CN110891942A

CN110891942A - Oxadiazole derivative, preparation method and medical application thereof

Info

Publication number: CN110891942A
Application number: CN201880045377.5A
Authority: CN
Inventors: 蔡家强; 游泽金; 何云; 曾宏; 钮晓达; 宋宏梅; 王英; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2017-07-14
Filing date: 2018-07-04
Publication date: 2020-03-17
Anticipated expiration: 2038-07-04
Also published as: WO2019011170A1; CN110891942B

Abstract

An oxadiazole derivative represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, a pharmaceutical composition and a kit containing the same, a preparation method thereof, and a use thereof in preparation of a medicament for preventing or treating indoleamine 2,3-Use of a dioxygenase-mediated immunosuppression in the manufacture of a medicament for the treatment of a disease.

Description

Oxadiazole derivative, preparation method and medical application thereof

Technical Field

The invention relates to a class of IDO (indoleamine 2, 3-dioxygenase) inhibitors containing a 1,2, 5-oxadiazole structure, pharmaceutical compositions containing the same, a preparation method thereof and application thereof in preparing medicaments for preventing or treating diseases caused by IDO-mediated immunosuppression.

Background

Due to unlimited growth, infiltration and metastasis of malignant tumors, three conventional treatment methods (surgery, radiotherapy and chemotherapy) clinically adopted at present cannot completely remove or completely kill tumor cells, so that tumor metastasis or recurrence often occurs. The tumor immunotherapy is a new therapy for tumor therapy following surgery, radiotherapy and chemotherapy because of the characteristics of safety, effectiveness, low adverse reaction and the like, and obtains the anti-tumor effect by mobilizing the natural defense mechanism of a host (such as inhibiting IDO-mediated tumor immune escape mechanism) or giving a naturally-generated substance with strong targeting property.

IDO is currently the only small molecule drug target for tumor immunotherapy entering the clinical research stage. IDO is a heme-containing monomeric enzyme first found in cells by Hayaishi group (Hayaishi o. et al, Science,1969,164, 389-396) in 1967, and its cDNA-encoded protein consists of 403 amino acids, has a molecular weight of 45kDa, is a rate-limiting enzyme that catalyzes the catabolism of tryptophan via the kynurenine pathway, is widely distributed in tissues other than liver of human and other mammals (e.g., rabbit, mouse), and is the only rate-limiting enzyme that catalyzes the catabolism of tryptophan other than liver. Tryptophan is one of the essential amino acids in mammals, is the main regulator of T cell activation, and is also an essential amino acid for cell proliferation and survival. It is required for the biosynthesis of the neurotransmitter 5-hydroxytryptamine, for the synthesis of the cofactor Nicotinamide Adenine Dinucleotide (NAD), and is an important component in the immune system response to tumors ("immune evasion"). Depletion of tryptophan levels is associated with adverse effects on the proliferation and function of lymphocytes and reduced immune system responses.

IDO is overexpressed in many human tumors and high expression is associated with poor prognosis of the disease, resistance to chemotherapy, and the like. Increased IDO expression promotes tryptophan metabolic depletion, thereby blocking T cell activation, resulting in T cell arrest in the mid-G1 phase, thereby inhibiting T cell proliferation and also inhibiting T cell immune responses. T cells may not be stimulated any more once they stop proliferating, which is the mechanism of immune action of IDO in vivo (MellorA. et al, biochem. Biophys. Res. Commun. 2005,338(1):20-24.LeRond S. et al, J. exp. Med. 2002,196(4): 447-. Under normal conditions, IDO expressed in the placenta protects the fetus from maternal rejection, while IDO highly expressed in tumors mediates immune escape from the tumor. IDO on antigen presenting cells such as macrophages, dendritic cells can also induce immune tolerance of T cells to tumor antigens by inhibiting T cell proliferation activation. Therefore, IDO is a potential target for cancer immunotherapy.

Besides tumors, IDO is also associated with the onset of diseases such as depression, senile dementia, cataract, etc. Furthermore, IDO has been implicated in neurological and psychiatric disorders, including mood disorders and other chronic diseases characterized by IDO activation and tryptophan degradation, such as viral infections (e.g., AIDS), alzheimer's disease, autoimmune diseases, bacterial infections such as lyme disease and streptococcal infections, and the like.

1-methyltryptophan (1-methyltrypophan), an oral small molecule IDO inhibitor developed by NewLink Genetics, is currently undergoing a second phase of clinical trials in the united states, primarily for the treatment of metastatic breast cancer and solid tumors; the IDO small molecule inhibitor INCB-24360, which is being developed by Incyte corporation, is in clinical phase three trials, mainly used for treating various cancers including myelodysplastic syndrome. Disclosed inhibitor patent applications for selective inhibition of IDO include WO2004094409, WO2006122150, WO2007075598, WO2010005958, WO2014066834, WO2016155545, and the like.

Therefore, the IDO inhibitor has good application prospect in the pharmaceutical industry as a medicine, but no IDO inhibiting medicine is on the market at present. In order to achieve better tumor treatment and better meet market needs, there is a great need to develop a new generation of highly potent and low-toxic selective IDO inhibitors for treating patients suffering from diseases or conditions affected by the activity of the enzyme.

Disclosure of Invention

The present invention provides a safe and effective IDO inhibitor having a novel structure. In particular, the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof,

wherein:

R₁selected from optionally substituted C_6-10Aryl or optionally substituted 5-6-or 8-10-membered heteroaryl containing 1 to 4 identical or different heteroatoms selected from N, O, S;

R₂,R₃each independently selected from hydrogen, halogen, cyano, hydroxy, nitro, substituted or unsubstituted C_1-12Alkyl, substituted or unsubstituted C_2-12Alkenyl, substituted or unsubstituted C_3-12Cycloalkyl, substituted or unsubstituted C_5-12Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or R on the same or different carbon atoms₂And R₃、R₂And R₂、R₃And R₃May be independently linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group;

part represents a single bond or a double bond;

y is selected from N (R)₄)_m，C(R₅)_nWhen more than one R is simultaneously present₄Or R₅When they are the same or different and each is independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstitutedC_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₅May be linked to the carbon atom to which it is attached to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

z is selected from N (R)₆)_n，C(R₇)_qWhen more than one R is simultaneously present₆Or R₇When they are the same or different and each is independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₆May be linked to the nitrogen atom to which it is attached to form an optionally substituted 4-8 membered heterocyclic group; when q is equal to or greater than 2, R₇May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

w is selected from N (R)₈)(R₉)_m，C(R₁₀)_qWhen more than one R is simultaneously present₈、R₉Or R₁₀When they are the same or different and each is independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂，R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or notSubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heterocyclyl containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered polycyclyl containing at least one heteroatom selected from N, O, S; or, when q is equal to or greater than 2, R₁₀May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group;

x is selected from N (R)₁₃),C(R₁₄)(R₁₅),O,S；

R₁₁、R₁₂Are respectively selected from hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

R₁₃、R₁₄and R₁₅Are respectively selected from hydrogen, substituted or unsubstituted C_1-4An alkyl group; or, R₁₄And R₁₅And the carbon atoms to which they are attached together form a substituted or unsubstituted C_3-12Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl containing at least one heteroatom selected from N, O, S;

p is an integer selected from 1 to 6;

m is an integer selected from 0 to 1;

n is an integer selected from 1-2;

q is an integer selected from 2 to 3;

y, W and Z are not carbon at the same time;

in (1),

one and only one is a double bond;

when R is₁Is composed of

R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂or-NHCH₃Z is C (R)₇)_qWherein q is 2, R₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of

R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂Z is N (R)₆)_nWherein n is 1, R₆X is not O or S when independently selected from hydrogen or cyano;

said "substituted" means, but is not limited to, substitution with: halogen, cyano, nitro, hydroxy, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl, sulfonyl, sulfinyl, acyl, amido, sulfonamido, ester.

Through a large number of experiments, the inventor of the invention discovers that, surprisingly, the compound shown in the general formula I not only has very high IDO enzyme inhibition activity, but also the experiments of the compound on the intracellular IDO enzyme inhibition activity show that the compound has very high intracellular IDO enzyme inhibition activity. The influence of the compounds on the activity of IDO enzyme in cells is determined by NFK Green method, and IC of a plurality of compounds for inhibiting the activity of IDO enzyme in Hela cells₅₀Values below 10nM or lower.

The present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.

The present invention provides a kit comprising a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the invention.

The present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression.

The present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture of same, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prevention or treatment of a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression.

The present invention provides a method for preventing or treating diseases caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression, which comprises administering a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention.

The present invention provides a method for preventing or treating diseases caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression, which comprises administering a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention, and one or more other therapeutic agents.

In particular, the invention provides compounds of formula II

Wherein:

y is selected from NR₄，C(R₅)₂(ii) a Wherein R is₄Or R₅May be the same or different and are each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₅To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

z is selected from N (R)₆)，C(R₇)₂(ii) a Wherein R is₆Or R₇May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 containing 1-4 heteroatoms, which may be the same or different, selected from N, O, SA membered or 8-10 membered heteroaryl; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

w is selected from N (R)₈)(R₉)，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heterocyclyl containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered polycyclyl containing at least one heteroatom selected from N, O, S; or, R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group;

y, W and Z are not carbon at the same time;

when R is₁Is composed of

R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂or-NHCH₃Z is C (R)₇)₂Wherein R is₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of

R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂Z is NR₆Wherein R is₆X is not O or S when independently selected from hydrogen or cyano;

X，R₁，R₂，R₃，R₁₁，R₁₂，R₁₃，R₁₄，R₁₅p is as defined in formula I.

In particular, the present invention provides compounds of formula I or II wherein X is selected from NR₁₃O, S, radical R₁₃As defined in formula I.

In particular, the present invention provides compounds of formula III:

wherein:

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆Or R₇May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heterocyclyl containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered polycyclyl containing at least one heteroatom selected from N, O, S; or, R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group;

y, W and Z are not carbon at the same time;

x is selected from NR₁₃,O,S；

When R is₁Is composed of

Y is-NH-and W is-NH₂or-NHCH₃Z is C (R)₇)₂Wherein R is₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of

Y is-NH-and W is-NH₂Z is NR₆Wherein R is₆X is not O or S when independently selected from hydrogen or cyano;

R₁，R₁₁，R₁₂，R₁₃as defined in formula I.

In particular, the present invention provides compounds of formula IV,

wherein:

y is NR₄，R₄Selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₂CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

x is selected from NR₁₃,O,S；

When R is₁Is composed of

when R is₁Is composed of

R₁，R₁₁，R₁₂，R₁₃as defined in formula I.

In particular, the present invention provides compounds represented by the general formula IV-1:

wherein:

z is NR₆，R₆Selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

when R is₁Is composed of

Y is-NH-and W is-NH₂，R₆X is not O or S when independently selected from hydrogen or cyano;

X，W，R₁，R₄，R₈，R₉，R₁₀，R₁₁，R₁₂，R₁₃as defined in formula IV.

In particular, the present invention provides a compound represented by the general formula IV-2:

z is CHR₇，R₇Selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

when R is₁Is composed of

Y is-NH-and W is-NH₂or-NHCH₃，R₇X is not O or S when independently selected from hydrogen or nitro;

In particular, the present invention provides compounds of formula V-1:

wherein:

z is selected from N (R)₆)₂，C(R₇)₃(ii) a Wherein R is₆Or R₇May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₆To the nitrogen atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or, R₇To which the carbon atom to which it is attached is linked to optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

x is selected from NR₁₃,O,S；

R₁，R₁₁，R₁₂，R₁₃As defined in formula I.

In particular, the present invention provides compounds of formula V-2,

wherein:

R₅selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1-4 heteroatoms, which may be the same or different, selected from N, O, S;

z is selected from N (R)₆)₂，C(R₇)₃(ii) a Wherein R is₆Or R₇May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₆To the nitrogen atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or, R₇Are connected with the carbon atoms connected with the same to form a connecting chamberOptionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl;

x is selected from NR₁₃,O,S；

R₁，R₁₁，R₁₂，R₁₃As defined in formula I.

In particular, the present invention provides compounds of formula I:

wherein R is₁Selected from optionally substituted C_6-10Aryl or optionally substituted 5-6-or 8-10-membered heteroaryl containing 1 to 4 identical or different heteroatoms selected from N, O, S;

R₂，R₃each independently selected from hydrogen, halogen, cyano, hydroxy, nitro, substituted or unsubstituted C_1-12Alkyl radical, isSubstituted or unsubstituted C_2-12Alkenyl, substituted or unsubstituted C_3-12Monocyclic alkyl, substituted or unsubstituted C_5-12Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or R on the same or different carbon atoms₂And R₃、R₂And R₂、R₃And R₃May be independently linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group);

part represents a single bond or a double bond;

y is selected from N (R)₄)_m，C(R₅)_nM is an integer selected from 0 to 1, n is an integer selected from 1 to 2, R₄And R₅Each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₅May be linked to the carbon atom to which it is attached to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); when n is 2, two R₅May be the same or different;

z is selected from N (R)₆)_n，C(R₇)_qN isAn integer selected from 1 to 2, q is an integer selected from 2 to 3, R₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₆May be linked to the nitrogen atom to which it is attached to form an optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); when q is equal to or greater than 2, R₇May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); when there are more than one R₆Or R₇When each R is₆May be the same or different, each R₇May be the same or different;

w is selected from NR₈(R₉)_m，C(R₁₀)_qM is an integer selected from 0 to 1, q is an integer selected from 2 to 3, R₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂，R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or，R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or, when q is equal to or greater than 2, R₁₀May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); when there are more than one R₁₀When each R is₁₀May be the same or different;

x is selected from NR₁₃,CR₁₄R₁₅,O,S；

R₁₁、R₁₂Are respectively selected from hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when multiple R's are present simultaneously₁₁Or a plurality of R₁₂When each R is₁₁Each R, which may be the same or different, is₁₂May be the same or different;

R₁₃、R₁₄and R₁₅Each independently selected from hydrogen, substituted or unsubstituted C_1-4An alkyl group; or, R₁₄And R₁₅And the carbon atoms to which they are attached together form a substituted or unsubstituted C_3-12Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl (e.g., 4-10 membered heterocycloalkyl) containing at least one heteroatom selected from N, O, S;

p is an integer selected from 1 to 6;

when a plurality of m exist at the same time, each m may be the same or different;

when a plurality of n exist at the same time, each n may be the same or different;

when a plurality of q exist at the same time, each q may be the same or different;

y, W and Z are not carbon at the same time;

in (1),

one and only one is a double bond;

when R is₁Is composed of

said "substituted" means, but is not limited to, substitution with: halogen, cyano, nitro, hydroxy, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, R₁₆SO₂，R₁₆SO，R₁₆CO，R₁₆R₁₇NCO，R₁₆R₁₇NSO₂，R₁₆OCO, wherein R₁₆、R₁₇Independently selected from hydrogen and C_1-4Alkyl when multiple R are present₁₆Or a plurality of R₁₇When each R is₁₆Each R, which may be the same or different, is₁₇May be the same or different.

In particular, the present invention provides compounds of formula II:

wherein R is₄And R₅Each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₅To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); wherein two R are₅May be the same or different;

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-to 8-memberedHeterocyclyl (e.g., 4-8 membered heterocycloalkyl); wherein two R are₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered polycyclocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or, two and three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); wherein each R is₁₀May be the same or different;

y, W and Z are not carbon at the same time;

when R is₁Is composed of

In particular, the present invention provides compounds of formula III:

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); wherein two R are₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered polycyclocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); wherein each R is₁₀May be the same or different;

y, W and Z are not carbon at the same time;

x is selected from NR₁₃,O,S；

When R is₁Is composed of

when R is₁Is composed of

R₁，R₁₁，R₁₂，R₁₃as defined in formula I.

In particular, the present invention provides compounds of formula IV:

wherein R is₄Selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₂CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂, R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); wherein two R are₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered polycyclocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or, R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); wherein each R is₁₀May be the same or different;

x is selected from NR₁₃,O,S；

When R is₁Is composed of

when R is₁Is composed of

R₁，R₁₁，R₁₂，R₁₃as defined in formula I.

In particular, the present invention provides a compound represented by the general formula IV-1:

wherein R is₆Selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

when R is₁Is composed of

Y is-NH-and W is-NH₂，R₆X is not O or S when selected from hydrogen or cyano;

R₇selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

when R is₁Is composed of

Y is-NH-and W is-NH₂or-NHCH₃，R₇When selected from hydrogen or nitro, X is not O or S;

In particular, the present invention provides compounds represented by the general formula V-1:

wherein:

z is selected from N (R)₆)₂，C(R₇)₃(ii) a Wherein R is₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₆To the nitrogen atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); or, R₇To which the carbon atom to which it is attached is linked to optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); wherein each R is₆May be the same or different; each R is₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered polycyclocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or, R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); wherein each R is₁₀May be the same or different;

x is selected from NR₁₃,O,S；

R₁，R₁₁，R₁₂，R₁₃As defined in formula I.

In particular, the present invention provides compounds represented by the general formula V-2:

R₅selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group containing at least one heteroatom selected from N, O, S (e.g., 4-10 membered heterocycloalkyl), substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

z is selected from N (R)₆)₂，C(R₇)₃(ii) a Wherein R is₆Or R₇May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₆To the nitrogen atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); or alternatively, two or three R₇To which the carbon atom to which it is attached is linked to optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); wherein each R is₆May be the same or different; each R is₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered polycyclocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); each R is₁₀May be the same or different;

x is selected from NR₁₃,O,S；

R₁，R₁₁，R₁₂，R₁₃As defined in formula I.

In particular, the present invention provides compounds of formulae I to V (including IV-1, IV-2, V-1 and V-2):

wherein R is₁Selected from optionally substituted C_6-10An aryl group;

preferably, R₁Selected from optionally substituted phenyl;

preferably, R₁Selected from phenyl substituted by one or more halogens;

preferably, R₁Is selected from

Particularly preferably, R₁Is composed of

In particular, the present invention provides compounds of the general formulae I to II:

wherein R is₂，R₃Each independently selected from hydrogen, halogen, cyano, hydroxy, nitro, substituted or unsubstituted C_1-12Alkyl, substituted or unsubstituted C_2-12Alkenyl, substituted or unsubstituted C_3-12Monocyclic alkyl, substituted or unsubstituted C_5-12Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or R on the same or different carbon atoms₂And R₃、R₂And R₂、R₃And R₃May be independently linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group (e.g., 4-to 8-membered heteroCycloalkyl groups).

In particular, the present invention provides compounds of formulae I to IV (including IV-1, IV-2):

wherein R is₄Selected from hydrogen, cyano, nitro, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8An alkenyl group;

preferably, R₄Selected from hydrogen, substituted or unsubstituted C_1-4An alkyl group;

further preferably, R₄Is hydrogen or methyl;

particularly preferably, R₄Is hydrogen.

In particular, the present invention provides compounds represented by the general formulae I, II, III and V-2:

wherein R is₅Is hydrogen.

wherein R is₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

preferably, R₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-4An alkyl group;

preferably, R₆Or R₇Each independently selected from: hydrogen, cyano, nitro, methylsulfonyl, NH₂- (C ═ O) -, sulfonamido, ethanesulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, cyclohexylsulfonyl, phenylsulfonyl, -CH₂CF₃，-CH₂CN；

Particularly preferably, R₆Or R₇Each independently of the otherIs selected from: hydrogen, cyano, nitro, methylsulfonyl, NH₂- (C ═ O) -, sulfonamido, ethanesulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, benzenesulfonyl, -CH₂CF₃。

wherein R is₁₁、R₁₂Are respectively selected from hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when multiple R's are present simultaneously₁₁Or a plurality of R₁₂When each R is₁₁Each R, which may be the same or different, is₁₂May be the same or different.

wherein R is₁₃、R₁₄And R₁₅Each independently selected from hydrogen, substituted or unsubstituted C_1-4An alkyl group; or, R₁₄And R₁₅And the carbon atoms to which they are attached together form a substituted or unsubstituted C_3-12Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl (e.g., 4-10 membered heterocycloalkyl) containing at least one heteroatom selected from N, O, S.

