CN118005606A

CN118005606A - TEAD inhibitors

Info

Publication number: CN118005606A
Application number: CN202311497105.8A
Authority: CN
Inventors: 张学军; 臧杨; 杨辉; 李超; 李金平; 李莉娥; 杨俊�; 朱圣姬; 李禹琼
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: 2022-11-10
Filing date: 2023-11-10
Publication date: 2024-05-10
Also published as: WO2024099435A1

Abstract

The invention provides a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate and a pharmaceutically acceptable salt or prodrug thereof, which can obviously inhibit the activity of TEAD transcription as a TEAD inhibitor and can be used for preventing and/or treating diseases related to TEAD expression increase.

Description

TEAD inhibitors

The application requires enjoying:

priority of prior application filed by 11.10.2022 to China national intellectual property office with patent application number 2022114083146 entitled "TEAD inhibitor";

Priority of prior application filed by the national intellectual property office of China at 2023, 3 and 10 under the name of TEAD inhibitor with patent application number 2023102475409;

the entirety of this prior application is incorporated by reference into the present application.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a TEAD inhibitor and application thereof.

Background

The Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades that are involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stem, extracellular matrix deposition, injury repair, organ development, etc. Upon activation of the Hippo signaling pathway by upstream GPCRs, mechanical stress, etc., the NF2 (neurofibromatosis type, neurofibrin 2) activates MST1/2 (MAMMALIAN STERILE 20-LIKE KINASE 1/2), MST1/2 activates LAST1/2 (large tumor suppressor kinase 1/2), activated LATS1/2 phosphorylates YAP (Yes Associated Protein, yes-associated protein)/TAZ (Transcriptional coactivator with PDZ-binding motif, transcriptional co-activator with PDZ binding motif), the phosphorylated YAP/TAZ localizes to the cytoplasm and degrades in a ubiquitin-dependent manner, while the unphosphorylated YAP/TAZ migrates to the nucleus and binds to several nuclear transcription factors including TEADs, forming a transcriptional complex, inducing expression of several downstream target genes including CTGF (Connective tissue growth factor ), cyr61 (MYSTEINE RICH angiogenic inducer 61, cysteine-rich angiogenesis inducer 61) and AXL (AXL receptor tyrosine kinase, receptor tyrosine kinase AXL), thereby promoting the pathophysiological processes of the organism.

TEADs/TEAD (Transcriptional Enhanced Associate Domains, transcription enhancement related domain) is the ultimate effector of the Hippo signaling pathway, with four family members, TEAD1, TEAD2, TEAD3 and TEAD4, respectively, all TEADs subtypes have a DNA-binding TEA domain at the N-terminus and a YAP/TAZ binding domain at the C-terminus, which are highly conserved in mammals, but differ greatly in the linker linking the TEA domain and the transactivation domain, with overall homology between 61% and 73% for the four TEADs subtypes. TEADs functions are mediated by their interaction with nuclear co-activators, YAP being the primary nuclear co-activator interacting with TEADs.

YAP/TAZ-TEADs activation promotes tumor development, and inhibition of YAP/TAZ interaction with TEADs has potential in treating tumors. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP/TAZ-TEADs complex is often overactivated or overexpressed, resulting in cancer progression. This over-activation is typically caused by alterations in genes upstream of the Hippo signaling pathway, especially in malignant mesothelioma patients, 40% -50% of tumor NF2 mutations or deletions, <25% of tumor MST1 or LAST1/2 mutations or deletions, 70% of YAP is highly expressed, and over-activation of the YAP/TAZ-TEADs complex helps promote proliferation, metastasis, epithelial to mesenchymal transition (EMT) and maintenance of tumor stem cells. The interaction of YAP and TEADs is critical for initiating transcription programs to drive tumorigenesis and proliferation, and DNA binding domain defect TEADs is capable of blocking gene mutation mediated tumorigenesis upstream of the Hippo signaling pathway, suggesting that inhibiting YAP/TAZ interactions with TEADs has an anti-tumor effect. INVENVA PHARMA discloses that inhibition of YAP/TAZ interaction with TEADs can significantly inhibit proliferation of tumor cells (WO 2017064277). Other researches also show that the downstream proteins CTGF and CYR61 of YAP/TAZ-TEADs can induce tumor cells to generate drug resistance to chemotherapeutics such as taxol and the like, and YAP/TAZ-TEADs has become an alternative survival way of drug resistant cancer cells. These all demonstrate the potential to inhibit YAP/TAZ interactions with TEADs for the treatment of tumors, particularly those that are overactive or mutated upstream of the Hippo signaling pathway.

Some YAP/TAZ and TEADs interaction inhibitors (VT-01, IK-930) have entered the clinical stage at present, and YAP/TAZ and TEADs interaction inhibition may be promising novel anti-tumor therapies.

Disclosure of Invention

The invention provides a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof; the compound can obviously inhibit the activity of TEAD transcription as a TEAD inhibitor, and can be used for preventing and/or treating diseases related to the increase of TEAD expression.

In a first aspect of the invention, there is provided a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

Wherein,

Ring A is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;

ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;

Each X ₁、X₂、X₃ is independently N or CR _a;

W is O, NH;

L is absent or-CH ₂-、-CH₂CH₂-、-CH₂CH₂CH₂ -;

R ₁、R₂、R_a is each independently hydrogen, halogen, hydroxy, amino, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, -SF ₅, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl; the C ₁-C₆ alkyl, C ₁-C₆ alkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl optionally substituted with 1,2 or 3 substituents, the same or different, selected from the group consisting of: halogen, hydroxy, amino, -SF ₅、C₁-C₆ alkyl;

When R ₁ is plural, the R ₁ are the same or different;

When R ₂ is plural, the R ₂ are the same or different;

When R _a is plural, the R _a are the same or different;

Each R ₃、R₄ is independently selected from: hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl;

m is 0,1,2 or 3;

n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention,For-W-L-is-NH-CH ₂ -or-O-CH ₂ -.

In a preferred embodiment, ring A is a 6-12 membered bicyclic saturated carbocycle; preferably, ring A is

In a preferred embodiment of the present invention,Is that

In a preferred embodiment, ring B is a 6-12 membered bicyclic or 8-15 membered tricyclic ring, said 6-12 membered bicyclic or 8-15 membered tricyclic ring being a 5 membered N-containing heteroaromatic ring and being a saturated heterocycle; preferably, the 6-12 membered bicyclic or 8-15 membered tricyclic ring is an imidazo saturated heterocycle.

In a preferred embodiment, when ring B is a 6-12 membered bicyclic ring, ring B isWherein ring B' is a5 membered heteroaryl ring having 1, 2,3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when the heteroatoms are plural; ring B "is a 5-or 6-membered saturated heterocyclic ring having 1, 2,3 or 4 heteroatoms selected from N, O, S, which are the same or different when the heteroatoms are plural.

In a preferred embodiment, when ring B is a 6-12 membered bicyclic ring, ring B isWherein ring B "is a 5-or 6-membered saturated heterocyclic ring having 1,2,3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when the number of heteroatoms is plural.

In a preferred embodiment, ring B is a 6-12 membered bicyclic ring, -L-W-is not-O-orNot benzene rings or pyridine.

In a preferred embodiment of the present invention,Is that

In a preferred embodiment, -W-L-is-NH-CH ₂-、-O-CH₂ -, -NH-, -O-; preferably, -L-W-is-NH-CH ₂ -or-O-CH ₂ -.

In a preferred embodiment, when ring B is an 8-15 membered tricyclic ring, ring B isWherein ring B' "is a 6-10 membered fused ring; preferably, ring B' "is a 6-10 membered saturated and ring, optionally containing 1,2 or 3 heteroatoms; preferably, the ring B is

In a preferred embodiment of the present invention,Does not contain a group covalently bound to an amino acid residue; preferably, wherein each R ₂、R₃、R₄ is independently hydrogen or C ₁-C₆ alkyl; more preferably, each R ₂、R₃、R₄ is independently hydrogen or methyl.

In a preferred embodiment, the compound of formula I has the structure:

Wherein,

Ring A is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring;

Ring B is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring;

Each X ₁、X₂、X₃ is independently N or CRa;

W is O, NH;

L is absent or-CH ₂-、-CH₂CH₂-、-CH₂CH₂CH₂ -;

r ₁、R₂, ra are each independently hydrogen, halogen, hydroxy, amino, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, -SF ₅, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl; the C ₁-C₆ alkyl, C ₁-C₆ alkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl optionally substituted with 1, 2 or 3 substituents, the same or different, selected from the group consisting of: halogen, hydroxy, amino, -SF ₅、C₁-C₆ alkyl;

When R ₁ is plural, the R ₁ are the same or different;

When R ₂ is plural, the R ₂ are the same or different;

When Ra is plural, the R _a are the same or different;

m is 0,1,2 or 3;

n is 0, 1, 2 or 3.

In a preferred embodiment, the compound of formula I satisfies one or more of the following conditions:

i) R ₁ is-SF ₅;

ii) X ₁、X₂ is N;

iii) Ring a is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;

iv) ring B is a 6-12 membered bicyclic ring, and-L-W-is not-O-;

in a preferred embodiment, the ring a is a saturated carbocyclic ring; preferably, the ring A is a parallel ring or a spiro ring.

In a preferred embodiment, ring B isWherein ring B' is an aromatic ring having 1,2, 3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when the number of heteroatoms is plural;

ring B "is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1,2, 3 or 4 (preferably 1 or 2) heteroatoms selected from N, O, S, said heteroatoms being the same or different when the heteroatoms are plural.

In a preferred embodiment, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has a structure of formula II

Wherein each R ₂₁、R₂₂ is independently selected from: hydrogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl; or alternatively

R ₂₁、R₂₂ together with the imidazole to which they are attached form ring B'; ring B "is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1,2, 3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when there are multiple heteroatoms;

The ring B "is optionally substituted with 1,2 or 3 identical or different R ₂; the R ₂ is selected from halogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl.

In a preferred embodiment, the compound of formula II satisfies one or more of the following conditions:

i) R ₁ is-SF ₅;

ii) X ₁、X₂ is N;

iii) Ring a is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;

iv) R ₂、R₃ together with the groups to which they are jointly attached form a ring B ", and-L-W-is not-O-;

v) R ₁ is fluoromethyl, fluoroethyl, fluoropropyl; preferably, the fluoromethyl group is-CF ₃、CH₂F、CHF₂;

vi) ring A is a benzene ring;

vii) R ₂₁ is methyl, R ₂₂ is H;

viii) -W-L-is-NH-CH ₂ -.

In a preferred embodiment, the radicalsFor

In a preferred embodiment, the ring A is

In a preferred embodiment of the present invention,Is that

In a preferred embodiment of the present invention,ForIn a preferred embodiment,ForIn a preferred embodiment,ForIn a preferred embodiment, each R ₁ is independently F or methyl.

In a preferred embodiment of the present invention,For

In a preferred embodiment of the present invention,Is that

In a preferred embodiment, R ₁ is F or methyl.

In a preferred embodiment, X ₁、X₂ is N.

In a preferred embodiment, X ₁ is CRa and X ₂ is N.

In a preferred embodiment, X ₁、X₂ is CRa.

In a preferred embodiment, ra is hydrogen.

In a preferred embodiment, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has a structure of formula Ia

Preferably, X ₁、X₂ is N;

preferably, X ₁ is CH and X ₂ is N;

Preferably, X ₁、X₂ is CH.

In a preferred embodiment, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has a structure of formula Ib

Preferably, X ₁、X₂ is N;

preferably, X ₁ is CH and X ₂ is N;

Preferably, X ₁、X₂ is CH.

In a preferred embodiment, the compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has a structure of formula Ic

In a preferred embodiment, X ₁、X₂ is N.

In a preferred embodiment, X ₁ is CH and X ₂ is N.

In a preferred embodiment, X ₁、X₂ is CH.

In a preferred embodiment, R ₂ is methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl.

In a preferred embodiment, R ₂ is methyl.

In a preferred embodiment, the compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has a structure of formula Ic-1, formula Ic-2 or formula Ic-3

In a preferred embodiment of the present invention,For

In a preferred embodiment, R ₁ is F or-CH ₃.

In a preferred embodiment, ring B "is a 5 or 6 membered saturated heterocyclic ring, said heteroatom being selected from N or O.

In a preferred embodiment, the radicalsSelected from the group consisting of

Preferably, the method comprises the steps of,For

In a preferred embodiment, the compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has structure Id

Preferably, X ₁ is N, X ₂ is CH, R ₂ is methyl, ethyl or propyl, W is O, NH;

Preferably, R ₂ is methyl;

preferably, L is-CH ₂ -;

Preferably, the method comprises the steps of, For

In a preferred embodiment, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has the structure If

Wherein R ₁、R₂, W, L are as defined above;

Preferably, R ₁ is fluoromethyl, fluoroethyl, fluoropropyl; preferably, the fluoromethyl group is-CF ₃、CFH₂、CF₂ H;

preferably, ring A is a benzene ring;

preferably, R ₂₁ is methyl and R ₂₂ is H;

preferably, -W-L-is-NH-CH ₂ -;

Preferably, the method comprises the steps of, For

In a preferred embodiment, W is O or-NH-, L is absent or-CH ₂.

In a preferred embodiment, W is O and L is absent.

In a preferred embodiment, W is O and L is-CH ₂ -.

In a preferred embodiment, W is-NH-and L is absent.

In a preferred embodiment, W is-NH-, and L is-CH ₂ -.

In a preferred embodiment, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, has structure Ie

Wherein,Is an 8-15 membered tricyclic ring.

In a preferred embodiment of the present invention,For

In a preferred embodiment of the present invention,Is that

In a preferred embodiment, the first and second embodiments,Selected from: Preferably,/> For

In a preferred embodiment, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is selected from the group consisting of:

In a preferred embodiment, the "group covalently bound to an amino acid residue" refers to a group capable of covalently binding an amino acid residue (e.g., cysteine, lysine, histidine, or other residue capable of being covalently modified) present in a binding pocket of a target protein (e.g., TEAD) to irreversibly inhibit the protein. In some embodiments, refers to a group capable of covalently binding Cys359 of hTEAD1, cys405 of hTEAD1, cys380 of hTEAD2, cys368 of hTEAD3, and/or Cys367 of hTEAD 4. In some embodiments, a group capable of covalently binding Ser356 of hTEAD1, ser345 of hTEAD2, and/or Ser365 of Ser377, hTEAD3, and/or Ser364 of hTEAD 4. In some embodiments, refers to a group capable of covalently binding Lys336 of hTEAD1, lys357 of hTEAD2, lys345 of hTEAD3, and/or Lys344 of hTEAD 4.

In a preferred embodiment, the "group covalently bound to an amino acid residue" contains a "leaving group," which is a group that undergoes nucleophilic displacement, including, but not limited to, halogen-, alkenyl-, alkynyl-, nitro-, oxo-containing groups. Suitable leaving groups are well known in the art, see, for example, "Advanced Organic Chemistry", jerry March,5th Ed. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium moieties. Examples of suitable leaving groups include, but are not limited to, chloro, iodo, bromo, fluoro, acetoxy, methanesulfonyloxy (methanesulfonyloxy), toluenesulfonyloxy, trimethylsulfonyloxy, nitro-phenylsulfonyloxy (nosyloxy) and bromo-phenylsulfonyloxy (brosyloxy), oxo 、NO₂、CN、-NHC(O)CH＝CH₂、-C(O)CH＝CH₂、-CH₂CH＝CH₂、-C(O)OCH₂Cl、-C(O)OCH₂F、-C(O)OCH₂CN、-C(O)CH₂Cl、-C(O)CH₂F、-C(O)CH₂CN、-CH₂C(O)CH₃、-S(O)₂-F、-O- pyridinyl, -O-pyrimidinyl, -O-CF ₃, substituted(E.g.)。

Typical non- "leaving groups" are alkyl groups, such as methyl. For example Not "groups covalently bound to amino acid residues".

