗪-2-胺(I-39B)(25.0g,83.3mmol)溶解于醋酸(250mL)中,氮气保护下于15℃滴加浓硫酸(73.5g,750mmol),滴加完毕后,再滴加亚硝酸钠(11.5g,166mmol)的水(69.0mL)溶液,并于20℃搅拌12小时。反应结束后直接过滤,浓缩得到化合物3-溴-5-碘吡嗪-2-醇(I-39C)(15.0g,产率为59.8%)。Dissolve 3-bromo-5-iodopyrazin-2-amine (I-39B) (25.0g, 83.3mmol) in acetic acid (250mL), add concentrated sulfuric acid (73.5g, 750mmol) dropwise at 15°C under nitrogen protection After the dropwise addition, a solution of sodium nitrite (11.5 g, 166 mmol) in water (69.0 mL) was added dropwise, and stirred at 20° C. for 12 hours. After the reaction was completed, it was directly filtered and concentrated to obtain compound 3-bromo-5-iodopyrazin-2-ol (I-39C) (15.0 g, yield 59.8%).
LC-MS,M/Z(ESI):300.9[M+H]
+
LC-MS, M/Z(ESI):300.9[M+H] +
1H NMR(400MHz,DMSO-d6)δ12.8(s,1H),7.89(s,1H)
1 H NMR (400MHz,DMSO-d6)δ12.8(s,1H),7.89(s,1H)
第三步:3-溴-5-(3-(噁烷-2-氧基)丙-1-炔-1-基)吡嗪-2-醇(I-39D)的合成The third step: the synthesis of 3-bromo-5-(3-(oxane-2-oxyl)prop-1-yn-1-yl)pyrazin-2-ol (I-39D)
3-bromo-5-(3-(oxan-2-yloxy)prop-1-yn-1-yl)pyrazin-2-ol(I-39D)3-bromo-5-(3-(oxan-2-yloxy)prop-1-yn-1-yl)pyrazin-2-ol(I-39D)
把3-溴-5-碘吡嗪-2-醇(I-39C)(7.50g,24.9mmol),2-丙-2-炔氧代四氢吡喃(3.67g,26.1mmol)和三乙胺(8.83g,87.2mmol)溶解于乙腈(100mL)中,加入碘化亚铜(237mg,1.25mmol)和三苯基膦二氯化钯(874mg,1.25mmol),置换氮气三次,反应液在20℃下搅拌12小时。反应结束后加水(20.0mL)淬灭,用乙酸乙酯(45mL)萃取,然后用饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩得到棕色油状物,经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1)得到化合物3-溴-5-(3-(噁烷-2-氧基)丙-1-炔-1-基)吡嗪-2-醇(I-39D)(2.52g,产率32.2%)。3-Bromo-5-iodopyrazin-2-ol (I-39C) (7.50g, 24.9mmol), 2-prop-2-yne oxytetrahydropyran (3.67g, 26.1mmol) and triethyl Amine (8.83g, 87.2mmol) was dissolved in acetonitrile (100mL), copper iodide (237mg, 1.25mmol) and triphenylphosphine palladium dichloride (874mg, 1.25mmol) were added, nitrogen was replaced three times, and the reaction solution was Stir at 20°C for 12 hours. After the reaction was completed, add water (20.0 mL) to quench, extract with ethyl acetate (45 mL), and then wash with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oil, which was passed through column layer Analysis and purification (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain the compound 3-bromo-5-(3-(oxane-2-oxyl)prop-1-yn-1-yl)pyridine Azin-2-ol (I-39D) (2.52 g, 32.2% yield).
LC-MS,M/Z(ESI):313.0[M+H]
+
LC-MS, M/Z(ESI):313.0[M+H] +
1H NMR(400MHz,CDCl
3)δ7.74-7.64(m,1H),7.46(br s,1H),4.85(t,J=3.2Hz,1H),4.56-4.39(m,2H),3.96-3.81(m,1H),3.65-3.48(m,1H),1.91-1.71(m,2H),1.57(br d,J=6.0Hz,4H)
1 H NMR (400MHz, CDCl 3 ) δ7.74-7.64 (m, 1H), 7.46 (br s, 1H), 4.85 (t, J=3.2Hz, 1H), 4.56-4.39 (m, 2H), 3.96 -3.81(m,1H),3.65-3.48(m,1H),1.91-1.71(m,2H),1.57(br d,J=6.0Hz,4H)
第四步:3-溴-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39E)的合成The fourth step: 3-bromo-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-2-((2-(trimethyl Synthesis of silyl)ethoxy)methoxy)pyrazine (I-39E)
3-bromo-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine(I-39E)3-bromo-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine(I -39E)
把3-溴-5-(3-(噁烷-2-氧基)丙-1-炔-1-基)吡嗪-2-醇(I-39D)(2.50g,7.98mmol)和二异丙基乙胺(2.06g,15.9mmol)溶于二氯甲烷(25mL)中,缓慢滴加(氯甲氧基)乙基-三甲基-硅烷(1.60g,9.58mmol),反应液氮气保护下在25℃下搅拌2小时。反应结束后加水(20.0mL)淬灭,用乙酸乙酯(50mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,浓缩得到棕色油状物,经柱层析纯化(石油醚:乙酸乙酯(V/V)=5:1)得到化合物3-溴-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39E)(2.30g,产率64.9%)。3-Bromo-5-(3-(oxane-2-oxyl)prop-1-yn-1-yl)pyrazin-2-ol (I-39D) (2.50g, 7.98mmol) and diiso Propylethylamine (2.06g, 15.9mmol) was dissolved in dichloromethane (25mL), and (chloromethoxy)ethyl-trimethyl-silane (1.60g, 9.58mmol) was slowly added dropwise, and the reaction liquid nitrogen protection Stir at 25°C for 2 hours. After the reaction was completed, add water (20.0 mL) to quench, extract with ethyl acetate (50 mL), wash the organic phase with saturated brine (10 mL), then dry over anhydrous sodium sulfate, filter, concentrate to obtain a brown oil, and pass through the column layer Analysis and purification (petroleum ether: ethyl acetate (V/V) = 5:1) to obtain the compound 3-bromo-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1 -Alkyn-1-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39E) (2.30 g, 64.9% yield).