In particular, the present invention provides compounds of the general formulae I to III:

wherein Y is selected from N (R)₄)_m，C(R₅)_nM is an integer selected from 0 to 1, n is an integer selected from 1 to 2, R₄And R₅Each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₅May be linked to the carbon atom to which it is attached to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); when n is 2, two R₅May be the same or different;

preferably, Y is selected from NR₄，C(R₅)₂；

Preferably, Y is selected from NH, CH₂；

More preferably, Y is selected from NH.

wherein W is selected from NR₈(R₉)_m，C(R₁₀)_qM is an integer selected from 0 to 1, q is an integer selected from 2 to 3, R₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂，R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted heterocyclic ring containing at least one heteroatom selected from the group consisting of N, O, S4-10 membered heteromonocyclic group (e.g., 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., 4-10 membered polycyclic heterocycloalkyl); or, when q is equal to or greater than 2, R₁₀May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group); when there are more than one R₁₀When each R is₁₀May be the same or different;

preferably, W is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 identical or different heteroatoms selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered polycyclocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl); or, R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-8 membered heterocyclic group (e.g., a 4-8 membered heterocycloalkyl group);

preferably, W is NR₈R₉(ii) a Wherein R is₈Or R₉Each independently selected from: hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted C_6-10An aryl group; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 5-6 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 5-6 membered monocyclic heterocycloalkyl) or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S (e.g., a 4-10 membered polycyclic heterocycloalkyl);

more preferablyW is NR₈R₉(ii) a Wherein R is₈Or R₉Each independently selected from: hydrogen, substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted phenyl; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl or an optionally substituted 4-10 membered spiroheterocyclyl containing at least one heteroatom selected from N, O, S;

particularly preferably, W is selected from amino, tert-butylamino, phenylamino, benzylamino, isopropylamino, dimethylamino, morpholinyl, piperidinyl, tetrahydropyrrolyl, methylamino, cyclohexylamino, ethylamino, cyclopropylamino,

In particular, the present invention provides compounds of the general formulae I to IV, V-1, V-2:

wherein Z is selected from N (R)₆)_n，C(R₇)_qN is an integer selected from 1 to 2, q is an integer selected from 2 to 3, R₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, a substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S (e.g., a 4-to 10-membered heterocycloalkyl group), and a substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₆May be linked to the nitrogen atom to which it is attached to form an optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); when q is equal to or greater than 2, R₇May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl (e.g., 4-8 membered heterocycloalkyl); when there are more than one R₆Or R₇When each R is₆May be the same or different, each R₇May be the same or different;

preferably, Z is selected from NR₆Or C (R)₇)₂，R₆And R₇Each independently selected from: cyano, nitro, R₁₁SO₂，R₁₁R₁₂NSO₂，R₁₁R₁₂NCO, trifluoroethyl;

R₁₁、R₁₂independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, phenyl.

Preferably, Z is CHR₇，R₇Is nitro.

In particular, the present invention provides compounds of formulae I to V (including IV-1 and, IV-2, V-1 and V-2):

wherein R is₁₃Selected from H, substituted or unsubstituted C_1-4An alkyl group;

preferably, R₁₃Is H.

wherein, theBy "substituted" is meant, but not limited to, substitution with: halogen, cyano, nitro, hydroxy, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, R₁₆SO₂,R₁₆SO,R₁₆CO,R₁₆R₁₇NCO,R₁₆R₁₇NSO₂，R₁₆OCO, wherein R₁₆、R₁₇Independently selected from hydrogen and C_1-4Alkyl when multiple R are present₁₆Or a plurality of R₁₇When each R is₁₆Each R, which may be the same or different, is₁₇May be the same or different;

preferably, said "substituted" means independently substituted with: fluorine, chlorine, bromine, hydroxyl, methyl or methoxy. In particular, the invention provides compounds of formulae I to V (including IV-1, IV-2, V-1 and V-2), X being selected from NH, O, S.

According to some embodiments of the invention, the compound of the invention is selected from, but not limited to:

according to some embodiments of the present invention, there is provided a pharmaceutically acceptable salt of a compound of formulae I through V (including IV-1, IV-2, V-1, and V-2) as the hydrochloride salt thereof.

In particular, the invention provides pharmaceutically acceptable salts of compounds of formulae I to V (including IV-1, IV-2, V-1 and V-2) as:

preparation method

It is still another object of the present invention to provide a method for preparing the compound of the present invention, which is carried out according to the following reaction scheme 1, reaction scheme 2, reaction scheme 3 or reaction scheme 4:

reaction scheme 1

The first step is carried out in the presence of an organic or inorganic base and/or a condensation agent;

the second step is carried out at a temperature of from 20 to 180 deg.C (e.g. from 40 to 80 deg.C, such as 65 + -2 deg.C) in the presence of an amine reagent.

Reaction scheme 2

The first step is carried out at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an organic or inorganic base and/or a condensing agent;

the second step is carried out under alkaline conditions at a temperature of from 20 to 180 deg.C (e.g. from 40 to 80 deg.C, such as 65. + -. 2 deg.C).

Reaction scheme 3

The first step is carried out under alkaline conditions at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃);

the second step is carried out at a temperature of 20 to 180 ℃ (e.g., 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an organic or inorganic base and/or a condensing agent;

the third step is carried out at a temperature of 20 to 180 ℃ (e.g., 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an amine reagent.

Reaction scheme 4

The first step is carried out in an aprotic solvent in the presence of an organic or inorganic base at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃);

The third step is carried out under alkaline conditions with methyl iodide at a temperature of 20 to 180 deg.C (e.g., 40 to 80 deg.C, e.g., 65. + -. 2 deg.C).

The fourth step is carried out at a temperature of from 20 to 180 ℃ such as from 40 to 80 ℃ such as 65. + -. 2 ℃ in the presence of an amine reagent.

In a preferred embodiment, the above reaction is carried out under an inert gas blanket.

In a preferred embodiment, protic solvents that may be used in the process for the preparation of the compounds of the present invention include, but are not limited to, water, methanol, ethanol, acetic acid and the like, with tert-butanol being particularly preferred.

In a preferred embodiment, aprotic solvents that may be used in the methods of preparing the compounds of the present invention include, but are not limited to, ethyl acetate, dichloromethane, toluene, DMF, DMSO, DMI, HMPA, 1, 2-dichloroethane, acetonitrile, N-methylpyrrolidone, and the like.

In preferred embodiments, organic bases that can be used in the methods of making the compounds of the present invention include, but are not limited to, sodium tert-butoxide, triethylamine, DIPEA, pyridine or DMAP; inorganic bases that can be used in the process for preparing the compounds of the present invention include, but are not limited to, NaH, NaOH, Na₂CO₃Or K₂CO₃。

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The term "optionally substituted" means that the group is substituted or unsubstituted.

The term "about" means within. + -. 10%, preferably within. + -. 5%, more preferably within. + -. 2% of the stated value.

The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C_1-12Alkyl "means having 1 to 12 carbon atomsIs optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl", e.g. CF₃、C₂F₅、CHF₂、CH₂F、CH₂CF₃、CH₂Cl or-CH₂CH₂CF₃Etc.).

As used herein, the term "alkenyl" is defined as an unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight or branched chain containing 2 to 10, e.g., 2 to 6, carbon atoms. For example, as used herein, the term "C_2-8Alkenyl "means a straight or branched chain alkenyl group containing 2 to 8 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl, optionally substituted with one or more (e.g. 1,2, 3 or 4) suitable substituents.

As used herein, the term "alkynyl" is defined as an unsaturated straight or branched chain aliphatic hydrocarbon radical containing at least one carbon-carbon triple bond. In some embodiments, alkynyl groups have 2 to 10, e.g., 2 to 6, carbon atoms. For example, as used herein, the term "C_2-6Alkynyl "refers to straight or branched chain alkynyl groups containing 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl, which are optionally substituted with one or more (e.g. 1,2, 3 or 4) suitable substituents.

As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic group containing saturation or partial unsaturation (e.g., containing 1 or 2 double bonds). "monocycloalkyl" is preferably 3-10 membered monocycloalkyl, more preferably 3-8 membered monocycloalkyl, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl. "Polycycloalkyl" includes "bridged cyclic", "fused cyclic" and "spirocyclic", where "bridged cyclic" refers to a monocyclic alkyl group in which any two nonadjacent carbon atoms are replaced by one or moreAlkylene bridge formed of multiple (e.g., 1-3) additional carbon atoms (i.e., - (CH)₂)_tA bridging group of the form, where t is, for example, 1,2 or 3). Representative examples of bicyclic bridged ring groups include, but are not limited to: bornyl, bicyclo [2.2.1]Heptenyl, bicyclo [3.1.1]Heptylalkyl, bicyclo [2.2.1]Heptylalkyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.2]Nonyl, bicyclo [3.3.1]Nonyl, bicyclo [4.2.1]Nonyl, and the like. "Heterocycloalkyl" includes cycloalkyl rings fused to phenyl, monocycloalkyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, and cycloalkyl includes, but is not limited to: benzocyclobutene, benzocyclobutane, benzocyclohexane, benzocycloheptane, pyridocyclobutane, pyridocyclopentane, pyridocyclohexane, 2, 3-dihydro-1-H-indene, 2, 3-cyclopentenopyridine, 5, 6-dihydro-4H-cyclopentyl [ B]Thiophene, decalin, and the like. "spirocycloalkyl" refers to a bicyclic group formed by two cycloalkyl groups sharing a common carbon atom. The polycycloalkyl group may be 5-18 membered, preferably 6-15 membered, more preferably 6-12 membered. The polycyclic alkyl group is preferably a bicycloalkyl group. The monocycloalkyl or polycycloalkyl group can be linked to the parent molecule through any of the carbon atoms in the cycloalkyl ring. For example, as used herein, the term "C_3-12Cycloalkyl "refers to cycloalkyl groups containing 3 to 12 carbon atoms, including monocycloalkyl, spirocyclic, and cycloalkylo groups, optionally substituted with one or more (e.g., 1,2, 3, or 4) suitable substituents.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi-electron system. In some embodiments, aryl has 6 to 14, e.g., 6 to 10 carbon atoms. For example, as used herein, the term "C_6-10Aryl "means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)₂、C_1-6Alkyl, etc.).

As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system having, for example, 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms, and which contains one or more heteroatoms (e.g., 1,2, 3 or 4) which may be the same or different (e.g., oxygen, nitrogen or sulfur), and which may be benzo-fused in each case. For example, as used herein, the term "5-6 membered heteroaryl" means a heteroaryl group containing 5 to 6 ring atoms. In particular, examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof.

The term "halogen", as used herein, is defined to include F, Cl, Br or I. The term "halo" means substituted with a halogen atom as defined above.

The term "alkoxy," as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. C_1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

The term "alkylthio" as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. C_1-6Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, and the like.

The term "cycloalkyloxy," as used herein, means a cycloalkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. C_3-10Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy, and the like.

As used herein, the term "heterocyclyl" refers to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic group having, for example, 3 to 10 (preferably having 3 to 8, 4 to 10, or 4 to 8, more preferably having 3 to 6, or 5 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 2-9 (e.g., 2,3, 4, 5,6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1,2, 3, or 4) heteroatoms independently selected from N, O and S. For example, a "4-8 membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 3-7 (e.g., 2,3, 4, 5,6, or 7) ring carbon atoms and one or more (e.g., 1 or 2) heteroatoms independently selected from N, O and S. For example, a "4-10 membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 3-9 (e.g., 2,3, 4, 5,6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1,2, 3, or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

The term "monoheterocyclyl" refers to a saturated (i.e., monocyclic heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic group having, for example, 3-10 (preferably having 3-8, 4-10, or 4-8, more preferably having 3-6, or 5-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.

The term "polycyclyl" refers to a saturated (i.e., polycycloheterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) polycyclic group having, for example, 3-10 (preferably 3-8, 4-10, or 4-8, more preferably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.

The term "polycyclic heterocycloalkyl" includes "bridged heterocyclyl", "fused heterocycloalkyl" and "spiroheterocyclyl", the bridged heterocyclyl "referring to a monocyclic ringAny two non-adjacent ring atoms of the heterocycloalkyl group are bridged by a straight chain group of 1 to 3 additional atoms (e.g., carbon atoms and heteroatoms, such as 1 to 3 additional carbon atoms, such as 1 additional heteroatom) (the straight chain group includes, but is not limited to: -CH₂-、-O-、-NH-、-S-、-CH₂CH₂-、-CH₂O-、-CH₂S-、-CH₂NH-、-CH₂-, representative examples of bridged heterocyclic groups include, but are not limited to:

and the like. "fused-ring heterocycloalkyl" includes bicyclic fused-ring heterocycloalkyl formed by a monocyclic heterocycloalkyl ring fused to a phenyl, monocycloalkyl, monocyclic heterocycloalkyl, or monocyclic heteroaryl, including but not limited to: 2, 3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuranyl, indolinyl, 2, 3-dihydrobenzo [ b]Thienyl, dihydrobenzopyranyl, 1,2, 3, 4-tetrahydroquinolyl, and the like. "spiroheterocyclyl" refers to a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing a carbon atom, including, but not limited to:

and the like.

In the present invention, the heterocyclic group may be attached to the parent molecule through any of the ring atoms in the heterocyclic ring. The ring atom is preferably a carbon atom and/or a nitrogen atom constituting the ring skeleton.

The term "substituted" means that one or more (e.g., 1,2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a group is described as "optionally substituted," the group may be (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a group is described as optionally substituted with one or more of a list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen present) may each be replaced with an independently selected optional substituent.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2,3, 4, 5 or 10, under reasonable conditions.

Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

The invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)²H、³H) (ii) a Isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶Cl); isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen (e.g. of¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S)。

The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, dihydropyrimidine groups may exist in solution in equilibrium with the following tautomeric forms. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: a pharmaceutically acceptable salt, ester, solvate, metabolite or prodrug thereof, which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound of the invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, adipate, aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, mesylate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, palmitate, pamoate, phosphate/biphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, dihydrogenphosphate, pyroglutamate, saccharate, salt, and the like, Tartrate, trifluoroacetate and xinafoate (xinofoate).

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycinate, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.

For a review of suitable Salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from each of the compounds of the general formulae or specific formulae herein, including physiologically hydrolyzable esters (compounds of the invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves also be esters.

The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987(E.B.Roche editions, American Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, for example, as described in Protective Groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The bonds in the structural diagrams represented herein by the wavy lines "-" are intended to indicate that the structure represents the cis or trans isomer, or a mixture of the cis and trans isomers in any proportion.

The group "Ms-" is used herein to denote methanesulfonyl.

Pharmaceutical composition and kit

Another object of the present invention is to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

In the pharmaceutical compositions of the present invention, pharmaceutically acceptable carriers that can be employed include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms. Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.

The compound of the invention may be present in the pharmaceutical composition in an amount or amount of from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150mg, especially 1-50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.

According to one embodiment of the invention, the pharmaceutical composition may further comprise one or more other therapeutic agents, such as other anti-cancer agents, including but not limited to:

may be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

Examples of macromolecular forms of anticancer agents are biological molecules, such as naturally or artificially prepared proteins. Specific proteins include, but are not limited to, cytokines, such as GM-CSF; interleukins, such as IL-2 (including recombinant IL-II ("RIL 2") and Canarypox (Canarypox) IL-2), IL-10, IL-12 and IL-18; interferons such as interferon a-2 a, interferon a-2 b, interferon a-N1, interferon a-N3, interferon beta-Ia and interferon gamma-Ib; PD-1 inhibitors and PD-L1 inhibitors, such as pembrolizumab and Nivolumab.

Small molecule forms of anti-cancer agents, including but not limited to anti-cancer agents, antibiotics, anti-inflammatory agents, and steroids.

Examples of anti-cancer agents include, but are not limited to, acivicin; aclarubicin; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; altretamine; an apramycin; amenthraquinone acetate; amsacrine; anastrozole; an atramycin; asparaginase enzyme; a triptyline; azacitidine; azatepa; (ii) azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; bisnefaede dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib (COX-2 inhibitor); chlorambucil; a sirolimus; cisplatin; cladribine; krestist mesylate; cyclophosphamide; cytarabine; dacarbazine; actinomycin D; daunorubicin hydrochloride; decitabine; (ii) dexomaplatin; tizanoguanine; dizyguanine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotandrosterone propionate; azomycin; edatrexae; eflornithine hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine; sodium phosphate estramustine; etanidazole; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; (iii) flucitabine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; ifosfamide; ilofovir dipivoxil; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; (ii) maxolone; maytansine; mechlorethamine hydrochloride; megestrol acetate; (ii) estrene acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; meltupipide; mitodomide; mitorubin; mitoxantrone; mitosin; mitomycin; mitospirane culturing; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noggin; oxaliplatin; oshuzuren; paclitaxel; a pemetrexed; a calicheamicin; nemadectin; pelamicin sulfate; cultivating phosphoramide; pipobroman; piposulfan; piroxantrone hydrochloride; (ii) a plicamycin; pramipexole; sodium porfimer; porphyrins; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; (ii) lybodenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium phosphono-aspartate; a sparamycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; streptonigrin; a streptozocin; a sulfochlorophenylurea; a talithromycin; sodium tegafur; docetaxel; tegafur; tiloxanthraquinone hydrochloride; temoporfin; (ii) teniposide; a tiroxiron; cheese in the testis; (ii) a thiopurine; thioguanine; thiotepa; a thiazolfuzoline; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; tritrosa glucuronide; triptorelin; tobramzole hydrochloride; uramustine; uretipi; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinblastine epoxy sulfate; vinorelbine tartrate; vinblastine sulfate; vinzolidine sulfate; (ii) vorozole; zeniplatin; 1, neat setastine; zorubicin hydrochloride.

Other anti-cancer drugs include, but are not limited to, 20-Epi-1, 25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; an acylfulvene; (ii) Alexanox; aldesleukin; ALL-TK antagonist; altretamine; estramustine; amifostine; (ii) aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; an angiogenesis inhibitor; an antagonist D; an antagonist G; anrlex; anti-dorsal morphogenetic protein-1; anti-androgens, prostate cancer; an antiestrogen; anti-neoplastic ketones; an antisense oligonucleotide; alfedimycin glycinate; an apoptosis gene modulator; a modulator of apoptosis; no glance sideways at purine nucleic acid; Ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; amoxicillin; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azalomycin; n-thymine; baccatin III derivatives; balanol; batimastat; a BCR/ABL antagonist; chromanol; benzoyl echinocandin star; a BETA lactam derivative; betulinic acid; a BFGF inhibitor; bicalutamide; a bisantrene group; dinitropropinyl spermine; (ii) bisnefarde; bistetraene A; bizelesin; briprimine; titanium is distributed; butyl alumine; calcipotriol; calphos protein C; a camptothecin derivative; capecitabine; carboxamide-amino-triazole; carboxamide triazoles; CaRest M3; CARN 700; an inhibitor derived from cartilage; folding to get new; casein kinase Inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; (ii) Chlorlins; a chloroquinoxaline sulfonamide drug; (ii) cicaprost; a cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; collismycin A; CollismycinB; combretastatin a 4; combretastatin analogs; conagenin; crambescidin 816; clinatot; cyclopeptide 8 from nostoc; a cyclopeptide a derivative from nostoc; curacin A; cyclopentaquinone; cycloplatam; cypemycin; cytarabine Ocfosfate; a cytolytic factor; cytostatin; daclizumab; decitabine; dehydromembrane ecteinascidin B; deslorelin; dexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; diazaquinone; dynastine B; didox; diethyl norspermine; dihydro-5-azacytidine; a dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; etokomustine; edifulin; epidolumab; eflornithine; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine analogue; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flutemastine; a flusterone; fludarabine; fluorodaunorubicin hydrochloride; fowler; fulvestrant; fostrexed; fotemustine; gadolinium deuteroporphyrin; gallium nitrate; galocitabine; ganirelix; a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisamide; hypericin; ibandronic acid; idarubicin; idoxifene; iloperidone; ilofovir dipivoxil; ilomastat; imatinib; imiquimod; immunostimulatory peptides; an insulin-like growth factor-1 receptor inhibitor; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; iododoxorubicin; medicinal potato; iprop; isradine; isobengazole; isohomohaliconidrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N-triacetic acid; lanreotide; leinamycin; leguminous kiosks; mushroom polysaccharide sulfate; leptin statin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprorelin + estrogen + progesterone; leuprorelin; levamisole; liazole; a linear polyamine analog; a lipophilic glycopeptide; a lipophilic platinum compound; lissoclinamide 7; lobaplatin; earthworm phosphatide; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium porphyrinates; lysofylline; dissolving the peptide; maytansine; manostatin A; marimastat; (ii) maxolone; maspin; inhibitors of gene lytic factors; a matrix metalloproteinase inhibitor; (ii) a melanoril; malbaruron; 1, meperiline; methioninase; metoclopramide; an inhibitor of MIF; mifepristone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; mitoxin fibroblast growth factor-Saporin (Saporin); mitoxantrone; mofagotine; moraxest; erbitux, human chorionic gonadotropin; monophosphoryl lipid A + cell wall Sk of the lactic acid mycobacterium; mopidanol; a nitrogen mustard anti-cancer agent; indian ocean sponge B; a mycobacterial cell wall extract; myriapporone; n-acetyldinaline; an N-substituted benzamidine; nafarelin; nagrethip; naloxone + tebuconazole; napavin; naphterpin; a nartostim; nedaplatin; nemorubicin; neridronic acid; a linonactam; nisamycin; a nitrogen oxide modifier; a nitroxide antioxidant; nitrilyn; obblimmersen (Genasense); o6-benzylguanine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; an oral cytokine inducer; oxaliplatin; an oxateclone; oxaliplatin; oxaunomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; a Palau amine; palmitoyl rhizomycin; pamidronic acid; panaxatriol; panomifen; para-bacteriocin (paramactin); pazeliptin; a pemetrexed; peldesine (Peldesine); pentosan polysulfate sodium; pentostatin; pentrozole; perfluorobromoalkane; cultivating phosphoramide; sinapyl alcohol; phenazinomycin; phenyl acetate; a phosphatase inhibitor; a streptolysin; pilocarpine hydrochloride; pirarubicin; pirtroxine; placetinA; placetin B; inhibitors of plasminogen activation; synthesizing platinum; a platinum compound; synthesizing platinum-triamine; sodium porfimer; a podomycin; prednisone; propyldi-acridone; prostaglandin J2; a proteolytic degradation inhibitor; a protein a-based immunomodulator; inhibitors of protein kinase C; inhibitors of protein kinase C; microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; a glycoxethyl hemoglobin polyethylene oxide conjugate; a Raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; (ii) a Ras inhibitor; Ras-GAP inhibitors; demethylated reteplatin; sodium etidronate rhenium Re 186; rhizomycin; a ribozyme; RII retinoamide; rohitukine; romurtide; loquimex; rubiginone B1; ruboxyl; safrog; the Saintopin; SarCNU; sarcophylol A; sargrastim; sdi 1 mimetics; semustine; aging-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium boron carbonate; sodium phenyl acetate; solverol; a growth regulator binding protein; sonaming; a spa acid; spicamycin D; spiromustine; splenopentin; natural substance spongin 1; squalamine; a stipamide; a matrix lytic enzyme inhibitor; sulfinosine; a superactive vasoactive intestinal peptide antagonist; (ii) Suradista; suramin; adding indolizinetriol; tamustine; tamoxifen methyl iodide; taulomustine; tazarotene; sodium tegafur; tegafur; a Tellurapyrylium; a telomerase inhibitor; temoporfin; (ii) teniposide; tetrachlorodecane oxide; tetrazomine; thalblistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thymotreonam; thyroid stimulating hormone; tin (ll) ethyl porphyrin; tirapazamine; titanocene dioxide; topsentin; toremifene; a translation inhibitor; tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; tyrphostins; an UBC inhibitor; ubenimex; urogenital sinus growth inhibitory factor; a urokinase receptor antagonist; vapreotide; variolin B; vilareol; ver amine; verdins; verteporfin; vinorelbine; vinxaline; vitaxin; (ii) vorozole; zanoteron; zeniplatin; benzal vitamin C; and neat stastatin ester.