In a second aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as described in any one of the first aspects, and a pharmaceutically acceptable carrier.

In a third aspect, the present invention provides a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, comprising:

Preparing a medicament, pharmaceutical composition or formulation for preventing and/or treating a disease associated with increased expression of TEAD; and/or the number of the groups of groups,

Preparing a medicament, pharmaceutical composition or formulation for reducing/inhibiting TEAD expression, increased TEAD activity; and/or the number of the groups of groups,

Preparing a medicament, pharmaceutical composition or formulation for reducing/inhibiting the Hippo signaling pathway;

In a preferred embodiment, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.

In a preferred embodiment, the disease is a cell proliferative disorder.

In a preferred embodiment, the cell proliferative disorder is cancer.

In a preferred embodiment, the cancer is selected from: mesothelioma, ovarian cancer, cholangiocarcinoma, hematologic cancer, lymphoma, myeloma, leukemia, cancers of the nervous system, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer, and vascular cancer.

The present invention also provides a method of treating a disease comprising administering to a patient a therapeutically effective amount of at least one of a compound of formula (I), a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, or pharmaceutical composition thereof.

In a preferred embodiment of the invention, the disease is a disease associated with increased TEAD expression. The TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4.

In a preferred embodiment of the invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.

In some embodiments, the patient mammal, preferably a human.

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.

Advantageous effects

The present inventors have made extensive and intensive studies and have unexpectedly developed a novel TEAD inhibitor, particularly a TEAD inhibitor which does not contain a group covalently bonded to an amino acid residue; the TEAD inhibitor can obviously inhibit the activity of TEAD transcription, and can be used for preventing and/or treating diseases related to the increase of TEAD expression; the TEAD inhibitor has excellent pharmacokinetic property, good patentability and obvious effect of inhibiting the growth of the NCI-H226 mesothelioma.

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.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

The definition of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED," vols. A (2000) and B (2001), plenum Press, new York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, 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 invention. 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 equivalent to OCH ₂. As used herein,Representing the attachment site of the group. As used herein, "R ₁," "R1," and "R ¹" are synonymous and interchangeable. For other symbols such as R ₂, the meaning of like definition is the same.

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.

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 0 to 5" should be understood to describe each integer of 0, 1,2, 3,4, and 5.

In the present application, the term "halogen" means fluorine, chlorine, bromine, iodine, alone or as part of other substituents.

As used herein, the term "alkyl" alone or as part of another substituent means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, free of unsaturation, having, for example, 1 to 6 carbon atoms, and linked to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl and hexyl. The alkyl group may be unsubstituted or substituted with one or more suitable substituents. The alkyl group can also be an isotopic isomer of a naturally abundant alkyl group that is enriched in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

The term "C ₁-C₆ alkyl" when used alone or as part of another substituent is understood to mean a straight or branched chain 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. The term "C ₁-C₃ alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2 or 3 carbon atoms. In particular, the groups have 1,2 or 3 carbon atoms ("C ₁-C₃ alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

The term "cycloalkyl" or "carbocyclyl" alone or as part of another substituent refers to a cyclic alkyl group. The term "m-n membered cycloalkyl" or "C _m-C_n cycloalkyl" is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-10 membered cycloalkyl" or "C ₃-C₁₀ cycloalkyl" refers to a cyclic alkyl group containing 3 to 10 carbon atoms, which may contain 1 to 3 rings. The cyclic alkyl group includes a single ring, a double ring, a triple ring, a spiro ring or a bridged ring. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, cycloalkyl groups may be cycloalkyl groups fused to aryl or heteroaryl groups.

The term "heterocycloalkyl", "heterocycle" or "heterocyclyl", when used alone or as part of another substituent, refers to cycloalkyl groups in which one or more (in some embodiments 1,2, or 3) carbon atoms are replaced with heteroatoms such as, but not limited to N, O, S and P. The term "m-n membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms. For example, the term "5-10 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 5 to 10 atoms. In some embodiments, the heterocycloalkyl group can be a heterocycloalkyl group fused with an aryl or heteroaryl group.

The term "heteroaryl" or "heteroaryl ring" when used alone or as part of another substituent means a monocyclic or polycyclic aromatic ring system in which 1 to 3 atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to N, O, S or P. Such as furyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl. Heteroaryl groups may optionally be fused to a benzene ring and may also be monocyclic, bicyclic, tricyclic, spiro, or bridged.

The term "halo" may be used interchangeably with the term "halo substituted" alone or as part of another substituent. "haloalkyl" or "halogen substituted alkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the 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.

The term "bicyclic" or "bicyclic" refers to two rings sharing one or more atoms, including spiro or fused rings.

The term "spiro" refers to a polycyclic group, alone or as part of another substituent, that shares a single carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably a single spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:

the term "fused ring" refers to the sharing of 2 or more atoms (called spiro atoms) between two monocyclic rings, which may contain one or more double bonds. The monocyclic ring may be a saturated, unsaturated or partially unsaturated ring. The monocyclic ring may be carbocyclyl, heterocycloalkyl, or heteroaryl.

Compounds provided herein, including intermediates useful in the preparation of compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof. "protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like, as well as isotopes and the like. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable hydroxyl protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.

In the present application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. 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.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. 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.

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.

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. The absolute configuration of a solid center is represented by wedge-shaped keys and dashed keys.

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.

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

In the present application, the term "solvate" means that the compound of the present application or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent which is bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.

In the present application, the term "prodrug" refers to a compound of the present application that can be converted into a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the application 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 application 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 a radioisotope, such as deuterium (² H), tritium (³ H), iodine-125 (¹²⁵ I) or C-14 (¹⁴ C). 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.

In the present application, 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. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively

(Iv) Alleviating symptoms caused by the disease or condition.

The reaction temperature of each step may be appropriately selected depending on the solvent, starting material, reagent, etc., and the reaction time may be appropriately selected depending on the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is finished, the target compound can be separated and purified from the reaction system according to a common method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and the like. Under the condition of not influencing the next reaction, the target compound can also directly enter the next reaction without separation and purification. The various steps of the reaction of the present invention are preferably carried out in an inert solvent including, but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.

Detailed Description

The invention will be further illustrated with reference to specific examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. Upon a complete understanding of the present invention, experimental methods without specific references in the following examples, generally according to conventional conditions or according to conditions suggested by the manufacturer, may make insubstantial changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of the present invention.

Preparation of intermediate A1

5-Bromo-6-chloropyridine-3-sulfonyl chloride (10.0 g,34.4 mmol) was dissolved in dichloromethane (50 mL), N-diisopropylethylamine (8.89 g,68.8 mmol) was added, nitrogen blanketed, and 1- (4-methoxyphenyl) -N-methyl methylamine (5.20 g,34.4 mmol) was added at 0deg.C and stirred at room temperature for 2 hours. The reaction solution was washed with water (20 ml×2), the organic phase was collected and concentrated to give a crude product which was slurried with petroleum ether/ethyl acetate (120 mL, v: v=10:1), the cake was collected by filtration, and the compound 5-bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A1) (11.86 g, yield: 85.0%) was obtained after drying in vacuo.

LC-MS,M/Z(ESI):405.1[M+H]⁺。

Preparation of intermediate A2

The first step: synthesis of methyl (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 a) and methyl (1R, 3r, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 b)

Cyclopent-3-ene-1-carboxylic acid methyl ester (10.0 g,79.3 mmol) was dissolved in tetrahydrofuran (100 mL), sodium iodide (6 g,40.0 mmol) was added, and (trifluoromethyl) trimethylsilane (28.2 g,198.3 mmol) was added and the reaction was refluxed overnight. After the completion of the reaction, the reaction mixture was concentrated, the residue was dissolved in methylene chloride (100 mL), washed with a sodium thiosulfate solution (0.1 m,50 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (V/V) =49:1) to give methyl (1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 a) (9.06 g, yield 64.9%) and methyl (1 r,3r,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 b) (2.46 g, yield 17.6%) respectively.

A2-2a:¹H NMR(600MHz,CDCl3)δ3.68(s,3H),2.88–2.79(m,1H),2.31–2.19(m,4H),2.03–1.98(m,2H).

A2-2b：¹H NMR(600MHz,CDCl3)δ3.66(s,3H),3.17–3.10(m,1H),2.40–2.26(m,4H),2.05–1.97(m,2H).

And a second step of: synthesis of (1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-carboxamide (A2-3)

Methyl (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 a) (1.0 g,5.7 mmol) was dissolved in an methanolic ammonia solution (10 mL, 7M) and stirred at room temperature for two days. After the reaction was completed, the reaction mixture was concentrated to obtain a crude white solid, (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxamide (A2-3) (0.91 g, yield 99.0%) which was directly used for the next reaction.

Fourth step: synthesis of ((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methylamine (A2-4)

(1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-carboxamide (A2-3) (0.9 g,5.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium aluminum hydride (0.43 g,11.2 mmol) was added at 0deg.C under argon, and the reaction was refluxed overnight. After the completion of the reaction, the mixture was cooled to room temperature, quenched with water (1 mL) at 0℃for 15 minutes under stirring, then with 15% aqueous sodium hydroxide (0.5 mL) under stirring at room temperature for 15 minutes, filtered, and the cake was washed with ethyl acetate (50 mL), and the filtrate was collected, dried over anhydrous sodium sulfate and concentrated to give crude ((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) methylamine (A2-4) (0.6 g, yield 73.2%) as a yellow oil, which was used directly in the next reaction.

Fifth step: synthesis of 5-bromo-6- ((((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A2)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A2-4) (182 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), ((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) methylamine (66 mg,0.45 mmol) was added and reacted with N, N-diisopropylethylamine (174 mg,1.35 mmol) at 120℃for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:2) to give 5-bromo-6- ((((1 r,3s,5 s) -6, 6-difluoro bicyclo [3.1.0] hexane-3-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A2) (100 mg, yield 43.0%).

LC-MS,M/Z(ESI):517.1[M+H]⁺

Preparation of intermediate A3

Referring to the procedure for intermediate A2, (1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylic acid methyl ester (A2-2 a) was replaced with (1 r,3r,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylic acid methyl ester (A2-2 b) to afford intermediate A3.

Preparation of intermediate A4

The synthetic route is as follows:

the first step: synthesis of (1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-carboxylic acid (A4-1)

Methyl (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 a) (1.0 g,5.7 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide (682.6 mg,28.5 mmol) and water (5 mL) were added, methanol (5 mL) was further added, and stirring was continued at room temperature overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (5 mL) was added to the residue, the pH of the solution was then adjusted to 6 with dilute hydrochloric acid (2 mol/L), followed by extraction with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylic acid (A4-1) (0.8 g, yield 87.0%).

¹H NMR(400MHz,CDCl₃)δ10.46(s,1H),2.94–2.80(m,1H),2.37–2.16(m,4H),2.08–1.96(m,2H).

And a second step of: synthesis of tert-butyl ((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hex-3-yl) carbamate (A4-2)

(1R, 3s, 5S) -6, 6-Difluorobyclo [3.1.0] hexane-3-carboxylic acid (A4-1) (0.8 g,4.9 mmol) and triethylamine (595 mg,5.9 mmol) were added to t-butanol (20 mL), diphenyl azide phosphate (1.48 g,5.4 mmol) was added and the reaction was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, dissolved in ethyl acetate (50 mL), washed with sodium hydrogencarbonate solution (1M, 60 mL), dried over anhydrous sodium sulfate, and concentrated to give crude ((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hex-3-yl) carbamic acid tert-butyl ester (A4-2) which was directly used in the next reaction.

And a third step of: synthesis of (1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-amine hydrochloride (A4-3)

Tert-butyl ((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hex-3-yl) carbamate (A4-2) (1.15 g,4.9 mmol) was dissolved in dioxane hydrochloride (20 mL, 4M) and stirred at room temperature for 2 hours. After the reaction, the mixture was concentrated to give crude (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-amine hydrochloride (A4-3) (0.83 g, yield 100%) as a white solid, which was used directly in the next reaction.

Fourth step: synthesis of 5-bromo-6- (((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A4)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A4-3) (182 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and crude (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-amine hydrochloride (84.8 mg,0.5 mmol) and N, N-diisopropylethylamine (174 mg,1.35 mmol) were added to react the reaction at 120℃for 1.5 hours. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =4:1) to give the compound 5-bromo-6- (((1 r,3s,5 s) -6, 6-difluoro bicyclo [3.1.0] hexane-3-yl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A4) (145 mg, yield 64.2%).

LC-MS,M/Z(ESI):502.1[M+H]⁺

Preparation of intermediate A5

Referring to the procedure for intermediate A4, (1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylic acid methyl ester (A2-2 a) was replaced with (1 r,3r,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylic acid methyl ester (A2-2 b) to afford intermediate A5.

Preparation of intermediate A6

The first step: synthesis of 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A6-2)

To a solution of 1- (4-methoxyphenyl) -N-methyl methylamine (6.63 g,43.9 mmol) and diisopropylethylamine (9.58 mL,54.8 mmol) in dichloromethane (100 ml) was added dropwise 3-bromo-4-fluorobenzene-1-sulfonyl chloride (A6-1) (10 g,36.6 mmol) under nitrogen at 0 ℃. The reaction mixture was stirred under nitrogen at 0 ℃ for 0.5 hours. Then the temperature is raised to 25 ℃ and stirred for 2 hours under the protection of nitrogen. After the completion of the reaction, the reaction mixture was diluted with 100mL of methylene chloride, the organic phase was washed with aqueous hydrochloric acid (0.5M, 150 mL), the organic phase was collected, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give a crude product, which was slurried with petroleum ether/methyl tert-butyl ether (10/1, v/v) (100 mL) to give 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A6-2) (12 g, yield 70.6%).

And a second step of: synthesis of 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A6-3)

To a solution of 3-bromo-4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (A6-2) (12 g,30.9 mmol) and bis-pinacolato borate (11.77 g,46.4 mmol) in 1, 4-dioxane (20 mL) was added anhydrous potassium acetate (6.07 g,61.8 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (2.262 g,3.09 mmol) under nitrogen at 25 ℃. The reaction mixture was stirred at 110℃for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered with celite, and the filtrate was concentrated to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =100:1-1:1) to give 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A6-3) (10.0 g, yield 74.7%) as a white solid.

The first step: synthesis of (R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (A6-5)

2,4, 5-Tribromo-1H-imidazole (17.74 g,58.2 mmol) was dissolved in anhydrous tetrahydrofuran (85 mL), n-butyllithium (2.5M, 23.3mL,58.2 mmol) was added dropwise at-78deg.C under nitrogen protection, stirring was continued at-78deg.C for 45 min after the addition, then (R) -2-methyl ethylene oxide (33.8 g, 552 mmol) was added, stirring was allowed to naturally return to room temperature, the reaction was allowed to proceed for 2 days, quenching reaction was performed by adding 40mL saturated ammonium chloride at 0deg.C, ethyl acetate (100 mL. Times.3) was extracted, the organic phase was dried over anhydrous Na ₂SO₄, filtered, and concentrated to give crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=3:1) to give (R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (A6-5) (13.01 g, yield: 79%) as a white solid.

