WO2022206084A1

WO2022206084A1 - Use of thiazole compound in preparation of drug for treating and preventing cancer

Info

Publication number: WO2022206084A1
Application number: PCT/CN2022/000051
Authority: WO
Inventors: 牛彦; 徐萍; 吕子睿; 许凤荣
Original assignee: 北京大学
Priority date: 2021-03-29
Filing date: 2022-03-24
Publication date: 2022-10-06
Also published as: CN116456980A

Abstract

A thiazole compound represented by general formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a use thereof as a STAT3 pathway inhibitor. The compound has strong inhibitory activity on the proliferation of tumor cells, and can be used for treating cancer.

Description

Use of thiazole compounds in the preparation of drugs for treating and preventing cancer

Field of Invention

The invention provides thiazole compounds and their use as STAT3 pathway inhibitors, the compounds have strong inhibitory activity on the proliferation of tumor cells, and can be used for the treatment of cancer.

Background technique

STAT3 (signal transducer and activator of transcription 3, STAT3) pathway is an important member of the signal transduction and transcription activator protein family, with dual functions of signal transduction and transcription activation. So far, seven STAT family members have been reported in mammalian cells, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. Among them, STAT3 is widely present in various cells and tissues and can be used by many cytokine activation.

Under normal circumstances, there are well-established inhibitory mechanisms in cells, such as protein inhibitor of activated STAT (PIAS), suppressors of cytokine signaling (SDCS), and some tyrosine protein phosphatase (protein tyrosine phosphatases (PTPs), including SHP-2, PTP1B, PTPeC, TC45, SHP-1), so that the activation of the STAT3 signaling pathway is tightly controlled at low levels. However, in a variety of tumor cells, STAT3 is continuously activated and expressed at a high level, such as ovarian cancer, pancreatic cancer, prostate cancer, head and neck cancer, breast cancer, leukemia and non-small cell lung cancer, and is closely related to tumor and tumor Formation and development, angiogenesis is closely related to tumor immunosuppression.

Therefore, inhibiting the overactivated STAT3 pathway has become an important target for anti-tumor therapy. It is of great value to find highly effective STAT3 activation inhibitors with high safety, sufficient cell permeability and reliable pharmacokinetic properties.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound, and its use in the manufacture of a medicament for the treatment/prevention of cancer, wherein the compound is a compound of general formula (I), or a pharmaceutically acceptable salt or hydrate thereof or solvate:

in,

R ₁ is selected from H, halogen, -CN, -NO ₂ , -N ₃ , -OR _a , -NR _b R _c , C _1-6 alkyl or C _1-6 haloalkyl;

R ₂ is selected from H, halogen, -CN, -NO ₂ , -N ₃ , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -S(O) R _a , -S(O) ₂ R _a , -S(O)NR _b R _c , -S(O) ₂ NR _b R _c , -S(O) ₂ OR _a , -P(O)R _b R _c , -P(O) ₂ R _a , -P(O)(NR _b R _c ) ₂ , -P(O) ₂ NR _b R _c , C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ is selected from H, halogen, -CN, -NO ₂ , -N ₃ , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -S(O) R _a , -S(O) ₂ R _a , -S(O)NR _b R _c , -S(O) ₂ NR _b R _c , -S(O) ₂ OR _a , -P(O)R _b R _c , -P(O) ₂ R _a , -P(O)(NR _b R _c ) ₂ , -P(O) ₂ NR _b R _c , C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ is selected from H, halogen, -CN, -NO ₂ , -N ₃ , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -S(O) R _a , -S(O) ₂ R _a , -S(O)NR _b R _c , -S(O) ₂ NR _b R _c , -S(O) ₂ OR _a , -P(O)R _b R _c , -P(O) ₂ R _a , -P(O)(NR _b R _c ) ₂ , -P(O) ₂ NR _b R _c , C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R is selected from H, halogen, -CN or _-NO2 ;

wherein R _a , R _b and R _c are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkane radical, 3- to 7-membered heterocyclyl, _C _6-10 aryl, or 5- to 10-membered heteroaryl; or R and R together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl or 5- to ₁₀ -membered heterocyclyl 10-membered heteroaryl.

