CN117843633A

CN117843633A - Sulfoximine compounds, pharmaceutical compositions and uses thereof

Info

Publication number: CN117843633A
Application number: CN202211219635.1A
Authority: CN
Inventors: 高善云; 候英杰; 李晶晶; 张朝波; 许艳晓; 屠汪洋; 于冰; 张毅翔; 李乐平
Original assignee: Shanghai Haihe Pharmaceutical Co Ltd
Current assignee: Shanghai Haihe Pharmaceutical Co Ltd
Priority date: 2022-09-30
Filing date: 2022-09-30
Publication date: 2024-04-09

Abstract

The invention relates to a sulfoximine compound shown in a formula (I), a pharmaceutical composition and application thereof. The compound of the formula (I) has ENPP1 inhibition activity, low in-vivo clearance rate and good oral bioavailability, and the compound of the formula (I) and the pharmaceutical composition containing the compound of the formula (I) can be used for preparing medicines for preventing and/or treating diseases or disorders, in particular diseases or disorders mediated by abnormal ENPP1 activity.

Description

Sulfoximine compounds, pharmaceutical compositions and uses thereof

Technical Field

The invention relates to an ENPP1 inhibitor, in particular to a sulfoximine compound shown in a formula (I), a pharmaceutical composition containing the compound and application of the compound in preparing medicaments for treating and/or preventing ENPP1 related diseases, especially tumors and infectious diseases.

Background

As a first line of defense of the body against pathogens, the immune system of the human body plays a non-negligible role in the process of combating tumor cells. STING (Stimulator of Interferon Gene) is an interferon gene stimulator consisting of 378 amino acids and plays an important role in immunization against tumor cells. STING may be activated by binding to cGAMP (cyclic GMP-AMP synthase), thereby recruiting TANK-binding kinase 1 (tbk 1), resulting in phosphorylation of interferon regulatory factor 3 (Interferon Regulatory Factor, irf 3). Phosphorylated IRF3 produces type I interferon (type I interferon, IFN) and other cytokines that, in combination with iFN, elicit an immune response in the human adaptive immune system to tumor cells and infectious diseases.

The extramembranous nucleotide pyrophosphatase-phosphodiesterase 1 (ENPP 1) is one of 7 enzymes in the ENPP family, a type two transmembrane glycoprotein. The research shows that ENPP1 has high hydrolyzability and can decompose various substrates including phosphodiester bonds and pyrophosphoric acid bonds, and ATP is one of main targets of ENPP 1. ENPP1 not only hydrolyzes ATP to AMP and PPi, but also hydrolyzes cGAMP, inhibiting the number of cGAMP in the human body and reducing STING activity. Therefore, the activity of ENPP1 inhibits the immune response of the immune system of the human body to the tumor and the infectious diseases through STING, and the inhibition of the activity of ENPP1 is beneficial to the stability of cGAMP and the activity rise of STING, so that the resistance of the immune system of the human body to the tumor and the infectious diseases is improved. In addition, ENPP1 was demonstrated to have more prominent expression than usual in human breast tumors, which not only suggests that ENPP1 is a potential predictive marker for breast cancer, but also highlights its potential and reliability as a target for anticancer drugs.

In addition to the prominent manifestation of ENPP1 inhibitors in tumors, studies have shown that ENPP1 expression is associated with a variety of infectious diseases caused by bacteria or viruses. Thus, ENPP1 inhibitors are also useful in the treatment of infectious diseases.

Despite the variety of treatment options available for cancer patients, there remains a need for effective and safe therapeutic agents and their preferred use in combination therapies.

Disclosure of Invention

The inventors have unexpectedly found that the compounds of formula (I) below have good ENPP1 inhibitory activity, as well as good physical, chemical stability and in vivo pharmacokinetic properties, including lower clearance and higher oral bioavailability, and thus are excellent in pharmaceutical properties and are useful as ENPP1 inhibitors.

Accordingly, in one aspect of the present invention, there is provided a sulfoximine compound represented by the following formula (I), and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof:

in a second aspect of the present invention, there are provided a process for preparing a sulfoximine compound represented by formula (I), an intermediate for preparing the same, and a process for preparing the intermediate.

In a third aspect of the present invention, there is provided a composition comprising a sulfoxide imine compound as shown in formula (I), and one or more of its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically-labeled compounds.

In one embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the sulfoximine compounds of formula (I), and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically-labeled compounds thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In one embodiment, the pharmaceutical composition further comprises one or more additional therapeutic agents.

In one embodiment, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.

The sulfoximine compound has ENPP1 inhibition activity, can regulate STING activity in vivo, and can be used as selective extracellular inhibition of ENPP1 activity so as to increase extracellular level of cGAMP and activate an interferon gene stimulating factor (STING) pathway.

Accordingly, in a fourth aspect of the present invention there is provided an ENPP1 inhibitor comprising one or more selected from the group consisting of sulfoximine compounds of formula (I), and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically-labelled compounds thereof, or a pharmaceutical composition comprising the same.

In a fifth aspect of the present invention, there is provided the use of a sulphoxide imine compound of formula (I), and one or more of its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically-labelled compounds, or a pharmaceutical composition as defined above, said use being selected from the group consisting of:

a. use in the manufacture of a medicament for inhibiting ENPP1 activity;

b. use in the manufacture of a medicament for increasing STING activity;

c. use in the manufacture of a medicament for increasing extracellular levels of cGAMP;

d. use in the manufacture of a medicament for modulating an immune response in an individual;

e. use in the manufacture of a medicament for the treatment and/or prophylaxis of an ENPP1 mediated disease or disorder, in particular cancer or an infectious disease or disorder.

In a sixth aspect of the invention, there is also provided a method of treatment.

In one embodiment, a method of inhibiting ENPP1 receptor activity in a subject is provided, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the sulfoximine compound or the pharmaceutical composition.

In one embodiment, there is provided a method of treating and/or preventing an ENPP1 mediated disease or disorder, in particular cancer or an infectious disease or condition, comprising administering to a patient in need thereof an effective amount of a first therapeutic agent and optionally a second therapeutic agent, wherein the first therapeutic agent is a compound of the invention and the second therapeutic agent is one or more other therapeutic agents.

In addition, the present invention provides a product or kit comprising a compound of the invention as defined above, or a combined preparation of said pharmaceutical composition and one or more other active agents for simultaneous, separate or sequential use in anticancer therapy.

The beneficial effects are that:

by adopting LC-MS and/or ELISA analysis, the compounds of the formula (I) have high selectivity and inhibition activity on ENPP1, lower in-vivo clearance rate and better oral bioavailability; specifically, the compounds of the present invention have IC of 1. Mu.M or less for ENPP1 kinase ₅₀ IC with value preferably less than or equal to 0.5 mu M ₅₀ IC having a value of 0.35. Mu.M or less more preferably ₅₀ IC having a value, even more preferably ∈0.05. Mu.M ₅₀ Values. In particular, the present invention also finds that compounds of one configuration show an inhibitory activity on ENPP1 that is superior to compounds of another configuration.

Detailed Description

Numerous specific details are set forth in the following description in order to provide a better understanding of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details.

In one aspect, the present invention provides compounds of formula (I), and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically-labeled compounds thereof:

Wherein,is a single bond or a double bond;

X ¹ is N, bond or CR ¹ ；

X ² N, NR of a shape of N, NR ² Or CR (CR) ² ；

X ³ N, NR of a shape of N, NR ³ -C (=o) -or CR ³ ；

X ⁴ N, NR of a shape of N, NR ⁴ -C (=o) -or CR ⁴ ；

X ⁵ N, NR of a shape of N, NR ⁵ Or CR (CR) ⁵ ；

X ⁶ Is N, -C (=O) -or CR ⁶ ；

Y ¹ Is hydrogen or C ₁ -C ₃ An alkyl group;

Y ² is C ₁ -C ₄ Alkyl or C ₃ -C ₆ Cycloalkyl;

R ⁷ 、R ⁸ each independently selected from: hydrogen, C ₁ -C ₃ An alkyl group;

ring a is selected from: c (C) ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, each independently containing 1, 2 or 3 heteroatoms selected from N, O, S; wherein ring A is optionally selected from halogen, CN, OH, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and C ₁ -C ₃ One or more substituents in the haloalkyl group;

ring B is an aromatic ring;

R ¹ 、R ² 、R ³ 、R ⁴ each independently selected from: hydrogen, halogen, CN, OR ^a 、C ₁ -C ₆ An alkyl group; the C is ₁ -C ₆ Alkyl optionally substituted with one or more halogens;

R ⁵ independently selected from: hydrogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

R ⁶ independently selected from: hydrogen, CN, ORa, C ₁ -C ₃ Alkyl and C ₃ -C ₆ Cycloalkyl;

wherein each R ^a Each independently selected from: hydrogen, C ₁ -C ₄ Alkyl, said C ₁ -C ₄ The alkyl group is optionally substituted with one or more halogens.

In particular, compounds of formula (I) are shown below by formula (I'), wherein the corresponding substituents are each as described above:

in one embodiment, there is provided a compound of formula (I), wherein X ¹ Is N or CR ¹ The method comprises the steps of carrying out a first treatment on the surface of the Specifically, provided are compounds represented by the following formula (II) and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof:

wherein X is ¹ Is N or CR ¹ ；X ² Is N or CR ² ；X ³ N, NR of a shape of N, NR ³ -C (=o) -or CR ³ ；X ⁴ N, NR of a shape of N, NR ⁴ -C (=o) -or CR ⁴ The method comprises the steps of carrying out a first treatment on the surface of the And X is ³ 、X ⁴ Other substituents are as in formula (I), except for-C (=o) -.

Preferably X ¹ Is CR (CR) ¹ The method comprises the steps of carrying out a first treatment on the surface of the More preferably X ¹ Is CR (CR) ¹ ，X ² Is CR2; further preferably, X ¹ Is CR (CR) ¹ ，X ² Is CR (CR) ² And X is ³ is-C (=O) -, X ⁴ N, NR of a shape of N, NR ⁴ The method comprises the steps of carrying out a first treatment on the surface of the Or, X ¹ Is CR (CR) ¹ ，X ² Is CR (CR) ² And X is ³ N, NR of a shape of N, NR ³ ，X ⁴ is-C (=o) -.

In another embodiment, there is provided a compound of formula (I), wherein X ¹ Is a bond (i.e. X ¹ Absence of presence); specifically, provided are compounds represented by the following formula (III) and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof:

wherein X is ² N, NR of a shape of N, NR ² Or CR (CR) ² ；X ³ Is N or CR ³ ；X ⁴ N, NR of a shape of N, NR ⁴ Or CR (CR) ⁴ The method comprises the steps of carrying out a first treatment on the surface of the The other substituents are as in formula (I); preferably X ⁴ Is N or NR ⁴ 。

In a specific embodiment, X ⁵ 、X ⁶ At least one of which is independently selected from N and NR ⁿ (if any) wherein R ⁿ For X ⁵ Is referred to as R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the The other substituents are as described above; preferably X ⁵ 、X ⁶ At least one of which is independently selected from N, or X ⁵ 、X ⁶ Only one of which is independently selected from N and NR if any ⁿ 。

In one embodiment, X ⁵ Is N or NR ⁵ 。

In a specific embodiment, X ⁵ Is N; preferably X ⁵ Is N, X ⁶ Is N or CR ⁶ The method comprises the steps of carrying out a first treatment on the surface of the More preferably X ⁵ Is N, X ⁶ Is CR (CR) ⁶ ；。

In a specific embodiment, X ⁵ Is NR (NR) ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Preferably X ⁵ Is NR (NR) ⁵ ，X ⁶ is-C (=o) -.

In one embodiment, X ⁶ Is N. Preferably X ⁶ Is N, X ⁵ Is CR (CR) ⁵ 。

In a specific embodiment, X ¹ 、X ² 、X ³ 、X ⁴ At least one of N and NR ⁿ (if any), or X ¹ 、X ² 、X ³ 、X ⁴ Are all CR ⁿ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁿ For X ¹ Is referred to as R ¹ For X ² Is referred to as R ² For X ³ Is referred to as R ³ For X ⁴ Is referred to as R ⁴ . Preferably X ¹ 、X ² 、X ³ 、X ⁴ Only one of which is selected from N or NR ⁿ 。

In a specific embodiment, X ¹ 、X ² 、X ³ 、X ⁴ At least one of which is selected from N; more preferably X ² 、X ³ Or X ⁴ Each independently is N; further preferably, X ² Is N or X ⁴ Is N; more preferably X ⁴ Is N.

In a specific embodiment, X ¹ Is N and X ² Is CR2, X ³ is-C (=O) -or CR ³ ，X ⁴ is-C (=O) -or CR ⁴ 。

In a specific embodiment, X ² Is N or NR ² And X is ¹ Is CR (CR) ¹ Or a bond, X ³ is-C (=O) -or CR ³ ，X ⁴ is-C (=O) -or CR ⁴ 。

In a specific embodiment, X ³ Is N or NR ³ And X is ¹ Is CR (CR) ¹ Or a bond, X ² Is CR (CR) ² ，X ⁴ is-C (=O) -or CR ⁴ 。

In a specific embodiment, X ⁴ Is N or NR ⁴ And X is ¹ Is CR (CR) ¹ Or a bond, X ² Is CR (CR) ² ，X ³ is-C (=O) -or CR ³ 。

In a specific embodiment, X ¹ Is a bond (i.e. X ¹ Absence) or CR ¹ Preferably X ¹ Is a key.