LC-MS,M/Z(ESI):282.80[M+H]⁺。

And a second step of: synthesis of (R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (A6-6)

(R) -5, 6-dibromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (13.0 g,46.1 mmol) was dissolved in anhydrous tetrahydrofuran (72 mL), n-butyllithium (2.5M, 18.4mL,46.1 mmol) was added dropwise at-78℃and reacted at-78℃for 2 hours, quenched by adding 25mL saturated ammonium chloride at 0℃and extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous Na ₂SO₄, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=3:1) to give (R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (A6-6) (6.88 g, yield: 73.4%) as a white solid.

LC-MS,M/Z(ESI):202.9[M+H]⁺。

And a third step of: synthesis of (R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) benzenesulfonamide (A6)

4-Fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (2.28 g,5.25 mmol) and (R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (1.06 g,5.25 mmol) were dissolved in 1, 4-dioxane (20 mL), followed by 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (0.38 g,0.52 mmol), sodium carbonate (1.38 g,12.98 mmol), water (4 mL). The reaction was carried out at 100℃for 21 hours under nitrogen substitution 3 times. Cooled to room temperature, the reaction solvent was removed by evaporation, water (40 mL) was added, extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1-1:2) gave (R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) benzenesulfonamide (A6) (1.104 g, yield: 48.8%).

LC-MS,M/Z(ESI):432.3[M+H]⁺。

Preparation of intermediate A7

The synthetic route is as follows:

the first step: synthesis of 2- (Benzenothio) -5-chloropyrazine (A7-2)

Benzyl mercaptan (13.8 g,111 mmol) was dissolved in tetrahydrofuran (200 mL), sodium hydride (6.67 g,166 mmol) was added in portions at 0deg.C, stirred at 0deg.C for 2 hours, and 2, 5-dichloropyrazine (18.2 g,122 mmol) was added in portions to the reaction solution, which was then reacted at 0deg.C for 2 hours. The reaction was quenched by slowly dropping a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (100 ml×2), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1 to 0:1) to give the compound 2- (phenylmethylthio) -5-chloropyrazine (A7-2) (25.0 g, yield 95.0%).

And a second step of: synthesis of 5-chloropyrazine-2-sulfonyl chloride (A7-3)

2- (Benzenothio) -5-chloropyrazine (16.0 g,67.6 mmol) and thionyl dichloride (72.9 g,540 mmol) were dissolved in water (100 mL) and dichloromethane (100 mL) and reacted at 0deg.C for 2 hours. The reaction mixture was separated, the aqueous phase was extracted with methylene chloride (100 mL), and the organic phases were combined, washed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated by filtration to give the compound 5-chloropyrazine-2-sulfonyl chloride (A7-3) (14.0 g, yield 97.2%).

And a third step of: synthesis of 5-chloro-N-methyl-pyrazine-2-sulfonamide (A7)

5-Chloropyrazine-2-sulfonyl chloride (14.0 g,65.7 mmol) was dissolved in dichloromethane (90.0 mL), N-diisopropylethylamine (25.5 g, 197mmol) and methylamine hydrochloride (5.32 g,78.8 mmol) were added, and then reacted for 2 hours with stirring at 25 ℃. The reaction solution was added to water (100 mL), followed by extraction with methylene chloride (100 mL), washing the organic phase with saturated brine (100 ml×2), drying over anhydrous sodium sulfate, filtering and concentrating to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1-0:1) to give the compound 5-chloro-N-methyl-pyrazine-2-sulfonamide (A7) (3.00 g, yield 21.9%).

Preparation of intermediate A8

The synthetic route is as follows:

the first step: synthesis of N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A8-1)

5-Chloro-N-methyl-pyrazine-2-sulfonamide (A7, 1.00g,4.82 mmol) and (4- (trifluoromethyl) phenyl) methylamine (1.01 g,5.78 mmol) were dissolved in N, N-dimethylformamide (50.0 mL), N-diisopropylethylamine (3.11 g,14.4 mmol) was added and the reaction stirred at 25℃for 2 hours. The reaction solution was added to water (200 mL), then extracted with ethyl acetate (100 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration to give the compound N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A8-1) (1.20 g, yield 71.9%).

And a second step of: 6-bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A8)

N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (300 mg, 866. Mu. Mol) was dissolved in acetonitrile (8 mL), N-bromosuccinamide (154 mg, 866. Mu. Mol) and carbon tetrachloride (2 mL) were added and the mixture was stirred at 0℃for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 ml×2), the organic phases were combined, concentrated to give a crude product, which was purified by separation on a silica gel column (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) to give the compound 6-bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A8) (200 mg, yield 54.3%).

Preparation of intermediate A9

The synthetic route is as follows:

The first step: synthesis of N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A9-1)

5-Chloro-N-methylpyrazine-2-sulfonamide (93 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and (3- (trifluoromethyl) phenyl) methylamine (236.5 mg,1.35 mmol) was added and reacted at 150℃for 1.5 hours with microwaves. After the completion of the reaction, the mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 mL. Times.3) was extracted, and the organic phases were combined, dried successively with water (20 mL) and anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give the compound N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A9-1) (121.3 mg, yield: 78.2%).

LC-MS,M/Z(ESI):347.1[M+H]⁺。

And a second step of: synthesis of 6-bromo-N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A9)

N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (121.3 mg,0.35 mmol) was dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinimide (90.8 mg,0.51 mmol) was added and reacted overnight at room temperature. After the completion of the reaction, water (20 mL) was added, followed by extraction with ethyl acetate (20 ml×3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=4:1) to give the compound 6-bromo-N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (A9) (118.4 mg, yield: 79.5%).

LC-MS,M/Z(ESI):425.1[M+H]⁺。

Preparation of intermediate A10

The synthetic route is as follows:

The first step: synthesis of 3-azabicyclo [3.1.0] hexane-2-one (A10-2)

Referring to the synthesis method of patent CN114728167A, 3-azabicyclo [3.1.0] hexane hydrochloride (A10-1) is used as a raw material for synthesis to obtain white solid 3-azabicyclo [3.1.0] hexane-2-ketone (A10-2).

¹H NMR(400MHz,DMSO-d6)δ7.02(s,1H),3.37-3.33(m,1H),3.14(d,1H),1.90(dq,1H),1.61(tddd,1H),1.00(dt,1H),0.44(q,1H).

And a second step of: synthesis of methyl 2- (2-oxo-3-azabicyclo [3.1.0] hex-3-yl) acetate (A10-3)

Sodium hydride (480 mg,12.0mmol, 60%) was added to tetrahydrofuran (25 mL) at 0℃under nitrogen, 3-azabicyclo [3.1.0] hexane-2-one (A10-2) (0.97 g,10.0 mmol) was added dropwise to anhydrous tetrahydrofuran (20 mL), and after the addition was completed, the mixture was stirred at room temperature for 30 minutes, and methyl bromoacetate (1.84 g,12.0 mmol) was added thereto and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction was quenched by adding water (20 mL) at 0℃to extract (30 mL. Times.3) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give methyl 2- (2-oxo-3-azabicyclo [3.1.0] hex-3-yl) acetate (A10-3) (1.37 g, yield: 81.0%) as a liquid, which was directly used in the next reaction.

And a third step of: synthesis of 2- (2-oxo-3-azabicyclo [3.1.0] hexane-3-yl) acetamide (A10-4)

Methyl 2- (2-oxo-3-azabicyclo [3.1.0] hex-3-yl) acetate (A10-3) (1.37 g,8.10 mmol) was added to a methanolic ammonia solution (40 mL, 7M) and reacted at 60℃for 4 hours. After the completion of the reaction, the mixture was concentrated to give solid 2- (2-oxo-3-azabicyclo [3.1.0] hexane-3-yl) acetamide (A10-4) (1.23 g, yield: 98.5%) which was used directly in the next reaction.

LC-MS,M/Z(ESI):155.1[M+H]⁺。

Fourth step: synthesis of 2-bromo-5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazole (A10)

(2-Oxo-3-azabicyclo [3.1.0] hexane-3-yl) acetamide (A10-4) (1.23 g,8.0 mmol) was dissolved in acetonitrile (15 mL), followed by addition of phosphorus tribromoxide (4.59 g,16.0 mmol), heating to 80℃and reacting for 3 hours, and stirring at room temperature overnight. After the completion of the reaction, the crude product was concentrated, dichloromethane (50 mL) was added, the pH was adjusted to 8 with saturated aqueous sodium carbonate, separated, aqueous dichloromethane was extracted (50 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give 2-bromo-5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazole (a 10) (0.65 g, yield: 41.0%) as a yellow oil. LC-MS, M/Z (ESI): 199.1[ M+H ] ⁺.

Preparation of intermediate 5A

The synthetic route is as follows:

(2R) -6-bromo-2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazole (5.0 g,24.6 mmol) was dissolved in tetrahydrofuran (30.0 mL), n-butyllithium (2.5M, 19.7 mmol) was slowly added under nitrogen protection at-70℃and reacted at-70℃for 1 hour. Tributyltin chloride (12.0 g,36.9 mmol) was then slowly added under nitrogen at-70℃and the temperature was slowly raised to 25℃for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (V/V) =3/1 to 0/1) to give the compound tributyl- [ (2R) -2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl ] stannane (6.00 g, yield 59.0%).

EXAMPLE 1 preparation of Compound I-1

The synthetic route is as follows:

the first step: synthesis of 5-bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [ [4- (pentafluoro-lambda ⁶ -mercapto) phenyl ] methylamino ] pyridine-3-sulfonamide (B1-2)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (intermediate A1) (2.00 g,10.0 mmol) and (4- (pentafluoro-. Lambda. ⁶ -sulfanyl) phenyl) methylamine (1.99 g,7.39 mmol) were dissolved in N, N-dimethylformamide (15.0 mL), and N, N-diisopropylethylamine (3.82 g,29.6 mmol) was added thereto, and the reaction mixture was warmed to 60℃and reacted for 6 hours. After the completion of the reaction, the reaction solution was concentrated by direct filtration, and separated and purified (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) by a silica gel column to give 5-bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [ [4- (pentafluoro- λ ⁶ -mercapto) phenyl ] methylamino ] pyridine-3-sulfonamide (B1-2) (2.40 g, yield 53.9%).

And a second step of: synthesis of N- [ (4-methoxyphenyl) methyl ] -N-methyl-5- (1-methylimidazol-4-yl) -6- [ [3- (pentafluoro-lambda ⁶ -mercapto) phenyl ] methoxy ] pyridine-3-sulfonamide (B1-3)

5-Bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [ [4- (pentafluoro-lambda ⁶ -mercapto) phenyl ] methylamino ] pyridine-3-sulfonamide (B1-2) (200 mg, 331. Mu. Mol), tributyl- (1-methylimidazol-4-yl) stannane (123 mg, 331. Mu. Mol) was dissolved in toluene (20.0 mL), tetrakis (triphenylphosphine) palladium (38.3 mg, 33.2. Mu. Mol) was added, nitrogen was substituted three times, and reacted at 110℃for 6 hours. After the reaction, the reaction solution was directly filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) to give N- [ (4-methoxyphenyl) methyl ] -N-methyl-5- (1-methylimidazol-4-yl) -6- [ [3- (pentafluoro- λ6-mercapto) phenyl ] methoxy ] pyridine-3-sulfonamide (B1-3) (150 mg, yield 74.9%).

LC-MS,M/Z(ESI):604.1[M+H]⁺

And a third step of: synthesis of N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((4- (pentafluoro-lambda ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (I-1)

N- [ (4-methoxyphenyl) methyl ] -N-methyl-5- (1-methylimidazol-4-yl) -6- [ [3- (pentafluoro-. Lamda. ⁶ -mercapto) phenyl ] methoxy ] pyridine-3-sulfonamide (B1-3) (150 mg, 248. Mu. Mol) was dissolved in trifluoroacetic acid (5.00 mL), and the reaction solution was stirred at 60℃for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, added to water (50.0 mL), the pH of the solution was adjusted to about 7 with a saturated sodium hydrogencarbonate solution, then extracted with ethyl acetate (50 mL. Times.2), and the organic phase was washed with a saturated brine (80 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative high performance liquid chromatography (column: phenomenex luna C, 150, 25mm, 10 μm; solvent: a=water+formic acid (0.05%), b=acetonitrile; gradient: 35% -65%,10 min) to give the compound N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((4- (pentafluoro-l 6-sulfanyl) benzyl) amino) pyridine-3-sulfonamide (I-1) (70.0 mg, 37.8% yield).

LC-MS,M/Z(ESI):484.1[M+H]⁺

¹H NMR(CDCl₃,400MHz)δ9.80(br s,1H),8.46(d,1H),7.95(d,1H),7.70(d,2H),7.45–7.49(m,3H),7.34(d,1H),4.90(d,2H),4.26–4.32(m,1H),3.79(s,3H),2.68(d,3H).

EXAMPLE 2 preparation of Compound I-2

The synthetic route is as follows:

The first step: synthesis of 5-bromo-N- (4-methoxybenzyl) -N-methyl-6- ((4- (pentafluoro-lambda ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (B2-2)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (intermediate A1) (900 mg,2.22 mmol) and (3- (pentafluoro-. Lamda. ⁶ -sulfanyl) phenyl) methylamine (598 mg,2.22 mmol) were dissolved in tetrahydrofuran (5 mL), N-diisopropylethylamine (1.15 g,8.87 mmol) was added, and the reaction was warmed to 55℃and stirred for 6 hours. After the completion of the reaction, the reaction mixture was concentrated by direct filtration, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) to give 5-bromo-N- (4-methoxybenzyl) -N-methyl-6- ((4- (pentafluoro- λ ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (B2-2) (1.00 g, yield 74.8%).

And a second step of: synthesis of N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((4- (pentafluoro-lambda ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (B2-3)

5-Bromo-N- (4-methoxybenzyl) -N-methyl-6- ((4- (pentafluoro-. Lamda. ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (B2-2) (200 mg, 331. Mu. Mol), tributyl- (1-methylimidazol-4-yl) stannane (123 mg, 331. Mu. Mol) was dissolved in toluene (20 mL), tetrakis (triphenylphosphine) palladium (38.3 mg, 33.2. Mu. Mol) was added, nitrogen was substituted three times, and stirred at 110℃for 6 hours. After the reaction, the reaction solution was directly filtered and concentrated. Purification by silica gel column (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) afforded N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((4- (pentafluoro- λ ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (B2-3) (150 mg, yield 74.9%).

LC-MS,M/Z(ESI):604.1[M+H]⁺

And a third step of: synthesis of N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((3- (pentafluoro-lambda ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (I-2)

N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((4- (pentafluoro-. Lamda. ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (B2-3) (150 mg, 248. Mu. Mol) was dissolved in trifluoroacetic acid (5.00 mL) and stirred at 60℃for 2 hours. After completion of the reaction, the reaction mixture was added to water (50 mL), the pH of the solution was adjusted to about 7 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate (50 mL. Times.2), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product. Then isolated by preparative high performance liquid chromatography (column: phenomenex luna C, 150, 25mm, 10 μm; solvent: a=water+formic acid (0.05%), b=acetonitrile; gradient: 36% -66%,10 min) to give the compound N-methyl-5- (1-methyl-1H-imidazol-4-yl) -6- ((3- (pentafluoro- λ ⁶ -sulfanyl) benzyl) amino) pyridine-3-sulfonamide (I-2) (32.0 mg, 17.4%).

LC-MS,M/Z(ESI):484.1[M+H]⁺

¹H NMR(DMSO,400MHz)δ9.86(m,1H),8.22(d,1H),8.01(d,1H),7.83–7.88(m,3H),7.76(d,1H),7.53–7.64(m,2H),7.15–7.22(m,1H),4.87(d,2H),3.75(s,3H),2.40(d,3H).

