CN116640117A

CN116640117A - Triazole LPAR1 antagonists and uses thereof

Info

Publication number: CN116640117A
Application number: CN202211617453.XA
Authority: CN
Inventors: 张学军; 臧杨; 杨辉; 雷四军; 王洪强; 杨俊�; 李莉娥; 常少华
Original assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Humanwell Healthcare Group Co ltd; Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2021-12-15
Filing date: 2022-12-15
Publication date: 2023-08-25
Also published as: WO2023109878A1

Abstract

The invention provides a novel compound which is effective in antagonizing LPAR1, and is a compound shown in the following formula, or a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in the following formula:

Description

Triazole LPAR1 antagonists and uses thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, in particular to an antagonist of triazole LPR1, and more particularly relates to an antagonist of triazole LPR1 and application thereof in preparation of medicines.

Background

Lysophosphatidic acid (LPA) is a key endogenous lipid signaling molecule of molecular weight 430-480Da, which is widely present both intracellular and extracellular in various tissues of the human body, such as various body fluids, saliva, urine, cerebrospinal fluid, blood, bronchoalveolar lavage fluid (BALF) and the like (Kaffe E et al Cancers (Basel).2019; 11 (11): 1626.). LPA is mainly produced from membrane phospholipids by two pathways: (1) phospholipase D (PLD) -phospholipase A2 (PLA 2) pathway; (2) PLA 2-lysophospholipase D (LysoPLD) pathway. The Enpp2 gene encodes an autologous chemotactic protein (ATX) that is a pyrophosphatase/phosphodiesterase enzyme that has lysophospholipase D (LysoPLD) activity and hydrolyzes extracellular Lysophosphatidylcholine (LPC) to the corresponding LPA and free choline (Choi JW et al, annu Rev Pharmacol. 2010; 50:157186.) and this response is the major source of LPA and inhibition of ATX activity inhibits LPA production by more than 80% throughout the body (Kaffe E et al Cancers (Basel).2019; 11 (11): 1626.).

LPA mediates a variety of functions through interaction 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, myelination, and the like. LPA can bind to and function as six lysophosphatidic acid receptors (LPARs), respectively: LPAR1-LPAR6.LPA regulates a variety of physiological/pathological processes including vascular and neural development, hair follicle development, lymphocyte transport, bone development, fibrosis, regulation of fat mass, cholestatic pruritus, neuropathic pain, embryo implantation, obesity and glucose homeostasis, spermatogenesis, 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 is the earliest identified and most widely distributed LPA receptor, a 41kDa membrane protein consisting of 364 amino acids, widely expressed in tissues and organs of the human body, where mRNA levels in brain, heart, colon, small intestine and placenta are high, and mRNA levels in other organs and tissues are relatively low. LPAR1 activates the downstream pathways of Akt, rho, mitogen-activated protein kinase, and phospholipase C by coupling to GαI/o, GαQ/11, and Gα12/13, although LPA-LPAR1 signaling has been shown to play an important role in the developmental stages of the nervous system, no significant toxicity was found in the systemic inhibition of adult individuals. However, inhibition of LPAR3 signals produces significant reproductive toxicity, and thus compounds need to avoid inhibition of LPAR3 signals.

Diseases with significant relevance to LPAR1 are mainly fibrotic diseases, tumors, neuropathic pain, RA (rheumatoid arthritis), certain central diseases, etc.

Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) is a chronic, progressive, fibrotic interstitial pneumonia characterized by diffuse alveolitis and alveolar structural disorders, and is mainly manifested as common interstitial pneumonia in imaging and histopathology. IPF originates from repeated damage to the tissues of alveolar tissue, and such damage can trigger a series of physiological events, including (I) disruption of homeostasis; (II) cause an inflammatory response; (III) cell proliferation, migration and differentiation; (IV) matrix and tissue reconstruction; and (V) wound contracture and scarring, many of which are controlled by coordinated release of biochemical factors at and around the site of injury, in which LPA plays an important role. The pathologically elevated LPA concentrations may continue 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 injured lung tissue BALF (Tager AM et al Proceedings of the American Thoracic Society, 2008.) BALF (alveolar lavage fluid) LPA levels in IPF patients are higher than in normal control groups, inhibiting LPA signaling significantly reduces chemotactic response of fibroblasts to IPF BALF.

In preclinical studies, treatment of LPAR1 gene deficient mice with bleomycin resulted in the finding that LPAR1 gene knockouts have significant protection in mice and that in LPAR1 deficient mice, bleomycin treated fibroblasts have significantly reduced aggregation. LPA induces endothelial cell barrier dysfunction and vascular leakage, and increases vascular permeability in early stages of tissue injury repair, which accelerates tissue repair, but LPA-LPAR1 mediated increases vascular permeability in the IPF process, which promotes fibrosis development. In another bleomycin-induced preclinical model of IPF, bleomycin treatment resulted in significant elevation of LPA levels in bronchoalveolar lavage fluid following lung injury,and causes pulmonary fibrosis, vascular leakage and death, these pathological changes are in LPAR1 ^-/- Obvious reduction in mice; LPAR1 antagonist AM966 reduced total protein content and LDH activity in alveolar lavage fluid in bleomycin model, suggesting that AM966 reduced blood vessel leakage and epithelial cell death in LPA-mediated IPF and other interstitial lung diseases. These show that LPAR1 is a promising target for treatment of IPF, and that the use of LPAR1 antagonist BMS-986020 significantly slowed the reduction in lung capacity and alleviated the clinical symptoms in patients with idiopathic pulmonary fibrosis in a randomized, double-blind, placebo-controlled clinical trial, whose second-generation compound BMS-986278 was undergoing phase II clinical trials for treatment of IPF (Swaney JS et al, br J Pharmacol.2010;160 (7): 1699-1713.).

Radiation lung fibrosis is a common and serious complication of lung cancer radiation therapy. LPAR1/LPAR3 antagonists VPC12249 inhibit expression of transforming growth factor β1 and connective tissue growth factor in vivo, resulting in reduced mouse fibroblast proliferation, slowing the progression of radiopulmonary fibrosis, suggesting that LPAR1 antagonists also have the potential to treat radiopulmonary 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 replication of hepatitis C virus, inhibiting ATX-LPA signaling reduces replication of hepatitis C virus, which may be associated with LPAR1 and LPAR3, and hepatitis is a key factor in the occurrence of liver fibrosis, suggesting that antagonizing LPAR1 may have the potential to treat liver fibrosis (Farquour MJ et al, J hepatol.2017;66 (5): 919-929.); in another study, downregulating LPAR1 signaling reduced α -SMA, CTGF and TGF- β1 expression, thereby significantly improving thioacetamide-induced liver fibrosis, which further demonstrates that LPAR1 antagonists can be used to treat liver fibrosis.

LPA promotes the progression of renal fibrosis by LPAR 1. In unilateral ureteral obstruction (UUUO) -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.). The ATX-LPA-LPAR1 signal stimulates fibroblast migration and proliferation in LPAR1 ^-/- UFO-induced kidney fibrosis was significantly reduced on mice or after pretreatment with LPAR1/3 antagonist Ki16425, and expression of pro-fibrotic cytokines (connective tissue growth factor and transforming growth factor-beta) was also significantly down-regulated when LPAR1 signaling was blocked. This suggests that LPAR1 antagonists may be useful in the treatment of renal fibrosis.

Fetal Hydrocephalus (FH) is a common neurological disease of newborns that occurs in close association with LPAR1 signals. In preclinical mice intracranial hemorrhage models, LPAR1 expressed by Neural Precursor Cells (NPC) is overactivated by exposing the mouse embryo brain to blood or LPA, resulting in skin destruction and thinning, ultimately leading to FH. (Yung YC et al, sci Transl Med.2011;3 (99): 99ra 87.). Pretreatment with Ki16425 (LPAR 1/3 antagonist) in a mouse-related model reduced the probability and severity of hemorrhagic hydrocephalus (PHH) production, suggesting that LPAR1 antagonists may be useful in the treatment of fetal hydrocephalus.

LPA-LPAR1 signals have a remarkable pro-tumor effect. LPA promotes tumor cell survival, proliferation, increases migration and tissue invasion in vitro, activates vascular endothelial growth factor and activates metalloproteinase, promoting cisplatin resistance of tumor cells. LPAR1 signals down regulate the expression of tumor suppressor p53 in hepatoma cells; LPA activates PI3K and P38MPAK signaling pathways through LPAR1, promoting MMP-9 expression and HCC invasion; LPA-LPAR1 is also able to promote invasiveness through GTPase RhoA and Rho-associated protein kinase (ROCK); it also induces Protein Kinase C (PKC) and nuclear factor κB (NF-kB) to promote epithelial to mesenchymal transition (EMT); in addition, the positive effect of LPA-LPAR1 on angiogenesis can also promote the development of cancer, as new blood vessels are essential for the development of solid tumors. These findings indicate that LPAR1 antagonists have great potential in the treatment of related tumors (Xiang H et al, J cancer.2020;11 (12): 3519-3535.).

Human peripheral nerve injury can result in a pain state called neuropathic pain, symptoms including persistent burning pain and abnormal sensations, such as hypersensitivity and hyperalgesia, LPAR1 signalingIs associated with the occurrence of neuropathic pain. Damage to the nervous system, which results in leakage of serum from the site of injury, can be one of the etiologies of neuropathic pain by exposing nerve cells in large numbers to LPA. Studies by Makoto Inoue et al indicate that behavioral abnormalities caused by nerve damage and pain-sensitive animal models can be simulated by antagonist pretreatment of LPAR1 or targeted deletion of LPAR1 to eliminate pain-sensitive symptoms, and by intrathecal injection of LPA. Another study showed that LPA can cause neuropathic pain by activating LPAR1, releasing nociceptive factor P, and LPAR1 ^-/- The mice were resistant to neuropathic pain caused by partial sciatic nerve ligation. These results indicate that LPA-LPAR1 signaling plays a key role in the onset 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 (RA) is a chronic autoimmune disease, and LPAR1 signaling is associated with the occurrence of RA. As compared to osteoarthritis patients, the level of LPAR1 and/or LPAR2 expression in the synovium of rheumatoid arthritis patients was elevated, preclinical studies showed that gene knockout of LPAR1 completely eliminates RA symptoms, pharmacological antagonism of LPAR1 reduced disease severity, and reduced inflammation and bone erosion (Kaffe E et al, cancers (Basel).2019; 11 (11): 1626.Published 2019Oct 23.doi:10.3390/cancer 11111626). Antagonizing LPAR1 signaling also reduces proliferation and sensitizes RA patients to Tumor Necrosis Factor (TNF) -mediated apoptosis of FLS, and LPA is also involved in the production of Interleukins (IL) -6, IL-8 and cyclooxygenase-2 (COX-2) in RA FLS. These results show that LPAR1 is a very promising target for the treatment of rheumatoid arthritis (Orosa B et al, annals of the Rheumatic Diseases,2014,73 (1): 298-305.).

Disclosure of Invention

The present invention aims to solve, at least to some extent, one of the above technical problems or at least to provide a useful commercial choice.

In a first aspect of the invention, the invention provides a compound of formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I):

wherein R is ¹ Selected from unsubstituted or substituted R ^1a Substituted C _3-6 Cycloalkyl, unsubstituted or substituted by R ^1a Substituted 3-6 membered heterocyclyl;

the R is ^1a Selected from-CN, halogen;

X ¹ and X ² Each independently selected from C (R) ^1b ) And N, and X ¹ And X ² Not at the same time N, R ^1b Selected from-H, -CN, halogen, -OH, and optionally substituted C _1-6 An alkyl group;

R ² selected from-H, -CN, halogen, unsubstituted or substituted by R ^2a Substituted C _1-6 An alkyl group; the R is ^2a Selected from-CN, halogen;

R ³ selected from-H, -CN, halogen, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, C _4-8 Bridged cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl; the R is ^3a 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 absent, or selected from-N (R ⁴ )-、-O-、-N(R ⁴ ) -CO-O-and-O-CO-N (R) ⁴ )-；

R ⁴ Selected from-H, C _1-3 Alkyl, C substituted by halogen _1-3 An alkyl group;

L ² absent, or selected from unsubstituted or C _1-3 Alkyl substituted C _1-3 Alkylene, phenyl, 5-8 membered heteroaryl;

R ⁵ selected from-H, -F, methyl.

In another aspect of the invention, the invention provides a compound of formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I):

R ¹ selected from-H, unsubstituted or substituted by R ^1a Substituted C _3-6 Cycloalkyl, unsubstituted or substituted by R ^1a Substituted C _3-6 A heterocycloalkyl group; the R is ^1a Selected from-CN, halogen;

X ¹ and X ² Each independently selected from C (R) ¹ ) And N, and X ¹ And X ² Not both are N;

R ³ selected from-H, -CN, halogen, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl; the R is ^3a Selected from halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen substituted C _1-6 An alkyl group;

L ¹ absent, or selected from-N (R ⁴ ) -and-N (R) ⁴ )-CO-O-；

R ⁵ 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 a straight chain alkyl group, a branched chain alkyl group.

As will be appreciated by those skilled in the art, in accordance with the conventions used in the art, in the structural formulae of the present application,for depicting chemical bonds, which are points where a moiety or substituent is attached to a core structure or a backbone structure.

According to some embodiments of the application, of the compounds of formula (I),selected from the group consisting of

According to certain embodiments of the present application, when R in a compound of formula (I) ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 In the case of cycloalkyl, the R ^1a Is one or more, when there are a plurality of R ^1a When the R is ^1a The same or different.

According to certain embodiments of the present application, when R in a compound of formula (I) ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 In the case of cycloalkyl, the R ^1a Selected from-CN, fluorine, chlorine, bromine, iodine.

According to certain embodiments of the present application, when R in a compound of formula (I) ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 In the case of cycloalkyl, the C _3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl.

According to certain embodiments of the present application, when R in a compound of formula (I) ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 When heterocycloalkyl, said C _3-6 The number of heteroatoms in the heterocycloalkyl group is 1-2.

According to certain embodiments of the present invention, when R in a compound of formula (I) ¹ Is unsubstituted or substituted by R ^c Substituted C _3-6 When heterocycloalkyl, said C _3-6 The heteroatom in the heterocycloalkyl group is selected from O, N, S.

According to certain embodiments of the present invention, in the compounds of formula (I), R ¹ Is unsubstituted or substituted by R ^1a Substituted cyclopropyl, said R ^1a Selected from-CN, fluorine, chlorine.

According to certain embodiments of the present invention, in the compounds of formula (I), R ¹ Is cyclopropyl.

According to certain embodiments of the present invention, when R in a compound of formula (I) ² Is unsubstituted or substituted by R ^2a Substituted C _1-6 In the case of alkyl, said R ^2a Is one or more, when there are a plurality of R ^2a When the R is ^2a The same or different.

According to certain embodiments of the present invention, when R in a compound of formula (I) ² Is unsubstituted or substituted by R ^2a Substituted C _1-6 In the case of alkyl, said R ^2a Is one or more, when there are a plurality of R ^2a When the R is ^2a Selected from-CN, fluorine, chlorine.

According to certain embodiments of the present invention, when R in a compound of formula (I) ² Is unsubstituted or substituted by R ^2a Substituted C _1-6 When alkyl, the C _1-6 The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.

According to certain embodiments of the present invention, in the compounds of formula (I), R ² Is unsubstituted or substituted by R ^2a Substituted methyl, said R ^2a Selected from-CN, fluorine, chlorine.

According to certain embodiments of the present invention, in the compounds of formula (I), R ² Is methyl.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclic group, phenyl, C _3-8 In the case of bridged cycloalkyl, 5-to 8-membered heteroaryl, the R ^3a Is one or the number ofPlural, when plural R's exist ^3a When the R is ^3a The same or different.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl, R being as defined in the specification ^3a Is one or more, when there are a plurality of R ^3a When the R is ^3a The same or different.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclic group, phenyl, C _3-8 In the case of bridged cycloalkyl, 5-to 8-membered heteroaryl, the R ^3a Selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl, R being as defined in the specification ^3a Selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a Substituted C _1-6 When alkyl, the C _1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a Substituted C _3-8 In the case of cycloalkyl, said C _3-8 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

According to the present inventionIn certain embodiments of the invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a Substituted C _3-8 In the case of bridged cycloalkyl radicals, the radicals C _3-8 Bridged cycloalkyl radicals are

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a In the case of a substituted 4-8 membered heterocyclic group, the heteroatom is selected from N, O and S, and the number of the heteroatom is 1-2.

According to certain embodiments of the present invention, when R in a compound of formula (I) ³ Is unsubstituted or substituted by R ^3a In the case of substituted 5-8 membered heteroaryl, the 5-8 membered heteroaryl is selected from thiophene, furan, oxazole, thiazole, triazole, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl'

According to certain embodiments of the present invention, in the compounds of formula (I), R ³ 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 certain embodiments of the present invention, in the compounds of formula (I), R ³ 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 certain embodiments of the present invention, when R in a compound of formula (I) ⁴ Is C _1-3 Alkyl or C substituted by halogen _1-3 When alkyl, the C _1-3 Alkyl is methyl, ethyl, n-propyl, isopropyl.

According to certain embodiments of the present invention, in the compounds of formula (I), L ² Absent, or selected from

According to some embodiments of the invention, the compound of formula (I) is a compound of formula (I-A):

wherein:

R ⁵ selected from the group consisting of-H, -F, methyl'

wherein:

R ³ selected from-H, -CN, halogen, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl; the R is ^3a Selected from halogen, C _3-6 Cycloalkyl;

L ¹ absent, or selected from-N (R ⁴ ) -or-N (R) ⁴ )-CO-O-；

L ² absent, or selected from unsubstituted or C _1-3 Alkyl substituted C _1-3 Alkylene, phenyl, 5-8 membered heteroaryl.

According to certain embodiments of the present invention, R in the compound of formula (I-A) ² Selected from methyl, ethyl, n-propyl, isopropyl, preferably R ² Selected from methyl;

R ³ selected from the group consisting of-F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, phenyl, pyridyl, cyclopropyl, cyclobutyl,

L ¹ 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-；

L ² Absent, or selected from

According to certain embodiments of the present invention, R in the compound of formula (I-A) ² Selected from methyl group,Ethyl, n-propyl, isopropyl, preferably R ² Selected from methyl;

R ³ selected from the group consisting of-F, -Cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, phenyl, pyridyl, cyclopropyl, cyclobutyl,

L ¹ Absent, or selected from-NH-, -N (CH) ₃ )-、-NH-CO-O-、-N(CH ₃ )-CO-O-；

L ² Absent, or selected from

According to certain embodiments of the present invention, in the compounds of formula (I-A), -L ¹ -L ² -R ³ Selected from the group consisting of

Undefined groups are as described in any of the previous schemes.

According to some embodiments of the invention, the compound of formula (I) is a compound of formula (I-B):

Wherein:

wherein:

R ³ selected from-H, -CN, halogen, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl;

the R is ^3a Selected from halogen, C _1-6 Alkyl, C _3-6 Cycloalkyl, halogen substituted C _1-6 An alkyl group;

L ² absent, or selected from unsubstituted or C _1-3 Alkyl substituted C _1-3 An alkylene group.

According to certain embodiments of the present invention, R in the compound of formula (I-B) ³ Selected from-H, -CN, -F, -Cl, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl radicals、C _4-8 Bridged cycloalkyl, phenyl, pyridinyl, undefined groups as described in any of the previous schemes.

According to certain embodiments of the present invention, R in the compound of formula (I-B) ³ Selected from-H, -CN, -F, -Cl, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, phenyl, pyridinyl, undefined groups as described in any of the previous schemes.

According to certain embodiments of the present invention, of the compounds of formula (I-B), L ² -R ³ Selected from the group consisting of n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl, fluoro-n-butyl, Undefined groups are as described in any of the previous schemes.

