WO2017181849A1

WO2017181849A1 - Indoleamine 2,3-dioxygenase inhibitor, preparation method therefor, and application

Info

Publication number: WO2017181849A1
Application number: PCT/CN2017/079585
Authority: WO
Inventors: 吴盛华; 李凯龙; 包如迪
Original assignee: 江苏豪森药业集团有限公司; 上海翰森生物医药科技有限公司
Priority date: 2016-04-20
Filing date: 2017-04-06
Publication date: 2017-10-26

Abstract

The present invention relates to an indoleamine 2,3-dioxygenase inhibitor having the structure of formula (I), a preparation method therefor, and an application. The IDO inhibitor is an N'-hydroxyl-N-phenylformamidine derivative, has high inhibitory activity on IDO, effectively inhibits IDO activity, and may also be used to inhibit patient immunosuppression. The inhibitor may be widely applied to treat or prevent cancers or tumours, viral infections, depression, neurodegenerative diseases, trauma, age-related cataracts, organ transplant rejection or autoimmune diseases, and has the potential to be developed into a new generation of immunosuppressors.

Description

Indoleamine 2,3-dioxygenase inhibitor and preparation method and application thereof

Technical field

The invention belongs to the field of drug development, and particularly relates to a guanamine 2,3-dioxygenase inhibitor and a preparation method and application thereof.

Background technique

Indoleamine 2,3-dioxygenase (IDO) is a protease involved in the metabolism of tryptophan. Tryptophan is one of the eight essential amino acids. In vivo, tryptophan can be used to synthesize proteins. Tryptophan can also be used as a precursor substrate to synthesize serotonin and melatonin through the methoxypurine metabolic pathway (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones that are involved in the regulation of various neurological and physiological processes in the body. In addition, tryptophan can also produce metabolites such as kynurenine through the kynurenine metabolic pathway. The first step in the kynurenine metabolic pathway is the tryptophan L-color ammonia catalyzed by indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO). Acid degradation to N-formyl-kynurenine, N-formyl-kynurenine forms kynurenine under the catalysis of kynurenine carboxamide, and kynurenine can be further metabolized. 3-hydroxyanthranilic acid, quinolinic acid, picolinic acid. Quinolinic acid is neurotoxic, while picolinic acid has neuroprotective effects. Canine uridine and 3-hydroxyanthranilic acid are involved in the regulation of lymphocyte activity leading to inhibition of the immune system.

In addition to placental tissue, indoleamine 2,3-dioxygenase is not expressed in most tissue cells under normal health conditions. In the region of inflammation, inflammatory cytokines such as interferon gamma can induce an increase in the expression of indoleamine 2,3-dioxygenase. The results of various experiments prove that the high expression of indoleamine 2,3-dioxygenase in tissue cells can lead to inhibition of the immune system of the tissue microenvironment, or immune suppression or immune checkpoint. . High expression of placental tissue indoleamine 2,3-dioxygenase prevents immune rejection of the fetus. The high expression of indoleamine 2,3-dioxygenase in the inflammatory region prevents excessive immune responses and prevents excessive damage to cellular tissues. One of the mechanisms leading to inhibition of immunity is that high expression of indoleamine 2,3-dioxygenase causes local L-tryptophan depletion, which is sensed by surrounding lymphocytes through mechanisms such as GCN2, causing CD8+ cytotoxic T cells. Cell cycle arrest or apoptosis occurs. Another mechanism that leads to inhibition of immunity is the high expression of indoleamine 2,3-dioxygenase, which causes an increase in kynurenine. After kynurenine formation, it leaves the cell and enters the extracellular matrix, and then enters the nearby lymph. The cells regulate CD8+ T cells and regulatory Treg cells by binding to AHR transcription factors, and the activity of CD8+ cytotoxic T cells is inhibited, while the number of regulatory Treg cells is increased and activated, resulting in inhibition of immunity.

In many different types of tumors, indoleamine 2,3-dioxygenase is abnormally highly expressed, including hematological tumors and solid tumors such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and throat cancer. The abnormally high expression of indoleamine 2,3-dioxygenase was positively correlated with poor tumor prognosis. Tumor cell escape immune monitoring is a key step in the further development of cancer and cancer. The abnormally high expression of indoleamine 2,3-dioxygenase in tumors may be the escape of tumor cells. A major mechanism of immunological monitoring, inhibition of the activity of indoleamine 2,3-dioxygenase may activate the suppressed immune system to inhibit tumor growth, so indoleamine 2,3-dioxygenase Inhibitors, as an immune checkpoint inhibitor, have attracted a lot of interest in the medical community. There are two kinds of indoleamine 2,3-dioxygenase (IDO), IDO-1 and IDO-2. The main inhibitory of the above immunity is IDO-1. The role of IDO-2 in immune suppression is not yet very clear. Tryptophan 2,3-dioxygenase (TDO) is also abnormally highly expressed in many types of tumors, and some tumors also exhibit double positive IDO and TDO, so some people think that it can also suppress TDO immune checkpoints. The purpose of cancer treatment. Because normal liver cells express TDO, it is unclear whether TDO inhibitors affect liver function and normal tryptophan metabolism, but there is no abnormality in the mouse model of TDO knockout, indicating that TDO inhibitors may not affect liver function and normality. The metabolism of tryptophan. The mechanism by which IDO and TDO cause immune suppression is basically the same, so IDO/TDO bispecific inhibitors have also attracted interest in the pharmaceutical industry. IDO/TDO bispecific inhibitors will be suitable for IDO positive, TDO positive, IDO/TDO double positive. Patient.

Many metabolites of the kynurenine metabolic pathway of tryptophan are associated with schizophrenia, depression, and neuronal degeneration, and indoleamine 2,3-dioxygenase inhibitors may also be useful in the treatment of these diseases. Canine uridine can be converted to canine urinary quinolinic acid under the catalysis of kynurenine aminotransferase. Canine urinary quinolinic acid is an NMDA antagonist, which is common in the central nervous system of patients with schizophrenia. Canine urinary quinolinic acid levels. Quinolinic acid is neurotoxic and can cause neuronal apoptosis and neurodegeneration. Indoleamine 2,3-dioxygenase is not only involved in the metabolism of tryptophan, but also involved in the metabolism of tryptamine. The serotonin can be converted to 5-- under the catalysis of indoleamine 2,3-dioxygenase. Hydroxamic acid, a decrease in serotonin may be one of the factors leading to depression.

Currently, the development of indoleamine 2,3-dioxygenase inhibitors is in the early stages, including NewLink's Indoximod, NLG-919 (IDO/TDO bispecific), Incyte's Epacadostat (INCB024360), and BMS, Flexus. , Iomet, Iteos, Curadev and other companies IDO or TDO inhibitors. Patent WO2016041489A1 discloses a series of sulfonimido compounds which have good inhibitory activity against indoleamine 2,3-dioxygenase (IDO), but the best compound 6 disclosed in this patent is relative to INCB-24360. Exposure to exposure (AUC) is limited and T _1/2 is short, which is not conducive to clinical development; Compound 13 (Compound 6 prodrug), although prolonged by T _1/2 , is not as effective as INCB- 24360, therefore, further development of compounds with a suitable T _1/2 for clinical administration, while having a high exposure (AUC) has attracted many scientists around the world to work hard for this.

Summary of the invention

The inventors discovered N'-hydroxy-N-phenylformamidine derivatives after a series of studies, which have high inhibitory activity against indoleamine 2,3-dioxygenase (IDO), while tryptophan 2 , 3-dioxygenase (TDO) has no inhibitory activity and has a very good exposure (AUC) in the PK animal model, while having a T _1/2 that is well suited for clinical applications. Such compounds are effective in inhibiting the activity of IDO and can also be used to inhibit immunosuppression in patients. It can be widely used to treat or prevent cancer or tumors, viral infections, depression, neurodegenerative diseases, trauma, age-related cataracts, organ transplant rejection or autoimmune diseases, and is expected to be developed into a new generation of immunosuppressive agents.

In one aspect, the present invention provides a (Z)-N'-hydroxy-N-phenylformamidine derivative having the structure of the following formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

among them:

Z type and E type; preferably Z type;

X is selected from C _1-8 alkyl or C _3-8 cycloalkyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C _1-8 Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C _0-8 -S(O) _r R ₈ , -C _0-8 -OR ₅ , -C _0-8 -C(O) OR ₅ , -C _0-8 -C(O)R ₆ , -C _0-8 -OC(O)R ₆ , -C _0-8 -NR ₇ R ₈ , -C _0-8 -C(O) Substituted by a substituent of NR ₇ R ₈ , -N(R ₇ )-C(O)R ₆ or -N(R ₇ )-C(O)OR ₅ ;

R _{1 is} selected from the following structures:

Y is selected from -S(O) ₂ - or -C(O)-C(O)-;

Z is selected from a bond, O, S or -NR ₇ -;

R ₂ is selected from hydrogen, deuterium, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _{5- 10} aryl, 5-10 membered heteroaryl or C _0-8 alkylcarbonyl,

Optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo Substituting C _1-8 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl , C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C _{0 -8} -S(O) _r R ₄ , -C _0-8 -OR ₅ , -C _0-8 -C(O)OR ₅ , -C _0-8 -C(O)R ₆ , -C _{0- _{8 -OC (O) R 6,}} -C 0-8 -NR 7 R 8, -C 0-8 -C (O) NR 7 R 8, -N (R 7) -C (O) R 6 , or - Substituted by a substituent of N(R ₇ )-C(O)OR ₅ ;

R _{3 is} selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, C _1-8 alkyl, C _2-8 alkenyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-8 alkoxy, C _3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C _5-10 aryloxy, 5-10 membered heteroaryl Alkoxy group, -C _0-8 -S(O) _r R ₄ , -C _0-8 -C(O)OR ₅ , -C _0-8 -OC(O)R ₆ , -C _0-8 - NR ₇ R ₈ , -C _0-8 -C(O)NR ₇ R ₈ , -N(R ₇ )-C(O)R ₆ or -N(R ₇ )-C(O)OR ₅ ,

R _{4 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _2-8 alkenyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C _1-8 alkylamino group, a di C _1-8 alkylamino group or a C _1-8 alkanoylamino group;

R _{5 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-8 cycloalkyl, halogen substituted C _1-8 alkyl or hydroxy substituted C _1-8 alkyl;

R _{6 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, halogen substituted C _1-8 alkyl, halogen Substituting a C _1-8 alkoxy group, a hydroxy-substituted C _1-8 alkyl group or a hydroxy-substituted C _1-8 alkoxy group;

R ₇ , R ₈ , R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _2-8 chain Alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl or C _1-8 alkanoyl, or And R ₇ and R ₈ , R ₉ and R ₁₀ and the nitrogen atom to be bonded form a 3-8 membered heterocycloalkyl group,

Optionally further substituted with one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C _1-8 alkyl, trifluoromethyl, C _{2 8} -alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _1-8 alkoxy, C _1-8 alkoxycarbonyl, C _1-8 Alkylcarbonyl, C _1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C _1-8 alkylamino or di C Substituted by a substituent of a _1-8 alkylamino group;

r is 0 to 2.

As a further preferred embodiment, the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the compound of the formula (II):

among them:

X is selected from C _1-6 alkyl or C _3-8 cycloalkyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C _1-8 Substituted by a substituent of an alkyl group, a halogen-substituted C _1-8 alkyl group or a C _3-8 cycloalkyl group; R ₇ , R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, and C _1-8 alkyl. , C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, C _1-8 alkyl substituted C _5-10 aryl, 5-10 membered heteroaryl, C _1-8 alkanoyl or -C _0-8 -C(O)OR ₅ , or R ₉ and R ₁₀ and the nitrogen atom to be bonded form a 5-6 membered heterocycloalkyl group,

Optionally further substituted with one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C _1-8 alkyl, trifluoromethyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclic, C _1-8 alkoxy, C _1-8 alkoxycarbonyl, C _1-8 alkylcarbonyl, C _1-8 alkylcarbonyloxy, 3- 8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C _5-10 aryl, C _5-10 aryloxy, C _5-10 arylthio, 5-10 membered heteroaryl Substituted by a substituent of a 5-10 membered heteroaryloxy group, a 5-10 membered heteroarylthio group, an amino group, a mono C _1-8 alkylamino group or a di C _1-8 alkylamino group.

As a further preferred embodiment, the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Formula (IIA) or (IIB) ) Compound:

among them:

X is selected from ethyl, cyclobutyl, cyclohexyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, decyl, cyano, nitro, trifluoromethyl, C _1-8 alkyl or C Substituted by a substituent of a _3-8 cycloalkyl group;

R ₇ , R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _5-10 aryl group, C _1-8 alkyl substituted C _5-10 aryl group, 5-10 membered heteroaryl group, C _1-8 alkanoyl group or -C _0-8 -C(O)OR ₅ , or R ₉ , R ₁₀ form a 5-6 heterocycloalkyl group with the attached nitrogen atom.

As a most preferred embodiment, the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the following compounds:

As a further preferred embodiment, the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the group consisting of the compound of the formula (III):

Z is selected from a bond or -NR ₇ -;

R _{2 is} selected from the group consisting of hydrogen, hydrazine, and C _1-8 alkyl;

R _{3 is} selected from the group consisting of hydrazine, hydroxy, amino, C _1-8 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _{1 -8} alkoxy, C _3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C _5-10 aryloxy, 5-10 membered heteroaryloxy, -C _0-8 - S(O) _r R ₄ , -C _0-8 -C(O)OR ₅ or -C _0-8 -OC(O)R ₆ ;

r is 0 to 2.