EXAMPLE 3 preparation of Compound I-5

The synthetic route is as follows:

The first step: synthesis of (R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl)) benzyl) amino) benzenesulfonamide (B5-2)

(R) -4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) benzenesulfonamide (A6) (350 mg,0.81 mmol) and (4- (trifluoromethyl) phenyl) methylamine (709 mg,4.05 mmol) were dissolved in dimethyl sulfoxide (3 mL) and reacted with microwaves at 140℃for 2 hours. Cooled to room temperature, water (20 mL) was added, ethyl acetate was extracted (20 ml×3), the organic phases were combined, washed successively with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was purified by column chromatography over silica gel (petroleum ether: ethyl acetate (V/V) =1:1 to 1:2) to give the compound (R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl)) benzyl) amino) benzenesulfonamide (B5-2) (0.19 g, yield 38.9%).

LC-MS,M/Z(ESI):587.2[M+H]⁺

And a second step of: synthesis of (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (I-5)

(R) -N- (4-methoxybenzyl) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl)) benzyl) amino) benzenesulfonamide (B5-2) (185 mg,0.32 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (20 ml×3), and the crude product was purified by silica gel column chromatography (dichloromethane: methanol (V/V) =10:1) to give compound (R) -N-methyl-3- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (I-5) (59 mg, yield 40.2%).

LC-MS,M/Z(ESI):467.4[M+H]⁺。

¹H NMR(400MHz,DMSO-d6)δ8.55(t,1H),7.75–7.67(m,3H),7.55(d,2H),7.35–7.28(m,2H),6.99(q,1H),6.59(d,1H),5.50–5.40(m,1H),4.61(d,2H),4.38(dd,1H),3.85(dd,1H),2.34(d,3H),1.53(d,3H). EXAMPLE 4 preparation of Compound I-6

The synthetic route is as follows:

The first step: synthesis of 5-bromo-N- (4-methoxybenzyl) -N-methyl-6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B6-2)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (intermediate A1) (3.00 g,7.39 mmol) was dissolved in dimethyl sulfoxide (40.0 mL), N-diisopropylethylamine (2.87 g,22.1 mmol) and (4- (trifluoromethyl) phenyl) methylamine (1.68 g,9.61 mmol) were added, and the reaction was stirred at 90℃for 8 hours. To the reaction solution was added water (200 mL), followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound 5-bromo-N- (4-methoxybenzyl) -N-methyl-6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B6-2) (3.80 g, yield 94.4%).

LC-MS,M/Z(ESI):545.1[M+H]⁺.

And a second step of: synthesis of (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B6-3)

5-Bromo-N- (4-methoxybenzyl) -N-methyl-6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B6-2) (227 mg, 968. Mu. Mol) and tributyl- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) stannane (intermediate 5A,438mg,1.06 mmol) were dissolved in toluene (5 mL), tetrakis (triphenylphosphine) palladium (111 mg, 96.8. Mu. Mol) was added and stirred under nitrogen at 110℃for 4 hours. The reaction solution was added to water (200 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by column chromatography over silica gel (petroleum ether: ethyl acetate (V/V) =50:1 to 0:1) to give the compound (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B6-3) (250 mg, yield 43.9%)

LC-MS,M/Z(ESI):588.1[M+H]⁺

And a third step of: (R) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (I-6)

(R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (150 mg, 255. Mu. Mol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 60℃for 2 hours. The reaction solution was added to a saturated aqueous potassium carbonate solution, the pH was adjusted to 7 with 1M diluted hydrochloric acid, followed by extraction with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was isolated and purified by preparative high performance liquid chromatography (column: YMC TRIART C18150 x 25mm x 5 μm; solvent: a=water+0.05 volume formic acid (99%), b=acetonitrile; gradient: 51% -81%,8.5 min) to give the compound (R) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((4- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (I-6) (29.8 mg, 23.7% yield).

LC-MS,M/Z(ESI):468.2[M+H]⁺

¹H NMR(DMSO-d₆)δ9.18(m,1H),8.20(d,1H),7.92(d,1H),7.69(d,2H),7.53(d,2H),7.49(s,1H),7.19(m,1H),5.37–5.55(m,1H),4.83(d,2H),4.39(m,1H),3.86(m,1H),2.41(d,3H),1.53(d,3H)

Example 5: preparation of Compound I-7

The synthetic route is as follows:

The first step: synthesis of 5-bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [ [3- (trifluoromethyl) phenyl ] methylamino ] pyridine-3-sulfonamide (B7-2)

5-Bromo-6-chloro-N- [ (4-methoxyphenyl) methyl ] -N-methyl-pyridine-3-sulfonamide (intermediate A1) (600 mg,1.48 mmol) and [3- (trifluoromethyl) phenyl ] methylamine (284 mg,1.63 mmol) were dissolved in dimethyl sulfoxide (5.00 mL), N-diisopropylethylamine (573 mg,4.44 mmol) was added, and the mixture was heated to 90℃for 2 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (50.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give the compound 5-bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [ [3- (trifluoromethyl) phenyl ] methylamino ] pyridine-3-sulfonamide (B7-2) (800 mg, yield 99.3%) as a brown oil.

And a second step of: synthesis of (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((3- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B7-3)

5-Bromo-N- [ (4-methoxyphenyl) methyl ] -N-methyl-6- [ [3- (trifluoromethyl) phenyl ] methylamino ] pyridine-3-sulfonamide (B7-2) (800 mg,1.47 mmol) and tributyl- [ (2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl ] stannane (667 mg,1.62 mmol) were dissolved in toluene (5 mL), tetrakis (triphenylphosphine) palladium (169 mg, 146. Mu. Mol) was added and the mixture was heated to 100℃for reaction for 6 hours. After the reaction was completed, the reaction solution was directly filtered, concentrated, and purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) to give the compound (R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((3- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B7-3) (600 mg, yield 69.5%).

And a third step of: synthesis of (R) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -6- ((3- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (I-7)

(R) -N- (4-methoxybenzyl) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((3- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (B7-3) (600 mg,1.02 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred at 60℃for 2 hours. After the reaction, the reaction mixture was added to water (50 mL), pH was adjusted to 7 with saturated aqueous potassium carbonate, extracted with ethyl acetate (50 ml×2), the organic phases combined, washed with saturated brine (80 mL), dried over sodium sulfate, and concentrated to give a crude product. Then, the compound (R) -N-methyl-5- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -6- ((3- (trifluoromethyl) benzyl) amino) pyridine-3-sulfonamide (I-7) (200 mg, 39.4% yield) was obtained by separation and purification by preparative high performance liquid chromatography, separation method being (column: YMC TRIART C18.150X 25mm X5 um; solvent: A=water+formic acid (0.05%), B=acetonitrile; gradient: 50% -70%,10 min).

LC-MS,M/Z(ESI):468.1[M+H]⁺

¹H NMR(CDCl₃,400MHz)δ8.53(s,1H),7.96-8.07(m,1H),7.40-7.71(m,6H),7.27(s,1H),7.11-7.15(m,1H),5.44-5.50(m,1H),4.95(s,2H),4.38(br d,1H),3.85(br d,1H),2.71(s,3H),1.68(d,3H).

Example 6: preparation of Compound I-11

The synthetic route is as follows:

the first step: synthesis of methyl 2- (3-oxo-morpholine) acetate (B11-2)

Morpholin-3-one (B11-1) (10.0 g,98.9 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (4.35 g,109 mmol) was added in portions, the reaction was stirred at 25℃for 1 hour, and methyl bromoacetate (16.6 g,109 mmol) was added to the reaction and stirred at 25℃for 9 hours. To the reaction solution was slowly added water (200 mL), followed by extraction with methylene chloride (200 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to give crude methyl 2- (3-oxomorpholine) acetate (B11-2) (15.0 g, yield 87.6%).

And a second step of: synthesis of 2- (3-oxo-morpholine) acetamide (B11-3)

Methyl 2- (3-oxomorpholine) acetate (B11-2) (3.00 g,17.3 mmol) was dissolved in methanol (10.0 mL), and methanolic ammonia (7M, 30 mL) was added to the reaction mixture and reacted at 60℃for 4 hours. The reaction mixture was concentrated directly to give crude 2- (3-oxo-morpholine) acetamide (B11-3) (1.20 g, yield 43.8%).

And a third step of: synthesis of 2-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B11-4)

2- (3-Oxo-morpholine) acetamide (B11-3) (1.00 g,6.32 mmol) was dissolved in acetonitrile (10.0 mL) and phosphorus tribromooxide (9.06 g,31.6 mmol) was added under nitrogen and reacted at 90℃for 2 hours. To the reaction solution was added a saturated potassium carbonate solution (100 mL), followed by extraction with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 2-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B11-4) (800 mg, yield 62.3%).

LC-MS,M/Z(ESI):203.0[M+H]+。

Fourth step: synthesis of 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B11-5)

2-Bromo-6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazine (B11-4) (476 mg,2.34 mmol) and 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A6-3) (1.02 g,2.34 mmol) were dissolved in acetonitrile (10.0 mL) and water (5.0 mL), potassium carbonate (648 mg,4.69 mmol) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (171 mg, 234. Mu. Mol) were added, and then reacted under nitrogen protection at 95℃for 10 hours with stirring. The reaction solution was concentrated to give a crude product, which was then separated by preparative high performance liquid chromatography (column: 3PhenomenexLuna C18 150*40mm*15 μm; solvent: a=water+trifluoroacetic acid (0.05%), b=acetonitrile; gradient: 20% -50%,11 minutes) to give 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B11-5) (200 mg, yield 19.8%).

Fifth step: synthesis of 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- (((4- (trifluoromethyl) phenyl) methyl) amino) benzenesulfonamide (168-6)

5- (Trifluoromethyl) pyridin-2-amine (147 mg, 904. Mu. Mol) and 3- (5, 6-dihydro-8H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -4-fluoro-N- (4-methoxybenzyl) -N-methylbenzenesulfonamide (B11-5) (195 mg, 452. Mu. Iota mol) were dissolved in N, N-dimethylformamide (5.0 mL), sodium hydride (27.1 mg,678 mol) was added at 0℃and the mixture was reacted at 20℃under nitrogen for 1 hour. The reaction was added dropwise to 1M hydrochloric acid (100 mL), neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to give a crude product. Then, the mixture was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =50:1 to 5:1) to give 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- (((4- (trifluoromethyl) phenyl) methyl) amino) benzenesulfonamide (B11-6) (150 mg, yield 57.9%).

Sixth step: 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- (((4- (trifluoromethyl) phenyl) methyl) amino) benzenesulfonamide (I-11)

3- (6, 8-Dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N- (4-methoxybenzyl) -N-methyl-4- (((4- (trifluoromethyl) phenyl) methyl) amino) benzenesulfonamide (200 mg, 349. Mu. Mol) was dissolved in trifluoroacetic acid (7.70 mg,67.5 mmol) and reacted at 60℃for 2 hours. The reaction solution was added to water (40.0 mL), neutralized with saturated sodium hydrogencarbonate solution, then extracted with ethyl acetate (40.0 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. Then isolated by reverse phase preparative high performance liquid chromatography (column: 3_PhenomenexLuna C18 150*25mm*10 μm; solvent: a=water+formic acid (0.05%), b=acetonitrile; gradient: 32% -62%,9 min) to give 3- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-2-yl) -N-methyl-4- (((4- (trifluoromethyl) phenyl) methyl) amino) benzenesulfonamide (I-11) (35.0 mg, 31.4% yield).

LC-MS,M/Z(ESI):467.2[M+H]⁺。

¹HNMR(400MHz,CDCl3)δ7.87(d,1H),7.58(d,2H),7.49-7.46(m,3H),7.28(s,1H),6.52(d,1H),4.86(s,2H),4.59(s,2H),4.24(b,1H),4.11(s,4H),2.61(s,3H),.

Example 7: preparation of Compound I-14

The synthetic route is as follows:

The first step: synthesis of 6- ((((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B14-2)

5-Bromo-6- ((((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (intermediate A2) (100 mg,0.19 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (70.5 mg,0.19 mmol) and tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) were added, and the mixture was stirred overnight at 120 ℃. After the completion of the reaction, the reaction mixture was cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred at room temperature for 30 minutes, then water (20 mL) was added, ethyl acetate (20 ml×3) was added, the organic phases were combined, dried successively with water (20 mL), anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give compound 6- ((((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B14-2) (80 mg, yield 79.8%).

LC-MS,M/Z(ESI):518.3[M+H]⁺

And a second step of: synthesis of 6- ((((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-14)

6- ((((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexyl-3-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B14-2) (80 mg,0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution until the aqueous phase had a pH of 7-8, and the organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane: methanol (V/V) =10:1) to give 6- ((((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-14) (28 mg, yield 45.6%).

LC-MS,M/Z(ESI):398.3[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ9.51(t,1H),8.23(d,1H),7.94(d,1H),7.85(s,1H),7.81(d,1H),7.14(q,1H),3.74(s,3H),3.49(t,2H),2.41(d,3H),2.29–2.18(m,1H),2.14–2.03(m,4H),1.83–1.72(m,2H).

EXAMPLE 8 preparation of Compound I-15

Referring to the preparation of compound I-14, intermediate A2 is replaced with intermediate A3 to give compound 6- ((((1 r,3r,5 s) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-15).

LC-MS,M/Z(ESI):398.3[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ9.46(t,1H),8.23(d,1H),7.95–7.92(d,1H),7.84(s,1H),7.81(d,1H),3.74(s,3H),3.42(dd,2H),2.75(dd,1H),2.41(d,3H),2.28–2.16(m,3H),2.15–2.00(m,2H),1.83–1.71(m,1H),1.48–1.41(m,1H).

EXAMPLE 9 preparation of Compound I-16

The synthetic route is as follows:

The first step: synthesis of 6- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexyl-3-yl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B16-2)

5-Bromo-6- (((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (intermediate A4) (95.5 mg,0.19 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (70.5 mg,0.19 mmol) was added and reacted with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol), under argon, overnight at 120 ℃. After the completion of the reaction, the reaction mixture was cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =1:1), to give 6- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B16-2) (68 mg, yield: 71.1%).

LC-MS,M/Z(ESI):504.2[M+H]⁺

And a second step of: synthesis of 6- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexyl-3-yl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-16)

6- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexyl-3-yl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B16-2) (68 mg,0.14 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution until the aqueous phase had a pH of 7-8, and the organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane: methanol (V/V) =10:1) to give compound 6- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexyl-3-yl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-16) (31 mg, yield 59.9%).

LC-MS,M/Z(ESI):384.5[M+H]⁺。

¹H NMR(400MHz,DMSO-d⁶)δ9.47(d,1H),8.26(d,1H),7.94(d,1H),7.83(s,1H),7.81(d,1H),7.15(q,1H),4.50(dt,1H),3.74(s,3H),2.48–2.42(m,2H),2.41(d,3H),2.23–2.20(m,1H),2.18(d,1H),1.90(ddd,2H).

EXAMPLE 10 preparation of Compound I-17

Referring to the preparation of compound I-16, intermediate A4 is replaced with intermediate A5 to give compound 6- (((1 r,3r,5 s) -6, 6-difluoro bicyclo [3.1.0] hexyl-3-yl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-17).

LC-MS,M/Z(ESI):384.1[M+H]⁺。

¹H NMR(400MHz,DMSO-d⁶)δ9.58(d,1H),8.25(d,1H),7.93(d,1H),7.83(s,1H),7.79(d,1H),7.16(q,1H),4.88–4.74(m,1H),3.73(s,3H),2.71–2.57(m,2H),2.41(d,3H),2.27–2.22(m,1H),2.21–2.16(m,1H),1.51(dd,2H).