According to some embodiments of the invention, the compound of formula (I) is a compound of formula (I-C):

wherein R is ³ Selected from-H, -CN, halogen, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, C _4-8 Bridged cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl; the R is ^3a 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;

According to some embodiments of the invention, the compound of formula (I) is a compound of formula (I-D):

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According to some embodiments of the invention, the compound of formula (I) is a compound of formula (I-E):

wherein R is ³ Selected from-H, -CN, halogen, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, C _4-8 Bridged cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl;the R is ^3a 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;

According to some embodiments of the invention, the compound of formula (I) is a compound of formula (I-F):

According to some embodiments of the invention, the compound of formula (I) may be any of the following:

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in a second aspect of the present invention, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described above, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

In the pharmaceutical composition, the compound shown in the formula (I), or a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I) can be in a therapeutically effective dose.

In a third aspect of the application, the application also provides the use of a compound of formula (I) as described above, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease associated with LPAR.

In a fourth aspect of the application, there is provided a method of treating an LPAR-related disorder comprising the steps of: administering to a subject in need thereof a compound of formula (I) according to the first aspect of the application, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I), or a pharmaceutical composition according to the second aspect.

The LPAR-related disease is selected from the group consisting of fibrotic disease, tumor, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus.

The LPAR-related disease is selected from idiopathic pulmonary fibrosis, radiation pulmonary fibrosis, liver fibrosis, kidney fibrosis, tumor, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus'

Definition and description of terms

Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description.

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 herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.

Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectrometry and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present application. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH ₂ O is equal to OCH ₂ 。

Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both ends of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1, 2, 3, 4, 5, and 6. When a numerical range is understood as a "number," it is understood that both endpoints of the range are noted, as well as each integer within the range, and each fraction within the range. For example, a "number of 1 to 10" should be understood to describe not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

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.

In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers. The 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.

Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is 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 generally referred to as mixtures of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. Many geometric isomers of olefins, c=n double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, such double bonds include E and Z geometric isomers unless specified otherwise. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.

When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key.

Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. The compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of the racemic mixture of the compounds may be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active salified organic acid. Suitable resolving agents for use in the fractional recrystallisation process are, for example, D and L forms of optically active acids such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulphonic acids such as β -camphorsulphonic acid. Other resolving agents suitable for the fractional crystallization process include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methyl ephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Resolution of the racemic mixture may also be carried out by eluting on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC) may be used. The choice of the particular method and elution conditions, choice of chromatographic column can be selected by one skilled in the art based on the structure of the compound and the results of the assay. Further, any enantiomer or diastereomer of a compound described herein may also be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

For a drug or pharmacologically active agent, the terms "effective dose", "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

The term "solvate" refers to a compound of the invention or a salt thereof that includes a stoichiometric or non-stoichiometric solvent that binds with non-covalent intermolecular forces, and when the solvent is water, is a hydrate.

The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with radioisotopes, such as deuterium ² H) Tritium% ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.

The term "C _1-6 Alkyl "is understood to mean a straight-chain 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-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C ₁ -C ₃ Alkyl "), such as methyl, ethyl, n-propyl or isopropyl.

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.

The term "3-6 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated mono-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 mono-, bi-or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S. Unless otherwise indicated, they may be attached by carbon or nitrogen, where-CH _2- The radicals are optionally replaced by-C (O) -radicals; and wherein, unless otherwise indicated to the contrary, the ring nitrogen or ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein the-NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It will be appreciated that when the total number of S and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to one another. If the heterocyclic group is bicyclic or tricyclic, then The at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is a single ring, it must not be aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1, 1-dioxide, 1H-pyridin-2-one, and 2, 5-dioxoimidazolidinyl.

The term "5-8 membered heteroaryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 8 ring atoms, in particular 5 or 6 carbon atoms, and comprising 1 to 5 heteroatoms independently selected from N, O and S. Preferably 1 to 3-monovalent monocyclic, bicyclic or tricyclic aromatic ring groups independently selected from the heteroatoms of N, O and S, and additionally may be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

The term "bridged ring" refers to cyclic hydrocarbons in which any two rings in a compound share two carbon atoms that are not directly connected, and are classified into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, and the like, depending on the number of constituent rings. Non-limiting examples include:

the term "C _4-8 Bridged cycloalkyl "means a bridged ring having 4 to 8 carbon atoms, the bridged ring being as defined above.

The term "halo" or "halogen" is fluoro, chloro, bromo and iodo.

"haloalkyl" is meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more halogens (e.g., -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-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

Advantageous effects

According to a specific example of the present invention, the compounds of formula (I) of the present invention have good antagonism against LPAR1 as stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof.

According to a specific example of the present invention, the compounds of the present invention have good antagonism to LPAR1 and weak antagonism to LPAR3, i.e. the compounds of the present invention show excellent selectivity; the compound of the invention has better safety and no risk of cholestasis toxicity; the compound has excellent pharmacokinetic property and good patentability; the compound can obviously inhibit LPA-induced histamine release by antagonizing LPAR1, and can also obviously improve the pulmonary fibrosis symptoms of mice and rats induced by bleomycin.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Detailed Description

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Embodiments of the present invention provide compounds of formula (I), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, methods and intermediates for preparing compounds of formula (I), or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the invention in the manufacture of a medicament.

The reaction solvent used in each of the reaction steps described in the present invention is not particularly limited, and any solvent which dissolves the starting materials to some extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).

Liquid chromatography-mass spectrometry (LC-MS) was determined by a Waters acquisition H-class Uplc-QDA mass spectrometer and monitored using a ACQUITY UPLC BEH C, 2.1 x 50mm,1.7 μm 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 are maintained for 0.5min, the percentages being the volume percent of a certain solvent to the total solvent volume. Wherein solvent A1:0.1% formic acid in water; solvent B1: acetonitrile solution of 0.1% formic acid. The percentage is the volume percentage of solute in the solution.

Abbreviations for the present invention are defined as follows:

symbol or unit:

IC ₅₀ : half inhibition concentration, meaning the concentration at which half of the maximum inhibition effect is achieved

M: mol/L, for example n-butyllithium (14.56 mL,29.1mmol,2.5M in n-hexane) means an n-hexane solution of n-butyllithium at a molar concentration of 2.5mol/L

N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution

RT: retention time

Reagent:

DCM: dichloromethane (dichloromethane)

DIPEA: also written as DIEA, diisopropylethylamine, i.e. N, N-diisopropylethylamine

DMF: n, N-dimethylformamide

DMSO: dimethyl sulfoxide

EA: acetic acid ethyl ester

Et ₃ N: triethylamine

MeOH: methanol

PE: petroleum ether

THF: tetrahydrofuran (THF)

Test or detection methods:

HPLC: high performance liquid chromatography

SFC: supercritical fluid chromatography

Comparative example 1: control compound 1 and preparation thereof

Reference compound 1 was synthesized by reference to patent application WO2017223016 A1.

Comparative example 2: control compound 2 and preparation thereof

Reference compound 2 was synthesized by reference to patent application WO2017223016 A1.

Example 1: preparation of 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) 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 (target compound I-1)

The synthetic route for the target compound I-1 is shown below:

the first step: synthesis of (R) -4-nitrophenyl (1-phenylethyl) carbonate (I-1B)

(R)-4-nitrophenyl(1-phenylethyl)carbonate(I-1B)

To a solution of (R) -1-phenylethan-1-ol (0.5 g,4.09 mmol) in methylene chloride (10 mL) was slowly added 4-nitrophenylcarbyl chloride (0.99 g,8.03 mmol) and pyridine (0.647 g,8.19 mmol) at room temperature, reacted for 3 hours at room temperature, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-20:1) to give (R) -4-nitrophenyl (1-phenylethyl) carbonate (I-1B) (0.7 g, yield 59.5%) as a yellow solid.

LC-MS,M/Z(ESI):288.2[M+H] ⁺

And a second step of: synthesis of 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)

2-bromo-6-iodopyridin-3-ol (5 g,16.67 mmol), 2- (prop-2-yn-1-yloxy) tetrahydro-2H-pyran (2.34 g,16.67 mmol), cuprous iodide (317.53 mg,1.67 mmol), triethylamine (5.06 g,50.02 mmol) and bis (triphenylphosphine) palladium dichloride (1.17 g,1.67 mmol) were added to tetrahydrofuran (50 mL) at room temperature and reacted for 1 hour under nitrogen at room temperature. After completion of the reaction, 20mL of saturated brine was added to the reaction mixture, the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phase was washed with saturated brine (10 mL). Dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1-3:1) to give 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] ⁺

And a third step of: synthesis of 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)

2-bromo-6- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-ol (3.01 g,9.61 mmol), (1S, 3R) -3-hydroxycyclohexane-1-carboxylic acid methyl ester (2.28 g,14.42 mmol) and triphenylphosphine (5.04 g,19.22 mmol) were added to 30mL of anhydrous tetrahydrofuran at room temperature, cooled with ice water after nitrogen protection, and diisopropyl azodicarboxylate (3.89 g,19.22 mmol) was added dropwise at 0-10℃and reacted at 25℃for 3 hours. To the reaction mixture was added 30mL of saturated brine, which was extracted with ethyl acetate (30 mL. Times.3), and the organic phase was washed with saturated brine (10 mL). Dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1-4:1) to give methyl (1 s,3 s) -3- ((2-bromo-6- (3- (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (3.10 g, yield 71.3%).

Fourth step: synthesis of 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)

To a solution of methyl (1 s,3 s) -3- ((2-bromo-6- (3- (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (3 g,6.63 mmol) in N, N-dimethylformamide (30 mL) was added sodium azide (0.69 g,10.61 mmol) and the mixture was reacted at 100 ℃ under nitrogen for 24 hours at room temperature. After the reaction is finished, the reaction solution is filtered, and the filtrate is directly put into the next step.

Fifth step: synthesis of 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)

To a solution of methyl (1 s,3 s) -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 in N, N-dimethylformamide (30 mL) was added potassium carbonate (1.84 g,13.28 mmol), followed by methyl iodide (1.41 g,9.96 mmol) at 25 ℃ for 18 hours. 40mL of water was added to the reaction mixture, the mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phase was washed with saturated brine (10 mL). Dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1-3:1) to give methyl (1 s,3 s) -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 (500 mg, yield 14.6%).

Sixth step: synthesis of 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)

Methyl (1 s,3 s) -3- ((2-bromo-6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (400 mg,785.25 μmol), potassium phosphate (500.05 mg,2.36 mmol), 1-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (32.06 mg,39.26 μmol) and cyclopropylboronic acid (134.9 mg,1.57 mmol) were added to a solution of 1, 4-dioxane (6 mL) at 100 ℃ C. Under nitrogen protection for 16 hours. After the reaction, 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 give methyl (1 s,3 s) -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 (325 mg, yield 87.96%).

LC-MS,M/Z(ESI):471.4[M+H] ⁺

Seventh step: synthesis of 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)pyridi n-3-yl)oxy)cyclohexane-1-carboxylate(I-1I)

Methyl (1 s,3 s) -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 (550 mg,1.17 mmol) and pyridine p-toluenesulfonate (146.86 mg,584.41 μmol) were added to methanol (70 mL) at 65 ℃ for 3 hours at room temperature. After the reaction is finished, sodium bicarbonate (1 g) is added into the reaction solution to quench the reaction, and the reaction solution is 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 give methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (400 mg, yield 88.2%).

LC-MS,M/Z(ESI):387.3[M+H] ⁺

Eighth step: synthesis of 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)

Methyl (1S, 3S) -3- ((2-cyclopropyl-6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (500 mg,1.29 mmol) and diphenyl azide phosphate (712.13 mg,2.59 mmol) were added to tetrahydrofuran (8 mL) at room temperature, the reaction mixture was cooled by ice bath, and 1, 8-diazabicyclo undec-7-ene (393.94 mg,2.59 mmol) was added at 0-10℃and reacted at 0-25℃for 6 hours. After the reaction was completed, the reaction mixture was separated by a preparative plate (petroleum ether: ethyl acetate (V/V) =1:1) to give methyl (1 s,3 s) -3- ((6- (5- (azidomethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (480 mg, yield 90.2%).

Ninth step: synthesis of 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)

Methyl (1 s,3 s) -3- ((6- (5- (azidomethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (410 mg, 859.16. Mu. Mol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1 mL), triphenylphosphine (450.69 mg,1.72 mmol) was added to the reaction solution, and the mixture was stirred at 25 ℃ for 2 hours. After the reaction, the reaction mixture was concentrated to give a crude (1S, 3S) -3- ((6- (5- (aminomethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate.

LC-MS,M/Z(ESI):386.3[M+H] ⁺

Tenth step: synthesis of 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)meth yl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-1L)

(1S, 3S) -3- ((6- (5- (aminomethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (331.17 mg, 859.16. Mu. Mol) and triethylamine (86.94 mg, 859.16. Mu. Mol) were added to tetrahydrofuran (10 mL) at room temperature, and (R) -4-nitrophenyl (1-phenylethyl) carbonate (I-1B) (493.62 mg,1.72 mmol) was added to the reaction solution, followed by stirring at 25℃for 2 hours. After the reaction is completed, the reaction solution is 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 give methyl (1 s,3 s) -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) (450 mg, two step yield 98.1%).

LC-MS,M/Z(ESI):534.5[M+H] ⁺

Eleventh step: synthesis of (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

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-yloxy) cyclohexane-1-carboxylate (I-1L) (450 mg, 843.3. Mu. Mol) was added to tetrahydrofuran (6 mL) and water (2 mL), and lithium hydroxide monohydrate (141.55 mg,3.37 mmol) was added to the reaction mixture, followed by stirring at 25℃for 3 hours. After the reaction, the pH was adjusted to 3 to 4 with 1M hydrochloric acid, extracted with methylene chloride (20 mL. Times.3), and concentrated to give a crude product. The crude product was isolated and purified by prep. plate (petroleum ether: ethyl acetate (V/V) =1:1) to give (1 s,3 s) -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) (389.67 mg, yield 87.5%).

LC-MS,M/Z(ESI):520.3[M+H] ⁺

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)。

Example 2: preparation of 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 (target compound I-2)

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (propyl) carbamyl) oxy) methyl) -1H-1,2, 3-tr-iazole-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-2)

The synthetic route for the target compound I-2 is shown below:

the first step: preparation of methyl (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-carboxylate (I-2A)

(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methy l)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-2A)

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To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-1I) (500 mg,1.29 mmol) and pyridine (307 mg,3.88 mmol) in dichloromethane (5.00 mL) at 0 ℃ was added (4-nitrophenyl) carbonyl chloride (521 mg,2.59 mmol) and the reaction stirred at 25 ℃ for 2 hours. After completion of the reaction, the reaction was quenched with water (10.0 mL), the mixture was extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride (10.0 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to give methyl (I-2A) (700 mg, crude) cyclohexane-1-carboxylate (1, 3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) as a yellow oily crude compound, which was used directly in the next step.

LC-MS,M/Z(ESI):552.2[M+H] ⁺

And a second step of: synthesis of 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)

Methyl (1 s,3 s) -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-carboxylate (I-2A) (356 mg,645.46 μmol) and triethylamine (195.9 mg,1.94 mmol) were added to dichloromethane (6 mL) and after complete dissolution N-methylpropan-1-amine (141.62 mg,1.94 mmol) was added and stirred at 25 ℃ for 2H. After completion of the reaction, water (10 mL) was added to the reaction mixture to dilute it, dichloromethane (15 ml×3) was used to extract it, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified (petroleum ether: ethyl acetate=10:1-4:1) on a silica gel column to give methyl (I-2B) (280 mg, 89.3% yield) of the white solid compound (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (propyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) oxy) pyridin-3-yloxy) cyclohexane-1-carboxylate.

LC-MS,M/Z(ESI):486.5[M+H] ⁺ 。

And a third step of: synthesis of (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)

Methyl (1 s,3 s) -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) (275 mg,566.3 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), lithium hydroxide monohydrate (118.83 mg,2.83 mmol) was added and reacted for 12H at 25 ℃. After the reaction, the pH of the reaction mixture was adjusted to 3 to 4 with 1M hydrochloric acid at 0 to 10℃and extracted with methylene chloride (15 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was separated by reverse phase hplc (separation method: column Phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: solvent a=water+0.225 vol% formic acid, solvent b=acetonitrile; gradient: B% =40% -70%,10 min), then chiral chromatography was used to separate ((column: DAICEL CHIRALCEL OD (250 mm x 30mm,10 um)), mobile phase: solvent a=isopropanol+0.1 vol% aqueous ammonia, solvent b=supercritical carbon dioxide; gradient: B% =40% -40%, cyclic injection, once every 2.7 min) to give compound (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (propyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-2) (68.83 mg, yield 25.4%).

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] ⁺

Example 3: preparation of 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 (target compound I-3)

(1S, 3S) -3- ((6- (5- (((methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopropyleyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-3)

The synthetic route for the target compound I-3 is shown below:

the first step: synthesis of tert-butyl (cyclobutylmethyl) carbamate (I-3B)

tert-butyl(cyclobutylmethyl)carbamate(I-3B)

Cyclobutylmethylamine (500 mg,5.87 mmol) and triethylamine (1.31 g,12.92mmol,1.80 mL) were dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (1.28 g,5.87mmol,1.35 mL) was added to the reaction solution under nitrogen protection, and the reaction solution was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was directly concentrated to obtain crude t-butyl (cyclobutylmethyl) carbamate (I-3B) (780 mg, crude).

And a second step of: synthesis of tert-butyl (cyclobutylmethyl) (methyl) carbamate (I-3C)

tert-butyl(cyclobutylmethyl)(methyl)carbamate(I-3C)

Sodium hydrogen (259.07 mg,6.48mmol,60% content) was suspended in tetrahydrofuran (8 mL), then tert-butyl (cyclobutylmethyl) carbamate (600 mg,3.24 mmol) was added dropwise thereto under nitrogen protection at 0 ℃, after which the reaction solution was stirred at 0 ℃ for 1 hour, kept under nitrogen protection at 0 ℃, methyl iodide (689.53 mg,4.86mmol,302.4 μl) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude t-butyl (cyclobutylmethyl) (methyl) carbamate (I-3C) (645.43 mg, crude).

And a third step of: synthesis of 1-cyclobutyl-N-methyl-methylamine hydrochloride (I-3D)

1-cyclobutyl-N-methylmethanamine hydrochloride(I-3D)

Tert-butyl (cyclobutylmethyl) (methyl) carbamate (I-3C) (645.43 mg,3.24 mmol) was dissolved in methylene chloride (10 mL), and a 1, 4-dioxane solution (4M, 3.24 mL) of hydrogen chloride was added dropwise to the reaction solution under nitrogen at 0℃and then reacted at 25℃for 12 hours. After the completion of the reaction, the reaction solution was directly concentrated to give crude 1-cyclobutyl-N-methyl methylamine hydrochloride (I-3D) (580 mg, crude).

Fourth step: synthesis of 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)

Methyl (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-carboxylate (1-2A) (400 mg, 725.23. Mu. Mol) and 1-cyclobutyl-N-methyl methylamine hydrochloride (143.85 mg, 1.06. Mu. Mol) were dissolved in tetrahydrofuran (3.0 mL), N-diisopropylethylamine (234.33 mg,1.81mmol, 315.8. Mu.L) was added dropwise to the reaction mixture under nitrogen protection, and then reacted at 25℃for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture to dilute it, and then ethyl acetate (10 ml×3) was used to extract it, and the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to give crude (1 s,3 s) -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) (350 mg, crude).

LC-MS,M/Z(ESI):512.3[M+H] ⁺

Fifth step: synthesis of (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)

Methyl (1 s,3 s) -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 (223 mg, 435.88. Mu. Mol) and lithium hydroxide monohydrate (182.91 mg,4.36 mmol) were dissolved in tetrahydrofuran (3 mL) and water (0.6 mL) and reacted with stirring at 25 ℃ for 12 hours. After the reaction was completed, the crude product was separated by reverse phase high performance liquid chromatography (separation method: column Phenomenex Synergi C18:150:25:10 um; mobile phase: solvent a=water+0.225% formic acid, solvent b=acetonitrile; gradient: B%:45% -75%,10 min) to give (1 s,3 s) -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] ⁺

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).