In another aspect, the present invention provides a method of treating/preventing cancer in a subject, comprising administering to the subject a compound of general formula (I), or a pharmaceutically acceptable salt thereof, Hydrate or Solvate:

in,

R ₅ is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R is selected from H, halogen, -CN or _-NO2 ;

In yet another aspect, the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment/prevention of cancer:

in,

R ₅ is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R is selected from H, halogen, -CN or _-NO2 ;

In another aspect, the present invention provides the following compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof:

Other objects and advantages of the present invention will be apparent to those skilled in the art from the ensuing detailed description, examples and claims.

Description of drawings

Figure 1A shows the change curve of tumor volume of the mice in each group during the administration; Figure 1B shows the tumor-bearing volume of the surviving mice in each group after 28 days of administration; Figure 1C shows the tumor volume of the mice in each group during the administration Body weight change curve; Figure 1D shows the body weight values of surviving mice in each group after 28 days of administration. For Figure 1A, 1C, the results are represented by Mean±SD. For Figures 1B, 1D, each data point represents a specific measurement for an individual animal, and the horizontal line represents the mean value for each group. P value was calculated using Statistical Product and Service Solutions (SPSS) software two-tailed Student's t test, n.s.: no significant difference compared with blank solvent group; *: P<0.05; **: P<0.01; *** : P<0.001; when P<0.05, there is a significant difference compared with the blank solvent group.

Detailed description of the invention

definition

Definitions of specific functional groups and chemical terms are described in more detail below.

When numerical ranges are listed, each value and subranges within the range are intended to be included. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , _C2-6 , _C2-5 , _C2-4 , _C2-3 , _C3-6 , _C3-5 , _C3-4 , _C4-6 , _C4-5 , and _{C5 -6} alkyl.

"C _1-6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C _1-4 alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tertiary Butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-amyl (C ₅ ) and n-hexyl (C ₆ ). Whether or not the alkyl group is modified with "substituted" or not, each of the alkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.

"C _2-6 alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 alkenyl groups are preferred. Examples of C _2-6 alkenyl groups include: vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ) , 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), etc. The term "C _2-6 alkenyl" also includes heteroalkenyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. Whether or not the alkenyl group is modified with "substituted" or not, each of the alkenyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.

"C _2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some implementations Among the schemes, C _2-4 alkynyl groups are preferred. Examples of C _2-6 alkynyl groups include, but are not limited to: ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), ₂ -butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), etc. The term "C _2-6 alkynyl" also includes heteroalkynyl groups in which one or more ( For example, 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Whether or not the alkynyl group is modified with "substituted", each Independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are defined below.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Thus, "C _1-6 haloalkyl" refers to the aforementioned "C _1-6 alkyl" substituted with one or more halogen groups. In some embodiments, C _1-4 haloalkyl is particularly preferred, more preferably C _1-2 haloalkyl. Exemplary such _haloalkyl groups include, but are not limited to _: _-CF3 , _-CH2F , _-CHF2 , _-CHFCH2F , _-CH2CHF2 , _-CF2CF3 , _-CCl3 , _-CH2Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.

"C _3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, _C3-7 cycloalkyl is preferred, _C3-6 cycloalkyl is particularly preferred, and _C5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in the cycloalkyl system. Exemplary of such cycloalkyl groups include, but are not limited to: cyclopropyl (C3 ₎ , cyclopropenyl (C3 ₎ , cyclobutyl ( _C4 ), cyclobutene base (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cyclohexyl (C 6 ) Heptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptyl ( _C7 ), bicyclo[2.2.2]octyl (C8), _cyclononyl ( _C9 ), cyclononenyl ( _C9 ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), and the like. Whether or not the cycloalkyl group is modified with "substituted" or not, each of the cycloalkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

"3- to 10-membered heterocyclyl" alternatively refers to a group of 3- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen , sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. In some embodiments, 3- to 7-membered heterocyclyl groups are preferred, which are those having ring carbon atoms and 3- to 7-membered non-aromatic ring systems of 1 to 3 ring heteroatoms; in some embodiments, 3- to 6-membered heterocyclyl groups are particularly preferred, which are those having ring carbon atoms and 1 to 3 ring heteroatoms A 3- to 6-membered non-aromatic ring system; more preferably a 5- to 6-membered heterocyclic group, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclic group also includes wherein A ring system in which the above heterocyclyl ring is fused to one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to be expressed at The number of ring members in a heterocyclyl ring system. Whether or not the heterocyclyl group is modified with "substituted" or not, each of the heterocyclyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents group or one substituent, and suitable substituents are defined below.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridine, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom Cyclic groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxa oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include But not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiahexyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl Alkyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thiacyclooctyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as _5,6 -bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: indoline, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary ₆ -membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.