Example 11: preparation of Compound I-24

The synthetic route is as follows:

The first step: synthesis of ethyl (1R, 5S,6 r) -3, 3-difluorocyclo [3.1.0] hexane-6-carboxylate (B24-2)

The compound (1R, 5S,6 r) -3, 3-difluoro-3.1.0-hexane-6-ethyl formate (B24-2) is synthesized by taking cyclopent-3-en-1-ol as a raw material according to the reference patent US20150023913A 1.

And a second step of: synthesis of (1R, 5S,6 r) -3, 3-difluoro-bicyclo [3.1.0] hexane-6-carboxamide (B24-3)

(1R, 5S,6 r) -3, 3-difluorocyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (B24-2) (1.0 g,5.3 mmol) was dissolved in an methanolic ammonia solution (10 mL, 7M) and stirred at room temperature for two days. After the reaction was completed, the mixture was concentrated under reduced pressure to give the compound (1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-carboxamide (B24-3) (0.84 g, yield 99.0%) which was used directly in the next reaction.

And a third step of: synthesis of ((1R, 5S,6 r) -3, 3-difluoro-bicyclo [3.1.0] hexane-6-yl) methylamine (B24-4)

(1R, 5S,6 r) -3, 3-difluoro-bicyclo [3.1.0] hexane-6-carboxamide (B24-3) (0.84 g,5.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), lithium aluminum hydride (0.40 g,10.4 mmol) was slowly added at 0deg.C under argon protection, and the reaction was warmed to 60deg.C and stirred overnight. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water (1 mL) at 0deg.C, stirred for 15 minutes, further added with 15% sodium hydroxide solution (0.5 mL), stirred for 15 minutes at room temperature, filtered, the cake was washed with ethyl acetate (50 mL), the filtrate was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the compound ((1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methylamine (B24-4) (0.57 g, yield 75.0%).

Fourth step: synthesis of 5-bromo-6- ((((1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B24-5)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (A1) (182 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and ((1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methylamine (66 mg,0.45 mmol) was added to react with N, N-diisopropylethylamine (174 mg,1.35 mmol) at 120℃for 1 hour under microwave conditions. After the completion of the reaction, the reaction mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:2) to give the compound 5-bromo-6- (2- (1 r,5s,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B24-5) (105 mg, yield 45.0%).

LC-MS,M/Z(ESI):517.1[M+H]⁺。

Fifth step: synthesis of 6- ((((1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B24-6)

5-Bromo-6- (2- (1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B24-5) (100 mg,0.19 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (70.5 mg,0.19 mmol) was added and the mixture was reacted with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) overnight at 120℃under argon. After the reaction was completed, cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give compound 6- ((((1 r,5s,6 r) -3, 3-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazole-4-yl) pyridine-3-sulfonamide (B24-6) (80 mg, yield 79.8%).

LC-MS,M/Z(ESI):518.3[M+H]⁺。

Sixth step: synthesis of 6- ((((1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexan-6-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-24)

6- ((((1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hexan-6-yl) methyl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (80 mg,0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL x 3), and the organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane: methanol (V/V) =10:1) to give compound 6- ((((1 r,5s,6 r) -3, 3-difluoro bicyclo [3.1.0] hexane-6-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-24) (28 mg, yield 45.6%).

LC-MS,M/Z(ESI):398.3[M+H]⁺。

¹H NMR(400MHz,CDCl₃)δ9.31(s,1H),8.44(d,1H),7.90(d,1H),7.49(s,1H),7.30(d,1H),4.58(d,1H),3.75(s,3H),3.45(dd,2H),2.65(d,3H),2.44–2.29(m,2H),2.25–2.14(m,2H),1.39(s,2H),1.22–1.15(m,1H).

Example 12: synthesis of Compound I-25

The synthetic route is shown below

The first step: synthesis of 5-bromo-6- ((3, 3-difluorobicyclo [3.1.0] hexane-6-yl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B25-1)

5-Bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (intermediate A1) (182 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), rel- (1R, 5S,6 r) -3, 3-difluorobicyclo [3.1.0] hex-6-amine (WO 2017202742) (66 mg,0.45 mmol) and N, N-diisopropylethylamine (174 mg,1.35 mmol) were added and stirred at 120℃for 1 hour under microwave conditions. After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) and ethyl acetate (20 ml×3) were added to extract, and the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =3:2) to give the compound 5-bromo-6- ((3, 3-difluorobicyclo [3.1.0] hexane-6-yl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B25-1) (105 mg, yield 45.0%).

Fifth step: synthesis of 6- ((3, 3-difluorobicyclo [3.1.0] hexan-6-yl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B25-2)

5-Bromo-6- ((3, 3-difluorobicyclo [3.1.0] hexane-6-yl) amino) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (100 mg,0.19 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (70.5 mg,0.19 mmol) was added and reacted with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) under argon at 120℃overnight. After the reaction was completed, cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give compound 6- ((3, 3-difluorobicyclo [3.1.0] hexane-6-yl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B25-2) (80 mg, yield 79.8%).

Sixth step: synthesis of 6- ((3, 3-difluorobicyclo [3.1.0] hexan-6-yl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-25)

6- ((3, 3-Difluorobicyclo [3.1.0] hexane-6-yl) amino) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (80 mg,0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and stirring was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL x 3), and the crude product was purified by silica gel chromatography (dichloromethane: methanol (V/V) =10:1) to give compound 6- ((3, 3-difluoro bicyclo [3.1.0] hexane-6-yl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-25) (28 mg, yield 45.6%).

LC-MS,M/Z(ESI):383.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃)δ9.44(d,1H),8.30(d,1H),7.94(d,1H),7.80(s,2H),7.17-7.14(m,1H),3.71(s,3H),2.73(s,1H),2.49-2.47(m,2H),2.40(d,3H),2.30–2.26(m,2H),1.57(s,2H).

Example 13: preparation of target Compound I-28

The synthetic route is as follows:

The first step: synthesis of((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methanol (B28-2)

Methyl (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-carboxylate (A2-2 a) (0.98 g,5.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium aluminum hydride (0.43 g,11.2 mmol) was added at 0deg.C under argon, and the reaction was refluxed overnight. After the reaction was completed, it was cooled to room temperature, quenched with water (1 mL) at 0deg.C, stirred for 15 minutes, further with 15% sodium hydroxide solution (0.5 mL), stirred for 15 minutes at room temperature, filtered, the cake was washed with ethyl acetate, the filtrate was washed with water (10 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give crude ((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) methanol (B28-2) (0.6 g, yield 72.2%) as a yellow oil which was directly used in the next reaction.

And a second step of: synthesis of 5-bromo-6- (((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hex-3-yl) methoxy) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B28-3)

((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methanol (B28-2) (67 mg,0.45 mmol) was dissolved in N, N-dimethylformamide (5 mL), and stirred at 0℃under argon, sodium hydrogen (54 mg,1.35mmol, 60%) was added, stirred for 30 minutes, 5-bromo-6-chloro-N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (182 mg,0.45 mmol) was added, and stirred at room temperature for 2 hours. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:2) to give 5-bromo-6- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hex-3-yl) methoxy) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B28-3) (103 mg, yield: 44.2%) as a white solid.

LC-MS,M/Z(ESI):517.2[M+H]⁺。

And a third step of: synthesis of 6- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methoxy) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B28-4)

5-Bromo-6- (((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hex-3-yl) methoxy) -N- (4-methoxybenzyl) -N-methylpyridine-3-sulfonamide (B28-3) (98 mg,0.19 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (70.5 mg,0.19 mmol) and tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) were added and stirred overnight at 120℃under argon. After the completion of the reaction, the mixture was cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give 6- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) methoxy) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B28-4) (79.8 mg, yield: 81.2%). LC-MS, M/Z (ESI): 519.3[ M+H ] ⁺.

Fourth step: synthesis of 6- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methoxy) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide amine (I-28)

6- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) methoxy) -N- (4-methoxybenzyl) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (B28-4) (79.8 mg,0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution until the aqueous phase had ph=7-8, and the organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane: methanol (V/V) =10:1) to give compound 6- (((1 r,3s,5 s) -6, 6-difluoro bicyclo [3.1.0] hexane-3-yl) methoxy) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide amine (I-28) (31.4 mg, yield: 51.2%).

LC-MS,M/Z(ESI):399.2[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ8.67(d,1H),8.34(d,1H),7.77(d,1H),7.61–7.51(m,2H),4.41(d,2H),3.75(s,3H),2.47(s,1H),2.43(d,3H),2.23–2.12(m,4H),1.98–1.88(m,2H).

Example 14: preparation of Compound I-30

The synthetic route is as follows:

The first step: synthesis of 5- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) amino) -N-methylpyrazine-2-sulfonamide (30-2)

5-Chloro-N-methylpyrazine-2-sulfonamide (A7, 93mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), crude (1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-amine hydrochloride (84.8 mg,0.5 mmol) was added and reacted with N, N-diisopropylethylamine (174 mg,1.35 mmol) at 120℃for 1.5 hours. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate in this order, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give compound 5- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) amino) -N-methylpyrazine-2-sulfonamide (B30-1) (103 mg, yield 75.2%).

LC-MS,M/Z(ESI):305.1[M+H]⁺

And a second step of: synthesis of 6-bromo-5- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) amino) -N-methylpyrazine-2-sulfonamide (B30-2)

5- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) amino) -N-methylpyrazine-2-sulfonamide (B30-1, 103mg,0.34 mmol) was dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinimide (90.8 mg,0.51 mmol) was added, and the mixture was reacted overnight at room temperature. After the reaction, water (20 mL) was added, followed by extraction with ethyl acetate (20 ml×3), and the organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, followed by purification by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =4:1) to give the compound 6-bromo-5- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) amino) -N-methylpyrazine-2-sulfonamide (B30-2) (101.8 mg, yield: 78.5%).

LC-MS,M/Z(ESI):383.1[M+H]⁺。

And a third step of: synthesis of 5- (((1R, 3s, 5S) -6, 6-difluoro-bicyclo [3.1.0] hexane-3-yl) amino) -N-methyl-6- (1-methyl-1H-imidazol-4-yl) pyrazine-2-sulfonamide (I-30)

6-Bromo-5- (((1R, 3s, 5S) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) amino) -N-methylpyrazine-2-sulfonamide (101.8 mg,0.27 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (118.7 mg,0.32 mmol) was added and reacted with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) under argon at 120℃overnight. After the reaction was completed, cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, the mixture was extracted with ethyl acetate (20 ml×3), the organic phases were combined, dried successively with water (20 mL) and anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound 5- (((1 r,3s,5 s) -6, 6-difluorobicyclo [3.1.0] hexane-3-yl) amino) -N-methyl-6- (1-methyl-1H-imidazol-4-yl) pyrazine-2-sulfonamide (I-30) (58 mg, yield: 56.8%).

LC-MS,M/Z(ESI):385.2[M+H]⁺。

¹H NMR(400MHz,DMSO-d6)δ9.79(d,1H),8.31(s,1H),7.90(s,2H),7.35(q,1H),4.43(dt,1H),3.79(s,3H),2.56(d,3H),2.50–2.43(m,2H),2.22(dt,2H),1.96(ddd,2H).

Example 15: preparation of Compound I-36

The synthetic route is as follows:

The first step: synthesis of N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (B36-2)

5-Chloro-N-methyl-pyrazine-2-sulfonamide (intermediate A7, 200mg, 963. Mu. Mol) and (3- (trifluoromethyl) phenyl) methylamine (B36-1, 168mg, 963. Mu. Mol) were dissolved in N, N-dimethylformamide (10.0 mL), N-diisopropylethylamine (373 mg,2.89 mmol) was added, and the reaction was stirred at 25℃for 2 hours. The reaction solution was added to water (200 mL), then extracted with ethyl acetate (100 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonyl (B36-2) (200 mg, yield 59.9%).

And a second step of: 6-bromo-N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (B36-3)

N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (B36-2, 200mg, 577. Mu. Mol) and diisopropylethylamine (224 mg,1.73 mmol) were dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinamide (102 mg, 577. Mu. Mol) was added, and the mixture was stirred at 25℃for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 ml×2), and the organic phase was concentrated by drying to give the crude compound 6-bromo-N-methyl-5- [ [3- (trifluoromethyl) phenyl ] methylamino ] pyrazine-2-sulfonamide (B36-3) (150 mg, yield 61.1%).

And a third step of: 6- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (Compound I-36)

6-Bromo-N-methyl-5- [ [3- (trifluoromethyl) phenyl ] methylamino ] pyrazine-2-sulfonamide (B36-3, 100mg, 235. Mu. Mol) and 2- (tributylstannyl) -6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole (93.4 mg, 235. Mu. Mol) were dissolved in toluene (15 mL), tetrakis (triphenylphosphine) palladium (27.2 mg, 23.5. Mu. Mol) was added, nitrogen was substituted three times, and reacted at 100℃for 6 hours. The reaction solution was directly concentrated to give a crude product, which was then purified by preparative high performance liquid chromatography (column: phenomenex luna C18:150:25.mm.10 um; solvent: a=water+formic acid (0.05%), b=acetonitrile; gradient: 52% -82%,7 min) to give compound 6- (6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-2-yl) -N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (compound I-36) (13.0 mg, yield 10.5%).

LC-MS,M/Z(ESI):453.3[M+H]⁺

¹H NMR(CDCl₃,400MHz)δppm 8.44(s,1H),7.76(s,1H),7.69(s,1H),7.53-7.61(m,3H),7.44-7.51(m,2H),4.83(d,2H),4.09-4.26(m,2H),2.92-3.14(m,2H),2.66-2.76(m,5H).

Example 16: preparation of Compound I-54

The synthetic route is as follows:

6-bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (80.0 mg, 154. Mu. Mol) was dissolved in toluene (20 mL), tetrakis (triphenylphosphine) palladium (17.8 mg, 15.4. Mu. Mol) and tributyl- [ (2R) -2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl ] stannane (116 mg, 169. Mu. Mol) were added, nitrogen was replaced three times, and reacted at 100℃for 6 hours. The reaction solution was directly concentrated to give a crude product, which was then purified by preparative high performance liquid chromatography (column: phenomenex luna C, 150 x 25mm x 10 μm; solvent: a=water+formic acid (0.05%), b=acetonitrile; gradient: 52% -82%,7 min) to give the compound (R) -N-methyl-6- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (I-54) (15.0 mg, yield 19.9%).

¹H NMR(DMSO-d₆)δ:8.47(s,2H),8.23(s,1H),7.69(d,2H),7.64(s,1H),7.52-7.57(m,2H),5.45-5.52(m,1H),4.84(d,2H),4.41-4.47(m,1H),3.91(m,1H),2.57(br s,3H),1.54(d,3H)

LC-MS,M/Z(ESI):469.1[M+H]⁺

Example 17: preparation of Compound I-55

The synthetic route is as follows:

6-bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (100.0 mg,235 umol) was dissolved in N, N-dimethylformamide (1.0 mL), tetrakis (triphenylphosphine) palladium (27.2 mg, 23.5. Mu. Mol) and N-methyl-4- (tributyltin) imidazole (104.7 mg, 282.2. Mu. Mol) were added, argon was substituted three times, and the reaction solution was reacted at 110℃for 16 hours. The reaction mixture was cooled to room temperature, a saturated aqueous potassium fluoride solution (5 mL) and ethyl acetate (5 mL) were added thereto, stirred for 30 minutes, then filtered, the cake was rinsed with ethyl acetate (10 mL), the filtrate was collected, the layer was separated, the organic phase was washed with water (5 ml×2), saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated by filtration, and then purified by a silica gel column (dichloromethane: ethyl acetate (V/V) =5:1) to give the compound N-methyl-6- (1-methyl-1-hydroimidazol-4-yl) -5- ((4- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (compound I-55) (69.0 mg, yield 68.5%).