Example 4: preparation of 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 (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 (target compound I-4)

The synthetic route for the target compound I-4 is shown below:

the first step: synthesis of tert-butyl (R) - (1-cyclopropylethyl) carbamate (I-4B)

tert-butyl(R)-(1-cyclopropylethyl)carbamate(I-4B)

Isopropyl cyclopropane hydrochloride (500 mg,4.11 mmol) and triethylamine (915.30 mg,9.05mmol,1.26 mL) were dissolved in methylene chloride (5 mL) at room temperature, and di-tert-butyl dicarbonate (897.34 mg,4.11mmol, 944.57. Mu.L) was added to the reaction solution under nitrogen protection, and the reaction solution was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was directly concentrated to obtain crude t-butyl (R) - (1-cyclopropylethyl) carbamate (I-4B) (600 mg, crude).

And a second step of: synthesis of tert-butyl (R) - (1-cyclopropylethyl) (methyl) carbamate (I-4C)

tert-butyl(R)-(1-cyclopropylethyl)(methyl)carbamate(I-4C)

Sodium hydrogen (259.07 mg,6.48mmol,60% content) was suspended in tetrahydrofuran (8 mL), then a crude t-butyl (R) - (1-cyclopropylethyl) carbamate (600 mg,3.24 mmol) was added dropwise thereto under nitrogen protection at 0 ℃, after which the reaction solution was stirred at 0 ℃ for 1 hour, and then methyl iodide (689.53 mg,4.86mmol,302.4 μl) was added dropwise to the reaction solution under nitrogen protection at 0 ℃. The reaction was stirred at room temperature overnight. After completion of the reaction, water (10 mL) was added to the reaction mixture to dilute it, and then ethyl acetate (10 mL. Times.3) was used to extract it, and the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude t-butyl (R) - (1-cyclopropylethyl) (methyl) carbamate (I-4C) (1 g, crude).

And a third step of: synthesis of (R) -1-cyclopropyl-N-methylethan-1-amine hydrochloride (I-4D)

(R)-1-cyclopropyl-N-methylethan-1-amine hydrochloride(I-4D)

Tert-butyl (R) - (1-cyclopropylethyl) (methyl) carbamate (1 g,5.02 mmol) was dissolved in methylene chloride (10 mL), and a 1, 4-dioxane solution (4M, 5.02 mL) of hydrogen chloride was added dropwise to the reaction solution under nitrogen at 0℃and then reacted at 25℃for 12 hours. After the completion of the reaction, the reaction mixture was directly concentrated to give crude (R) -1-cyclopropyl-N-methylethan-1-amine hydrochloride (I-4D) (577 mg, crude).

Fourth step: synthesis of 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)met hyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-4E)

Methyl (1 s,3 s) -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-carboxylate (I-2A) (400 mg,725.23 μmol) and (R) -1-cyclopropyl-N-methylethylamine hydrochloride (143.85 mg,1.45 mmol) were dissolved in tetrahydrofuran (3.0 mL), and N, N-diisopropylethylamine (234.33 mg,1.81mmol,315.8 μl) was added dropwise to the reaction solution under nitrogen protection, followed by reaction at 25 ℃ for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture to dilute it, which was extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude (1 s,3 s) -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 methyl ester (I-4E) (350 mg).

LC-MS,M/Z(ESI):512.1[M+H] ⁺

Fifth step: (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)

Methyl (1 s,3 s) -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) (260 mg,508.20 μmol) and lithium hydroxide monohydrate (213.26 mg,5.08 mmol) were dissolved in tetrahydrofuran (3 mL) and water (0.6 mL) and reacted with stirring at 25 ℃ for 12 hours. After the reaction was completed, the crude product was separated by reverse phase high performance liquid chromatography (separation method: column Phenomenex Synergi C: 150: 25 um; mobile phase: solvent a=water+0.225 vol% formic acid, solvent b=acetonitrile; gradient: B% =43% -73%,10 min) to give (1 s,3 s) -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) (19.64 mg, yield 7.6%).

LC-MS,M/Z(ESI):498.2[M+H] ⁺

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).

Example 5: preparation of 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 (target compound I-5)

(1S, 3S) -3- ((6- (5- (((methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cy clopropylpyridin-3-yl) oxy) cyclohexane-1-carboxilic acid (target compound I-5)

The synthetic route for the target compound I-5 is shown below:

the first step: synthesis of 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-y l)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-5A)

To a mixture of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-2A) (350 mg,634 μmol) and N-methylbutan-1-amine (110 mg,1.27 mmol) in tetrahydrofuran (4.00 mL) was added diisopropylethylamine (205 mg,1.59mmol,276 μl) at room temperature, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (10.0 mL), extracted with ethyl acetate (10.0 mL), and the organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to give crude (1 s,3 s) -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) (250 mg).

LC-MS,M/Z＝500.2[M+H] ⁺

And a second step of: synthesis of (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)

To a solution of methyl (1 s,3 s) -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 (250 mg, 500. Mu. Mol) in methanol (2 mL) was added a solution of lithium hydroxide monohydrate (83.9 mg,2 mmol) in water (0.5 mL), and the mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was adjusted to pH 4 with 0.5M hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentratedObtaining a crude product. The crude product was purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a=water+0.225 vol% formic acid, solvent b=acetonitrile; gradient: B%:43% -73%,15 min) and separated by SFC (column: DAICEL CHIRALCEL OD (250 mm x 30mm,10 um); mobile phase: solvent a=methanol+0.1% nh) ₃ H ₂ O; solvent B = 30% -30% carbon dioxide, 3.7min;40 min) was 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) (89.2 mg, 174. Mu. Mol, yield 34.8%).

LC-MS,M/Z(ESI)：486.4[M+H] ⁺

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).

Example 6: preparation of 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 (target compound I-6)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((4-fluoro) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-6)

The synthetic route for the target compound I-6 is shown below:

the first step: synthesis of 4- ((tert-butoxycarbonyl) (methyl) amino) butyl 4-methylbenzenesulfonate (I-6B)

4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate(I-6B)

To a solution of 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 (578 mg,2.56 mmol) at room temperature, and the reaction was stirred at 25℃for 1 hour. Para-toluenesulfonyl chloride (488 mg,2.56 mmol) was added to the reaction solution, which was stirred at 25℃for 11 hours. The reaction mixture was quenched with water (5 mL), extracted 3 times with methylene chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-methylbenzenesulfonic acid 4- ((tert-butoxycarbonyl) (methyl) amino) butyl ester (I-6B) (700 mg, 783. Mu. Mol, yield 33%) as a yellow oily liquid.

And a second step of: synthesis of tert-butyl (4-fluorobutyl) (methyl) carbamate (I-6C)

tert-butyl(4-fluorobutyl)(methyl)carbamate

To a solution of 4- ((tert-butoxycarbonyl) (methyl) amino) butyl 4-methylbenzenesulfonate (I-6B) (700 mg,1.96 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added tetrabutylammonium fluoride (1M, 3.92 mL), and the reaction solution was stirred at 60℃for 16 hours. The reaction solution was directly concentrated to obtain a residue. The residue was purified by prep. plate (petroleum ether: ethyl acetate=5:1) to give tert-butyl (4-fluorobutyl) (methyl) carbamate (I-6C) as a yellow oily liquid (200 mg,974 μmol, yield 49.8%).

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)

And a third step of: synthesis of 4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D)

4-fluoro-N-methylbutan-1-amine hydrochloride(I-6D)

To a solution of tert-butyl N- (4-fluorobutyl) -N-methylcarbamate (180 mg, 876. Mu. Mol) in ethyl acetate (2 mL) at 0deg.C was added ethyl acetate hydrochloride solution (4M, 3 mL) and stirred at 25deg.C for 0.5 h. The reaction solution was concentrated under reduced pressure to give 4-fluoro-N-methylbutan-1-amine hydrochloride (I-6D) as a yellow oily liquid (120 mg).

Fourth step: synthesis of methyl (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) cyclohexanecarboxylate (I-6E)

(1S,3S)-methyl 3-((2-cyclopropyl-6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-m ethyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-6E)

To a solution of 4-fluoro-N-methyl-butan-1-amine (77.0 mg, 543.9. Mu. Mol) and ethyldiisopropyls (234.3 mg,1.81 mmol) in tetrahydrofuran (4 mL) was added methyl (1 s,3 s) -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-carboxylate (I-2A) (200 mg, 362. Mu. Mol) at room temperature, and the reaction solution was stirred at 25 ℃ for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was prepared from the plate (petroleum ether: ethyl acetate=1:1) to give methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((4-fluorobutyl) (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-6E) (105 mg,202 μmol, yield 55.9%)

LC-MS,M/Z(ESI)：518.4[M+H] ⁺

Fifth step: synthesis of (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)

To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((4-fluorobutyl) (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (105 mg,202 μmol) in methanol (2 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (42.5 mg,1.01 mmol), and the mixture was stirred at 25 ℃ for 12 hours. The pH was adjusted to 3 with 1M hydrochloric acid and extracted with ethyl acetate (3 mL. Times.4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase hplc (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: solvent a = water + 0.225% v/v formic acid, solvent B = acetonitrile; gradient: B% = 8% -68% for 15 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((4-fluorobutyl) (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (I-6) (48.8 mg,94.97 μmol, yield 46.82%).

LC-MS,M/Z(ESI)：504.4[M+H] ⁺

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).

Example 7: preparation of 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 (target compound I-7)

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (pentyl) carbamoyl) oxy) methyl) -1H-1,2, 3-tr-iazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-7)

The synthetic route for the target compound I-7 is shown below:

the first step: synthesis of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (amyl) carbamoyl) oxy) methyl))) -1H-1,2, 3-triazol-4-pyridinyl-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)

To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-2A) (150 mg,271.96 μmol) and N-methylpentan-1-amine (55.04 mg,543.92 μmol) in tetrahydrofuran (2.00 mL) was added diisopropylethylamine (87.87 mg,679.90 μmol,118.43 μl) and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (5.00 mL) was added to dilute, and extracted with ethyl acetate (5.00 mL), and the organic phase was washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to give methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (pentyl) carbamoyl) oxy) methyl))) -1H-1,2, 3-triazol-4-pyridinyl-3-yloxy) cyclohexanecarboxylate (I-7B) (90.0 mg) as a crude product.

LC-MS,M/Z(ESI)＝514.3[M+H] ⁺

And a second step of: synthesis of (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)

To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (amyl) carbamoyl) oxy) methyl))) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-7B) (90.0 mg,175.22 μmol) in tetrahydrofuran (2.00 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (73.53 mg,1.75 mmol) at room temperature, and the mixture was stirred overnight at room temperature. After the reaction, the reaction solution was concentrated to obtain a crude product, and the crude product was separated and purified by reverse phase high performance liquid chromatography (separation method: chromatographic column: phenomenex Synergi C18:150:25:10 um; mobile phase: solvent a=water+0.225 vol% formic acid, solvent b=acetonitrile; gradient: B% =43% -76%,20 minutes) to obtain (1 s,3 s) -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] ⁺

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).

Example 8: preparation of 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 (target compound I-8)

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((S) -2-methyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) cyclohexanecarboxylic acid (target compound I-8)

The synthetic route for the target compound I-8 is shown below:

the first step: synthesis of tert-butyl (S) - (2-methylbutyl) carbamate (I-8B)

(S)-tert-butyl(2-methylbutyl)carbamate(I-8B)

Cyclobutylmethylamine (360 mg,4.13 mmol) and triethylamine (501.52 mg,4.96mmol, 689.84. Mu.L) were dissolved in dichloromethane (5 mL), and di-tert-butyl dicarbonate (901.40 mg,4.13mmol, 948.85. Mu.L) was added to the reaction solution under nitrogen, and the reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction solution was directly concentrated to obtain crude t-butyl (S) - (2-methylbutyl) carbamate (I-8B) (773.5 mg).

And a second step of: synthesis of tert-butyl (S) - (2-methylbutyl) carbamate (I-8C)

(S)-tert-butyl methyl(2-methylbutyl)carbamate(I-8C)

Sodium hydrogen (330.39 mg,8.26mmol,60% purity) was suspended in tetrahydrofuran (8 mL), then tert-butyl (S) - (2-methylbutyl) carbamate (I-8B) (773.50 mg,4.13 mmol) was added dropwise thereto under nitrogen protection at zero degree, after which the reaction solution was stirred at 0℃for 1 hour, and then methyl iodide (879.35 mg,6.20mmol, 385.68. Mu.L) was added dropwise thereto under nitrogen protection at zero degree, and the reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to give crude t-butyl (S) - (2-methylbutyl) carbamate (I-8C) (831.43 mg).

And a third step of: synthesis of (S) -N, 2-dimethylbut-1-amine hydrochloride (I-8D)

(S)-N,2-dimethylbutan-1-amine hydrochloride(I-8D)

Tert-butyl (S) - (2-methylbutyl) carbamate (831.43 mg,4.13 mmol) was dissolved in methylene chloride (10 mL), dioxane hydrochloride (4M, 4.13 mL) was added dropwise to the reaction solution under nitrogen at 0℃and then reacted at 25℃for 12 hours. After completion of the reaction, the reaction mixture was directly concentrated to give crude (S) -N, 2-dimethylbutyl-1-amine hydrochloride (I-8D) (417.93 mg).

Fourth step: synthesis of 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)

Methyl (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) cyclohexanecarboxylate (I-2A) (150 mg, 271.96. Mu. Mol) and (S) -N, 2-dimethylbutyl-1-amine hydrochloride (93.59 mg, 679.91. Mu. Mol) were dissolved in tetrahydrofuran (0.5 mL), N-diisopropylethylamine (123.02 mg, 951.87. Mu. Mol, 165.80. Mu. L) was added dropwise to the reaction mixture under nitrogen, followed by reaction at 25℃for 2 hours. After the completion of the reaction, the reaction solution was separated and purified by a preparative plate (petroleum ether: ethyl acetate=1:1) to give 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) (77 mg, yield 55.1%).

LC-MS,M/Z(ESI):514.3[M+H] ⁺

Fifth step: synthesis of (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)

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-yloxy) cyclohexane-1-carboxylate (77 mg, 149.91. Mu. Mol) and lithium hydroxide monohydrate (62.91 mg,1.50 mmol) were dissolved in tetrahydrofuran (1 mL) and water (0.2 mL) and reacted with stirring at 25℃for 12 hours. After the reaction was completed, the crude product was separated by reverse phase high performance liquid chromatography (separation method: column Phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: solvent a=water+0.225% formic acid (volume), solvent b=acetonitrile; gradient: B% =47% -77%,15 min) to give ((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 (I-8) (24.95 mg, yield 33.31%).

LC-MS,M/Z(ESI):500.4[M+H] ⁺

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).

Example 9: preparation of 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 (target compound I-9)

(1S, 3S) -3- ((6- (5- (((methyl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopropyleyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-9)

The synthetic route for the target compound I-9 is shown below:

the first step: synthesis of (4-nitrophenyl) butyl carbonate (I-9B)

butyl(4-nitrophenyl)carbonate(I-9B)

To a solution of n-butanol (500 mg,6.75mmol, 617.28. Mu.L) and pyridine (1.60 g,20.24mmol,1.63 mL) in methylene chloride (5.00 mL) at 0deg.C was added 4-nitrophenylcarbyl chloride (2.72 g,13.49 mmol), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water (5.00 mL) and a saturated aqueous sodium chloride solution (5.00 mL), and the organic phase was dried over anhydrous sodium sulfate, and concentrated by filtration to give crude (4-nitrophenyl) butyl carbonate (I-9B) (500 mg).

And a second step of: synthesis of methyl (1S, 3S) -3- ((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)

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To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (hydroxymethyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-1I) (300 mg,776 μmol) in dichloromethane (5.00 mL) was slowly added in portions dessert-martin oxidant (578mg, 1.55 mmol) and the reaction stirred at 25 ℃ for 2 hours. After the completion of the reaction, the reaction solution was concentrated by filtration to give a crude product, which was prepared by chromatography on a silica gel plate (silica, petroleum ether: ethyl acetate=1:1) to give methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9C) (150 mg, 383. Mu. Mol, yield 49.4%, purity 98.3%) as a white solid.

LC-MS,M/Z(ESI):385.1[M+H] ⁺

And a third step of: synthesis of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- ((methylamino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (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)

To a solution of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (5-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexanecarboxylate (I-9C) (180 mg, 468.23. Mu. Mol) and methylamine hydrochloride (66.56 mg, 936.46. Mu. Mol) in methanol (3.00 mL) at 0deg.C was added sodium borohydride acetate (248.09 mg,1.17 mmol), and the reaction was stirred at room temperature overnight. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was isolated and purified (purification method: petroleum ether: ethyl acetate=1:1) using a preparative plate to give methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((methylamino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9D) (180 mg,352.35 μmol, yield 75.25%).

LC-MS,M/Z(ESI)＝400.2[M+H] ⁺

Fourth step: synthesis of methyl (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-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)

To a solution of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- ((methylamino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (90.0 mg, 225.29. Mu. Mol) and (4-nitrophenyl) butyl carbonate (107.79 mg, 450.58. Mu. Mol) in tetrahydrofuran (1.00 mL) was added diisopropylethylamine (72.79 mg, 563.22. Mu. Mol, 98.10. Mu.L) and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was isolated and purified (purification method: petroleum ether: ethyl acetate=1:1) using a preparative plate to give methyl (1 s,3 s) -3- ((6- (5- (((butoxycarbonyl) (methyl) amino) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9E) (80.0 mg, 160.13. Mu. Mol, yield 71.08%).

LC-MS,M/Z(ESI)＝500.2[M+H] ⁺

Fifth step: synthesis of (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 (target compound I-9)

To a solution of methyl (1 s,3 s) -3- ((6- (5- (((butoxycarbonyl) (methyl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9E) (80.0 mg,160.13 μmol) in tetrahydrofuran (1.50 mL) and water (0.40 mL) at room temperature was added lithium hydroxide monohydrate (67.20 mg,1.60 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was concentrated to a crude product, and the crude product was purified by high performance liquid chromatography (separation method: chromatographic column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: solvent a=water+0.225% formic acid (volume), solvent b=acetonitrile; gradient: B% =43% -76%,15 min) to give (1 s,3 s) -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] ⁺

¹ H NMR (400 mhz, chromarm-d) delta 7.95 (d, j=8.5 hz, 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). Example 10: preparation of 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) cyclohexane-1-carboxylic acid (target compound I-10)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((4-fluoro) carbonyl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-10)

The synthetic route for the target compound I-10 is shown below:

the first step: synthesis of 4-fluorobutyl carbonate (4-nitrophenyl) (I-10B)

4-fluorobutyl(4-nitrophenyl)carbonate(I-10B)

To a solution of 4-fluorobut-1-ol (200 mg,2.17mmol, 617.28. Mu.L) and pyridine (429.37 mg,5.43mmol, 438.13. Mu.L) in methylene chloride (5.00 mL) at 0deg.C was added 4-nitrophenylcarbyl chloride (656.48 mg,3.26 mmol), and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water (5.00 mL) and a saturated aqueous sodium chloride solution (5.00 mL), and the organic phase was dried over anhydrous sodium sulfate, and concentrated by filtration to give crude 4-fluorobutyl carbonate (4-nitrophenyl) (I-10B) (350 mg).

And a second step of: synthesis of methyl (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) 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)

To a solution of (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- ((methylamino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9D) (100 mg, 250.32. Mu. Mol) and 4-fluorobutyl carbonate (4-nitrophenyl) (I-10B) (128.77 mg, 500.64. Mu. Mol) in tetrahydrofuran (1.00 mL) was added diisopropylethylamine (80.88 mg, 625.80. Mu. Mol, 109.00. Mu. L) and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was isolated and purified (purification method: petroleum ether: ethyl acetate=1:1) using a preparative plate to give methyl (1 s,3 s) -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-carboxylate (I-10C) (80.0 mg, 154.56. Mu. Mol, yield 61.75%).

LC-MS,M/Z(ESI)＝518.3[M+H] ⁺

Fourth step: synthesis of (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)

To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((4-fluorobutoxy) carbonyl) (methyl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-10C) (80.0 mg,154.56 μmol) in tetrahydrofuran (1.50 mL) and water (0.40 mL) at room temperature was added lithium hydroxide monohydrate (64.86 mg,1.55 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction, the reaction solution was concentrated to obtain a crude product, and the crude product was separated and purified by reverse phase liquid phase high performance chromatography (separation method: chromatographic column: phenomenex Synergi C18:150:25:10 um; mobile phase: solvent a=water+0.225% formic acid, solvent b=acetonitrile; gradient: B% =41% -71%,20 min) to obtain (1 s,3 s) -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] ⁺

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).