"C _6-14 aryl" refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system (eg, having 6-14 ring carbon atoms and zero heteroatoms) 6, 10, or 14 pi electrons shared by a cyclic arrangement). In some embodiments, an aryl group has six ring carbon atoms ("C ₆ aryl"; eg, phenyl). In some embodiments , an aryl group having ten ring carbon atoms (" _C10 aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C ₁₄ aryl"; eg, anthracenyl). In some embodiments, C _6-10 aryl groups are particularly preferred, more preferably C ₆ aryl groups. Aryl groups also include ring systems in which the aforementioned aryl rings are fused to one or more cycloalkyl or heterocyclyl groups , and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Whether or not the aryl group is modified with "substituted", the aryl group Each of is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, appropriate substituents are defined below.

"5- to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, having shared in a cyclic arrangement 6 or 10 pi electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom is The numbers continue to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Whether or not the heteroaryl group is modified with "substituted" or not, each of the heteroaryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The base is defined as follows.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacyclotrienyl, oxeptrienyl, and thiacyclotrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indanyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthaloyl oxazinyl and quinazolinyl.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, _-NO2 , _-N3 , _-SO2H , _-SO3H , -OH, ^-ORaa , -ON( ^Rbb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , - Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P( =O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , - NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heterocyclyl Aryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups ;

Or two geminal hydrogens on a carbon atom are surrounded by groups =O, =S, =NN( ^Rbb ) ₂ , = ^NNRbbC (=O) ^Raa , = ^NNRbbC (=O) ^ORaa , = NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc substitution;

Each of R ^aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd groups group replacement;

Each of R ^bb is independently selected from: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O ) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkene alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne radyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each of ^Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups are combined to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd group substitution;

Each of ^Rdd is independently selected from: halogen, -CN, _-NO2 , _-N3 , -SO2H, _-SO3H , -OH, ^-ORee , -ON( ^Rff ₎₂ _, -N (R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ ^Ree , -OC(=O) ^Ree , -OCO ₂ ^Ree , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - ^NRff C(=O) ^{Ree,-NRffCO2Ree} ^, ^-NRffC (=O)N( ^Rff ) ₂ , _-C (= ^NRff ) ^ORee , ^-OC(=NRff ⁾ ^Ree , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ ^Ree , -SO ₂ N(R ^ff ) ₂ , -SO ₂ ^Ree , -SO ₂ OR ^ee , -OSO ₂ ^Ree , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , - SC(=S)SR ^ee , -P(=O) ₂ Re ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle aryl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two gem R ^dd substituents may combine to form =O or =S;

Each of R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon cyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

Each of ^Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently separated by 0, 1, 2, 3, 4, or 5 R ^gg group substitution;

Each of Rgg is independently: halogen, -CN, _-NO2 , _-N3 , ^-SO2H , _-SO3H , _-OH , _-OC1-6 alkyl, -ON( _C1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 _alkyl ), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C (=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl) C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , - NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _1- ₆ alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl) , -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C (=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl , -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl _{) 2} _, -OP(= O) (C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two geminal Rgg substituents may combine to form =O or =S; wherein X ^- for counter ions.

Exemplary substituents on nitrogen include, but are not limited to: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O )( ^NRcc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups attached to a nitrogen atom combine to form a heterocycle aryl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R The ^dd group is substituted and wherein R ^aa , R ^bb , R ^cc and R ^dd are as described above.