LC-MS,M/Z(ESI):445.2[M+H]
+
LC-MS, M/Z(ESI):445.2[M+H] +
第五步:3-溴-5-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39F)的合成The fifth step: 3-bromo-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)- Synthesis of 1H-1,2,3-triazol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39F)
3-bromo-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine(I-39F)3-bromo-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl) -2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39F)
把3-溴-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39E)(2.00g,4.51mmol),叠氮甲基(三甲基)硅烷(874mg,6.77mmol)溶解于四氢呋喃(10.0mL)中,氮气置换三次,加入五甲基环戊二烯基双(三苯基膦)氯化钌(II)(359mg,451μmol)和碘化亚铜(85.9mg,451μmol),反应液于66℃搅拌12小时。反应结束后直接过滤,滤液浓缩,得到粗品用柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物3-溴-5-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39F)(710mg,产率27.4%)。3-Bromo-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-2-((2-(trimethylsilane Base) ethoxy) methoxy) pyrazine (I-39E) (2.00g, 4.51mmol), azidomethyl (trimethyl) silane (874mg, 6.77mmol) was dissolved in tetrahydrofuran (10.0mL), Nitrogen was replaced three times, pentamethylcyclopentadienyl bis(triphenylphosphine) ruthenium (II) chloride (359mg, 451μmol) and cuprous iodide (85.9mg, 451μmol) were added, and the reaction solution was stirred at 66°C for 12 Hour. After the reaction was completed, it was directly filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain the compound 3-bromo-5-(5-(((tetrahydro -2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-2- ((2-(Trimethylsilyl)ethoxy)methoxy)pyrazine (I-39F) (710 mg, 27.4% yield).
LC-MS,M/Z(ESI):574.2[M+H]
+
LC-MS, M/Z(ESI):574.2[M+H] +
1H NMR(400MHz,CDCl
3)δ8.17(d,J=3.5Hz,1H),5.57-5.49(m,1H),5.35-5.28(m,1H),4.84-4.78(m,1H),4.72(br d,J=2.2Hz,1H),4.67(d,J=11.7Hz,1H),3.98-3.90(m,1H), 3.68(t,J=7.9Hz,2H),3.60-3.54(m,1H),1.91-1.77(m,2H),1.64-1.51(m,6H),1.02-0.95(m,2H),0.15(s,9H),0.02(s,9H)
1 H NMR (400MHz, CDCl 3 ) δ8.17(d, J=3.5Hz, 1H), 5.57-5.49(m, 1H), 5.35-5.28(m, 1H), 4.84-4.78(m, 1H), 4.72(br d, J=2.2Hz, 1H), 4.67(d, J=11.7Hz, 1H), 3.98-3.90(m, 1H), 3.68(t, J=7.9Hz, 2H), 3.60-3.54( m,1H),1.91-1.77(m,2H),1.64-1.51(m,6H),1.02-0.95(m,2H),0.15(s,9H),0.02(s,9H)
第六步:3-环丙基-5-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39G)的合成The sixth step: 3-cyclopropyl-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl Synthesis of )-1H-1,2,3-triazol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39G)
3-cyclopropyl-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine(I-39G)3-cyclopropyl-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl) -2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39G)
把3-溴-5-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39F)(700mg,1.22mmol)和环丙基硼酸(136mg,1.59mmol)溶解于1,4-二氧六环(10mL)和水(1mL)中,氮气置换三次,再加入磷酸钾(778mg,3.67mmol)和三苯基膦二氯化钯(85.8mg,122μmol),反应液于90℃下搅拌12小时。反应完全后,加入水(20.0mL),用乙酸乙酯(45mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物3-环丙基-5-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39G)(520mg,产率79.6%)。3-bromo-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1 , 2,3-triazol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39F) (700mg, 1.22mmol) and cyclo Propylboronic acid (136mg, 1.59mmol) was dissolved in 1,4-dioxane (10mL) and water (1mL), replaced with nitrogen three times, then potassium phosphate (778mg, 3.67mmol) and triphenylphosphine dichloride were added Palladium chloride (85.8mg, 122μmol), and the reaction solution was stirred at 90°C for 12 hours. After the reaction was complete, water (20.0 mL) was added, extracted with ethyl acetate (45 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product that was passed through a column Chromatographic purification (petroleum ether: ethyl acetate (V/V) = 1:1), to obtain compound 3-cyclopropyl-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy Base)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-2-((2-(trimethylsilyl )ethoxy)methoxy)pyrazine (I-39G) (520 mg, 79.6% yield).
LC-MS,M/Z(ESI):534.4[M+H]
+
LC-MS, M/Z(ESI):534.4[M+H] +
第七步:3-环丙基-5-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-醇(I-39H)的合成The seventh step: 3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3- Synthesis of Triazol-4-yl)pyrazin-2-ol (I-39H)
3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-ol(I-39H)3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-ol (I-39H)
把3-环丙基-5-(5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1-((三甲基甲硅烷基)甲基)-1H-1,2,3-三唑-4-基)-2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)吡嗪(I-39G)(500mg,936μmol)溶解于四氢呋喃(5.00mL)中,并向其中加入四丁基氟化氨(1M,2.87mL),反应液在氮气保护下于66℃搅拌12小时。反应完全后,加入水(10mL),用乙酸乙酯(30mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗产物经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物3-环丙基-5-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-醇(I-39H)(250mg,产率80.5%)。3-cyclopropyl-5-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H -1,2,3-triazol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine (I-39G) (500 mg, 936 μmol) dissolved In tetrahydrofuran (5.00 mL), tetrabutylammonium fluoride (1M, 2.87 mL) was added thereto, and the reaction solution was stirred at 66° C. for 12 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added, extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product that was passed through a column Chromatographic purification (petroleum ether: ethyl acetate (V/V) = 1:1), the compound 3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran- 2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-ol (I-39H) (250 mg, 80.5% yield).