Example 11: preparation of 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 (target compound I-11)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((4-isopropyl-2-yl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-11)

The synthetic route for the target compound I-11 is shown below:

the first step: synthesis of methyl (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-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)

To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-9C) (70.0 mg,182 μmol) and 4-isopropylpyrimidin-2-amine (37.4 mg,273 μmol) in methanol (1.00 mL) at room temperature was added glacial acetic acid (21.8 mg,364 μmol), the reaction solution was stirred at 60 ℃ for 6 hours and then cooled to 25 ℃, and sodium cyanoborohydride (22.8 mg,364 μmol) was added to the reaction solution, and the reaction solution was further stirred at 25 ℃ for 12 hours. After completion of the reaction, quenched with water (5.0 mL), extracted with ethyl acetate (5.00 mL), and the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl (I-11B) (120 mg, crude) as a yellow oil, (1 s,3 s) -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-carboxylate (120 mg, crude) which was used directly in the next step.

LC-MS,M/Z(ESI):506.3[M+H] ⁺

And a second step of: synthesis of (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)

Methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (((4-isopropylpyrimidin-2-yl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (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 ℃ for 12 hours. After the reaction was completed, the reaction solution was pH-adjusted to 3-4 with 1M hydrochloric acid at 0-10 ℃, then extracted with dichloromethane, and the organic phase was concentrated to give a crude product, which was purified by reverse phase hplc (column Phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a=water+0.225 vol% formic acid, solvent b=acetonitrile; gradient: B% =39% -72%,11 min), then resolved by chiral column (column AICEL CHIRALCEL OD (250 mm x 30mm,10 um), mobile phase: solvent a=0.1% ammonia+isopropanol, solvent b=supercritical carbon dioxide, gradient: B% =40% -40%, once every 3.8 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (((4-isopropylpyrimidin-2-yl) amino) methyl) -1H-1,2, 3-triazol-4-yl) oxy) cyclohexane-1-carboxylic acid (target compound) (11.5 mg, yield, 46.8 mg).

LC-MS,M/Z(ESI):492.5[M+H] ⁺

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).

Example 12: preparation of 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 (target compound I-12)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- ((4- (cyclopropylethyl) -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)

The synthetic route for the target compound I-12 is shown below:

the first step: synthesis of methyl (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-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) -3- ((6- (5- (azidomethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-1J) (210 mg,510. Mu. Mol), (3-cyclopropylprop-1-yn-1-yl) trimethylsilane (388.68 mg,2.55 mmol), copper sulfate (81.46 mg, 510.38. Mu. Mol) and sodium L-ascorbate (101.11 mg, 510.38. Mu. Mol) were added to tetrahydrofuran (3.0 mL) and water (1.0 mL) at room temperature and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was quenched with water (15.0 mL), extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1 to 2:1) to give methyl (I-12B) (220 mg, yield 87.7%) of compound (1 s,3 s) -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-carboxylate as a white solid.

LC-MS,M/Z(ESI):492.5[M+H] ⁺

And a second step of: synthesis of (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 (target Compound I-12)

Methyl (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-carboxylate (I-12B) (210 mg, 427.19. Mu. Mol) was dissolved in tetrahydrofuran (3.0 mL) and water (1.0 mL) at room temperature, and lithium hydroxide monohydrate (107.55 mg,2.56 mmol) was added thereto, and the mixture was stirred at 25℃for 10 hours. After the reaction is completed, the pH of the reaction solution is adjusted to 3-4 by 1N hydrochloric acid at 0-10 ℃, dichloromethane is used for extraction, and the organic phase is concentrated to obtain a crude product. The crude product was purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a = water + 0.225% formic acid by volume, solvent B = acetonitrile; gradient: B% = 38% -68%,10 min) followed by chiral resolution (column: AICEL CHIRALCEL OD (250 mm x 30mm,10 um), mobile phase: solvent a = 0.1% ammonia + isopropanol, solvent B = supercritical carbon dioxide, gradient: B% = 35% -35%, continuous injection, once every 4.0 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((4- (cyclopropylmethyl) -1H-1,2, 3-triazol-1-yl) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) oxy) pyridin-3-yl) cyclohexane-1-carboxylic acid (I-12) (70.3 mg,33.5% yield.

LC-MS,M/Z(ESI):478.1[M+H] ⁺

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).

Example 13: preparation of 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 (target compound I-13)

(1S, 3S) -3- ((6- (5- (((5- (cyclyl methyl) -1,2, 4-oxadizol-3-yl) amino) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cycl opyrropyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-13)

The synthetic route for the target compound I-13 is shown below:

the first step: synthesis of methyl (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-carboxylate (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)

To a solution of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (5-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9C) (130 mg, 338. Mu. Mol) and 5- (cyclobutylmethyl) -1,2, 4-oxadiazol-3-amine (77.7 mg, 507. Mu. Mol) in methanol (1.50 mL) was added glacial acetic acid (40.6 mg, 676. Mu. Mol) at room temperature, the reaction was stirred at 60℃for 12 hours and then cooled to 25℃and sodium cyanoborohydride (42.5 mg, 676. Mu. Mol) was added and the reaction was stirred at 25℃for 12 hours. After completion of the reaction, the reaction was quenched with water (5.00 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 the crude compound, methyl (I-13B) (140 mg, crude) cyclohexane-1-carboxylate (1 s,3 s) -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) methyl ester (140 mg, crude) which was used directly in the next step.

LC-MS,M/Z(ESI):522.2[M+H] ⁺

And a second step of: synthesis of (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)

(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. Mu. Mol) was dissolved in tetrahydrofuran (3.0 mL) at room temperature, then water (1.0 mL) and lithium hydroxide monohydrate (5.51 mg,1.32 mmol) were added thereto, and the mixture was stirred at 25℃for 12 hours. After the reaction is completed, the pH of the reaction solution is adjusted to 3-4 by 1N hydrochloric acid at 0-10 ℃, then dichloromethane extraction is carried out, and the organic phase is concentrated to obtain a crude product. The crude product was then purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a = water + 0.225% formic acid by volume, solvent B = acetonitrile; gradient: B% = 46% -76%,11 min), followed by chiral resolution (column: AICEL CHIRALCEL OD (250 mm x 30mm,10 um), mobile phase: solvent a = 0.1% ammonia + isopropanol, solvent B = supercritical carbon dioxide, gradient: B% = 39% -72%, continuous injection once every 3.8 min) to give (1 s,3 s) -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, 34.2%).

LC-MS,M/Z(ESI):508.5[M+H] ⁺

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).

Example 14: preparation of 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) 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 (target compound I-14)

The synthetic route for the target compound I-14 is shown below:

the first step: synthesis of (S) -4-nitrophenyl pent-2-ylcarbonate (I-14B)

(S)-4-nitrophenyl pentan-2-yl carbonate(I-14B)

(R) -pentan-2-ol (300 mg,3.40 mmol) and pyridine (803 mg,10.2 mmol) were added to dichloromethane (5.00 mL) at room temperature, then 4-nitrophenylcarbyl chloride (685 mg,3.40 mmol) was slowly added at 0-10℃and after the addition was completed, stirring was carried out at room temperature for 2.0 hours, and the reaction mixture was prepared by column chromatography (petroleum ether: ethyl acetate (V/V) =50:1 to 20:1) to give (S) -4-nitrophenylcarbon-pentan-2-yl carbonate (I-14B) (600 mg, yield 69.6%) as a yellow oil.

And a second step of: synthesis of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((((R) -pentan-2-yl) oxy) carbonyl) amino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexene-1-carboxylate (I-14C)

(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((((R)-pentan-2-yloxy)carbonyl)amino)methy l)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate(I-14C)

(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) (161 mg, 417. Mu. Mol) and triethylamine (126 mg,1.25 mmol) were added to tetrahydrofuran (5.00 mL) at room temperature, and then (S) -4-nitrophenyl pent-2-yl carbonate (I-14B) (158 mg, 626. Mu. Mol) was added, and the reaction solution was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction was concentrated to give a crude product, which was prepared by column chromatography (petroleum ether: ethyl acetate=10:1-3:1) to give methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((((R) -pentan-2-yl) oxy) carbonyl) amino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexene-1-carboxylate (I-14C) (200 mg, yield 95.8%).

LC-MS,M/Z(ESI):500.2[M+H] ⁺

And a third step of: (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)

Methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((((R) -pentan-2-yl) oxy) carbonyl) amino) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexene-1-carboxylate (I-14C) (200 mg,400 μmol) 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 to 4 with 1N hydrochloric acid, followed by extraction with methylene chloride, and the organic phase was concentrated to obtain a crude product. The crude product was then purified by reverse phase high performance liquid chromatography (column Phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a = water +0.225 vol% formic acid, solvent B = acetonitrile; gradient: B% = 45% -75%,7 min), followed by chiral resolution (column AICEL CHIRALCEL OD (250 mm x 30mm,10 um), mobile phase: solvent a = 0.1% ammonia + isopropanol, solvent B = supercritical carbon dioxide, gradient: B% = 40% -40%, continuous injection once every 3.8 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((((R) -pentan-2-yloxy) carbonyl) amino) methyl) -1H-1,2, 3-triazol-4-yl) oxy) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (I-14) (130 mg, yield 67.5%).

LC-MS,M/Z(ESI):486.4[M+H] ⁺

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).

Example 15: preparation of target Compound I-15

(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 (title compound I-15)

(1S, 3S) -3- ((6- (5- (((methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cy clobutylpy din-3-yl) oxy) cyclohexanecarbonicacid (target compound I-15)

The synthetic route for the target compound I-15 is shown below:

/>

the first step: synthesis of 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)

To a solution of elemental magnesium (360 mg,14.8 mmol) in tetrahydrofuran (15.0 mL) was added bromocyclobutane (1.00 g,7.41 mmol) at 60℃and the reaction was stirred at 60℃for 3 hours. 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 (1.06 g,1.85 mmol) and palladium tetrakis triphenylphosphine (321 mg, 277. Mu. Mol) were added to the reaction mixture under nitrogen and the reaction mixture was stirred at 60℃for 2 hours. After the reaction was completed, water and ethyl acetate were added thereto, and the organic phase was concentrated to give a crude product, which was prepared by preparative plate (petroleum ether: ethyl acetate=3:1) to give 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) (650 mg, yield 64.1%) as a yellow oil.

LC-MS,M/Z(ESI):547.4[M+H] ⁺

And a second step of: synthesis of 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)py ridin-3-ol(I-15C)

To a solution of 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) (530 mg, 969. Mu. Mol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride in tetrahydrofuran (1M, 3.88 mL) at room temperature, and the reaction mixture was stirred at 60℃for 12 hours. After the completion of the reaction, the reaction mixture was directly concentrated, and the yellow oily liquid 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) (230 mg, yield 68.9%) was obtained by separation and purification through a preparative plate (petroleum ether: ethyl acetate=2:1).

LC-MS,M/Z(ESI):345.2[M+H] ⁺

And a third step of: synthesis of methyl (1S, 3S) -3- ((2-cyclobutyl-6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (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)

To a toluene solution (3 mL) of 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) at 0deg.C was added diisopropyl azodicarboxylate (270 mg,1.34mmol, 259. Mu.L) and the mixture was stirred at 25deg.C for 12 hours. The reaction mixture was prepared via the preparation plate (petroleum ether: ethyl acetate=1:1) to give methyl (1 s,3 s) -3- ((2-cyclobutyl-6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-15D) (200 mg, yield 61.8%) as a yellow oily compound.

LC-MS,M/Z(ESI):485.3[M+H] ⁺

Fourth step: synthesis of methyl (1S, 3S) -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)pyridi n-3-yl)oxy)cyclohexane-1-carboxylate(I-15E)

To a solution of methyl (1 s,3 s) -3- ((2-cyclobutyl-6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-15D) (200 mg,412.72 μmol) in methanol (3 mL) was added pyridine p-toluenesulfonate (20.7 mg,82.5 μmol) and the mixture stirred at 60 ℃ for 12 hours at room temperature. The reaction mixture was prepared via the preparative-plate (petroleum ether: ethyl acetate=1:2) to give methyl (1 s,3 s) -3- ((2-cyclobutyl-6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-15E) (220 mg) as a yellow oil.

LC-MS,M/Z(ESI):410.0[M+H] ⁺

Fifth step: synthesis of methyl (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-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)

To a solution of methyl (1S, 3S) -3- ((2-cyclobutyl-6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-15E) (220 mg, 549. Mu. Mol) and pyridine (130 mg,1.65 mmol) in methylene chloride (3 mL) at 0℃was added phenyl (4-nitrophenyl) chloroformate (166 mg, 824. Mu. Mol) and the reaction was stirred at 25℃for 12 hours. After the reaction was completed, the reaction was concentrated to give methyl (1 s,3 s) -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) (300 mg) as a yellow oil.

LC-MS,M/Z(ESI):566.2[M+H] ⁺

Sixth step: synthesis of methyl (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-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)

To a solution of (1 s,3 s) -3- ((2-cyclobutyl-6- (1-methyl-5- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H) 1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-15F) (300 mg,530 μmol) and diisopropylethylamine (205 mg,1.59 mmol) in tetrahydrofuran (3 mL) was added N-methylbutan-1-amine (92.4 mg,1.06 mmol) and the mixture was stirred at 25 ℃ for 0.5H. The reaction mixture was prepared via the preparative plate (petroleum ether: ethyl acetate=2:1) to give (1 s,3 s) -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 (I-15G) (150 mg, yield 55.2%).

LC-MS,M/Z(ESI):514.2[M+H] ⁺

Seventh step: synthesis of (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)

(1S, 3S) -3- ((6- (5- (((butyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cy clobutylpy din-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-15)

To a solution of methyl (1 s,3 s) -3- ((6- (5- (((butyl (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclobutyl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-15G) (150 mg,292 μmol) in methanol (3 m L) and water (0.3 mL) was added water and lithium hydroxide (61.2 mg,1.46 mmol) at room temperature, and the mixture was stirred at 25 ℃ 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. The crude product was then purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a = water + 0.225% formic acid by volume, solvent B = acetonitrile; gradient: B% = 54% -84%,11 min) to give (1 s,3 s) -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, 29.2% yield).

LC-MS,M/Z(ESI):500.4[M+H] ⁺

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).

Example 16: preparation of 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 (target compound I-16)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((2-cyclopropylethyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-16)

The synthetic route for the target compound I-16 is shown below:

the first step: synthesis of methyl (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) 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)

Methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-2A) (120 mg,217.57 μmol) and 2-cyclopropyl-N-methylethylamine hydrochloride (3.78 mg,543.92 μmol) were added to tetrahydrofuran (1.5 mL) at room temperature, and then N, N-diisopropylethylamine (98.42 mg,761.49 μmol) was added dropwise, and the reaction mixture was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was prepared using a preparative plate (petroleum ether: ethyl acetate=2:1) to give methyl (I-16A) (100 mg, yield 89.8%) as a yellow oily compound (1 s,3 s) -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-carboxylate.

LC-MS,M/Z(ESI):512.7[M+H] ⁺

And a second step of: synthesis of (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 (target compound I-16)

Methyl (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) cyclohexanecarboxylate (I-16A) (100 mg, 195. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL) at room temperature, then 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, the pH of the reaction solution was adjusted to 4 to 5 with 1M hydrochloric acid, followed by extraction with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was separated by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a = water + 0.225% formic acid by volume, solvent B = acetonitrile; gradient: B% = 56% -89%,11 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((2-cyclopropylethyl) (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylic acid (I-16) (15.6 mg, 16.0% yield).

LC-MS,M/Z(ESI):498.3[M+H] ⁺

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)

Example 17: preparation of 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 (target compound I-17)

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((5-propyl-1, 2, 4-oxazo-3-yl) amino) methyl) -1H-1,2, 3-triazo-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-17)

The synthetic route for the target compound I-17 is shown below:

the first step: synthesis of methyl (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-carboxylate (I-17B)

(1S,3S)-methyl3-((2-cyclopropyl-6-(1-methyl-5-(((5-propyl-1,2,4-oxadiazol-3-yl)amino)methy l)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (5-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexanecarboxylate (I-9C) (100 mg, 260. Mu. Mol) and 5-propyl-1,2, 4-oxadiazol-3-amine (82.6 mg, 650. Mu. Mol) in methanol (2.00 mL) was added glacial acetic acid (5.62 mg, 260. Mu. Mol) dropwise, the reaction solution was stirred at 60℃for 12 hours and then cooled to room temperature, and sodium cyanoborohydride (24.5 mg, 390. Mu. Mol) was added, and the reaction solution was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was prepared via a preparative plate (petroleum ether: ethyl acetate=1:1) to give methyl (1 s,3 s) -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-carboxylate (I-17B) (52.0 mg,104 μmol, yield 40.3%).

LC-MS,M/Z(ESI):505.2[M+H] ⁺

And a second step of: synthesis of (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-oxazo-3-yl) amino) methyl) -1H-1,2, 3-triazo-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-17)

Methyl (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-carboxylate (I-17B) (50.0 mg, 100. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL) at room temperature, and 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, the pH of the reaction solution was adjusted to 4 to 5 with 1N aqueous hydrochloric acid, followed by extraction with ethyl acetate and concentration of the organic phase to give a crude product. The crude product was then separated and purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150, 25mm 10um; mobile phase: solvent a = water + 0.225% formic acid by volume, solvent B = acetonitrile; gradient: B% = 40% -70%,10 min) to give (1 s,3 s) -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) (1.70 mg,3.51 μmol, yield 3.48%).

LC-MS,M/Z(ESI):482.5[M+H] ⁺

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)

Example 18: preparation of target Compound I-18

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (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- (((3, 3-trifluoro-propyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-18)

The synthetic route for the target compound I-18 is shown below:

the first step: synthesis of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (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)ox y)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-18B)

To a solution of (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-2A) (300 mg,543 μmol) and 3, 3-trifluoro-N-methylpropan-1-amine (177 mg,1.09 mmol) in tetrahydrofuran (3.00 mL) was added N, N-diisopropylethylamine (210 mg,1.63 mmol), and the reaction was stirred at 25 ℃ for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was prepared via a preparative plate (petroleum ether: ethyl acetate=1:1) as a yellow oil (1 s,3 s) -methyl (1 s, 173 μmol, yield 31.8%) 3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-18B).

LC-MS,M/Z(ESI):540.2[M+H] ⁺

And a second step of: synthesis of (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (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- (((3, 3-trifluoro-propyl) carbamyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-18)

Methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-18B) (100 mg,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, the pH of the reaction solution was adjusted to 4 to 5 with 1N hydrochloric acid, followed by extraction with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was then separated and purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10um; mobile phase: solvent a = water + 0.225% v/v formic acid, solvent B = acetonitrile; gradient: B% = 43% -73%,10 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylic acid (target compound I-18) (58.2 mg,109 μmol, 59.1%) in 59.1% yield.

LC-MS,M/Z(ESI):526.3[M+H] ⁺

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).

Example 19: preparation of 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 (target compound I-19)

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl-3-ylmethyl) carbamoyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-19)

The synthetic route for the target compound I-19 is shown below:

the first step: synthesis of methyl (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) 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)

To a solution of methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (300 mg,543 mmol) and N-methyl-1- (oxetan-3-yl) methylamine (110 mg,1.09 mmol) in tetrahydrofuran (3.00 mL) was added N, N-diisopropylethylamine (210 mg,1.63 mmol) and the reaction stirred at 25 ℃ for 0.5H. After the completion of the reaction, the reaction mixture was concentrated to give a crude product, which was prepared via a preparation plate (petroleum ether: ethyl acetate=0:1) to give methyl (1 s,3 s) -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-carboxylate (I-19B) (100 mg,169 μmol, yield 31.2%) as a yellow oil.