It is another object of the present invention to provide a process for preparing a pharmaceutical composition of the present invention, said process comprising combining a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

It is another object of the present invention to provide a pharmaceutical kit comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention.

Methods of treatment and uses

It is another object of the present invention to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression.

Another object of the present invention is to provide a use of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture of the same or the pharmaceutical composition of the present invention for the preparation of a medicament for the prevention or treatment of a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression.

It is another object of the present invention to provide a method for preventing or treating diseases caused by indoleamine 2, 3-dioxygenase (IDO) -mediated immunosuppression, which comprises administering a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention.

It is another object of the present invention to provide a method for preventing or treating diseases caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression, which comprises administering a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of the present invention, and one or more other therapeutic agents.

According to one embodiment of the present invention, the diseases caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression include, but are not limited to, cancer, viral infections, alzheimer's disease, depression, immune system disorders, and the like, as well as related conditions or disorders caused by the above-mentioned diseases. As used herein, the term "cancer" refers to a cell proliferative disease state, including but not limited to: leukemia, lymphoma, bladder cancer, bone cancer, brain tumor, medulloblastoma, glioma, breast cancer, adenoma/carcinoid, adrenocortical cancer, pancreatic islet cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, colorectal cancer, skin cancer, esophageal cancer, eye cancer, gallbladder cancer, gastric cancer, head and neck cancer, liver cancer, melanoma, kaposi's sarcoma, kidney cancer, oral cancer, lung cancer, nasopharyngeal cancer, neuroblastoma, ovarian cancer, pancreatic cancer, thyroid cancer, parathyroid penis cancer, prostate cancer, urinary tract cancer, vaginal cancer, vulvar cancer, anal cancer, sarcoma, and the like, including metastases of the foregoing cancers.

The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

As used herein, unless otherwise specified, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

As used herein, unless otherwise indicated, the term "preventing" means preventing additional symptoms, preventing a potential metabolic trigger of a symptom, inhibiting the disease or disorder, e.g., arresting the occurrence of a disease or disorder.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

In the present invention, diseases caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression include, but are not limited to, cancer, viral infections, alzheimer's disease, depression, other immune system disorders, and the like, as well as related conditions or diseases caused by such disorders.

Detailed Description

Examples

In order to make the objects and technical solutions of the present invention clearer, the present invention is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.

The abbreviations herein have the following meanings:

the structure of the compound is shown by¹HNMR or MS.¹The HNMR is determined by JEOL Eclipse 400 NMR instrument and CD as solvent₃OD、CDCl₃DMSO-d6, internal standard TMS. Chemical shifts (δ) are given in units of parts per million (ppm).

The MS measurement instrument was an Agilent (ESI) mass spectrometer, manufactured by Agilent, model number Agilent 6120B.

Preparative high performance liquid chromatography was prepared using Shimadzu LC-8A preparative liquid chromatography (YMC, ODS, 250X 20mml column).

Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20cm) from Merck was used, and thin layer chromatography separation and purification was performed using GF 254(0.4 to 0.5nm) from a cigarette bench.

The reaction was monitored by Thin Layer Chromatography (TLC) or LCMS. The developer system used included: a dichloromethane and methanol system, a normal hexane and ethyl acetate system, a petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to different polarities of the compounds or is adjusted by adding triethylamine and the like.

The microwave reaction used a BiotageInitiator + (400W, rt. about.300 ℃ C.) microwave reactor.

Column chromatography generally uses Qingdao ocean silica gel of 200-300 meshes as a carrier. The system of eluents comprises: the volume ratio of the solvent is adjusted according to different polarities of the compounds or a small amount of triethylamine is added for adjustment.

The reaction temperature was room temperature (20 ℃ C. to 30 ℃ C.) unless otherwise specified

The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Texas Chemical, and the like.

Example A:

3- (4- ((2-aminoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one-hydrochloride (114a)

First step of

Compound SM-1(0.50g, 4.76mmol), triethylamine (0.72g, 7.13mmol) and 10mL of dichloromethane were added to a 100mL single-neck flask, Troccl (0.44mL, 6.18mmol) was added dropwise under ice bath, the temperature was maintained at 5 ℃ or lower, and the flask was allowed to warm to room temperature and stirred overnight. Work-up gave compound SM-2(0.51g, crude) which was used directly in the next step.

Second step of

Adding the compound SM-3(13.20g, 0.20mol) and 280mL of 45 ℃ warm water into a 1L single-neck bottle, stirring at 45 ℃ to dissolve, cooling to 0 ℃, adding sodium nitrite (15.17g, 0.22mol) and 22mL of 6N hydrochloric acid, keeping the temperature of the system not higher than 5 ℃, continuously stirring for 15min in ice bath after dripping, and then moving to room temperature to stir for 1.5 h. And cooling to 0 ℃ again, dropwise adding 50% hydroxylamine aqueous solution (39.60g, 0.60mol), keeping the temperature not higher than 5 ℃, and after dropwise adding, moving to room temperature for further reaction for 1 h. 60mL of water was added to dissolve the solid, and the mixture was refluxed at 100 ℃ for 2 hours, and then stirred at room temperature overnight. The reaction solution was acidified to pH 7 in an ice bath to obtain 28.00g of a solid, which was then slurried to obtain compound SM-4(26.12g, yield: 91.3%).

The third step

Compound SM-4(10.00g, 0.07mol), distilled water 140mL, glacial acetic acid 70mL, 6N hydrochloric acid 35mL were added to a 500mL three-necked flask, the flask was placed at 60 ℃ to dissolve and clarify, the reaction solution was placed at 0 ℃, sodium chloride (12.26g, 0.21mol) was added, the mixture was stirred for 5min, 16.6mL of an aqueous solution of sodium nitrite (4.78g, 0.07mol) was added dropwise, the mixture was stirred at room temperature for 2h, and a large amount of solid was precipitated, yielding Compound SM-5(5.12g, yield: 45.0%).

The fourth step

Compound SM-5(2.61g, 16.08mmol), 3-bromo-4-fluoroaniline (2.60g, 13.67mmol), and 200mL of distilled water were charged into a 1L three-necked flask, stirred at 60 ℃ for 10min, 23mL of an aqueous solution of sodium bicarbonate (2.03g, 24.12mmol) was added dropwise thereto, and stirring was continued for 20min after completion of the dropwise addition, whereupon a large amount of solid was precipitated, yielding compound SM-6(7.88g, yield: 79.3%).

The fifth step

Compound SM-6(7.80g, 24.61mmol), CDI (4.39g, 27.07mmol), and 86mL of tetrahydrofuran were added to a 250mL single-neck flask and refluxed at 67 ℃ for 1 h. Post-treatment gave compound SM-7(8.44g, yield: 99.9%).

The sixth step

Dissolving compound SM-7(0.686g, 1mmol) and compound SM-2(1.07g, 1.4mmol) in DCM (2mL), adding TFA (2.35g, 19.6mmol) dropwise at a temperature not exceeding 20 deg.C, adding triethylsilane (0.581g, 2.5mmol) dropwise, and reacting at room temperature for 2 h. Cooled to-5 ℃, saturated aqueous sodium bicarbonate solution was added dropwise, pH was adjusted to 7-8, and post-treatment gave compound SM-8(950mg, crude) which was used directly in the next step.

Seventh step

Compound SM-8(0.1g, 0.17mmol) was dissolved in THF (2mL), and glacial acetic acid (0.108g, 1.8mmol), Zn (0.056g, 0.85mmol) were added and reacted at room temperature for 3 h. 1mL of hydrochloric acid was added, and the mixture was directly concentrated to obtain the title compound 114a (38mg, yield: 47.9%).

MS(ESI,m/z):385.0[M+H]⁺

Example B:

3- (4- (2-Aminoethoxy) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one hydrochloride (128a)

First step of

Adding the compound SM-7(10.00g, 29.33mmol) and trifluoroacetic acid (190mL, 2.56mol) into a 1L three-necked bottle, dropwise adding 30% hydrogen peroxide (114mL, 1.12mol) under the protection of Ar gas, moving to 45 ℃ after dropwise adding, and stirring overnight. Diluting with water, extracting with ethyl acetate, adjusting with saturated sodium sulfite under ice bath until the color of potassium iodide starch paper is not changed, and separating and purifying the crude product with silica gel column chromatography to obtain compound SM-9(7.3g, yield: 67.1%).

Second step of

The compound SM-9(0.58g, 1.56mmol), N- (tert-butoxycarbonyl) ethanolamine (0.50g, 3.12mmol), 2N sodium hydroxide solution (4.7mL, 9.35mmol) and 25mL of tetrahydrofuran were put in a 100mL single-neck flask and stirred at 40 ℃ until uniform. Work-up gave compound SM-10(0.60g, crude) which was used directly in the next step.

The third step

Compound SM-10(0.60g, 1.29mmol), CDI (0.42g, 2.59mmol), and 20mL of ethyl acetate were added to a 50mL single-neck flask and refluxed at 67 ℃ for 2 h. The crude product obtained by the post-treatment was separated and purified by silica gel column chromatography to give compound SM-11(0.25g, yield: 33.1%).

The fourth step

Compound SM-11(0.25g, 0.52mmol), 4N hydrochloric acid/1, 4-dioxane solution (2mL, 8.00mmol), and 4mL dichloromethane were added to a 10mL single-neck flask and stirred at room temperature for 2 h. The reaction was concentrated directly to afford the title compound 128a (203mg, crude).

MS(ESI,m/z):386.0[M+H]⁺

Example C:

3- (4- ((2-aminoethyl) thio) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one hydrochloride (130a)

First step of

Compound SM-9(2.0g, 5.4mmol), 2-tert-butoxycarbonylaminoethanethiol (1.43g, 8mmol), 2.0M sodium hydroxide solution (16mL, 32.4mmol), and tetrahydrofuran (40mL) were added to a 100mL single-neck flask and stirred at room temperature for 12 h. Work-up gave compound SM-12(2.5g, crude).

Second step of

Crude SM-12(2.5g), N-carbonyldiimidazole (1.28g, 7.9mmol), and tetrahydrofuran (25mL) were added to a 100mL single-neck flask and reacted at reflux for 2 h. The crude product obtained by the post-treatment was separated and purified by silica gel column chromatography to obtain Compound SM-13(2.1g, yield 78%).

The third step

Compound SM-13(2.1g, 41.9mmol) was dissolved in carbon dichloride (10mL), 4.0M HCl/1, 4-dioxane solution (10mL) was added under ice bath, and after the addition was complete, the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure at a low temperature to obtain a solid, which was then slurried to obtain compound 130a (1.7g, yield: 93%).

MS(ESI,m/z):502.0[M+H]⁺

Example D:

dimethylsulphonylsulfinyl dithioate (134a)

After adding a sodium hydroxide solution (1.4mL, 20M) to a DMF solution (10mL) of methanesulfonamide (2.0g, 21.0mmol) at room temperature for 30min, the reaction was cooled to 0 ℃ and carbon disulfide (0.8mL) was added and the reaction was maintained at 0 ℃ for 30 min. Then sodium hydroxide solution (0.65mL, 20M), carbon disulfide (0.4mL) was added. After the reaction is carried out for 30min at the temperature of 0 ℃, the temperature is slowly raised to room temperature for reaction for 30min, then the temperature is reduced to 0 ℃, and methyl iodide (2.6mL) is added into the reaction system. After keeping the temperature at 0 ℃ for reaction for 30min, the temperature is raised to room temperature for reaction for 1.5 h. Work-up gave the title compound 134a (2.2g, crude).

MS(ESI,m/z):199[M+H]⁺

Example E:

dimethylethylsulfonylthionyldithioate (177c)

Dissolving ethyl sulfonamide (4.0g, 36.7mmol) in N, N-dimethylformamide (20mL) at room temperature, adding sodium hydroxide solution (2.6mL, 20M), reacting for 0.5h, cooling the reaction system to 0 ℃, adding carbon disulfide (1.8mL), and reacting for 0.5h at 0 ℃; sequentially adding sodium hydroxide solution (1.2mL, 20M) and carbon disulfide (0.8mL), keeping the temperature at 0 ℃, stirring and reacting for 0.5h, slowly heating to room temperature and reacting for 0.5 h; then cooling the reaction system to 0 ℃, adding methyl iodide (4.6mL, 73.4mmol) into the reaction system, keeping the temperature at 0 ℃ for reaction for 0.5h, then heating to room temperature and stirring for reaction for 1.5 h. Work-up the crude product was isolated and purified by silica gel column chromatography to give the title compound 177c (3.62g, 46.1%).

MS(ESI,m/z):214.0[M+H⁺]

Example 1:

4- ((2- ((1-amino-2-nitrovinyl) amino) ethyl) amino) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (1)

First step of

Compound 114a (100mg, 0.23mmol), 114b (45mg,0.27mmol), triethylamine (70mg,0.69mmol), and ethanol (10mL) were placed in a 50mL reaction flask, and the temperature was raised to 78 ℃ for 2h under reflux. The reaction mixture was concentrated under reduced pressure to give compound 114c (102mg, crude) which was used directly in the next step.

Second step of

The crude compound 114c (102mg) was dissolved in 10mL of ethanol, 7.0M ammonia in ethanol (0.17mL,1.48mmol) was added dropwise, and after the addition, the reaction was refluxed at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 1(6mg, yield: 5.9%).

MS(ESI,m/z):445[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.87(s,1H),8.89(s,1H),8.37(s,1H),7.33(t,J＝8.8 Hz,1H),7.25(dd,J＝6.3,2.2Hz,1H),7.18(t,J＝8.7Hz,1H),7.11(dd,J＝6.0,2.5Hz,1H),7.09(s,1H),6.97(dd,J＝12.3,4.0Hz,1H),6.75(dd,J＝7.7,4.4Hz,1H),6.47(s,1H),6.35(d,J＝8.9Hz,1H),3.34(m,4H).

Example 2:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (cyclopropylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (2)

First step of

Adding 173a (2g, 16.5mmol) and DMF (15mL) into a 50mL reaction bottle, stirring at room temperature for 5min, adding 20M sodium hydroxide (1.65mL, 33mmol), cooling to 0 ℃, reacting for 0.5h, adding carbon disulfide (1mL, 16.5mmol), moving to room temperature, reacting for 0.5h, cooling to 0 ℃, adding methyl iodide (2mL, 33mmol), reacting for 20min at 0 ℃, and moving to room temperature, reacting for 1.5 h. The crude product obtained by the post-treatment was isolated and purified by silica gel column chromatography to give compound 173b (2.3g, yield: 62%).

Second step of

Compound 166c (150mg, 0.42mmol), compound 173b (141mg,0.63mmol), DMF (5mL), and triethylamine (85mg, 0.84mmol) were sequentially added to a 50mL reaction flask, the temperature was raised to 70 ℃ to react for 2h, and ammonia (1mL,25.96mmol) was added to react at 70 ℃ overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 2(45mg, yield: 21%).

MS(ESI,m/z):505.0[M+H]⁺

¹H NMR(400MHz,DMSO-d6)11.48(s,1H),8.91(s,1H),7.19(t,J＝8.8Hz,1H),7.11(dd,J＝6.1,2.8Hz,1H),7.08–6.47(m,4H),6.29(s,1H),3.34–3.25(m,4H),2.46(s,1H),0.81(d,J＝8.8Hz,4H).

Example 3:

n- (3-bromo-4-fluorophenyl) -4- ((2- (3, 3-dimethyl-2- (methylsulfonyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (3)

First step of

Compound 166c (100mg,0.28mmol) was dissolved in DMF (5mL), and triethylamine (0.18mL,1.25mmol) and compound 134a (83mg,0.42mmol) were added in that order to react at 70 ℃ for 2 h. After disappearance of the starting material, concentration under reduced pressure gave compound 169a (124mg, crude) which was used directly in the next step.

Second step of

Compound 169a (124mg, crude) was dissolved in aqueous dimethylamine (0.5mL) and reacted at 60 ℃ for 2 h. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 3(28mg, yield: 14.5%).

MS(ESI,m/z)：507.3[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.88(s,1H),8.40(s,1H),7.26(s,1H),7.20(t,J＝8.8Hz,1H),7.13(dd,J＝5.9,2.4Hz,1H),3.49(s,4H),2.96(s,6H),2.86(s,3H).

Example 4:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) -3- (2,2, 2-trifluoroethyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (4)

Compound 169a (129mg, crude) was dissolved in aqueous trifluoroethylamine (0.5mL) and reacted at 60 ℃ for 2 h. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 4(35mg, yield: 11.7%).

MS(ESI,m/z)：561.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.45(s,1H),8.91(s,1H),7.55(d,J＝43.7Hz,2H),7.18(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.7Hz,1H),6.77(m,1H),6.32(t,J＝5.3Hz,1H),4.04(s,2H),3.42(s,4H),2.80(s,3H).

Example 5:

n- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N '-hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) mercapto) ethyl) -N' - (methylsulfonyl) morpholine-4-carboxamidine (5)

Compound 152b (20mg, 0.04mmol), morpholine (7mg,0.08mmol), DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 5(4mg, yield: 17.6%).

MS(ESI,m/z):566.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),8.99(s,1H),7.45(t,J＝4.9Hz,1H),7.18(t,J＝8.8Hz,1H),7.11(dd,J＝5.9,2.6Hz,1H),6.74–6.67(m,1H),3.66–3.53(m,6H),3.47–3.35(m,6H),2.84(s,3H).

Example 6:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (2- (2- (methylsulfonyl) guanidine) ethoxy) -1,2, 5-oxadiazole-3-carboxamidine (6)

A solution of compound 128a (100mg, 0.26mmol), compound 134a (77mg, 0.39mmol) and triethylamine (53mg, 0.52mmol) in acetonitrile was reacted at 70 ℃ for 16 h. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, and then an aqueous ammonia solution (0.5mL, 20%) was added thereto, and the temperature was raised to 90 ℃ for reaction for 4 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 6(15mg, yield: 12%).

MS(ESI,m/z)：480.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.45(s,1H),9.01(s,1H),7.18(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.7Hz,1H),6.92(s,1H),6.72(ddd,J＝8.8,4.0,2.8Hz,2H),4.27(t,J＝5.2Hz,2H),3.43–3.38(m,2H),2.79(s,3H).

Example 7:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (2- (2- (methylsulfonyl) guanidine) ethylthio) -1,2, 5-oxadiazole-3-carboxamidine (7)

A solution of compound 130a (100mg, 0.25mmol), compound 134a (75mg, 0.37mmol) and triethylamine (66mg, 0.65mmol) in acetonitrile was reacted at 70 ℃ for 16 h. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, and then an aqueous ammonia solution (0.5mL, 20%) was added thereto, and the temperature was raised to 90 ℃ for reaction for 4 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 7(15mg, yield: 8%).

MS(ESI,m/z)：496.0[M+H⁺].

¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),8.99(s,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),7.01(d,J＝8.9Hz,1H),6.77–6.56(m,3H),3.47(dd,J＝12.0,6.0Hz,2H),3.32–3.28(m,2H),2.79(s,3H).

Example 8:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (2,2, 2-trifluoroethyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (8)

First step of

Compound 114a (1.00g, 2.38mmol), DIPEA (0.98mL, 5.94mmol) and 15mL of anhydrous acetonitrile were put into a 50mL single-neck flask, and after stirring at room temperature, benzoylthioisocyanate (503mg, 3.88mmol) was added, and after completion of the addition, the reaction was allowed to proceed at room temperature overnight. The crude product obtained by the post-treatment was purified by silica gel column chromatography to give compound 136b (0.8g, yield: 61.5%).

Second step of

Compound 136b (0.60g, 1.09mmol), methanol (18 mL), and water (5mL) were placed in a 50mL single-neck flask, and after stirring at room temperature, sodium hydroxide (438mg, 10.92mmol) was added, and after completion of the addition, the reaction was continued at room temperature for 2 hours. The crude product obtained by the post-treatment was separated and purified by silica gel column chromatography to give compound 136c (0.45g, yield: 99.3%).