The term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergy, etc., and with reasonable benefit/risk Those salts in proportionate proportions. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or salts formed with organic acids such as acetic, oxalic, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using methods conventional in the art, eg, ion exchange methods. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor acid salt, camphorsulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate , malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, Pectin Acetate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Stearate, Succinate, Sulfate, Tartrate, Thiocyanate, tosylate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, Calcium, magnesium salts, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations with counter ions such as halides, hydroxide, formate, sulfate, phosphate, Nitrates, lower alkyl sulfonates and aryl sulfonates.

Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

The term "solvate" refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of that compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R x H ₂ O, where R is the compound, and x is a number greater than 0. A given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5 H _{2 )} O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R 2 H ₂ O) and hexahydrate (R 6 H ₂ O)).

"Subjects" for administration include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, eg, mammals, eg, primates (eg, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"Disease," "disorder," and "condition" are used interchangeably herein.

Unless otherwise specified, the term "treatment" as used herein includes the effect that occurs when a subject suffers from a particular disease, disorder or condition, which reduces the severity of, or delays or slows down, the disease, disorder or condition or development of a disorder ("therapeutic treatment"), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").

"Combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, a compound of the present invention may be administered concurrently or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit The unit dosage forms are administered simultaneously.

In a specific embodiment, the present invention provides a compound, and its use in the manufacture of a medicament for the treatment/prevention of cancer, wherein the compound is a compound of general formula (I), or a pharmaceutically acceptable salt thereof , hydrate or solvate:

in,

R ₅ is selected from H, C _1-6 _{alkyl or C 1-6} _haloalkyl ;

R is selected from H, halogen, -CN or _-NO2 ;

In another specific embodiment, the present invention provides the above compounds and uses, wherein R ₁ is selected from H, halogen, -CN, -NO ₂ , -N ₃ or -OH, preferably H, halogen or -OH, more Preferably it is H or -OH.

In another specific embodiment, the present invention provides the above compounds and uses, wherein R ₂ is selected from H, halogen, -CN, -NO ₂ , -N ₃ , -C(O)R _a , -C(O) OR _a , -C(O)NR _b R _c , -S(O) ₂ OH, C _1-6 alkyl or C _1-6 haloalkyl, preferably H, halogen, -CN, -NO ₂ , -N ₃ . C _1-6 alkyl or C _1-6 haloalkyl, more preferably H, halogen, C _1-6 alkyl or C _1-6 haloalkyl.

In another specific embodiment, the present invention provides the above compounds and uses, wherein _R3 is selected from H, halogen, -CN, _-NO2 , _-N3 , -C(O) _Ra , -C(O) OR _a , -C(O)NR _b R _c , -S(O) ₂ OH, C _1-6 alkyl or C _1-6 haloalkyl, preferably H, halogen, -CN, -NO ₂ , -N ₃ , C _1-6 alkyl or C _1-6 haloalkyl, more preferably H, halogen, -N ₃ , C _1-6 alkyl or C _1-6 haloalkyl.

In another specific embodiment, the present invention provides the above compounds and uses, wherein R ₄ is selected from H, halogen, -CN, -NO ₂ , -N ₃ , -C(O)R _a , -C(O) OR _a , -C(O)NR _b R _c , -S(O) ₂ OH, C _1-6 alkyl or C _1-6 haloalkyl, preferably H, halogen, -CN, -NO ₂ , -N ₃ . C _1-6 alkyl or C _1-6 haloalkyl, more preferably H, halogen, C _1-6 alkyl or C _1-6 haloalkyl.

_In another specific embodiment, the present invention provides compounds and uses as described above, wherein R5 is H.

In another specific embodiment, the present invention provides the above compounds and uses, wherein:

R ₁ is H or -OH;

R ₂ is H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ is H, halogen, -N ₃ , C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ is H, C _1-6 alkyl or C _1-6 haloalkyl;

_R5 is H.

In another specific embodiment, the present invention provides the above-mentioned compounds and uses, wherein at least one of R ₂ and R ₃ is a non-hydrogen group.

In another specific embodiment, the present invention provides the above compounds and uses, wherein R is halogen, preferably Cl or Br, more preferably Br.

In another specific embodiment, the present invention provides the above-mentioned compounds and uses, wherein the compounds have the structure of general formula (I-1):

wherein each group is as defined above.