LC-MS,M/Z(ESI):514.2[M+H] ⁺

And a second step of: synthesis of (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-yloxy) cyclohexane-1-carboxylate (100 mg, 194. Mu. Mol) was dissolved in tetrahydrofuran (0.750 mL), then water (0.250 mL) and lithium monohydrate (81.7 mg,1.95 mmol) were added thereto, the mixture was stirred at room temperature for 12 hours after completion of the reaction, the pH of the reaction solution was adjusted to 4-5 with 1N aqueous hydrochloric acid, then extracted with ethyl acetate, the organic phase was concentrated to give the crude product, the crude product was purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C18:150.25 mm; mobile phase: solvent A = water +0.225 vol% formic acid; gradient: B% = acetonitrile; gradient: 30% = 60%) (1.5 mg) was obtained as a solution of (1H.) (5) and (1.95 mg) was obtained as a solution of (1N) to give (1N) methyl) 1H-1-3-triazol 3-yl) methyl-3- (((3.1.95 mg) cyclohexyl) amino) 2-3-methyl) 2-3-carboxylate, 82.4. Mu. Mol, 42.3% yield).

LC-MS,M/Z(ESI):500.3[M+H] ⁺

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).

Example 20: preparation of 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-carboxylic acid (target compound I-20)

(1S, 3S) -3- ((6- (5- (((methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2- (o-xylan-3-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxiicacid (target compound I-20)

The synthetic route for the target compound I-20 is shown below:

the first step: synthesis of 2- (Oxethan-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)

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) (2.00 g,3.50 mmol), 3-bromooxetane (958 mg,7.00 mmol), zinc (457 mg,7.00 mmol), sodium iodide (254 mg,3.50mm mol) and 1, 2-dimethoxyethane nickel chloride (76.8 mg, 349. Mu. Mol) trifluoroacetic acid (39.8 mg, 349. Mu. Mol) pyridine-2-carboxamidine hydrochloride (55.1 mg, 349. Mu. Mol) N, N dimethylacetamide (30 mL) were mixed at room temperature and the mixture was stirred under nitrogen atmosphere at 60℃for 12 hours. After completion of the reaction, 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 give 2- (oxyethane-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) (600 mg, yield 31.2%) as a yellow oily compound.

LC-MS,M/Z(ESI):549.4[M+H] ⁺

And a second step of: synthesis of 6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) -2- (oxy-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)

To a solution of 2- (oxyethane-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 (800 mg,1.46 mmol) in tetrahydrofuran (8.00 mL) was added tetrabutylammonium fluoride solution (1 m,2.92 mL) at room temperature and the reaction mixture was stirred at 60 ℃ for 12 hours. After the completion of the reaction, the reaction was concentrated to give a crude product, which was prepared by a preparative plate (petroleum ether: ethyl acetate=1:1) to give 6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) -2- (oxy-3-yl) pyridin-3-ol (I-20B) as a yellow solid (440 mg, yield 87.1%).

LC-MS,M/Z(ESI):349.2[M+H] ⁺

And a third step of: synthesis of methyl (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-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)

To a solution of 6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) -2- (oxy-3-yl) pyridin-3-ol (383 mg,2.43 mmol) and triphenylphosphine (636 mg,2.43 mmol) in toluene (10.0 mL) at 0deg.C was added diisopropyl azodicarboxylate (490 mg,2.43 mmol) and the mixture stirred at 25deg.C for 12 hours. After the completion of the reaction, the reaction was concentrated to give a crude product, which was prepared by a preparative plate (petroleum ether: ethyl acetate=1:2) to give methyl (1 s,3 s) -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-carboxylate (I-20C) (550 mg, yield 46.1%).

LC-MS,M/Z(ESI):487.3[M+H] ⁺

Fourth step: synthesis of 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-carboxylate (I-20D)

methyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(oxetan-3-yl)pyri din-3-yl)oxy)cyclohexane-1-carboxylate(I-20D)

To a solution of methyl (1 s,3 s) -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-carboxylate (I-20C) (550 mg,1.13 mmol) in methanol (10 mL) was added pyridine p-toluenesulfonate (28.4 mg,113 μmol) and the mixture stirred at 60 ℃ for 12 hours at room temperature. After completion of the reaction, the reaction was concentrated to give a crude product, which was prepared by synthesis of methyl (1 s,3 s) -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) as a yellow oil (200 mg, yield 43.9%) via a preparative plate (petroleum ether: ethyl acetate=1:2).

LC-MS,M/Z(ESI):412.0[M+H]+

Fifth step: synthesis of 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)

To a solution of methyl (1 s,3 s) -3- ((6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2- (oxetan-3-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (200 mg, 496. Mu. Mol) and pyridine (117 mg,1.49 mmol) in dichloromethane (10.0 mL) at zero ℃ were added 4-nitrophenylcarb-yl chloride (120 mg, 596. Mu. Mol) and the reaction stirred at 25 ℃ for 2 hours. After the completion of the reaction, the reaction was concentrated to give a crude product, which was prepared via a preparative plate (petroleum ether: ethyl acetate=1:1) to give methyl (1 s,3 s) -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) (180 mg, yield 70.9%) as a yellow oil.

Sixth step: synthesis of 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)

To a solution of methyl (1 s,3 s) -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) (180 mg,317 μmol) and diisopropylethylamine (122 mg,951 μmol) in tetrahydrofuran (2.00 mL) was added N-methylbutan-1-amine (55.2 mg,634 μmol) at room temperature, and the reaction mixture was stirred at 25 ℃ for 0.5 hours. After the completion of the reaction, the reaction was concentrated to give a crude product, which was prepared via a preparation plate (petroleum ether: ethyl acetate=2:1) to give methyl (1 s,3 s) -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) (120 mg, yield 73.3%) as a yellow oil.

LC-MS,M/Z(ESI):516.4[M+H] ⁺

Seventh step: synthesis of (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-yloxy) cyclohexane-1-carboxylic acid (target Compound I-20)

To a solution of methyl (1 s,3 s) -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) (120 mg,232 μmol) in methanol (2.00 mL) and water (0.40 mL) was added lithium hydroxide monohydrate (39.0 mg,930 μmol) at room temperature, and the mixture was stirred at 25 ℃ for 12 hours. After the reaction, the reaction solution was adjusted to pH 4 with 1M hydrochloric acid, extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was then purified by reverse phase high performance liquid chromatography (column: phenomenex Synergi C, 150 x 25mm x 10 μm; mobile phase: solvent a = water + 0.225% formic acid by volume, solvent B = acetonitrile; gradient: B% = 38% -68%,11 min) to give (1 s,3 s) -3- ((6- (5- (((butyl (meth) 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) (55.7 mg, yield 47.2%).

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).

Example 21: preparation of 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 (target compound I-21)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((5-cyclopropyl-1, 2, 4-oxazoyl-3-yl) amino) methyl) -1-methyl-1H-1,2, 3-triazoyl-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-21)

The synthetic route for the target compound I-21 is shown below:

the first step: synthesis of N-cyanocyclopropanecarboxamide (I-21B)

N-cyanocyclopropanecarboxamide

Cyanoamide (1.21 g,28.7 mmol) was dissolved in methylene chloride (10.0 mL) at room temperature, cyclopropylcarbonyl chloride (1.00 g,9.57 mmol) was added, nitrogen was replaced, and the mixture was stirred well and reacted at 25℃for 12 hours. After the reaction was completed, N-cyanocyclopropanecarboxamide (I-21B) (1.00 g, crude product) was directly obtained by concentration and used in the next step.

¹ H NMR(400MHz,DMSO-d6)δ6.19(s,1H),1.64-1.57(m,1H),0.91-0.78(m,4H)

And a second step of: synthesis of 5-cyclopropyl-1,2, 4-oxadiazol-3-amine (I-21C)

5-cyclopropyl-1,2,4-oxadiazol-3-amine(I-21C)

N-cyanocyclopropanecarboxamide (I-21B) (1.00 g,9.08 mmol) was dissolved in ethanol (10.0 mL), hydroxylamine hydrochloride (946 mg,13.6 mmol), potassium carbonate (1.88 g,13.6 mmol) was added, nitrogen was replaced, and the mixture was stirred at 70℃for 2 hours. After the reaction was completed, the crude product was concentrated and purified by liquid chromatography (column: 120g Flash Column Welch Ultimate XB_C18 20-40 μm; solvent: a=water+0.225 vol% aqueous ammonia (99%), b=acetonitrile; gradient: 0% -10%,10 min) to give 5-cyclopropyl-1,2, 4-oxadiazol-3-amine (I-21C) (160 mg, yield 14.0%).

LC-MS,M/Z(ESI):126.1[M+H] ⁺

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)

And a third step of: synthesis of 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) 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-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9C) (50.0 mg, 130. Mu. Mol) and 5-cyclopropyl-1, 2, 4-oxadiazol-3-amine (I-21C) (24.4 mg, 195. Mu. Mol) were dissolved in dichloromethane (1.00 mL), titanium chloride (101 mg, 390. Mu. Mol) was added in place of nitrogen, stirred at 25℃for 2 hours, and sodium cyanoborohydride (16.3 mg, 260. Mu. Mol) was added and reacted at 25℃for 2 hours. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), then washed with saturated brine (15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified (petroleum ether: ethyl acetate (V/V) =2:1) by plate separation on silica gel to give methyl (1 s,3 s) -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) (40.0 mg, yield 62.3%).

LC-MS,M/Z(ESI):494.2[M+H] ⁺

Fourth step: synthesis of (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)

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) (40.0 mg, 81.0. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), an aqueous solution of lithium hydroxide monohydrate (17.0 mg, 405. Mu. Mol) (0.20 mL) was added, heated to 25 ℃, stirred for 12 hours, pH=1 was adjusted by adding aqueous dilute hydrochloric acid, extracted with ethyl acetate (10 mL), then washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product, purified by preparative high performance liquid chromatography (column: waters Xb 150 mm 5 μm; solvent: A=0.225% water+0.0.0% vol.% (99% B=67%), to give (1 s,3 s) -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] ⁺

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)

Example 22: preparation of 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 (target compound I-22)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((4- (difluoromethyl) pyrimid-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)

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The synthetic route for the target compound I-22 is shown below:

the first step: (E) 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)

Pyridine (545 mg,6.89 mmol) was dissolved in dichloromethane (12.0 mL) at room temperature, vinyloxoethane (414 mg,5.75 mmol) was added at-70℃and difluoroacetic anhydride (1.20 g,6.89 mmol) was added dropwise, and after completion of the addition, the mixture was slowly warmed to 25℃and stirred for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude (E) -4-ethoxy-1, 1-difluorobut-3-en-2-one (I-22B) (1.00 g, crude) which was used directly in the next step.

And a second step of: synthesis of 4- (difluoromethyl) pyrimidin-2-amine (I-22C)

4-(difluoromethyl)pyrimidin-2-amine(I-22C)

Sodium hydroxide ((255 mg,6.39 mmol) was added to a solution of guanidine hydrochloride (509 mg,5.33 mmol) in ethanol (5.00 mL) and was added dropwise to a solution of (E) -4-ethoxy-1, 1-difluorobut-3-en-2-one (I-22B) (800 mg,5.33 mmol) in dichloromethane (10.0 mL), the reaction was stirred under nitrogen at 25℃for 2 hours after completion of the reaction, concentrated under reduced pressure, and the crude product was purified by beating to give 4- (difluoromethyl) pyrimidin-2-amine (I-22C) (400 mg, 51.7% yield).

¹ H NMR(400MHz,DMSO-d6)δ8.42(d,1H),7.00(s,2H),6.80-6.53(m,1H),6.77(s,1H)

And a third step of: synthesis of 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)

Methyl (1S, 3S) -3- ((2-cyclopropyl-6- (5-formyl-1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-9C) (50.0 mg, 130. Mu. Mol) and 4- (difluoromethyl) pyrimidin-2-amine (I-22C) (28.3 mg, 195. Mu. Mol) were dissolved in dichloromethane (1.00 mL), titanium chloride (101 mg, 390. Mu. Mol) was added, nitrogen was replaced, stirring was continued at 25℃for 2 hours, and sodium cyanoborohydride (16.3 mg, 260. Mu. Mol) was added and stirring was continued at 25℃for 2 hours. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), the organic phase was washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was isolated and purified (petroleum ether: ethyl acetate (V/V) =2:1) on a silica gel plate to give methyl (1 s,3 s) -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) (50.0 mg, yield 74.8%).

LC-MS,M/Z(ESI):514.1[M+H] ⁺

Fourth step: synthesis of (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)

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-yloxy) methyl (I-22D) (50.0 mg, 97.3. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), aqueous lithium hydroxide monohydrate (20.4 mg, 486. Mu. Mol) was added (0.20 mL), the reaction was stirred at 25℃for 12 hours, the pH of the reaction was adjusted to 1 by adding aqueous dilute hydrochloric acid, the ethyl acetate (10.0 mL) was used to extract, the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product using preparative liquid chromatography (column: waters Xb 150 x 25mm 5 μm; solvent: A = water + 0.225% volume% aqueous (99%) and aqueous solution (70%) was used to obtain aqueous solution (7% aqueous solution) and aqueous solution of water (((0.25 mg) was purified to obtain 7- ((3, 3-methyl) 1-1H-1-triazol-2-yl) methyl) 1- ((1, 2-methyl-1H-2-yl) pyridine-2-yl) oxy), yield 20.0%).

LC-MS,M/Z(ESI):500.1[M+H] ⁺

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)

Example 23: preparation of target Compound 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) carbamyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-23)

The target compound I-23 can be synthesized by referring to the compound I-18, and 3, 3-trifluoro-N-methylpropan-1-amine is replaced by N-isopropylmethylamine.

LC-MS,M/Z(ESI):472.2[M+H]

Example 24: preparation of target Compound 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-difluoroopyl) (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxilic acid (target compound I-24)

The synthetic route for the target compound I-24 is shown below:

the first step: synthesis of 3- (1, 3-dioxy isoindolin-2-yl) propanal (I-24B)

3-(1,3-dioxoisoindolin-2-yl)propanal(I-24B)

2- (3-hydroxypropyl) isoindoline-1, 3-dione (5.00 g,24.3 mmol) was dissolved in methylene chloride (50.0 mL), and dess-Martin oxidant (12.90 g,30.4 mmol) was added at 0℃to replace nitrogen, followed by stirring at 25℃for 2 hours. After completion of the reaction, the reaction mixture 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 over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1 to 3:1) to give 3- (1, 3-dioxo-isoindolin-2-yl) propanal (I-24B) (1.80 g, yield 34.3%).

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)

And a second step of: synthesis of 2- (3, 3-difluoropropyl) isoindoline-1, 3-dione (I-24C)

2-(3,3-difluoropropyl)isoindoline-1,3-dione(I-24C)

3- (1, 3-Dioxyindol-2-yl) propanal (I-24B) (1.80 g,8.86 mmol) was dissolved in tetrahydrofuran (18.0 mL), bis (2-methoxyethyl) aminosulfur trifluoride (5.88 g,26.5 mmol) was added at 0deg.C, heated to 25deg.C, stirred for 12 hours, ice water solution was added dropwise, extracted with ethyl acetate (60 mL), the organic phase was washed with saturated brine (60 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was isolated and purified by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1 to 5:1) to give 2- (3, 3-difluoropropyl) isoindoline-1, 3-dione (I-24C) (510 mg, yield 25.5%).

LC-MS,M/Z(ESI):226.1[M+H] ⁺

And a third step of: synthesis of tert-butyl (3, 3-difluoropropyl) aminomethyl ester (I-24D)

tert-butyl(3,3-difluoropropyl)carbamate(I-24D)

2- (3, 3-difluoropropyl) isoindoline-1, 3-dione (I-24C) (300 mg,1.33 mmol) was dissolved in ethanol (10.0 mL), hydrazine hydrate (100 mg,2.66 mmol) was added under nitrogen, nitrogen was replaced, and the mixture was heated to 70℃and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and ethyl acetate solution of hydrogen chloride (4 m,10.0 ml) was added to the filtrate and stirred at room temperature for 10 minutes. The above solution was concentrated directly, ethyl acetate (10 mL), triethylamine (383 mg,3.79 mmol) and di-tert-butyl dicarbonate (275 mg,1.26 mmol) were added sequentially to the residue, the reaction solution was stirred at 25℃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 give crude tert-butyl (3, 3-difluoropropyl) carbamate (I-24D) (220 mg, crude).

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)

Fourth step: 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) carbamate (I-24D) (200 mg,1.02 mmol) was dissolved in tetrahydrofuran (5.00 mL), sodium hydrogen (81.9 mg,2.04 mmol) was added at 0 ℃ and stirred for 15 minutes, methyl iodide (270 mg,2.04 mmol) was added dropwise at 0 ℃ and the reaction mixture was warmed to 25 ℃ and stirred for 30 minutes, the reaction mixture was added dropwise to a saturated ice water solution of ammonium chloride, extracted with ethyl acetate (15 mL) and then washed with saturated brine (15 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was isolated and purified (petroleum ether: ethyl acetate (V/V) =5:1) using column chromatography plates to give tert-butyl (3, 3-difluoropropyl) (methyl) carbamate (I-24E) (110 mg, yield 46.6%).

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)

Fifth step: synthesis of 3, 3-difluoro-N-methylpropan-1-amine hydrochloride (I-24F)

3,3-difluoro-N-methylpropan-1-amine hydrochloride(I-24F)

Tert-butyl (3, 3-difluoropropyl) (methyl) carbamate (I-24E) (110 mg, 476. Mu. Mol) was dissolved in ethyl acetate (1.00 mL), hydrochloric acid/ethyl acetate (4.00M, 1.00 mL) was added under nitrogen, nitrogen was replaced, stirred at 25℃for 0.5 hour, and concentrated to give 3, 3-difluoro-N-methylpropan-1-amine hydrochloride (I-24F) (65.2 mg, crude).

Sixth step: synthesis of methyl (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-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)

3, 3-difluoro-N-methylpropan-1-amine hydrochloride (I-24F) (65.2 mg, 598. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), N-diisopropylethylamine (231 mg,1.79 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-carboxylate (I-2A) (330 mg, 598. Mu. Mol) was added, nitrogen was replaced, and stirred at 25℃for 0.5 hours. After completion of the reaction, quenched with water (10.0 mL), 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, concentrated, and the residue was isolated and purified (petroleum ether: ethyl acetate (V/V) =1:1) with a silica gel plate to give methyl (1 s,3 s) -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-carboxylate (I-24G) (58.0 mg, yield 18.5%).

LC-MS,M/Z(ESI):522.1[M+H] ⁺

Seventh step: synthesis of (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-difluoroopyl) (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxilic acid (target compound I-24)

Methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((3, 3-difluoropropyl) (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-24G) (58.0 mg,111 μmol) was dissolved in tetrahydrofuran (2.00 mL), an aqueous solution of lithium hydroxide monohydrate (46.6 mg,1.11 mmol) (0.50 mL) was added, heated to 25 ℃, stirred for 12 hours, pH was adjusted to 1 by addition of dilute aqueous hydrochloric acid, 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, concentrated to give the crude product by preparative liquid chromatography (column: phenomenex Luna C.25 mm x 25 μm; solvent a = water + 0.225% ammonia (99%) by volume, B = acetonitrile; gradient: 36% -66%,10 min) to afford (1 s,3 s) -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) (20.0 mg, yield 35.4%).

LC-MS,M/Z(ESI):508.0[M+H] ⁺

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)

Example 25: preparation of target Compound I-25

(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 (target compound I-25)

(1S, 3S) -3- ((6- (5- (((cyclobutyl (methyl) carbamyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-25)

The synthetic route for the target compound I-25 is shown below:

the first step: synthesis of methyl (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-carboxylate (I-25B)

methyl (1S, 3S) -3- ((6- (5- (((cyclobutyl (methyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2,3-tria zol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carbox-ylate (target compound I-25)

N-methylcyclobutylamine (20.0 mg, 164. Mu. Mol) was dissolved in tetrahydrofuran (0.50 mL), N-diisopropylethylamine (49.2 mg, 380. Mu. Mol), (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-carboxylate (I-2A) (70.0 mg, 126. Mu. Mol) was added, nitrogen was replaced, and stirred at 25℃for 0.5 hours. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), then washed with saturated brine (15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product which was isolated and purified by column chromatography (petroleum ether: ethyl acetate (V/V) =2:1) to give methyl (1 s,3 s) -3- ((6- (5- (((cyclobutyl (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-25B) (50.0 mg, yield 79.1%).