LC-MS,M/Z(ESI):427.0[M+H]⁺

¹H NMR(DMSO-d6)δ10.14(t,1H),8.26(s,1H),7.91(d,2H),7.67(d,2H),7.54(d,2H),7.35(q,1H),4.86(d,2H),3.78(s,3H),2.56(d,3H).

Example 18: preparation of Compound I-56

The synthetic route is as follows:

6-bromo-N-methyl-5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (118.4 mg,0.28 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (118.7 mg,0.32 mmol) was added and reacted with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol), protected with argon, at 120℃overnight. After the completion of the reaction, the mixture was cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give N-methyl-6- (1-methyl-1H-imidazol-4-yl) -5- ((3- (trifluoromethyl) benzyl) amino) pyrazine-2-sulfonamide (I-56) (77.5 mg, yield: 65.3%).

LC-MS,M/Z(ESI):427.1[M+H]⁺。

¹H NMR(400MHz,DMSO-d6)δ10.15(t,1H),8.29(s,1H),7.94(d,1H),7.92(s,1H),7.72(s,1H),7.66(d,1H),7.62(d,1H),7.57(t,1H),7.38(q,1H),4.88(d,2H),3.80(s,3H),2.58(d,3H).

Example 19: preparation of target Compound I-57

The synthetic route is as follows:

The first step: synthesis of 3- (difluoromethyl) -4-fluorobenzonitrile (B57-2)

4-Fluoro-3-formylbenzonitrile (1 g,6.71 mmol) was dissolved in dichloromethane (20 mL), diethylaminosulfur trifluoride (3.24 g,20.13 mmol) was added at 0deg.C, and stirred overnight at room temperature. After the completion of the reaction, the reaction solution was slowly added dropwise to a saturated aqueous sodium hydrogencarbonate solution, stirred at 0℃for 20 minutes, the solution was separated, the aqueous phase was extracted with methylene chloride (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 3- (difluoromethyl) -4-fluorobenzonitrile (B57-2) (1.09 g, yield: 95.0%) which was directly used for the next reaction.

And a second step of: synthesis of (3- (difluoromethyl) -4-fluorophenyl) methylamine (B57-3)

3- (Difluoromethyl) -4-fluorobenzonitrile (B57-2) (1.09 g,6.4 mmol) was dissolved in methanol (20 mL), wet nickel powder (0.2 g) was added under nitrogen blanket, nitrogen was substituted 3 times, hydrogen was substituted 3 times, and the reaction was carried out under hydrogen balloon at room temperature overnight. After the completion of the reaction, the filtrate was filtered and concentrated to give liquid (3- (difluoromethyl) -4-fluorophenyl) methylamine (B57-3) (1.03 g, yield: 92.3%) which was directly used in the next reaction.

LC-MS,M/Z(ESI):176.2[M+H]⁺。

And a third step of: synthesis of 5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methylpyrazine-2-sulfonamide (B57-4)

5-Chloro-N-methylpyrazine-2-sulfonamide (93 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and (3- (difluoromethyl) -4-fluorophenyl) methylamine (236.5 mg,1.35 mmol) was added and reacted with triethylamine (136.6 mg,1.35 mmol) at 70℃for 1 hour under microwave. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give colorless liquid 5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methylpyrazine-2-sulfonamide (B57-4) (135.9 mg, yield: 87.2%).

LC-MS,M/Z(ESI):347.1[M+H]⁺。

Fourth step: synthesis of 6-bromo-5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methylpyrazine-2-sulfonamide (B57-5)

5- ((3- (Difluoromethyl) -4-fluorobenzyl) amino) -N-methylpyrazine-2-sulfonamide (121.3 mg,0.35 mmol) was dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinimide (90.8 mg,0.51 mmol) was added, and the mixture was reacted overnight at room temperature. After the completion of the reaction, water (20 mL) was added, followed by extraction with ethyl acetate (20 ml×3), the organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =4:1) to give the compound 6-bromo-5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methylpyrazine-2-sulfonamide (B57-5) (118.4 mg, yield: 79.5%).

LC-MS,M/Z(ESI):425.1[M+H]⁺。

Fifth step: synthesis of 5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methyl-6- (1-methyl-1H-imidazol-4-yl) pyrazine-2-sulfonamide (I-57)

6-Bromo-5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methylpyrazine-2-sulfonamide (B57-5, 118.4mg,0.28 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (118.7 mg,0.32 mmol) was added and reacted with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol), under argon, at 120℃overnight. After the completion of the reaction, the mixture was cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =1:1) to give 5- ((3- (difluoromethyl) -4-fluorobenzyl) amino) -N-methyl-6- (1-methyl-1H-imidazol-4-yl) pyrazine-2-sulfonamide (I-57) (89.4 mg, yield: 75.3%).

LC-MS,M/Z(ESI):427.1[M+H]⁺。

¹H NMR(400MHz,DMSO-d6)δ10.11(t,1H),8.30(s,1H),7.93(d,1H),7.91(s,1H),7.66–7.55(m,2H),7.41–7.31(m,2H),7.18(t,1H),4.81(d,2H),3.80(s,3H),2.58(d,3H).

Example 20: preparation of Compound I-58

The synthetic route is as follows:

the first step: synthesis of 3- (difluoromethyl) benzonitrile (B58-2)

3-Formyl-benzonitrile (B58-1, 1g,6.71 mmol) was dissolved in dichloromethane (20 mL), diethylaminosulfur trifluoride (3.24 g,20.13 mmol) was added at 0deg.C, and stirred overnight at room temperature. After the completion of the reaction, the reaction solution was slowly added dropwise to a saturated aqueous sodium hydrogencarbonate solution, stirred at 0℃for 20 minutes, separated, extracted with aqueous methylene chloride (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 3- (difluoromethyl) benzonitrile (B58-2) (1.09 g, yield: 95.0%) which was directly used in the next reaction.

And a second step of: synthesis of (3- (difluoromethyl) phenyl) methylamine (B58-3)

3- (Difluoromethyl) benzonitrile (B58-2) (1.09 g,6.4 mmol) was dissolved in methanol (20 mL), and wet nickel powder (0.2 g) was added under nitrogen atmosphere, nitrogen was substituted 3 times, hydrogen was substituted 3 times, and the reaction was carried out under hydrogen balloon at room temperature overnight. After the completion of the reaction, filtration and concentration of the filtrate gave liquid (3- (difluoromethyl) phenyl) methylamine (B58-3) (1.03 g, yield: 92.3%) which was used directly in the next reaction. LC-MS, M/Z (ESI): 158.1[ M+H ] ⁺.

And a third step of: synthesis of 5- ((3- (difluoromethyl) benzyl) amino) -N-methylpyrazine-2-sulfonamide (B58-4)

5-Chloro-N-methylpyrazine-2-sulfonamide (B58-3) (93 mg,0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and (3- (difluoromethyl) phenyl) methylamine (236.5 mg,1.35 mmol) was added to react with triethylamine (136.6 mg,1.35 mmol) for 1 hour at 70℃under microwave. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give colorless liquid 5- ((3- (difluoromethyl) benzyl) amino) -N-methylpyrazine-2-sulfonamide (B58-4) (135.9 mg, yield: 87.2%).

LC-MS,M/Z(ESI):329.1[M+H]⁺。

Fourth step: synthesis of 6-bromo-5- ((3- (difluoromethyl) benzyl) amino) -N-methylpyrazine-2-sulfonamide (B58-5)

5- ((3- (Difluoromethyl) benzyl) amino) -N-methylpyrazine-2-sulfonamide (B58-4) (121.3 mg,0.35 mmol) was dissolved in N, N-dimethylformamide (10 mL), N-bromosuccinimide (90.8 mg,0.51 mmol) was added, and reacted overnight at room temperature. After the completion of the reaction, water (20 mL) was added, followed by extraction with ethyl acetate (20 ml×3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =4:1) to give the compound 6-bromo-5- ((3- (difluoromethyl) benzyl) amino) -N-methylpyrazine-2-sulfonamide (B58-5) (118.4 mg, yield: 79.5%).

LC-MS,M/Z(ESI):407.0[M+H]⁺。

Fifth step: synthesis of 5- ((3- (difluoromethyl) benzyl) amino) -N-methyl-6- (1-methyl-1H-imidazol-4-yl) pyrazine-2-sulfonamide (I-58)

6-Bromo-5- ((3- (difluoromethyl) benzyl) amino) -N-methylpyrazine-2-sulfonamide (B58-5) (118.4 mg,0.28 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-methyl-4- (tri-N-butyltin) imidazole (118.7 mg,0.32 mmol) was added to the mixture, and the mixture was reacted overnight at 120℃under argon with tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol). After the completion of the reaction, the mixture was cooled to room temperature, saturated aqueous potassium fluoride (5 mL) was added, stirred for 30 minutes, water (20 mL) was further added, ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give 5- ((3- (difluoromethyl) benzyl) amino) -N-methyl-6- (1-methyl-1H-imidazol-4-yl) pyrazine-2-sulfonamide (I-58) (89.4 mg, yield: 75.3%).

LC-MS,M/Z(ESI):409.1[M+H]⁺。

¹H NMR(400MHz,DMSO)δ10.10(t,1H),8.27(s,1H),7.90(d,2H),7.53-7.42(m,4H),7.35(dd,1H),6.99(t,1H),4.83(d,2H),3.78(s,3H),2.56(d,3H).

Example 21: preparation of Compound I-59

The synthetic route is as follows:

The first step: synthesis of 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B59-1)

4-Fluoro-N- (4-methoxybenzyl) -N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (A6-3) (1.14 g,2.62 mmol) and 2-bromo-5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazole (0.52 g,2.63 mmol) were dissolved in 1, 4-dioxane (20 mL), and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (0.19 g,0.26 mmol), sodium carbonate (0.69 g,6.49 mmol), water (4 mL) were added. The reaction was carried out at 100℃for 21 hours under nitrogen blanket with 3 times of nitrogen substitution. Cooled to room temperature, concentrated under reduced pressure to remove the solvent, water (40 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phases combined and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =1:1 to 1:2) afforded compound 4-fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B59-1) (0.55 g, yield: 49.5%).

LC-MS,M/Z(ESI):428.2[M+H]⁺。

And a second step of: synthesis of N- (4-methoxybenzyl) -N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) -4- (4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (B59-2)

4-Fluoro-N- (4-methoxybenzyl) -N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) benzenesulfonamide (B59-1) (346.3 mg,0.81 mmol) was dissolved in dimethyl sulfoxide (3 mL), and reacted with (4- (trifluoromethyl) phenyl) methylamine (709 mg,4.05 mmol) at 140℃for 2 hours by microwave. Cooled to room temperature, water (20 mL), ethyl acetate extracts (20 mL. Times.3), the combined organic phases, water washes (15 mL), saturated brine washes (15 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1 to 1:2) afforded the compound N- (4-methoxybenzyl) -N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) -4- (4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (B59-2) (0.35 g, yield: 74.2%). LC-MS, M/Z (ESI): 583.2[ M+H ] ⁺.

And a third step of: synthesis of N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) -4- ((4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (I-59)

N- (4-methoxybenzyl) -N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) -4- (4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (B59-2) (0.35 g,0.60 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (20 mL) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution until the aqueous phase had a pH of 7 to 8, and the crude product was purified by silica gel chromatography (dichloromethane: methanol (V/V) =10:1) to give the compound N-methyl-3- (5, 5a,6 a-tetrahydrocyclopropyl [3,4] pyrrolo [1,2-a ] imidazol-2-yl) -4- ((4- (trifluoromethyl) benzyl) amino) benzenesulfonamide (I-59) (136.7 mg, yield: 49.2%).

LC-MS,M/Z(ESI):463.0[M+H]⁺。

¹H NMR(400MHz,DMSO-d6)δ9.24(t,1H),7.75(d,1H),7.71(d,2H),7.56(d,2H),7.50(s,1H),7.30(dd,1H),6.97(d,1H),6.58(d,1H),4.66(d,2H),4.25–4.14(m,1H),4.04(d,1H),2.46–2.38(m,2H),2.33(d,3H),1.25(dd,1H),0.61(d,1H).

Example 22: preparation of Compound I-60

The synthetic route is as follows:

The first step: synthesis of 2, 4-difluoro-N- ((4-methoxyphenyl) methyl) -N-methyl-benzenesulfonamide (B60-2)

2, 4-Difluorobenzenesulfonyl chloride (B60-1) (10.0 g,47.0 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (14.2 g,141 mmol) and 1- (4-methoxyphenyl) -N-methyl-methylamine (7.47 g,49.3 mmol) were added, and the reaction was stirred at 20℃for 1 hour. After completion of the reaction, 1M hydrochloric acid (100 mL) was added to the reaction mixture, extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, and concentrated by filtration to give a crude compound 2, 4-difluoro-N- ((4-methoxyphenyl) methyl) -N-methyl-benzenesulfonamide (B60-2) (15.0 g, yield 97.4%).

And a second step of: synthesis of 2, 4-difluoro-3-iodo-N- ((4-methoxyphenyl) methyl) -N-methyl-benzenesulfonamide (B60-3)

2, 4-Difluoro-N- ((4-methoxyphenyl) methyl) -N-methyl-benzenesulfonamide (B60-2) (3.00 g,9.16 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to-70℃and lithium diisopropylamide (5.50 mL, 2M) was slowly added under nitrogen protection, the reaction solution was stirred for an additional 0.5 hour, then iodine (3.49 g,13.7 mmol) was dissolved in tetrahydrofuran (10.0 mL) and added dropwise to the reaction solution. The reaction solution was slowly warmed to 0 ℃ and stirred for 0.5 hours. After the completion of the reaction, the reaction mixture was poured into saturated ammonium chloride (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, filtered and concentrated to give the crude compound 2, 4-difluoro-3-iodo-N (- ((4-methoxyphenyl) methyl)) -N-methyl-benzenesulfonamide (B60-3) (4.00 g, yield 96.3%).

And a third step of: synthesis of 2, 4-difluoro-3-iodo-N-methyl-benzenesulfonamide (B60-4)

2, 4-Difluoro-3-iodo-N (- ((4-methoxyphenyl) methyl)) -N-methyl-benzenesulfonamide (B60-3) (3.00 g,6.62 mmol) was dissolved in trifluoroacetic acid (30.0 mL), and the reaction mixture was heated to 70℃and stirred for 1 hour. After the completion of the reaction, the reaction mixture was added to a sodium carbonate solution (200 mL), followed by extraction with methylene chloride (200 mL), and the organic phase was washed with saturated brine (200 mL), followed by drying over sodium sulfate, and filtration and concentration to give the crude compound 2, 4-difluoro-3-iodo-N-methyl-benzenesulfonamide (B60-4) (2.00 g, yield 90.7%).