The third step

Compound 136c (0.20g, 0.48mmol), methyl iodide (0.59mL, 9.60mmol), and 10mL of anhydrous methanol were added to a 50mL single-neck flask and stirred at 60 ℃ for 2 h. The reaction was concentrated under reduced pressure to give compound 136d (0.28g, crude) which was used directly in the next step.

The fourth step

Compound 136d (0.13g, 0.30mmol), tetrahydrofuran 2.5mL, and trifluoroethylamine (1.0mL, 12.74mmol) were added to a 10mL one-neck flask and reacted at 66 ℃ overnight. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 8(20mg, yield: 18.9%).

MS(ESI,m/z):483.0[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.02(s,1H),8.86(s,1H),8.40(s,1H),8.29–7.64(m,2H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.1,2.7Hz,1H),6.77(ddd,J＝8.9,4.1,2.8Hz,1H),6.52(s,1H),4.06(q,J＝9.3Hz,2H),3.37(s,4H).

Example 9:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (9)

First step of

Compound 139a (100mg,0.24mmol) was dissolved in acetonitrile (2mL), and triethylamine (83uL,0.60mmol) and compound 139b (96mg,0.48mmol) were added in that order to conduct a reaction under reflux. After the starting material disappeared, the reaction solution was concentrated under reduced pressure to give compound 139c (129mg, crude) which was used directly in the next step.

Second step of

Compound 139c (129mg,0.24mmol) was dissolved in aqueous ammonia (2mL) and reacted at 90 ℃ for 2h with a sealed tube. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 9(26mg, yield: 25%).

MS(ESI,m/z)：479.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),8.90(s,1H),7.19(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.4Hz,1H),6.92(brs,1H),6.80-6.74(m,1H),6.66(brs,1H),2.79(s,3H),2.00(q,J＝7.6Hz,2H).

Example 10:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2((1- (methylamino) -dinitrovinyl) -amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (10)

Compound 114a (100mg,0.24mmol), compound 114b (59mg,0.36mmol), and triethylamine (49mg,0.48mmol) were added in this order to 5ml of ethanol, and reacted at 80 ℃ for 2 hours. After the raw materials are reacted, the temperature is reduced to 60 ℃, 1ml of methylamine water solution is added, and the reaction is continued for 2 hours at the temperature of 60 ℃. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 10(25mg, yield: 23%).

MS(ESI,m/z)：459.4[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),10.20(s,1H),8.92(s,1H),7.31(d,J＝8.5Hz,1H),7.18(t,J＝8.8Hz,1H),7.12(dd,J＝6.0,2.5Hz,1H),6.80–6.71(m,1H),6.63(d,J＝42.8Hz,1H),6.41(s,1H),3.52(d,J＝33.0Hz,3H),3.31–3.13(m,4H).

Example 11:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2(((1- (2-hydroxyethyl) amino) -dinitrovinyl) -amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (11)

Compound 114a (100mg,0.24mmol), compound 114b (59mg,0.36mmol), and triethylamine (49mg,0.48mmol) were added in this order to 5ml of ethanol, and reacted at 80 ℃ for 2 hours. After the raw materials are reacted, the temperature is reduced to 60 ℃,0.5 ml of ethanolamine is added, and the reaction is continued for 2 hours at the temperature of 60 ℃. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 11(20mg, yield: 17%).

MS(ESI,m/z)：489[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),9.95(s,1H),8.93(s,1H),7.35–7.21(m,1H),7.18(t,J＝8.8Hz,1H),7.12(dd,J＝6.0,2.6Hz,1H),6.78–6.71(m,1H),6.56(d,J＝86.6Hz,1H),6.40(s,1H),3.46(s,5H),2.78(d,J＝48.3Hz,4H).

Example 12:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (2- (2- (2,2, 2-trifluoroethyl) guanidino) ethoxy) -1,2, 5-oxadiazole-3-carboxamidine (12)

First step of

Compound 128a (0.35g, 0.83mmol), DIPEA (0.34mL, 2.08mmol) and 6mL of anhydrous acetonitrile were charged into a 25mL single-neck flask, and after stirring at room temperature, benzoylthioisocyanate (176mg, 1.08mmol) was added, and after completion of addition, the reaction was continued at room temperature overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give compound 149b (102mg, yield: 22.5%).

Second step of

Compound 149b (102mg, 0.19mmol), methanol 9mL, and water 2.5mL were charged into a 25mL single-neck flask, and after stirring at room temperature, sodium hydroxide (76mg, 1.90mmol) was added, and after completion of the addition, the reaction was continued at room temperature for 2 h. The crude product obtained by the post-treatment was isolated and purified by thin layer chromatography to give compound 149c (61mg, yield: 76.3%).

The third step

Compound 149c (61mg, 0.15mmol), methyl iodide (0.18mL, 2.93mmol), and 5mL of anhydrous methanol were charged into a 25mL single-necked flask and reacted at 60 ℃ for 2 h. The reaction was concentrated under reduced pressure to give 149d (70mg, crude) which was used directly in the next step.

The fourth step

The crude compound 149d (70mg, 0.16mmol), tetrahydrofuran 1.5mL, and trifluoroethylamine (1.5mL, 19.11mmol) were added to a 10mL single-necked flask and reacted at 66 ℃ overnight. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 12(29mg, yield: 39.9%).

MS(ESI,m/z):484.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.56(s,1H),9.01(s,1H),8.66–7.45(m,3H),7.20–7.06(m,2H),6.79–6.69(m,1H),4.35(t,J＝5.0Hz,2H),4.12–3.95(m,2H),3.50(s,2H).

Example 13:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (2,2, 2-trifluoroethyl) guanidino) ethyl) thio) -1,2, 5-oxadiazole-3-carboxamidine (13)

First step of

Compound 130a (0.35g, 0.80mmol), DIPEA (0.33mL, 2.00mmol) and 6mL of anhydrous acetonitrile were put into a 25mL single-neck flask, and after stirring at room temperature, benzoylthioisocyanate (169mg, 1.04mmol) was added, and after completion of the addition, the reaction was continued at room temperature overnight. The crude product obtained by the post-treatment was isolated and purified by silica gel column chromatography to give compound 150b (0.30g, yield: 66.4%).

Second step of

Compound 150b (0.30g, 0.53mmol), methanol 10mL, and water 3mL were added to a 25mL single-neck flask, and after stirring at room temperature, sodium hydroxide (212mg, 5.30mmol) was added, and after completion of the addition, the reaction was continued at room temperature for 2 h. The crude product obtained by the post-treatment was isolated and purified by thin layer chromatography to give compound 150c (192mg, yield: 83.1%).

The third step

Compound 150c (192mg, 0.44mmol), methyl iodide (0.54mL, 8.79mmol), and 10mL of dry methanol were added to a 25mL single-necked flask and reacted at 60 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 150d (202mg, crude) which was used directly in the next step.

The fourth step

Compound 150d (202mg, 0.45mmol), tetrahydrofuran 2.5mL, and trifluoroethylamine (2.5mL, 31.85mmol) were added to a 25mL one-neck flask and reacted at 66 ℃ overnight. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 13(102mg, yield: 46.4%).

MS(ESI,m/z):500.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.81(s,1H),8.99(s,1H),8.36(s,1H),8.05(s,1H),7.17(t,J＝8.6Hz,1H),7.11(dd,J＝5.9,2.5Hz,1H),6.78–6.65(m,1H),4.04(d,J＝9.3Hz, 2H),3.53(d,J＝6.1Hz,2H),3.33(s,2H).

Example 14:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((2-nitro-1- (anilino) vinyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (14)

First step of

Compound 114b (100mg, 0.61mmol), aniline (62mg,0.67mmol), and ethanol (50mL) were added to a microwave tube and reacted at 85 ℃ for 2 h. The reaction was cooled to room temperature and compound 151a (181mg, crude) was concentrated under reduced pressure and used directly in the next step.

Second step of

Compound 114a (80mg, 0.19mmol), crude compound 151a (90mg), triethylamine (58mg,0.57mmol), and ethanol (15mL) were added to a 50mL reaction flask, and the mixture was heated to 78 ℃ for reflux reaction for 18 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and separated by silica gel column chromatography to give compound 151b (43mg, yield: 41%).

The third step

Compound 151b (43mg, 0.079mmol) was dissolved in tetrahydrofuran/water (6mL/2mL), and lithium hydroxide (10mg,0.24mmol) was added thereto, followed by reaction at room temperature for 2 hours. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 14(12mg, yield: 29%).

MS m/z(ESI):521.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.49(s,1H),10.40-10.28(m,1H),9.13-9.02(m,1H),8.94(s,1H),7.45(t,J＝7.7Hz,2H),7.32(t,J＝7.4Hz,1H),7.31-7.18(m,2H),7.21–7.09(m,2H),6.78–6.68(m,1H),6.44(t,J＝5.8Hz,1H),6.17-6.02(m,1H),3.70-3.56(m,2H),3.61-3.53(m,2H).

Example 15:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (2- (3-methyl-2- (methylsulfonyl) guanidino) ethylthio-1, 2, 5-oxadiazole-3-carboxamidine (15)

First step of

Compound 130a (150mg, 0.34mmol) was dissolved in methanol (5mL), and sodium hydroxide solution (2M) was added to the reaction solution until the pH was 12 to 13, and the reaction was carried out at room temperature for 30 min. Work-up afforded compound 152a (120mg, crude) which was used directly in the next step.

Second and third step

Compound 152a (70mg, 0.17mmol) and compound 134a (53mg, 0.26mmol) were dissolved in DMF (3mL), DIPEA (47mg, 0.34mmol) was added and reacted at 50 ℃ for 2 h. After the reaction of the raw materials is finished, one fourth of the reaction solution is taken, and aqueous methylamine solution (0.5mL, 40%) is added to continue the reaction at 50 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure, and then separated and purified by high performance liquid chromatography to give the title compound 15(5mg, yield: 23%).

MS m/z(ESI):510.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),8.99(s,1H),7.18(t,J＝8.7Hz,2H),7.10(dd,J＝6.0,2.7Hz,1H),7.05(d,J＝4.8Hz,1H),6.75–6.65(m,1H),3.52(dd,J＝12.0,6.0Hz,2H),3.33–3.28(m,2H),2.78(s,3H),2.69(d,J＝4.6Hz,3H).

Example 16:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (3- (2-hydroxyethyl) -2- (methylsulfonyl) guanidino) ethylthio) -1,2, 5-oxadiazole-3-carboxamidine (16)

Compound 152b (19mg, 0.45mmol) was dissolved in t-butanol, ethanolamine (15mg, 0.27mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and then separated and purified by high performance liquid chromatography to give the title compound 16 (50mg, yield: 50%).

MS m/z(ESI):540.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.76(s,1H),8.99(s,1H),7.31(s,1H),7.25–7.13(m,2H),7.13–7.05(m,1H),6.71(dd,J＝8.4,3.0Hz,1H),4.96(s,1H),3.56–3.46(m,4H),3.34–3.29(m,2H),3.17(s,2H),2.80(d,J＝2.3Hz,3H),2.54(d,J＝2.7Hz,1H).

Example 17:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2-cyanoguanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (17)

Compound 114a (100mg,0.24mmol) was dissolved in t-butanol (2mL), and sodium dicyandiamide (26mg,0.29mmol) was added to the solution, and the reaction was refluxed. After the raw materials disappeared, the system was cooled to room temperature, and 2N NaOH aqueous solution (0.2mL) was added to react at room temperature for 30 min. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 17(31mg, yield: 30%).

MS(ESI,m/z)：426.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆):δ11.45(brs,1H),8.90(s,1H),7.19(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.4Hz,1H),7.07-6.58(m,4H),6.26(t,J＝5.26Hz,1H),3.32-3.25(m,4H).

Example 18:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (isopropylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (18)

First step of

Adding the compound 168a (500mg, 4.06mmol) and DMF (7.50mL) into a 50mL reaction bottle, stirring for 5min at room temperature, adding 20M sodium hydroxide (0.41mL, 8.12mmol), cooling to 0 ℃, reacting for 0.5h, adding carbon disulfide (0.25mL, 4.06mmol), moving to room temperature, reacting for 0.5h, cooling to 0 ℃, adding methyl iodide (0.51mL, 8.12mmol), reacting for 20min at 0 ℃, moving to room temperature, and reacting for 1.5 h. Work-up gave compound 168b (0.90g, crude) which was used directly in the next step.

Second step of

Compound 114a (336mg, 0.80mmol), compound 168b (200mg,0.88mmol), acetonitrile (5mL), and triethylamine (0.33mL, 2.40mmol) were sequentially charged into a 50mL reaction flask, the temperature was raised to 50 ℃ to react for 3 hours, compound 114a (84mg, 0.20mmol) and triethylamine (0.15mL, 1.10mmol) were further added to react at 50 ℃ for 1.5 hours, and the reaction mixture was cooled and used in the next step.

The third step

To the reaction solution containing compound 168c, ammonia water (1mL,25.96mmol) was added, the reaction was carried out at 50 ℃ for 1.5h, ammonia water (1mL,25.96mmol) was added, the temperature was raised to 75 ℃ and the reaction was carried out under reflux for 2.5h, ammonia water (1mL,25.96mmol) was further added, and the temperature was raised to 85 ℃ and the reaction was carried out overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 18(50mg, two-step yield: 12.4%).

MS(ESI,m/z):507.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.90(s,1H),7.19(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.6Hz,1H),7.03–6.50(m,4H),6.30(s,1H),3.36(m,4H),3.04–2.88(m,1H),1.18(d,J＝6.7Hz,6H).

Example 19:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((1- (tert-butylamino) -2-nitro) amino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (19)

First step of

Compound 114b (100mg, 0.61mmol), tert-butylamine (68mg,0.92mmol), triethylamine (185mg, 1.83mmol) and ethanol (8mL) were added to a microwave tube and reacted at 85 ℃ for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give compound 156a (126mg, crude).

Second step of

Compound 114a (80mg, 0.19mmol), compound 156a (126mg, crude), triethylamine (58mg,0.57mmol), and ethanol (15mL) were added to a 50mL reaction flask, and the temperature was raised to 78 ℃ for reflux reaction for 18 h. Work-up gave compound 156b (45mg, crude).

The third step

Compound 156b (45mg, crude) was dissolved in tetrahydrofuran/water (6mL/2mL), lithium hydroxide (7mg,0.17mmol) was added, and the reaction was continued at room temperature for 2 h. The crude product obtained by the post-treatment was purified by high performance liquid chromatography to give the title compound 19(5mg, three-step total yield: 5.3%).

MS(ESI,m/z):501.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.45(s,1H),10.62(s,1H),8.91(s,1H),7.19(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.6Hz,1H),6.78–6.58(m,3H),6.47–6.38(m,1H),3.48–3.35(m,4H),1.36(s,9H).

Example 20:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2 ((((1- (2-hydroxyethyl) amino) -dinitrovinyl) -amino) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (20)

Compound 152a (100mg, 0.66mmol), compound 114b (66mg,0.39mmol), triethylamine (54mg,0.53mmol), and ethanol (5mL) were added to a 50mL reaction flask, and the temperature was raised to 85 ℃ for 2h under reflux. Then the temperature is reduced to 60 ℃,0.2 ml of ethanolamine is added, and the reaction lasts for 12 hours at 60 ℃ after the addition is finished. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 20(10mg, yield: 7.4%).

MS(ESI,m/z):406.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.77(s,1H),10.22(s,1H),8.99(s,1H),7.43(s,1H),7.18(t,J＝8.8Hz,1H),7.11(d,J＝3.2Hz,1H),6.68(m,2H),4.97(s,1H),3.75–3.47(m,4H),3.33–3.13(m,4H).

Example 21:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2 ((-dinitro-1- (phenylamino) vinyl) amino) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (21)

First step of

Compound 114b (165mg, 1mmol), aniline (112mg,1.2mmol), triethylamine (303mg,3mmol), and ethanol (5mL) were added to a 20mL microwave tube and reacted at 85 ℃ for 2 h. The reaction solution was concentrated under reduced pressure and used directly in the next reaction.

Second step of

Compound 151a (100mg, 0.266mmol), compound 152a (2mL,0.39mmol), triethylamine (54mg,0.53mmol), and ethanol (3mL) were added to a 50mL reaction flask, and the temperature was raised to 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 21(7mg, yield: 4.9%).

MS(ESI,m/z):538.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.80(s,1H),10.29(s,1H),9.31(s,1H),8.99(s,1H),7.45(t,J＝7.7Hz,2H),7.36–7.23(m,3H),7.16(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.4Hz,1H),6.68(dd,J＝7.6,4.8Hz,1H),6.11(s,1H),3.81(s,2H),3.50(s,2H).

Example 22:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((1- (tert-butylamino) -2-nitro) amino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (22)

First step of

Compound 114b (100mg, 0.61mmol), tert-butylamine (68mg,0.92mmol), triethylamine (185mg, 1.83mmol) and ethanol (8mL) were added to a microwave tube and reacted at 85 ℃ for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give compound 156a (117mg, crude).

Second step of

Compound 130a (80mg, 0.18mmol), compound 156a (117mg, crude), triethylamine (55mg,0.54mmol), and ethanol (15mL) were added to a 50mL reaction flask, and the temperature was raised to 78 ℃ for reflux reaction for 18 h. Work-up gave compound 159a (15mg, crude).

The third step

Compound 159a (15mg, crude) was dissolved in tetrahydrofuran/water (6mL/2mL), lithium hydroxide (3mg,0.07mmol) was added, and the reaction was continued at room temperature for 2 h. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 22(1mg, three-step total yield: 1.1%).

MS(ESI,m/z):518.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.78(s,1H),11.42(s,1H),8.99(s,1H),8.59(s,1H),7.20–7.11(m,2H),6.78–6.69(m,1H),6.42–6.31(m,1H),3.73–3.52(m,4H),1.13–1.02(m,9H).

Example 23:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) -3-phenylguanidino) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (23)

First step of

Compound 134a (200mg, 1.00mmol), aniline (81mg,0.90mmol), triethylamine (400mg,4.00mmol), and ethanol (2mL) were placed in a 5mL microwave tube, and the temperature was raised to 90 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give compound 160a (50mg, yield: 20.4%).

Second step of

Compound 160a (50mg, 0.20mmol), compound 152a (74mg,0.20mmol), DIPEA (51mg,0.40mmol) were dissolved in DMF (2mL) and reacted at 70 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 23(40mg, yield: 35.0%).

MS(ESI,m/z):572.0[M+H]⁺。

¹H NMR(400MHz,DMSO-d₆)δ11.76(s,1H),8.99(s,1H),8.74(s,1H),7.44–7.25(m,5H),7.24–7.13(m,2H),7.10(dd,J＝6.0,2.7Hz,1H),6.72–6.65(m,1H),3.64(s,2H),3.40(d,J＝6.0Hz,2H),2.89(s,3H).

Example 24:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) -3-cyclohexylguanidino) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (24)

Compound 152b (20mg, 0.04mmol), cyclohexylamine (6mg,0.06mmol), DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 24(4mg, yield: 17.3%).

MS(ESI,m/z):578.0[M+H]⁺.

¹H NMR(400MHz,CD₃OD)δ7.08(dd,J＝5.9,2.7Hz,1H),7.04(t,J＝8.7Hz,1H),6.80–6.74(m,1H),3.61(t,J＝6.3Hz,2H),3.36(t,J＝6.5Hz,2H),2.89(s,3H),1.89(d,J＝10.0Hz,2H),1.73(d,J＝12.8Hz,2H),1.59(s,1H),1.42–1.22(m,6H).

Example 25:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) -3-isopropylpiperidinyl) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (25)

Compound 152b (20mg, 0.04mmol), isopropylamine (5mg,0.08mmol), DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 25(4mg, yield: 18.1%).

MS(ESI,m/z):538.0[M+H]⁺.

¹H NMR(400MHz,CD₃OD)δ7.08(dd,J＝5.9,2.5Hz,1H),7.04(t,J＝8.7Hz,1H),6.80–6.72(m,1H),3.61(t,J＝6.4Hz,2H),3.36(t,J＝6.5Hz,2H),2.89(s,3H),1.20(d,J＝6.4Hz,6H).

Example 26:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) -3-tert-butylpipetyl) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (26)

Compound 152b (20mg, 0.04mmol), tert-butylamine (14mg,0.20mmol) and DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted in a sealed tube at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 26(4mg, yield: 16.9%).

MS(ESI,m/z):552.0[M+H]⁺.

¹H NMR(400MHz,CD₃OD)δ7.08(dd,J＝5.9,2.7Hz,1H),7.04(t,J＝8.6Hz,1H),6.80–6.75(m,1H),3.62(t,J＝6.7Hz,2H),3.35(t,J＝6.9Hz,2H),2.90(s,3H),1.40(s,9H).

Example 27:

n- (3-bromo-4-fluorophenyl) -N '-hydroxy-4- ((2- (2-N' - (methylsulfonyl) piperidine-1-carbamimidoyl) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (27)

Compound 152b (20mg, 0.04mmol), piperidine (7mg,0.08mmol), DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 27(5mg, yield: 22.1%).

MS(ESI,m/z):564.0[M+H]⁺.

¹H NMR(400MHz,CD₃OD)δ7.09(dd,J＝5.9,2.7Hz,1H),7.04(t,J＝8.7Hz,1H),6.80–6.73(m,1H),3.68(t,J＝6.4Hz,2H),3.46–3.41(m,4H),3.36(t,J＝6.4Hz,2H),2.96(s,3H),1.67–1.56(m,6H).