In one embodiment, X ¹ Is a bond or CR ¹ And X is ⁵ Is N or NR ⁵ 。

In one embodiment, X ¹ Is a bond or CR ¹ And X is ⁶ Is N.

In a specific embodiment, X ³ 、X ⁴ Is selected from-C (=o) -; preferably X ³ is-C (=o) -.

In a specific embodiment, X ³ is-C (=O) -, and X ⁴ Is NR (NR) ⁴ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R ⁴ Is H or C ₁ -C ₄ An alkyl group.

In a specific embodiment, X ⁴ is-C (=O) -, and X ³ Is NR (NR) ³ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R ³ Is H or C ₁ -C ₄ An alkyl group.

In a specific embodiment, R ¹ 、R ² 、R ³ 、R ⁴ Each independently selected from: hydrogen, halogen, CN, OH, C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and halo C ₁ -C ₄ An alkoxy group; preferably, R ¹ 、R ² 、R ³ 、R ⁴ Each independently selected from: hydrogen, halogen, CN, OH, C ₁ -C ₃ Alkyl, halogenated C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy and halo C ₁ -C ₃ An alkoxy group; more preferably, R ¹ 、R ² Each independently selected from: hydrogen, F, cl, CN, OH and C ₁ -C ₃ An alkyl group; r is R ³ 、R ⁴ Each independently selected from hydrogen, F, cl, OH, C ₁ -C ₃ Alkyl, halogenated C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy and halo C ₁ -C ₃ An alkoxy group.

In a specific embodiment, R ⁵ Selected from: hydrogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl groups.

In a specific embodiment, R ⁶ Selected from: hydrogen, CN, OH, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₃ Haloalkoxy groups.

In one embodiment of the present invention, in one embodiment,or the corresponding group is selected from the following structures: /> Preferably selected from the following structures: /> Further preferably, the structure is selected from the following:

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、R ⁵ 、R ⁶ 、Y ¹ As defined previously.

In a specific embodiment, ring a is selected from: c (C) ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocycloalkyl; wherein ring A is optionally selected from halogen, CN, OH, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and C ₁ -C ₃ The substituents of the haloalkyl group are substituted one or more times, for example one or two times;

preferably, ring a is optionally selected from F, cl, CN, OH, C ₁ -C ₃ Alkyl and C ₁ -C ₃ The substituents of the alkoxy groups are substituted one or more times, for example one or two times; the other substituents are as described above. In a specific embodiment, ring a is an optionally substituted pyrrole ring, furan ring, thiophene ring, pyrazole ring, thiazole ring, oxazole ring, imidazole ring, pyran ring, pyrazine ring, indoline ring, isoindoline ring, azacyclopentane ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, naphthalene ring, quinoline ring, isoquinoline ring, indole ring, isoindole ring, indazole ring, or benzimidazole ring; the substituted substituent is selected from one or more of F, cl, CN, OH, C ₁ -C ₃ Alkyl and C ₁ -C ₃ An alkoxy group;

preferably, ring a is an optionally substituted or unsubstituted pyrazole ring, pyrrole ring, imidazole ring, furan ring, thiophene ring, azacyclopentane ring, pyran ring, pyrazine ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, or naphthalene ring; the substituted substituents are selected from one or more F, cl, CN, OH, C ₁ -C ₃ Alkyl and C ₁ -C ₃ An alkoxy group; the other substituents are as described above.

In a specific embodiment, ring a is selected from:

wherein q is 0, 1 or 2;

each R ⁹ Identical or different, independently selected from halogen, CN, OH, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and C ₁ -C ₃ A haloalkyl group; preferably, each R ⁹ Independently selected from F, cl, CN, C ₁ -C ₃ Alkyl or C ₁ -C ₃ An alkoxy group; the other substituents are as described above.

In some embodiments, R ⁷ 、R ⁸ Each independently selected from hydrogen and C ₁ -C ₃ An alkyl group; preferably selected from hydrogen, methyl; the other substituents are as described above.

In some embodiments, Y ¹ Is hydrogen or C ₁ -C ₃ An alkyl group; preferably hydrogen or methyl.

In some embodiments, Y ² Is C ₁ -C ₄ Alkyl or C ₃ -C ₆ Cycloalkyl; preferably methyl or cyclopropyl; the other substituents are as described above.

In a specific embodiment, the compound of formula (I) is selected from the group consisting of the following formulas (I) ₁ )-(I ₇ ) The structure is as follows:

wherein X is ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、Y ¹ 、Y ² Ring a is as defined previously.

In one embodiment, there is provided a structural compound as follows:

in another aspect, the invention provides a process for preparing the compounds of the invention.

In one embodiment, the invention also provides intermediates useful in the preparation of the compounds of the invention and methods for their preparation.

In another aspect, the present invention provides compositions comprising a sulfoxide imine compound as shown in formula (I), and one or more of its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds.

In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the sulfoximine compounds of formula (I), and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

In certain embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated for any suitable route of administration, such as intravenous administration, intramuscular administration, oral administration, rectal administration, inhalation administration, nasal administration, topical administration, ocular administration, or otic administration. In other embodiments of the pharmaceutical composition, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, solution, emulsion, ointment, eye or ear drop.

In one embodiment, the pharmaceutical composition further comprises one or more other therapeutic agents common in the pharmaceutical arts.

In another aspect, the present invention provides an ENPP1 inhibitor comprising a sulfoximine compound represented by formula (I), and one or more of its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds, or said pharmaceutical composition.

In another aspect, the present invention provides use of a sulfoxide imine compound represented by formula (I), and one or more of stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof, or a pharmaceutical composition as described above, said use being selected from the group consisting of:

a. use in the manufacture of a medicament for inhibiting ENPP1 activity;

b. use in the manufacture of a medicament for increasing STING activity;

In another aspect, the present invention provides a method of treating and/or preventing an ENPP1 mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a sulfoximine compound of formula (I), and one or more of stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof, or a pharmaceutical composition or said pharmaceutical composition, and optionally at least one other therapeutic agent in a therapeutically effective amount.

In one embodiment, the compounds of the invention or the composition and one or more other therapeutic agents are used simultaneously, separately or sequentially.

In some embodiments, the ENPP 1-mediated disease or disorder includes, but is not limited to, a tumor, an infectious disease or disorder, particularly a cancer, such as a recurrent or refractory cancer, a metastatic cancer, and the like.

In another embodiment, the tumor is a solid tumor or a hematological malignancy.

In another embodiment, the solid tumor includes, but is not limited to: breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, cancer of the reproductive system, cancer of the gastrointestinal system, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gall bladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline bundle cancer, and unknown primary cancer.

In another embodiment, the hematological malignancy includes, but is not limited to: leukemia, lymphoma or myeloma.

In another embodiment, the infectious disease or disorder includes, but is not limited to: herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papilloma virus infection, hepatitis B virus infection, hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, ebola virus infection, marburg virus infection, zika virus infection, listeria monocytogenes infection, mycobacterium tuberculosis infection, francisco infection, legionella pneumophila infection, chlamydia trachomatis infection, streptococcus pneumoniae infection, gonococcus infection.

It is understood that within the scope of the present invention, the technical features defined in the technical solutions of the present invention and the technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein. It is also to be understood that each individual element of an embodiment is its own separate embodiment.

Other features of the invention will be apparent from the foregoing description of exemplary embodiments, which are given for the purpose of illustration of the invention and are not intended to be limiting thereof.

Description of the terms

In the present invention, unless explicitly stated otherwise, terms used in the present invention have the meanings defined below. Terms not explicitly defined herein have the general meaning commonly understood by those skilled in the art.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The short dash ("-") that is not between two letters or symbols represents the attachment site for a substituent. For example, -O (C) _1- C ₃ Alkyl) means that the group is attached to the rest of the molecule through an oxygen atom. However, "-" may be omitted when the attachment site for the substituent is apparent to those skilled in the art, for example, for a halogen, hydroxy, etc. substituent.

When the radicals carry wavy linesWhen the wavy line indicates the attachment of the group to the remainder of the molecule Position.

As used herein,represents a single bond or a double bond. The person skilled in the art can determine +.>It is within the ability of the person skilled in the art to represent a single bond or a double bond. Those skilled in the art will appreciate that the relevant rings may be saturated, partially saturated or aromatic.

As used herein, "heteroatom" refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, particularly nitrogen or oxygen, each of which may be substituted or unsubstituted, including oxidized forms thereof. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S (O) -and-S (O) ₂ -, wherein R is hydrogen, C ₁ -C ₄ Alkyl or nitrogen protecting groups (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, t-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-phenyl, 3, 4-dimethoxybenzyl, etc.). Any heteroatom having an unsatisfied valence is considered to have a hydrogen atom sufficient to satisfy the valence unless otherwise indicated.

As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. Preferred halogens as substituents are fluorine and chlorine.

As used herein, "alkyl" refers to a fully saturated straight or branched monovalent hydrocarbon group. The alkyl group preferably contains 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 to 3 carbon atoms. The number preceding the alkyl group indicates the number of carbon atoms. For example, "C ₁ -C ₄ Alkyl "means an alkyl group having 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. Whether the term "alkyl" occurs alone or as part of another group such as haloalkyl, alkoxy, or the like,this definition applies.

As used herein, "alkoxy" refers to an alkyl group as defined herein, i.e., an alkyl-O-group, attached through an oxygen bridge, the number preceding the alkoxy group representing the number of carbon atoms. For example, "C _1- C ₄ Alkoxy "denotes alkoxy having 1 to 4 carbon atoms, i.e. -O-C _1-4 An alkyl group. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentoxy, hexoxy, and the like. Preferably, the alkoxy groups contain from about 1 to about 4 carbons, and the like.

As used herein, "cycloalkyl" refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, bi-or tricyclic, preferably having 3 to 6 ring carbon atoms, more preferably 3 to 5, 4 to 5 ring carbon atoms. "C ₃ -C ₆ Cycloalkyl "is intended to include C ₃ 、C ₄ 、C ₅ And C ₆ Cycloalkyl groups; and so on. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.

As used herein, "haloalkyl" refers to an alkyl group as defined herein wherein one or more hydrogen atoms, for example 1, 2, 3, 4, 5 or 6 hydrogen atoms, for example 1, 2 or 3 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. For example "C ₁ -C ₃ Haloalkyl "is intended to include C ₁ 、C ₂ And C ₃ A haloalkyl group. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-difluoroethyl, 1, -difluoropropyl and 1, 1-trifluoropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include alkyl groups as defined herein wherein one or more hydrogen atoms are replaced by fluorine atoms. "haloalkyl" herein is preferably the replacement of up to three hydrogen atoms in an alkyl group with halogen.

As used herein, "haloalkoxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge, wherein one or moreThe hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, for example 1, 2 or 3 hydrogen atoms, are replaced by halogen. For example, "C ₁ -C ₃ Haloalkoxy "or" C ₁ To C ₃ Haloalkoxy "is intended to include C ₁ 、C ₂ And C ₃ Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-trifluoroethoxy. Examples of haloalkoxy groups also include "fluoroalkoxy".

As used herein, "aryl" is a monocyclic, bicyclic or tricyclic carbocyclic hydrocarbon group of 6 to 10, 6 to 9 ring carbon atoms formed by the fusion of one or more rings, wherein at least one ring is aromatic and the other rings (if present) may be aromatic or non-aromatic. Preferred aryl groups are those having 6-10 ring carbon atoms, i.e., 6-to 10-membered aryl groups, which include: monocyclic aryl (e.g., phenyl); or a fused bicyclic ring system, wherein one ring is aromatic and the other ring is aromatic (e.g., in naphthyl) or non-aromatic (e.g., in indane, tetrahydronaphthalene). Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, or indanyl, and the like.

As used herein, "heteroaryl" refers to a 5-10 membered, preferably 5-7 membered or 5-6 membered aromatic ring system containing 1-8, preferably 1-4, still preferably 1-3, more preferably 1 or 2 heteroatoms selected from N, O or S, including monocyclic or bicyclic or fused polycyclic, the remaining ring atoms being carbon atoms. Preferably a 5-7 membered heteroaryl or a 5-6 membered heteroaryl, each containing 1,2 or 3 heteroatoms selected from N, O or S. Examples of heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, 1H-benzo [ d ] [1,2,3] triazolyl, and the like.

As used herein, "heterocycle" refers to a 4-8 membered saturated or partially unsaturated non-aromatic heterocycle comprising one to four heteroatoms selected from oxygen, nitrogen and sulfur: mono-, bi-or tricyclic heterocycles containing one to three nitrogen atoms and/or one oxygen or sulfur atom or one or two oxygen and/or sulfur atoms in addition to the carbocycle members; if the ring contains more than one oxygen atom, they are not directly adjacent; such as, but not limited to, oxetanyl, azetidinyl, azepanyl, and the like.

As used herein, "carbocycle" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon group of 3-12 carbon atoms. Carbocycles preferably have 3 to 8 ring carbon atoms, for example containing 3 to 7, or 4 to 7 ring carbon atoms. Exemplary monocyclic carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, and the like. Exemplary bicycloalkanes include tetrahydronaphthalene, decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

As used herein, the term "-C (=o) -" is carbonyl. "=o" means an oxo group, i.e., an oxygen atom is connected to other atoms through a double bond.