LC-MS,M/Z(ESI):332.2[M+H]
+
LC-MS, M/Z(ESI):332.2[M+H] +
第八步:(1S,3S)-3-((3-环丙基-5-(1-甲基-5-((噁烷-2-氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39I)的合成The eighth step: (1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-((oxane-2-oxyl)methyl)-1H-1,2, Synthesis of methyl 3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-39I)
methyl(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylatemethyl(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate
把3-环丙基-5-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-醇(I-39H)(250mg,754μmol),(1S,3R)-3-羟基环己甲酸甲酯(179mg,1.13mmol)和三苯基膦(395mg,1.51mmol)溶解于甲苯(2.5mL)中,氮气置换三次,并于10℃滴加偶氮二甲酸二异丙酯(305mg,1.51mmol),反应液于室温下搅拌12小时。反应完全后,加入水(10mL)淬灭,用乙酸乙酯(20mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物(1S,3S)-3-((3-环丙基-5-(1-甲基-5-((噁烷-2-氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39I)(240mg,产率为59.9%)。3-cyclopropyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole- 4-yl)pyrazin-2-ol (I-39H) (250mg, 754μmol), (1S,3R)-3-Hydroxycyclohexanecarboxylic acid methyl ester (179mg, 1.13mmol) and triphenylphosphine (395mg, 1.51 mmol) was dissolved in toluene (2.5 mL), replaced with nitrogen three times, and diisopropyl azodicarboxylate (305 mg, 1.51 mmol) was added dropwise at 10°C, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched by adding water (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product Purified by column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain compound (1S, 3S)-3-((3-cyclopropyl-5-(1-methyl-5- ((Oxane-2-oxyl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I -39I) (240 mg, 59.9% yield).
LC-MS,M/Z(ESI):472.2[M+H]
+
LC-MS, M/Z(ESI):472.2[M+H] +
1H NMR(400MHz,CDCl
3)δ8.78-8.52(m,1H),6.32(br s,3H),5.51(br s,1H),5.30-5.10(m,2H),5.05-4.89(m,4H),4.66(br s,1H),4.15(s,3H),3.88-3.79(m,1H),3.73-3.67(m,3H),3.58-3.48(m,1H),2.91-2.77(m,1H),2.50-2.40(m,1H),2.36-2.25(m,1H),2.02(br s,1H),1.90-1.70(m,4H),1.69-1.64(m,1H),1.12(br t,J=4.6Hz,2H),1.08-1.02(m,2H)
1 H NMR (400MHz, CDCl 3 )δ8.78-8.52(m,1H),6.32(br s,3H),5.51(br s,1H),5.30-5.10(m,2H),5.05-4.89(m ,4H),4.66(br s,1H),4.15(s,3H),3.88-3.79(m,1H),3.73-3.67(m,3H),3.58-3.48(m,1H),2.91-2.77( m,1H),2.50-2.40(m,1H),2.36-2.25(m,1H),2.02(br s,1H),1.90-1.70(m,4H),1.69-1.64(m,1H),1.12 (br t,J=4.6Hz,2H),1.08-1.02(m,2H)
第九步:(1S,3S)-3-((3-环丙基-5-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39J)的合成The ninth step: (1S,3S)-3-((3-cyclopropyl-5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl )pyrazin-2-yl)oxy)cyclohexane-1-methyl carboxylate (I-39J) synthesis
methyl(1S,3S)-3-((3-cyclopropyl-5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-39J)methyl(1S,3S)-3-((3-cyclopropyl-5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy) cyclohexane-1-carboxylate (I-39J)
把(1S,3S)-3-((3-环丙基-5-(1-甲基-5-((噁烷-2-氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39I)(240mg,508μmol)和对甲苯磺酸吡啶盐(127mg,508μmol)溶解于乙醇(5mL)中,反应液在氮气保护下于60℃搅拌12小时。反应完全后,直接浓缩,得到粗品经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物(1S,3S)-3-((3-环丙基-5-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39J)(197mg,粗品)。(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-((oxane-2-oxyl)methyl)-1H-1,2,3-tri Azol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-39I) (240 mg, 508 μmol) and pyridinium p-toluenesulfonate (127 mg, 508 μmol) were dissolved in ethanol (5 mL), the reaction solution was stirred at 60° C. for 12 hours under nitrogen protection. After the reaction was complete, it was directly concentrated, and the crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain the compound (1S,3S)-3-((3-cyclopropyl- 5-(5-(Hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-39J) (197 mg, crude).
LC-MS,M/Z(ESI):388.2[M+H]
+
LC-MS, M/Z(ESI):388.2[M+H] +
第十步:(1S,3S)-3-((3-环丙基-5-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲 基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39K)的合成The tenth step: (1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl) Synthesis of oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-39K)
methyl(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-39K)methyl(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2, 3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate (I-39K)
把(1S,3S)-3-((3-环丙基-5-(5-(羟甲基)-1-甲基-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39J)(105mg,271μmol)和吡啶(64.3mg,813μmol)溶解于二氯甲烷(5.00mL)中,冰浴下加入对硝基氯甲酸苯酯(109mg,542μmol),搅拌0.5小时后,加入甲基(3,3,3-三氟丙基)胺盐酸盐(85.8mg,524μmol),反应液升至室温搅拌0.5小时。反应完后,加入水(5mL)淬灭,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,滤液浓缩,得到粗品经柱层析纯化(石油醚:乙酸乙酯(V/V)=1:1),得到化合物(1S,3S)-3-((3-环丙基-5-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39K)(50.4mg,产率为35.5%)。LC-MS,M/Z(ESI):541.4[M+H]
+