LC-MS,M/Z(ESI):498.2[M+H] ⁺

And a second step of: synthesis of (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 (target compound I-25)

Methyl (1 s,3 s) -3- ((6- (5- (((cyclobutyl (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) -2-cyclopropylpyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-25B) (50.0 mg,100 μmol) was dissolved in tetrahydrofuran (1.00 mL), an aqueous solution of lithium hydroxide monohydrate (21.0 mg,502 μmol) (0.20 mL) was added, heated to 25 ℃, stirred for 12 hours, pH was adjusted to 1 with a dilute hydrochloric acid solution, extracted with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (10.0 mL) and then dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product (1-3-methyl-1-triazol-1-yl) oxy) cyclohexane-1-carboxylate (10.0 mL) using a preparation liquid chromatography (wasxbridge 150 x 5 μm; solvent: a=0.225 vol% aqueous solution (99%) b=acetonitrile; 42% -72 min), 7% aqueous gradient, purification (1 mg) of 1-methyl-1-triazol-1H-1-yl) oxy) cyclohexane-1- (((3.0 mL) ethyl acetate).

LC-MS,M/Z(ESI):484.2[M+H] ⁺

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)

Example 26: preparation of target Compound 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-difluoroboroyl) (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)

The synthetic route for the target compound I-26 is shown below:

the first step: synthesis of tert-butyl N-vinyl-N-methylcarbamate (I-26B)

tert-butyl N-ethenyl-N-methylcarbamate(I-26B)

Sodium hydrogen (2.10 g,52.3mmol, 60%) was added to tetrahydrofuran (20.0 mL) under nitrogen blanket and ice bath, tert-butyl N-vinylcarbamate (5.00 g,34.9 mmol) was added slowly, after stirring for 0.5 h, methyl iodide (7.43 g,52.3mmol,3.26 mL) was added, and the reaction was then stirred at 25℃for 16 h. After completion of the reaction, the mixture was quenched with water (10.0 mL), extracted with ethyl acetate (30.0 mL), and the organic phase was washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1) to give t-butyl N-vinyl-N-methylcarbamate (I-26B) (3.50 g, yield 63.7%).

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)。

And a second step of: 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-vinyl-N-methylcarbamate (500 mg,3.18 mmol) was dissolved in tetrahydrofuran (10.0 mL), and trimethyl (trifluoromethyl) silane (1.13 g,7.95 mmol) and sodium iodide (1.00 g,6.68 mmol) were added, and the reaction mixture was heated to 66℃and stirred for 4 hours. After the reaction was completed, filtration, concentration of the filtrate, and separation and purification of the crude product by column chromatography (petroleum ether: ethyl acetate (V/V) =20:1) gave tert-butyl N- (2, 2-difluorocyclopropyl) -N-methylcarbamate (I-26D) (500 mg, yield 75.87%).

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)

And a third step of: synthesis of 2, 2-difluoro-N-methylcyclopropane-1-amine hydrochloric acid (I-26E)

2,2-difluoro-N-methylcyclopropan-1-amine hydrochloride(I-26E)

Tert-butyl N- (2, 2-difluorocyclopropyl) -N-methylcarbamate (500 mg,2.41 mmol) was dissolved in ethyl acetate (30.0 mL), and an ethyl acetate solution of hydrogen chloride (4M, 3.02 mL) was added thereto, and the reaction solution was stirred at 25℃for 4 hours. After the completion of the reaction, the mixture was directly filtered and concentrated to give 2, 2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E) (302 mg, yield 87.1%).

Fourth step: 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)

2, 2-difluoro-N-methylcyclopropane-1-amine hydrochloride (I-26E) (200 mg,1.39 mmol) was dissolved in methylene chloride (5.00 mL), N-diisopropylethylamine (180 mg,1.39 mmol) was added, and the reaction solution was stirred at 25℃for 12 hours. After completion of the reaction, water (10.0 mL) was added to quench the reaction, extracted with ethyl acetate (15.0 mL), and the organic phase was washed with saturated brine (15.0 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound N- (2, 2-difluorocyclopropyl) -N-methyl-1H-imidazole-1-carboxamide (I-26F) (280 mg, crude).

Fifth step: synthesis of (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)

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) (200 mg, 517. Mu. Mol) was dissolved in tetrahydrofuran (5.00 mL), lithium hydroxide monohydrate (217 mg,5.18 mmol) and water (2.0 mL) were added, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the pH was adjusted to 1 by adding a dilute aqueous hydrochloric acid solution, 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 give the 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 product).

LC-MS,M/Z(ESI):373.2[M+H] ⁺

Sixth step: synthesis of (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- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (I-26G) (100 mg, 268. Mu. Mol) was dissolved in t-amyl alcohol (3.0 mL), N- (2, 2-difluorocyclopropyl) -N-methyl-1H-imidazole-1-carboxamide (108 mg, 537. Mu. Mol) was slowly added to the reaction solution under nitrogen protection, and after the addition, the reaction solution was heated to 60℃and potassium t-butoxide (1M, 671. Mu. L) was added dropwise, followed by stirring for 2 hours. The reaction solution was cooled to room temperature, diluted hydrochloric acid was added to adjust the pH to 1, extraction was performed 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 give the crude product which was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C1875*30mm*3um; solvent: A=water (HCl), B=acetonitrile; gradient: 40% -60%,8 min) to give the 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] ⁺

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)

Example 27: preparation of target Compound 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) carbamyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-27)

The synthetic route for the target compound I-27 is shown below:

the first step: synthesis of N-benzyl-3-fluoro-N-methylpropan-1-amine (Compound I-27C)

N-benzol-3-fluoro-N-methylpropan-1-amine (Compound 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 (11.7 g,85.1 mmol), and the reaction was stirred at 60℃for 12 hours. After the reaction, the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give N-benzyl-3-fluoro-N-methylpropan-1-amine (I-27C).

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)

And a second step of: synthesis of 3-fluoro-N-methylpropan-1-amine hydrochloride (Compound I-27D)

3-fluoro-N-methylpropan-1-amine hydrochloride (Compound I-27D)

N-benzyl-3-fluoro-N-methylpropan-1-amine (I-27C) (2.00 g,11.0 mmol) was dissolved in hydrochloric acid/methanol (20.0 mL), palladium hydroxide/carbon (774 mg, 10%) was added under nitrogen, the reaction system was replaced with hydrogen and stirred under an atmosphere of hydrogen (50 Psi) at 40℃for 24 hours. After the completion of the reaction, filtration was carried out, and the filtrate was concentrated under reduced pressure to give 3-fluoro-N-methylpropan-1-amine hydrochloride (1.2 g, yield 85.2%).

And a third step of: synthesis of methyl (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-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-carboxylate

Methyl (1 s,3 s) -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-carboxylate (I-2A) (400 mg,725 μmol), 3-fluoro-N-methylpropan-1-amine hydrochloride (I-27D) (101 mg,797 μmol) was dissolved in tetrahydrofuran (5.00 mL), the reaction liquid cooled to 0 ℃, diisopropylethylamine (187 mg,1.45 mmol) was added dropwise, followed by stirring at 25 ℃ for 0.5 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 phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by thin layer silica gel plate (petroleum ether: ethyl acetate (V/V) =1:1) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- ((((3-fluoropropyl) (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) oxy) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-27E) (302 mg, yield 82.6%).

LC-MS,M/Z(ESI):504.3[M+H] ⁺

Fourth step: synthesis of (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) cyclohexanecarboxylic acid (target compound I-27)

Methyl (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-carboxylate (300 mg, 595. Mu. Mol) was dissolved in tetrahydrofuran (9.00 mL) and water (3.00 mL), and lithium hydroxide monohydrate (250 mg,5.96 mmol) was added and the reaction mixture was stirred at 25℃for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 2 with diluted hydrochloric acid (1 mol/L), and extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was separated by preparative high performance liquid chromatograph (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 34% -54%,8 minutes) to give (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] ⁺

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)

Example 28: preparation of target Compound 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-fluororopyl) (methyl) carbamyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-28)

The synthetic route for the target compound I-28 is shown below:

the first step: synthesis of 1- (benzyl (methyl) amino) propan-2-ol (I-28B)

1-(benzyl(methyl)amino)propan-2-ol(I-28B)

N-methyl-1-phenylmethylamine (4.17 g,34.4 mmol) was dissolved in ethanol (50.0 mL), 2-methyl-oxaprozin (6.00 g,103 mmol) was added to replace nitrogen, and the reaction solution was stirred at 60℃for 12 hours. After the completion of the reaction, the solvent was concentrated and removed, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1 to 5:1) to give 1- (benzyl (methyl) amino) propan-2-ol (I-28B) (2.60 g, yield 42.1%).

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)

And a second step of: synthesis of N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C)

N-benzyl-2-fluoro-N-methylpropan-1-amine(I-28C)

1- (benzyl (methyl) amino) propan-2-ol (I-28B) (500 mg,2.79 mmol) was dissolved in dichloromethane (5 mL), cesium fluoride (127 mg, 836. Mu. Mol), diethylaminosulfur trifluoride (1.35 g,8.37 mmol) and trifluoroacetic acid (3.18 mg, 27.8. Mu. Mol) were added at 0℃and heated to 25℃and stirred for 12 hours, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL) and then washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated directly to give a crude product, which was isolated and purified (petroleum ether: ethyl acetate (V/V) =2:1) using a silica gel plate to give N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C) (200 mg, 39.5% yield).

LC-MS,M/Z(ESI):182.1[M+H] ⁺

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)

And a third step of: synthesis of 2-fluoro-N-methylpropan-1-amine hydrochloride (I-28D)

2-fluoro-N-methylpropan-1-amine hydrochloride(I-28D)

N-benzyl-2-fluoro-N-methylpropan-1-amine (I-28C) (200 mg,1.10 mmol) was dissolved in methanol (10.0 mL), palladium on carbon (10%, 0.02 g) was added under nitrogen protection, the reaction system replaced with hydrogen, the reaction mixture was heated to 25℃and stirred for 12 hours, filtered through celite, ethyl acetate hydrochloride (4.00M, 5.00 mL) was added to the filtrate and stirred at room temperature for 10 minutes, and crude 2-fluoro-N-methylpropan-1-amine hydrochloride (I-28D) (52.0 mg, crude) was obtained by direct concentration.

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)

Fourth step: synthesis of methyl (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-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)

2-fluoro-N-methylpropan-1-amine hydrochloride (I-28D) (23.1 mg, 253. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), N-diisopropylethylamine (98.4 mg, 761. Mu. Mol), (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-carboxylate (I-2A) (140 mg, 253. Mu. Mol) was added, and the reaction solution was stirred at 25℃for 12 hours under nitrogen. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), the organic phase was washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was isolated and purified (petroleum ether: ethyl acetate (V/V) =1:1) on a silica gel plate to give methyl (1 s,3 s) -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-carboxylate (I-28E) (80.0 mg, yield 62.5%).

LC-MS,M/Z(ESI):504.1[M+H] ⁺

Fifth step: synthesis of (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)

Methyl (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-carboxylate (80.0 mg, 158. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), and an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (66.6 mg,1.59 mmol) was added and the reaction mixture was stirred at 25℃for 12 hours. After the reaction was completed, the reaction mixture was added with a diluted hydrochloric acid aqueous solution to adjust the pH to 1, extracted with ethyl acetate (10.0 mL), and the organic phase was washed with saturated brine (10.0 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by preparative liquid chromatography (column: phenomenex Luna C18:150×25mm×10um; solvent: a=water+0.225 vol% aqueous ammonia (99%), b=acetonitrile; gradient: 40% -70%,10 min) to give (1 s,3 s) -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] ⁺

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)

Example 29: preparation of target Compound 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-difluororopyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexanecarboxylic acid (target compound I-29)

The synthetic route for the target compound I-29 is shown below:

the first step: synthesis of 1- (benzyl (methyl) amino) propan-2-one (I-29C)

1-(benzyl(methyl)amino)propan-2-one

N-methylbenzylamine (5.00 g,41.2 mmol) and diisopropylethylamine (5.44 g,42.0 mmol) were dissolved in acetonitrile (13.0 mL) and replaced with nitrogen three times, and monochloroacetone (4.08 g,44.15 mmol) was slowly added dropwise to the reaction solution at 15℃followed by heating to 25℃and stirring for 12 hours. After the completion of the reaction, the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution, extracted with methylene chloride (15 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration to give 1- (benzyl (methyl) amino) propan-2-one (I-29C) (6.40 g, yield 87.5%).

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)

And a second step of: synthesis of N-benzyl-2, 2-difluoro-N-methylpropan-1-amine (I-29D)

N-benzyl-2,2-difluoro-N-methylpropan-1-amine

To a 100mL three-necked flask under nitrogen protection was added 1- (benzyl (methyl) amino) propan-2-one (I-29C) (2.00 g,11.2 mmol), cesium fluoride (257 mg,1.69 mmol) and methylene chloride (20.0 mL), the reaction solution was cooled to 10℃and diethylaminosulfur trifluoride (5.46 g,33.8 mmol) and trifluoroacetic acid (12.8 mg, 112. Mu. Mol) were slowly added dropwise, followed by stirring at 25℃for 12 hours. After the completion of the reaction, the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution, extracted with methylene chloride (15.0 ml×3), and 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) to give N-benzyl-2, 2-difluoro-N-methylpropan-1-amine (I-29D) (950 mg,4.77mmol, yield 42.2%).

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)

And a third step of: synthesis of 2, 2-difluoro-N-methylpropan-1-amine hydrochloride (I-29E)

2,2-difluoro-N-methylpropan-1-amine hydrochloride(I-29E)

N-benzyl-2, 2-difluoro-N-methylpropan-1-amine (I-29D) (850 mg,4.27 mmol) was dissolved in hydrochloric acid/methanol (10.0 mL), palladium hydroxide (29.9 mg, 213. Mu. Mol) was added, and the reaction mixture was stirred under a hydrogen atmosphere (50 Psi) at a temperature of 40℃for 24 hours. After the reaction was completed, the filtrate was collected by filtration, and concentrated under reduced pressure to give 2, 2-difluoro-N-methylpropan-1-amine hydrochloride (I-29E) (250 mg, crude product).

Fourth step: synthesis of methyl (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-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)

Methyl (1 s,3 s) -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-carboxylate (I-2A) (280 mg,507 μmol), 2-difluoro-N-methylpropan-1-amine hydrochloride (I-29E) (110.79 mg,1.02 mmol) was dissolved in tetrahydrofuran (5.00 mL), the reaction liquid cooled to 0 ℃, diisopropylethylamine (196 mg,1.52 mmol) was added dropwise, followed by stirring for 2 hours at 25 ℃. After the completion of the reaction, water (10 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (15 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by thin layer silica gel plate (petroleum ether: ethyl acetate (V/V) =1:1) to give methyl (1 s,3 s) -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-carboxylate (I-29F) (105 mg, yield 39.6%).

LC-MS,M/Z(ESI):522.2[M+H] ⁺

Fifth step: synthesis of (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)

Methyl (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-carboxylate (I-29F) (100 mg, 191. Mu. Mol) was dissolved in tetrahydrofuran (6.00 mL) and water (2.00 mL), and lithium hydroxide monohydrate (80.4 mg,1.92 mmol) was added, and the reaction mixture was stirred at 25℃for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 2 with dilute hydrochloric acid (1 mol/L), and extracted with ethyl acetate (15 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 35% -55%,8 minutes) to give (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] ⁺

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)

Example 30: preparation of target Compound I-30

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (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)

(1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((2, 2-trifluoro-ethyl) carbonyl) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-30)

The synthetic route for the target compound I-30 is shown below:

the first step: synthesis of methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (2, 2-trifluoroethyl) aminocarbonyl) 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)ox y)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-30B)

2, 2-trifluoro-N-methyl-ethylamine hydrochloride (97.6 mg, 652. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), N-diisopropylethylamine (246 mg,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-carboxylate (I-2A) (300 mg, 543. Mu. Mol) was added, and the reaction was stirred under nitrogen at 25℃for 12 hours. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), then washed with saturated brine (15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product which was isolated and purified (petroleum ether: ethyl acetate (V/V) =1:1) on a silica gel plate to give methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (2, 2-trifluoroethyl) aminocarbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-30B) (240 mg, yield 83.9%).

LC-MS,M/Z(ESI):526.1[M+H] ⁺

And a second step of: synthesis of (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (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)

Methyl (1S, 3S) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (2, 2-trifluoroethyl) aminocarbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-30B) (250 mg, 475. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), and an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (199.63 mg,4.76 mmol) was added, and the reaction mixture was stirred at 25℃for 12 hours. After the reaction was completed, diluted hydrochloric acid aqueous solution was added to adjust the pH to 1, extracted with ethyl acetate (10.0 mL), and the organic phase was washed with saturated brine (10.0 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by preparative high performance liquid chromatography (column Phenomenex Luna C, 150 x 25mm x 10um; solvent: a=water+0.225% by volume aqueous ammonia (99%), b=acetonitrile; gradient: 40% -70%,10 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (1-methyl-5- (((methyl (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) (34.0 mg, yield 14.0%).

LC-MS,M/Z(ESI):512.4[M+H] ⁺

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)

Example 31: preparation of target Compound 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) carbamyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-31)

The synthetic route for the target compound I-31 is shown below:

the first step: (1S, 3S) -3- ((2-cyclopropyl-6- (5- (((cyclopropyl (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1,2, 3-)

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-meth yl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-31B)

N-methylcyclopropylamine (44.1 mg, 620. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), 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-carboxylate (I-2A) (284 mg, 516. Mu. Mol), N, N-diisopropylethylamine (200 mg,1.55 mmol) was added, and the reaction solution was stirred at 25℃for 0.5 hours. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), then washed with saturated brine (15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give crude silica gel plate isolated and purified (petroleum ether: ethyl acetate (V/V) =1:1) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (((cyclopropyl (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) oxy) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-31B) (210 mg, yield 84.0%).

LC-MS,M/Z(ESI):483.4[M+H] ⁺

And a second step of: synthesis of (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

Methyl (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (((cyclopropyl (methyl) aminocarbonyl) oxy) methyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-31B) (210 mg,434 μmol) was dissolved in tetrahydrofuran (2.00 mL), lithium hydroxide monohydrate (182 mg,4.34 mmol) in water (0.50 mL) was added, the reaction was stirred at 25 ℃ for 12 hours, the pH was adjusted to 1 by adding dilute aqueous hydrochloric acid, ethyl acetate (10 mL) was extracted, the organic phase was washed with saturated brine (10 mL) and then dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product (1 s) -3- (3 s-methyl-1-triazol-2-oxy) 1-carbonyl) 1- (((1, 3 s-methyl) 1-triazol-yl) oxy) pyridine (((10 mL) ethyl acetate) was purified using SFC (column DAICEL CHIRALCEL OJ (250 mm,10 um); solvent: a=methanol+0.1% by volume of ammonia (99%) b=acetonitrile; gradient: 30% to 4.6 min).

LC-MS,M/Z(ESI):469.5[M+H] ⁺

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)

Example 32: preparation of 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 (target compound I-32)

(1S, 3S) -3- ((6- (5- (((4-cyclopyrimidin-2-yl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopyridin-3-yl) oxy) cyclo-hexane-1-carboxic acid (target compound I-32)

The synthetic route for the target compound I-32 is shown below:

the first step: synthesis of 2-chloro-4-cyclobutylpyrimidine (I-32B)

2-chloro-4-cyclobutylpyrimidine(I-32B)

2-Chloropyrimidine (3.00 g,26.1 mmol) was dissolved in methylene chloride (15.0 mL), to which was added an aqueous solution (15.0 mL) of ring Ding Jiasuan (2.36 g,23.5 mmol), silver nitrate (889 mg,5.24 mmol) and ammonium persulfate (5.98 g,26.1 mmol), and the reaction solution was stirred at 25℃for 16 hours. After completion of the reaction, water (30.0 mL) was added thereto, the mixture was extracted with methylene chloride (75.0 mL), and the organic phase was washed with saturated brine (60.0 mL), then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate (V/V) =5:1) to give 2-chloro-4-cyclobutylpyrimidine (I-32B) (2.25 g, yield 78.5%).