Herein, alkyl, alkoxy, carbocycle, cycloalkyl, heteroaryl, carbonyl, and the like groups may be substituted with substituents including, but not limited to: OH, boc, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl; NRR', C (O) R, SO ₂ R, C (O) NRR 'OR C (O) OR, and each R and R' is independently selected from: h and substituted or unsubstituted alkyl.

As used herein, "optional," "optional," or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event occurs as well as instances where the event does not. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. "optionally substituted with halogen" includes the case of "substituted with halogen" and the case of "unsubstituted with halogen", for example, substituted with 0 to 3 halogens. It will be appreciated by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable substitution patterns.

When any variable occurs more than one time in any constituent or formula of a compound, its definition at each occurrence is independent of the definition at each other occurrence. Thus, for example, if a group is shown to be substituted with 0-3R, the group may be unsubstituted or substituted with up to three R, and R is independently selected at each occurrence from the definition of R. For example, one or more substitutions applied in the definition of ring A, i.e., when ring A is 6-to 10-membered aryl and 5-to 10-membered heteroaryl, these groups are unsubstituted or substituted with one or more, e.g., two, substituent groups independently selected at each occurrence from the given definition. This applies similarly to the definition of other similar situations.

When the valence of a substituent shows a valence that connects two atoms through the ring, then the substituent may be bonded to any atom on the ring. When a substituent is listed without specifying the atom to which the substituent is attached to the remainder of the compound of the formula shown, then the substituent may be bonded via any atom in the substituent.

Combinations of substituents and/or variables are permissible only if such compositions result in stable compounds.

When a dashed ring is used in the ring structure, this means that the ring structure may be saturated, partially saturated or unsaturated.

The term "substituted", "substituted" or "substituted with … …" as used herein means that one or more hydrogen atoms on a given atom or group is replaced with one or more substituents selected from a given set of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =o), then two hydrogen atoms on a single atom are replaced with oxygen. No oxo substituents are present on the aromatic moiety. When a ring system (e.g., a carbocycle or heterocycle) is substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond is part of the ring (i.e., within the ring). Such combinations are permissible only if the combination of substituents and/or variables result in chemically correct and stable compounds. Chemically correct and stable compounds means that the compounds are stable enough to be separated from the reaction mixture and to determine the chemical structure of the compounds and can then be formulated into a formulation having at least practical utility. For example, where substituents are not explicitly listed, the terms "substituted", "substituted" or "substituted with … …" as used herein mean that one or more hydrogen atoms on a given atom or group are independently substituted with one or more, e.g., 1, 2, 3 or 4 substituents. When an atom or group is substituted with multiple substituents, the substituents may be the same or different.

The term "pharmaceutically acceptable" or "pharmaceutically acceptable" includes substances or compositions that must be chemically/toxicologically compatible with other ingredients, including formulations and/or mammals treated therewith.

Unless otherwise indicated, the term "compound of the invention" or "compound of the invention" is meant to include one or more of the formulae (I) or sub-formulae thereof, as defined herein, of the invention, e.g. formulae (II), (III), (I) ₁ )、(I ₂ )、(I ₃ )、(I ₄ )、(I ₅ )、(I ₆ )、(I ₇ ) Or pharmaceutically acceptable salts thereof, as well as all isomers such as stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, internal addition products of isomers, and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties (e.g., polymorphs, solvates and/or hydrates). When a moiety capable of forming a salt is present, then a salt, particularly a pharmaceutically acceptable salt, is also included. The presence of a tautomer or internal addition product of an isomer can be identified by one skilled in the art using tools such as NMR. The compounds of formula (I) of the inventionInternal addition products of tautomers and isomers as depicted herein can be readily formed.

When reference is made herein to formula (I), the term also includes sub-formulae thereof, e.g., formulae (II), (III), (I) ₁ )、(I ₂ )、(I ₃ )、(I ₄ )、(I ₅ )、(I ₆ )、(I ₇ )。

As used herein, "pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, benzoic acid, fumaric acid, tartaric acid, salicylic acid, mandelic acid, carbonic acid, and the like. Those skilled in the art will appreciate that the acid addition salts may be prepared by reacting the compounds with an appropriate inorganic or organic acid via any of a number of known methods.

As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, medicaments, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, the like, and combinations thereof, as are well known to those of ordinary skill in the art.

Those skilled in the art will recognize that the compounds of the present invention may contain chiral centers and as such may exist in different isomeric forms. As used herein, "isomers" refer to different compounds having the same molecular formula but differing in the arrangement and configuration of the atoms.

As used herein, an "enantiomer" is a pair of stereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term is used to refer to the racemic mixture. When indicating the stereochemistry of the compounds of the present invention, a single stereoisomer (e.g., (1 s,2 s)) of known relative and absolute configuration having two chiral centers is specified using conventional RS systems; single stereoisomers with known relative configurations, but unknown absolute configurations, are marked with asterisks (e.g., (1R, 2R)); the racemate having two letters (e.g., (1 rs,2 rs) is a racemic mixture of (1 r,2 r) and (1 s,2 s), and (1 rs,2 sr) is a racemic mixture of (1 r,2 s) and (1 s,2 r)). "diastereomers" are stereoisomers which have at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry was indicated according to the Cahn-lngold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on their direction of rotation (right-hand or left-hand) of plane polarized light at the sodium D-line wavelength. Alternatively, the resolved compound may be defined by the respective retention times of the corresponding enantiomer/diastereomer via chiral HPLC.

Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R) -or (S) -in absolute stereochemistry.

Geometrical isomers may occur when a compound contains a double bond or some other feature that imparts a certain amount of structural rigidity to the molecule. If the compound contains a double bond, the substituent may be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration.

"conformational isomers" are isomers that differ by rotation about one or more valences.

"rotamers" are conformational isomers that differ by rotation of only a single valence.

"atropisomers" refer to structural isomers that are based on axial or planar chirality resulting from limited rotation in the molecule.

Unless otherwise indicated, the compounds of the present invention are intended to include all such possible isomers, including racemic mixtures, optically active forms and intermediate mixtures. The optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

The compounds of the invention may be isolated in optically active or racemic forms. The optically active form can be prepared by resolution of the racemic form or by synthesis from optically active starting materials. All processes for preparing the compounds of the invention and intermediates prepared therein are considered to be part of the present invention. When enantiomeric or diastereoisomeric products are prepared, they may be separated by conventional methods, such as by chromatography or fractional crystallization.

Depending on the process conditions, the end products of the invention are obtained in free (basic) or salt form. The free form and salt form of these end products are within the scope of the invention. One form of the compound may be converted to another form if desired. The free base or acid may be converted to a salt; salts may be converted to free compounds or other salts; the mixture of isomeric compounds of the invention may be separated into the individual isomers.

Pharmaceutically acceptable salts are preferred. However, other salts may be useful, for example in isolation or purification steps, which may be used during preparation and are therefore contemplated as being within the scope of the present invention.

As used herein, "pharmaceutically acceptable" is used interchangeably with "pharmaceutically acceptable" and refers to compositions useful in preparing pharmaceuticals that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, including acceptable for veterinary as well as human medicine.

As used herein, "solvate" refers to a physical combination of a compound of the invention with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonds. In some cases, the solvate will be able to separate, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular and/or non-ordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric amount of solvent molecules. "solvate" includes both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

As used herein, "polymorphs" refer to crystalline forms having the same chemical structure/composition but different spatial arrangements of molecules and/or ions that form the crystals. The compounds of the present invention may be provided as amorphous or crystalline solids. Freeze-drying methods may be used to provide the compounds of the present invention as solids.

Any formula given herein is also intended to represent unlabeled as well as isotopically-labeled forms of the compounds. Isotopically-labeled compounds have structures described by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., respectively ² H (D), ³ H (T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² p、 ³⁵ S、 ³⁶ Cl、 ¹²⁵ I. The invention includes different isotopically-labelled compounds as defined herein, for example, wherein a radioisotope such as ³ H、 ¹³ C and C ¹⁴ Those of C. Such isotopically-labeled compounds are useful in metabolic studies (with ¹⁴ C) Kinetic studies of the reaction (e.g. using ² H or ³ H) Detection or imaging techniques, e.g. Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), involving drugs Or substrate tissue distribution assays, or may be used in the radiation treatment of patients. In particular the number of the elements to be processed, ¹⁸ f or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the present invention can generally be prepared by carrying out the procedures described below or in the examples and preparations by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

Moreover, by heavier isotopes, in particular deuterium (i.e ² Substitution of H or D) may also achieve certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context can be considered as a substituent of the compounds of the present invention. The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. "isotopically enriched factor" means the ratio between the isotopic abundance and the natural abundance of a given isotope.

Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by carrying out procedures analogous to those described herein by substituting an appropriate isotopically-labeled reagent for the other unlabeled reagent used. Such compounds have a variety of potential uses, for example as standards and reagents for determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors or for imaging of compounds of the invention that bind to biological receptors in vivo or in vitro.

As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that can elicit a biological or medical response in an individual or ameliorate symptoms, slow or delay the progression of a disease, or prevent a disease, etc. The "therapeutically effective amount" may be determined by the attending physician or veterinarian practitioner and will vary with factors including the compound, the condition being treated, the severity of the condition being treated, the age and associated health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian practitioner, etc.

As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. Individual also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred embodiment, the individual is a human.

As used herein, "inhibition" refers to the alleviation or inhibition of a particular patient, symptom or condition or disease, or a significant reduction in biological activity or process baseline activity.

As used herein, the term "treating" any disease or disorder in one embodiment refers to ameliorating the disease or disorder (i.e., preventing or slowing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter that may not be perceived by the patient. In another embodiment, "treating" refers to modulating a disease or condition physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both.

As used herein, "preventing" refers to administering one or more pharmaceutical substances, particularly the compounds of the invention and/or pharmaceutically acceptable salts thereof, to an individual having a constitution susceptible to the disease, in order to prevent the individual from suffering from the disease.

When chemical reactions are involved, "treating," "contacting," and "reacting" refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction to produce the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates formed in the mixture that ultimately lead to the formation of the indicated and/or desired product.

Generally, the term "about" is used herein to adjust a given value to be above or below 20%, such as 10%, such as 5% of that value.

Technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Pharmaceutical composition and administration

The compounds of the invention may be administered to an individual in the form of a pharmaceutical composition, which may optionally comprise one or more pharmaceutically acceptable excipients.

The compounds of the present invention may be administered by a variety of known routes including oral, rectal, intragastric, intracranial and parenteral, such as intravenous, intramuscular, intranasal, intradermal, subcutaneous, and the like. Particularly preferred are oral, intranasal and parenteral administration. Depending on the route of administration, different pharmaceutical formulations are required, and some of these routes of administration may require a protective coating to the pharmaceutical formulation to prevent degradation of the compounds of the invention, for example, within the digestive tract.

The compounds of the present invention may be formulated as syrups, solutions or injections, sprays, tablets, capsules, lozenges, liposomes or suppositories, and the like.

Particularly preferred pharmaceutical forms for administration of the compounds of the present invention are those suitable for injectable use, including sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the final solution or dispersion form must be sterile and fluid. Typically, such solutions or dispersions will comprise a solvent or dispersion medium containing, for example, a water-buffered aqueous solution such as a biocompatible buffer, ethanol or a polyol such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. The compounds of the invention may also be formulated as liposomes, particularly for parenteral administration. Liposomes offer the advantage of increased half-life in circulation (if compared to free drug) and prolonged more uniform release of the entrapped drug.

Sterilization of infusions and injections may be accomplished by art-recognized techniques including, but not limited to, the addition of preservatives such as antibacterial or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, or thimerosal. In addition, isotonic agents, such as sugars or salts, particularly sodium chloride, may also be incorporated into the infusion and injection solutions.

The production of sterile injectable solutions containing one or more compounds of the invention is accomplished by the following methods: the desired amounts of each compound are incorporated into a suitable solvent having the various ingredients listed above as appropriate, and then sterilized. To obtain sterile powders, the above solutions are vacuum dried or freeze dried as desired. Preferred diluents of the present invention are water, physiologically acceptable buffers, physiologically acceptable buffered saline solutions or saline solutions. Preferred carriers are cocoa butter and vitebesole.

Excipients that may be used with the various pharmaceutical forms of the compounds of the present invention may be selected from the following non-limiting list: a) Binders such as lactose, mannitol, crystalline sorbitol, hydrogen phosphate, sugar, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and/or polyvinylpyrrolidone, and the like; b) Lubricants, for example magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oils, leucine, glycerides and sodium stearyl fumarate; c) Disintegrants, for example starch, croscarmellose, sodium methylcellulose, agar, bentonite, alginic acid, carboxymethylcellulose and/or polyvinylpyrrolidone and the like. Other suitable pharmaceutical carriers and their formulations are well known in the art, for example, as described in the following documents: remington: the Science and Practice of Pharmacy, E.W. Martin, eds., mack Publishing Companv, 19 th edition, iston, pa.

In one embodiment, the formulation is for oral administration and the formulation comprises one or more or all of the following ingredients: pregelatinized starch, talc, polyvinylpyrrolidone K30, croscarmellose sodium, sodium stearyl fumarate, gelatin, titanium dioxide, sorbitol, monosodium citrate, xanthan gum, titanium dioxide, flavoring agent, sodium benzoate, and sodium saccharin.