As a still further preferred embodiment, the (Z)-N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the compound of the formula (III) has the following two Way of expression:

As a still further preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

Z is selected from a bond or -NR ₇ -;.

R _{2 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl;

R _{3 is} selected from the group consisting of hydroxyl, amino, C _1-8 alkyl or -C _0-8 -S(O) _r R ₄ ;

r is 0 to 2.

The present invention also relates to an intermediate for preparing a compound of the formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (IV), a stereoisomer thereof Or a pharmaceutically acceptable salt thereof:

among them:

Z, R ₂ and R _{3 are} as defined in the formula (III).

The invention further relates to a process for the preparation of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound of the formula (IV) is ring-opened under basic conditions to give a compound of the formula (III);

among them:

X, R ₂ and R _{3 are} as defined in the formula (III). According to another aspect of the present invention, there is provided a process for the preparation of the above-mentioned N'-hydroxy-N-phenylformamidine derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

among them:

X, R _{1 are} as defined for the compound of formula (I).

Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to another aspect of the present invention, there is provided a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the preparation of a medicament for inhibiting indoleamine 2 The activity of 3-dioxygenase is either used to inhibit immunosuppression in patients.

According to another aspect of the present invention, there is provided a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating or preventing a patient Cancer or tumor, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or autoimmune disease; preferably, wherein the cancer or tumor is selected from the group consisting of lung cancer, bone cancer, stomach cancer, pancreatic cancer, Skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophagus Cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urinary tract cancer, penile cancer, prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphoma, transitional cell carcinoma, bladder cancer, kidney cancer Or ureteral cancer, renal cell carcinoma, renal pelvic cancer, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, solid tumor of children, lymphocytic lymphoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, tumor angiogenesis, spinal tumor, brain stem glioma, pituitary adenoma, melanoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma , a combination of T cell lymphoma, chronic or acute leukemia, and said cancer.

As a further preferred embodiment, the use refers to a therapeutically effective amount of the aforementioned compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition and an anti-CTLA-4 antibody, Combination of anti-PD-1 antibody, anti-PD-L1 antibody, antiviral agent, chemotherapeutic agent, immunosuppressant, radiation, anti-tumor vaccine, anti-viral vaccine, cytokine therapy or tyrosine kinase inhibitor; preferably, The cytokine is preferably IL-2, IL-3, IL-4 or IL-5, the chemotherapeutic agent is preferably a cytotoxic agent, and the anti-PD-1 antibody is preferably a Keytruda antibody.

Another aspect of the invention provides a method of modulating guanamine 2,3-dioxygenase activity, comprising administering a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable The salt, or the aforementioned pharmaceutical composition, is contacted with the indoleamine 2,3-dioxygenase; preferably, the modulation is preferably an inhibitory effect.

Another aspect of the invention provides a method of inhibiting immunosuppression in a patient, the method comprising treating An effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, is administered to a patient.

Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. The method exhibits outstanding efficacy and fewer side effects, wherein the cancer or tumor is selected from the group consisting of lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tubes Cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer , urethral cancer, penile cancer, prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphoma, transitional cell carcinoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic cancer, Hodgkin's disease, non-Hodge Gold lymphoma, soft tissue sarcoma, solid tumor of children, lymphocytic lymphoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, tumor angiogenesis, spinal tumor, brain stem glioma, pituitary gland A combination of tumor, melanoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, chronic or acute leukemia, and said cancer.

DRAWINGS

Figure 1 is a detection spectrum of the compound of Example 15, the abscissa is the retention time (unit: min); the ordinate is the response value (unit: mV);

Figure 2 is the optical isomer ₁ detection spectrum, the abscissa is the retention time (unit: min); the ordinate is the response value (unit: mV);

Figure 3 is a photodetection spectrum of optical isomer 2, the abscissa is the retention time (unit: min); the ordinate is the response value (unit: mV).

detailed description

DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"C _1-8 alkyl" means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C _0-8 means no carbon atom or C. _{a 1-8} alkyl group, preferably a linear alkyl group having 1 to 6 carbon atoms, more preferably a linear alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-Butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl , 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-di Hexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl , 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof.

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C _3-8 cycloalkyl" refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.""Alkyl" means a cycloalkyl group comprising from 5 to 10 carbon atoms, for example, a non-limiting example of a monocyclic cycloalkyl group comprising a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, Cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl and cyclohexyl; polycyclic cycloalkyl includes spiro, fused ring and A cycloalkyl group of a bridged ring.

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. The "5-10 membered heterocyclic group" means a ring group containing 5 to 10 ring atoms, and the "3-8 membered heterocyclic group" means a ring group containing 3 to 8 ring atoms, preferably a 5-6 membered heterocyclic group. .

Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably morphinyl.

Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

"Aryl" means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated π-electron system (ie, having a ring adjacent to a carbon atom) a group, "C _5-10 aryl" means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group" means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) _r (where r is an integer 0, 1, 2), 5- A 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms, and a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.

"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C _2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and _C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons. . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

"Alkoxy" means -O-(alkyl) wherein alkyl is as defined above. The C _1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.

"Halo-substituted C _1-8 alkyl" means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

The hydrogen on the "halo-substituted C _1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"Halogen" means fluoro, chloro, bromo or iodo.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Stereoisomerization" includes three types of geometric isomerism (cis-trans isomerization), optical isomerism, and conformational isomerism.

The present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ) internally labeled as tetramethylsilane (TMS).

LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer. The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification for TLC is 0.15mm~0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

Starting materials in the examples of the invention are known and commercially available or can be synthesized or synthesized according to methods known in the art.

Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, and the solvent was a dry solvent.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The solution in the examples means an aqueous solution unless otherwise specified. The temperature of the reaction is room temperature. The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

Monitoring of the progress of the reaction in the examples using the thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) reaction using the developer system: dichloromethane and methanol system, n-hexane and ethyl acetate system The volume ratio of the petroleum ether and ethyl acetate systems, acetone, and solvent can be adjusted depending on the polarity of the compound. Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.

Synthesis of intermediates

Step 1: 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carbonoxaxan 1b

Propyl dicyanohydrin (20 g, 303 mmol) was dissolved in 350 ml of water, heated at 45 ° C for 5 minutes, sodium nitrite (23 g, 333.3 mmol) was added under ice bath, and 6N HCl (3.4 ml) was added when the temperature was raised to 10 ° C. The temperature was raised to 16 ° C, the temperature was stirred at 16-18 ° C for 1.5 hours, cooled to 13 ° C, 50% aqueous hydroxylamine solution (61.7 g, 909 mmol) was added in one portion, and the temperature was sharply increased to 27 ° C, and stirred at this temperature. After one hour, it was refluxed for another 2 hours, cooled to room temperature and stirred overnight. 6N HCl (49 ml) was added dropwise in an ice bath, and the pH was adjusted to 7, and then the mixture was stirred under ice-bath, and solids were separated, filtered, and the filter cake was washed with water and dried. Compound 4-Amino-N'-hydroxy-1,2,5-oxadiazol-3-carbohydroindole 1b (40 g, 92%).

MS m/z (ESI): 143.9.

¹³ C NMR (400 MHz, CD ₃ OD, ppm): δ 154.5, 144.4, 139.7.

Step 2: 4-Amino-N-hydroxy-1,2,5-oxadiazol-3-carbamimidyl chloride 1c

The compound 4-amino-N'-hydroxy-1,2,5-oxadiazol-3-carboindole (8.4 g, 59 mmol) was dissolved in 100 ml of water and glacial acetic acid (60 ml), and 6N HCl ( 29 ml), heating to complete dissolution, then adding NaCl (10.36 g, 59.5 mmol), and then adding an aqueous solution (14 ml) of sodium nitrite (3.99 g, 5.78 mmol) in an ice bath, and stirring at a temperature of 0 ° C for 1.5 hours. After stirring to room temperature, the solid is precipitated, filtered, and the filter cake is washed with water and dried to give the compound 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carbamimidyl chloride 1c (4 g, 42 %).

MS m/z (ESI): 162.9.

^{_{13 CNMR (400MHz, CD 3 OD}} , ppm): δ154.3,141.9,127.0.

Step 3: 4-Amino-N'-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carbonoxaxanthene 1d

The compound 4-amino-N-hydroxy-1,2,5-oxadiazol-3-carbamimidyl chloride (4.0 g, 24.7 mmol) was dissolved in ethyl acetate (40 ml). 2-methoxyethane-1-amine (2.29 ml, 25.9 mmol) was stirred for 5 minutes, then triethylamine (5.16 ml, 37.05 mmol) was added and stirred for two hours until the reaction was completed, washed with water, and washed with saturated brine. The organic phase was dried over sodium and concentrated under reduced vacuum to give compound 4-amino-N'-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carbooxazepine 1d (4.5g, 92%).

MS m/z (ESI): 202.1.

^{1 H NMR (400MHz, DMSO,} ppm): δ10.67 (s, 1H), 6.28 (s, 2H), 6.14 (s, 1H), 3.56 (m, 2H), 3.44 (m, 2H), 3.28 ( s, 3H).

Step 4: N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbonoxaxan 1e

The compound 4-amino-N'-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazol-3-carboindole (4.5 g, 22.3 mmol) was dissolved in water. (40 ml), potassium hydroxide (4.15 g, 74.1 mmol) was added to reflux for 48 hours until the reaction was completed. The mixture was extracted with ethyl acetate. Compound N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carbonoxaxan 1e (2.8 g, 62%).

MS m/z (ESI): 202.1.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ10.53 (s, 1H), 6.22 (s, 2H), 6.15 (s, 1H), 3.56 (m, 2H), 3.50 (m, 2H) , 3.37 (s, 3H).

Step 5: N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carbamimidyl chloride 1f

The compound N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carboindole (2.8 g, 13.93 mmol) was dissolved in 6N HCl. (14 ml) After the solution was clarified, sodium chloride water (2.2 g, 41.79 mmol) was added, then water (14 ml) and ethyl acetate (14 ml) were added, and sodium nitrite (1.0 g, The mixture was stirred for 2 hours, and the mixture was stirred for 2 hr. : petroleum ether (3/20) was washed to give the compound N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carbamimidyl chloride 1f (2.2g, 72%).

MS m/z (ESI): 221.1.

^{1 HNMR (400MHz, DMSO-d} 6, ppm): δ13.47 (s, 1H), 6.22 (s, 2H), 5.99 (s, 1H), 3.43 (m, 2H), 3.53 (m, 2H), 3.28(s,3H).

Step 6: N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carb miscellaneous Xanthene 1g

The compound N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carbamimidoyl chloride (2.2 g, 10 mmol) was added to water (14 ml) Heating to 60 ° C, adding 3-bromo-4-fluoroaniline (2.06 g, 11 mmol), stirring for 10 minutes, then adding sodium bicarbonate (1.26 g, 15 mmol) at 60 ° C for 30 minutes, until the reaction is complete, with The mixture was extracted with ethyl acetate. EtOAc was evaporated.

MS m/z (ESI): 374.0.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ11.54 (s, 1H), 8.86 (s, 2H), 7.10 (m, 1H), 6.81 (m, 1H), 6.15 (m, 1H) 3.53 (m, 2H), 3.39 (m, 2H), 3.29 (m, 3H).

Step 7: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-yl)- 1,2,4-Evil Diazol-5(4H)-one 1h

The compound N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-carbon The oxime (3.9 g, 10.4 mmol) was added to ethyl acetate (50 ml), heated to 60 ° C, and 1,1'-carbonyldiimidazole (2.53 g, 15.6 mmol) was added, stirred for 30 minutes, and the organic phase was washed with 1N HCl. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo.

Step 8: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1, 2,4-Evil 2 Oxazol-5(4H)-one 1i

Compound 8 (4 g, 10 mmol) was added to dichloromethane (25 ml), and a solution of boron tribromide in dichloromethane (25 ml, 25 mmol) was added dropwise at -78 ° C, and the mixture was stirred to room temperature, and the conversion of the starting materials was completely monitored by LC-MS. The reaction mixture was adjusted to aq. EtOAc (EtOAc m.

MS m/z (ESI): 385.9.

Step 9: 2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-Evil 2 Zyrid-3-yl)amino)ethyl methanesulfonate 1j

The compound 4-(3-bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2 , 4-oxadiazol-5(4H)-one (2g, 5.2mmol) was added to ethyl acetate (15ml). methanesulfonyl chloride (593mg, 5.2mmol) was added at room temperature, followed by triethylamine (526mg, 5.2mmol) The LC-MS was used to monitor the conversion of the starting material, and the reaction was stopped. The organic phase was washed with water, washed with saturated brine and dried over anhydrous sodium sulfate.

MS m/z (ESI): 463.9.

Step 10: 3-(4-((2-azidoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4-Evil 2 Oxazol-5(4H)-one 1k

The compound 2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 , 2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate (9.8 g, 21.1 mmol) was added to DMF (45 ml) at room temperature, sodium azide (1.7 g, 26.4 mmol), 50 ° C After stirring for 4 hours, LC-MS was used to monitor the conversion of the starting materials. The reaction was stopped. Water and ethyl acetate were added. The organic phase was washed with water, brine, and dried over anhydrous sodium sulfate. , 100%).

MS m/z (ESI): 411.0.