Example 28:

n- (3-bromo-4-fluorophenyl) -4- ((2- (-2-benzenesulfonylguanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (28)

First step of

Compound 166a (3.14g,20.0mmol) was dissolved in DMF (10mL), 20.0M aqueous NaOH (1.4mL,28.0mmol) was added, the mixture was stirred at room temperature for 0.5h, the system was cooled to 0 ℃ and CS was added₂(0.8mL,13.3mmol), reacting at 0 deg.C for 0.5h, and sequentially adding 20.0M NaOH aqueous solution (0.6mL,12.0mmol) and CS₂(0.4mL,6.7mmol), stirring was continued at 0 ℃ for 0.5h and then warmed to room temperature for 0.5 h. Then, the reaction was cooled to 0 ℃ and MeI (2.5mL,40.0mmol) was added and the resulting system was stirred at 0 ℃ for 0.5h and allowed to warm to room temperature for 1.5 h. Work-up gave compound 166b (4.8g, crude) which was used directly in the next step.

Second step of

Compound 114a (210mg,0.50mmol) was dissolved in methanol (5mL), and 2.0M aqueous NaOH (0.5mL,1.0mmol) was added and reacted at room temperature for 0.5 h. Work-up gave compound 166c (180mg, crude) which was used directly in the next step.

The third step

Compound 166c (180mg,0.50mmol) was dissolved in acetonitrile (5mL), and triethylamine (0.18mL,1.25mmol) and compound 166b (261mg,1.0mmol) were added in this order to react at 70 ℃ for 1 h. After disappearance of the starting material, concentration under reduced pressure gave compound 166d (286mg, crude) which was used directly in the next step.

The fourth step

Compound 166e (286mg,0.5mmol) was dissolved in aqueous ammonia (5mL) and reacted at 60 ℃ for 2 h. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 28(16mg, yield: 5.2%).

MS(ESI,m/z)：541.4[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.33(brs,1H),9.26(s,1H),8.29(s,1H),7.74(dd,J＝5.2,1.6Hz,2H),7.49-7.33(m,6H),7.25(t,J＝7.6Hz,2H),3.94(t,J＝8.0Hz,2H),3.65(t,J＝8.0Hz,2H).

Example 29:

n- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -N "- (methylsulfonyl) -2-oxa-6-aza-spiro [3.3] heptane-6-carboxamidine (29)

Compound 166c (100mg,0.28mmol), compound 134a (141mg,0.63mmol), DMF (3mL), and triethylamine (57mg,0.56mmol) were sequentially added to a 50mL reaction flask, the temperature was raised to 70 ℃ to react for 2h, 172a (159mg,0.84mmol) and DIPEA (200mg) were then added, the temperature was raised to 80 ℃ to react for 3h, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 29(17mg, yield: 8.3%).

MS(ESI,m/z):561.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.39(s,1H),8.90(s,1H),7.19(t,J＝8.8Hz,1H),7.13(dd,J＝6.0,2.8Hz,1H),6.85(s,1H),6.82–6.77(m,1H),6.35(t,J＝5.2Hz,1H),4.66(s,4H),4.29(s,4H),3.31(s,4H),2.81(s,3H).

Example 30:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (cyclopropylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (30)

First step of

Adding 173a (2g, 16.5mmol) and DMF (15mL) into a 50mL reaction flask, stirring at room temperature for 5min, adding 20M sodium hydroxide (1.65mL, 33mmol), cooling to 0 ℃ to react for 0.5h, adding carbon disulfide (1mL, 16.5mmol), moving to room temperature to react for 0.5h, cooling to 0 ℃, adding methyl iodide (2mL, 33mmol), reacting at 0 ℃ for 20min, moving to room temperature to react for 1.5h, and separating and purifying the crude product obtained after the post-treatment by silica gel column chromatography to obtain 173b (2.3g, yield: 62%).

Second step of

Compound 166c (150mg, 0.42mmol), compound 173b (141mg,0.63mmol), DMF (5mL), and triethylamine (85mg, 0.84mmol) were sequentially added to a 50mL reaction flask, the temperature was raised to 70 ℃ to react for 2h, and ammonia (1mL,25.96mmol) was added to react at 70 ℃ overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 30(45mg, yield: 21%).

MS(ESI,m/z):505.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)11.48(s,1H),8.91(s,1H),7.19(t,J＝8.8Hz,1H),7.11(dd,J＝6.1,2.8Hz,1H),7.08–6.47(m,4H),6.29(s,1H),3.34–3.25(m,4H),2.46(s,1H),0.81(d,J＝8.8Hz,4H).

Example 31:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2-carbamoylguanidine) ethyl) thio) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (31)

Compound 133b (33mg, 0.08mmol), dioxane (3.0mL), and concentrated hydrochloric acid (1.0mL) were sequentially added to a 10mL reaction flask, the temperature was raised to 45 ℃ to react for 4.5 hours, the reaction solution was cooled, 2N sodium hydroxide was added to adjust the system pH to 12, the reaction was carried out at room temperature for 1 hour, glacial acetic acid was adjusted the system pH to 7, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 31(3mg, yield: 8.6%).

MS(ESI,m/z):461.0[M+H⁺]。

¹H NMR(400MHz,DMSO)δ11.81(s,1H),8.99(s,1H),8.30(s,1H),8.17–7.42(m,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),6.71–6.67(m,1H),6.18(s,1H),3.53(t,J＝5.8Hz,2H),3.34(t,J＝6.2Hz,2H).

Example 32:

n- (3-bromo-4-fluoroaniline) -4- ((2- (3, 3-dimethyl-2- (methylsulfonyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (32)

Compound 152b (30mg, 0.06mmol), aqueous dimethylamine solution (20mg,0.44mmol), and DIPEA (30mg,0.23mmol) were dissolved in DMF (1mL) and reacted at 70 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 32(3mg, yield: 9.6%).

MS(ESI,m/z):524.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.72(s,1H),8.99(s,1H),7.27(t,J＝5.5Hz,1H), 7.18(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.7Hz,1H),6.69(ddd,J＝8.8,4.0,2.8Hz,1H),3.62(dd,J＝12.0,6.2Hz,2H),3.33–3.31(m,2H),2.95(s,6H),2.81(s,3H).

Example 33:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (ethylsulfonyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (33)

Compound 166c (100mg,0.28mmol), compound 177a (87.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, ammonia (2mL) was added, the temperature was raised to 55 ℃ to react overnight, and the crude product obtained by the after-treatment was isolated and purified by high performance liquid chromatography to give the title compound 33(15mg, yield: 10.9%).

MS(ESI,m/z):493.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),8.91(s,1H),7.20(t,J＝8.8Hz,1H),7.11(dd,J＝6.1,2.7Hz,1H),7.06–6.47(m,4H),6.32–6.28(m,1H),3.41–3.30(m,4H),2.90–2.71(m,2H),1.16(t,J＝7.3Hz,3H).

Example 34:

n- (3-bromo-4-fluorophenyl) -4- ((2- (3-cyclopropyl-2- (methylsulfonyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (34)

Compound 152b (20mg, 0.04mmol), cyclopropylamine (5mg,0.07mmol), DIPEA (20mg,0.15mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 34(5mg, yield: 23.3%).

MS(ESI,m/z):536.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),8.99(s,1H),7.36(d,J＝5.6Hz,1H),7.18(t,J＝8.8Hz,2H),7.10(dd,J＝6.0,2.7Hz,1H),6.73–6.67(m,1H),3.56(dd,J＝12.1, 6.1Hz,2H),3.39(s,2H),2.77(s,3H),2.43(s,1H),0.76(d,J＝5.5Hz,2H),0.53(s,2H).

Example 35:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((1- (dimethylamino) -2-nitrovinyl) amino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (35)

Compound 166c (100mg,0.28mmol), 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, and dimethylamine aqueous solution (2mL) was added thereto, and the temperature was raised to 55 ℃ to react overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 35(33mg, yield: 25.0%).

MS(ESI,m/z):473.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.36(s,1H),8.97(s,1H),8.46(s,1H),7.18(t,J＝8.8Hz,1H),7.20–7.10(m,1H),6.85–6.71(m,1H),6.40–6.31(m,2H),3.51–3.43(m,4H),2.91(s,6H).

Example 36:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (3-methyl-2- (methylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (36)

Compound 166c (70mg, 0.17mmol) and compound 134a (53mg, 0.26mmol) were dissolved in DMF (3mL), DIPEA (47mg, 0.34mmol) was added and reacted at 50 ℃ for 2 h. After the reaction of the raw materials is finished, one fourth of the reaction solution is taken, and aqueous methylamine solution (0.5mL, 40%) is added to continue the reaction at 50 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 36(23mg, yield: 21%).

MS m/z(ESI):493.3[M+H⁺].

¹H NMR(400MHz,DMSO-d₆)δ11.45(s,1H),8.90(s,1H),7.19(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),7.09(s,1H),7.02(m,1H),6.78(m,1H),6.33(s,1H),3.42(s,4H),2.79(s,3H),2.70(d,J＝4.6Hz,3H).

Example 37:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (3- (2-hydroxyethyl) -2- (methylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (37)

Compound 169a (19mg, 0.45mmol) was dissolved in t-butanol, and ethanolamine (15mg, 0.27mmol) was added to the solution to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 37(20mg, yield: 29%).

MS m/z(ESI):523.3[M+H⁺].

¹H NMR(400MHz,DMSO-d₆)δ11.48(s,1H),8.90(s,1H),7.20(dd,J＝10.7,6.8Hz,3H),7.13(dd,J＝6.1,2.7Hz,1H),6.79(ddd,J＝8.8,4.0,2.8Hz,1H),6.35(s,1H),4.99(s,1H),3.51(s,4H),3.38(s,4H),3.18(dd,J＝10.7,5.3Hz,2H),2.81(s,3H).

Example 38:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (3-isopropyl-2- (methylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (38)

Compound 169a (20mg, 0.04mmol), isopropylamine (5mg,0.08mmol) and DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 38(17mg, yield: 18.9%).

MS(ESI,m/z):521.4[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.59(s,1H),8.89(s,1H),7.19(t,J＝8.6Hz,2H),7.11(m,1H),6.78(m,2H),6.37(s,1H),3.75(s,4H),2.78(s,3H),1.11(d,J＝6.3Hz,6H).

Example 39:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((1- (isopropylamino) -2-nitrovinyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (39)

Compound 166c (100mg,0.28mmol), compound 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, isopropylamine (49.6mg, 0.84mmol) was added thereto, the temperature was raised to 55 ℃ to react overnight, and the crude product obtained by post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 39(18mg, yield: 13.2%).

MS(ESI,m/z):487.2[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.45(s,1H),10.20–10.11(m,1H),8.92(s,1H),7.42–7.25(m,1H),7.18(t,J＝8.8Hz,1H),7.11(dd,J＝6.0,2.6Hz,1H),6.81–6.72(m,1H),6.69–6.62(m,1H),6.47–6.41(m,1H),3.81–3.74(m,1H),3.43–3.32(m,4H),1.16(d,J＝6.2Hz,6H).

Example 40:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((1- (morpholinyl) -2-nitrovinyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (40)

Compound 166c (200mg, 0.56mmol), compound 114b (134.6mg, 0.68mmol), N-diisopropylethylamine (0.22g, 1.68mmol), and N, N-dimethylformamide (8mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, morpholine (147mg, 1.68mmol) was added, the reaction mixture was warmed to 55 ℃ for overnight reaction, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give title compound 40(100mg, yield: 34.8%).

MS(ESI,m/z):515.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.46(s,1H),8.91(s,1H),8.70(s,1H),7.21–7.14(m,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.79–6.71(m,1H),6.43–6.33(m,2H),3.67–3.56(m,4H),3.49–3.41(m,4H),3.27–3.17(m,4H).

Example 41:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2-carbamoylguanidine) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (41)

Compound 122b (200mg, 0.44mmol), dioxane (5.00mL), and concentrated hydrochloric acid (1.50mL) were sequentially added to a 25mL reaction flask, the temperature was raised to 45 ℃ to react for 3 hours, the reaction solution was cooled, 2N sodium hydroxide was added to adjust the system pH to 12, and the reaction was carried out at room temperature for 1 hour, glacial acetic acid was adjusted the system pH to 7, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 41(59mg, yield: 30.1%).

MS(ESI,m/z):444.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.89(s,1H),8.32(s,2H),7.18(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.95–5.87(m,4H),3.42–3.39(m,4H).

Example 42:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- (2- (2- (benzenesulfonyl) guanidino) ethoxy) -1,2, 5-oxadiazole-3-carboxamidine (42)

First step of

Compound 187a (3.14g,20.0mmol) is dissolved in DMF (10mL), 20.0M aqueous NaOH (1.4mL,28.0mmol) is added, the mixture is stirred at room temperature for 0.5h, the system is cooled to 0 ℃, and CS is added₂(0.8mL,13.3mmol), reacting at 0 deg.C for 0.5h, and sequentially adding 20.0M NaOH aqueous solution (0.6mL,12.0mmol) and CS₂(0.4mL,6.7mmol), stirring was continued at 0 ℃ for 0.5h and then warmed to room temperature for 0.5 h. Then, the reaction was cooled to 0 ℃ and MeI (2.5mL,40.0mmol) was added and the resulting system was stirred at 0 ℃ for 0.5h and allowed to warm to room temperature for 1.5 h. Work-up gave compound 187b (4.8g, crude).

Second step of

Compound 187b (1.30g,5.0mmol) was dissolved in methanol (14mL), and 7.0M aqueous ammonia solution in methanol (1.1mL,7.5mmol) was added and reacted at 50 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 187c (1.15g, crude) which was used directly in the next step.

The third step

Compound 187c (1.15g,5.0mmol) was dissolved in acetonitrile (10mL), di-tert-butyl dicarbonate (1.14mL,5.25mmol), DMAP (31mg,0.25mmol) were added, and the reaction was carried out at room temperature for 2h, followed by workup to give compound 187d (1.65g, crude) which was used in the next step as it was.

The fourth step

Compound 128a (150mg,0.36mmol) was dissolved in acetonitrile (4mL), and DIPEA (0.16mL,0.90mmol) and compound 187d (178mg,0.54mmol) were added in this order to react at 70 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 187f (240mg, crude) which was used directly in the next step.

The fifth step

Compound 187f (240mg,0.36mmol) was dissolved in a mixed solution of dichloromethane (4mL) and trifluoroacetic acid (1mL) and reacted at room temperature for 0.5 h. After cooling to 0 ℃, a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the system pH to 7-8, and 187g (204mg, crude product) of the obtained compound was worked up and used directly in the next step.

The sixth step

187g (204mg,0.36mmol) of the compound was dissolved in MeOH (3mL), and 2.0M aqueous NaOH (0.36mL,0.72mmol) was added and reacted at room temperature for 0.5 h. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give title compound 42(58mg, yield: 29.7%).

MS(ESI,m/z)：542.3[M+H⁺].

¹H NMR(400MHz,DMSO-d6):δ11.45(s,1H),9.00(s,1H),7.79-7.31(m,2H),7.56-7.45(m,3H),7.14(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.8Hz,1H),7.02(brs,1H),6.79(brs,2H),6.72-6.67(m,1H),4.22(t,J＝4.4Hz,2H),3.40(t,J＝4.4Hz,2H).

Example 43:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (benzenesulfonyl) guanidino) ethyl) mercapto) -1,2, 5-oxadiazole-3-carboxamidine (43)

First step of

Compound 130a (110mg,0.25mmol) was dissolved in acetonitrile (2.5mL), DIPEA (0.11mL,0.62mmol) and compound 188a (125mg,0.38mmol) were added sequentially, reacted at 70 ℃ for 2h, and the reaction mixture was concentrated under reduced pressure to give compound 188c (171mg, crude) which was used in the next step.

Second step of

Compound 188c (171mg,0.25mmol) was dissolved in a mixed solution of dichloromethane (4mL) and trifluoroacetic acid (1mL) and reacted at room temperature for 0.5 h. Cooling to 0 ℃, dropwise adding a saturated sodium bicarbonate aqueous solution, adjusting the pH of the system to 7-8, and post-treating the obtained compound 188d (146mg, crude product) for direct use in the next step.

The third step

Compound 188d (146mg,0.25mmol) was dissolved in MeOH (3mL), and 2.0M aqueous NaOH (0.25mL,0.50mmol) was added and reacted at room temperature for 0.5 h. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give title compound 43(27mg, yield: 19.3%).

MS(ESI,m/z)：558.4[M+H⁺].

¹H NMR(400MHz,CDCl₃):δ7.86(d,J＝7.6Hz,2H),7.53(t,J＝7.6Hz,1H),7.46(t,J＝7.6Hz,2H),7.15(dd,J＝5.6,2.4Hz,1H),7.11(brs,1H),6.98(t,J＝8.4Hz,1H),6.84-6.78(m,1H),6.68(brs,1H),3.61(brs,2H),3.27(t,J＝6.0Hz,2H).

Example 44:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((Z) -3- (2, 2-difluoroethyl) -2- (methylsulfonyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (44)

Compound 152b (20mg, 0.04mmol), 2-difluoroethylamine (7mg,0.08mmol), and DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 44(4mg, yield: 18.3%).

MS(ESI,m/z):560.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),8.98(s,1H),7.48(s,1H),7.42(s,1H),7.17(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),6.70(ddd,J＝8.9,4.0,2.8Hz,1H),6.09(t,J＝55.8Hz,1H),3.56(d,J＝5.9Hz,4H),3.36(s,2H),2.82(s,3H),0.95(d,J＝6.5Hz,2H).

Example 45:

n- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N '-hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) mercapto) ethyl) -N' - (methylsulfonyl) morpholine-4-carboxamidine (45)

Compound 152b (20mg, 0.04mmol), 2,2, 2-trifluoroethylamine (7mg,0.08mmol), DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 45(2mg, yield: 8.6%).

MS(ESI,m/z):578.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),8.98(s,1H),7.61(s,2H),7.17(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),6.70(ddd,J＝8.9,4.0,2.9Hz,1H),4.05(s,2H),3.59(d,J＝5.8Hz,2H),3.36(s,2H),2.81(s,3H).

Example 46:

n- (3-bromo-4-fluorophenyl) -4- ((2- (3-ethyl-2- (methylsulfonyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (46)

Compound 152b (20mg, 0.04mmol), ethylamine (7mg,0.15mmol), DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 46(4mg, yield: 19.1%).

MS(ESI,m/z):524.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.48(s,1H),8.99(s,1H),7.25(t,J＝5.5Hz,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),7.03(t,J＝5.4Hz,1H),6.70(ddd,J＝8.9,4.1,2.8Hz,1H),3.53(dd,J＝12.0,6.1Hz,2H),3.35(s,2H),3.17–3.08(m,2H),2.79(s,3H),1.07(t,J＝7.1Hz,3H).

Example 47:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((1- (cyclopropylamino) -2-nitro-vinyl) amino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (47)

Compound 166c (100mg,0.28mmol), compound 134a (56mg, 0.33mmol), DIPEA (1.40mL, 8.40mmol) and DMF (3.00mL) were sequentially added to a 10mL reaction flask, the temperature was raised to 70 ℃ to react for 2h, the reaction mixture was cooled, cyclopropylamine (2.00mL) was added, the temperature was raised to 70 ℃ to react for 2.5h, and the crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 47(13mg, yield: 9.6%).

MS(ESI,m/z):485.1[M+H⁺]。

¹H NMR(400MHz,DMSO)δ11.56(s,1H),10.06(s,1H),8.92(s,1H),7.65–7.35(m,1H),7.18(t,J＝8.8Hz,1H),7.12(dd,J＝6.0,2.6Hz,1H),6.78–6.68(m,2H),6.41(s,1H),3.53-3.36(m,4H),0.79(s,2H),0.58(s,2H).

Example 48:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((1- (cyclohexylamino) -2-nitrovinyl) amino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (48)

Compound 166c (100mg,0.28mmol), 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, cyclohexylamine (83.2mg, 0.84mmol) was added, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 48(50mg, yield: 34.0%).

MS(ESI,m/z):527.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ7.18(t,J＝8.7Hz,1H),7.13–7.06(m,1H),6.83–6.77(m,1H),6.72–6.61(m,1H),3.49–3.40(m,5H),1.87–1.81(m,2H),1.68–1.59(m,2H),1.59–1.51(m,1H),1.39–1.32(m,6H).

Example 49:

n- (3-bromo-4-fluorophenyl) -4- ((2- (3-cyclopropyl-2- (methylsulfonyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (49)

Compound 169a (20mg, 0.04mmol), morpholine (7mg,0.08mmol) and DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 49(14mg, yield: 17.6%).

MS(ESI,m/z):519.3[M+H⁺].

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.88(s,1H),7.30(s,1H),7.18(dd,J＝11.8,5.7Hz,2H),7.11(dd,J＝6.1,2.7Hz,1H),6.79(ddd,J＝8.8,4.1,2.8Hz,1H),6.39(s,1H),2.78(s,3H),2.43(s,1H),0.75(d,J＝5.4Hz,2H),0.52(m,2H).

Example 50:

n- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N '-hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -N' - (methylsulfonyl) morpholine-4-carboxamidine (50)

Compound 169a (20mg, 0.04mmol), morpholine (7mg,0.08mmol) and DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 h. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 50(16mg, yield: 13.1%).