In one embodiment, the compounds of the invention are administered intranasally, either in a dry powder inhaler or from the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes such as 1, 2-tetrafluoroethane (HFA 134A) ^TM ) Or 1,2, 3-heptafluoropropane (HFA 227 EA) ^TM ) The spray in a pressurized container, pump, nebulizer or atomizer of carbon dioxide, or other suitable gas is applied. The pressurized container, pump, nebulizer or atomizer may contain a solution or suspension of the compound of the invention, for example a solution or suspension using ethanol and a propellant as solvents, which may also contain a lubricant, for example sorbitan trioleate.

Typical dosage ranges for the compounds of the invention are 0.001-1000mg active ingredient per kg body weight per day. The dose may be administered once or in divided doses per day. Determination of the appropriate dosage is determined by the attending physician, as appropriate, based on the type and severity of the condition to be treated, the health and past medical history of the individual, the concomitant medication, the particular compound administered, and the route of administration, among other factors. The compounds of the present invention may be used in amounts outside of this dosage range, as desired.

Pharmaceutical combination

The compounds of the present invention may be used for the uses described herein, alone or in combination with one or more other active agents or therapies, which may have or produce the same or different pharmacological efficacy. The compounds of the invention may be administered simultaneously with, before or after the other active agents or therapies.

When the compounds of the present invention are administered in combination with other active agents, the dosage of the other active agents administered in combination will of course vary depending upon factors such as the drug in use, the condition to be treated, the general health of the patient, the judgment of the physician or veterinarian, and the like. The compounds of the invention may be administered simultaneously, separately or sequentially with other active agents in combination via the same or different routes of administration. They may be contained in the same pharmaceutical composition or may be a combination product in separate form, for example in the form of a kit. They may be prepared and/or formulated by the same or different manufacturers. Moreover, the compounds of the invention and other active agents may (i) be administered prior to delivery of the combination product to a physician (e.g., in the case of a kit comprising a compound of the invention and an additional drug); (ii) By the physician himself immediately prior to administration (or under the direction of the physician); (iii) Added to the combination therapy by the patient himself, for example during sequential administration of the compound of the invention and the other active agent.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more other active agents. Optionally, the pharmaceutical composition may comprise pharmaceutically acceptable excipients as described above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for separately retaining the compositions, such as a container, a separate bottle or a separate foil pouch. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.

The kits of the invention may be used for administration of different dosage forms, such as oral and parenteral dosage forms, for administration of separate compositions at different dosage intervals, or for stepwise increasing the separate compositions relative to one another. To aid compliance, the kits of the invention generally contain instructions for administration.

In the combination therapies of the invention, the compounds of the invention and the other therapeutic agents may be prepared and/or formulated by the same or different manufacturers. Moreover, the compounds of the invention and other therapeutic agents may be incorporated together into a combination therapy, which may be (i) performed prior to dispensing the combination product to a physician (e.g., for a kit comprising the compounds of the invention and other therapeutic agents); (ii) By the physician himself (or under the direction of the physician) immediately prior to administration; (iii) By the patient himself, for example during sequential administration of the compounds according to the invention and further therapeutic agents.

General synthetic method

The compounds of the present invention may be prepared by a variety of methods, including those set forth below, those set forth in the examples, or the like. Suitable general synthetic schemes are depicted below. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The starting materials may be obtained commercially or may be prepared by the methods below, methods similar to those set forth below, or methods known in the art. The variables in the formula have the same meaning as above, unless otherwise indicated.

In one embodiment, the compounds of the invention may be synthesized by the following general synthetic scheme, wherein the variables are as defined herein, and the specific reaction conditions are as described in the examples.

Scheme 1

Preparation of a compound of formula A2: trimethyl orthoformate (HC (OMe)) ₃ ) And 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, heating and stirring to react for 2 hours, then adding the compound A1 of the general formula, and continuing to react at the temperature for 2 hours. And cooling the reaction liquid to room temperature, precipitating solid, filtering, and collecting the solid to obtain the compound shown in the general formula A2.

Preparation of a compound of formula A3: dissolving a compound of the general formula A2 in diphenyl ether, stirring and reacting for 1 hour at 230 ℃, cooling the reaction liquid to room temperature, adding petroleum ether, separating out solids, filtering, and collecting the solids to obtain the compound of the general formula A3.

Preparation of a compound of formula A4: and (3) carrying out heating reaction on the general formula A3 and concentrated nitric acid in a propionic acid solution for 4 hours, and carrying out nitration reaction to obtain the compound of the general formula A4.

Preparation of a compound of formula A5: after reacting the compound of the general formula A4 with phosphorus oxychloride for 1 hour under heating, removing the solvent, adding ice water into the residue, adjusting the pH to 8 with ammonia water, extracting with dichloromethane, drying, filtering and purifying to obtain the compound of the general formula A5.

Preparation of a compound of formula A7: and adding the compounds of the general formula A5 and the general formula A6 into DMF solution containing N, N-diisopropylethylamine, heating and reacting for 2 hours, and carrying out substitution reaction to obtain the compound of the general formula A7.

Preparation of a compound of formula A8: and (3) adding the compound of the general formula A7 into a methanol solvent containing iron powder and ammonium chloride to perform a reduction reaction to obtain the compound of the general formula A8.

Preparation of a compound of formula A9: adding the compound of the general formula A8 and triethyl orthoformate into 1, 4-dioxane, reacting for 3 hours at 100 ℃, and carrying out ring closure reaction to obtain the compound of the general formula A9.

Preparation of a compound of formula a 11: adding the compound of the general formula A8, N, N' -carbonyl diimidazole and 4-dimethylaminopyridine into N, N-dimethylformamide, heating to 60 ℃ for reaction for 4 hours under the protection of argon, and purifying to obtain the compound of the general formula A11.

Preparation of compounds of the general formulae a10, a 12: and respectively adding the compound of the general formula A9 or A11 into an ethanol solution containing iodobenzene diacetic acid and ammonium acetate, reacting for 2.5 hours at 20 ℃, concentrating, and purifying to obtain the compound of the general formula A10 and A12.

In this application, when chemical names and structural formulas are not identical, the structural formulas should be shown unless it can be inferred that the chemical names are correct instead of the structural formulas according to the context.

As will be clearly understood by those skilled in the art, not all hydrogen atoms are explicitly indicated in some of the compound formulae given herein for simplicity. When free valences are present for carbon or nitrogen atoms in the compound, it indicates the presence of an unidentified hydrogen.

The compounds of the present invention may be prepared according to the methods, reaction schemes and examples provided herein in a variety of ways known to those of skill in the art of organic synthesis. The compounds of the present invention may be synthesized using methods described below in combination with synthetic methods known in the art of organic chemistry or by alternative methods as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and for the transformations carried out. Those skilled in the art of organic synthesis will appreciate that the functional groups present on the molecule should be consistent with the intended transformations. This sometimes requires judgment to change the order of synthesis steps or to select a particular operational scheme relative to others to obtain the desired compounds of the invention.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percent, parts by weight, or volume percent (when liquid).

For purposes of illustration, the reaction schemes depicted below provide potential pathways for synthesizing the compounds of the invention, as well as key intermediates. For a more detailed description of the individual reaction steps, see the examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents may be readily substituted to provide various derivatives and/or reaction conditions. In addition, most of the compounds prepared by the methods described below may be further modified according to the present invention using conventional chemistry well known to those skilled in the art.

In the preparation of the compounds of the invention, protection of the distal functional group of the intermediate may be necessary. The need for such protection will vary depending on the nature of the distal functional group, the conditions of the preparation process. The need for such protection is readily ascertainable by one skilled in the art.

The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified. The starting materials may generally be obtained from commercial sources or readily prepared using methods known to those skilled in the art.

In various embodiments, the laboratory instrument instructions (e.g. ¹ H NMR was recorded by Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance, ¹³ c NMR was recorded by Varian Mercury-400 or Varian Mercury-500 or Varian Mercury-600 nuclear magnetic resonance apparatus, chemical shifts expressed as delta (ppm); mass spectra were recorded by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) type mass spectrometers; silica gel for reversed phase preparative HPLC separation of 200-300 mesh)。

Abbreviations

Synthesis of key intermediates

Intermediate 1a: 5-chloro-2-methoxy-1, 8-naphthyridine

Step 1: synthesis of 5- (((6-methoxypyridin-2-yl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

Containing HC (OMe) ₃ To a single vial (250 mL) of (100 mL) was added the compound 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (12.7 g,88.61 mmol). After stirring the reaction at 100℃for 2 hours, compound 1a-1 (5.0 g,40.28 mmol) was added and the reaction was continued at that temperature for 2 hours. After the reaction solution was cooled to room temperature, a solid was precipitated, filtered, and the solid was collected to give the product compound 1a-2 (10 g, yellow solid), yield: 89%. ¹ H-NMR(400MHz，CDCl ₃ -d)：δ9.30(d，J＝13.6Hz，1H)，7.63-7.59(m，1H)，6.63-6.57(m，2H)，3.99(s，3H)，1.76(s，6H).

Step 2: synthesis of 7-methoxy-1, 8-naphthyridin-4 (1H) -one

1a-2 (5.0 g,17.98 mmol) was added into a single-necked flask (250 mL) containing diphenyl ether (50 mL), the mixture was stirred at 230℃for 1 hour, petroleum ether was added after the reaction solution was cooled to room temperature, and the solid was separated out, filtered and collected to give a product 1a-3 (2.9 g, yellow solid), yield: 94%. ¹ H-NMR(400MHz，CDCl ₃ -d)：δ11.97(s，1H)，8.30(d，J＝8.8Hz，1H)，7.78-7.75(m，1H)，6.79(d，J＝8.8Hz，1H)，6.05-6.03(m，1H)，3.96(s，3H).

Step 3: 7-methoxy-3-nitro-1, 8-naphthyridin-4-ol

1a-3 (4.0 g,22.7 mmo) was added sequentially at room temperature in a 250mL single-necked flask containing 40mL propionic acidl), concentrated nitric acid (1.5 mL), stirring at 145 ℃ overnight, filtering the reaction solution, washing the filter cake with ethanol and n-hexane, and vacuum drying to obtain the product 1a-4 (2.0 g, grey solid), yield: 39.8%, LCMS (ESI): m/z 222.0[ M+H ]] ⁺ ；RT＝0.980min(2.50min). ¹ H NMR(400MHz，DMSO-d ₆ )：δ8.96(s，1H)，8.46(d，J＝8.8Hz，1H)，6.99(d，J＝8.8Hz，1H)，4.02(s，3H).

Step 4: 5-chloro-2-methoxy-6-nitro-1, 8-naphthyridine

1a-4 (500 mg,2.26 mmOl), thionyl chloride (1.08 mg,9.04 mmOl) and DMF (4 drops) were sequentially added at room temperature in a 100mL single-port bottle containing 8mL of dichloromethane, stirred and reacted for 4 hours at 40 ℃, the reaction liquid was diluted with water, dichloromethane was extracted, the organic phase was successively washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a product 1a (520 mg, yellow solid), yield: 96.2%, LCMS (ESI): m/z 240.1[ M+H ] ] ⁺ ；RT＝1.507min(2.50min).

Intermediate 2a:

step 1: 8-Methoxyquinolin-4-ol

A single-necked flask containing 600mL of ethanol was charged with 2a-1 (75.0 g,610 mmol), 2-dimethyl-1, 3-dioxane-4, 6-dione (105.0 g, 730 mmol) and triethyl orthoformate (216 g,1464 mmol), and the mixture was stirred at 90℃for 2 hours, cooled to room temperature, filtered, and the solid was washed with ethanol and dried. Diphenyl ether (600 mL) was heated to 280 ℃, the solid was slowly added and stirred at 280 ℃ for another 15 minutes after the addition was completed. The reaction solution was cooled to room temperature, poured into petroleum ether, filtered, and the solid was slurried with ethyl acetate and filtered to give product 2a-2 (44.0 g, brown solid), yield: 41.3%; LCMS (ESI): m/z 176.1[ M+H ] +; rt=1.05 min (2.00 min).

Step 2: 8-methoxy-3-nitroquinolin-4-ol

Into a single-necked flask containing 700mL of propionic acid were charged 2a-2 (22.0 g,125.7 mmol) and fuming nitric acid (15.8 g,251.4 mmol), and the reaction was stirred at 100℃for 3 hours, cooled to 0℃and filtered, and the solid was washed with petroleum ether to give 2a-3 (18.0 g, yellow solid), yield: 65.1%; LCMS (ESI): m/z 221.1[ M+H ] +; rt= 1.401min (2.50 min).

Step 3: 4-chloro-8-methoxy-3-nitroquinoline

Into a three-necked flask containing 300mL of methylene chloride was charged 2a-3 (22.0 g,100.0 mmol), thionyl chloride (29.8 g,250.0 mmol) and DMF (3 mL) were added under ice-bath, and the reaction was stirred at 40℃for 16 hours. Concentration, beating the solid with water, filtration and washing the solid with petroleum ether gave product 2a (17.5 g, yellow solid), yield: 73.5%; LCMS (ESI): m/z 239.0[ M+H ] +; rt= 1.703min (2.50 min).