LC-MS,M/Z(ESI):168.1[M+H] ⁺

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)

And a second step of: synthesis of 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-triazo l-4-yl)-2-cyclopropylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-32C)

/>

2-Chloropyrimidine (109 mg, 646. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), to which was added 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) (200 mg, 517. Mu. Mol), and potassium t-butoxide (1.00M, 646. Mu.L) was added dropwise to the reaction solution at 0℃and the mixture was gradually warmed to 25℃after the completion of the addition and stirred for 16 hours. After completion of the reaction, ice water (10.0 mL) was added to quench, extraction was performed with ethyl acetate (15.0 mL), then saturated brine (15.0 mL) was used for washing, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained village product was isolated and purified (petroleum ether: ethyl acetate (V/V) =1:1) by silica gel plate to give methyl (1 s,3 s) -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-carboxylate (I-32C) (210 mg, yield 78.2%).

LC-MS,M/Z(ESI):518.2[M+H] ⁺

And a third step of: synthesis of (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)

Methyl (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-carboxylate (I-32C) (190 mg, 366. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), to this was added an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (76.8 mg,1.83 mmol), and the reaction mixture was stirred at 25℃for 12 hours, the pH was adjusted to 1 by adding a dilute hydrochloric acid solution, extracted with ethyl acetate (10.0 mL), and the organic phase was washed with saturated brine (10.0 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was purified by preparative liquid chromatography (column Phenomenex Luna C, 75 x 30mm x 3um; solvent: a=water+0.225% ammonia (99%) by volume, b=acetonitrile; gradient: 42% -72%,7 min) to give (1 s,3 s) -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) (33.4 mg, 18% yield).

LC-MS,M/Z(ESI):504.2[M+H] ⁺

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)

Example 33: preparation of target Compound I-33

(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)

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((3, 3-difluorobutyl) methyl) carbamyl) oxy) me-thyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-33)

The synthetic route for the target compound I-33 is shown below:

the first step: synthesis of methyl (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-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)

1- (3, 3-Difluorocyclobutyl) -N-methyl-methylamine (73.5 mg, 543. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), N-diisopropylethylamine (246 mg,1.90 mmol) and methyl (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-carboxylate (I-2A) (300 mg, 543. Mu. Mol) were added in this order, and the reaction solution was stirred at 25℃for 1 hour. After completion of the reaction, quenched with water (10 mL), extracted with ethyl acetate (15 mL), and the organic phase was washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was isolated and purified (ethyl acetate) using a silica gel plate to give methyl (1 s,3 s) -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-carboxylate (I-33B) (146 mg, yield 49.0%).

LC-MS,M/Z(ESI):548.3[M+H] ⁺

And a second step of: synthesis of (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)

Methyl (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-carboxylate (I-33B) (136 mg, 248. Mu. Mol) was dissolved in tetrahydrofuran (1.00 mL), an aqueous solution of lithium hydroxide monohydrate (104 mg,2.48 mmol) (0.20 mL) was added, the reaction solution was stirred at 25℃for 12 hours, then diluted hydrochloric acid aqueous solution was added to adjust the pH to 2-3, 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 to give the crude product using preparative liquid chromatography (column Phenomenex Luna C, 150X 25 um; solvent: A=water+0.225 volume% acetonitrile; gradient: 42% aqueous ammonia; 10% purification was carried out using aqueous ammonia (99%) for 72% to 72 min), to obtain (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] ⁺

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)

Example 34: preparation of target Compound I-34

(1S, 3S) -3- ((2-cyclopropyl-6- (5- (((ethyl (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- (((2, 2-trifluoro-ethyl) carbamoyl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-34)

The synthetic route for the target compound I-34 is shown below:

the first step: synthesis of N-ethyl-N- (2, 2-trifluoroethyl) -1H-imidazole-1-carboxamide (I-34B)

N-ethyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide(I-34B)

N-ethyl-2, 2-trifluoro-ethylamine hydrochloride (100 mg, 786. Mu. Mol), triethylamine (95.5 mg, 944. Mu. Mol) were dissolved in methylene chloride (1.00 mL), carbonyldiimidazole (153 mg, 944. Mu. Mol) was added at 0℃and the reaction mixture was stirred at 25℃for 2 hours. After completion of the reaction, quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), then washed with saturated brine (15.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by separation on a silica gel plate (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound N-ethyl-N- (2, 2-trifluoroethyl) -1H-imidazole-1-carboxamide (I-34B) (82.0 mg, yield 47.1%).

LC-MS,M/Z(ESI):222.2[M+H] ⁺

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)

And a second step of: synthesis of (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)

Methyl (1S, 3S) -3- ((2-cyclopropyl-6- (5- (hydroxymethyl) -1-methyl-1H-1,2, 3-triazol-4-yl) pyridin-3-yloxy) cyclohexane-1-carboxylate (I-1I) (150 mg, 388. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (162 mg,3.88 mmol) was added, the reaction solution was stirred at 25℃for 12 hours, the pH was adjusted to 1 by the addition of dilute aqueous hydrochloric acid (1 mol/L), extracted with ethyl acetate (10.0 mL), and the organic phase was washed with saturated brine (10.0 mL) and 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-yloxy) cyclohexane-1-carboxylate (I-34C) (100 mg).

LC-MS,M/Z(ESI):373.4[M+H] ⁺

And a third step of: synthesis of (1S, 3S) -3- ((2-cyclopropyl-6- (5- (((ethyl (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)

N-ethyl-N- (2, 2-trifluoroethyl) -1H-imidazole-1-carboxamide (I-34B) (64.1 mg, 290. Mu. Mol) was dissolved in tert-amyl alcohol (1.00 mL), and (1S, 3S) -3- ((2-cyclopropyl-6- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) oxy) pyridin-3-yl) cyclohexane-1-carboxylic acid (I-34C) (60 mg, 161. Mu. Mol) was added, and the reaction mixture was warmed to 60℃and then a solution of potassium tert-butoxide in tetrahydrofuran (1.00M, 966. Mu.L) was slowly added dropwise thereto and stirred at 60℃for 2 hours. After completion of the reaction, quenched with water (2 mL), adjusted to pH 4 by addition of 6M aqueous hydrochloric acid, extracted with ethyl acetate (15 ml×3), the organic phase washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product purified by preparative high performance liquid chromatography (column: phenomenex Luna C18:150:25:10 um; solvent: a=water+0.225 vol% trifluoroacetic acid (99%), b=acetonitrile; gradient: 44% -74%,10 min) to give (1 s,3 s) -3- ((2-cyclopropyl-6- (5- (((ethyl (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) (10.0 mg, 11.5% yield).

LC-MS,M/Z(ESI):526.2[M+H] ⁺

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)

Example 35: preparation of target Compound 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-difluorobutyl) (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)

The synthetic route for the target compound I-35 is shown below:

the first step: synthesis of methyl (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-carboxylate (I-35B)

methyl(1S,3S)-3-((2-cyclopropyl-6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)met hyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate(I-35B)

Methyl 3, 3-difluoro-N-methyl-cyclobutylamine hydrochloride (1 a) (314 mg,1.99 mmol), N-diisopropylethylamine (702 mg,5.44 mmol) 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-carboxylate (I-2A) (1.00 g,1.81 mmol) were added sequentially to tetrahydrofuran (2.00 mL) and the reaction was stirred at 25℃for 0.5H. After the completion of the reaction, water (20.0 mL) was added to quench, extraction was performed with ethyl acetate (15 ml×3), and the organic phases were combined, washed with saturated brine (30 mL) in this order, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound (1 s,3 s) -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-carboxylate (I-35B) (200 mg, yield 20.6%).

LC-MS,M/Z(ESI):534.6[M+H] ⁺

And a second step of: synthesis of (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)

Methyl (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-carboxylate (I-35B) (200 mg, 374. Mu. Mol) was dissolved in 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℃for 12 hours. After the reaction, a diluted hydrochloric acid aqueous solution was added to adjust the pH to 1, extraction was performed with ethyl acetate (15.0 mL), the organic phase was washed with saturated brine (10.0 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative high performance liquid chromatography (column: phenomenex Luna C18:150:25:10 um; solvent: a=water+0.225 vol% aqueous ammonia (99%), b=acetonitrile; gradient: 36% -66%,10 min) to give (1 s,3 s) -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] ⁺

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)

Example 36: preparation of target Compound I-36

Synthesis of (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)

(1S, 3S) -3- ((6- (5- (((bicyclo [1.1.1] pentan-1-yl) oxy) methyl) -1-methyl-1H-1,2, 3-triazol-4-yl) -2-cyclopropyleldin-3-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-36)

The synthetic route for the target compound I-36 is shown below:

the first step: synthesis of methyl (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-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-carboxylate

N-methylbicyclo [1.1.1] pentan-1-amine hydrochloride (31.9 mg, 239. Mu. Mol) 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) methyl cyclohexane-1-carboxylate (I-2A) (120 mg, 217. Mu. Mol) were dissolved in tetrahydrofuran (2 mL), N-diisopropylethylamine (84.3 mg, 652. Mu. Mol) was added dropwise at 25℃and stirred for 12 hours. After completion of the reaction, quenched with water (10.0 mL), extracted with ethyl acetate (15 mL), the organic phase was washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was isolated and purified (petroleum ether: ethyl acetate (V/V) =1:1) on a silica gel plate to give methyl (1 s,3 s) -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-carboxylate (I-36B) (80 mg, yield 64.22%).

LC-MS,M/Z(ESI):510.4[M+H] ⁺

And a second step of: synthesis of (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)

Methyl (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-carboxylate (I-36B) (80.0 mg, 156. Mu. Mol) was dissolved in tetrahydrofuran (2 mL), and an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (32.9 mg, 784. Mu. Mol) was added, and the reaction mixture was stirred at 25℃for 12 hours. After completion of the reaction, a diluted aqueous hydrochloric acid solution (1 mol/L) was added to adjust pH to 1, 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 to give a crude product which 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]+

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).

Example 37: preparation of target Compound I-37

Synthesis of (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)

(1S, 3S) -3- ((2-cyclyl-6- (1-methyl-5- (((methyl (propyl) carbamyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxic acid (target compound I-37)

The synthetic route for the target compound I-37 is shown below:

the first step: synthesis of methyl (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-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- ((((4-nitrophenoxy) carbonyl) oxy) methyl) -1H) 1,2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate (I-15F) (300 mg, 530. Mu. Mol) was dissolved in tetrahydrofuran (5.00 mL), purged three times with nitrogen, methyl (propyl) amine (97 mg,1.33 mmol) was slowly added at 0℃and after the addition was completed, the reaction solution was stirred at 25℃for 0.5 hours. After the completion of the reaction, water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (15 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by a thin layer silica gel plate (petroleum ether: ethyl acetate (V/v=1:1)) to give the compound (1 s,3 s) -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-carboxylate (I-37B) (200 mg, yield 75.4%).

LC-MS,M/Z(ESI):500.3[M+H] ⁺

And a second step of: synthesis of (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)

Methyl (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-carboxylate (I-37B) (200 mg, 400. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), an aqueous solution (1 mL) of lithium hydroxide monohydrate (167 mg,4.00 mmol) was added, and the reaction solution was stirred at 25℃for 12 hours. After the reaction was completed, the pH was adjusted to 1 by adding a diluted hydrochloric acid aqueous solution, 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 give a crude product which was purified by preparative liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 40% -60%,8 min) to give the 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 (target compound I-37) (74.1 mg, yield 38.1%).

LC-MS,M/Z(ESI):486.2[M+H] ⁺

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).

Example 38: preparation of target Compound I-38

(1S, 3S) -3- ((4-cyclopropyl-2- (1-methyl-5- (((methyl (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)

(1S, 3S) -3- ((4-cyclopropyl-2- (1-methyl-5- (((3, 3-trifluoro-propyl) carboyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrimid-5-yl) oxy) cyclohexane-1-carboxic acid (target compound I-38)

The synthetic route for the target compound I-38 is shown below:

the first step: synthesis of 2-chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B)

2-chloro-4-cyclopropyl-5-methoxypyrimidine(I-38B)

2, 4-dichloro-5-methoxy-pyrimidine (10.0 g,55.8 mmol), cyclopropylboronic acid (4.80 g,55.8 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen, followed by addition of potassium phosphate (23.7 g,111 mmol), triphenylphosphine palladium dichloride (1.22 g,2.79 mmol) and water (6.04 g,335 mmol) and stirring at 60℃for 16 h. After completion of the reaction, water (20.0 mL) was added, and extracted with ethyl acetate (150 mL), then washed with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =10:1) to give compound 2-chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B) (9.10 g, yield 88.2%).

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)

And a second step of: synthesis of 4-cyclopropyl-5-methoxy-2- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidine (I-38C)

4-cyclopropyl-5-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine

2-chloro-4-cyclopropyl-5-methoxypyrimidine (I-38B) (8.50 g,46.0 mmol), 2- (prop-2-yn-1-yloxy) oxazolidine (9.60 g,69.0 mmol) was dissolved in acetonitrile (100 mL), cesium carbonate (30.0 g,92.0 mmol) and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (1.63 g,2.30 mmol) were added and the reaction solution was stirred at 90℃for 12 hours under nitrogen protection. After completion of the reaction, quenched with water (50.0 mL), extracted with ethyl acetate (150 mL), then washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a brown oil, which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =2:1) to give the 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] ⁺

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)

And a third step of: synthesis of 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)me thyl)-1H-1,2,3-triazol-4-yl)pyrimidine(I-38D)

4-cyclopropyl-5-methoxy-2- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidine (I-38C) (4.50 g,15.6 mmol), azidomethyl (trimethyl) silane (2.52 g,19.5 mmol) was dissolved in tetrahydrofuran (50.0 mL), replaced three times with nitrogen, pentamethylcyclopentadienyl bis (triphenylphosphine) ruthenium (II) chloride (621.39 mg, 780.33. Mu. Mol) and cuprous iodide (297.23 mg,1.56 mmol) were added and the reaction was stirred at 55℃for 12 hours. After the reaction, the mixture was directly filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =2:1) to give the compound 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) (3.10 g, yield 47.5%).

LC-MS,M/Z(ESI):418.2[M+H] ⁺

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)

Fourth step: synthesis of 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-tr iazol-4-yl)pyrimidine(I-38E)

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) (I-38D) was dissolved in N, N-dimethylformamide (10.0 mL), tetrabutylammonium fluoride (2.08 g,7.96 mmol) was added and the reaction stirred at 25℃for 0.5H. After completion of the reaction, quenched with water (10.0 mL), extracted with ethyl acetate (15.0 mL), then washed with saturated brine (15.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 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) (1.20 g, yield 48.0%).

Fifth step: synthesis of 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)p yrimidin-5-ol(I-38F)

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 methyl mercaptide (892 mg,12.7 mmol) was added thereto, and the reaction solution was stirred at 120℃for 2 hours under nitrogen. After completion of the reaction, water (20 mL) was added, extracted with ethyl acetate (30 mL), then washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 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) (1.05 g, yield 94.7%).

LC-MS,M/Z(ESI):332.2[M+H] ⁺

Sixth step: synthesis of methyl (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-carboxylate (I-38G)

(1S,3S)-3-((4-cyclopropyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-tr iazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-38G)

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) (1.00 g,3.02 mmol), (1S, 3R) -3-hydroxycyclohexylcarboxylic acid methyl ester (620.62 mg,3.92 mmol) and triphenylphosphine (1.58 g,6.04 mmol) were dissolved in toluene (10.0 mL), replaced with nitrogen three times, and diisopropyl azodicarboxylate (1.22 g,6.04 mmol) was added dropwise at 10℃and the reaction stirred at room temperature for 12 hours. After completion of the reaction, quench by addition of water (10 mL). Extraction with ethyl acetate (20 mL) and washing of the organic phase with saturated brine (10 mL), then drying over anhydrous sodium sulfate, filtration and direct concentration gives crude product, which is purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound (1 s,3 s) -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-carboxylate (I-38G) (1.01G, 70.9% yield).

LC-MS,M/Z(ESI):472.4[M+H] ⁺

Seventh step: synthesis of 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)pyrimi din-5-yl)oxy)cyclohexane-1-carboxylate(I-38H)

Methyl (1 s,3 s) -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-carboxylate (I-38G) (500 mg,1.06 mmol) and p-toluenesulfonic acid (53.2 mg,212 μmol) were dissolved in ethanol (5 mL) and stirred at 60 degrees under nitrogen for 12 hours, after completion of the reaction, the reaction was directly concentrated to give a brown solid which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound (1 s,3 s) -3- ((4-cyclopropyl-2- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-5-yl) oxy) cyclohexane-1-carboxylate (I-38H) (205 mg, 60.6% yield).

LC-MS,M/Z(ESI):388.3[M+H] ⁺

Eighth step: synthesis of methyl (1S, 3S) -3- ((4-cyclopropyl-2- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) aminocarbonyl) 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)ox y)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate(I-38I)

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) (105 mg, 271.02. Mu. Mol) and pyridine (64.31 mg, 813.05. Mu. Mol) were dissolved in methylene chloride (5.00 mL), phenyl p-nitrochloroformate (109.25 mg, 542.03. Mu. Mol) was added under ice-bath conditions, and after the reaction solution was stirred for 0.5 hours, methyl (3, 3-trifluoropropyl) amine hydrochloride (85.85 mg, 524.85. Mu. Mol) was added, followed by stirring at room temperature for 0.5 hours. After completion of the reaction, water (5.00 mL) was added to quench, extraction was performed 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 give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give the compound (1 s,3 s) -3- ((4-cyclopropyl-2- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) aminocarbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-5-yl) oxy) cyclohexane-1-carboxylate (I-38I) (52.0 mg, yield 36.6%).

LC-MS,M/Z(ESI):541.4[M+H] ⁺

Ninth step: (1S, 3S) -3- ((4-cyclopropyl-2- (1-methyl-5- (((methyl (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)

Methyl (1S, 3S) -3- ((4-cyclopropyl-2- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) aminocarbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrimidin-5-yl) oxy) cyclohexane-1-carboxylate (I-38I) (52.0 mg, 96.2. Mu. Mol) was dissolved in tetrahydrofuran (2.50 mL), lithium hydroxide monohydrate (40.3 mg, 962. Mu. Mol) and water (2.00 mL) were added and stirred at room temperature for 12 hours. After completion of the reaction, the pH was adjusted to 1 by adding a diluted hydrochloric acid aqueous solution, extracted with ethyl acetate (10 mL), then washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product which was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; solvent: A=water+0.01% HCl, B=acetonitrile; gradient: 37% -57%,8 min) to give the compound (1S, 3S) -3- ((4-cyclopropyl-2- (1-methyl-5- (((methyl (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] ⁺

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)

Example 39: preparation of target Compound I-39

(1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- (((methyl (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)

(1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- (((3, 3-trifluoro-propyl) carbamyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylic acid (target compound I-39)

The synthetic route for the target compound I-39 is shown below:

the first step: synthesis of 3-bromo5-iodopyrazin-2-amine (I-39B) 3-bromo5-iodopyrazine-2-amine (I-39B)

5-iodopyrazin-2-amine (I-39A) (25 g,113.12 mmol) was dissolved in N, N-dimethylformamide (250 mL) under nitrogen, N-bromosuccinimide (22.15 g,124.44 mmol) was slowly added in an ice bath, and after the addition was completed, the reaction solution was stirred at 20℃for 12 hours. After completion of the reaction, the mixture was quenched with water (500 mL), extracted with ethyl acetate (500 mL. Times.3), and the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 3-bromo-5-iodopyrazin-2-amine (I-39B) (25.0 g, 73.6% yield).

LC-MS,M/Z(ESI):299.9[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ8.26-8.00(m,1H),5.05(br s,2H)

And a second step of: synthesis of 3-bromo-5-iodopyrazin-2-ol (I-39C)

3-bromo-5-iodopyrazin-2-ol(I-39C)

3-bromo-5-iodopyrazin-2-amine (I-39B) (25.0 g,83.3 mmol) was dissolved in acetic acid (250 mL), concentrated sulfuric acid (73.5 g,750 mmol) was added dropwise at 15℃under nitrogen, and after the addition was completed, a solution of sodium nitrite (11.5 g,166 mmol) in water (69.0 mL) was added dropwise and stirred at 20℃for 12 hours. After completion of the reaction, the mixture was directly filtered and concentrated to give 3-bromo-5-iodopyrazin-2-ol (I-39C) (15.0 g, yield 59.8%).