Step 11: 3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4- evil Diazol-5(4H)-one hydroiodinated 1l

The compound 3-(4-((2-azidoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1, 2,4-oxadiazol-5(4H)-one (9.0 g, 21.9 mmol) was added to methanol (160 ml), sodium iodide (14.3 g, 131.74 mmol) was added at room temperature, stirred for 5 minutes, and trimethyl group was added dropwise. Chlorosilane (15.6 ml, 131.7 mmol) in methanol (32 ml) was stirred at room temperature for 4 hours. LC-MS was used to monitor the conversion of the starting materials and the reaction was stopped. The reaction mixture was poured into sodium thiosulfate (23 g) under ice bath. Aqueous solution (900 ml), which was crystallised, filtered and dried to give compound 1l (10.5 g, 91%).

MS m/z (ESI): 387.0.

Synthesis of Example Compounds

Embodiment 1

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Ethyl)oxyaldehyde amide (1)

Step 1: N ¹ -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5-evil Diazol-3-yl)amino)ethyl)oxyaldehyde amide 1m.

3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100 mL vial -1,2,4-oxadiazole-5(4H)-one 1 1 (300 mg, 0.78 mmol), oxalylamide (138 mg, 1.56 mmol) dissolved in N,N-dimethylformamide (8 mL) O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroboric acid (375.6 mg, 1.17 mmol) followed by N,N-diisopropylethylamine (0.5 mL, 2.34) mmol), at room temperature for 2 hours, water (50 mL), precipitated solid was filtered, solid was dried to give ^{N 1 - (2 - ((} 4- (4- (3- bromo-4-fluorophenyl) -5 -carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 1 m (105 mg ), the yield was 32.0%.

MS m/z (ESI): 456.0, 458.0 (M, M+2).

Step ^{two: (Z) -N 1 - (} 2 - ((4- (N- (3- bromo-4-fluorophenyl) -N'- hydroxyamino azomethine group) -1,2,5 evil Diazole -3-yl)amino)ethyl)oxyaldehyde amide 1.

N ¹ -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-carboyl) in a 100 mL vial Zyridin-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide (105 mg, 0.23 mmol) dissolved in tetrahydrofuran / methanol (5 mL / 5 mL), sodium hydroxide (46 mg, 1.15 mmol) was dissolved in water (2 mL) and added to the above solution and allowed to react at room temperature for 2 hours. The reaction was completed with EtOAc (3 mL). , filtration, concentration of the filtrate, separation and purification by preparative silica gel plate (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to obtain (Z)-N ¹ - (2 -((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazol-3-yl)amino)ethyl) Oxyaldehyde amide 1 (36.6 mg), yield 40.0%.

MS m/z (ESI): 430.0, 432.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.43 (s, 1H), 8.88 (s, 1H), 8.83 (s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.18 (t, J = 8.8 Hz, 1H), 7.12 (dd, J ₁ = 6.0 Hz, J ₂ = 2.8 Hz, 1H), 6.75 (m, 1H), 6.30 (t, J = 6.0 Hz, 1H), 3.36 (m, 4H).

Embodiment 2

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Ethyl)-N ² -methyloxyaldehyde amide (2)

Step 1: methyl 2-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 2b.

3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100 mL vial -1,2,4-oxadiazol-5(4H)-one 1 1 (385 mg, 1.0 mmol), dimethyl oxalate (141.6 mg, 1.2 mmol) dissolved in methanol (15 mL), sodium methoxide (130 mg, 2.4 Methyl), reacted at room temperature overnight, and LC-MS monitored the conversion of the starting material completely and stopped the reaction. A saturated ammonium chloride solution (30 mL) was added, EtOAc (EtOAc m. ((2-(4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonylacetate 2b (200 mg), yield 50.0%.

MS m/z (ESI): 471.0, 473.0 (M, M+2).

Step 2: (Z)-N ¹ -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)-N ² -methyloxyaldehyde amide 2.

Methyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-) in a 100 mL vial Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (200 mg, 0.42 mmol) was dissolved in methanol (5 mL). A 40% methylamine solution (2 mL) was added to the above solution, and reacted at room temperature for 3 hours, and the conversion of the starting material was monitored by LC-MS to stop the reaction. Add water (30 mL), and extract with ethyl acetate (30 mL×2). : dichloromethane/methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) (Z)-N ¹ -(2-((4-(N-(3-bromo-4-)) Fluorophenyl)-N'-hydroxycarbamimidoyl-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -methyloxyaldehyde amide 2 (57.5 mg), The yield was 29.6%.

MS m/z (ESI): 444.0, 446.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.42 (s, 1H), 8.88 (s, 1H), 8.86 (m, 1H), 8.68 (m, 1H), 7.18 (t, J = 8.8 Hz, 1H), 7.10 (dd, J ₁ = 6.0 Hz, J ₂ = 2.8 Hz, 1H), 6.74 (m, 1H), 6.30 (t, J = 6.0 Hz, 1H), 3.38 (m, 4H), 2.66 (d, J = 4.0 Hz, 3H).

Embodiment 3

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Ethyl)-N ² -ethyloxyaldehyde amide (3)

Step 1: N ¹ -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl) amino) ethyl) -N ² - oxo ethyl aldehyde amide 3b.

Methyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-) in a 100 mL vial Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (240 mg, 0.51 mmol) was dissolved in methanol (15 mL). A 1 M solution of ethylamine (2 mL) was added to the above solution and allowed to react at room temperature for 3 hours. The reaction was completed with EtOAc (EtOAc) (EtOAc) and concentrated to give ^{N 1 - (2 - ((} 4- (4- (3- bromo-4-fluorophenyl) -4,5-dihydro-5-carbonyl-1,2,4-oxadiazol-3 - yl) -1,2,5-oxadiazol-3-yl) amino) ethyl) -N ² - oxo ethyl aldehyde amide 3b (190mg), a yield of 78.5%.

MS m/z (ESI): 471.0, 473.0 (M, M+2).

Step 2: (Z)-N ¹ -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)-N ² -ethyloxyaldehydeamide 3.

N ¹ -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-carboyl) in a 100 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -ethyloxyaldehyde amide (190 mg, 0.39 mmol) dissolved in tetrahydrofuran / methanol (8 mL / 8 mL) Sodium hydroxide (62.7 mg, 1.57 mmol) was dissolved in water (4 mL) and added to the above solution, and allowed to react at room temperature for 2 hours. LC-MS monitored the conversion of the starting material completely and stopped the reaction. A saturated aqueous solution of ammonium chloride (30 mL) was added, and ethyl acetate (30 mL EtOAc) was evaporated. Purification (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give (Z)-N1-(2-((4-(N-(3-br 4-fluorophenyl)-N'-hydroxycarbamimidoyl-1,2,5-oxadiazol-3-yl)amino)ethyl)-N2-ethyloxyaldehydeamide 3 (80.0 mg ), the yield was 43.1%.

MS m/z (ESI): 458.0, 460.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.42 (s, 1H), 8.88 (s, 1H), 8.86 (m, 1H), 8.75 (t, J = 6.0Hz, 1H), 7.18 ( t, J = 8.8 Hz, 1H), 7.10 (dd, J ₁ = 6.0 Hz, J ₂ = 2.4 Hz, 1H), 6.74 (m, 1H), 6.31 (t, J = 6.0 Hz, 1H), 3.38 ( m, 4H), 3.15 (m, 2H), 1.04 (m, 3H).

Embodiment 4

(Z)-N ¹ -benzyl-N ² -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidyl)-1,2 ,5-Evil 2 Zyrid-3-yl)amino)ethyl)oxyaldehyde amide (4)

Step 1: N ¹ -benzyl-N ² -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2, 4-oxadiazole-3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 4b.

Methyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-) in a 100 mL vial Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (200 mg, 0.42 mmol) was dissolved in methanol (15 mL). Benzylamine (1 mL) was added to the above solution and allowed to react at room temperature for 3 hours. The reaction was completed with EtOAc (EtOAc). , N ¹ -benzyl-N ² -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4) -oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 4b (190 mg), yield 82.0%.

MS m/z (ESI): 546.0, 548.0 (M, M+2).

Step 2: ((Z)-N ¹ -benzyl-N ² -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidyl) 1,1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 4

N ¹ -Benzyl-N ² -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1) in a 100 mL vial , 2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide (190 mg, 0.35 mmol) dissolved in tetrahydrofuran / methanol (8 mL / 8 mL), sodium hydroxide (100 mg, 2.5 mmol) was dissolved in water (4 mL) and added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the conversion of the starting material completely and stopped the reaction. A saturated aqueous solution of ammonium chloride (30 mL) was added, and ethyl acetate (30 mL EtOAc) was evaporated. Purification (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give (Z)-N ¹ -benzyl-N ² -(2-((4) -(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidyl)-1,2,5-oxadiazol-3-yl)amino)ethyl)oxyaldehyde amide 4 (60.9 mg), yield 39.0%.

MS m/z (ESI): 520.0, 522.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.42 (s, 1H), 9.35 (t, J = 6.0Hz, 1H) ,, 8.87 (m, 2H), 7.30 (m, 2H), 7.24 (m, 2H), 6.74 (m, 1H), 6.33 (t, J = 6.0 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 3.38 (m, 4H).

Embodiment 5

(Z)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole-3 -based ammonia Ethyl)-2-morpholino-2-carbonylacetamide (5)

Step 1: N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-) Base)-1,2,5-evil Diazol-3-yl)amino)ethyl)-2-morpholino-2-carbonylacetamide 5b.

Methyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-) in a 100 mL vial Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (170 mg, 0.36 mmol) was dissolved in methanol (15 mL). Morpholine (1 mL) was added to the above solution and allowed to react at room temperature for 3 hours. LC-MS monitored the conversion of the starting material completely and stopped the reaction. Ethyl acetate (50 mL) was added and washed with EtOAc EtOAc EtOAc (EtOAc m. (4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazole -3-yl)amino)ethyl)-2-morpholino-2-carbonylacetamide 5b (120 mg), yield 63.4%.

MS m/z (ESI): 526.0, 528.0 (M, M+2).

Step 2: (Z)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyaminoimino))-1,2,5-Ethylene Azole 3-yl)amino)ethyl)-2-morpholino-2-carbonylacetamide 5.

N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) in a 100 mL vial 3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-2-morpholino-2-carbonylacetamide (120 mg, 0.23 mmol) dissolved in tetrahydrofuran / methanol (8 mL /8 mL), sodium hydroxide (50 mg, 1.25 mmol) was dissolved in water (4 mL) and added to the above solution, and reacted at room temperature for 2 hours. The reaction was completed with EtOAc (3 mL). , filtration, concentration of the filtrate, separation and purification by preparative silica gel plate (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give (Z)-N- (2- ((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamimidyl)-1,2,5-oxadiazol-3-yl)amino)ethyl)- 2-morpholino-2-carbonylacetamide 5 (30.7 mg), yield 30.1%.

MS m/z (ESI): 500.0, 502.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.45 (s, 1H), 8.89 (s, 1H), 8.83 (m, 1H), 7.20 (t, J = 8.8Hz, 1H), 7.11 ( Dd, J ₁ = 6.0 Hz, J ₂ = 2.8 Hz, 1H), 6.77 (m, 1H), 6.24 (t, J = 6.0 Hz, 1H), 3.58 (m, 4H), 3.48 (m, 4H), 3.36 (m, 4H).

Embodiment 6

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Ethyl)-N ² -methoxyoxyaldehyde amide (6)

Step 1: Ethyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 6b.

3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100 mL vial -1,2,4-oxadiazol-5(4H)-one hydroiodinated 1 l (2.5 g, 4.88 mmol), dissolved in tetrahydrofuran (30 mL), ethyl 2-chloro-2-carbonyl The acid ester (730 mg, 5.37 mmol) was added triethylamine (1.23 g, 12.2 mmol), and the mixture was reacted for 2 hr. Ethyl acetate extraction (50 mL x 2), combined organic phase, washed with saturated brine and filtered over anhydrous sodium sulfate. -fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl Amino)-2-carbonylacetate 6b (1.1 g), yield 46.5%.

MS m/z (ESI): 484.9 (M, M + H) ⁺ .

Step 2: (Z)-2-((2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)amino)-2-carbonylacetic acid 6c.

Ethyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-) in a 100 mL vial Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (700 mg, 1.44 mmol) was dissolved in ethanol (10 mL). 2N sodium hydroxide (1 ml, 2.0 mmol) was reacted at 90 ° C for 3 hours. The conversion of the starting material was monitored by LC-MS, and the reaction mixture was concentrated. Extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated to give (Z)-2-((4-(N-N-(3-bromo-4-fluorobenzene) -N'-hydroxycarbamimidoyl-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonylacetic acid 6c (600 mg), yield 97.0%.

MS m / z (ESI): 429.0 (MH) -.

Step 3: 2-((2-(4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5-evil Azoxa-3-yl)amino)ethyl)amino)-2-carbonylacetic acid 6d.

(Z)-2-((2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2, in a 50 mL vial 5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonylacetic acid (600 mg, 1.39 mmol) was dissolved in ethyl acetate (20 mL). CDI (271 mg, 1.67 mmol). . LC-MS monitoring The raw materials are completely converted. It was washed with 1N hydrochloric acid, washed with water, brine, and brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated to give 2-((4-(4-(4-bromo-4-fluorophenyl)-5-) Carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonylacetic acid 6d (370 mg), yield 58.3%.

MS m / z (ESI): 454.9 (MH) -.

Step 4: N ¹ -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)-N ² -methoxyoxyaldehyde amide 6e.

2-((2-(4-(4-(3-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 50 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonylacetic acid (100 mg, 0.22 mmol) dissolved in DMF (5 mL) Hydroxylamine hydrochloride (20 mg, 0.22 mmol), HATU (130 mg, 0.33 mmol), DIPEA (70 mg, 0.55 mmol) LC-MS monitored the conversion of the starting material completely. Extraction with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash column chromatography to give ^{N 1 - (2 - ((} 4- (4- (3- bromo-4-fluorophenyl 5-)carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -methoxyoxyaldehyde amide 6e (30 mg), yield 28.1%.