Intermediate 3a

Step 1: 2-fluoro-4- (methylthio) benzonitrile

3a-1 (2.00 g,14.69 mmol), 1, 2-dichloroethane (50 mL) and dimethyl disulfide (1.80 g,19.10 mmol) were sequentially added to a dry 100mL three-necked flask at room temperature. T-butyl nitrite (2.36 mL,19.83 mmOl) was slowly added dropwise under nitrogen blanket heated to 60 ℃. Stirred at 60℃for 3 hours. After completion of the reaction, the reaction mixture was diluted with methylene chloride (50 mL) and washed with dilute hydrochloric acid (2.0M, 30 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: ea=10:1) to give product 3a-2 (1.68 g, yellow solid), yield: 68.39%: ¹ H-NMR(400MHz，CDCl ₃ -d)：δ7.48(dd，J ₁ ＝6.8Hz，J ₂ ＝8.0Hz，1H)，7.06-6.99(m，2H)，2.52(s，3H).

step 2: (2-fluoro-4- (methylthio) phenyl) carboxamide

3a-2 (1.68 g,10.05 mmol), methanol (40 mL), ammonia (4 mL) and Raney Nickel (2.00 g) were added sequentially at room temperature in a dry 100mL single-necked flask. Heated to 25 ℃ under the protection of hydrogen and reacted for 16 hours. After the reaction, the mixture was filtered under reduced pressure, and the filtrate was concentrated. Chromatography column for crude product (DCMMeoh=10:1) to give product 3a (1.32 g, yellow oil), yield: 76.72%, LCMS (ESI): m/z 155.1[ M+H-NH ] ₃ ] ⁺ ；RT＝0.649min(2.50min).

Intermediate 4a:

step 1: 3-fluoro-4- (methylthio) benzonitrile

To a 100mL three-necked flask containing 20mL of LDMF was added successively 4a-1 (2.0 g,14.4 mmol) and an aqueous solution of sodium methyl mercaptan (1.14 g,15.8 mmol). After 2 hours of reaction at room temperature, the reaction solution is diluted by water, solid is separated out, filtered, and the solid is washed and dried by water to obtain a product 4a-2 (2.2 g, white solid) with the yield: 91.7 percent, ¹ H NMR(400MHz，CDCl ₃ )：δ7.43-7.41(m，1H)，7.30-7.23(m，2H)，2.52(s，3H).

step 2: (3-fluoro-4- (methylthio) phenyl) carboxamide

Into a 100mL single-necked flask containing 20mL of methanol, 4a-2 (1.7 g,10.2 mmol), raney-Ni (170 mg,10% wt) and aqueous ammonia (4 mL) were sequentially added, respectively. The reaction was carried out at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated to give crude 4a (1.7 g, yellow oil). LCMS (ESI): m/z 155.2[ M+H-17 ]] ⁺ ；RT＝0.661min(2.50min).

Intermediate 5a:

step 1: (4- (methylthio) phenyl) carboxamide

5a-1 (3.5 g,23.4 mmol) and lithium aluminum hydride (70.2 mL,70.2 mmol) were added sequentially to a 250mL three-necked flask containing 35mL THF, and after 4 hours of reaction at room temperature under nitrogen, the reaction was quenched by dropwise addition of 1.5mL water, 1.5mL aqueous sodium hydroxide (15%), filtered, and the solvent removed to give crude 5a (2.2 g, transparent oil), LCMS (ESI): m/z 137.3[ M+H ]] ⁺ ；RT＝0.887min(2.50min).

Example 1 preparation of Compound 1

Step 1: 8-methoxy-N- (4- (methylthio) benzyl) -3-nitroquinolin-4-amine

5a (1.5 g,9.8 mmol), N-ethyl-N-isopropyl-2-amine (2.53 g,19.6 mmol) and 2a (4.67 g,19.6 mmol) were added sequentially at room temperature in a 250mL single-port flask containing 50mL of isopropanol, reacted at 80℃for 1 hour, the reaction solution was filtered to give the product 1-1 (2.8 g, yellow solid), yield: 80.6%, LCMS (ESI): m/z 356.1[ M+H ]] ⁺ ；RT＝1.260min (2.50min).

Step 2: 8-methoxy-N4- (4- (methylthio) benzyl) quinoline-3, 4-diamine

To a 250mL single-necked flask containing 60mL of methanol/water (10/1), 1-1 (1.5 g,4.2 mmol), iron powder (1.42 g,25.3 mmol) and ammonium chloride (1.8 g,33.6 mmol) were successively added and reacted at 70℃for 6 hours. The reaction was filtered, the filtrate was diluted with water, extracted with dichloromethane, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by column (DCM: meoh=15:1) to give product 1-2 (500 mg, yellow solid), yield: 36.4%, LCMS (ESI): m/z 326.1[ M+H ]] ⁺ ；RT＝0.980min(2.50min).

Step 3.6-methoxy-1- (4- (methylthio) benzyl) -1H-imidazo [4,5-c ] quinoline

In a single-necked flask containing 3mL of 1, 4-dioxane, 1-2 (100 mg,0.31 mmol) and triethoxymethane (114 mg,0.77 mmol) were sequentially added, the reaction was carried out at 100℃for three hours, the reaction solution was diluted with water, extracted with methylene chloride, the organic phase was successively washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed to give the product 1-3 (80 mg, yellow solid), LCMS (ESI): m/z336.1[ M+H ] ] ⁺ ；RT＝0.907min(2.50min).

Step 4 imino (4- ((6-methoxy-1H-imidazo [4, 5-c)]Quinolin-1-yl) methyl) phenyl) (methyl) -lambda ⁶ -sulfanones

Sequentially adding 1-3 (1)00mg,0.3 mmol), iodobenzene diacetic acid (87 mg,0.9 mmol), ammonium acetate (92 mg,1.2 mmol), 3 hours at 20℃and direct prep-HPLC (0.1% formic acid) after concentration gives product 1 (20 mg, white solid), yield: 18.3%, LCMS (ESI): m/z366.95[ M+H ]] ⁺ ；RT＝0.874min(6.00min)； ¹ H NMR(400MHz，DMSO-d ₆ )：δ9.20(s，1H)，8.61(s，1H)，7.87(d，J＝8.4Hz，2H)，7.65(d，J＝7.6Hz，1H)，7.47-7.43(m，1H)，7.29(d，J＝8.4Hz，2H)，7.13(d，J＝7.6Hz，1H)，6.11(s，2H)，4.18(s，1H)，3.95(s，3H)，2.30(s，3H).

Example 2 preparation of Compound 2

Step 1: 7-methoxy-N- (4- (methylthio) benzyl) -3-nitro-1, 8-naphthyridin-4-amine

1a (400 g,1.67 mmol), N-ethyl-N-isopropyl-2-amine (640 g,5.01 mmol) and 5a (383 g,2.50 mmol) were added sequentially at room temperature to a 100mL single-port flask containing 30mL of isopropyl alcohol, reacted overnight at 80℃and the reaction mixture was diluted with water, extracted with dichloromethane, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and the residue was purified by column (PE: EA=1:2) to give the product 2-1 (200 mg, yellow solid), yield: 33.6%, LCMS (ESI): m/z357.1[ M+H ]] ⁺ ；RT＝1.460min(2.50min).

Step 2: 7-methoxy-N4- (4- (methylthio) benzyl) -1, 8-naphthyridine-3, 4-diamine

In a single-necked flask containing methanol/water (4 mL, 10/1), 2-1 (117 mg,0.33 mmol), iron powder (92 mg,1.65 mmol) and ammonium chloride (88 mg,1.65 mmol) were sequentially added and reacted overnight at 70 ℃. Filtration, dilution of the filtrate with water, extraction of the dichloromethane, subsequent washing of the organic phase with water and saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave product 2-2 (80 mg, yellow solid), yield: 74.7%, LCMS (ESI): m/z 327.1[ M+H ] ] ⁺ ；RT＝0.933min(2.50min).

Step 3: 7-methoxy-1- (4- (methylthio) benzyl) -1, 3-dihydro-2H-imidazo [4,5-c ] [1,8] naphthyridin-2-one

In a single-necked flask containing 3mL of THF, 2-2 (80 mg,0.24 mmol) and CDI (79 mg,0.49 mmol) were sequentially added, the reaction was carried out at 60℃for 1 hour, the reaction solution was diluted with water, dichloromethane was extracted, the organic phase was successively washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 2-3 (90 mg, yellow solid), LCMS (ESI): m/z 353.0[ M+H ]] ⁺ ；RT＝1.050min(2.50min).

Step 4: 7-methoxy-1- (4- (thio-methylsulfonylimide) benzyl) -1, 3-dihydro-2H-imidazo [4,5-c ] [1,8] naphthyridin-2-one

In a single-necked flask containing 3mL of chloroform, 2-3 (90 mg,0.26 mmol), iodobenzene diacetic acid (247 mg,0.77 mmol), ammonium acetate (80 mg,1.04 mmol) were sequentially added, reacted at 20℃for 3 hours, and after removing the solvent, the product 2 (15 mg, white solid) was purified by prep-HPLC (0.1% formic acid), yield: 15.3%, LCMS (ESI): m/z 383.95[ M+H ]] ⁺ ；RT＝3.016min(6.00min). ¹ H NMR(400MHz，DMSO-d ₆ )：δ8.67(s，1H)，8.23(d，J＝9.2Hz，1H)，7.87(d，J＝8.4Hz，2H)，7.43(d，J＝8.4Hz，2H)，6.97(d，J＝9.2Hz，1H))，5.60(s，2H)，4.18(s，1H)，3.95(s，3H)，3.01(s，3H).

Example 3 preparation of Compound 5

Step 1: 4-chloro-1-methyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine

5-1 (400 mg,2.03 mmol) was added to a three-necked flask containing DMF (15 mL), naH (122 mg,3.05 mmol) was added under an ice bath, and after 1 hour of reaction at room temperature, methyl iodide (432 mg,3.05 mmol) was added and reaction was carried out at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with saturated brine, concentrated, and purified by column chromatography (PE: ea=1:1) to give product 5-2 (300 mg, yellow solid), yield: 65.5％；LCMS(ESI)：m/z 212.1[M+H] ⁺ ；RT＝1.648min(2.50min).

Step 2: 1-methyl-N- (4- (methylthio) benzyl) -5-nitro-1H-pyrrole [2,3-b ] pyridin-4-amine

In a single vial containing 30mL of isopropanol, 5-2 (1.3 g,6.14 mmol), N-ethyl-N-isopropyl-2-amine (1.6 g,12.3 mmol) and 5a (1.4 g,9.21 mmo1) were added sequentially, reacted overnight at 80 ℃, the reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified by column (PE: ea=2:1) to give the product 5-3 (500 mg, yellow solid), yield: 24.7%, LCMS (ESI): m/z 329.0[ M+H ]] ⁺ ；RT＝1.784min(2.50min).

Step 3: 1-methyl-N4- (4- (methylthio) benzyl) -1H-pyrrole [2,3-b ] pyridine-4, 5-diamine

5-3 (500 mg,1.5 mmol), iron powder (595 mg,10.6 mmol) and ammonium chloride (567 mg,10.6 mmol) were added sequentially at room temperature to a single flask containing methanol/water (10/1, 5 mL) and reacted overnight at 70 ℃. The reaction was filtered, the filtrate was diluted with water, extracted with dichloromethane, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the residue after concentration of the filtrate under reduced pressure was purified by column (DCM: meoh=10:1) to give product 5-4 (300 mg, brown solid), yield: 60.6%; LCMS (ESI): m/z 299.1[ M+H ] ] ⁺ ；RT＝0.900min(2.50min).

Step 4: 6-methyl-1- (4- (methylthio) benzyl) -1, 6-dihydroimidazo [4,5-d ] pyrrole [2,3-b ] pyridine

To a single-necked flask containing 3mL of 1, 4-dioxane was added 5-4 (130 mg,0.44 mmol) and triethoxymethane (161 mg,1.09 mmol) in this order, and the reaction was carried out at 100℃for 3 hours, the reaction solution was diluted with water, extracted with methylene chloride, the organic phase was successively washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a product 5-5 (100 mg, yellow solid), LCMS (ESI): m/z 309.1[ M+H ]] ⁺ ；RT＝1.280min(2.50min).

Step 5: imino (methyl) (4- ((6-methylimidazole [4,5-d ] pyrrole [2,3-b ] pyridin-1 (6H) -yl) methyl) phenyl) -l 6-sulfane

5-5 (100 mg,0.32 mmol), iodobenzene diacetic acid (313 mg,0.97 mmol) and ammonium acetate (99 mg,1.28 mmol) were sequentially added to a 50mL single-port flask containing 3mL of chloroform at room temperature, and reacted at 20℃for 3 hours, and the reaction mixture was concentrated and then prepared by prep-HPLC (0.1% formic acid) to give the product 5 (33 mg, white solid) in the yield: 29.9%, LCMS (ESI): m/z339.90[ M+H ]] ⁺ ；RT＝3.292min(6.00min). ¹ H NMR(400MHz，DMSO-d ₆ )：δ8.67(s，1H)，8.41(s，1H)，7.87(d，J＝8.4Hz，2H)，7.44-7.41(m，3H)，6.57(d，J＝5.6Hz，1H)，5.84(s，2H)，4.17(s，1H)，3.87(s，3H)，3.01(s，3H).