Fourth step: synthesis of 2-fluoro-3-iodo-N-methyl-4 (- ((4- (trifluoromethyl) phenyl)) methylamino) benzenesulfonamide (B60-5)

2, 4-Difluoro-3-iodo-N-methyl-benzenesulfonamide (B66-4) (1.50 g,4.50 mmol) and (4- (trifluoromethyl) phenyl) methylamine (788 mg,4.50 mmol) were dissolved in dimethyl sulfoxide (20.0 mL), N-diisopropylethylamine (2.33 g, 33.9. Mu. Mol) was added, and the reaction solution was stirred under nitrogen at 105℃for 6 hours. After the completion of the reaction, the reaction mixture was added to 1M hydrochloric acid (100 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, and concentrated by filtration to give the crude compound, 2-fluoro-3-iodo-N-methyl-4 (- ((4- (trifluoromethyl) phenyl)) methylamino)), benzenesulfonamide (B66-5) (400 mg, yield 18.1%).

Fifth step: synthesis of 2-fluoro-N-methyl-3 (- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl)) -4 (- ((4- (trifluoromethyl) phenyl)) methylamino)) benzenesulfonamide (I-60)

2-Fluoro-3-iodo-N-methyl-4 (- ((4- (trifluoromethyl) phenyl) methylamino)) benzenesulfonamide (B60-5) (100 mg, 204. Mu. Mol) and tributyl- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) stannane (84.6 mg, 204. Mu. Mol) were dissolved in toluene (40.0 mL), and tetrakis (triphenylphosphine) palladium (23.6 mg, 20.4. Mu. Mol) was added under nitrogen protection, and the reaction solution was stirred at 100℃for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated directly to give a crude product, which was then separated by preparative high performance liquid chromatography (column: waters Xbridge 150 x 25mm x 5 μm; solvent: a=water+aqueous ammonia, b=acetonitrile; gradient: 43% -73%) to give compound 2-fluoro-N-methyl-3- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (I-60) (30.0 mg, yield 30.1%).

LC-MS,M/Z(ESI):483.1(M-H)⁺

¹H NMR(CDCl₃,400MHz)δ:7.59(br d,2H),7.45-7.50(m,3H),7.11(d,1H),6.27(d,1H),5.41-5.51(m,1H),4.57(s,2H),4.34-4.45(m,2H),3.86(m,1H),2.64(d,3H),1.68(d,3H)

Example 23: preparation of Compound I-61

The synthetic route is as follows:

The first step: synthesis of 5-bromo-2, 4-difluoro-N-methyl-benzenesulfonamide (B61-2)

5-Bromo-2, 4-difluoro-benzenesulfonyl chloride (B61-1) (10.0 g,64.3 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (10.4 g,102 mmol) and methylamine hydrochloride (2.36 g,34.9 mmol) were added, and the reaction solution was stirred at 20℃for 1 hour. After completion of the reaction, water (200 mL) was added to the reaction mixture, the mixture was extracted with methylene chloride (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated by filtration to give a crude compound, 5-bromo-2, 4-difluoro-N-methyl-benzenesulfonamide (B61-2) (8.0 g, yield 81.5%).

And a second step of: synthesis of 5-bromo-2-fluoro-N-methyl-4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (B61-3)

5-Bromo-2, 4-difluoro-N-methyl-benzenesulfonamide (B61-2) (3.00 g,10.4 mmol) and (4- (trifluoromethyl) phenyl) methylamine (2.02 g,11.5 mmol) were dissolved in dimethyl sulfoxide (20.0 mL), N-diisopropylethylamine (5.42 g, 41.9. Mu. Mol) was added, and the reaction was stirred under nitrogen at 100℃for 2 hours. After the completion of the reaction, the reaction mixture was added to a sodium carbonate solution (200 mL), followed by extraction with ethyl acetate (200 mL), washing the organic phase with saturated brine (200 mL), drying over sodium sulfate, and concentration by filtration gave the crude compound 5-bromo-2-fluoro-N-methyl-4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (B61-3) (1.00 g, yield 21.6%).

And a third step of: synthesis of 2-fluoro-N-methyl-5- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (I-61)

5-Bromo-2-fluoro-N-methyl-4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (B61-3) (200 mg, 453. Mu. Mol) and tributyl- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) stannane (224 mg, 543. Mu. Mol) were dissolved in toluene (40.0 mL), tetrakis (triphenylphosphine) palladium (53.3 mg, 45.3. Mu. Mol) was added under nitrogen protection, and stirred at 100℃for 3 hours under nitrogen protection. After the reaction was completed, the reaction liquid was cooled to room temperature, and concentrated under direct reduced pressure to give a crude product, which was then separated by preparative high performance liquid chromatography (column: phenomenex μna C18 150 x 25mm x 10 μm; solvent: a=water+trifluoroacetic acid, b=acetonitrile; gradient: 38% -68%) to give the compound 2-fluoro-N-methyl-5- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (I-61) (30.0 mg, yield 12.3%).

LC-MS,M/Z(ESI):485.2[M+H]⁺

¹H NMR(CDCl₃,400MHz)δ:7.78(d,1H),7.61(br d,2H),7.48(br d,2H),6.93(s,1H),6.19(d,1H),5.36-5.53(m,1H),4.50-4.57(m,2H),4.46(br s,1H),4.32-4.40(m,1H),3.83(m,1H),2.66(s,3H),1.69(d,3H)

Example 24: preparation of Compound I-62

The synthetic route is as follows:

the first step: synthesis of 3-bromo-4, 5-difluoro-benzenesulfonyl chloride (B62-2)

A first part: cuprous chloride (142 mg,1.44 mmol) was added to water (10.0 mL) and the temperature was controlled at-5℃to which thionyl chloride (8.58 g,72.1 mmol) was added dropwise and reacted for 1 hour. A second part: 3-bromo-4, 5-difluoroaniline (B62-1) (3.00 g,14.4 mmol) was added in portions to concentrated hydrochloric acid (40.0 mL, 12M), sodium nitrite (1.09 g,15.8 mmol) was dissolved in hydrochloric acid (6.0 mL, 12M), and the reaction mixture was added dropwise at a controlled temperature of-5℃to 5℃and stirring was continued for 0.5 hours. The second part of reaction liquid is added into the first part of reaction liquid, the temperature is controlled between-5 ℃ and 5 ℃ in the reaction process, and the reaction liquid is continuously stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into water (30.0 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, and concentrated by filtration to give the compound 3-bromo-4, 5-difluoro-benzenesulfonyl chloride (B62-2) (4.00 g, yield 95.1%).

And a second step of: synthesis of 3-bromo-4, 5-difluoro-N-methyl-benzenesulfonamide (B62-3)

3-Bromo-4, 5-difluoro-benzenesulfonyl chloride (B62-2) (4.00 g,13.7 mmol) was dissolved in dichloromethane (10.0 mL), N-diisopropylethylamine (5.55 g,42.9 mmol) and methylamine hydrochloride (1.02 g,15.0 mmol) were added, and the reaction was reacted at 20℃for 1 hour. After completion of the reaction, hydrochloric acid (1 mol/L,100 mL) was added to the reaction mixture, extracted with methylene chloride (200 mL), and the organic phase was washed with saturated brine (200 mL), then dried over sodium sulfate, and concentrated by filtration to give the crude compound 3-bromo-4, 5-difluoro-N-methyl-benzenesulfonamide (B62-3) (2.30 g, yield 58.5%).

And a third step of: synthesis of 3-bromo-5-fluoro-N-methyl-4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (B62-4)

3-Bromo-4, 5-difluoro-N-methyl-benzenesulfonamide (B62-3) (1.2 g,4.19 mmol) was dissolved in dimethyl sulfoxide (20.0 mL), and N, N-diisopropylethylamine (1.63 g,12.5 mmol) and (4- (trifluoromethyl) phenyl) methylamine (284 mg,4.19 mmol) were added thereto, and the reaction was stirred under nitrogen at 120℃for 2 hours. After the completion of the reaction, the reaction mixture was added to hydrochloric acid (1 mol/L,100 mL), followed by extraction with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound 3-bromo-5-fluoro-N-methyl-4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (B62-4) (1.50 g, yield 81.0%).

Fifth step: synthesis of 3-fluoro-N-methyl-5- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (I-62)

3-Bromo-5-fluoro-N-methyl-4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (B62-4) (400 mg, 906. Mu. Mol) and tributyl- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) stannane (374 mg, 906. Mu. Mol) were dissolved in toluene (40.0 mL), and tetrakis (triphenylphosphine) palladium (10.6 mg, 9.04. Mu. Mol) was added under nitrogen and the reaction solution was stirred at 100℃for 3 hours under nitrogen. After the reaction, the mixture was concentrated to give a crude product, which was then separated by preparative high performance liquid chromatography (column: 3_PhenomenexLuna C18 150*25mm*10 μm; solvent: a=water+formic acid, b=acetonitrile; gradient: 55% -85%,7 min) to give the compound 3-fluoro-N-methyl-5- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -4- ((4- (trifluoromethyl) phenyl) methylamino) benzenesulfonamide (I-62) (30.0 mg, yield 6.23%).

LC-MS,M/Z(ESI):485.2[M+H]⁺

¹H NMR(DMSO-d₆)δ:8.43-8.51(m,1H),7.68(d,2H),7.58(d,1H),7.51(d,2H),7.39(s,1H),7.15-7.22(m,2H),5.43-5.52(m,1H),4.65-4.74(m,2H),4.39(d,1H),3.82-3.90(m,1H),2.35-2.39(m,3H),1.54(d,3H)

Example 25: preparation of Compound I-63

The synthetic route is as follows:

the first step: synthesis of 2-bromo-6-fluoro-3-iodopyridine (B63-2)

2-Bromo-6-fluoropyridin-3-amine (B63-1) (7.00 g,36.6 mmol) and cuprous iodide (13.9 g,73.3 mmol) were added to acetonitrile (100 mL), tert-butyl nitrite (2.67 g,54.9 mmol) was added at 0deg.C, and the reaction mixture was warmed to 80deg.C and stirred for 10 hours. The reaction solution was cooled to room temperature, then added to water (200 mL), followed by extraction with ethyl acetate (300 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:0 to 10:1) to give compound 2-bromo-6-fluoro-3-iodopyridine (B63-2) (7.00 g, yield 46.8%).

And a second step of: 6- (Benzenothio) -2-bromo-3-iodopyridine (B63-3)

Sodium hydrogen (1.12 g,17.5mmol, 60%) was added to tetrahydrofuran (100 mL), benzyl mercaptan (2.18 g,17.5 mmol) was added under nitrogen, the reaction stirred at 0deg.C for 1 hour, and 2-bromo-6-fluoro-3-iodopyridine (B63-2) (6.50 g,15.9 mmol) was added dropwise to the reaction, and stirring was continued for 1 hour at 25deg.C. The reaction solution was added to HCl (200 mL, 1M), followed by extraction with ethyl acetate (300 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 6- (phenylmethylthio) -2-bromo-3-iodopyridine (B63-3) (7.0 g).

And a third step of: 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4)

6- (Benzenothio) -2-bromo-3-iodopyridine (B63-3) (5.00 g,12.3 mmol) was added to acetonitrile (20.0 mL), acetic acid (3.70 g,61.5 mmol), water (1.11 g,61.5 mmol) and dichlorodimethyl hydantoin (4.85 g,24.6 mmol) were sequentially added, and the reaction was stirred at 20℃for 1 hour. The reaction solution was added to water (200 mL), followed by extraction with ethyl acetate (300 mL), washing of the organic phase with saturated brine (200 mL), drying over sodium sulfate, filtration and concentration to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1 to 0:1) to give a crude compound 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4) (3.10 g, yield 65.8%).

Fourth step: 6-bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5)

Methylamine hydrochloride (823mg, 12.1 mmol) and triethylamine (2.46 g,24.3 mmol) were added to dichloromethane (20.0 mL), 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4) (3.10 g,8.11 mmol) was further added, and the reaction solution was stirred at 25℃for 4 hours. The reaction solution was concentrated directly, and the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) to give compound 6-bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5) (1.50 g, yield 49.0%).

Fifth step: 6-bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyridine-2-sulfonamide (B63-6)

6-Bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5) (1.50 g,3.98 mmol) and 4- (trifluoromethyl) benzylamine (836 mg,4.77 mmol) were added to a toluene solution (30.0 mL), tris (biphenylmethylene acetone) dipalladium (3.10 g,8.11 mmol), (1, 1 '-binaphthyl) -2,2' -methylenebis (diphenylphosphine) (99.1 mg, 159. Mu. Mol) and potassium t-butoxide (669 mg,5.97 mmol) were sequentially added, and the reaction solution was stirred under nitrogen at 80℃for 8 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and then separated by preparative high performance liquid chromatography (column: waters Xbridge150 x 25mm x 5 μm; solvent: a=water+aqueous ammonia, b=acetonitrile; gradient: 38% -68%) to give compound 6-bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyridine-2-sulfonamide (B63-6) (50.0 mg, yield 2.96%).

Sixth step: (R) -N-methyl-6- (2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) -5- ((4- (trifluoromethyl) benzyl) amino) pyridine-2-sulfonamide (I-63)

6-Bromo-N-methyl-5- ((4- (trifluoromethyl) benzyl) amino) pyridine-2-sulfonamide (20.0 mg, 47.1. Mu. Mol) was dissolved in toluene (20.0 mL), tetrakis (triphenylphosphine) palladium (544. Mu.g, 0.471. Mu. Mol), cuprous iodide (897. Mu.g, 4.71. Mu. Mol) and tributyl- ((2R) -2-methyl-2, 3-dihydroimidazo [2,1-b ] oxazol-6-yl) stannane (23.3 mg, 56.5. Mu. Mol) were added and the reaction solution stirred at 100℃for 6 hours under nitrogen. The reaction solution is directly concentrated to obtain crude product. Then isolated by preparative high performance liquid chromatography (column: phenomenex l μna C18150 x 25mm x 10 μm; -solvent: a=water+formic acid (0.05%), b=acetonitrile; gradient: 52% -82%,7 min) to give compound (R) -N-methyl-6- (2-methyl-2, 3-dihydroimidazo [2,1-B ] oxazol-6-yl) -5- ((4- (trifluoromethyl) benzyl) amino) pyridine-2-sulfonamide (I-63) (2.51 mg, 10.5% yield).

LC-MS,M/Z(ESI):468.3[M+H]⁺

¹H NMR(CDCl₃)δ:8.95-9.21(m,1H),7.54-7.64(m,3H),7.42-7.51(m,3H),6.66-6.80(m,1H),5.33-5.53(m,1H),4.49-4.64(m,3H),4.36(m,1H),3.77-3.92(m,1H),2.62-2.76(m,3H),1.37(d,3H)

Example 26: preparation of Compound I-64

The synthetic route is as follows:

The first step: synthesis of ethyl (1R, 5S, 6R) -2-oxybicyclo [3.1.0] hexane-6-carboxylate (B64-2)

(Ethoxycarbonylmethyl) dimethyl sulfonium bromide (5.05 g,43.8 mmol) and tetramethylguanidine (5.05 g,43.8 mmol) were dissolved in acetonitrile (30 mL), stirred at 25℃for 10 minutes, 2-cyclopenten-1-one (B64-1) (10.0 g,43.8 mmol) was added, and the reaction solution was stirred at 25℃for 4 hours. After the reaction, the reaction mixture was concentrated directly to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =50:1 to 3:1) to give the compound (1 r,5s,6 r) -2-oxybicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (B64-2) (5.00 g, yield 81.3%).

And a second step of: synthesis of ethyl (1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-carboxylate (B64-3)

Ethyl (1R, 5S, 6R) -2-oxybicyclo [3.1.0] hexane-6-carboxylate (B64-2) (5.00 g,29.7 mmol) was dissolved in dichloromethane (20.0 mL), and diethylaminosulfur trifluoride (9.58 g,59.5 mmol) was added thereto, and the reaction solution was stirred at 25℃for 4 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =5:1 to 0:1) to give compound (1 r,5r,6 r) -2, 2-difluorobicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (B64-3) (5.00 g, yield 88.4%).