MS m/z (ESI): 484.0 (MH) ^- .

Step 5: (Z)-N ¹ -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole 3-yl)amino)ethyl)-N ² -methoxyoxyaldehyde amide 6.

N ¹ -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 50 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -methoxyoxyaldehyde amide (30 mg, 0.06 mmol) dissolved in ethanol (5 mL) Sodium hydroxide (0.3 ml, 0.6 mmol) was reacted overnight at room temperature. LC-MS monitored the conversion of the starting material completely. Extraction with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography to give a thin layer ^{(Z) -N 1 - (2} - ((4- (N- (3- bromo 4-fluorophenyl)-N'-hydroxycarbamimidoyl-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -methoxyoxyaldehyde amide 6 ( 6.0 mg), yield 21.7%.

MS m/z (ESI): 457.9.0 (MH) ^- .

¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 7.0 (m, 1H), 6.94 (m, 1H), 6.74 (m, 1H), 3.63 (s, 3H), 3.42 (4, 2H), 3.33 (m, 2H).

Example 7

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Ethyl)-N ² -cyclopropyl oxy aldehyde amide (7)

Step 1: methyl 2-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- 1,1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 7b.

3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100 mL vial -1,2,4-oxadiazol-5(4H)-one 1 1 (385 mg, 1.0 mmol), dimethyl oxalate (141.6 mg, 1.2 mmol) dissolved in methanol (15 mL), sodium methoxide (130 mg, 2.4 Methyl), reacted at room temperature overnight. LC-MS monitored the conversion of the starting material completely and stopped the reaction. A saturated ammonium chloride solution (30 mL) was added, EtOAc (EtOAc m. ((2-(4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonylacetate 7b (200 mg), yield 50.0%.

MS m/z (ESI): 471.0, 473.0 (M, M+2).

Step ^{two: (Z) -N 1 - (} 2 - ((4- (N- (3- bromo-4-fluorophenyl) -N'- hydroxyamino azomethine group) -1,2,5 evil Diazole -3-yl)amino)ethyl)-N ² -cyclopropyl oxy aldehyde amide 7.

Methyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a sealed bottle Diazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (100 mg, 0.21 mmol) dissolved in ethanol (5 mL) Cyclopropylamine (0.5 mL) was added to the above solution, and the reaction was carried out at 90 ° C overnight. LC-MS monitored the conversion of the starting material completely and stopped the reaction. After adding water (30 mL), the mixture was extracted with ethyl acetate (30 mL EtOAc). -N1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazol-3-yl) Amino)ethyl)-N2-cyclopropyloxyaldehydeamide 7 (30 mg) in a yield of 30.3%.

MS m/z (ESI): 470.0 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.87 (s, 1H), 8.77 (s, 1H), 7.18 (m, 1H), 7.15 (m, 1H), 6.72 (m, 1H), 6.34 (m, 1H), 2.75 (m, 1H), 0.62 (m, 4H).

Example eight

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Ethyl)-N ² -hydroxyoxyaldehyde amide (8)

Step 1: Ethyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole) -3- -1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate 8b.

3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) in a 100 mL vial -1,2,4-oxadiazol-5(4H)-one hydroiodinated 1 l (2.5 g, 4.88 mmol), dissolved in tetrahydrofuran (30 mL), ethyl 2-chloro-2-carbonyl The acid ester (730 mg, 5.37 mmol) was added triethylamine (1.23 g, 12.2 mmol), and the mixture was reacted for 2 hr. The organic phase was extracted with ethyl acetate (50 mL×2), washed with saturated brine and filtered over anhydrous sodium sulfate. 4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino) Amino)-2-carbonylacetate 8b (1.1 g), yield 46.5%.

MS m/z (ESI): 484.9 (M, M + H) ⁺ .

Step 2: N ¹ -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)-N ² -hydroxyoxyaldehyde amide 8c

Ethyl 2-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a one-neck bottle Diazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)-2-carbonyl acetate (70 mg, 0.14 mmol) dissolved in methanol (5 mL), ice A 50% aqueous solution of hydroxylamine (0.1 mL) was added to the above solution under a bath, and a saturated sodium hydroxide solution (0.2 ml) was added dropwise, and the mixture was reacted at 0 ° C for 30 minutes. LC-MS was used to observe the conversion of the starting material, the reaction was stopped, concentrated, and the mixture was adjusted to neutral with 2N hydrochloric acid, water was added, and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated sodium chloride (30 mL) over sodium sulfate, filtered and the filtrate was concentrated to give ^{N 1 - (2 - ((} 4- (4- (3- bromo-4-fluorophenyl) -4,5-dihydro-1,2-5-carbonyl, 4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -hydroxyoxyaldehyde amide 8c (60 mg).

MS m/z (ESI): 472.0 (M+H) ⁺ .

Step 3: (Z)-N ¹ -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)ethyl)-N ² -hydroxyoxyaldehyde amide amide 8.

N ¹ -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 50 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -hydroxyoxyaldehyde amide (60 mg, 0.13 mmol) dissolved in ethanol (5 mL). Sodium (0.2 ml, 0.4 mmol) was reacted overnight at room temperature. LC-MS monitored the conversion of the starting material completely. Extraction with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by thin layer chromatography to give fast ^{(Z) -N 1 - (2} - ((4- (N- (3- bromo 4-fluorophenyl)-N'-hydroxycarbamimidoyl-1,2,5-oxadiazol-3-yl)amino)ethyl)-N ² -hydroxyoxyaldehyde amide 8 (24.0 mg ), the yield was 41.5%.

MS m/z (ESI): 444.0 (MH) ^- .

¹ H NMR (400 MHz, MeCD ₃ OD, ppm) δ 7.04 (m, 1H), 6.94 (m, 1H), 6.71 (m, 1H), 3.43 (m, 2H), 3.36 (m, 2H).

Example nine

(Z)-N ¹ -(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamoyl)-1,2,5-oxadiazole- 3-base) ammonia Base) propyl) oxyaldehyde amide (9)

Step 1: N ¹ -(2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5-evil Diazol-3-yl)amino)propyl)oxyaldehyde amide 9b.

3-(4-((1-Aminopropan-2-yl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluoro) in a 25 mL vial Phenyl)-1,2,4-oxadiazol-5(4H)-one hydroiodinated 1 l (2.5 g, 4.88 mmol), dissolved in DMF (3 mL), 2-amino-2-carbonylacetic acid (18.6) </ RTI></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; , washed with brine, dried over anhydrous sodium sulfate filtered, and concentrated to give ^{N 1 - (2 - ((} 4- (4- (3- bromo-4-fluorophenyl) -4,5-dihydro-1-carbonyl , 2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)propyl)oxyaldehyde amide 9b (36 mg), yield 40.0%.

MS m/z (ESI): 470.0 (M + H) ⁺ .

Step 2: (Z)-N ¹ -(2-((4-(N-(3-Bromo-4-fluorophenyl)-N'-hydroxycarbamoyl))-1,2,5- Diazole -3-yl)amino)propyl)oxyaldehydeamide 9

N ¹ -(2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 50 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)propyl)oxyaldehyde amide (36 mg, 0.07 mmol) was dissolved in ethanol (5 mL). 0.4 mmol), reacted overnight at room temperature. LC-MS monitored the conversion of the starting material completely. Extraction with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by thin layer chromatography to give fast ^{(Z) -N 1 - (2} - ((4- (N- (3- bromo 4-fluorophenyl)-N'-hydroxycarbamimidoyl-1,2,5-oxadiazol-3-yl)amino)propyl)oxyaldehyde amide 9 (13.0 mg), yield 41.8 %.

MS m/z (ESI): 444.0 (M+H) ⁺ .

^{_{1 H NMR (400MHz, CD 3}} OD, ppm) δ7.02 (m, 1H), 6.94 (m, 1H), 6.71 (m, 1H), 3.70 (m, 1H), 3.36 (m, 2H), 1.15 (m, 3H).

Example ten

(Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(sulfamoylamino)cyclohexyl)amino)-1,2,5-oxadiazole -3- Carbon oxonium (10)

Step 1: 4-amino-N'-hydroxy-N-(4-hydroxycyclohexyl)-1,2,5-oxadiazole-3-carbonoxaxanthene 10b

The compound 4-amino-N-hydroxy-1,2,5-oxadiazol-3-carbamimidoyl chloride (9 g, 55 mmol) was dissolved in ethyl acetate (100 mL). -Aminocyclohexane-1-ol (7.0 g, 61 mmol). The reaction solution was stirred at 0 ° C for 30 min, triethylamine (11.5 ml, 82.5 mmol) was slowly added, and the mixture was stirred at 0 ° C for 30 min. The reaction mixture was poured into water, and the organic phase was separated, washed with saturated brine, and evaporated. Crude product with dichloromethane (30ml) Recrystallization, the compound 4-amino-N'-hydroxy-N-(4-hydroxycyclohexyl)-1,2,5-oxadiazol-3-carboindole 10b (12 g) was obtained in a yield of 89%. .

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ10.7 (s, 1H), 6.25-6.35 (br, 2H), 5.67 (d, 1H), 4.50 (d, 1H), 3.65-3.75 ( m, 1H) 3.28-3.38 (m, 1H), 1.69-1.83 (m, 4H), 1.25-1.40 (m, 2H), 1.05-1.20 (m, 2H).

Step 2: N'-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazole-3-carbonoxaxanthene 10c

The compound 4-amino-N'-hydroxy-N-(4-hydroxycyclohexyl)-1,2,5-oxadiazol-3-carboindole 10b (12 g, 49.8 mmol) was suspended in water (60 ml) In the middle, KOH (8.3 g, 0.15 mol) was slowly added. The reaction solution was heated to reflux for 48 hours and then cooled to room temperature. Ethyl acetate (50 ml x 3) was extracted, washed with brine, dried over anhydrous sodium sulfate. 2,5-oxadiazole-3-carbonhypoxanthene 10c (3.6 g), yield 30%.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ10.5 (s, 1H), 6.19-6.25 (br, 2H), 5.96 (d, 1H), 4.58 (d, 1H), 3.40-3.48 ( m, 1H) 3.20-3.30 (m, 1H), 1.98-2.08 (m, 2H), 1.78-1.88 (m, 2H), 1.22-1.32 (m, 4H).

Step 3: N-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carbamimidoyl chloride 10d

The compound N'-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carboindole 10c (3.6 g, 14.9 mmol) was suspended in 6N HCl (30 ml) In the middle, stirring was continued to obtain a clear solution, and sodium chloride (2.62 g, 44.8 mmol) was added at 0 °C. An aqueous solution of sodium nitrite (1.03 g, 14.9 mmol) (5 ml) was slowly added to the reaction mixture at 0 ° C, and the mixture was stirred at 0 ° C for 2 hr. The reaction solution was filtered, and the solid was collected and dried to give N-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carbamimidyl chloride 1d (3.1 g ), the yield was 79%.

MS m/z (ESI): 259 (M-H).

Step 4: N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carbon Xanthene 10e

The compound N-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carbamimidoyl chloride 10d (2.4g, 9.2mmol) and 3-bromo- 4-Fluoroaniline (1.75 g, 9.2 mmol) was suspended in water (35 ml) and then heated to 60 ° C for 5 min. Sodium hydrogencarbonate (1.16 g, 13.8 mmol) was added in one portion to the reaction mixture at 60 °C. The reaction solution was stirred at 60 ° C for 20 minutes and cooled to room temperature. Ethyl acetate (50 ml x 3) was extracted, washed with brine, dried over anhydrous sodium sulfate. -((4-Hydroxycyclohexyl)amino)-1,2,5-oxadiazole-3-carbonoxaxan 10e (3.8 g).

MS m/z (ESI): 413 (M+H).

Step 5: 4-(3-Bromo-4-fluorophenyl)-3-(4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-1, 2,4- evil Diazol-5(4H)-one 10f

The compound N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-carbooxa脒10e (3.8 g, crude) was dissolved in ethyl acetate (40 ml). N,N-carbonyldiimidazole (1.47 g, 9.2 mmol) was slowly added at 0 ° C, and the reaction mixture was stirred at 0 ° C for 2 hours. After warming to room temperature, the mixture was washed with EtOAcq. The crude product was recrystallized from dichloromethane (30 ml) to afford 4-(3-bromo-4-fluorophenyl)-3-(4-((4-hydroxycyclohexyl)amino)-1,2,5- Azoxa-3-yl)-1,2,4-oxadiazole-5(4H)-one 10f (3.76 g), yield 92%.

MS m/z (ESI): 438 (M-H).

Step 6: 4-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-Evil 2 Zyrid-3-yl)amino)cyclohexyl methanesulfonate 10g

The compound 4-(3-bromo-4-fluorophenyl)-3-(4-((4-hydroxycyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-1,2 4-oxadiazole-5(4H)-one 10f (1.36 g, 3.1 mmol) was dissolved in ethyl acetate (20 mL). The reaction was stirred at 0 ° C for 5 min then triethylamine (1.3 mL, 9.3 mmol) was slowly added. The reaction mixture was stirred at 0 ° C for 60 min. The crude column was separated (petroleum ether: ethyl acetate = 1:1) to give 4-((4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1, 2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclohexylmethanesulfonate 10 g (1.3 g), yield 85%.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): 8.01-8.07 (m, 1H), 7.55-7.70 (m, 2H), 6.25 (d, 1H), 4.55-4.65 (m, 1H), 3.33- 3.43 (m, 1H) 3.20 (s, 3H), 1.92-2.08 (m, 4H), 1.43-1.68 (m, 4H).