Put (1S,3S)-3-((3-cyclopropyl-5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazine -2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-39J) (105mg, 271μmol) and pyridine (64.3mg, 813μmol) were dissolved in dichloromethane (5.00mL) and added under ice-cooling Phenyl p-nitrochloroformate (109 mg, 542 μmol) was stirred for 0.5 hours, then methyl (3,3,3-trifluoropropyl)amine hydrochloride (85.8 mg, 524 μmol) was added, and the reaction solution was raised to room temperature and stirred 0.5 hours. After the reaction, add water (5mL) to quench, extract with ethyl acetate (10mL), wash the organic phase with saturated brine (10mL), then dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product that is passed through the column layer Analysis and purification (petroleum ether: ethyl acetate (V/V) = 1: 1), the compound (1S, 3S)-3-((3-cyclopropyl-5-(1-methyl-5-(( (Methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy) Methyl cyclohexane-1-carboxylate (I-39K) (50.4 mg, 35.5% yield). LC-MS, M/Z(ESI):541.4[M+H] +
第十一步:(1S,3S)-3-((3-环丙基-5-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸(目标化合物I-39)The eleventh step: (1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl) )oxyl)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxyl)cyclohexane-1-carboxylic acid (target compound I-39)
(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid(目标化合物I-39)(1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3 -triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid (target compound I-39)
把(1S,3S)-3-((3-环丙基-5-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸甲酯(I-39K)(50.0mg,92.5μmol)溶解于四氢呋喃(2.00mL)中,加一水合氢氧化锂(38.8mg,925μmol)和水(1mL),室温下搅拌12小时。反应完全后,加入稀盐酸水溶液调节pH至1,用乙酸乙酯(10mL)萃取,有机相用饱和食盐水(10mL)洗涤,然后用无水硫酸钠干燥,过滤,减压浓缩,得到粗品用制备薄层硅胶板纯化(乙酸乙酯),得到化合物(1S,3S)-3-((3-环丙基-5-(1-甲基-5-(((甲基(3,3,3-三氟丙基)氨基羰基)氧基)甲基)-1H-1,2,3-三唑-4-基)吡嗪-2-基)氧基)环己烷-1-甲酸(目标化合物I-39)(42.0mg,产率85.46%)。Put (1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)aminocarbonyl)oxy) Methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid methyl ester (I-39K) (50.0mg, 92.5μmol) Dissolve in tetrahydrofuran (2.00 mL), add lithium hydroxide monohydrate (38.8 mg, 925 μmol) and water (1 mL), and stir at room temperature for 12 hours. After the reaction was complete, dilute hydrochloric acid aqueous solution was added to adjust the pH to 1, extracted with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product Purification on preparative thin-layer silica gel plates (ethyl acetate) gave the compound (1S,3S)-3-((3-cyclopropyl-5-(1-methyl-5-(((methyl(3,3, 3-trifluoropropyl)aminocarbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid ( Target compound I-39) (42.0 mg, yield 85.46%).
LC-MS,M/Z(ESI):527.2[M+H]
+
LC-MS, M/Z(ESI):527.2[M+H] +
1H NMR(400MHz,CDCl
3)δ8.28(br s,1H),5.54(br s,2H),4.90-4.72(m,1H),4.38(s,3H),3.60-3.34(m,2H),3.04-2.79(m,4H),2.57-2.47(m,1H),2.44-2.33(m,1H),2.31-2.17(m,2H),2.10-1.92(m,3H),1.84-1.66(m,4H),1.24-1.12(m,4H)
1 H NMR (400MHz, CDCl 3 )δ8.28(br s,1H),5.54(br s,2H),4.90-4.72(m,1H),4.38(s,3H),3.60-3.34(m,2H ),3.04-2.79(m,4H),2.57-2.47(m,1H),2.44-2.33(m,1H),2.31-2.17(m,2H),2.10-1.92(m,3H),1.84-1.66 (m,4H),1.24-1.12(m,4H)
生物学活性及相关性质测试例Biological activity and related properties test cases
测试例1:LPAR1体外钙流测定试验Test Example 1: In vitro calcium flux assay of LPAR1
化合物对LPAR1拮抗作用的测定在高表达人LPAR1的CHO稳转细胞株中进行。试验前18小时,将细胞以15,000细胞/孔的密度接种在含20μL DMEM/F12(1:1)培养基的384孔黑壁透明底板中,并保持在37℃/5%CO
2中孵育18小时,然后每孔细胞内加入20μL/孔染料溶液,放回37℃培养箱中继续避光孵育30min,再在室温避光条件下孵育10min,细胞内加入10μL/孔不同终浓度的化合物,平衡20min,最后向细胞中加入12.5μL/孔的LPA溶液(终浓度5nM),用FLIPR检测荧光信号值。以化合物浓度为X轴,荧光信号值为Y轴,通过软件Prism计算化合物的拮抗作用(IC
50值)。
The antagonism of the compound on LPAR1 was determined in a CHO stably transfected cell line highly expressing human LPAR1. Eighteen hours before the experiment, cells were seeded at a density of 15,000 cells/well in a 384-well black-walled transparent bottom plate containing 20 μL DMEM/F12 (1:1) medium, and incubated at 37°C/5% CO 2 for 18 hours. Then add 20 μL/well dye solution to each well of cells, put them back into the 37°C incubator and continue to incubate in the dark for 30 minutes, and then incubate at room temperature in the dark for 10 minutes, add 10 μL/well of compounds with different final concentrations into the cells, and balance After 20 min, 12.5 μL/well of LPA solution (final concentration 5 nM) was finally added to the cells, and the fluorescence signal value was detected by FLIPR. Taking the compound concentration as the X axis and the fluorescence signal value as the Y axis, the antagonistic effect (IC 50 value) of the compound was calculated by the software Prism.
表1测试化合物对LPAR1的拮抗作用Table 1 Antagonism of test compounds against LPAR1
测试化合物test compound | IC50(nM)IC50(nM) |
对照化合物1Control compound 1 | 243.8243.8 |
对照化合物2Control compound 2 | 251.6251.6 |
化合物I-3Compound I-3 | 47.4747.47 |
化合物I-5Compound I-5 | 48.1648.16 |
化合物I-7Compound I-7 | 38.8338.83 |
化合物I-8Compound I-8 | 39.4239.42 |
化合物I-11Compound I-11 | 113.3113.3 |
化合物I-13Compound I-13 | 130.6130.6 |
化合物I-15Compound I-15 | 39.7539.75 |
化合物I-18Compound I-18 | 45.6845.68 |
化合物I-25Compound I-25 | 150.9150.9 |
化合物I-32Compound I-32 | 85.5585.55 |
化合物I-33Compound I-33 | 119.6119.6 |
化合物I-35Compound I-35 | 42.2242.22 |
化合物I-36Compound I-36 | 201.5201.5 |
LPAR1实验钙流试验结果表明,本发明化合物对LPAR1具有良好的拮抗作用,与对照化合物相比,大多数发明化合物显示出更优异的LPAR1拮抗作用。LPAR1 experiment Calcium flow test results show that the compounds of the present invention have good antagonism to LPAR1, and compared with the control compounds, most of the compounds of the invention show better LPAR1 antagonism.