MS(ESI,m/z):549.4[M+H⁺].

¹H NMR(400MHz,DMSO-d₆)δ11.49(s,1H),8.88(s,1H),7.35(t,J＝5.3Hz,1H),7.19(t,J＝8.8Hz,1H),7.11(dt,J＝7.2,3.6Hz,1H),6.79(ddd,J＝8.8,4.1,2.8Hz,1H),6.44(t,J＝5.7Hz,1H),3.57(m,4H),3.24(d,J＝10.3Hz,3H),2.85(s,3H),1.23(s,4H).

Example 51:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((-2-nitro-1- (piperidin-1-yl) ethenyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (51)

Compound 166c (100mg,0.28mmol), compound 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.18g, 1.40mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, piperidine (102mg, 0.84mmol) was added, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 51(45mg, yield: 31.4%).

MS(ESI,m/z):513.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.45(s,1H),8.90(s,1H),8.73(s,1H),7.18(t,J＝8.8Hz,1H),7.11(dd,J＝6.1,2.7Hz,1H),6.83–6.72(m,1H),6.40–6.32(m,2H),3.52–3.40(m,4H),3.24–3.17(m,4H),1.59–1.52(m,6H).

Example 52:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((-2-nitro-1- (2-oxa-6-azaspiro [3.3] heptan-6-yl) vinyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (52)

Compound 166c (100mg,0.28mmol), compound 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, and 2-oxa-6-aza-spiro [3,3] heptane (83mg, 0.84mmol) was added thereto, and the mixture was heated to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 52(42mg, yield: 28.6%).

MS(ESI,m/z):527.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),9.96(s,1H),9.05(s,1H),7.23–7.08(m,2H),6.81–6.72(m,1H),6.43(t,J＝5.8Hz,1H),6.11(s,1H),4.73–4.65(m,4H),4.48–4.41(m,4H),3.57–3.51(m,2H),3.56–3.42(m,2H).

Example 53:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((1- ((2, 2-difluoroethyl) amino) -2-nitrovinyl) amino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (53)

Compound 166c (100mg,0.28mmol), compound 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction was cooled to room temperature, difluoroethylamine (68.0mg, 0.84mmol) was added, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 53(20mg, yield: 14.1%).

MS(ESI,m/z):509.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.44(s,1H),10.37(s,1H),8.90(s,1H),7.53–7.47(m,1H),7.18(t,J＝8.8Hz,1H),7.18–7.10(m,1H),6.79–6.70(m,2H),6.43–6.36(m,1H),6.28–6.17(m,1H),3.78–3.67(m,2H),3.37–3.29(m,4H).

Example 54:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (3- (1-methylcyclopropyl) -2- (methylsulfonyl) guanidino) ethylmercapto) -1,2, 5-oxadiazole-3-carboxamidine (54)

Compound 152b (20mg, 0.04mmol), 1-methylcyclopropylamine (10mg,0.16mmol) and DIPEA (10mg,0.08mmol) were dissolved in DMF (1mL) and reacted at 100 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure and then separated and purified by high performance liquid chromatography to give the title compound 54(2mg, yield: 9.1%).

MS(ESI,m/z):550.0[M+H⁺]。

¹H NMR((400MHz,DMSO-d₆)δ7.07(dd,J＝6.0,2.7Hz,1H),7.04(dd,J＝9.8,7.5Hz,1H),6.76(ddd,J＝8.8,4.1,2.7Hz,1H),3.67(d,J＝6.1Hz,2H),3.39(dd,J＝8.2,4.4Hz,2H),2.87(s,3H),1.34(s,3H),0.81(t,J＝5.7Hz,2H),0.75(t,J＝5.7Hz,2H).

Example 55:

n- (3-bromo-4-fluorophenyl) -4- ((2- ((Z) -3- (tert-butyl) -2- (methylsulfonyl) guanidino) ethyl) aminopropyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (55)

Compound 114a (100mg,0.24mmol), compound 134a (53mg, 0.26mmol), TEA (0.10mL, 0.71mmol), and acetonitrile (3.00mL) were sequentially added to a 10mL reaction flask, heated to 50 ℃ for reaction for 2 hours, after the reaction liquid was cooled, tert-butylamine (2.00mL) was added, heated to 80 ℃ for reaction overnight, 2N sodium hydroxide was added to adjust the system pH to 12, and the reaction was carried out at room temperature for 1 hour with glacial acetic acid to adjust the system pH to 7. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 55(7mg, yield: 5.5%).

MS(ESI,m/z):535.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.44(s,1H),8.90(s,1H),7.19(t,J＝8.8Hz,1H),7.10(dd,J＝6.1,2.7Hz,1H),6.96–6.72(m,2H),6.35(t,J＝5.6Hz,1H),3.44–3.36(m,4H),2.78(s,3H),1.31(s,9H).

Example 56:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((2-nitro-1- ((2,2, 2-trifluoroethyl) amino) vinyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (56)

Compound 166c (100mg,0.28mmol), 114b (67.3mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction was cooled to room temperature, trifluoroethylamine (68.0mg, 0.84mmol) was added, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 56(14mg, yield: 9.5%).

MS(ESI,m/z):527.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.44(s,1H),10.42(s,1H),8.92(s,1H),7.91–7.83(m,1H),7.17(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.81–6.70(m,2H),6.43–6.38(m,1H),4.35–4.28(m,2H),3.48–3.40(m,4H).

Example 57:

n- (3-bromo-4-fluorophenyl) -4- ((2- (3-cyclohexyl-2- (methylsulfonyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (57)

Compound 166c (200mg, 0.56mmol), compound 134a (168mg, 0.82mmol), TEA (0.3mL), and acetonitrile (5.00mL) were sequentially charged into a 10mL reaction flask, heated to 60 ℃ to react for 2h, and after the reaction solution was cooled, cyclohexylamine (0.5mL) was added, and heated to 80 ℃ to react for 2 h. The crude product obtained by the post-treatment was isolated and purified by silica gel column chromatography to give the title compound 57(123mg, yield: 39%).

MS(ESI,m/z):561.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),8.89(s,1H),7.19(t,J＝8.8Hz,2H),7.11(m,1H),6.94(s,1H),6.81–6.74(m,1H),6.33(m,1H),3.37(d,J＝2.0Hz,4H),2.77(s,3H),1.85–1.74(m,2H),1.62(m,2H),1.52(m,1H),1.21(m,6H).

Example 58:

n- (3-bromo-4-fluorophenyl) -N '-hydroxy-4- ((2- (N' - (methylsulfonyl) piperidine-1-carbamimidoyl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (58)

Compound 166c (200mg, 0.56mmol), compound 134a (168mg, 0.82mmol), TEA (0.3mL), and acetonitrile (5.00mL) were sequentially added to a 10mL reaction flask, the temperature was raised to 60 ℃ to react for 2 hours, and after the reaction solution was cooled, piperidine (0.5mL) was added, the temperature was raised to 80 ℃ to react for 2 hours. The crude product obtained by the post-treatment was isolated and purified by silica gel column chromatography to give the title compound 58(55mg, yield: 18%).

MS(ESI,m/z):547.1[M+H⁺].

¹H NMR(400MHz,DMSO-d₆):δ11.41(s,1H),8.88(s,1H),7.23–7.14(m,2H),7.11(m,1H),6.78(m,1H),6.44(t,J＝5.6Hz,1H),3.48–3.41(m,2H),3.37(m,6H),2.84(s,3H),1.55(m,2H),1.48(m,4H)

Example 59:

n- (3-bromo-4-fluorophenyl) -4- ((2- (3-ethyl-2- (methylsulfonyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (59)

Compound 166c (200mg, 0.56mmol), compound 134a (168mg, 0.82mmol), TEA (0.3mL), and acetonitrile (5.00mL) were sequentially added to a 10mL reaction flask, the temperature was raised to 60 ℃ to react for 2 hours, and after the reaction solution was cooled, an aqueous ethylamine solution (1mL) was added, and the temperature was raised to 80 ℃ to react for 2 hours. The crude product obtained by the post-treatment was isolated and purified by silica gel column chromatography to give the title compound 59(77mg, yield: 27%).

MS(ESI,m/z):506.1[M+H⁺].

¹H NMR(400MHz,DMSO-d₆):δ11.44(s,1H),8.89(s,1H),7.19(t,J＝8.8Hz,1H),7.16–7.09(m,2H),7.01(m,1H),6.78(m,1H),6.31(m,1H),3.37(s,4H),3.13(m,2H),2.78(s,3H),1.07(t,J＝7.2Hz,3H).

Example 60:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2- (methylsulfonyl) -3-phenylguanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (60)

Compound 216a (55. mu.L, 0.50mmol), compound 134a (100mg, 0.50mmol), TEA (340. mu.L, 2.50mmol), and absolute ethanol (2.00mL) were sequentially added to a 2.0-5.0mL microwave tube, microwave-reacted at 95 ℃ for 10h, compound 166c (179mg, 0.50mmol) was further added, microwave-reacted at 90 ℃ for 2.5h, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 60(33mg, yield: 11.9%).

MS(ESI,m/z):555.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.44(s,1H),8.90(s,1H),8.71(s,1H),7.35(t,J＝7.8Hz,2H),7.29(d,J＝7.6Hz,3H),7.21–7.15(m,2H),7.11(dd,J＝6.1,2.7Hz,1H),6.78–6.74(m,1H),6.36(t,J＝5.6Hz,1H),3.55–3.39(m,4H),2.88(s,3H).

Example 61:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2-carbamoyl-3- (2-hydroxyethyl) guanidino) ethyl) thio) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (61)

First step of

Compound 130a (2.00g, 4.57mmol), compound 217a (1.10g, 4.57mmol), and acetonitrile (20mL) were added to a 50mL reaction flask, stirred well at room temperature, then TEA (1.60mL, 11.43mmol) was added to the system and reacted at room temperature for 0.5h, and the resulting compound 217b (1.90g, crude) was worked up and used directly in the next step.

Second step of

Compound 217b (300mg, 0.55mmol), dioxane (6.00mL), and concentrated hydrochloric acid (1.00mL) were sequentially added to a 25mL reaction flask, the temperature was raised to 40 ℃ to react for 6 hours, the reaction solution was cooled, ethanolamine (3.00mL) was added, the temperature was raised to 80 ℃ to react for 2 hours, the pH of the system was adjusted to 7 with glacial acetic acid, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 61(17mg, two-step yield: 9.8%).

MS(ESI,m/z):505.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),9.53(s,1H),8.97(s,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),7.02–6.07(m,2H),5.59(s,2H),4.89(s,1H),3.54–3.49(m,2H),3.47(t,J＝5.6Hz,2H),3.38–3.34(m,2H),3.16(s,2H).

Example 62:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2-carbamoyl-3- (2-hydroxyethyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (62)

First step of

After adding compound 114a (3.00g, 7.81mmol), compound 217a (1.90g, 7.81mmol) and acetonitrile (30mL) to a 100mL reaction flask and stirring well at room temperature, TEA (1.70mL, 11.72mmol) was added to the system and reacted at room temperature for 0.5h, the resulting compound 221a (2.70g, crude) was worked up and used directly in the next step.

Second step of

Compound 221a (150mg, 0.28mmol), dioxane (3.00mL), and concentrated hydrochloric acid (0.50mL) were sequentially added to a 25mL reaction flask, the temperature was raised to 40 ℃ to react for 6 hours, the reaction mixture was cooled, ethanolamine (2.00mL) was added, the temperature was raised to 80 ℃ to react for 2 hours, the pH of the system was adjusted to 7 with glacial acetic acid, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 62(7mg, two-step yield: 7.4%).

MS(ESI,m/z):488.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.48(s,1H),9.50(s,1H),8.88(s,1H),7.19(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.79–6.75(m,1H),6.32(t,J＝5.4Hz,1H),5.59(s,2H),4.92(s,1H),3.47(t,J＝5.6Hz,2H),3.41–3.35(m,4H),3.18(s,2H).

Example 63:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (cyclopropylsulfonyl) -3- (2-hydroxyethyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (63)

Compound 166c (100mg,0.28mmol), compound 173b (70mg,0.31mmol), acetonitrile (3mL), and triethylamine (56mg, 0.55mmol) were sequentially charged into a 25mL reaction flask, heated to 70 ℃ to react for 2h, ethanolamine (0.5mL) was added to react for 2h at 70 ℃, and the crude product obtained after the work-up was isolated and purified by high performance liquid chromatography to give the title compound 63(7mg, yield: 4.6%).

MS(ESI,m/z):549.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)：δ11.42(s,1H),8.89(s,1H),7.28–7.15(m,3H),7.12(m,1H),6.78(m,1H),6.33(s,1H),4.93(s,1H),3.49(t,J＝5.2Hz,2H),3.37(s,4H),3.17(m,2H),2.44(m,1H),0.86–0.74(m,4H).

Example 64:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (ethylsulfonyl) -3- (2-hydroxyethyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (64)

Compound 152a (100mg, 0.27mmol), compound 177a (70.3mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, ethanolamine (61.0mg, 0.81mmol) was added thereto, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 64(36mg, yield: 24.5%).

MS(ESI,m/z):554.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ12.32(s,1H),9.26(s,1H),7.92(dd,J＝6.0,2.8Hz,1H),7.67–7.62(m,1H),7.39(t,J＝8.8Hz,1H),7.35–7.27(m,2H),4.98(s,1H),3.57–3.43(m,4H),3.39–3.31(m,4H),2.89–2.81(m,2H),1.25–1.06(m,3H).

Example 65:

n- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N '-hydroxyamidine) -1,2, 5-oxadiazol-3-yl) mercapto) ethyl) -N' - (ethylsulfonyl) morpholine-4-carboxamidine (65)

Compound 152a (100mg, 0.27mmol), compound 177a (70.3mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, morpholine (70.5mg, 0.81mmol) was added, and the temperature was raised to 65 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 65(50mg, yield: 32.5%).

MS(ESI,m/z):580.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),8.99(s,1H),7.41(t,J＝5.4Hz,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),6.78–6.61(m,1H),3.71–3.51(m,6H),3.50–3.38(m,4H),3.41–3.33(m,2H),2.93–2.84(m,2H),1.19(t,J＝7.3Hz,3H).

Example 66:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (cyclopropylsulfonyl) -3- (2-hydroxy-2-methylpropyl) guanidino) ethyl) aminopropyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (66)

Compound 166c (100mg,0.28mmol), compound 173b (70mg,0.31mmol), acetonitrile (3mL), and triethylamine (56mg, 0.55mmol) were sequentially added to a 25mL reaction flask, and the mixture was heated to 70 ℃ to react for 2 hours, followed by addition of 225a (0.3mL) and reaction at 70 ℃ for 2 hours. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 66(13mg, yield: 6.2%).

MS(ESI,m/z):577.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)：δ11.42(s,1H),8.90(s,1H),7.30(m,1H),7.19(m,2H),7.11(m,1H),6.78(m,1H),6.32(m,1H),4.79(s,1H),3.37(s,4H),3.02(s,2H),2.49–2.42(m,1H),1.11(s,6H),0.87–0.77(m,4H).

Example 67:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- ((2-nitro-1- (pyrrolidin-1-yl) vinyl) amino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (67)

Compound 166c (100mg,0.28mmol), compound 114b (60mg,0.36mmol), triethylamine (57mg,0.56mmol), and acetonitrile (5mL) were placed in a 50mL reaction flask, and the temperature was raised to 85 ℃ for 2h under reflux. Then the temperature is reduced to 80 ℃, compound 226a (0.3ml) is added, and after the addition is finished, the reaction is carried out for 3h at 80 ℃. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 67(11mg, yield: 7.9%).

MS(ESI,m/z):499.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)：δ11.53(s,1H),9.26(s,1H),8.91(s,1H),7.18(m,1H),7.13(m,1H),6.77(m,1H),6.43(s,1H),6.40(m,1H),3.55(m,2H),3.48–3.43(m,2H),3.41(d,J＝6.4Hz,4H),1.85(t,J＝6.4Hz,4H).

Example 68:

n- (3-bromo-4-fluorophenyl) -4- ((2- (-2- (ethylsulfonyl) -3- ((R) -2-hydroxypropyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (68)

Compound 152a (100mg, 0.27mmol), 177a (70.3mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, and (R) -2-amino-1-propanol (61mg, 0.81mmol) was added thereto, and the mixture was heated to 55 ℃ to react overnight, and then the crude product obtained by the after-treatment was isolated and purified by high performance liquid chromatography to give title compound 68(47mg, yield: 31.1%).

MS(ESI,m/z):568.1[M+H⁺].

¹H NMR(400MHz,DMSO-d₆)δ11.73(s,1H),8.99(s,1H),7.33–7.25(m,2H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),6.77–6.70(m,1H),4.98(s,1H),3.84–3.69(m,1H),3.58–3.51(m,2H),3.18–3.05(m,1H),2.93–2.85(m,3H),1.15(t,J＝7.3Hz,3H),1.06(d,J＝6.2Hz,3H).

Example 69:

n- (3-bromo-4-fluorophenyl) -4- ((2- (-2- (ethylsulfonyl) -3- ((S) -2-hydroxypropyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (69)

Compound 152a (100mg, 0.27mmol), compound 177a (70.3mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, and (S) -2-amino-1-propanol (61mg, 0.81mmol) was added thereto, followed by warming to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 69(40mg, yield: 26.5%).

MS(ESI,m/z):568.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.73(s,1H),8.99(s,1H),7.35–7.22(m,2H),7.18(t,J＝8.8Hz,1H),7.10(dd,J＝6.0,2.7Hz,1H),6.77–6.70(m,1H),4.98(s,1H),3.83–3.67(m,1H),3.56–3.51(m,2H),3.17–3.05(m,1H),2.93–2.85(m,3H),1.15(t,J＝7.3Hz,3H),1.06(d,J＝6.2Hz,3H).

Example 70:

n- (3-bromo-4-fluorophenyl) -4- ((2- (-2- (ethylsulfonyl) -3- (2-hydroxy-2-methylisopropyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (70)

Compound 152a (100mg, 0.27mmol), compound 177a (70.3mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, 1-amino-2-methyl-2-propanol (72.1mg, 0.81mmol) was added thereto, and the mixture was heated to 55 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 70(67mg, yield: 43.2%).

MS(ESI,m/z):582.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.73(s,1H),8.99(s,1H),7.40–7.21(m,2H),7.18(t,J＝8.8Hz,1H),7.09(dd,J＝6.0,2.7Hz,1H),6.78–6.69(m,1H),4.78(s,1H),3.62–3.43(m,2H),3.37–3.30(m,2H),3.08–3.00(m,2H),2.93–2.81(m,2H),1.16(t,J＝7.3Hz,3H),1.10(s,6H).

Example 71:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (ethylsulfonyl) -3- (2-hydroxyethyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (71)

Compound 166c (100mg,0.28mmol), compound 177a (72.4mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, ethanolamine (51.3mg, 0.84mmol) was added thereto, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 71(63mg, yield: 42.0%).

MS(ESI,m/z):537.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),8.90(s,1H),7.41–7.15(m,2H),7.18–7.11(m,1H),6.83–6.75(m,1H),6.37–6.30(m,1H),4.93(s,1H),3.55–3.48(m,2H),3.42–3.35(m,4H),3.23–3.16(m,2H),2.91–2.83(m,2H),1.19–1.10(m,3H).

Example 72:

n- (2- ((4- (-N- (3-bromo-4-fluorophenyl) -N '-hydroxyamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -N' - (ethylsulfonyl) morpholine-4-carboxamidine (72)

Compound 166c (100mg,0.28mmol), compound 177a (72.4mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction was cooled to room temperature, morpholine (73.1mg, 0.84mmol) was added, and the temperature was raised to 65 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 72(70mg, yield: 44.6%).

MS(ESI,m/z):563.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.38(s,1H),8.89(s,1H),7.34–7.28(m,1H),7.19(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.83–6.77(m,1H),6.41(t,J＝5.8Hz,1H),3.66–3.54(m,4H),3.49–3.40(m,2H),3.44–3.37(m,6H),2.98–2.90(m,2H),1.23–1.15(m,3H).

Example 73:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (1-methyl-2- (methylsulfonyl) guanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (73)

Compound 234a (100mg, 0.27mmol), compound 134a (66.0mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were placed in a microwave tube and the temperature was raised to 85 ℃ for 4 hours. The reaction mixture was cooled to room temperature, and an aqueous ammonia solution (3mL, 33% m/m) was added thereto, and the mixture was heated to 55 ℃ for reaction overnight. The crude product obtained by the post-treatment was isolated and purified by high performance liquid chromatography to give the title compound 73(43mg, yield: 32.6%).

MS(ESI,m/z):493.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.38(s,1H),8.91(s,1H),7.19(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),7.04(s,2H),6.83–6.75(m,1H),6.37(t,J＝5.7Hz,1H),3.61–3.56(m,2H),3.45–3.36(m,2H),2.90(s,3H),2.77(s,3H).

Example 74:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (ethylsulfonyl) -3- (2-methoxyethyl) guanidino) ethyl) mercapto) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (74)

Compound 152a (100mg, 0.27mmol), compound 177a (70.3mg, 0.33mmol), N-diisopropylethylamine (0.11g, 0.81mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction was cooled to room temperature, 2-methoxyethylamine (60.8mg, 0.81mmol) was added, and the temperature was raised to 55 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give title compound 74(47mg, yield: 30.9%).