LC-MS,M/Z(ESI):300.9[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)δ12.8(s,1H),7.89(s,1H)

And a third step of: synthesis of 3-bromo-5- (3- (oxalan-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)

3-bromo-5-iodopyrazin-2-ol (I-39C) (7.50 g,24.9 mmol), 2-prop-2-ynyloxotetrahydropyran (3.67 g,26.1 mmol) and triethylamine (8.83 g,87.2 mmol) were dissolved in acetonitrile (100 mL), cuprous iodide (237 mg,1.25 mmol) and triphenylphosphine palladium dichloride (874 mg,1.25 mmol) were added, nitrogen was replaced three times, and the reaction solution was stirred at 20℃for 12 hours. After the completion of the reaction, quenched with water (20.0 mL), extracted with ethyl acetate (45 mL), then washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a brown oil, which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound 3-bromo-5- (3- (oxa-2-yloxy) prop-1-yn-1-yl) pyrazin-2-ol (I-39D) (2.52 g, yield 32.2%).

LC-MS,M/Z(ESI):313.0[M+H] ⁺

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)

Fourth step: synthesis of 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)me thoxy)pyrazine(I-39E)

3-bromo-5- (3- (oxalan-2-yloxy) prop-1-yn-1-yl) pyrazin-2-ol (I-39D) (2.50 g,7.98 mmol) and diisopropylethylamine (2.06 g,15.9 mmol) were dissolved in dichloromethane (25 mL) and (chloromethoxy) ethyl-trimethyl-silane (1.60 g,9.58 mmol) was slowly added dropwise and stirred at 25℃for 2 hours under protection of reactive liquid nitrogen gas. After completion of the reaction, quenched with water (20.0 mL), extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oil which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =5:1) to give the compound 3-bromo-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-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] ⁺

Fifth step: synthesis of 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-tri azol-4-yl)-2-((2-(trimethylsilyl)ethoxy)methoxy)pyrazine(I-39F)

3-bromo-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) -2- ((2- (trimethylsilyl) ethoxy) methoxy) pyrazine (I-39E) (2.00 g,4.51 mmol), azidomethyl (trimethyl) silane (874 mg,6.77 mmol) was dissolved in tetrahydrofuran (10.0 mL), replaced three times with nitrogen, pentamethylcyclopentadienyl bis (triphenylphosphine) ruthenium (II) chloride (399 mg, 451. Mu. Mol) and cuprous iodide (85.9 mg, 451. Mu. Mol) were added and the reaction was stirred at 66℃for 12 hours. After the reaction was completed, the filtrate was directly filtered, and concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give 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, yield 27.4%).

LC-MS,M/Z(ESI):574.2[M+H] ⁺

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)

Sixth step: synthesis of 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)

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) (700 mg,1.22 mmol) and cyclopropylboronic acid (136 mg,1.59 mmol) were dissolved in 1, 4-dioxane (10 mL) and water (1 mL), replaced three times with nitrogen, and potassium phosphate (778 mg,3.67 mmol) and triphenylphosphine palladium dichloride (85.8 mg, 122. Mu. Mol) were added and the reaction was stirred at 90℃for 12 hours. After completion of the reaction, 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 give the crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound 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) (520 mg, yield 79.6%).

LC-MS,M/Z(ESI):534.4[M+H] ⁺

Seventh step: synthesis of 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)p yrazin-2-ol(I-39H)

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. Mu. Mol) was dissolved in tetrahydrofuran (5.00 mL), tetrabutylammonium fluoride (1M, 2.87 mL) was added thereto, and the reaction solution was stirred under nitrogen for 12 hours at 66 ℃. After completion of the reaction, 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 give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give 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, yield 80.5%).

LC-MS,M/Z(ESI):332.2[M+H] ⁺

Eighth step: synthesis of methyl (1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- ((oxazolidin-2-yloxy) methyl) -1H-1,2, 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-carboxylate

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, 754. Mu. Mol), (1S, 3R) -methyl 3-hydroxycyclohexacarboxylate (178 mg,1.13 mmol) and triphenylphosphine (399 mg,1.51 mmol) were dissolved in toluene (2.5 mL), replaced with nitrogen three times, and diisopropyl azodicarboxylate (305 mg,1.51 mmol) was added dropwise at 10℃and the reaction stirred at room temperature for 12 hours. After completion of the reaction, water (10 mL) was added to quench, extraction was performed 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 give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound (1 s,3 s) -3- ((3-cyclopropyl-5- (1-methyl-5- ((oxazolidin-2-yloxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylic acid methyl ester (I-39I) (240 mg, yield 59.9%).

LC-MS,M/Z(ESI):472.2[M+H] ⁺

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)

Ninth step: synthesis of 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)pyrazi n-2-yl)oxy)cyclohexane-1-carboxylate(I-39J)

Methyl (1 s,3 s) -3- ((3-cyclopropyl-5- (1-methyl-5- ((oxazolidin-2-yloxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylate (I-39I) (240 mg,508 μmol) and pyridinium p-toluenesulfonate (127 mg,508 μmol) were dissolved in ethanol (5 mL) and the reaction was stirred under nitrogen at 60 ℃ for 12 hours. After completion of the reaction, the crude product was directly concentrated to give methyl (1 s,3 s) -3- ((3-cyclopropyl-5- (5- (hydroxymethyl) -1-methyl-1H-1, 2, 3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylate (I-39J) (197 mg, crude) purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1).

LC-MS,M/Z(ESI):388.2[M+H] ⁺

Tenth step: synthesis of methyl (1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) aminocarbonyl) 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)ox y)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate(I-39K)

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) (105 mg, 271. Mu. Mol) and pyridine (64.3 mg, 813. Mu. Mol) were dissolved in methylene chloride (5.00 mL), phenyl p-nitrochloroformate (109 mg, 542. Mu. Mol) was added while stirring for 0.5 hours, and after stirring for 0.5 hours, methyl (3, 3-trifluoropropyl) amine hydrochloride (85.8 mg, 524. Mu. Mol) was added, the reaction mixture was warmed to room temperature and stirred for 0.5 hours. After completion of the reaction, water (5 mL) was added to quench, extraction was performed with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound (1 s,3 s) -3- ((3-cyclopropyl-5- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) aminocarbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylate (I-39K) (50.4 mg, yield 35.5%). LC-MS, M/Z (ESI) 541.4[ M+H ] ] ⁺

Eleventh step: (1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- (((methyl (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)

Methyl (1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- (((methyl (3, 3-trifluoropropyl) aminocarbonyl) oxy) methyl) -1H-1,2, 3-triazol-4-yl) pyrazin-2-yl) oxy) cyclohexane-1-carboxylate (I-39K) (50.0 mg, 92.5. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), lithium hydroxide monohydrate (38.8 mg, 925. Mu. Mol) and water (1 mL) were added and stirred at room temperature for 12 hours. After completion of the reaction, the pH was adjusted to 1 by adding a diluted hydrochloric acid aqueous solution, extracted with ethyl acetate (10 mL), and the organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product which was purified by preparing a thin-layer silica gel plate (ethyl acetate) to give the compound (1S, 3S) -3- ((3-cyclopropyl-5- (1-methyl-5- (((methyl (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] ⁺

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)

Biological Activity and related Property test cases

Test example 1: LPAR1 in vitro calcium flux assay

The compounds were assayed for LPAR1 antagonism in CHO stable cell lines highly expressing human LPAR 1. Cells were seeded at a density of 15,000 cells/well in 384 Kong Heibi clear plates containing 20. Mu.L of DMEM/F12 (1:1) medium and maintained at 37 ℃/5% CO at 18 hours prior to the assay ₂ After 18 hours, 20. Mu.L/Kong Ranliao solution was added to each well of cells, the cells were returned to the 37℃incubator for 30 minutes in a continuous dark place, incubated at room temperature for 10 minutes in a dark place, 10. Mu.L/well of the compound at different final concentrations were added to the cells, equilibrated for 20 minutes, and finally 12.5. Mu.L/well of LPA solution (final concentration 5 nM) was added to the cells and the fluorescence signal value was detected with FLIPR. In the form of compoundsConcentration is X-axis, fluorescence signal value is Y-axis, antagonism of compound is calculated by software Prism (IC ₅₀ Values).

TABLE 1 test of compounds for antagonism of LPAR1

Test compounds	IC50(nM)
		Control Compound 1	243.8
Control Compound 2	251.6
		Compound I-3	47.47
Compound I-5	48.16
		Compound I-7	38.83
Compound I-8	39.42
		Compound I-11	113.3
Compound I-13	130.6
		Compound I-15	39.75
Compound I-18	45.68
		Compound I-25	150.9
Compound I-32	85.55
		Compound I-33	119.6
Compound I-35	42.22
		Compound I-36	201.5

The results of LPAR1 experimental calcium flux experiments showed that the compounds of the present invention have good antagonism to LPAR1, and most of the inventive compounds showed superior LPAR1 antagonism compared to the control compounds.

Test example 2: inhibition assay of BSEP bile efflux transporter by Compounds

Inhibition of BSEP (Bile salt export pump) bile efflux transporter by compounds assays were performed using vesicles (GenoMembrane) expressing a humanized BSEP bile efflux transporter. Compounds at different concentrations were pre-incubated with vesicles for 5min, while Negative Control (NC) and Positive Control (PC) groups were set up: NC group preincubate vesicles with blank buffer at 37 ℃ for 5min, PC group preincubate positive inhibitors with vesicles at 37 ℃ for 5min. Followed by incubation with the probe substrate at 37℃for 5 minutes with the addition of ATP or AMP, respectively. With pre-chilled Buffer B1 (10 Xbuffer B1 (Stopping and Washi)ng Buffer): 100mM Hepes-Tris,1000mM KNO3,500mM Sucrose) termination assay. The test sample was transferred to a 96-well filter plate, filtered by a vacuum pump, then repeatedly washed 5 times with 0.2mL of pre-chilled Buffer B1, the vesicles on the filter plate were dissolved with 50 μl of 80% methanol, the filtrate was collected by centrifugation at 2000 rpm for 2 minutes, repeated once, the two filtrates were combined together, and mixed well to obtain approximately 100 μl of filtrate, and pre-chilled methanol with internal standard was added and centrifuged at 12,000 rpm for 5 minutes. The supernatant was used for LC-MS/MS quantitative detection of the amount of substrate transported. IC for inhibiting bile efflux transporter activity of a compound was calculated by software Prism using compound concentration as X-axis and relative activity (% of NC) as Y-axis ₅₀ Value and inhibition ratio.

The transport rate (activity) and relative activity under different conditions were calculated according to the following formulas:

substrate active transport rate (pmol/min/mg) =

TABLE 2 test of Compounds for inhibition of BSEP bile efflux transporter

Test compounds	IC ₅₀ (μM)
		Control Compound 1	89.8
Control Compound 2	195.5
		Compound I-18	350.0
Compound I-24	218
		Compound I-27	>200

The inhibition test result of the BSEP bile excretion transporter shows that the compound has no obvious inhibition effect on the BSEP bile excretion transporter and no risk of cholestasis toxicity.

Test example 3: caco-2 cell permeability assay

Caco-2 cells were grown at 1X 10 ⁵ Individual cells/cm ² The cells were inoculated onto 96-well Transwell plates and the medium was refreshed every 4-5 days until the 28 th day the cells formed a dense monolayer. Caco-2 cell membrane layer integrity was verified with HBSS solution containing 100. Mu.M fluorescein. The following experiments were then carried out in the presence and absence of eladridar (10 μm): in groups A to B, the compound was added to the dosing side of a 96-well Transwell plate at a final concentration of 2. Mu.M, the receiving side was buffered, and the plate was then incubated with CO ₂ 37 ℃ and 5 percent CO in an incubator ₂ Standing and incubating for 2 hours under the saturated humidity condition; at the end of incubation, the drug administration side and the receiver side were sampled simultaneously, all samples were mixed with acetonitrile containing an internal standard, centrifuged at 3200g for 10 minutes, and the supernatant was taken and then tested for compound concentration by LC-MS/MS. Groups B to A were examined under the same conditions, and Papp (10) was calculated according to the following formula ^-6 cm/sec), and the discharge rate.

Apparent permeability coefficient (Papp) = (receiving side volume/(membrane area x incubation time))× (receiving side drug concentration at end of incubation)/(drug concentration at dosing side at start of incubation)

Rate of Efflux (ER) =papp _(B-A) /Papp _(A-B)

Experimental results show that the compound has higher permeability, no obvious discharge and good drug property.

Test example 4: pharmacokinetic test in mice

Mouse pharmacokinetic experiments Male ICR mice, 20-25g, were used, fasted overnight. 3 mice were taken and orally administered with 10mg/kg by intragastric administration. Blood was collected 15, 30 minutes and 1, 2, 4, 8, 24 hours before and after dosing. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

The results of the mouse pharmacokinetic experiments show that compared with the control compound, the compound of the invention has better pharmacokinetic properties and good patentability.

Test example 5: rat pharmacokinetic test

Rat pharmacokinetic experiments Male SD rats, 180-240g, were used, fasted overnight. 3 rats were taken and given 10mg/kg orally by gavage. Blood was collected 15, 30 minutes and 1, 2, 4, 8, 24 hours before and after dosing. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

The rat pharmacokinetic experiment result shows that compared with the control compound, the compound of the invention has better pharmacokinetic property and good patentability.

Test example 6: dog pharmacokinetic test

Dog pharmacokinetic experiments were performed using male Beagle dogs, 8-10kg, overnight fasted. 3 Beagle dogs were taken and administered orally by gavage at 5mg/kg. An additional 3 Beagle dogs were taken and given 1mg/kg intravenously. Blood was collected 15, 30 minutes and 1, 2, 4, 8, 24 hours before and after dosing. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

TABLE 6 results of oral gavage administration pharmacokinetic experiments in dogs

The dog pharmacokinetic experiment result shows that compared with the control compound, the compound of the invention has larger exposure and good patentability.

Test example 7: bleomycin-induced pulmonary fibrosis pharmacodynamic assay

Male mice were fed adaptively for 1 week, and after reaching the standard, the animals were randomly divided into a control group, a model group and a dosing group according to their weights. After isoflurane anesthesia: evenly administering 50 mu L of bleomycin in the lungs of the model group and the administration group to establish a pulmonary fibrosis model of the mice, and evenly administering 50 mu L of physiological saline in the lungs of the control group; after 7 days, continuous administration is carried out for 15 days, after the administration is finished, animals are deeply anesthetized by pentobarbital sodium, alveolar lavage fluid (BALF) is collected and immediately put into a wet ice box for temporary storage for subsequent index detection; fixing part of animal lung with 10% neutral formalin buffer solution for preparing pathological tissue section; and (3) accurately weighing and recording the other part of animal lung, placing the animal lung in a freezing tube, immediately placing the animal lung in liquid nitrogen, and transferring the animal lung and the collected BALF supernatant to an ultralow temperature-80 ℃ refrigerator for storage, so as to be used for detecting indexes such as the level of hydroxyproline in alveolar lavage fluid and lung tissues, the expression condition of Collagen I and the like.

The results of the bleomycin-induced pulmonary fibrosis drug efficacy test show that the compound of the invention can significantly improve bleomycin-induced pulmonary fibrosis symptoms of mice by antagonizing LPAR 1.

Claims

1. A compound which is a compound of formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I):

wherein:

R ¹ selected from unsubstituted or substituted R ^1a Substituted C _3-6 Cycloalkyl, unsubstituted or substituted by R ^1a Substituted 3-6 membered heterocyclyl; the R is ^1a Selected from-CN, halogen;

R ⁵ selected from-H, -F, methyl.

2. A compound according to claim 1, wherein,

selected from->

And/or when R ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 In the case of cycloalkyl, the R ^1a Is one or more, when there are a plurality of R ^1a When the R is ^1a The same or different;

and/or when R ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 In the case of cycloalkyl, the R ^1a Selected from-CN, fluoro, chloro, bromo, iodo;

and/or when R ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 In the case of cycloalkyl, the C _3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl;

and/or when R ¹ Is unsubstituted or substituted by R ^1a Substituted C _3-6 When heterocycloalkyl, said C _3-6 The number of heteroatoms in the heterocycloalkyl group is 1-2;

and/or when R ¹ Is unsubstituted or substituted by R ^c Substituted C _3-6 When heterocycloalkyl, said C _3-6 The heteroatom in the heterocycloalkyl group is selected from O, N, S.

3. A compound according to claim 1, wherein,

when R is ² Is unsubstituted or substituted by R ^2a Substituted C _1-6 In the case of alkyl, said R ^2a Is one or more, when there are a plurality of R ^2a When the R is ^2a The same or different;

and/or when R ² Is unsubstituted or substituted by R ^2a Substituted C _1-6 In the case of alkyl, said R ^2a Is one or more, when there are a plurality of R ^2a When the R is ^2a Selected from-CN, fluorine, chlorine;

and/or when R ² Is unsubstituted or substituted by R ^2a Substituted C _1-6 When alkyl, the C _1-6 The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl.

4. A compound according to claim 1, wherein,

when R is ³ Is unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, C _4-8 Bridged cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, R is as defined above ^3a Is one or more, when there are a plurality of R ^3a When the R is ^3a The same or different;

and/or when R ³ Is unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, C _4-8 Bridged cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, R is as defined above ^3a Selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl;

and/or when R ³ Is unsubstituted or substituted by R ^3a Substituted C _1-6 When alkyl, the C _1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl;

And/or when R ³ Is unsubstituted or substituted by R ^3a Substituted C _3-8 In the case of cycloalkyl, said C _3-8 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl;

and/or when R ³ Is unsubstituted or substituted by R ^3a Substituted C _3-8 In the case of bridged cycloalkyl radicals, the radicals C _3-8 Bridged cycloalkyl radicals are

And/or when R ³ Is unsubstituted or substituted by R ^3a When the substituted 4-8 membered heterocyclic group is adopted, the heteroatom is selected from N, O and S, and the number of the heteroatom is 1-2;

and/or when R ³ Is unsubstituted or substituted by R ^3a In the case of a substituted 5-8 membered heteroaryl, the 5-8 membered heteroaryl is selected from thiophene, furan, oxazole, thiazole, triazole, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl.

5. A compound according to claim 1, wherein,

when R is ⁴ Is C _1-3 Alkyl or C substituted by halogen _1-3 When alkyl, the C _1-3 Alkyl is methyl, ethyl, n-propyl, isopropyl;

and/or L ² Absent, or selected from

6. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-a):

7. a compound according to claim 6, characterized in that:

R ² selected from methyl, ethyl, n-propyl, isopropyl, preferably R ² Selected from methyl;

L ² Absent, or selected from

8. A compound according to claim 6, characterized in that:

-L ¹ -L ² -R ³ selected from the group consisting of

9. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-B):

10. the compound of claim 9, wherein R ³ Selected from-H, -CN, -F, -Cl, unsubstituted or substituted by R ^3a The substituted following groups: c (C) _1-6 Alkyl, C _3-8 Cycloalkyl, C _4-8 Bridged cycloalkyl, phenyl, pyridyl.

11. The compound according to claim 9, wherein-L ² -R ³ Selected from the group consisting of n-propyl, isopropyl, n-butyl, n-pentyl, fluoro-n-propyl, fluoro-n-butyl,

12. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-C):

13. the compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-D):

14. the compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-E):

15. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-F):

16. the compound of claim 1, which is a compound of the formula:

17. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 16.

18. Use of a compound according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for the treatment of a disease associated with LPAR.

19. The use according to claim 18, wherein the LPAR-associated disease is selected from the group consisting of fibrotic diseases, tumors, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus.

20. The use according to claim 18, wherein the LPAR-associated disease is selected from idiopathic pulmonary fibrosis, radiopulmonary fibrosis, liver fibrosis, kidney fibrosis, tumors, neuropathic pain, rheumatoid arthritis, fetal hydrocephalus.