测试例2:化合物对BSEP胆汁外排转运体的抑制作用测定试验Test Example 2: Determination of the inhibitory effect of compounds on BSEP bile efflux transporters
化合物物对BSEP(Bile salt export pump)胆汁外排转运体的抑制作用测试试验使用表达人源性BSEP胆汁外排转运体的囊泡(GenoMembrane)来进行。不同浓度的化合物与囊泡预孵育5分钟,同时设置阴性对照(NC)组和阳性对照(PC)组:NC组为囊泡与空白缓冲液37℃预孵育5分钟,PC组为阳性抑制剂与囊泡37℃预孵育5分钟。随后在分别加入ATP或AMP的条件下,与探针底物在37℃孵育5分钟。用预冷的Buffer B1(10×Buffer B1(Stopping and Washing Buffer):100mM Hepes-Tris,1000mM KNO3,500mM Sucrose)终止试验。将试验样本转移到96孔滤板上,用真空泵抽滤,随后用0.2mL预冷的Buffer B1反复洗5次,用50μL 80%甲醇溶解滤板上的囊泡,收集后2000转离心2分钟收集滤液,重复一次,将两次的滤液合并在一起,混匀,得到大约100μL的滤液,加入含内标的预冷甲醇,于12,000转离心5min。取上清液用于LC-MS/MS定量检测被转运的底物的含量。以化合物浓 度为X轴,相对活性(%of NC)为Y轴,通过软件Prism计算化合物抑制胆汁外排转运体活性的IC
50值以及抑制率。
The inhibitory effect test of compounds on BSEP (Bile salt export pump) bile efflux transporter was carried out using vesicles (GenoMembrane) expressing human BSEP bile efflux transporter. Compounds with different concentrations were pre-incubated with vesicles for 5 minutes, and negative control (NC) group and positive control (PC) group were set at the same time: NC group was pre-incubated with vesicles and blank buffer at 37°C for 5 minutes, and PC group was positive inhibitor Pre-incubation with vesicles at 37°C for 5 minutes. This was followed by incubation with the probe substrate at 37° C. for 5 minutes with the addition of ATP or AMP, respectively. The experiment was terminated with pre-cooled Buffer B1 (10×Buffer B1 (Stopping and Washing Buffer): 100mM Hepes-Tris, 1000mM KNO3, 500mM Sucrose). Transfer the test sample to a 96-well filter plate, filter it with a vacuum pump, then wash it 5 times with 0.2 mL pre-cooled Buffer B1, dissolve the vesicles on the filter plate with 50 μL 80% methanol, and centrifuge at 2000 rpm for 2 minutes after collection Collect the filtrate, repeat once, combine the two filtrates together, mix well to obtain about 100 μL of filtrate, add pre-cooled methanol containing internal standard, and centrifuge at 12,000 rpm for 5 min. The supernatant was used for quantitative detection of the content of the transported substrate by LC-MS/MS. Taking the compound concentration as the X-axis and the relative activity (% of NC) as the Y-axis, the IC 50 value and the inhibition rate of the compounds inhibiting the bile efflux transporter activity were calculated by software Prism.
按以下公式计算不同条件下的转运速率(活性)和相对活性:The transport rate (activity) and relative activity under different conditions were calculated according to the following formula:
底物主动转运速率(pmol/min/mg)=Substrate active transport rate (pmol/min/mg) =
表2测试化合物对BSEP胆汁外排转运体的抑制作用Table 2 Inhibitory effect of test compounds on BSEP bile efflux transporter
测试化合物test compound | IC 50(μM) IC50 (μM) |
对照化合物1Control compound 1 | 89.889.8 |
对照化合物2Control compound 2 | 195.5195.5 |
化合物I-18Compound I-18 | 350.0350.0 |
化合物I-24Compound I-24 | 218218 |
化合物I-27Compound I-27 | >200>200 |
BSEP胆汁外排转运体的抑制试验结果表明,本发明化合物对BSEP胆汁外排转运体无明显抑制作用,无胆汁淤积毒性风险。The results of the inhibition test of the BSEP bile efflux transporter show that the compound of the present invention has no obvious inhibitory effect on the BSEP bile efflux transporter, and has no risk of cholestatic toxicity.
测试例3:Caco-2细胞渗透性试验Test Example 3: Caco-2 Cell Permeability Test
将Caco-2细胞以1×10
5个细胞/cm
2接种到96孔Transwell板上,每4~5天更新一次培养基,直到第28天细胞形成致密的单层膜。用含100μM荧光黄的HBSS溶液验证Caco-2细胞膜层完整性。然后在Elacridar(10μM)存在和不存在的条件下开展以下试验:在A到B组,以2μM的终浓度将化合物加入至96孔Transwell板的给药侧,接收侧则加入缓冲液,然后将板在CO
2培养箱中37℃、5%CO
2的饱和湿度条件下静置孵育2小时;孵育结束,给药侧和接收侧同时取样,将所有样品与含有内标的乙腈混合后,以3200g离心10分钟,取上清,然后以LC-MS/MS检测化合物浓度。以同样的条件检测B到A组,最后按以下公式计算Papp(10
-6cm/sec)、外排率。
Caco-2 cells were seeded on 96-well Transwell plates at 1×10 5 cells/cm 2 , and the medium was renewed every 4 to 5 days until the cells formed a dense monolayer on the 28th day. The integrity of the Caco-2 cell membrane layer was verified with HBSS solution containing 100 μM lucifer yellow. Then, the following experiments were carried out in the presence and absence of Elacridar (10 μM): in groups A to B, the compound was added to the administration side of the 96-well Transwell plate at a final concentration of 2 μM, and the buffer was added to the receiving side, and then Plates were incubated in a CO2 incubator at 37°C and saturated humidity of 5% CO2 for 2 hours; at the end of the incubation, samples were taken from the administration side and the receiving side at the same time. After centrifugation for 10 minutes, the supernatant was collected, and the concentration of the compound was detected by LC-MS/MS. Groups B to A were detected under the same conditions, and finally Papp (10 -6 cm/sec) and efflux rate were calculated according to the following formula.