MS(ESI,m/z):568.0[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),8.99(s,1H),7.37–7.28(m,1H),7.29–7.20(m,1H),7.18(t,J＝8.8Hz,1H),7.09(dd,J＝6.0,2.7Hz,1H),6.78–6.71(m,1H),3.61–3.50(m,6.0Hz,2H),3.48–3.41(m,2H),3.37–3.31(m,4H),3.35–3.26(m,2H),2.90–2.82(m,2H),1.15(t,J＝7.3Hz,3H).

Example 75:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (ethylsulfonyl) -3- ((R) -2-hydroxyisopropyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (75)

Compound 166c (100mg,0.28mmol), 177a (72.4mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, and (R) -2-amino-1-propanol (63.0mg, 0.84mmol) was added thereto, and the mixture was heated to 55 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 75(16mg, yield: 10.4%).

MS(ESI,m/z):551.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.42(s,1H),8.90(s,1H),7.35–7.27(m,1H),7.25–7.17(m,2H),7.12(dd,J＝6.1,2.7Hz,1H),6.82–6.74(m,1H),6.33(s,1H),4.97(s,1H),3.81–3.72(m,1H),3.44–3.31(m,4H),3.18–3.09(m,1H),3.01–2.76(m,3H),1.16(t,J＝7.4Hz,3H),1.05(d,J＝6.2Hz,3H).

Example 76:

n- (3-bromo-4-fluorophenyl) -4- ((2- (2- (ethylsulfonyl) -3- ((S) -2-hydroxyisopropyl) guanidino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (76)

Compound 166c (100mg,0.28mmol), compound 177a (72.4mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were charged into a 50mL reaction flask, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction mixture was cooled to room temperature, and (S) -2-amino-1-propanol (63.0mg, 0.84mmol) was added thereto, and the mixture was heated to 55 ℃ for reaction overnight. The crude product obtained by the workup was isolated and purified by high performance liquid chromatography to give the title compound 76(14mg, yield: 9.1%).

MS(ESI,m/z):551.1[M+H⁺]。

¹H NMR(400MHz,DMSO-d₆)δ11.42(s,1H),8.90(s,1H),7.35–7.27(m,1H),7.25– 7.17(m,2H),7.12(dd,J＝6.1,2.7Hz,1H),6.82–6.74(m,1H),6.33(s,1H),4.97(s,1H),3.81–3.72(m,1H),3.44–3.31(m,4H),3.18–3.06(m,1H),3.04–2.77(m,3H),1.16(t,J＝7.4Hz,3H),1.05(d,J＝6.2Hz,3H).

Example 77:

n- (3-chloro-4-fluorophenyl) -4- ((2- ((-1- (dimethylamino) -2-nitro-vinyl) amino) ethyl) amino) -N' -hydroxy 1,2, 5-oxadiazole-3-carboxamidine

First step of

Compound 166c (200mg, 0.57mmol), 114b (141mg, 0.86mmol), N-diisopropylethylamine (0.3g, 2mmol) and N, N-dimethylformamide (5mL) were placed in a 50mL reaction flask and the temperature was raised to 70 ℃ for reaction for 2 hours. LC-MS monitoring the reaction to completion, adding dimethylamine aqueous solution (2mL), reacting at 55 deg.C for 1h, LC-MS monitoring the reaction to completion, pouring the reaction solution into water, extracting with ethyl acetate (15 mL. times.3) for three times, washing the organic layer twice with saturated saline, and anhydrous Na₂SO₄After drying, filtration, concentration of the solvent under reduced pressure to dryness, and purification by Pre-HPLC gave the title compound 77(86mg, yield: 35%). MS (ESI, M/z):429.1[ M + H]+。

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),8.93(s,1H),8.46(s,1H),7.22(t,J＝8.8Hz,1H),7.00–7.02(m,1H),6.73(m,1H),6.36(s,2H),3.44–3.46(m,4H),2.91(s,6H)

Example 78

N- (3, 4-difluorophenyl) -4- ((2- (((Z) -1- (dimethylamino) -2-nitro) amino) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine

First step of

Adding the compound SM-5(3.0g, 18.5mmol), 270b (2.39g, 18.5mmol) and tetrahydrofuran/water (15mL/15mL) into a 250mL three-necked flask, stirring at 60 ℃ for 10min, gradually dropwise adding 25mL of an aqueous solution of sodium bicarbonate (2.33g, 27.8mmol) into the system, after dropwise adding, continuing to stir at 60 ℃ for 1h, precipitating a large amount of solid, monitoring by LC-MS until the reaction is complete, cooling the reaction solution to room temperature, adding 20mL of water, filtering, washing the filter cake with water, and drying to obtain the compound 270c (4.4g, yield: 93.2%).

Second step of

Compound 270c (4.4g, 17.3mmol), CDI (4.39g, 20.8mmol), ethyl acetate (40mL) were added to a 250mL single-neck flask and the temperature was raised to 67 ℃ for 1 h. TLC monitored reaction completion, reaction liquid cooled to room temperature, added 40mL ethyl acetate, 1N hydrochloric acid (40 mL. times.1), saturated brine washed (40 mL. times.2), dried over anhydrous sodium sulfate filtered, filtrate concentrated under reduced pressure to give compound 270d (4.2g, yield: 86.6%).

The third step

Compound 270d (4.2g, 14.9mmol) and 270e (5.85g, 17.9mmol) were dissolved in dichloromethane (40mL), and trifluoroacetic acid (22mL, 298.0mmol) and triethylsilane (4.33g, 37.3mmol) were added to the mixture in an ice-water bath, followed by dropwise addition and stirring at room temperature for 2 h. LC-MS (liquid chromatography-mass spectrometry) is used for monitoring the reaction to be complete, 40mL of dichloromethane is added into the reaction solution, the reaction solution is washed by saturated sodium bicarbonate water solution (40mL multiplied by 2), saturated salt water (40mL multiplied by 2), anhydrous sodium sulfate is used for drying and filtering, the solvent is concentrated to be dry by decompression, petroleum ether is used for beating, and then the filtration and the drying are carried out to obtain the compound 270f (7.1g, yield: 86.5%). MS (ESI, M/z) 547.2[ M + H ] +.

The fourth step

Compound 270f (7.1g, 13.0mmol), tetrahydrofuran (25mL), and 25mL of an aqueous solution of sodium hydroxide (1.56g, 39.0mmol) were charged into a 100mL reaction flask, reacted at room temperature for 3 hours, LC-MS monitored until the reaction was complete, the reaction mixture was poured into water, extracted twice with ethyl acetate (50 mL. times.2), the organic phase was washed with saturated brine (40 mL. times.2), dried over anhydrous sodium sulfate and filtered, and the solvent was concentrated under reduced pressure to dryness to give 270g of compound (3.1g, yield: 79.8%). MS (ESI, M/z) 299.1[ M + H ] +.

The fifth step

270g (300mg, 1.00mmol) of the compound, 114b (198mg, 1.20mmol), N-diisopropylethylamine (388mg, 3.00mmol) and N, N-dimethylformamide (6mL) were put into a 50mL reaction flask and heated to 55 ℃ for reaction for 2 hours. Monitoring by LC-MS until the reaction is complete, cooling the reaction solution to room temperature, adding 2mL of dimethylamine aqueous solution, heating to 55 ℃ for reaction for 1h, monitoring by LC-MS until the reaction is complete, pouring the reaction solution into ice water, extracting with ethyl acetate (30mL multiplied by 3) for three times, washing the organic layer twice with saturated saline solution, and obtaining anhydrous Na₂SO₄After drying, filtration, concentration of the solvent under reduced pressure to dryness, and purification by Pre-HPLC gave title compound 78(135.0mg, yield: 32.5%). MS (ESI, M/z):413.1[ M + H]+。

¹H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),8.92(s,1H),8.47(s,1H),7.22(dd,J＝19.7,9.1Hz,1H),6.89–6.80(m,1H),6.62–6.50(m,1H),6.41–6.32(m,2H),3.52–3.43(m,4H),2.91(s,6H).

Example 79:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (2-sulfamoylguanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

First step of

SM-7(6.78g, 19.80mmol), 278b (3.84g, 29.70mmol) were dissolved in 150mL of dichloromethane, TFA (30mL, 0.40mol) was added dropwise at a temperature not exceeding 20 ℃ and triethylsilane (10mL, 59.40mmol) was slowly added dropwise and the reaction was allowed to proceed overnight at room temperature, the end of the reaction was monitored by LCMS, the reaction was cooled and the solvent was directly spin dried, and the resulting solid was purified by slurrying with MTBE (6g, yield: 74.17%). MS (ESI, M/z) 409.0[ M + H ] +.

Second step of

278c (0.80g, 1.96mmol) and absolute methanol (20mL) are sequentially added into a 100mL three-necked flask, and after stirring uniformly at room temperature, HCl gas is slowly introduced into the system for 2 hours, the reaction is carried out at room temperature for 3 hours, the reaction end point is monitored by LCMS, the reaction solution is cooled, the solvent is directly dried by spinning, DMF (3mL) is added for dissolution, TEA is used for adjusting the system pH to 7, and the mixture is separated and purified by high performance liquid chromatography to obtain 278d (0.30g, yield: 34.72%). MS (ESI, M/z) 441.0[ M + H ] +.

The third step

Compound 278d (0.30g, 0.68mmol), 278e (1.32g, 13.75mmol) and anhydrous methanol (30mL) were added to a 100mL reaction flask, reacted at 45 ℃ for 10h, reaction completion was monitored by LCMS, solvent was removed under reduced pressure, diluted with water, the aqueous layer was extracted twice with ethyl acetate, the organic phase was washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate and purified by thin layer chromatography to give 278f (100mg, yield: 29.07%). MS (ESI, M/z) 505.0[ M + H ] +.

The fourth step

278f (100mg, 0.20mmol) and 20mL of anhydrous methanol were put into a 100mL single-neck flask, and after stirring uniformly at room temperature, the pH of the system was adjusted to 13 with 2M sodium hydroxide, and stirred at room temperature for 1 hour, the reaction was monitored by LCMS for completion, the pH of the system was adjusted to 7 with glacial acetic acid, most of the solvent was removed by swirling, 20mL of ethyl acetate was added, the organic phase was washed with water (20mL × 3), with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, concentrated and lyophilized to obtain the title compound 79(84mg, yield: 87.50%). MS (ESI, M/z) 479.0[ M + H ] +.

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),8.90(s,1H),8.28(s,1H),7.30(d,J＝8.6Hz,1H),7.19(t,J＝8.8Hz,1H),7.11(dd,J＝6.1,2.7Hz,1H),6.83–6.71(m,1H),6.49(s,2H),6.23(t,J＝5.8Hz,1H),3.23(dd,J＝13.1,6.7Hz,2H),2.23(t,J＝7.6Hz,2H),1.92–1.78(m,2H).

Example 80

N- (3-bromo-4-fluorophenyl) -N '-hydroxy-4- ((2-N' - (methylsulfonyl) piperazine-1-carboxyformamide) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hydrochloride

First step of

Compound 166c (200mg, 0.57mmol), 134a (171mg, 0.86mmol), N-diisopropylethylamine (0.3g, 2mmol) and N, N-dimethylformamide (5mL) were placed in a 50mL reaction flask and the temperature was raised to 70 ℃ for reaction for 2 hours. LC-MS monitored to completion of the reaction, piperazine (490mg, 5.7mmol) was added, the reaction was continued at 70 ℃ for 3h, LC-MS monitored to completion of the reaction, the reaction solution was poured into water, extracted three times with ethyl acetate (15 mL. times.3), the organic layer was washed twice with saturated brine, dried over anhydrous Na2SO4, filtered, the solvent was concentrated under reduced pressure to dryness, and then purified by Pre-HPLC (0.05% aqueous hydrochloric acid and acetonitrile) to give the title compound 80-1(75mg, yield: 23%). MS (ESI, M/z) 550[ M + H ] +.

¹H NMR(400MHz,DMSO-d₆)δ11.41(s,1H),9.26(s,2H),8.91(s,1H),7.65(s,1H),7.20(t,J＝8.8Hz,1H),7.13(dd,J＝6,2.8Hz,1H),6.82–6.74(m,1H),6.43(s,1H),3.67–3.59(m,4H),3.49–3.42(m,2H),3.42–3.35(m,2H),3.11(s,4H),2.87(s,3H).

Example 81:

n- (3-bromo-4-fluorophenyl) -N' -hydroxy- (4- (Z) -4- (methylamino) -4- (sulfonamido) butyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

First step of

Dissolving SM-7(1.62g, 4.75mmol), 290b (0.77g, 4.75mmol) in 15mL of dichloromethane, adding TFA (7.00mL, 0.095mol) dropwise at a temperature not exceeding 20 ℃, slowly adding triethylsilane (2.28mL, 14.25mmol) dropwise, reacting at room temperature for 2h after dropwise addition, monitoring the end point of the reaction by LCMS, and carrying out post-treatment: the reaction solution was cooled to-5 ℃, a saturated aqueous sodium bicarbonate solution was added dropwise, the pH was adjusted to 7-8, extraction was performed three times with DCM, organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 290c (1.20g, yield: 57.15%). MS (ESI, m/z): 442.0[ M +1].

Second step of

Compound 290c (0.10g, 0.23mmol), aqueous methylamine (0.31mL, 2.27mmol), and dry methanol (5mL) were added to a 25mL reaction flask, reacted overnight at 65 deg.C, LCMS monitored the reaction for completion, and the solvent was removed under reduced pressure to give 290d (crude, 100mg) which was used directly in the next step. MS (ESI, M/z) 415.0[ M + H ] +.

The third step

290d (crude 100mg, 0.23mmol), CDI (45mg,0.27mmol) and ethyl acetate (3mL) were put into a 25mL single-neck flask, refluxed at 67 ℃ for 1 hour, and after completion of the reaction, the reaction mixture was cooled, the solvent was dried, and 20mL of ethyl acetate, 1N hydrochloric acid (25 mL. times.3), water (25 mL. times.2), saturated brine (25 mL. times.1), dried over anhydrous sodium sulfate and purified by thin layer chromatography to obtain 290e (70mg, yield: 70.0%). MS (ESI, M/z) 441.0[ M + H ] +.

The fourth step

290e (390mg, 0.89mmol), Na₂HPO₄(252mg, 1.77mmol) and acetonitrile (30mL) were added to a 100mL single-neck flask, stirred well at room temperature, then trimethoxy onium tetrafluoroborate (337mg, 1.77mmol) was added to the system, the reaction was allowed to proceed overnight at room temperature, LCMS was used to monitor completion of the reaction, the reaction was cooled, the solvent was dried, ethyl acetate (50mL), water (50 mL. times.2), saturated brine (50 mL. times.1), anhydrous sodium sulfate was dried, and the reaction was concentrated to give 290f (crude, 0.04g) which was used directly in the next step. MS (ESI, M/z) 455.0[ M + H ]]+。

The fifth step

290f (crude 400mg), sulfamide (100mg, 1.04mmol) and absolute methanol (10mL) were added to a 50mL single-neck flask and reacted overnight at 45 deg.C, LCMS monitored reaction completion, the reaction was cooled, concentrated and purified by HPLC, and after removal of acetonitrile, 290g of aqueous solution was obtained and used directly in the next step. MS (ESI, M/z) 519.0[ M + H ] +.

The sixth step

To 290g of the above aqueous solution was added anhydrous methanol (10mL), stirred at room temperature, adjusted to pH 12 with 2N sodium hydroxide, reacted at room temperature for 1 hour, monitored by LCMS for completion of the reaction, adjusted to pH 7 with glacial acetic acid, methanol was removed by rotation, added ethyl acetate 50mL, washed with water (50mL × 2), washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, concentrated and lyophilized to obtain the title compound 81(32mg, two-step yield: 7.94%). MS (ESI, M/z) 493.0[ M + H ] +.

¹H NMR(400MHz,DMSO-d₆)δ11.48(s,1H),8.90(s,1H),8.09(d,J＝4.6Hz,1H),7.19(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.77(m,1H),6.37(d,J＝6.8Hz,2H),6.22(t,J＝5.9Hz,1H),3.23(dd,J＝13.4,6.8Hz,2H),2.69–2.60(m,5H),1.99–1.87(m,2H).

Example 82

N- (3-chloro-4-fluorophenyl) -N '-hydroxy-4- ((2-N' - (methylsulfonyl) piperazine-1-carboxyformamide) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hydrochloride

First step of

Compound 166c (200mg, 0.64mmol), 134a (191mg, 0.96mmol), N-diisopropylethylamine (0.3g, 2mmol) and N, N-dimethylformamide (5mL) were placed in a 50mL reaction flask and the temperature was raised to 70 ℃ for reaction for 2 hours. LC-MS monitors the reaction to be complete, piperazine (490mg, 5.7mmol) is added, the reaction is continued for 5h at 70 ℃, LC-MS monitors the reaction to be complete, the reaction solution is poured into water, ethyl acetate (15 mL. times.3) is extracted for three times, the organic layer is washed twice with saturated saline solution, and anhydrous Na₂SO₄After drying, filtration, concentration of the solvent under reduced pressure to dryness, and purification by Pre-HPLC (0.05% aqueous hydrochloric acid and acetonitrile) gave title compound 82-1(79mg, yield: 23%). MS (ESI, M/z) 504.1[ M + H ]]+。

¹H NMR(400MHz,DMSO-d₆)δ11.46(s,1H),9.489(s,2H),8.92(s,1H),7.79(s,1H),7.21-7.19(t,J＝8.8Hz,1H),7.03-7.01(m,1H),6.81–6.74(m,1H),6.44(s,1H),3.67–3.61(m,4H),3.49–3.43(m,2H),3.42–3.36(m,2H),3.11(s,4H),2.87(s,3H).

Example 83

N- (3-bromo-4-fluorophenyl) -N-hydroxy-4- ((2- (2-sulfamoylguanidino) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine

First step of

Compound 166c (100mg,0.28mmol), 310b (68.0mg, 0.34mmol), N-diisopropylethylamine (0.11g, 0.84mmol), and N, N-dimethylformamide (5mL) were placed in a 50mL reaction flask and heated to 70 ℃ for 2 h. LC-MS monitors the reaction to be complete, the reaction solution is cooled to room temperature, 0.5mL of ammonia solution is added, the temperature is raised to 50 ℃ for reaction overnight, LC-MS monitors the reaction to be complete, the reaction solution is poured into ice water, ethyl acetate (10mL multiplied by 3) is extracted for three times, an organic layer is washed twice by saturated saline, dried by anhydrous Na2SO4, filtered, the solvent is concentrated to be dry under reduced pressure, and then the title compound 83(21mg, yield: 15.7%) is obtained after purification by Pre-HPLC. MS (ESI, M/z) 480.1[ M + H ] +.

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),8.91(s,1H),7.20(t,J＝8.8Hz,1H),7.12(dd,J＝6.1,2.7Hz,1H),6.85–6.70(m,2H),6.63–6.50(m,2H),6.34–6.23(m,1H),6.19–6.08(m,2H),3.39–3.28(m,4H).

Biological assay

Experimental example 1 screening for IDO inhibitory Activity

Enzyme activity screening of IDO inhibitors by NTRC NFK GreenScreen^TMhIDO kit.

The experimental method comprises the following steps:

preparing an enzyme solution: the IDO enzyme reaction buffer was prepared on the day and used in a pre-ice bath for 3 h.

Addition of compound and enzyme: after the compound was diluted with DMSO gradient, it was diluted 50-fold with 0.05mM sodium phosphate buffer (pH 6.5), 5 μ L per well was added to the corresponding 384-well plate, 10 μ L of IDO enzyme solution (diluted with the buffer in the kit, final IDO enzyme concentration in the system was 25nM) was added, and the reaction was carried out at room temperature with light for 30 min.

Adding a reaction substrate: mu.L of 0.4mM L-tryptophan (final concentration of the system: 0.1mM) was added to each reaction well, and the reaction was carried out for 60min at room temperature in the absence of light.

Adding a color developing agent: add 5. mu.L NFK Green to each reaction well and react at 37 ℃ for 4h under a closed lid.

And (3) detection: the fluorescence value is detected by a microplate reader, and the Ex./Em. is 400 +/-25 nm/510 +/-20 nm.

Data processing: compound inhibition (%) - (1-S)_avg/C_avg)×100％，S_avgAverage value of fluorescence readings for the test compound, C_avgThe average value of the fluorescence readings of the negative control group; IC of Compounds 1 to 70₅₀The ratio is (100-Y)/YxC, Y is the inhibition rate (%) of the test compound, and C is the concentration of the test compound. IC of Compounds 71-76₅₀The formula Y is 100/(1+10^ ((log IC) in GraphPad Prism software)₅₀-X) X HillSlop), Y is the inhibition rate of the compound to be tested, and X is the logarithmic value of the concentration of the compound to be tested.

As a result:

TABLE 1 IC inhibition of IDO enzymes by the compounds of the invention₅₀

Compound numbering	IC ₅₀(nM)	Compound numbering	IC ₅₀(nM)
1	83.9	39	69.4
2	34.3	40	32.0
3	43.2	41	24.5
6	47.2	44	91.4
7	58.6	45	92.6
8	75.6	47	54.8
9	26.0	49	103.8
10	39.8	50	68.2
11	29.1	51	19.9
12	61.1	52	59.3
13	61.5	53	18.2
15	70.7	56	63.2

16	56.0	58	60.8
17	41.9	59	18.9
18	48.4	61	70.6
19	63.6	62	47.9
20	50.4	63	51.7
25	101.4	65	86.1
27	93.9	66	63.9
29	34.7	67	40.2
30	34.3	68	55.9
31	63.0	69	55.1
32	48.0	70	98.1
33	39.9	71	30.2
34	118.6	72	62.5
35	47.5	73	61.9
36	44.5	75	96.76
37	9.7	76	34.1

As can be seen from table 1, the compounds of the present invention have a significant inhibitory effect on IDO enzyme activity.