Step 7: 3-(4-((4-Azidocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4- evil Diazol-5(4H)-one 10h

The compound 4-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 , 2,5-oxadiazol-3-yl)amino)cyclohexyl methanesulfonate 10 g (0.9 g, 1.74 mmol) dissolved in N,N-dimethylformamide (10 ml), then sodium azide was added (340 mg, 5.21 mmol). The reaction solution was heated to 90 ° C and stirred for 60 minutes. TLC showed the reaction was completed and evaporated to dryness to give crude 3-(4-((4-azicyclocyclohexyl)amino)-1,2,5-oxadiazole-3- 4-(3-Bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one 10h (800 mg).

Step 8: 3-(4-((4-Aminocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1, 2,4- evil Diazol-5(4H)-one 10i

The compound 3-(4-((4-azidocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1, 2,4-oxadiazol-5(4H)-one 10h (350mg) was dissolved in glacial acetic acid (10ml), then zinc powder (490g, 7.5mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness EtOAc. The sodium salt was dried and concentrated in vacuo to give a crude material. The crude column was separated (stone dichloromethane: methanol = 30:1) to give 3-(4-((4-aminocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-( 3-Bromo-4-fluorophenyl)-1,2,4-oxadiazole-5(4H)-one 10i (250 mg), yield 76%.

MS m/z (ESI): 439 (M+H).

Step 9: tert-butyl (N-(4-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxole) Diazole-3- 1,1,2,5-oxadiazol-3-yl)amino)cyclohexyl)sulfamoyl)carbamate 10j

The compound chlorosulfonyl isocyanate (126 mg, 0.89 mmol) was dissolved in dichloromethane (5 ml), and t-butanol (65 mg, 0.89 mmol) was added at 0 ° C and stirred for 20 minutes to give intermediate solution A. The compound 3-(4-((4-aminocyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2 , 4-oxadiazole-5(4H)-one 10i (260 mg, 0.59 mmol) was dissolved in dichloromethane (10 ml). At 0 ° C, intermediate solution A was added, stirred for 5 minutes, then triethylamine was added. (0.25 ml, 1.78 mmol), stirred at 0 ° C for 30 minutes. Then, ethyl acetate (50 ml) was added, and brine was evaporated. The crude column was separated (petroleum ether: ethyl acetate = 1:1) to give the compound t-butyl (N-(4-((4-(4-(4-bromo-4-fluorophenyl)-5-carbonyl)- 4,5-Dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclohexyl)sulfamoyl)carbamate 10j (140 mg), yield 38%.

MS m/z (ESI): 616 (M-H).

Step 10: 3-(4-((4-(sulfonylamino)cyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorobenzene Base)-1,2,4-oxadiazole-5(4H)-one 10k

The compound tert-butyl (N-(4-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-carboyl) Zyridin-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclohexyl)sulfamoyl)carbamate 10j (120 mg) dissolved in dichloromethane (3 ml) at 0 ° C Next, trifluoroacetic acid (3 ml) was slowly added. The reaction mixture was stirred at 0 ° C for 30 min, then concentrated in vacuo and evaporated to dryness crystals crystals -yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one 10k (120 mg, brown viscous).

Step 11: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(sulfamoylamino)cyclohexyl)amino)-1,2,5 - Oxadiazole-3-carbon oxonium 10

The compound 3-(4-((4-(sulfamoylamino)cyclohexyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) -1,2,4-oxadiazole-5(4H)-one 10k (100mg, crude) is dissolved in methanol (2ml), sodium hydroxide (15mg, 0.375mmol, 2M aqueous solution) is added to the reaction solution, then Stir at room temperature for 30 minutes. The reaction solution was adjusted to pH 7 with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate and brine. The organic phase was dried over anhydrous sodium The crude product was recrystallized from dichloromethane to give compound (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((4-(sulfamoylamino)cyclohexyl)amino -1,2,5-oxadiazol-3-carbohydroindole 10 (50 mg, white solid), yield 53%.

MS m/z (ESI): 490 (M-H).

^{1 H NMR (400MHz, DMSO-} d 6, ppm): 11.6 (s, 1H), 8.91 (s, 1H), 7.18-7.22 (m, 1H), 7.10-7.15 (m, 1H), 6.79-6.85 ( m,1H), 6.51 (s, 2H), 6.43 (d, 1H), 6.06 (d, 1H), 3.43-3.50 (m, 1H), 3.23 - 3.33 (m, 1H), 1.62-1.85 (m, 8H).

Embodiment 11

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(sulfamoylamino)cyclobutyl)amino)-1,2,5-oxadi Oxazole-3- Carbon oxonium (11)

Step 1: 3-Aminocyclobutan-1-ol trifluoroacetate 11b

Tert-butyl(3-hydroxycyclobutyl)carbamate 11a (9 g, 48 mmol) was dissolved in dichloromethane (20 ml), trifluoroacetic acid (20 ml) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 3 hr.

^{1 H NMR (400MHz, MeOD,} ppm): 5.43-5.49 (m, 1H), 4.43-4.49 (m, 0.7H), 3.99-4.06 (m, 1H), 3.84-3.91 (m, 0.7H), 2.67 -2.78 (m, 4.3H), 2.33 - 2.47 (m, 3.4H).

Step 2: 4-Amino-N'-hydroxy-N-(3-hydroxycyclobutyl)-1,2,5-oxadiazol-3-carbonoxaxanthene 11d

The compound 3-aminocyclobutan-1-ol trifluoroacetate 11b (9 g, 48 mmol) was dissolved in ethyl acetate (25 ml), and then potassium carbonate (13.5 g, , a free 1b solution was obtained. The compound 4-amino-N-hydroxy-1,2,5-oxadiazol-3-carbamimidoyl chloride (6.6 g, 40 mmol) was dissolved in ethyl acetate (25 mL). A solution of free 3-aminocyclobutan-1-ol trifluoroacetate 1b was added. The reaction solution was stirred at 0 ° C for 30 min, then triethylamine (16.7 ml, 120 mmol) was slowly added and stirred at 0 ° C for 30 min. The reaction mixture was poured into water, and the organic phase was separated, washed with saturated brine, and evaporated. The crude product was purified by column ( petroleum ether: ethyl acetate = 1:1) to give 4-amino-N--hydroxy-N-(3-hydroxycyclobutyl)-1,2,5-oxadiazole-3- Carbonium xanthene 11d (4.2 g), yield 49%.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ10.7 (s, 1H), 6.25-6.30 (m, 3H), 4.92 (d, 1H), 4.43-4.53 (m, 1H) 4.18-4.27 (m, 1H), 2.15-2.24 (m, 2H), 2.03-2.09 (m, 2H).

Step 3: N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazole-3-carbonoxaxan 11e

The compound 4-amino-N'-hydroxy-N-(3-hydroxycyclobutyl)-1,2,5-oxadiazole-3-carbonoxaxan 11d (4.2 g, 19.7 mmol) was suspended in water. In (20 ml), KOH (3.3 g, 59.1 mmol) was slowly added. The reaction was heated to reflux for 48 hours and then cooled to room temperature. Ethyl acetate (50 ml x 3) was extracted, washed with brine, dried over anhydrous sodium sulfate and evaporated. 2,5-oxadiazole-3-carbonheteroazepine 11e (2.2 g), yield 52%.

MS m/z (ESI): 212 (M-H).

Step 4: N-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbamimidoyl chloride 11f

The compound N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carboindole 11e (1.8 g, 8.4 mmol) was suspended in 6N HCl (30 ml), stirring was continued to obtain a clear solution, and sodium chloride (1.46 g, 25.2 mmol) was added at 0 °C. An aqueous solution of sodium nitrite (0.58 g, 8.4 mmol) (2 ml) was slowly added to the reaction mixture at 0 ° C, and the mixture was stirred at 0 ° C for 2 hours. Ethyl acetate (50 ml x 3) was extracted, washed with brine, dried over anhydrous sodium sulfate. 2,5-oxadiazole-3-carbamimidoyl chloride 11f (1.95 g), yield 100%.

MS m/z (ESI): 231 (M-H).

Step 5: N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbon Xanthene 11g

The compound N-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbamimidoyl chloride 11f (1.95 g, 8.4 mmol) and 3-bromo 4-Fluoroaniline (1.59 g, 8.4 mmol) was suspended in water (25 ml) and then heated to 60 ° C for 5 minutes. Sodium hydrogencarbonate (1.06 g, 12.6 mmol) was added in one portion to the reaction mixture at 60 °C. The reaction solution was stirred at 60 ° C for 20 minutes and cooled to room temperature. Ethyl acetate (50 ml x 3) was extracted, washed with brine, dried over anhydrous sodium sulfate. -((3-Hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbonoxaxan 11 g (3.24 g, crude).

Step 6: 4-(3-Bromo-4-fluorophenyl)-3-(4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-1 , 2,4- evil Diazol-5(4H)-one 11h

The compound N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-carbooxy 11g (3.24g, crude) was dissolved in ethyl acetate (20ml). N,N-carbonyldiimidazole (1.36g, 8.4mmol) was slowly added at 0 ° C, stirred at 0 ° C for 2 hours, slowly rising The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by column ( petroleum ether: ethyl acetate = 1:1) to give 4-(3-bromo-4-fluorophenyl)-3-(4-((3-hydroxycyclobutyl)amino)-1 , 2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 11h (1.66 g), yield 47%.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ8.02-8.05 (m, 1H), 7.65-7.69 (m, 1H), 7.57-7.62 (m, 1H), 6.60 (d, 1H), 5.07 (d, 1H), 4.20-4.28 (m, 1H) 3.96-4.06 (m, 1H), 2.21-2.25 (m, 2H), 2.10-2.16 (m, 2H).

Step 7: 3-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-Evil 2 Zyrid-3-yl)amino)cyclobutyl methanesulfonate 11i

The compound 4-(3-bromo-4-fluorophenyl)-3-(4-((3-hydroxycyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-1, 2,4-oxadiazol-5(4H)-one 1h (0.5 g, 1.2 mmol) was dissolved in ethyl acetate (10 mL). The reaction was stirred at 0 ° C for 5 min then triethylamine (0.51 mL, 3.6 mmol). The reaction mixture was stirred at 0 ° C for 60 min. The crude column was separated (petroleum ether: ethyl acetate = 1:1) to give 3-((4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1, 2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclobutylmethanesulfonate 11i (0.56 g), yield 94%.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ8.07-8.09 (m, 1H), 7.69-7.73 (m, 1H), 7.57-7.62 (m, 1H), 6.86 (d, 1H), 5.14-5.19(m,1H)4.14-4.19(m,1H), 3.18(s,3H),2.57-2.61(m,4H).

Step 8: 3-(4-((3-Azidocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)- 1,2,4-Evil Diazol-5(4H)-one 11j

The compound 3-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1 , 2,5- Oxadiazol-3-yl)amino)cyclobutyl methanesulfonate 11i (504 mg, 1.03 mmol) was dissolved in N,N-dimethylformamide (5 ml), then sodium azide (198 mg, 3.09 mmol). The reaction solution was heated to stir at 90 ° C for 60 minutes, and the reaction was completed by TLC, then evaporated to dryness in vacuo to give crude 3-(4-((3-azidecyclobutyl)amino)-1,2,5- Zyrid-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazole-5(4H)-one 11j (450 mg).

MS m/z (ESI): 435 (M-H).

Step 9: 3-(4-((3-Aminocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 , 2,4- evil Diazol-5(4H)-one 11k

The compound 3-(4-((3-azidocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1 2,4-oxadiazol-5(4H)-one 11j (450 mg) was dissolved in glacial acetic acid (10 ml), then zinc powder (670 g, 10.3 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness EtOAcjjjjjjjjjjjjjj The crude column was separated (dichloromethane:methanol = 30:1) to give 3-(4-((3-aminocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-( 3-Bromo-4-fluorophenyl)-1,2,4-oxadiazole-5(4H)-one 11k (350 mg), yield 82%.

MS m/z (ESI): 409 (M-H).

Step 10: tert-butyl (N-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxole) Diazole-3- 1,1,2,5-oxadiazol-3-yl)amino)cyclobutyl)sulfamoyl)carbamate 11l

The compound chlorosulfonyl isocyanate (102 mg, 0.72 mmol) was dissolved in dichloromethane (5 ml), and t-butanol (54 mg, 0.72 mmol) was added at 0 ° C and stirred for 20 min to give intermediate solution A. The compound 3-(4-((3-aminocyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1, 2,4-oxadiazol-5(4H)-one 11k (200mg, 0.48mmol) was dissolved in dichloromethane (10ml). At 0 ° C, the intermediate solution A was added, stirred for 5 minutes, then added to the three Amine (0.20 ml, 1.44 mmol) was stirred at 0 °C for 30 min. Then, ethyl acetate (50 ml) was added, and brine was evaporated. The crude column was separated (petroleum ether: ethyl acetate = 1:1) to give the compound tert-butyl (N-(3-((4-(4-(4-(4-bromo-4-fluorophenyl)-5-carbonyl)- 4,5-Dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclobutyl)sulfamoyl)carbamate 11l (110mg), yield 26%.

MS m/z (ESI): 588 (M-H).