表观渗透系数(Papp)=(接受侧体积/(膜面积×孵育时间))×(孵育结束时接受侧药物浓度)/(孵育开始时给药侧药物浓度)Apparent permeability coefficient (Papp) = (receiving side volume/(membrane area × incubation time)) × (drug concentration on the receiving side at the end of incubation)/(drug concentration on the administration side at the beginning of incubation)
外排率(ER)=Papp
(B-A)/Papp
(A-B)
Efflux rate (ER) = Papp (BA) /Papp (AB)
实验结果表明,本发明化合物渗透性较高,无明显外排,成药性好。Experimental results show that the compound of the invention has high permeability, no obvious efflux, and good druggability.
测试例4:小鼠药代动力学试验Test Example 4: Pharmacokinetic test in mice
小鼠药代动力学试验,使用雄性ICR小鼠,20-25g,禁食过夜。取3只小鼠,口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g,2-8℃离心6分钟,收集血浆,于-80℃保存。取各时间点血浆,加入3-5倍量含内标的乙腈溶液混合,涡旋混合1分钟,13000转/分钟4℃离心10分钟,取上清液加入3倍量水混合,取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房 室模型分析。For the mouse pharmacokinetic test, use male ICR mice, 20-25g, fasted overnight. Take 3 mice, orally administer 10 mg/kg by gavage. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. The blood sample was 6800g, centrifuged at 2-8°C for 6 minutes, the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13,000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
小鼠药代动力学试验实验结果表明,与对照化合物相比,本发明化合物表现出更优良的药代动力学性质,成药性好。The experimental results of the mouse pharmacokinetic test show that, compared with the reference compound, the compound of the present invention exhibits better pharmacokinetic properties and good druggability.
测试例5:大鼠药代动力学试验Test Example 5: Rat Pharmacokinetic Test
大鼠药代动力学试验,使用雄性SD大鼠,180-240g,禁食过夜。取3只大鼠,口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g,2-8℃离心6分钟,收集血浆,于-80℃保存。取各时间点血浆,加入3-5倍量含内标的乙腈溶液混合,涡旋混合1分钟,13000转/分钟4℃离心10分钟,取上清液加入3倍量水混合,取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Rat pharmacokinetic test, using male SD rats, 180-240g, fasted overnight. Take 3 rats, orally administer 10 mg/kg by gavage. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. The blood sample was 6800g, centrifuged at 2-8°C for 6 minutes, the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13,000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
大鼠药代动力学试验实验结果表明,与对照化合物相比,本发明化合物表现出更优良的药代动力学性质,成药性好。The experimental results of the rat pharmacokinetic test show that, compared with the reference compound, the compound of the present invention exhibits better pharmacokinetic properties and good druggability.
测试例6:犬药代动力学试验Test Example 6: Dog Pharmacokinetic Test
犬药代动力学试验,使用雄性Beagle犬,8-10kg,禁食过夜。取3只Beagle犬,口服灌胃给药5mg/kg。取另外3只Beagle犬,静脉注射给药1mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g,2-8℃离心6分钟,收集血浆,于-80℃保存。取各时间点血浆,加入3-5倍量含内标的乙腈溶液混合,涡旋混合1分钟,13000转/分钟4℃离心10分钟,取上清液加入3倍量水混合,取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Canine pharmacokinetic test, using male Beagle dogs, 8-10kg, fasted overnight. Take 3 Beagle dogs, orally administer 5 mg/kg by gavage. Take another 3 Beagle dogs and give 1mg/kg intravenously. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. The blood sample was 6800g, centrifuged at 2-8°C for 6 minutes, the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13,000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
表6犬口服灌胃给药药代动力学试验结果Table 6 Dog oral gavage administration pharmacokinetic test results
犬药代动力学试验实验结果表明,与对照化合物相比,本发明化合物具有更大的暴露量,成药性好。The experimental results of the canine pharmacokinetic test show that, compared with the reference compound, the compound of the present invention has greater exposure and good druggability.
测试例7:博来霉素诱导的肺纤维化药效试验Test Example 7: Bleomycin-Induced Pulmonary Fibrosis Drug Efficacy Test
雄性小鼠适应性饲养1周,并体重达标后,根据动物体重随机分为对照组组,模型组和给药组。异氟烷麻醉后:模型组和给药组肺内均匀给予50μL的博来霉素以建立小鼠肺纤维化模型,而对照组肺内均匀给予50μL生理盐水;7天后连续给药15天,给药完成后,动物经戊巴比妥钠深度麻醉,收集肺泡灌洗液(BALF),并立即放到湿冰盒暂存,用于后续指标检测;部分动物肺放入10%中性福尔马林缓冲液固定,用于制备病理组织切片;另一部分动物肺准确称取重量并记录后,置于冻存管,立即放入液氮,和收集的BALF上清一并转移至超低温-80℃冰箱保存,用于后续检测肺泡灌洗液和肺组织羟脯氨酸水平、Collagen I表达情况等指标。The male mice were adaptively fed for 1 week, and after reaching the standard body weight, they were randomly divided into control group, model group and drug treatment group according to the animal body weight. After isoflurane anesthesia: 50 μL of bleomycin was uniformly administered into the lungs of the model group and the treatment group to establish a mouse pulmonary fibrosis model, while 50 μL of normal saline was uniformly administered into the lungs of the control group; after 7 days, the administration was continued for 15 days, After the administration was completed, the animals were deeply anesthetized with pentobarbital sodium, and the alveolar lavage fluid (BALF) was collected and immediately stored in a wet ice box for subsequent index detection; the lungs of some animals were placed in 10% neutral ethanol Formalin buffer was fixed for the preparation of pathological tissue sections; the other part of the animal lung was accurately weighed and recorded, placed in a cryopreservation tube, immediately placed in liquid nitrogen, and transferred together with the collected BALF supernatant to ultra-low temperature- Store in a refrigerator at 80°C for subsequent detection of alveolar lavage fluid and lung tissue hydroxyproline levels, Collagen I expression and other indicators.