EXAMPLE 2 intracellular IDO enzyme inhibitory Activity test

The effect of compounds on intracellular IDO enzyme activity was determined using the NFK Green method.

Reagent: NFK Green fluorescent dye (NTRC); l-tryptophan (Sigma-Aldrich); recombinant Human IFN-gamma Protein (R & D systems)

The experimental method comprises the following steps:

cell culture: in vitro monolayer culture of tumor cells, wherein the culture conditions are as follows: hela cells, DMEM plus 10% fetal bovine serum at 37 deg.C with 5% CO₂Cultured in an incubator. Digesting with pancreatin-EDTA for 2-3 times a week for passage. When the cells are in exponential growth phase, the cells are harvested, counted and plated. The cell concentration (10000 HeLa cells/well) was adjusted, and the cells were seeded in a 96-well plate at 70. mu.L/well. Marking on a 96-well plate cover and placing the 96-well plate cover into an incubator for cultureAnd (5) cultivating for 24 hours.

Compound preparation: dissolving a compound to be detected by DMSO to prepare a mother solution, sucking a proper amount of the mother solution into the culture solution, uniformly mixing, and configuring the medicine solution into a corresponding incubation concentration. Add 10. mu.L of the prepared compound solution to each well and continue incubating the cells for 1 h.

IDO stimulation and substrate addition: mu.L of 500ng/mL IFN-. gamma.IFN (Recombinant Human IFN-gamma Protein) (dissolved in complete medium at 50ng/mL) was added, together with 10. mu.L of sterile 0.5mM L-tryptophan solution (dissolved in 20mM Hepes at 0.05mM final concentration) and incubated for 48 h.

And (3) detection: after completion of incubation, 25. mu.L of the supernatant was transferred to 384-well plates, 5. mu.L of NFK Green was added to each well, and incubated at 37 ℃ for 4h with a lid. Fluorescence is detected by a microplate reader, and Ex./Em. is 400 +/-25 nm/510 +/-20 nm.

Data processing: the compound inhibition rate (%) is (1-Savg/Cavg) multiplied by 100%, Savg is the average value of the fluorescence readings of the compound to be detected, and the average value of the fluorescence readings of a Cavg negative control group; IC (integrated circuit)₅₀The formula Y is 100/(1+10^ ((log IC) in GraphPad Prism software)₅₀-X) X HillSlop), Y is the inhibition rate of the compound to be tested, and X is the logarithmic value of the concentration of the compound to be tested.

As a result:

TABLE 2 IC inhibition of IDO enzyme Activity in Hela cells by Compounds of the invention₅₀

Compound numbering	IC ₅₀(nM)	Compound numbering	IC ₅₀(nM)
2	4.1	41	7.7
3	2.1	44	6.8
7	5.6	45	2.4
9	8.8	50	3.6
15	6.2	51	5.2
17	3.7	53	7.8
19	7.7	56	5.1
25	8.8	59	4.9
28	3.0	63	4.7
29	10.8	65	4.3
30	4.1	66	2.8
31	12.0	67	4.0
32	7.5	68	4.2
33	6.2	69	6.5
34	8.7	70	5.8
35	6.4	71	3.1
36	9.2	72	2.1
37	2.7	73	2.5
39	4.3	75	2.9
40	2.9	76	3.1

As can be seen from Table 2, the compounds of the present invention have a significant inhibitory effect on the IDO enzyme in Hela cells.

EXAMPLE 3 Biochemical hERG experiment

By using

The hERG Fluorescence Polarization Assay Kit determines the effect of compounds on hERG channels.

The kit comprises:

hERG Fluorescence Polarization Assay Kit

the experimental method comprises the following steps:

the potential of compounds to induce prolongation of cardiac QT interval was assessed using a biochemical hERG assay kit (semer feishel) based on fluorescence polarization techniques. Adding a compound to be tested, a positive control (an antiarrhythmic drug E4031) and a negative control (an experimental buffer solution) into a microplate containing an hERG cell membrane, adding a tracer with high hERG affinity, incubating the microplate at 25 ℃ for 2 hours, detecting the change of a fluorescence polarization value (mP) by using a BMG PHARESTar multifunctional microplate reader, and finally calculating different concentrationsLower percent inhibition (%) to determine the half maximal Inhibitory Concentration (IC) of the compound₅₀) The range of (1).

Percent inhibition (%). 1- (mP of test compound mP-30 μ M E4031)/(mP of experimental buffer mP-30 μ M E4031)). times.100

When the percent inhibition is between 30 and 80, the IC can be calculated as follows₅₀The value of (c):

IC₅₀(100-percent inhibition)/percent inhibition X, where X is the test concentration of the compound

As a result:

TABLE 3 IC inhibition of hERG by the compounds of the invention₅₀

Compound numbering	IC ₅₀(μM)	Compound numbering	IC ₅₀(μM)
1	>10	44	>10
7	>10	45	>10
17	>10	50	>10
29	>10	51	>10
30	>10	53	>10
32	>10	56	>10
33	>10	59	>10
34	>10	63	>10
35	>10	65	9.07
36	>10	66	>10
37	>10	68	>10
39	>10	69	>10

40

>10

70

>10

As can be seen in Table 3, the compounds of the present invention have no significant inhibitory effect on hERG, indicating that the compounds are less likely to induce prolongation of cardiac QT intervals.

Experimental example 4 CYP enzyme inhibition test

Reagent:

P450-Glo^TMCYP1a2 Screening System, manufacturer: promega;

CYP2D6 Cyan Screening Kit, manufacturer: life;

P450-Glo^TMCYP3a4 Screening System, manufacturer: promega.

The experimental method comprises the following steps:

CYP1A2/CYP3A 4: according to the kit specification, pre-incubating an enzyme-substrate and a compound for 10min at room temperature, adding a G6PDH-G6P-NADP regeneration system to start reaction, adding a Detection buffer after reacting for a period of time, and detecting a chemiluminescent signal after 20 min. The inhibition was calculated using vehicle group (DMSO) as negative control and Membrance (inactive enzyme) as blank control.

CYP2D6 (Vivid): following pre-incubation of the enzyme-G6 PDH-G6P with the compound, the reaction was initiated by addition of NADP-substrate and the change in fluorescence signal with time was detected in the enzyme kinetic mode according to the kit instructions. The rate of inhibition was calculated using the ratio of fluorescence signal to reaction time (slope) in the linear range as the reaction rate, vehicle (DMSO) as negative control, and buff (no enzyme) as blank control.

Determining half Inhibitory Concentration (IC) of the compound according to the inhibition rate of the compound on P450 enzyme at different concentrations₅₀) The range of (1).

As a result:

TABLE 4 IC inhibition of CYP enzyme activity by the compounds of the invention₅₀

The test result shows that the compound of the invention has no obvious inhibition effect on CYP1A2, CYP2D6 and CYP3A4 enzymes.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

A compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof

Wherein:

R₁selected from optionally substituted C_6-10Aryl or optionally substituted 5-6-or 8-10-membered heteroaryl containing 1 to 4 identical or different heteroatoms selected from N, O, S;

R₂，R₃each independently selected from H, halogen, cyano, hydroxy, nitro, substituted or unsubstituted C_1-12Alkyl, substituted or unsubstituted C_2-12Alkenyl, substituted or unsubstituted C_3-12Monocyclic alkyl, substituted or unsubstituted C_5-12Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or R on the same or different carbon atoms₂And R₃、R₂And R₂、R₃And R₃May be independently linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group;

part represents a single bond or a double bond;

y is selected from N (R)₄)_m，C(R₅)_nM is an integer selected from 0 to 1, n is an integer selected from 1 to 2, R₄And R₅Each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or containing 1 to 4 identical or different heteroatoms selected from N, O, SUnsubstituted 5-6 or 8-10 membered heteroaryl; when n is 2, two R₅May be linked to the carbon atom to which it is attached to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; when n is 2, two R₅May be the same or different;

z is selected from N (R)₆)_n，C(R₇)_qN is an integer selected from 1 to 2, q is an integer selected from 2 to 3, R₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂，R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when n is 2, two R₆May be linked to the nitrogen atom to which it is attached to form an optionally substituted 4-8 membered heterocyclic group; when q is equal to or greater than 2, R₇May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl, when multiple R's are present₆Or R₇When each R is₆May be the same or different, each R₇May be the same or different;

w is selected from NR₈(R₉)_m，C(R₁₀)_qM is an integer selected from 0 to 1, q is an integer selected from 2 to 3, R₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂，R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Multiple ringAlkyl, substituted or unsubstituted 4-to 10-membered heterocyclic group containing at least one heteroatom selected from the group consisting of N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or, when q is equal to or greater than 2, R₁₀May be bonded to the carbon atom to which it is bonded to form optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; when there are more than one R₁₀When each R is₁₀May be the same or different;

x is selected from NR₁₃,CR₁₄R₁₅,O,S；

R₁₁、R₁₂Are respectively selected from hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; when multiple R's are present simultaneously₁₁Or a plurality of R₁₂When each R is₁₁Each R, which may be the same or different, is₁₂May be the same or different;

R₁₃、R₁₄and R₁₅Each independently selected from H, substituted or unsubstituted C_1-4An alkyl group; or, R₁₄And R₁₅And the carbon atoms to which they are attached together form a substituted or unsubstituted C_3-12Cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl containing at least one heteroatom selected from N, O, S;

p is an integer selected from 1 to 6;

when a plurality of m exist at the same time, each m may be the same or different;

when a plurality of n exist at the same time, each n may be the same or different;

when a plurality of q exist at the same time, each q may be the same or different;

y, W and Z are not carbon at the same time;

in (1),
one and only one is a double bond;

when R is₁Is composed of
R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂or-NHCH₃Z is C (R)₇)_qWherein q is 2, R₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of
R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂Z is N (R)₆)_nWherein n is 1, R₆X is not O or S when independently selected from hydrogen or cyano;

said "substituted" means, but is not limited to, independently substituted with: halogen, cyano, nitro, hydroxy, amino, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, R₁₆SO₂,R₁₆SO,R₁₆CO,R₁₆R₁₇NCO,R₁₆R₁₇NSO₂，R₁₆OCO, wherein R₁₆、R₁₇Independently selected from hydrogen andC_1-4alkyl when multiple R are present₁₆Or a plurality of R₁₇When each R is₁₆Each R, which may be the same or different, is₁₇May be the same or different.
The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has a structure represented by formula II,

wherein:

y is selected from NR₄，C(R₅)₂(ii) a Wherein R is₄And R₅Each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₅To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein two R are₅May be the same or different;

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or notSubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein two R are₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; wherein each R is₁₀May be the same or different;

y, W and Z are not carbon at the same time;

when R is₁Is composed of
R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂or-NHCH₃Z is C (R)₇)₂Wherein R is₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of
R₂、R₃Each independently selected from hydrogen, p is 2, Y is-NH-, and W is-NH₂Z is NR₆Wherein R is₆X is not O or S when independently selected from hydrogen or cyano;

X，R₁，R₂，R₃，R₁₁，R₁₂，R₁₃，R₁₄，R₁₅p is as defined in claim 1.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, wherein X is selected from NR₁₃,O,S，R₁₃As defined in claim 1 or 2.
A compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has a structure represented by formula III,

wherein:

y is selected from NR₄，C(R₅)₂(ii) a Wherein R is₄And R₅Each independently selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₅To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein two R are₅May be the same or different;

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein two R are₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl radical, i.e. aSubstituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; wherein each R is₁₀May be the same or different;

y, W and Z are not carbon at the same time;

x is selected from NR₁₃,O,S；

When R is₁Is composed of
Y is-NH-and W is-NH₂or-NHCH₃Z is C (R)₇)₂Wherein R is₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of
Y is-NH-and W is-NH₂Z is NR₆Wherein R is₆X is not O or S when independently selected from hydrogen or cyano;

R₁，R₁₁，R₁₂，R₁₃as defined in any one of claims 1 to 3.
The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has a structure represented by formula IV,

wherein:

R₄selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₂CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

z is selected from NR₆，C(R₇)₂(ii) a Wherein R is₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₇To the carbon atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein two R are₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; wherein each R is₁₀May be the same or different;

x is selected from NR₁₃,O,S；

When R is₁Is composed of
Y is-NH-and W is-NH₂or-NHCH₃Z is C (R)₇)₂Wherein R is₇X is not O or S when independently selected from hydrogen or nitro;

when R is₁Is composed of
Y is-NH-and W is-NH₂Z is NR₆Wherein R is₆X is not O or S when independently selected from hydrogen or cyano;

R₁，R₁₁，R₁₂，R₁₃as defined in any one of claims 1 to 4.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has the structure shown in formula IV-1,

wherein:

R₆selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

when R is₁Is composed of
Y is-NH-and W is-NH₂，R₆X is not O or S when independently selected from hydrogen or cyano;

X，W，R₁，R₄，R₈，R₉，R₁₀，R₁₁，R₁₂，R₁₃as defined in any one of claims 1 to 5.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has a structure represented by formula IV-2,

wherein the content of the first and second substances,

R₇selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

when R is₁Is composed of
Y is-NH-and W is-NH₂or-NHCH₃，R₇X is not O or S when independently selected from hydrogen or nitro;

X，W，R₁，R₄，R₈，R₉，R₁₀，R₁₁，R₁₂，R₁₃as defined in any one of claims 1 to 5.
The compound of any one of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has a structure represented by formula V-1,

wherein:

z is selected from N (R)₆)₂，C(R₇)₃(ii) a Wherein R is₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₆To the nitrogen atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or alternatively, two or three R₇To which the carbon atom to which it is attached is linked to optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein each R is₆May be the same or different; each R is₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉And R₁₀Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 membered heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉To the nitrogen atom to which it is attached to form an optionally substituted heterocycle containing at least one member selected from the group consisting of N, O, SA 4-10 membered heteromonocyclic group of atoms or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; wherein each R is₁₀May be the same or different;

x is selected from NR₁₃,O,S；

R₁，R₁₁，R₁₂，R₁₃As defined in claim 1.
The compound of any one of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound has a structure represented by formula V-2,

wherein:

R₅selected from hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S;

z is selected from N (R)₆)₂，C(R₇)₃(ii) a Wherein R is₆And R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, two R₆To the nitrogen atom to which it is attached to form an optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or alternatively, two or three R₇To which the carbon atom to which it is attached is linked to optionally substituted C_3-8Cycloalkyl or optionally substituted 4-8 membered heterocyclyl; wherein each R is₆May be the same or different; each R is₇May be the same or different;

w is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Monocyclic alkyl, substituted or unsubstituted C_5-10Polycycloalkyl, substituted or unsubstituted 4-10 member heterocyclic group containing at least one heteroatom selected from N, O, S, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or alternatively, two or three R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; each R is₁₀May be the same or different;

x is selected from NR₁₃,O,S；

R₁，R₁₁，R₁₂，R₁₃As defined in claim 1.
The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein R is₁Selected from optionally substituted C_6-10An aryl group; preferably, R₁Selected from optionally substituted phenyl; preferably, R₁Selected from phenyl substituted by one or more halogens; preferably, R₁Is selected from
Particularly preferably, R₁Is composed of
The compound of any one of claims 1-7 and 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein R is₄Selected from hydrogen, cyano, nitro, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8An alkenyl group; preferably, R₄Selected from hydrogen, substituted or unsubstituted C_1-4An alkyl group; further preferably, R₄Selected from hydrogen and methyl; particularly preferably, R₄Is hydrogen.
The compound of any one of claims 1-4, 9, and 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein, and R₅Is hydrogen.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein R is₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O, S; preferably, R₆Or R₇Each independently selected from: hydrogen, cyano, nitro, R₁₁SO₂,R₁₁CO,R₁₁R₁₂NSO₂,R₁₁R₁₂NCO，R₁₁OCO, substituted or unsubstituted C_1-4An alkyl group; preferably, R₆Or R₇Each independently selected from: hydrogen, cyano, nitro, methylsulfonyl, NH₂- (C ═ O) -, sulfonamido, ethanesulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, cyclohexylsulfonyl, phenylsulfonyl, -CH₂CF₃，-CH₂CN; particularly preferably, R₆Or R₇Each independently selected from: hydrogen, cyano, nitro, methylsulfonyl, NH₂- (C ═ O) -, sulfonamido, ethanesulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, benzenesulfonyl, -CH₂CF₃。
The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein W is selected from NR₈R₉，C(R₁₀)₃(ii) a Wherein R is₈、R₉Or R₁₀May be the same or different and are each independently selected from: the presence of hydrogen in the presence of hydrogen,substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_2-8Alkenyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-6 or 8-10 membered heteroaryl containing 1 to 4 identical or different heteroatoms selected from N, O, S; or, R ₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; or, R₁₀To which the carbon atom to which it is attached is linked to optionally substituted C_3-8A cycloalkyl group or an optionally substituted 4-to 8-membered heterocyclic group; preferably, W is NR₈R₉(ii) a Wherein R is₈Or R₉Each independently selected from: hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted C_6-10An aryl group; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted 5-6 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S or an optionally substituted 4-10 membered heteromonocyclic group containing at least one heteroatom selected from N, O, S; more preferably, W is NR₈R₉(ii) a Wherein R is₈Or R₉Each independently selected from: hydrogen, substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted phenyl; or, R₈And R₉And the nitrogen atom to which it is attached to form an optionally substituted morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl or an optionally substituted 4-10 membered spiroheterocyclyl containing at least one heteroatom selected from N, O, S; particularly preferably, W is selected from amino, tert-butylamino, phenylamino, benzylamino, isopropylamino, dimethylamino, morpholinyl, piperidinyl, tetrahydropyrrolyl, methylamino, cyclohexylamino, ethylamino, cyclopropylamino,
The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein R is₁₃Selected from H, substituted or unsubstituted C_1-4An alkyl group; preferably, R₁₃Is H.
The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein Z is selected from NR₆Or C (R)₇)₂，R₆And R₇Each independently selected from: cyano, nitro, R₁₁SO₂，R₁₁R₁₂NSO₂，R₁₁R₁₂NCO, trifluoroethyl;

R₁₁、R₁₂independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, phenyl;

preferably, Z is CHR₇，R₇Is nitro.
The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein said "substitution" represents independently substitution by: fluorine, chlorine, bromine, hydroxyl, methyl or methoxy.
The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein X is selected from NH, O, S.
The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the compound is selected from the group consisting of:
the compound of claim 19, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, wherein the pharmaceutically acceptable salt of the compound is the hydrochloride salt; the preferred hydrochloride salt is
A process for the preparation of a compound according to any one of claims 1 to 20, according to the following scheme 1, scheme 2, scheme 3 or scheme 4:

reaction scheme 1

The first step is carried out in the presence of an organic or inorganic base and/or a condensation agent;

the second step is carried out at a temperature of 20 to 180 ℃ (e.g., 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an amine reagent;

reaction scheme 2

The first step is carried out at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an organic or inorganic base and/or a condensing agent;

the second step is carried out under alkaline conditions at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃);

reaction scheme 3

The first step is carried out under alkaline conditions at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃);

the second step is carried out at a temperature of 20 to 180 ℃ (e.g., 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an organic or inorganic base and/or a condensing agent;

the third step is carried out at a temperature of 20 to 180 ℃ (e.g., 40 to 80 ℃, such as 65 ± 2 ℃) in the presence of an amine reagent;

reaction scheme 4

The first step is carried out in an aprotic solvent in the presence of an organic or inorganic base at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃);

the second step is carried out under alkaline conditions at a temperature of from 20 to 180 ℃ (e.g. from 40 to 80 ℃, such as 65 ± 2 ℃);

the third step is carried out under alkaline conditions with methyl iodide at a temperature of 20 to 180 ℃ (e.g., 40 to 80 ℃, such as 65 ± 2 ℃);

the fourth step is carried out at a temperature of from 20 to 180 ℃ such as from 40 to 80 ℃ such as 65. + -. 2 ℃ in the presence of an amine reagent.
A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture of same, and one or more pharmaceutically acceptable carriers.
A kit comprising a compound of any one of claims 1-20, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of claim 22.
Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the prevention or treatment of a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression, wherein the disease is preferably selected from the group consisting of cancer, viral infections, alzheimer's disease, depression and diseases of the immune system, wherein the medicament is preferably a medicament for administration by the oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal route, and wherein the medicament may further comprise one or more other therapeutic agents, such as other anticancer drugs.
A compound of any one of claims 1-20, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite, or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of claim 22, for use in the prevention or treatment of a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression; preferably, the disease is selected from cancer, viral infections, alzheimer's disease, depression and immune system diseases.
A method for preventing or treating a disease caused by indoleamine 2, 3-dioxygenase (IDO) mediated immunosuppression, comprising administering a prophylactically or therapeutically effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, hydrate, metabolite or prodrug thereof, or a mixture thereof, or a pharmaceutical composition of claim 22; preferably, the disease is selected from cancer, viral infections, alzheimer's disease, depression and immune system diseases.