In another specific embodiment, the present invention provides the aforementioned compounds and uses, wherein the compounds have the following structure:

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another specific embodiment, the present invention provides the above-mentioned compounds and uses, wherein the cancer is a cancer mediated by the STAT3 pathway, preferably glioma, colorectal cancer, gastric cancer, melanoma, ovarian cancer, pancreatic cancer , prostate cancer, head and neck cancer, breast cancer, leukemia or non-small cell lung cancer.

In another specific embodiment, the present invention provides the above compounds and uses, wherein the cancer is located in the brain.

In another specific embodiment, the present invention provides the above compounds and uses, wherein the cancer is a metastatic cancer that metastasizes to brain or bone tissue.

In another specific embodiment, the present invention provides the following compounds, or a pharmaceutically acceptable salt, hydrate or solvate thereof:

Without being bound by theory, it is currently believed that 5-nitrothiazoles can inhibit the enzyme-dependent electron transfer of pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs). Reacts, interferes with anaerobic energy metabolism, and exerts anti-parasitic and anti-anaerobic activity. The nitro substituent at the 5-position is crucial for its above activity. Specifically, under physiological conditions (pH=7.4), NTZ can exist in an anionic form (NTZ ⁻ , as shown in the figure below). As a non-competitive inhibitor of pyruvate or TPP, ^NTZ- can induce pyruvate release from PFOR protein by interfering with the interaction between pyruvate carboxyl group and TPP amino group, and play a role in the early stage of PFOR catalysis.

After replacing the 5-nitro group of the thiazole ring with halogen, the halogen compound no longer has anti-anaerobic microorganism activity due to the destruction of the resonance formula. Therefore, after oral administration of the 5-halogen-substituted compound, in addition to exerting antitumor activity, it also has the advantages of not significantly affecting the intestinal flora, avoiding or reducing the disturbance of the gastrointestinal flora, and has higher safety.

Example

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The raw materials or products for which the preparation method is not described in the present invention are all purchased from commercial products.

The synthetic method of the compound of the present invention is as follows:

Example 1: Preparation of TIZ (2-hydroxy-N-(5-nitrothiazol-2-yl)benzamide).

NTZ (2-acetoxy-N-(5-nitrothiazol-2-yl)benzamide) (5mmol) was placed in a 50mL round bottom flask, 15mL concentrated hydrochloric acid, 10 drops of concentrated sulfuric acid were added, and the mixture was heated at 50°C The reaction was stirred until the NTZ was completely hydrolyzed. The mixture was filtered, the solid was washed with distilled water until neutral, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain pale yellow TIZ solid, yield : 92%.

Example 2: General synthetic route of compounds 3, 8-11, 13-22, 24 (Scheme 1).

Route 1. Synthesis of compounds 3, 8-11, 13-22, 24

Reagents and reaction conditions: (a) thionyl chloride, pyridine, dichloromethane; (b) anhydrous tetrahydrofuran, triethylamine.

(a) The corresponding benzoic acid derivative (1.5 mmol, 1.0 equiv.) was dissolved in anhydrous dichloromethane (5 mL/mmol), and thionyl chloride (1.8 mmol, 1.2 equiv.) and two drops of pyridine were added to the reaction solution. , heated to reflux until the reaction was complete. The solvent and excess thionyl chloride were removed by rotary evaporation, and the residual solid was dissolved in anhydrous tetrahydrofuran, and the next reaction was carried out directly.

(b) 2-Amino-5-nitrothiazole (1.5 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (5 mL/mmol), and triethylamine (1.8 mmol, 1.2 equiv) was added to the reaction solution. At -15°C, the benzoyl chloride solution prepared in step (a) was added dropwise to the above precooled reaction solution. The reaction solution was returned to room temperature, heated to reflux overnight, reacted until the starting material was completely consumed, and the reaction was quenched by adding water. The reaction solution was extracted with ethyl acetate, the combined organic phases were washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.

Example 3: General synthetic route of

compounds

1, 2, 12 and 25 (Scheme 2).

Scheme 2. Synthesis of

compounds

1, 2, 12, 25

Reagents and reaction conditions: (a) sodium hydroxide, acetic anhydride, water; (b) thionyl chloride, pyridine, dichloromethane; anhydrous tetrahydrofuran, triethylamine; (c) concentrated hydrochloric acid, concentrated sulfuric acid, 50°C .