博来霉素诱导的肺纤维化药效试验结果表明,本发明化合物能通过拮抗LPAR1显著改善博来霉素诱导的小鼠肺纤维化症状。The results of the drug efficacy test on bleomycin-induced pulmonary fibrosis show that the compound of the present invention can significantly improve the symptoms of bleomycin-induced pulmonary fibrosis in mice by antagonizing LPAR1.
Claims (26)
- 一种化合物,所述化合物为式(I)所示化合物,或者式(I)所示化合物的立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:A compound, the compound is a compound shown in formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound shown in formula (I):其中:in:R 1选自无取代或被R 1a取代的C 3-6环烷基、无取代或被R 1a取代的3-6元杂环基;所述R 1a选自-CN、卤素; R 1 is selected from unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted by R 1a 3-6 membered heterocyclic group; said R 1a is selected from -CN, halogen;X 1和X 2各自独立地选自C(R 1b)和N,且X 1和X 2不同时为N,所述R 1b选自-H、-CN、卤素、-OH、任选取代的C 1-6烷基; X 1 and X 2 are each independently selected from C(R 1b ) and N, and X 1 and X 2 are not N at the same time, said R 1b is selected from -H, -CN, halogen, -OH, optionally substituted C 1-6 alkyl;R 2选自-H、-CN、卤素、无取代或被R 2a取代的C 1-6烷基;所述R 2a选自-CN、卤素; R 2 is selected from -H, -CN, halogen, unsubstituted or substituted C 1-6 alkyl by R 2a ; said R 2a is selected from -CN, halogen;R 3选自-H、-CN、卤素、无取代或被R 3a取代的以下基团:C 1-6烷基、C 3-8环烷基、C 4-8桥环烷基、4-8元杂环基、苯基、5-8元杂芳基;所述R 3a选自卤素、C 1-6烷基、C 3-6环烷基、4-8元杂环基、卤素取代的C 1-6烷基、卤素取代的C 3-6环烷基; R 3 is selected from the group consisting of -H, -CN, halogen, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4- 8-membered heterocyclyl, phenyl, 5-8 membered heteroaryl; said R 3a is selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, halogen substituted C 1-6 alkyl, halogen substituted C 3-6 cycloalkyl;L 1不存在,或选自-N(R 4)-、-O-、-N(R 4)-CO-O-和-O-CO-N(R 4)-; L 1 is absent, or selected from -N(R 4 )-, -O-, -N(R 4 )-CO-O- and -O-CO-N(R 4 )-;R 4选自-H、C 1-3烷基、被卤素取代的C 1-3烷基; R 4 is selected from -H, C 1-3 alkyl, C 1-3 alkyl substituted by halogen;L 2不存在,或选自无取代或被C 1-3烷基取代的C 1-3亚烷基、苯基、5-8元杂芳基; L 2 does not exist, or is selected from unsubstituted or substituted C 1-3 alkylene , phenyl, 5-8 membered heteroaryl;R 5选自-H、-F、甲基。 R 5 is selected from -H, -F, methyl.
- 根据权利要求1所述的化合物,其特征在于,The compound according to claim 1, characterized in that,和/或,当R 1为无取代或被R 1a取代的C 3-6环烷基时,所述R 1a的个数为一个或多个,当存在多个R 1a时,所述R 1a相同或不同; And/or, when R 1 is a C 3-6 cycloalkyl group that is unsubstituted or substituted by R 1a , the number of R 1a is one or more, and when there are multiple R 1a , the R 1a the same or different;和/或,当R 1为无取代或被R 1a取代的C 3-6环烷基时,所述R 1a选自-CN,氟、氯、溴、碘; And/or, when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , said R 1a is selected from -CN, fluorine, chlorine, bromine, iodine;和/或,当R 1为无取代或被R 1a取代的C 3-6环烷基时,所述C 3-6环烷基选自环丙基、环丁基、环戊基; And/or, when R 1 is a C 3-6 cycloalkyl group unsubstituted or substituted by R 1a , the C 3-6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl;和/或,当R 1为无取代或被R 1a取代的C 3-6杂环烷基时,所述C 3-6杂环烷基中的杂原子个数为1-2个; And/or, when R 1 is a C 3-6 heterocycloalkyl that is unsubstituted or substituted by R 1a , the number of heteroatoms in the C 3-6 heterocycloalkyl is 1-2;和/或,当R 1为无取代或被R c取代的C 3-6杂环烷基时,所述C 3-6杂环烷基中的杂原子选自O、N、S。 And/or, when R 1 is a C 3-6 heterocycloalkyl unsubstituted or substituted by R c , the heteroatoms in the C 3-6 heterocycloalkyl are selected from O, N, and S.
- 根据权利要求1所述的化合物,其特征在于,The compound according to claim 1, characterized in that,当R 2为无取代或被R 2a取代的C 1-6烷基时,所述R 2a的个数为一个或多个,当存在多个R 2a时,所述R 2a相同或不同; When R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more, and when there are multiple R 2a , the R 2a is the same or different;和/或,当R 2为无取代或被R 2a取代的C 1-6烷基时,所述R 2a的个数为一个或多个,当存在多个R 2a时,所述R 2a选自-CN、氟、氯; And/or, when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the number of R 2a is one or more, and when there are multiple R 2a , the R 2a is selected from From -CN, fluorine, chlorine;和/或,当R 2为无取代或被R 2a取代的C 1-6烷基时,所述C 1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基。 And/or, when R 2 is C 1-6 alkyl unsubstituted or substituted by R 2a , the C 1-6 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, tert-butyl, pentyl, hexyl.