Example 4 preparation of Compounds 18, 19

The steps are as follows: resolution of compound 1 gives compound 18 (isomer 1) and compound 19 (isomer 2)

Compound 1 (150 mg) was resolved on a chiral column, column model AD,250 x 25mm 10 μm, mobile phase: isopropanol (+0.1% 7.0mol/l methanolic ammonia) to give compound 18 (52.3 mg) and compound 19 (54.9 mg);

compound 18: peak time 2.09min; ee% > 99, lcms (ESI): m/z 367.05[ M+H ]] ⁺ ；(DMSO-d ₆ )：δ9.26(s，1H)，8.67(s，1H)，7.92(d，J＝8.4Hz，2H)，7.71(d，J＝7.6Hz，1H)，7.53-7.49(m，1H)，7.35(d，J＝8.4Hz，2H)，7.19(d，J＝7.6Hz，1H)，6.17(s，2H)，4.24(s，1H)，4.01(s，3H)，3.06(s，3H)；

Compound 19: the peak time is 3.25min; ee% > 99, lcms (ESI): m/z 367.05[ M+H ]] ⁺ ；(DMSO-d ₆ )：δ9.20(s，1H)，8.63(s，1H)，7.87(d，J＝8.4Hz，2H)，7.66(d，J＝7.6Hz，1H)，7.48-7.44(m，1H)，7.30(d，J＝8.4Hz，2H)，7.14(d，J＝7.6Hz，1H)，6.13(s，2H)，4.19(s，1H)，3.96(s，3H)，3.01(s，3H).

EXAMPLE 5 preparation of Compound 20

Step 1: 7-methoxy-1- (4- (methylthio) benzyl) -1H- [1,2,3] triazolo [4,5-c ] [1,8] naphthyridine

To a dry 25mL single-necked flask, 2-2 (150 mg,0.46 mmol) of 2M hydrochloric acid (5 mL) was successively added at room temperature, and an aqueous solution (1 mL) of sodium nitrite (38 mg,0.55 mmol) was added under ice-bath conditions. Stirring was carried out for 0.5 hour under ice bath conditions. The reaction was filtered and the filter cake purified by prep-HPLC (0.1% formic acid) to give product 20-1 (80 mg, yellow solid), yield: 52%. LCMS (ESI): m/z 338.0[ M+H ]] ⁺ ；RT＝1.57min(3.00min).

Step 2: imino (4- ((7-methoxy-1H- [1,2,3] triazol [4,5-c ] [1,8] naphthyridin-1-yl) methyl) phenyl) (methyl) -16-sulfane

To a dry 25mL single-necked flask, 20-1 (80 mg,0.24 mmol), iodobenzene diacetic acid (305 mg,0.95 mmol), ammonium acetate (55 mg,0.72 mmol) and ethanol (5 mL) were sequentially added at room temperature. Stirring for 2 hours at room temperature under nitrogen protection. The reaction was concentrated and the residue was purified by prep-HPLC (0.1% formic acid) to give product 20 (45 mg, white solid), yield: 52%; LCMS (ESI): m/z 373.0[ M+H ] ] ⁺ ；RT＝3.25min(15.00min). ¹ H-NMR(600MHz，DMSO-d ₆ )：9.70(s，1H)，8.65(d，J＝9.0Hz，1H)，8.78(d，J＝7.8Hz，2H)，8.38(d，J＝8.4Hz，2H)，7.25-7.23(m，1H)，6.52(s，2H)，4.20(s，1H)，4.04(s，3H)，3.01(s，3H).

Examples 6-21 preparation of Compounds 3-4, 6-17, 21, 22

Synthesized according to the methods described in examples 1, 2, 3, respectively, the structural formulae of the compounds of the examples are shown in the preceding tables

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EXAMPLE 22 preparation of Compound 23

Step 1:2, 2-dimethyl-5- (6-oxo-1, 6-dihydropyridin-2-yl)) amino) methylene-1, 3-dioxane-4, 6-dione

23-1 (14.0 g,127.14 mmol) was dissolved in 250mL HC (OMe) ₃ To the mixture was added isopropyl malonate (36.6 g,254.29 mmol), and the mixture was stirred at 110℃for 2 hours under nitrogen. The reaction solution was cooled to room temperature until solid was precipitated, filtered to obtain a cake, which was washed with ethanol, and the solvent was removed to obtain crude 23-2 (20 g, gray solid), yield: 59.5%. ¹ H NMR(400MHz，DMSO-d ₆ )：δ11.25-11.21(m，1H)，9.18(d，J＝14.0Hz，1H)，7.72-7.68(m，1H)，7.07(d，J＝7.6Hz，1H)，6.52(d，J＝8.0Hz，1H)，1.678(s，6H).

Step 2:2, 2-dimethyl-5- (1-methyl-6-oxo-1, 6-dihydropyridin-2-yl) amino) methylene) -1, 3-dioxane-4, 6-dione

23-2 (5 g,18.939 mmol) was dissolved in DMF (50 mL), and potassium carbonate (14 g,104.16 mmol) and methyl iodide (3.22 g,22.7 mmol) were added and stirred for 3 hours at 80℃under nitrogen. The reaction solution was poured into 500mL of water and extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed to give crude 23-3 (3 g, yellow solid), yield: 57%. ¹ H NMR(400MHz，DMSO-d ₆ )：δ11.57(d，J＝13.6Hz，1H)，8.86(d，J＝13.6Hz 1H)，8.15(d，J＝5.6Hz，1H)，7.56(d，J＝5.6Hz，1H)，3.96(s，3H)，1.72(s，6H).

Step 3: 5-hydroxy-1-methyl-1, 8-naphthyridin-2 (1H) -one

23-3 (3 g,10.79 mmol) was added to a 100mL single-necked flask containing 60mL diphenyl ether, nitrogen blanketThe mixture was stirred at 230℃for 1 hour. After cooling, 120mL of petroleum ether was added to the reaction mixture, and the mixture was filtered to give a crude product, which was washed with petroleum ether and dried to give the product 23-4 (1.55 g, gray solid), yield: 81.6%. ¹ H NMR(400MHz，DMSO-d ₆ )：δ11.97(s，1H)，8.29(d，J＝8.8Hz 1H)，7.78-7.75(m，1H)，6.79(d，J＝8.8Hz，1H)，6.04(d，J＝7.6Hz，1H)，3.97(s，3H).

Step 4: 5-hydroxy-1-methyl-6-nitro-1, 8-naphthyridin-2 (1H) -one

23-4 (1 g,5.68 mmol) and tetramethyl ammonium nitrate (1.5 g,11.36 mmol) were added to a single vial containing 20mL of methylene chloride, trifluoroacetic anhydride (2.38 g,11.36 mmol) was added at 0deg.C and stirred overnight at room temperature. The solvent was removed, ethyl acetate and aqueous extraction were added, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed to give crude 23-5 (621 mg, white solid), yield: 48.7%. LCMS (ESI): m/z222.1[ M+H ]] ⁺ ；RT＝1.041min(2.50min).

Step 5: 5-chloro-1-methyl-6-nitro-1, 8-naphthyridin-2 (1H) -one

23-5 (445 mg,2.0 mmol) was added to a single vial containing 10mL of dichloromethane, followed by thionyl chloride (0.284 mL,8.0 mmol 1) and 8 drops of DMF. Stirred at room temperature for 2 hours. After cooling, ethyl acetate and water were added for extraction. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent removed to give crude product, which was purified by silica gel column (PE: ea=4:1) to give product 23-6 (700 mg, grey solid). LCMS (ESI): m/z240.1[ M+H ] ] ⁺ ；RT＝1.176min(2.50min).

Step 6: 1-methyl-5- (4- (methylthio) benzyl) amino) -6-nitro-1, 8-naphthyridin-2 (1H) -one

23-6 (650 mg,2.7 mmol) was added to a single vial containing 50mL of acetonitrile, followed by DIEA (2.2 mL,13.59 mmol) and (4- (methylthio) phenyl) methylamine (500 mg,3.26 mmol) and stirred at 70℃for 4 hours. After removing the solvent, ethyl acetate was added for extraction. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed to give crude 23-7 (530 mg, yellow solid). LCMS (ESI): m/z 357.1[ M+H ]] ⁺ ；RT＝1.563min(2.5min).

Step 7: 6-amino-1-methyl-5- (4- (methylthio) benzyl) amino) -1, 8-naphthyridin-2 (1H) -one

23-7 (430 mg,1.2 mmol) was added to a 250mL single-necked flask containing 75mL of HF and 15mL of water, followed by ammonium chloride (458 mg,8.4 mmol) and iron powder (473 mg,8.4 mmol) and stirred overnight at 65 ℃. Filtration and removal of the solvent gave crude product, purification on a normal phase column (PE: ea=2:1) gave product 23-8 (260 mg, white solid), yield: 66.6%. LCMS (ESI): m/z 327.1[ M+H ]] ⁺ ；RT＝0.744min(2.5min).

Step 8: 6-methyl-1- (4- (methylthio) benzyl) -1, 6-dihydro-7H-imidazo [4,5-c ] [1,8] naphthyridin-7-one

23-8 (230 mg, 0.704 mmol) was added to a single-necked flask containing 20mL of 1, 4-dioxane, and triethylorthoformate (418 mg,2.82 mmol) was further added and stirred at 100deg.C for 1.5 hours. Removal of the solvent gave crude 23-9 (190 mg, brown solid). LCMS (ESI): m/z 337.0[ M+H ] ] ⁺ ；RT＝1.118min(2.5min).

Step 9: 6-methyl-1- (4- (S-methylsulfonylimide) benzyl) -1, 6-dihydro-7H-imidazo [4,5-c ] [1,8] naphthyridin-7-one

23-9 (130 mg, 0.383 mmol) was added to a single-necked flask containing 20mL of ethanol, followed by addition of (diacetoxyiodide) benzene (803 mg,1.16 mmol) and ammonium acetate (119 mg,1.54 mmol) and stirring at room temperature for 2 hours. The solvent was removed to give crude product which was prepared by HPLC (0.1% trifluoroacetic acid) to give product 23 (140 mg, white solid). Yield: 98%. LCMS (ESI): m/z368.05[ M+H ]] ⁺ ；RT＝3.057min(6.00min). ¹ H NMR(400MHz，DMSO-d ₆ )：δ9.69(s，1H)，8.92(s，1H)，8.58(d，J＝9.2Hz，1H)，7.96(d，J＝8.4Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.31(d，J＝9.2Hz，1H)，6.25(s，2H)，4.07(s，3H)，3.38(s，3H).

Examples 23-25 preparation of Compounds 24, 25, 26

Synthesized according to the methods described in examples 1, 5, respectively, the structural formulae of the compounds of the examples are shown in the preceding tables

EXAMPLE 26 preparation of Compound 27

Step 1: n- (7-methoxy-4- (4- (methylthio) benzyl) amino) -1, 8-naphthyridin-3-yl) cyclopropanecarboxamide

2-2 (50 mg,0.15 mmol), cyclopropylformic acid (17 mg,0.20 mmol), DIEA (77 mg,0.60 mmol), HATU (76 mg,0.20mmo 1) and 3mL DMF were added to a 50mL single port flask and stirred at room temperature for 2 hours, the mixture concentrated and purified via reverse column (0.1% formic acid) and lyophilized to give product 27-1 (40 mg, yellow solid, yield: 68% LCMS (ESI): M/z395.1[ M+H)] ⁺ ；RT＝1.39min(3.0min).

Step 2: 2-cyclopropyl-7-methoxy-1- (4- (methylthio) benzyl) -1H-imidazo [4,5-c ] [1,8] naphthyridine

27-1 (50 mg,0.13mmo 1), potassium carbonate (52 mg,0.38 mmo), 4mL of ethanol and 1mL of water were added to a 50mL three-necked flask, and the mixture was reacted at 70℃for 18 hours under nitrogen atmosphere. Concentrated by filtration under reduced pressure, and the residue was purified by reverse phase column (0.1% formic acid) and lyophilized to give product 27-2 (30 mg, yellow solid). Yield: 63%. LCMS (ESI): m/z 377.1[ M+H ]] ⁺ ；RT＝1.55min(3.0min).

Step 3: (4- ((2-cyclopropyl-7-methoxy-1H-imidazo [4,5-c ] [1,8] naphthyridin-1-yl) methyl) phenyl) (imino) (methyl) -l 6-sulfane

27-2 (50 mg,0.13 mmol), iodobenzene diacetic acid (171 mg,0.53 mmol), ammonium acetate (33 mg,0.43 mmol), absolute ethanol (5 mL) were added to a 50mL single-necked flask and reacted at room temperature for two hours. Concentration and residue purification by reverse phase column (0.1% formic acid), lyophilization gave product 27 (16.8 mg, white solid), yield: 31%. LCMS (ESI): m/z 382.1[ M+H ]] ⁺ ；RT＝1.21min(3.0min). ¹ H NMR(600MHz，DMSO)δ9.15(s，1H)，8.41(d，J＝9.2Hz，1H)，7.88(d，J＝8.4Hz，2H)，7.28(d，J＝8.4Hz，2H)，7.03(d，J＝9.0Hz，1H)，6.19(s，2H)，4.18(s，1H)，3.97(s，3H)，3.01(s，3H)，2.35-2.33(m，1H)，1.16-1.05(m，4H).