Step 11: 3-(4-((3-(Aminosulfonylamino)cyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4- Fluorobenzene Base)-1,2,4-oxadiazole-5(4H)-one 11m

The compound tert-butyl (N-(3-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxan Zin-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclobutyl)sulfamoyl)carbamate 11 l (110 mg) dissolved in dichloromethane (3 ml) Trifluoroacetic acid (3 ml) was slowly added at °C. The reaction solution was stirred at 0 ° C for 30 minutes. The mixture was evaporated to dryness in vacuo to give crude 3-(4-((3-(sulfamoylamino)cyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-( 3-Bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one 11 m (90 mg).

MS m/z (ESI): 488 (M-H).

Step 12: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(sulfamoylamino)cyclobutyl)amino)-1,2, 5- Oxadiazole-3-carbon oxonium 11

The compound 3-(4-((3-(sulfamoylamino)cyclobutyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorobenzene) -1,2,4-oxadiazole-5(4H)-one 11m (90mg, crude) was dissolved in methanol (2ml), sodium hydroxide (15mg, 0.375mmol, 2M aqueous solution) was added to the reaction solution. It was then stirred at room temperature for 30 minutes and the pH was adjusted to 7 with 1N HCl. The reaction mixture was extracted with ethyl acetate and brine. The organic phase was dried over anhydrous sodium The crude product was recrystallized from dichloromethane (1 ml) to afford (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(sulfamoylamino)) Base) amino)-1,2,5-oxadiazol-3-carbohydroindole 11 (11 mg), yield 13%.

MS m/z (ESI): 462 (M-H).

^{1 H NMR (400MHz, MeOD,} ppm): δ7.01-7.03 (m, 1H), 6.93-6.97 (m, 1H), 6.72-6.76 (m, 1H), 3.62-3.70 (m, 1H) 3.48- 3.57 (m, 1H), 2.71-2.79 (m, 2H), 1.83-1.93 (m, 2H).

Example twelve

tert-Butyl (Z)-(N-(4-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidyl)-1,2,5- Oxadiazole -3-yl)amino)cyclohexyl)sulfamoyl)carbamate (12)

The compound tert-butyl (N-(4-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-carboyl) Zyridin-3-yl)-1,2,5-oxadiazol-3-yl)amino)cyclohexyl)sulfamoyl)carbamate 12a (17 mg, 0.027 mmol) dissolved in methanol (0.3 ml), hydrogen Sodium oxide (2.2 mg, 0.054 mmol, 2M aqueous solution) was added to the mixture and then stirred at room temperature for 30 min. Concentration in vacuo gave the crude product. The crude product is washed with water to give tert-butyl(Z)-(N-(4-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyaminoimino))-1 , 2,5-oxadiazol-3-yl)amino)cyclohexyl)sulfamoyl)carbamate 12 (11 mg), yield 69%.

MS m/z (ESI): 590 (M-H).

^{1 H NMR (400MHz, DMSO-} d 6, ppm): 11.6 (s, 1H), 8.91 (s, 1H), 7.18-7.22 (m, 1H), 7.10-7.15 (m, 1H), 6.79-6.85 ( m, 1H), 6.02-6.12 (m, 1H), 3.43-3.50 (m, 1H), 3.23-3.33 (m, 1H), 1.62-1.85 (m, 8H), 1.36 (s, 9H).

Example thirteen

(Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(4-methylbenzenesulfonyl))) Amino) B Amino)-1,2,5-oxadiazole-3-carbonoxaxanthene (13)

Step 1: methylsulfinyl chloride 13b

The compound 1,2-dimethyldisulfane (3.4 g, 36 mmol) was dissolved in acetic acid (4.34 g, 72 mmol), and sulfonyl chloride (14.6 g, 108 mmol) was slowly added dropwise at -20 °C. The reaction solution was stirred at -20 ° C for 30 minutes, then slowly warmed to room temperature and stirred for 2 hours, and stirred at 35 ° C for 1 hour. The volatile component was concentrated under vacuum to give methanesulfonyl chloride 13b (6 g), yield 48%.

Step 2: N-p-toluenesulfonylsulfonimide chloride 13c

The compound chloramine T (1.5 g, 6.7 mmol) was added to toluene (50 ml) and heated to reflux for 5 hours while water was removed with a water separator and then cooled to room temperature. Methanesulfinyl chloride 1b (1 g, 10 mmol) was added to the reaction mixture, and the mixture was heated at 80 ° C for 2 hours, and then cooled to room temperature to remove solids. The reaction solution was concentrated in vacuo to give N-toluenesulfonimide acid chloride 13c (1.5 g).

^{_{1 H NMR (400MHz, CDCl 3}} , ppm): δ7.88 (d, 2H), 7.33 (d, 2H), 3.78 (s, 3H), 2.45 (s, 3H).

Step 3: N-(((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-) 3-base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)amino)(methyl)(carbonyl)-l6-sulfaninyl)-4-methylbenzenesulfonamide 13e

The compound N-p-toluenesulfonylsulfonimide chloride (175 mg, 0.65 mmol) was dissolved in tetrahydrofuran (10 ml), and 3-(4-((2-aminoethyl)amino) was slowly added at 0 °C. -1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (402 mg, 1.05 Mm). Reaction solution at 0 ° C After stirring for 30 minutes, it was added to water and extracted with ethyl acetate (15 ml x 3). The organic phase was dried over anhydrous sodium sulfate and evaporated and evaporated evaporated The crude product was separated by preparative thin layer chromatography (dichloromethane:methanol = 15:1) to afford N-(((2-(4-(4-(4-bromo-4-fluorophenyl)-5-carbonyl)- 4,5-Dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)(methyl)(carbonyl) -l6-sulfane subunit)-4-methylbenzenesulfonamide 13e (140 mg), yield 37%.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ8.08 (m, 1H), 7.98-8.02 (br, 1H), 7.69 (d, 2H), 7.60 (m, 1H) 7.32 (d, 2H ), 7.26 (br, 1H), 6.6 (m, 1H), 3.37-3.44 (m, 2H), 3.22-3.28 (m, 5H), 2.36 (s, 3H).

Step 4: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(4-methylbenzenesulfonyl))sulfonate Imidyl Amino)ethyl)amino)-1,2,5-oxadiazole-3-carbonoxaxanthene 13.

The compound N-(((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)amino)(methyl)(carbonyl)-l6-sulfaninyl)-4-methylbenzenesulfonamide 13e ( 35 mg, 0.056 mmol) was dissolved in methanol (1 ml), and sodium hydroxide (5 mg, 0.114 mmol, 2M aqueous solution) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 8 with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate and brine. The organic phase was dried over anhydrous sodium The crude product was recrystallized from dichloromethane to give compound (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(4) -Methylbenzenesulfonyl)sulfonimidoamino)ethyl)amino)-1,2,5-oxadiazol-3-carbohydrazine 13 (28 mg), yield 84%.

MS m/z (ESI): 590.0.

^{1 H NMR (400MHz, DMSO-} d 6, ppm): δ11.5 (s, 1H), 8.92 (s, 1H), 8.02 (m, 1H), 7.69 (d, 2H), 7.32 (d, 2H) , 7.14 (m, 1H), 7.09 (m 1H), 6.74 (m, 1H), 3.37-3.44 (m, 2H), 3.22-3.28 (m, 5H), 2.36 (s, 3H).

Embodiment 14

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(methylsulfonyl))))) ammonia 1,1,2,5-oxadiazol-3-carbonoxaxanthene (14)

Step 1: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl )-1,2,4- Oxadiazole-5(4H)-one 14b.

2-((4-(4-(3-Bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-) in a 100 mL vial 1,1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 1 l (2.6 g, 5.60 mmol) dissolved in N,N-dimethylformamide (25 mL), ice bath After cooling to 0 ° C, sodium methanethiolate (43.1 mg, 6.16 mmol) was added and stirred for 20 min. The reaction was completed with EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) , filtration, filtrate and silica gel, direct spin column chromatography, petroleum ether / ethyl acetate (5 / 1 to 3 / 1) to give 4- (3-bromo-4-fluorophenyl)-3- (4- ((2-(Methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 14b (1.0g ), the yield is 42.8%.

MS m/z (ESI): 416.0, 418.0 (M, M+2).

¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 7.62 (dd, J ₁ = 5.6 Hz, J ₂ = 2.4 Hz, 1H), 7.33 (m, 2H), 5.68 (t, J = 5.2 Hz, 1H) , 3.60 (dd, J ₁ = 12.8 Hz, J ₂ = 6.4 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.15 (s, 3H).

Step 2: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadiazole-3 - Base)-1,2,4-oxadiazole-5(4H)-one 14c.

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole- in a 100 mL vial - 3-yl)-1,2,4-oxadiazol-5(4H)-one (1.0g, 2.41mmol) dissolved in dichloromethane (30mL), cooled to -40 ° C with dry ice acetone bath, Peroxybenzoic acid (457 mg, 2.65 mmol) was dissolved in 5 mL of dichloromethane and added dropwise to the above solution. After the addition was completed, the dry ice acetone bath was removed. After about 20 minutes, the temperature was slowly raised to room temperature, and stirring was continued for 40 minutes at room temperature, LC- MS was monitored for complete conversion of the starting material, the reaction was quenched, water (50 mL) was added, and ethyl acetate (50 mL x 2) was evaporated. The organic phase was washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(A) Thiazinyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole-5(4H)-one 14c (0.9g), yield 90%.

MS m/z (ESI): 432.0, 434.0 (M, M+2).

Step 3: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimido)ethyl)amino)-1,2,5-oxa 2 Azole -3-yl)-1,2,4-oxadiazole-5(4H)-one 14d.

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)sulfinyl)ethyl)amino)-1,2 in a 100 mL vial , 5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (0.9g, 2.08mmol) was dissolved in chloroform (30mL), sodium azide (275.0mg) , 4.16 mmol), cooled to 0 ° C with an ice bath, concentrated sulfuric acid (0.5 mL) was added, the ice bath was removed, the oil bath was heated to 42 ° C, and the reaction was stirred overnight. The reaction was completed with EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) , filtered, and the filtrate was spun dry to give 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimido)ethyl)amino)-1,2, 5-oxadiazol-3-yl)-1,2,4-oxadiazole-5(4H)-one 14d (0.7g), yield 75.3%.

MS m/z (ESI): 447.0, 449.0 (M, M+2).

Step 4: N-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)(methyl)(carbonyl)-6-sulfaninyl)methanesulfonamide 14e.

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfimido)ethyl)amino)-1,2,5 in a 100 mL vial -oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1.5 g, 3.36 mmol) was dissolved in dichloromethane (30 mL), methanesulfonyl chloride (1 mL, 10 mmol) After stirring at room temperature for 15 minutes, the reaction was stirred overnight by adding triethylamine (1.5 mL, 10 mmol). The reaction was completed with EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) , filtration, filtrate and silica gel, direct spin column chromatography, ethyl acetate / methanol (30/1 to 20/1 to give N-((2-(4-(4-(3-bromo-4-fluorobenzene)) 5-)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl) (A ()(carbonyl)-6-sulfaninylene)methanesulfonamide 14e (0.65 g), yield 36.8%.

MS m/z (ESI): 525.0, 527.0 (M, M+2).

Step 5: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methyl-N-(methylsulfonyl))) B Base) amino)-1,2,5-oxadiazole-3-carbonoxaxanthene 14.

N-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 100 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)(methyl)(carbonyl)-6-sulfaninyl)methanesulfonamide (0.65 g, 1.24 mmol) Dissolved in tetrahydrofuran / methanol (8 mL / 8 mL), sodium hydroxide (250 mg, 6.20 mmol) dissolved in water (4 mL) was added to the above solution and allowed to react at room temperature for 2 hours. LC-MS was used to monitor complete conversion of the starting material, the reaction was stopped, and saturated ammonium chloride solution (30 mL) was added and extracted with ethyl acetate (30 mL x 2) The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and filtered. (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfimido)ethyl)amino)-1,2,5 - Oxadiazole-3-carbon oxetane 14 (345 mg), yield 55.0%.

MS m/z (ESI): 499.0, 501.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.45 (s, 1H), 8.92 (s, 1H), 7.18 (t, J = 8.8Hz, 1H), 7.12 (dd, J 1 = 6.0Hz , J ₂ = 2.8 Hz, 1H), 6.77 (m, 1H), 6.57 (t, J = 6.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 3H), 3.48 (s, 3H), 3.01(s,3H).

Example fifteen

(Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfonimido)ethyl)amino)- N'- Hydroxy-1,2,5-oxadiazole-3-carbonoxaxanthene (15)

Step 1: N-((2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3) -base)-1,2,5- Oxadiazol-3-yl)amino)ethyl)(methyl)(carbonyl)-l6-sulfaninyl)cyclopropanesulfonamide 15b.

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfimido)ethyl)amino)-1,2,5 in a 100 mL vial -oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1.5 g, 3.36 mmol) was dissolved in pyridine (30 mL), and propyl sulphonyl chloride (1.42 g, 10 mmol), DMAP (41 mg, 3.36 mmol), EtOAc EtOAc (EtOAc m. (50 mL) Wash, dry over anhydrous sodium sulfate, filtered, and then filtered and then evaporated to silica. -(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazole-3 -yl)amino)ethyl)(methyl)(carbonyl)-l6-sulfaninylene)cyclopropanesulfonamide 15b (0.65 g), yield 32.7%.

MS m/z (ESI): 551.0, 553.0 (M, M+2).

Step 2: (Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfinimidyl)ethyl) Amino)-N'-hydroxy-1,2,5-oxadiazole-3-carbonoxaxanthene 15.