- 根据权利要求1所述的化合物,其特征在于,The compound according to claim 1, characterized in that,当R 3为无取代或被R 3a取代的以下基团:C 1-6烷基、C 3-8环烷基、C 4-8桥环烷基、4~8元杂环基、苯基、5~8元杂芳基时,所述R 3a的个数为一个或多个,当存在多个R 3a时,所述R 3a相同或不同; When R 3 is unsubstituted or substituted by R 3a the following groups: C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocyclyl, phenyl , 5- to 8-membered heteroaryl, the number of R 3a is one or more, and when there are multiple R 3a , the R 3a is the same or different;和/或,当R 3为无取代或被R 3a取代的以下基团:C 1-6烷基、C 3-8环烷基、C 4-8桥环烷基、4~8元杂环基、苯基、5~8元杂芳基时,所述R 3a选自氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、正戊基、二氟甲基、三氟甲基、环丙基、环丁基; And/or, when R 3 is unsubstituted or substituted by R 3a the following groups: C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 bridged cycloalkyl, 4-8 membered heterocycle When radical, phenyl, 5-8 membered heteroaryl, said R 3a is selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, difluoro Methyl, trifluoromethyl, cyclopropyl, cyclobutyl;和/或,当R 3为无取代或被R 3a取代的C 1-6烷基时,所述C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基; And/or, when R 3 is unsubstituted or substituted by R 3a C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, pentyl, hexyl;和/或,当R 3为无取代或被R 3a取代的C 3-8环烷基时,所述的C 3-8环烷基为环丙基、环丁基、环戊基、环己基、环庚基、环辛基; And/or, when R 3 is unsubstituted or substituted by R 3a C 3-8 cycloalkyl, said C 3-8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl;和/或,当R 3为无取代或被R 3a取代的C 3-8桥环烷基时,所述的C 3-8桥环烷基为 And/or, when R 3 is a C 3-8 bridged cycloalkyl group that is unsubstituted or substituted by R 3a , the C 3-8 bridged cycloalkyl group is和/或,当R 3为无取代或被R 3a取代的4-8元杂环基时,所述杂原子选自N、O和S,所述杂原子数为1-2个; And/or, when R 3 is a 4-8 membered heterocyclic group unsubstituted or substituted by R 3a , the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1-2;和/或,当R 3为无取代或被R 3a取代的5-8元杂芳基时,所述5~8元杂芳基选自噻吩、呋喃、噁唑、噻唑、三氮唑、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、吡唑基、咪唑基。 And/or, when R 3 is a 5-8 membered heteroaryl group unsubstituted or substituted by R 3a , the 5-8 membered heteroaryl group is selected from thiophene, furan, oxazole, thiazole, triazole, pyridine Base, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl.
- 根据权利要求1所述的化合物,其特征在于,The compound according to claim 1, characterized in that,当R 4为C 1-3烷基或被卤素取代的C 1-3烷基时,所述C 1-3烷基为甲基、乙基、正丙基、异丙基; When R 4 is C 1-3 alkyl or C 1-3 alkyl substituted by halogen, the C 1-3 alkyl is methyl, ethyl, n-propyl, isopropyl;
- 根据权利要求6所述的化合物,其特征在于:The compound according to claim 6, characterized in that:R 2选自甲基、乙基、正丙基、异丙基,较佳地,R 2选自甲基; R 2 is selected from methyl, ethyl, n-propyl, isopropyl, preferably, R 2 is selected from methyl;R 3选自-F、-Cl、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、一氟甲基、苯基、吡啶基、环丙基、环丁基、 R is selected from -F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, phenyl, pyridyl, cyclopropyl, cyclo butyl,L 1不存在,或选自-NH-、-N(CH 3)-、-O-、-NH-CO-O-、-N(CH 3)-CO-O-、-O-CO-N(CH 3)-、 -O-CO-NH-; L 1 is absent, or selected from -NH-, -N(CH 3 )-, -O-, -NH-CO-O-, -N(CH 3 )-CO-O-, -O-CO-N (CH 3 )-, -O-CO-NH-;
- 根据权利要求9所述的化合物,其特征在于,R 3选自-H、-CN、-F、-Cl、无取代或被R 3a取代的以下基团:C 1-6烷基、C 3-8环烷基、C 4-8桥环烷基、苯基、吡啶基。 The compound according to claim 9, wherein R 3 is selected from the group consisting of -H, -CN, -F, -Cl, unsubstituted or substituted by R 3a : C 1-6 alkyl, C 3 -8 cycloalkyl, C 4-8 bridged cycloalkyl, phenyl, pyridyl.
- 一种药物组合物,其特征在于,包含有效剂量的权利要求1~16中任一项所述的化合物。A pharmaceutical composition, characterized by comprising an effective dose of the compound according to any one of claims 1-16.
- 权利要求1~16中任一项所述化合物,或权利要求17所述的药物组合物在制备治疗与LPAR相关疾病的药物中的用途。Use of the compound according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17 in the preparation of medicines for treating diseases related to LPAR.
- 根据权利要求18所述的用途,其中所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The use according to claim 18, wherein the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- 根据权利要求18所述的用途,其中所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The use according to claim 18, wherein said LPAR-related diseases are selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumors, neuropathic pain, rheumatoid arthritis, Fetal hydrocephalus.
- 权利要求1~16中任一项所述化合物,或权利要求17所述的药物组合物,用于治疗与LPAR相关疾病。The compound according to any one of claims 1-16, or the pharmaceutical composition according to claim 17, for treating diseases related to LPAR.
- 权利要求1~16中任一项所述化合物,或权利要求17所述的药物组合物,用于治疗选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The compound according to any one of claims 1-16, or the pharmaceutical composition according to claim 17, is used for the treatment of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- 权利要求1~16中任一项所述化合物,或权利要求17所述的药物组合物,用于治疗特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The compound according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17, for the treatment of idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumors, nerve Sexual pain, rheumatoid arthritis, fetal hydrocephalus.
- 一种治疗与LPAR相关疾病的方法,其特征在于,包括:给需要的对象施用有效量的权利要求1~16中任一项所述化合物,或权利要求17所述的药物组合物。A method for treating diseases related to LPAR, comprising: administering an effective amount of the compound according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17, to a subject in need.
- 根据权利要求24所述的方法,其特征在于,所述的LPAR相关疾病选自纤维化疾病、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The method according to claim 24, wherein the LPAR-related diseases are selected from fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, and fetal hydrocephalus.
- 根据权利要求24所述的方法,其特征在于,所述的LPAR相关疾病选自特发性肺纤维化、放射性肺纤维化、肝纤维化、肾纤维化、肿瘤、神经性疼痛、类风湿性关节炎、胎儿脑积水。The method according to claim 24, wherein the LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, tumor, neuropathic pain, rheumatoid Arthritis, fetal hydrocephalus.
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