EXAMPLE 27 Compound 28

Step 1:4- (8-methoxy-3-nitroquinolin-4-yl) amino) methylpiperidine-1-carboxylic acid tert-butyl ester

To a dry 25mL single-necked flask was added 4-chloro-8-methoxy-3-nitroquinoline (200 mg,0.84 mmol), tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (180 mg,0.84 mmol), DIEA (217 mg,1.68 mmol), dichloromethane (6 mL) in order at room temperature. Stirring at room temperature for 3 hours, concentrating the reaction solution, purifying the residue with reverse phase preparation column (0.1% formic acid), and drying to obtain product 28-2 (150 mg, yellow solid), yield: 43%. LCMS (ESI): m/z417.1[ M+H ] ] ⁺ ；RT＝1.63min(3.00min).

Step 2:4- (3-amino-8-methoxyquinolin-4-yl) amino) methylpiperidine-1-carboxylic acid tert-butyl ester

28-2 (150 mg,0.36 mmol), iron powder (60 mg,1.08 mmol), ammonium chloride (56 mg,1.08 mmol), THF (5 mL), and water (1 mL) were sequentially added to a dry 25mL single-necked flask at room temperature. Heating at 70deg.C under nitrogen for 4 hr, filtering the reaction solution, concentrating the filtrate, and purifying the residue with reverse phase preparation column (0.1% formic acid) to obtain product 28-3 (100 mg, pale yellow solid), yield: 72%. LCMS (ESI): m/z 387.2[ M+H ]] ⁺ ；RT＝1.45min(3.00min).

Step 3:4- (6-methoxy-1H-imidazo [4,5-c ] quinolin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

28-3 (100 mg,0.26 mmol) of triethyl orthoformate (1 mL), dioxane (3 mL) and heating at 80℃for 4 hours were successively added to a dry 25mL single-necked flask at room temperature. The reaction was concentrated and the residue was purified with reverse phase prep. column (0.1% formic acid) to give product 28-4 (90 mg, pale yellow solid), yield: 88%. LCMS (ESI): m/z 397.2[ M+H ]] ⁺ ；RT＝1.37min(3.00min).

Step 4: 6-methoxy-1- (piperidin-4-ylmethyl) -1H-imidazo [4,5-c ] quinoline

28-4 (90 mg,0.23 mmol) of hydrochloric acid in methanol (4M, 5 mL) and ethyl acetate (2 mL) were successively added to a dry 25mL single-neck flask at room temperature, reacted overnight, filtered, and the filtrate was concentrated, and the residue was purified with a reverse phase preparation column (0.1% formic acid) to give 28-5 (70 mg, yellow solid) as a product in a yield: 100%. LCMS (ESI): m/z 297.1[ M+H ] ] ⁺ ；RT＝0.91min(3.00min)

Step 5: 6-methoxy-1- (1- (S-methylsulfonylimide) piperidin-4-yl) methyl) -1H-imidazo [4,5-c ] quinoline

To a dry 25mL single-necked flask, triphenylphosphine dichloride (239 mg,0.72 mmol), triethylamine (97 mg,0.96 mmol) and a solution of N- (tert-butyldimethylsilyl) methanesulfonamide (125 mg,0.60 mmol) in chloroform (1 mL) were successively added at room temperature, and the mixture was stirred at room temperature under nitrogen for 15 minutes while stirring in ice bath, and the reaction solution was stirred at ice bath for 20 minutes. Compound 28-5 (70 mg,0.24 mmol) was dissolved in chloroform (1 mL) and the above reaction solution was added, the reaction solution was stirred at room temperature for 3 hours, the reaction solution was concentrated, acetonitrile (3 mL) and dioxane hydrochloride solution (1 mL) were added to the residue, stirred at room temperature for 1 hour, the reaction solution was concentrated, and purified by reverse phase preparation column (0.1% formic acid) to give product 28 (9 mg, milky white solid), yield: 10%. LCMS (ESI): m/z374.2[ M+H ]] ⁺ ；RT＝3.39min(15.00min). ¹ H-NMR(600MHz，CD3OD)：9.14(s，1H)，8.39(d，J＝8.00Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.75-7.71(m，1H)，7.31-7.29(m，1H)，4.71-3.68(m，2H)，3.91(s，3H)，3.89-3.81(m，2H)，2.79(s，3H)，2.68-2.61(m，2H)，2.19-2.18(m，1H)，1.78-1.75(m，2H)，1.58-1.52(m，2H).

EXAMPLE 28 preparation of Compound 33

Step 1:2- ((6-methoxypyridin-2-yl) amino) methylene) malonic acid diethyl ester

33-1 (5.0 g,40.3 mmol) diethyl 2- (ethoxymethylene) malonate (7.9 mg,36.6 mmol) was added to a 50mL single-necked flask, heated to 90 ℃,stirring is carried out for 2 hours. Cooled to room temperature, 100mL of n-hexane was added, and the resulting solid was placed in a dry ice acetone bath, filtered under reduced pressure, and dried in vacuo to give product 33-2 (7.5 g, white solid), yield: 64%. ¹ H NMR(600MHz，CDCl ₃ )δ11.03(d，J＝12.8Hz，1H)，9.19(d，J＝13.0Hz，1H)，7.55(t，J＝7.8Hz，1H)，6.50(d，J＝8.2Hz，1H)，6.44(d，J＝7.6Hz，1H)，4.34(q，J＝7.2Hz，2H)，4.27(q，J＝7.2Hz，2H)，1.41(t，J＝7.2Hz，3H)，1.35(t，J＝7.2Hz，3H).

Step 2: 4-hydroxy-7-methoxy-1, 8-naphthyridine-3-carboxylic acid ethyl ester

33-2 (7.5 g,25.5 mmol) and 70mL of diphenyl ether were added to a 250mL single-necked flask, warmed to 230℃and stirred for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with n-hexane, followed by vacuum drying to give 33-3 (1.7 g, yellow solid). Yield: 27%. LCMS (ESI): m/z 249.1[ M+H ]] ⁺ ；RT＝1.10min(3.0min).

Step 3: 4-chloro-7-methoxy-1, 8-naphthyridine-3-carboxylic acid ethyl ester

33-3 (1.6 g,6.45 mmol) and 20mL of phosphorus oxychloride were added to a 50mL single-necked flask, warmed to 110℃and stirred for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was made basic with aqueous sodium bicarbonate, then extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give product 33-4 (1.3 g, yellow solid). Yield: 77%. LCMS (ESI): m/z 267.0[ M+H ]] ⁺ ；RT＝1.56min(3.0min).

Step 4: 4-chloro-7-methoxy-1, 8-naphthyridine-3-carboxylic acid methyl ester

33-4 (200 mg,0.75 mmol) and anhydrous THF (5 mL) were added to a 50mL three-necked flask, cooled to-78deg.C under argon, and diisobutylaluminum hydride solution (1.5 mL,1.5 mmol) was slowly added dropwise thereto, and the mixture was stirred at a constant temperature for 1h. The mixture was extracted with water and ethyl acetate, the organic phase was collected, concentrated, purified by reverse column (0.1% formic acid), and lyophilized to give product 33-5 (50 mg, white solid), yield: 30%. LCMS (ESI): m/z 223.1[ M+H ] ] ⁺ ；RT＝1.19min(3.0min).

Step 5: 4-chloro-7-methoxy-1, 8-naphthyridine-3-carbaldehyde

33-5 (150 mg,0.67 mmol) and methylene chloride (10 mL) were added to a 50mL single-necked flask, followed by manganese dioxide (29 mg,3.35 mmol) and the mixture was stirred at room temperature overnight. Filtration and concentration of the filtrate under reduced pressure gave product 33-6 (110 mg,0.49mmol, yield 74%). LCMS (ESI): m/z 223.1[ M+H ] +; rt=1.19 min (3.0 min).

Step 6: 7-methoxy-1H-pyrazolo [4,3-c ] [1,8] naphthyridine

33-6 (110 mg,0.50 mmol) and methanol (10 mL) were added to a 50mL single vial followed by hydrazine hydrate (19.2 mg,0.60 mmol) and the mixture was heated to 90℃and stirred overnight. Cooled to room temperature, filtered, and the filter cake was washed with methanol to give product 33-7 (60 mg,0.30mmol, 60% yield): m/z 201.1[ M+H ]] ⁺ ；RT＝1.01min(3.0min).

Step 7: 7-methoxy-1- (4- (methylthio) benzyl) -1H-pyrazolo [4,3-c ] [1,8] naphthyridine

33-7 (50 mg,0.25 mmol) was added to a 50mL three-necked flask with DMF (5 mL) under argon. Cooled to 0deg.C, naH (12 mg,0.3 mmol) was added, stirred for 30 min, followed by (4- (bromomethyl) phenyl) (methyl) sulfonamide (65 mg,0.3 mmol), warmed to room temperature, and stirred for 2h. The mixture was extracted with ethyl acetate and water, and the organic phase was purified by silica gel column (DCM: meoh=20:1) to give product-8 (20 mg, yield 24%). LCMS (ESI): m/z 337.1[ M+H ] +; rt=1.64 min (3.0 min).

Step 8: imino (4- (7-methoxy-1H-pyrazolyl [4,3-c ] [1,8] naphthyridin-1-yl) methyl) phenyl) (methyl) -16-sulfane

33-8 (20 mg,0.06 mmol), iodobenzene diacetic acid (77 mg,0.24 mmol), ammonium acetate (14 mg,0.18 mmol), absolute ethanol (5 mL) were added to a 50mL single-necked flask and reacted at room temperature for two hours. Concentrated, and the residue was purified by reverse phase column (0.1% formic acid) and lyophilized to give product 33 (6.8 mg, white solid), yield: 23%. LCMS (ESI): m/z 368.1[ M+H ]] ⁺ ；RT＝1.21min(3.0min). ¹ H NMR(400MHz，DMSO)δ9.36(s，1H)，8.63(d，J＝9.0Hz，1H)，8.53(s，1H)，7.88-7.78(m，2H)，7.27(d，J＝8.4Hz，2H)，7.13(d，J＝8.8Hz，1H)，6.22(s，2H)，4.16(s，1H)，4.00(s，3H)，3.00(d，J＝0.7Hz，3H).

EXAMPLE 29 preparation of Compound 34

Step 1:4- (cyclopropylthio) benzonitrile

The compound 4-mercaptobenzonitrile (250 mg,1.85 mmol), cyclopropylboronic acid (239 mg,2.78 mmol), 2-bipyridine (289 mg,1.85 mmol), copper acetate (335 mg,1.85 mmol), and cesium carbonate (276 mg,1.85 mmol) were added to 1, 2-dichloroethane (20 mL), and the mixture was heated to 70℃with stirring for 16h. After the reaction solution was cooled, diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by a silica gel column (EA: pe=1:5) to give the product 34-2 (180 mg,1.03 mmol), a white solid, yield: 55%. ¹ H NMR(400MHz，DMSO)δ7.56-7.41(m，2H)，7.37-7.18(m，2H)，2.28(tt，J＝7.4，4.3Hz，1H)，1.15-0.96(m，2H)，0.64-0.49(m，2H).

Step 2: (4- (cyclopropylthio) phenyl) methylamine

34-2 (180 mg,1.03 mmol) was added to methanol (10 mL), raney nickel (242 mg,4.12 mmol) and ammonia water (1 mL) were added sequentially, hydrogen was replaced three times, and the reaction was performed at room temperature for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the product 34-3 (150 mg,0.838 mmol) as a colorless oil, yield: 81%. LCMS (ESI): m/z 163.1[ M-NH ] ₂ ] ⁺ ；RT＝1.16min(3.0min).

Step 3: n- (4- (cyclopropylsulfanyl) benzyl) -7-methoxy-3-nitro-1, 8-naphthyridin-4-amine

1a (150 mg, 0.6278 mmol), 34-3 (124 mg,0.690 mmol), DIEA (243 mg,1.88 mmol) and 5mL of acetonitrile were added to a 25mL single-necked flask, heated to 80℃and stirred for 2 hours. The mixture was concentrated and purified by reverse phase column (0.1% formic acid), and lyophilized to give product 34-4 (130 mg,0.34 mmol) as a yellow solid, yield: 54%. LCMS (ESI): m/z383.1[ M+H ]] ⁺ ；RT＝1.80min(3.0min).

Step 4: n4- (4- (cyclopropylsulfanyl) benzyl) -7-methoxy-1, 8-naphthyridine-3, 4-diamine

34-4 (130 mg,0.34 mmol), iron powder (95 mg,1.70 mmol), ammonium chloride (144 mg,2.72 mmol), THF (6 mL) and water (2 mL) were sequentially added to a 25mL three-necked flask, nitrogen gas was purged, and the temperature was raised to 60℃and stirred for 4 hours. After the reaction solution was cooled, it was filtered, the filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by reverse phase column (0.1% formic acid), and lyophilized to give 34-5 (80 mg,0.227 mmol) as a yellow solid, yield: 48.3%. LCMS (ESI): m/z353.0[ M+H ]] ⁺ ；RT＝1.53min(3.0min).

Step 5:1- (4- (cyclopropylthio) benzyl) -7-methoxy-1H-imidazo [4,5-c ] [1,8] naphthyridine

34-5 (80 mg,0.227 mmol), triethyl orthoformate (0.5 mL) and DMF (2 mL) were added to a 10mL single-necked flask, and the mixture was heated to 100deg.C under nitrogen and stirred for 4 hours. After cooling to room temperature, the reaction mixture was purified by reverse phase column (0.1% formic acid) and lyophilized to give 34-6 (40 mg,0.11 mmol) as a white solid, yield: 49%. LCMS (ESI): m/z 363.2[ M+H ] ] ⁺ ；RT＝6.34min(15min).