And a third step of: synthesis of (1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-carboxamide (B64-4)

Ethyl (1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-carboxylate (B64-3) (6.00 g,34.0 mmol) was dissolved in a methanol solution of ammonia (50.0 mL), and the reaction solution was slowly warmed to 80℃and stirred for 6 hours. After the completion of the reaction, the reaction liquid was cooled to room temperature, and concentrated under reduced pressure to give crude compound (1 r,5r,6 r) -2, 2-difluorobicyclo [3.1.0] hexane-6-carboxamide (B64-4) (4.00 g, yield 94.4%).

Fourth step: synthesis of ((1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexan-6-yl) methylamine (B64-5)

(1R, 5R, 6R) -2, 2-Difluorobicyclo [3.1.0] hexane-6-carboxamide (B64-4) (500 mg,31.0 mmol) was dissolved in tetrahydrofuran (10.0 mL), lithium aluminum hydride (1.49 mL, 2.5M) was added at 0℃and the reaction solution was slowly warmed to 50℃and stirred for 4 hours. After completion of the reaction, sodium sulfate decahydrate (5.00 g) was added to the reaction mixture, the mixture was filtered, the cake was washed with ethyl acetate (100 mL), and the filtrate was dried over anhydrous sodium sulfate, and concentrated by filtration to give a crude compound ((1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-yl) methylamine (B64-5) (450 mg, yield 98.7%).

Fifth step: synthesis of 5-bromo-6- ((((1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N-methylpyridine-3-sulfonamide (B64-7)

5-Bromo-6-chloro-N-methylpyridine-3-sulfonamide (B64-6) (850 mg,2.98 mmol) was dissolved in N, N-dimethylformamide (50.0 mL), ((1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-yl) methylamine (B64-5) (438 mg,2.98 mmol) and N, N-diisopropylethylamine (1.15 g,8.93 mmol) were added, and the reaction solution was stirred at 100℃for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was separated by preparative high performance liquid chromatography (column: waters Xbridge 150 x 25mm x 5um; solvent: a=water+aqueous ammonia, b=acetonitrile; gradient: 28% -58%) to give the compound 5-bromo-6- (((1 r,5r,6 r) -2, 2-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N-methylpyridine-3-sulfonamide (B64-7) (200 mg, yield 16.9%).

Sixth step: synthesis of 6- ((((1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexan-6-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-64)

5-Bromo-6- ((((1R, 5R, 6R) -2, 2-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N-methylpyridine-3-sulfonamide (B64-7) (200 mg, 504. Mu. Mol) and tributyl- (1-methylimidazol-4-yl) stannane (187 mg, 504. Mu. Mol) were dissolved in toluene (30.0 mL), and tetrakis (triphenylphosphine) palladium (58.3 mg, 50.4. Mu. Mol) was added under nitrogen protection, and the reaction solution was stirred at 100℃under nitrogen protection for 4 hours. After the completion of the reaction, water (50 mL) was added to the reaction mixture, the organic phase was washed with ethyl acetate (100 mL), dried over saturated brine (100 mL), filtered and concentrated to give a crude product, which was separated by preparative high performance liquid chromatography (column: C18×30mm; solvent: a=water+formic acid, b=acetonitrile; gradient: 25% -55%,7 minutes) to give compound 6- ((((1 r,5r,6 r) -2, 2-difluorobicyclo [3.1.0] hexane-6-yl) methyl) amino) -N-methyl-5- (1-methyl-1H-imidazol-4-yl) pyridine-3-sulfonamide (I-64) (104 mg, yield 52.3%).

LC-MS,M/Z(ESI):398.1[M+H]⁺

¹H NMR(CDCl₃,400MHz)δ:9.39(br s,1H),8.46(d,1H),7.90(d,1H),7.50(s,1H),7.30(s,1H),4.41(br d,1H),3.77(s,3H),3.59-3.66(m,1H),3.39-3.46(m,1H),2.67(d,3H),1.98-2.02(m,1H),1.87-1.92(m,1H),1.64-1.74(m,4H),1.42(br d,1H)

Example 27

The following compounds were prepared by reference to the preparation methods of the examples above.

Test example 1: TEADs-mediated transcriptional inhibition IC ₅₀ evaluation assay

HEK293T-TEAD Reporter Assay was used to detect TEADs-mediated transcriptional inhibition by small molecule compounds.

HEK293T-TEAD-LUC reporter cell line with DMEM+10% FBS+1% PS+200ug/ml Hygromycin as complete medium, cells in log phase were inoculated in 384 well plates, 2500 cells/well/35 uL, incubated overnight at 37℃with 5% CO ₂, 5uL of diluted compound (final DMSO concentration of 0.1%) was added every well the next day, positive control with DMSO only was set up, and signal with Okacid acid signal value of 2. Mu.M as negative control, then incubated for 48h at 37℃with 5% CO ₂, steady incubation was used after completionLuciferase ASSAY SYSTEM (Promega, E2550) and fluorescence signal values were measured on Envision 2104Multilabel Reader according to the instructions provided by the supplier. The inhibition was calculated by the following formula, and then the IC ₅₀ was calculated using Graphpad 7.0 by plotting the inhibition on the Y axis with the concentration Log value of the inhibitor as the X axis.

Inhibition% = (positive control signal-test well signal)/(positive control signal-negative control signal) ×100

TABLE 1 test of Compounds for TEADs transcriptional inhibitory Activity on HEK293T-TEAD-LUC reporter cell line cells

Test compounds	IC₅₀(nM)
		I-5	39.64
I-7	124
		I-14	47.8
I-16	152

The HEK293T-TEAD Reporter Assay result shows that the compound can obviously inhibit the TEADs transcriptional activity on HEK293T-TEAD-LUC reporter cell line cells.

Test example 2: test for inhibiting proliferation of malignant mesothelioma cells

The proliferation inhibition effect of the small molecule compound on malignant mesothelioma cells is detected by using an NCI-H226 cell proliferation test of NF2 mutation.

NCI-H226 (ATCC, cat#crl5826) was incubated with RPMI1640+10% fbs+1% ps as complete medium, cells in log phase were seeded in 96-well plates, 800 cells/well/195 μl,37 ℃ and incubated overnight with 5 μl of diluted compound (DMSO final concentration of 0.1%) per well the next day, positive control with DMSO alone was set up and signal with 1 μl of Staurosporine signal as negative control, then 37 ℃ and 5% CO ₂ incubated for 6 days, after which 100 μl of medium was aspirated, and fluorescent signal values were determined on Envision 2104Multilabel Reader using CELLTITER GLO ASSAY KIT (Promega, G7573) and following the instructions provided by the supplier. The inhibition was calculated by the following formula, and then plotted with the concentration Log value of the inhibitor as the X-axis and the inhibition as the Y-axis, and IC ₅₀ was calculated using graphpad 7.0.

TABLE 2 test Compounds for NCI-H226 cell proliferation inhibitory Activity

Test compounds	IC₅₀(nM)
		I-5	28.83
I-7	74.48
		I-14	23.21
I-16	88.25
		I-36	25.83
I-55	14.23
		I-56	47.48
I-62	40

The NCI-H226 cell proliferation test result shows that the compound can obviously inhibit proliferation of NCI-H226 (ATCC, cat#CRL 5826).

Test example 3: pharmacokinetic test

Mice pharmacokinetic experiments 3 male ICR mice, 20-25g, were used, fasted overnight, and administered orally by gavage (10 mg/kg). Blood was collected 15, 30 minutes and 1,2, 4, 8, 24 hours before and after dosing. Blood samples were centrifuged at 6800g 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 2: results of the pharmacokinetic test in mice

The results of the mouse pharmacokinetics test show that the compound of the invention has excellent pharmacokinetic properties and good patentability.

Test example 4: NCI-H226 mesothelioma mice tumor-bearing efficacy test

Nu/Nu nude mice (CRL) were adaptively fed for one week, NCI-H226 cells in the log phase were resuspended in PBS, 5×10 ⁶ NCI-H226 cells were inoculated subcutaneously at the rear right side of the mice at 100 μl/dose, tumor growth was observed periodically, and when tumors grew to an average volume of 80-100mm ³, tumor volumes and animal weights were measured and recorded before and during dosing, and after the end of treatment, the tumor growth inhibition was counted by the dosing group using the model group as a control group, and TGI was calculated.

The results of the drug effect test of tumor-bearing mice show that the compound has obvious effect of inhibiting the growth of the NCI-H226 mesothelioma.

The embodiments of the technical solution of the present application have been described above by way of example. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present application should be included in the scope of the present application as defined in the appended claims.

Claims

1. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

Wherein,

Each X ₁、X₂、X₃ is independently N or CR _a;

W is O, NH;

L is absent or-CH ₂-、-CH₂CH₂-、-CH₂CH₂CH₂ -;

When R ₁ is plural, the R ₁ are the same or different;

When R ₂ is plural, the R ₂ are the same or different;

When R _a is plural, the R _a are the same or different;

m is 0,1,2 or 3;

n is 0, 1, 2 or 3.

2. The compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions (1) to (11):

(1) For/> -W-L-is-NH-CH ₂ -or-O-CH ₂ -;

(2) Ring A is a 6-12 membered bicyclic saturated carbocycle; preferably, ring A is

(3)For

(4) Ring B is 6-12 membered bicyclic ring or 8-15 membered tricyclic ring, and the 6-12 membered bicyclic ring or 8-15 membered tricyclic ring is 5 membered N-containing heteroaromatic ring and saturated heterocycle; preferably, the 6-12 membered bicyclic or 8-15 membered tricyclic ring is an imidazo saturated heterocycle;

(5) When ring B is a 6-12 membered bicyclic ring, ring B is Wherein ring B' is a5 membered heteroaryl ring having 1, 2,3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when the heteroatoms are plural; ring B "is a 5-or 6-membered saturated heterocyclic ring having 1, 2,3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when the number of heteroatoms is plural;

(6) When ring B is a 6-12 membered bicyclic ring, ring B is Wherein ring B "is a 5-or 6-membered saturated heterocyclic ring having 1,2,3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when there are multiple heteroatoms;

(7) Ring B is a 6-12 membered bicyclic ring, -L-W-is not-O-or Not benzene ring or pyridine;

(8) For/>

(9) -W-L-is-NH-CH ₂-、-O-CH₂ -, -NH-, -O-; preferably, -L-W-is-NH-CH ₂ -or-O-CH ₂ -;

(10) When ring B is an 8-15 membered tricyclic ring, ring B is Wherein ring B' "is a 6-10 membered fused ring; preferably, ring B' "is a 6-10 membered saturated and ring, optionally containing 1,2 or 3 heteroatoms; preferably, the ring B is

(11)Does not contain a group covalently bound to an amino acid residue; preferably, wherein each R ₂、R₃、R₄ is independently hydrogen or C ₁-C₆ alkyl; more preferably, each R ₂、R₃、R₄ is independently hydrogen or methyl.

3. The compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to claim 1, wherein the compound of formula I has the structure:

Wherein,

Each X ₁、X₂、X₃ is independently N or CR _a;

W is O, NH;

L is absent or-CH ₂-、-CH₂CH₂-、-CH₂CH₂CH₂ -;

When R ₁ is plural, the R ₁ are the same or different;

When R ₂ is plural, the R ₂ are the same or different;

When R _a is plural, the R _a are the same or different;

m is 0,1,2 or 3;

n is 0, 1, 2 or 3;

preferably, the compound of formula I satisfies one or more of the following conditions:

i) R ₁ is-SF ₅;

ii) X ₁、X₂ is N;

iii) Ring a is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;

iv) ring B is a 6-12 membered bicyclic ring, and-L-W-is not-O-;

preferably, the ring a is a saturated carbocyclic ring; preferably, the ring A is a parallel ring or a spiro ring;

preferably, ring B is

Wherein ring B' is an aromatic ring having 1,2, 3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when the number of heteroatoms is plural;

Ring B "is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1,2, 3 or 4 heteroatoms selected from N, O, S, which are the same or different when the heteroatoms are plural.

4. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3, having the structure of formula II

The ring B "is optionally substituted with 1,2 or 3 identical or different R ₂; the R ₂ is selected from halogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl;

Preferably, the compound of formula II satisfies one or more of the following conditions:

i) R ₁ is-SF ₅;

ii) X ₁、X₂ is N;

iii) Ring a is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;

vi) ring A is a benzene ring;

vii) R ₂₁ is methyl, R ₂₂ is H;

viii) -W-L-is-NH-CH ₂ -;

preferably, the ring a is a saturated carbocyclic ring; preferably, the ring A is a parallel ring or a spiro ring.

5. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claim 1 to 4,Is that

6. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 to 5, wherein ring a is

Preferably, the ring A is

7. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 to 5 wherein the groupIs that

Preferably, the method comprises the steps of,For

Preferably, each R ₁ is independently F or methyl;

Preferably, the method comprises the steps of, For

Preferably, the method comprises the steps of,Is that

8. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 to 5,Is that

Preferably, the method comprises the steps of,Is that

9. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3, wherein the compound of formula I has the structure of formula Ia, ib or Ic

Wherein the rings A, R ₁、R₂₁、R₂₂、X₁、X₂, W, L, m, n are as defined in claim 1 or 3;

Ring B "is a saturated heterocyclic ring having 1,2, 3 or 4 heteroatoms selected from N, O, S, said heteroatoms being the same or different when there are multiple heteroatoms;

Preferably, R ₂ is methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl;

more preferably, R ₂ is methyl.

10. The compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 9, wherein the compound of formula I has the structure of formula Ic-1, formula Ic-2 or formula Ic-3

Wherein ring B ", R ₁、R₂、X₁、X₂, W, L, n are as defined in claim 9;

Preferably, the method comprises the steps of, For

11. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 9 or 10,

Radicals (C)Selected from the group consisting of

Preferably, the method comprises the steps of,For

12. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3, having structure Id

Preferably, R ₂ is methyl;

preferably, L is-CH ₂ -;

Preferably, the method comprises the steps of, For

13. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3, having the structure If

Wherein R ₁、R₂, W, L are as defined in claim 1 or 3;

preferably, ring A is a benzene ring;

preferably, R ₂₁ is methyl and R ₂₂ is H;

preferably, -W-L-is-NH-CH ₂ -;

Preferably, the method comprises the steps of, For

14. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 or 3 wherein X ₁、X₂ is N; or (b)

X ₁ is CRa, X ₂ is N; or (b)

X ₁、X₂ is CRa;

preferably, ra is hydrogen or F.

15. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3, having the structure Ie

Wherein,Is an 8-15 membered tricyclic ring;

Preferably, the method comprises the steps of, For

Preferably, the method comprises the steps of,For

More preferably, the process is carried out,For

16. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 3,Selected from:

Preferably, the method comprises the steps of, For

17. A compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, selected from the group consisting of:

。

18. A pharmaceutical composition comprising a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, as claimed in any one of claims 1 to 17, and a pharmaceutically acceptable carrier.

19. Use of a compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 17, or use of a pharmaceutical composition according to claim 18, comprising:

preferably, the TEAD includes: TEAD1, TEAD2, TEAD3, and TEAD4;

preferably, the disease is a cell proliferative disorder;

preferably, the cell proliferative disorder is cancer;

Preferably, the cancer is selected from: mesothelioma, ovarian cancer, cholangiocarcinoma, hematologic cancer, lymphoma, myeloma, leukemia, cancers of the nervous system, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer, and vascular cancer.