N-((2-(4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxo) in a 100 mL vial Zyrid-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)(methyl)(carbonyl)-l6-sulfaninyl)cyclopropanesulfonamide (0.65 g, 1.18) Ment) dissolved in tetrahydrofuran/methanol (10 mL/10 mL), sodium hydroxide (236 mg, 5.95 mmol) was dissolved in water (5 mL) and added to the above solution, and reacted at room temperature for 2 hours. The LC-MS was monitored by EtOAc (EtOAc) (EtOAc (EtOAc) Filtration, the filtrate was added with silica gel, and then directly purified by column chromatography, ethyl acetate / methanol (30/1 to 10/1) to give (Z)-N-(3-bromo-4-fluorophenyl)-4-( (2-(N-(cyclopropylsulfonyl)-S-methylsulfonimido)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazol-3-carbooxazepine脒15 (350mg), yield 54.0%.

MS m/z (ESI): 525.0, 527.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.43 (s, 1H), 8.90 (s, 1H), 7.18 (t, J = 8.8Hz, 1H), 7.12 (dd, J 1 = 6.0Hz , J ₂ = 2.8 Hz, 1H), 6.77 (m, 1H), 6.55 (t, J = 6.0 Hz, 1H), 3.93 (m, 1H), 3.80 (m, 3H), 3.47 (s, 3H), 2.64 (m, 1H), 0.95 (m, 4H).

Example sixteen

(Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfimidoyl)ethyl)amino)-N'-hydroxy-1, 2,5- Oxadiazole-3-carbon azapine (16)

Step 1: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(N,S-dimethylsulfonimido)ethyl)amino)-1,2,5 -evil Diazol-3-yl)-1,2,4-oxadiazole-5(4H)-one 16b

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfimido)ethyl)amino)-1,2,5- was added to a 100 mL vial Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (40 mg, 0.09 mmol), trimethyloxonium tetrafluoroboric acid (20 mg, 0.13 mmol), dichloromethane (8 mL), stirred at room temperature for 15 minutes, sodium carbonate (57.3 mg, 0.54 mmol) was added and allowed to react overnight at room temperature. The reaction was quenched, water (20 mL), EtOAc (EtOAc (EtOAc) (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give 4-(3-bromo-4-fluorophenyl)-3-(4-(( 2-(N,S-Dimethylsulfimido)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H) - Ketone 16b (20 mg, 50%).

MS m/z (ESI): 461.0, 463.0 (M, M+2).

¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.11 (dd, J ₁ = 6.4 Hz, J ₂ = 2.8 Hz, 1H), 7.74 (m, 1H), 7.60 (t, J = 8.8 Hz, 1H) ), 7.05 (t, J = 6.0 Hz, 1H), 3.66 (dd, J ₁ = 12.4 Hz, J ₂ = 6.4 Hz, 2H), 3.37 (t, J ₂ = 6.4 Hz, 2H), 2.99 (s, 3H), 2.65 (s, 3H).

Step 2: (Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfinamido)ethyl)amino)-N'-hydroxyl Base-1,2,5-oxadiazole-3-carbon oxonium 16

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(N,S-dimethylsulfonimido)ethyl)amino)-1) in a 100 mL vial, 2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.43 mmol) dissolved in tetrahydrofuran / methanol (6 mL / 6 mL), sodium hydroxide (9 mg, 0.22 mmol) dissolved in water (2 mL) was added to the above solution and allowed to react at room temperature for 2 hours. The reaction was completed with EtOAc (EtOAc). , filtration, concentration of the filtrate, separation and purification by preparative silica gel plate (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give (Z)-N- (3- Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfinamido)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3 -Carboroxaxene 16 (13.0 mg, 68%).

MS m/z (ESI): 435.0, 437.0 (M, M+2).

¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 7.18 (dd, J ₁ = 6.0 Hz, J ₂ = 3.6 Hz, 1H), 7.18 (dd, J ₁ = 5.6 Hz, J ₂ = 2.8 Hz, 1H) , 7.02 (t, J = 8.4 Hz, 1H), 6.90 (m, 1H), 6.76 (t, J = 6.0 Hz, 1H), 3.90 (m, 2H), 3.58 (m, 2H), 3.09 (s, 3H), 2.83 (s, 3H).

Example seventeen

(Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(N-methylethylsulfimido)ethyl)amino)-1,2 , 5- Oxadiazole-3-carbon oxetane (17)

Step 1: 4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(N-methylethyl)sulfonyl)ethyl)amino)-1,2,5- evil Diazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 17b

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(S-ethylsulfonimido)ethyl)amino)-1,2,5- was added to a 100 mL vial Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.65 mmol), trimethyloxonium tetrafluoroborate (115 mg, 0.78 mmol), dichloromethane (30 mL), stirred at room temperature for 15 minutes, sodium carbonate (414 mg, 3.9 mmol). The reaction was quenched, water (50 mL), EtOAc (EtOAc)EtOAc. (developing agent: dichloromethane / methanol = 15 / 1; eluent: ethyl acetate / methanol = 15 / 1) to give 4-(3-bromo-4-fluorophenyl)-3-(4-(( 2-(N-Methylethylsulfonimido)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)- Ketone 17b (130 mg, 42.1%).

MS m/z (ESI): 475.0, 477.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ8.12 (dd, J1 = 6.0Hz, J2 = 2.8Hz, 1H), 7.74 (m, 1H), 7.60 (t, J = 8.8Hz, 1H) , 7.00 (t, J = 6.0 Hz, 1H), 3.63 (dd, J ₁ = 12.8 Hz, J ₂ = 6.4 Hz, 2H), 3.40 (m, 1H), 3.30 (m, 1H), 3.16 (m, 2H), 2.64 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).

Step 2: (Z)-N-(3-Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfinamido)ethyl)amino)-N'-hydroxyl Base-1,2,5-oxadiazole-3-carbon oxonium 17

4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(N-methylethyl)sulfonyl)ethyl)amino)-1,2 in a 100 mL vial , 5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (130 mg, 0.27 mmol) dissolved in tetrahydrofuran/methanol (8 mL / 8 mL) 55 mg, 1.36 mmol) was dissolved in water (5 mL) and added to the above solution, and reacted at room temperature for 2 hours. The reaction was completed with EtOAc (3 mL). , filtration, concentration of the filtrate, separation and purification by preparative silica gel plate (developing agent: dichloromethane / methanol = 10/1; eluent: ethyl acetate / methanol = 10/1) to give (Z)-N- (3- Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfinamido)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3 - Cholesterol 17 (76.6 mg, 63.2%).

MS m/z (ESI): 448.0, 450.0 (M, M+2).

^{1 H NMR (400MHz, DMSO-} d 6, ppm) δ11.45 (s, 1H), 8.89 (s, 1H), 7.18 (t, J = 8.8Hz, 1H), 7.10 (dd, J 1 = 6.0Hz , J ₂ = 2.8 Hz, 1H), 6.76 (m, 1H), 6.56 (t, J = 6.0 Hz, 1H), 3.58 (dd, J ₁ = 12.8 Hz, J ₂ = 6.4 Hz, 2H), 3.31 ( m, 2H), 2.63 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).

Example 18

(R,Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfanimidoyl)ethyl)ammonium -N'-hydroxy-1,2,5-oxadiazol-3-carboindole (18-(R,Z)) and (S,Z)-N-(3-bromo-4- Fluorobenzene 4-((2-(N-(cyclopropylsulfonyl)-S-methylsulfonimido)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole -3-carbon oxonium (18-(S, Z))

The preparation method is as follows:

The invention adopts a preparation device (K-Prep LAB100S type supercritical fluid chromatography preparation instrument of YMC Corporation of Japan) and a chiral column (AD-H 4.6*250, particle size 5um) of the game, and 2.3457g of the compound of Example 15 (detection spectrum) Figure 1) Performing chiral isomer separation, collecting 8.56 min and 9.69 min, respectively. The sample solution was evaporated to remove the solvent to obtain 10.79 liters of optical isomer 10.79744 (ee% value: 99.322%, detection spectrum see Fig. 2) and 9.69 min optical isomer 20.9552 g (ee%) Value: 98.676%, the detection spectrum is shown in Figure 3).

The eluent was prepared: (A: ethanol, B: 0.1% DEA n-hexane, A: B = 30:70, volume ratio); detection wavelength: 214 nm; column temperature: 20 °C.

The chiral purity detection analysis method is as follows:

色谱柱型Column type	手性柱OJ-HChiral column OJ-H
柱子尺寸Column size	0.46cm I.D.×25cm L0.46cm I.D.×25cm L
进样量Injection volume	1.0ul1.0ul
流动相Mobile phase	MeOH＝100％MeOH=100%
流速Flow rate	1.0ml/min1.0ml/min
检测波长Detection wavelength	UV 254nmUV 254nm
柱温Column temperature	35℃35°C

The optical rotation is determined as follows:

Optical rotation tester: Perkin Elmer (PE) model Perkin Elmer 341, the results are as follows: blank:

WL(nm)WL(nm)	Arc[°]Arc[°]	Energy[#]能源[#]	Temp.[℃]Temp.[°C]
589589	00	7575	2020

sample:

样品sample	浓度[g/ml]Concentration [g/ml]	溶剂Solvent	WL(nm)WL(nm)	Arc[°]Arc[°]	OROT[°]OROT[°]
光学异构体18-(R,Z)①Optical isomer 18-(R,Z)1	0.01007(C＝1)0.01007 (C=1)	乙腈Acetonitrile	589589	-0.110-0.110	-10.9-10.9
光学异构体18-(S,Z)②Optical isomer 18-(S,Z)2	0.00999(C＝1)0.00999 (C=1)	乙腈Acetonitrile	589589	+0.096+0.096	+9.6+9.6

Biological evaluation

I. Enzymatic test for inhibition of IDO activity

Human indoleamine 2,3-dioxygenase (IDO) was purchased from BPS Bioscience Inc. The idoleamine 2,3-dioxygenase (IDO) enzymatic reaction was carried out in a 96-well plate with a reaction volume of 20 μL. The reaction conditions were: 40 nM IDO enzyme, 0.2 mM L-tryptophan, 50 mM KPB. (pH 6.5) buffer, 20 mM L-ascorbate, 10 μM methylene blue, 0.2 mg/mL catalase, solvent <1% different concentrations of dimethyl sulfoxide. After reacting at 30 ° C for 60 minutes, 5 μL of 30% (w/v) trichloroacetic acid (50 mM KPB buffer) was added to each well, and incubation was carried out at 50 ° C for 30 minutes to hydrolyze N-formyl-kynurenine to canine ammonia. acid. 25 μL of 2% (w/v) p-(dimethylamino)benzaldehyde (p-DMBA)/glacial acetic acid solution was added to each well, and the absorbance at 490 nm was read with a BioTek Synergy H1 plate reader (Molecular Devices).

The test compound stock solution was prepared as 10 mM with dimethyl sulfoxide. The experiment was diluted with dimethyl sulfoxide to the highest concentration of the test, then subjected to a 1:3 gradient dilution, generally diluted to 8 to 10 concentration points, each A multi-well was set at the concentration point, and each test contained one reference compound. Analysis of 490nm absorbance microplate reader reads the raw data, calculation points at different concentrations of the test compound to inhibit the activity of IDO, using GraphPad Prism software fitting the percent inhibition data analysis nonlinear compound obtained half inhibitory concentration ₅₀ value IC.

2. Cell model test for inhibition of IDO activity

Interferon gamma induces expression of IDO in Hela cells, a model used to test the inhibitory activity of compounds on indoleamine 2,3-dioxygenase (IDO). The culture medium of Hela cells (ATCC) was phenol red-free RPMI-1640 containing 100 μM L-tryptophan. The test compound storage solution was prepared as 10 mM with dimethyl sulfoxide. The experiment was diluted with dimethyl sulfoxide to the highest concentration in the experiment. The experiment was carried out with a medium serial dilution of 3 times, usually diluted to 8 to 10 concentration points. Multiple holes are provided for each concentration point. The final concentration of DMSO was 0.5% and each experiment contained an internal reference compound.

The procedure was as follows: 20,000 HeLa cells (ATCC) were added to each well in a 96-well culture plate overnight, and interferon gamma (final concentration 50 ng/mL) and different concentrations of the test compound and internal reference were administered 24 hours later. The compound is added to the cultured cells. After 24:00, 140 μL of supernatant/well was transferred to a new 96-well plate, 10 μL of 6.1 N trichloroacetic acid was added to each well, and incubation was carried out at 50 ° C for 30 minutes to hydrolyze N-formyl-kynurenine into dogs. Urinine. The reaction mixture was centrifuged (centrifugation at 2500 rpm for 10 minutes) to remove the precipitate, and 100 μL of the supernatant was transferred to another new 96-well plate, and 100 μL of 2% (w/v) p-(dimethyl) was added to each well. Amino)benzaldehyde (p-DMBA)/glacial acetic acid solution was read at 490 nm absorbance using a BioTek Synergy H1 plate reader (Molecular Devices).

Analysis of 490nm absorbance microplate reader reads the raw data, calculation points at different concentrations of the test compound to inhibit the activity of IDO, using GraphPad Prism software fitting the percent inhibition data analysis nonlinear compound obtained half inhibitory concentration ₅₀ value IC.

The compounds of the examples of the present invention were respectively determined by the above two test methods, and the results of the enzymatic and cytological IDO inhibitory activity IC ₅₀ values are shown in the following table:

The test results demonstrate that the compounds of the examples of the present invention have good enzymatic and cytological IDO inhibitory activities.

Third, rat plasma PK analysis

The pharmacokinetic test of the test compound was carried out using SD rats (Shanghai Shrek).

■ Mode of administration: single oral administration.