Step 6: cyclopropyl (imino) (4- ((7-methoxy-1H-imidazo [4,5-c ] [1,8] naphthyridin-1-yl) methyl) phenyl) -16-sulfone

34-6 (23 mg,0.0635 mmol), iodobenzene diacetic acid (82 mg,0.254 mmol), ammonium acetate (15 mg,0.190 mmol) and absolute ethanol (5 mL) were added to a 10mL single-necked flask and stirred at room temperature for 2h. The reaction was concentrated and the residue purified by reverse phase column (0.1% formic acid), prepared again by pre-HPLC (0.1% formic acid), and lyophilized to give 34 (9 mg,0.0229 mmol) as a white solid, yield: 36%. LCMS (ESI): m/z 394.2[ M+H ]]+；RT＝1.15min(3.0min). ¹ H NMR(600MHz，MeOD)δ9.28(s，1H)，8.56(s，1H)，8.36(d，J＝9.0Hz，1H)，7.95(d，J＝8.2Hz，2H)，7.38(d，J＝8.2Hz，2H)，7.02(d，J＝9.0Hz，1H)，6.13(s，2H)，4.10(s，3H)，2.73-2.58(m，1H)，1.29-1.19(m，1H)，1.07(t，J＝5.6Hz，2H)，0.93(dd，J＝8.2，6.0Hz，1H).

Examples 30-38 preparation of Compounds 29-32, 35-39

Synthesized according to the methods described in the examples above, respectively, the structural formulae of the compounds of the examples are shown in the preceding tables

Biological examples

Evaluation of ENPP1 inhibitory Activity of Compounds

The ENPP1 inhibitory activity of the compounds of the present invention was tested in a substrate 2',3' -cGAMP assay

The purpose of the experiment is as follows: according to established experimental methods, inhibition IC of the compounds of the present invention on ENPP1 was tested using 2',3' -cGAMP as substrate ₅₀ Values. STF-32 was used as a positive control compound (STF-32 was derived from document Cell Chemical Biology2020 (27), 1347-1358).

Experimental reagent: hENPP1-ECD-His (ChemPartner, cat.202103121201); AMP-Glo ^TM Assay Kit (Promega, cat: V5011); DMSO (Sigma, cat.D 8418-1L); 384-well white plate (Perkinelmer, cat.6007290); 2'3' -cGAMP (MCE, cat.HY-100564A)

The experimental method comprises the following steps:

1. preparing a 1 x reaction solution: 50mM Tris-HCl (pH 7.5), 10mM NaCl,0.5mM CaCl ₂ ，1μM ZnCl ₂ 0.01% Tween-20, 0.01% BSA.

2. Preparation of compound reaction solution: test compound and positive control compound STF-32 were dissolved in dimethyl sulfoxide (DMSO) and diluted to serial concentration solutions (serial concentrations 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05. Mu.M) and then each serial concentration solution of each compound was transferred with Echo550 to a 384-well reaction plate for test (final reaction volume was 5. Mu.L, final concentration was diluted 1000-fold accordingly), and single Kong Huo multiplex well test was set. The wells were transferred with 5nL of 100% DMSO in the smallest wells (substrate only, no enzyme, signal minimum, i.e., negative control wells), the largest wells (substrate present, enzyme present, no inhibitor, signal maximum, i.e., positive control wells).

3. A solution of 20nM 2 XhENPP 1-ECD-His protein was prepared from the 1 Xreaction solution.

4. A2X 2'3' -cGAMP substrate solution of 40. Mu.M was prepared from the 1X reaction solution.

5. 2.5. Mu.L of 2 XhENPP 1-ECD-His protein solution was added to each compound well and the largest well of the reaction plate, and 2.5. Mu.L of 1 Xreaction solution was added to the smallest well.

6. The reaction plate was centrifuged at 1000rpm for 1min and incubated at room temperature for 15 min.

7. To each well of the reaction plate, 2.5. Mu.L of 2X 2'3' -cGAMP substrate solution was added, and the mixture was centrifuged at 1000rpm for 1min and incubated at room temperature for 60 min.

8. mu.L of R1 solution (from AMP-Glo) was added to each well of the reaction plate ^TM Kit,1000rpm centrifugation for 1min, room temperature incubation for 120 min.

9. mu.L of R2 solution (from AMP-Glo) was added to each well of the reaction plate ^TM Kit,1000rpm centrifugation for 1min, room temperature incubation for 30 min.

10. The test results were recorded using a multifunctional microplate reader (2104 EnVision).

Data analysis

The inhibition rate was calculated using the following formula:

inhibition% = (maximum signal-compound signal)/(maximum signal-minimum signal) ×100

Where the "minimum signal" is the negative control Kong Junzhi and the "maximum signal" is the positive control Kong Junzhi.

Fitting dose-response curve:

the log value of concentration is taken as the X axis, the percent inhibition rate is taken as the Y axis, and the log (inhibitor) vs. response-variable slope fit curve of analytical software GraphPadprism5 is adopted to obtain the inhibition IC of the compound of the invention on enzyme activity ₅₀ Values.

The fitting formula is: y=bottom+ (top-bottom)/(1+10 ((log ic) ₅₀ -X) HillSlope), wherein bottom and top are the minimum and maximum values of the fit, respectively.

As shown in Table 1, the sulfoximine compounds of the present invention showed a better inhibition of ENPP1 kinase.

TABLE 1 inhibition of ENPP1 kinase by the compounds of the invention

Compounds of formula (I)	IC ₅₀ ，nM	Compounds of formula (I)	IC ₅₀ ，nM	Compounds of formula (I)	IC ₅₀ ，nM
						1	6.3	2	9.7	3	10
4	25	5	37	6	9.1
						7	80	8	19	9	5.5
10	3.5	11	25	12	10
						13	56	14	47	15	25
16	19	17	23	18	308
						19	4.5	20	28	21	97
22	28	23	17	24	8.6
						25	168	26	186	27	9.3
28	5.0	29	67	30	5.1
						31	5.1	32	4.8	33	7.5
34	7.3	35	8.8	36	23
						37	44	38	11	39	8.1
STF-32	6.2

As is clear from Table 1, the sulfoximine compounds of the present invention are all good ENPP1 inhibitors having IC of 1. Mu.M or less ₅₀ IC with value preferably less than or equal to 0.5 mu M ₅₀ IC having a value of 0.35. Mu.M or less, more preferably 0.05. Mu.M or less ₅₀ Values. Moreover, the inhibition of ENPP1 kinase by compound 18 and compound 19 is greatly different from each other among the configurational isomers, and the selectivity of ENPP1 kinase by compound 19 is much higher than that of compound 18.

Preliminary pharmacokinetic testing experiments

1. 6 healthy ICR mice, male, weighing 30-35g, were randomly divided into 2 groups of 3, and the test compounds were administered by intragastric (5 mg/kg) and intravenous injection (1 mg/kg) respectively:

fasted for 12 hours before the test, and the water is freely drunk. Unified feeding is performed 4h after administration.

2. Blood collection time point and sample treatment

Gastric lavage administration: 0.25h,0.5h,1.0h,2.0h,3.0h,4.0h,6.0h,8.0h and 24h post administration.

Intravenous administration: 5min,0.25h,0.5h,1.0h,2.0h,4.0h,6.0h,8.0h and 24h post administration.

Blood was continuously drawn and 3 animals were collected per time point. Plasma collection and processing: venous blood was collected from the retrobulbar venous plexus of the mice at the above-described set time points in 30-40. Mu.L, placed in EDTA-K2 test tubes, centrifuged at 3500rpm for 10min, and the plasma was isolated and frozen in a refrigerator at-20 ℃.

3. Sample testing and data analysis

The concentration of the compound in the plasma of the mice was determined by LC/MS method. Pharmacokinetic parameters were calculated after administration using the non-compartmental model of Phoenix 8.3 software (Pharsight, usa). The sulfonamide compound in the prior art has the defect of unstable metabolism, has higher in vivo clearance rate, and has almost zero oral bioavailability. The sulfoximine compound of the invention has lower in vivo clearance rate, better oral bioavailability and pharmacokinetic data shown in Table 2.

TABLE 2 mouse pharmacokinetics of the compounds of the invention

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Claims

1. Sulfoxide imines of formula (I), and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof:

Wherein,is a single bond or a double bond;

X ¹ is N, bond or CR ¹ ；

X ² N, NR of a shape of N, NR ² Or CR (CR) ² ；

X ³ N, NR of a shape of N, NR ³ -C (=o) -or CR ³ ；

X ⁴ N, NR of a shape of N, NR ⁴ -C (=o) -or CR ⁴ ；

X ⁵ N, NR of a shape of N, NR ⁵ Or CR (CR) ⁵ ；

X ⁶ Is N, -C (=O) -or CR ⁶ ；

Y ¹ Is hydrogen or C ₁ -C ₃ An alkyl group;

Y ² is C ₁ -C ₄ Alkyl or C ₃ -C ₆ Cycloalkyl;

ring B is an aromatic ring;

2. The sulfoximine compound of claim 1, and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically-labeled compounds thereof,

X ¹ 、X ² 、X ³ 、X ⁴ At least one of N and NR ⁿ Or X ¹ 、X ² 、X ³ 、X ⁴ Are all CR ⁿ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁿ For X ¹ Is referred to as R ¹ For X ² Is referred to as R ² For X ³ Is referred to as R ³ For X ⁴ Is referred to as R ⁴ ；

And/or

X ⁵ 、X ⁶ At least one of which is independently selected from N and NR ⁿ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁿ For X ⁵ Is referred to as R ⁵ ；

And/or the number of the groups of groups,

ring a is selected from: c (C) ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 4-6 membered heterocycloalkyl; wherein ring A is optionally selected from halogen, CN, OH, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and C ₁ -C ₃ The substituents of the haloalkyl groups are substituted one or more times; preferably, ring A is an optionally substituted pyrrole, furan, thiophene, pyrazole, thiazole, oxazole, imidazole, pyran, pyrazine, indoline, isoindoline, azacyclopentane, benzene, pyridine, piperidine, pyrimidine, naphthalene, quinoline, isoquinoline, indole, isoindole, indazole or benzimidazole ring, the substituted substituents being selected from one or more F, cl, CN, OH, C ₁ -C ₃ Alkyl and C ₁ -C ₃ An alkoxy group;

Y ¹ 、Y ² 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ ring B is as defined in claim 1.

3. The sulfoximine-based compound of claim 1 or 2, and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof,

R ¹ 、R ² 、R ³ 、R ⁴ Each independently selected from: hydrogen, halogen, CN, OH, C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and halo C ₁ -C ₄ An alkoxy group;

and/or R ⁵ Selected from: hydrogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

and/or R6 is selected from: hydrogen, CN, OH, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₃ Haloalkoxy groups;

Y ¹ 、Y ² 、R ⁷ 、R ⁸ ring a, ring B are as defined in claim 1 or 2, respectively.

4. The sulfoximine compound of any one of claim 1 to 3, and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof,selected from->

Preferably selected from:

wherein X is ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、R ⁵ 、R ⁶ 、Y ¹ Respectively as defined in any one of claims 1-3.

5. The sulfoximine compound of any one of claims 1-4, and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof, wherein said formula (I) is represented by the following (II) or (III):

wherein X is ¹ Is N or CR ¹ ；X ² Is N or CR ² ；X ³ N, NR of a shape of N, NR ³ -C (=o) -or CR ³ ；X ⁴ N, NR of a shape of N, NR ⁴ -C (=o) -or CR ⁴ The method comprises the steps of carrying out a first treatment on the surface of the And X is ³ 、X ⁴ Not both-C (=o) -;

wherein X is ² N, NR of a shape of N, NR ² Or CR (CR) ² ；X ³ Is N or CR ³ ；X ⁴ N, NR of a shape of N, NR ⁴ Or CR (CR) ⁴ ；

Wherein Y is ¹ 、Y ² 、R ¹ 、R ² 、R ³ 、R ⁴ 、X ⁵ 、X ⁶ 、R ⁷ 、R ⁸ Ring a is defined as in any one of claims 1 to 4, respectively.

6. The sulfoximine compound of any one of claims 1 to 5, wherein the compound of formula (I) is selected from the group consisting of stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically-labeled compounds thereof ₁ )-(I ₇ ) The structure is as follows:

wherein X is ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、R ¹ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、Y ¹ 、Y ² Ring a is as defined in any one of claims 1 to 5.

7. The sulfoximine compound of any one of claims 1-6, and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof, wherein said compound is selected from the group consisting of the structures:

8. a pharmaceutical composition comprising a therapeutically effective amount of one or more of the sulfoximine compounds of formula (I) as defined in any one of claims 1 to 7, and stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof, and optionally at least one pharmaceutically acceptable carrier, diluent or excipient.

9. An ENPP1 inhibitor comprising a sulfoximine compound of formula (I) as defined in any one of claims 1-7, and one or more of stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof, or a pharmaceutical composition as defined in claim 8.

10. Use of a sulphoxide imine compound of formula (I) according to claims 1 to 7, and one or more of its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labelled compounds, or of a pharmaceutical composition according to claim 8, said use being selected from the group consisting of:

a. use in the manufacture of a medicament for inhibiting ENPP1 activity;

b. use in the manufacture of a medicament for increasing STING activity;