■ Dosage: 20 mg/10 mL/kg.

■ Formulation formulation: 3% dimethylacetamide and 20% hydroxypropyl-β-cyclodextrin.

■Sampling point: 15 minutes, 0.5, 1, 2, 4, 6, 8, 24 hours before administration and 15 minutes after administration.

■ Plasma sampling and sample processing:

1) 0.2 ml of jugular vein blood was collected and placed in an EDTA-2K test tube. The plasma was separated by centrifugation at 6000 rpm for 5 minutes at 4 ° C, and stored at -80 ° C.

2) Add 160 μL of acetonitrile to 40 μL of plasma sample, standard, and internal reference, vortex for 3 minutes, centrifuge at 4000 rpm for 10 minutes, take 100 μL of the supernatant, then add 100 μL of non-ionized water to mix and take 10 μL. For LC/MS/MS analysis, the instrument used for plasma LC/MS/MS analysis was AB Sciex API 4000.

■ Liquid phase analysis:

●Liquid conditions: Shimadzu LC-20AD pump

●Column: phenomenex Gemiu 5um C18 50X 4.6mm

● Mobile phase: A solution is 0.1% formic acid aqueous solution, and B solution is acetonitrile.

●Flow rate: 0.8mL/min

● Elution time: 0-3.01 minutes, the eluent is as follows:

Time/minute

Liquid A

B liquid

0.010.01	70％70%	30％30%
11	10％10%	90％90%
22	10％10%	90％90%
2.012.01	70％70%	30％30%
33	70％70%	30％30%

■ Mass Spectrometry: Mass Spectrometer Setup Conditions: Cationic Electrospray Ionization (ESI) mode.

■ Test results: The main parameters of pharmacokinetics were calculated using WinNonlin 6.1. The experimental results are shown in the following table:

The test results prove that the compound of the present invention is obviously superior to the reference compound (INCB-24360), and has better pharmacokinetics, and the maximum pharmacokinetic parameters (Cmax) and drug exposure (AUC) are relatively high. The reference compound (INCB-24360) has been greatly improved.

4. Antitumor effect of the compound of the example in the PAN02 tumor-bearing mouse model

The present invention employs a PAN02 tumor-bearing mouse model to test the anti-tumor effect of the compounds of the examples. The PAN02 tumor-bearing mouse model is: the mouse pancreatic cancer cell line PAN02 was purchased from Guangzhou Jini Biotech Co., Ltd., and the culture solution used was DMEM containing 10% fetal calf serum. The mouse strain for tumor-bearing is C57/BL6, purchased from Shanghai Slack Laboratory Animal Co., Ltd. At the time of planting, PAN02 cells in the logarithmic growth phase were collected, mixed with the growth factor-reducing BD Matrigel Matrigel to 50 million/ml, and each mouse was subcutaneously implanted with 100 μl of 5 million cells. Animals were randomized when the tumor grew to approximately 100 cubic millimeters, with 8 animals per group, starting dosing (D0).

Mode of administration: intragastric administration, 2 times a day.

Dosage: 50 mg/10 mL/kg.

Formulation formulation: 3% dimethylacetamide and 20% hydroxypropyl-β-cyclodextrin.

■ Dosing cycle and tumor measurement: The dosing period was 13 days, the tumor volume was measured 3 times a week, the rats were weighed, and the data were recorded. The tumor volume (V) is calculated as: V = 1/2axb2 where a and b represent length and width, respectively. The formula for calculating T/C is: T/C (%) = 100 x ΔT / ΔC. Tumor inhibition rate (%) = 1 - T / C (%).

■ Test Results: The antitumor effect of the compound of Example 15 on the PAN02 tumor-bearing mouse model is shown in the following table.

As can be seen from the table, the compound inhibition rate of the compound of Example 15 in the PAN02 tumor-bearing mice was 74.8% at a dose of 50 mg/kg, which was significantly higher than the reference positive compound INCB 24360 (the tumor inhibition rate was 39.7%). ).

5. Antitumor effect of the compound of the example in the mouse model of Colon26 tumor-bearing

The present invention further employs a Colon26 tumor-bearing mouse model to test the anti-tumor effect of the example compounds. The Colon26 tumor-bearing mouse model is: Mouse colon cancer cell line Colon26 was purchased from Guangzhou Ginuo Biotechnology Co., Ltd., and the culture solution used was RPMI1640 containing 10% fetal bovine serum for tumor-bearing mice. The strain is Balb/c and was purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. At the time of planting, Colon26 cells in the logarithmic growth phase were collected and mixed to 10 million/ml, and each mouse was subcutaneously planted with 100 μl of one million cells. Animals were randomized when the tumor grew to approximately 100 cubic millimeters, with 8 animals per group, starting dosing (D0).

Mode of administration: intragastric administration, 2 times a day.

Dosage: 50 mg/10 mL/kg.

■ Test Results: The antitumor effect of the compound of Example 15 on the Colon26 tumor-bearing mouse model is shown in the following table.

As can be seen from the table, the compound inhibition rate of the compound of Example 15 in Colon26 tumor-bearing mice was 94.6% at a dose of 25 mg/kg, which was significantly higher than the reference positive compound INCB 24360 (the tumor inhibition rate was 78.4%). ).

Under the same experimental conditions, the dosage was adjusted. The antitumor effect of Example 15 and its optical isomers 18-1 and 18-2 on the Colon26 tumor-bearing mouse model is shown in the following table:

实施例及其给药剂量Examples and doses administered	抑瘤率(％)D12Tumor inhibition rate (%) D12
实施例15 10mg/kgExample 15 10 mg/kg	71.10％71.10%
实施例18-①10mg/kgExample 18-110 mg/kg	72.54％72.54%
实施例18-②10mg/kgExample 18-210 mg/kg	68.49％68.49%

It can be seen from the results in the table that the optically pure compound 18 obtained by the resolution of Example 15 has a similar inhibitory effect on Colon26 tumor-bearing mice and has a good inhibitory effect.

Claims

An N'-hydroxy-N-phenylformamidine derivative having the structure of the following formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

among them:

Z type and E type; preferably Z type;

X is selected from C 1-8 alkyl or C 3-8 cycloalkyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclic ring Alkoxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 Nonheteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S(O) r R 4 , -C 0-8 -OR 5 , -C 0-8 -C(O) OR 5 , -C 0-8 -C(O)R 6 , -C 0-8 -OC(O)R 6 , -C 0-8 -NR 7 R 8 , -C 0-8 -C(O) Substituted by a substituent of NR 7 R 8 , -N(R 7 )-C(O)R 6 or -N(R 7 )-C(O)OR 5 ;

R 1 is selected from the following structures:

Y is selected from -S(O) 2 - or -C(O)-C(O)-;

Z is selected from a bond, O, S or -NR 7 -;

R 2 is selected from hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl or C 0-8 alkylcarbonyl,

Optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo Substituting C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl , C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0 -8 -S(O) r R 4 , -C 0-8 -OR 5 , -C 0-8 -C(O)OR 5 , -C 0-8 -C(O)R 6 , -C 0- 8 -OC (O) R 6, -C 0-8 -NR 7 R 8, -C 0-8 -C (O) NR 7 R 8, -N (R 7) -C (O) R 6 , or - Substituted by a substituent of N(R 7 )-C(O)OR 5 ;

R 3 is selected from the group consisting of hydrogen, hydrazine, hydroxy, amino, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-8 alkoxy, C 3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C 5-10 aryloxy, 5-10 membered heteroaryl Alkoxy group, -C 0-8 -S(O) r R 4 , -C 0-8 -C(O)OR 5 , -C 0-8 -OC(O)R 6 , -C 0-8 - NR 7 R 8 , -C 0-8 -C(O)NR 7 R 8 , -N(R 7 )-C(O)R 6 or -N(R 7 )-C(O)OR 5 ,

Optionally further selected from one or more selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo Substituting C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl , C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C 0 -8 -S(O) r R 4 , -C 0-8 -OR 5 , -C 0-8 -C(O)OR 5 , -C 0-8 -C(O)R 6 , -C 0- 8 -OC (O) R 6, -C 0-8 -NR 7 R 8, -C 0-8 -C (O) NR 7 R 8, -N (R 7) -C (O) R 6 , or - Substituted by a substituent of N(R 7 )-C(O)OR 5 ;

R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;

R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;

R 6 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;

R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 2-8 chain Alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl or C 1-8 alkanoyl, or And R 7 and R 8 , R 9 and R 10 and the nitrogen atom to be bonded form a 3-8 membered heterocycloalkyl group,

Optionally further substituted with one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C 1-8 alkyl, trifluoromethyl, C 2 8 -alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 Alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, mono C 1-8 alkylamino or di C Substituted by a substituent of a 1-8 alkylamino group;

r is 0 to 2.
A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of the compound of the formula (II):

among them:

X is selected from C 1-6 alkyl or C 3-8 cycloalkyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 Substituted by a substituent of an alkyl group, a halogen-substituted C 1-8 alkyl group or a C 3-8 cycloalkyl group;

R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, C 1-8 alkyl substituted C 5-10 aryl, 5-10 a heteroaryl group, a C 1-8 alkanoyl group or a —C 0-8 —C(O)OR 5 , or a R 5 and R 10 and a nitrogen atom to be bonded form a 5-6 membered heterocycloalkyl group,

Optionally further substituted with one or more substituents selected from halo, hydroxy, mercapto, cyano, nitro, acetamido, azido, a sulfonyl group, mesyl group, C 1-8 alkyl, trifluoromethyl, C 3 -8 cycloalkyl, 3-8 membered heterocyclic, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3- 8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl Substituted by a substituent of a 5-10 membered heteroaryloxy group, a 5-10 membered heteroarylthio group, an amino group, a mono C 1-8 alkylamino group or a di C 1-8 alkylamino group.
A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of a compound of the formula (IIA) or (IIB):

among them:

X is selected from ethyl, cyclobutyl or cyclohexyl, optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, decyl, cyano, nitro, trifluoromethyl, C 1-8 alkyl or C Substituted by a substituent of a 3-8 cycloalkyl group;

R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-10 aryl group, C 1-8 alkyl substituted C 5-10 aryl group, 5-10 membered heteroaryl group, C 1-8 alkanoyl group or -C 0-8 -C(O)OR 5 , or R 9 and R 10 and the nitrogen atom to be bonded form a 5-6 membered heterocycloalkyl group.
A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, which is selected from the group consisting of the following compounds:
A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of the compound of the formula (III):

Z is selected from a bond or -NR 7 -;

R 2 is selected from hydrogen, hydrazine or C 1-8 alkyl;

R 3 is selected from the group consisting of hydrazine, hydroxy, amino, C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1 -8 alkoxy, C 3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C 5-10 aryloxy, 5-10 membered heteroaryloxy, -C 0-8 - S(O) r R 4 , -C 0-8 -C(O)OR 5 or -C 0-8 -OC(O)R 6 ;

R 4 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl, phenyl, p-methylphenyl, amino , a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;

R 5 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 3-8 cycloalkyl, halogen substituted C 1-8 alkyl or hydroxy substituted C 1-8 alkyl;

R 6 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, halogen substituted C 1-8 alkyl, halogen Substituting a C 1-8 alkoxy group, a hydroxy-substituted C 1-8 alkyl group or a hydroxy-substituted C 1-8 alkoxy group;

r is 0 to 2.
A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 5, which is selected from the group consisting of the following compounds:

among them:

Z, R 2 and R 3 are as described in claim 5.
A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 7, which is selected from the group consisting of the following compounds:
An intermediate for preparing the compound of the formula (III) according to claim 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (IV), and its stereoisomerism Or a pharmaceutically acceptable salt thereof:

among them:

Z, R 2 and R 3 are as described in claim 5.
A process for the preparation of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, which comprises the following steps:

The compound of the formula (IV) is ring-opened under basic conditions to give a compound of the formula (III);

among them:

X, R 2 and R 3 are as defined in claim 5.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, according to any one of claims 1 to 7, for the preparation of a medicament for use in the preparation of a medicament It inhibits the activity of indoleamine 2,3-dioxygenase or is used to inhibit immunosuppression in patients.
Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, according to any one of claims 1 to 7, for the preparation of a medicament for use in the preparation of a medicament For treating or preventing cancer or tumor, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or autoimmune disease in a patient; wherein the cancer or tumor is preferably from lung cancer, bone cancer, stomach cancer, Pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, Breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urinary tract cancer, penile cancer, prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphoma, transitional cell carcinoma, bladder Cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic cancer, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, solid tumor of children, lymphocytic lymphoma, central nervous system (CNS) tumor, primary Central nervous system lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, melanoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, chronic or A combination of acute leukemia and the cancer.
The use according to any one of claims 11 to 12, wherein a therapeutically effective amount of a compound of the formula (I) according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof Or the pharmaceutical composition according to claim 10, and an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an antiviral agent, a chemotherapeutic agent, an immunosuppressive agent, a radiation, an antitumor vaccine, an antiviral vaccine a cytokine therapy or a tyrosine kinase inhibitor is administered in combination; the cytokine is preferably IL-2, IL-3, IL-4 or IL-5, and the chemotherapeutic agent is preferably a cytotoxic agent, the anti-PD- The 1 antibody is preferably a Keytruda antibody.
A method of modulating guanamine 2,3-dioxygenase activity, the method comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-7, The construct or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10 is contacted with indoleamine 2,3-dioxygenase; the modulation is preferably an inhibitory effect.
A method of inhibiting immunosuppression in a patient, the method comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable thereof The salt, or the pharmaceutical composition of claim 10, is administered to a patient.