Before coupling the benzoic acid derivative with 2-amino-5-nitrothiazole according to the above method, the phenolic hydroxyl group of the corresponding benzoic acid was firstly protected by acetylation with acetic anhydride, and the acetylated protected coupling product was obtained after After deprotection under acidic conditions, the final product was obtained.

Acetylation protection of phenolic hydroxyl groups. 1.5 g of sodium hydroxide was dissolved in 20 mL of distilled water and transferred to a 100 mL round bottom flask. To the above solution was added the corresponding hydroxybenzoic acid (18.1 mmol) and stirred until complete dissolution. Finally, 4 ml of acetic anhydride was added to the solution at 0°C and stirred at room temperature until the reaction was complete. The mixture was filtered, and the obtained white solid was thoroughly washed with distilled water and dried to obtain an acetoxybenzoic acid derivative.

The compound to be deprotected (5 mmol) was placed in a 50 mL round-bottomed flask, 15 mL of concentrated hydrochloric acid and 10 drops of concentrated sulfuric acid were added, and the mixture was stirred and reacted at 50° C. until the raw materials were completely hydrolyzed. The mixture was filtered, the solid was washed with distilled water until neutral, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the deprotected product.

Example 4: General synthetic route of compounds 4-7, 23 (Scheme 3).

Scheme 3. Synthesis of compounds 4-7 and 23

Reagents and reaction conditions: (a) EDCI, HOBt, DIEA, DMF.

The compound is based on the corresponding benzoic acid derivatives and 2-amino-5-nitrothiazole as raw materials, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) and 1-hydroxybenzene Natriazole (HOBt) as the condensation reagent, N-diisopropylethylamine (DIEA) as the alkaline environment, N,N-dimethylformamide (DMF) as the solvent, is obtained through a one-step condensation reaction, and passed through a column Chromatographic separation and purification.

Specifically, benzoic acid derivative (1.5 mmol, 1.0 equiv), EDCI (2.25 mmol, 1.5 equiv) and HOBT (2.25 mmol, 1.5 equiv) were dissolved in 10 mL of DMF and stirred at room temperature for 30 minutes. 2-Amino-5-nitrothiazole (1.5 mmol, 1.0 equiv), DIEA (4.5 mmol, 3.0 equiv) were dissolved in 10 mL DMF and stirred at room temperature for 30 minutes. Then the above reaction solutions were mixed, and the reaction was stirred at room temperature until the starting materials were completely consumed, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the target product.

Example 5: General synthetic route to compound 26 (Scheme 4).

Scheme 4. Synthesis of compound 26

Reagents and reaction conditions: (a) propargyl bromide, potassium carbonate, DMF.

Compound 26 was obtained from compound 15 by N-propargylation of compound 15 with propargyl bromide.

Specifically, compound 15 (2.00 mmol, 1.0 equiv) was dissolved in 10 mL of anhydrous DMF, and potassium carbonate (9.44 mmol, 4.7 equiv) was added to the solution at 0°C and stirred for 30 minutes. After 30 minutes, under ice bath conditions, propargyl bromide (5.00 mmol, 2.5 equiv) was added dropwise to the reaction, the reaction was returned to room temperature, and the reaction was continued to stir until the starting material was completely consumed. Chloromethane extraction, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol gradient elution) to obtain compound 26.

Example 6: Preparation of 2-hydroxy-3-methyl-N-(thiazol-2-yl)benzamide (compound 27)

Take 3-methylsalicylic acid (2mmol, 0.305g) in a 50ml round bottom flask, dissolve with 8ml DMF, add HATU (2.4mmol, 0.910g), NMM (6mmol, 660μl) and 2-aminothiazole (2mmol in turn) , 0.203g), heated and stirred at 50°C overnight to monitor the reaction by TLC. After the reaction, water (25ml) was added to quench the reaction, extracted with ethyl acetate (30ml*3), the organic phases were combined, washed with saturated brine (40ml*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, column Chromatographic separation (petroleum ether/ethyl acetate=15:1) (v/v) gave 0.148 g of a white solid with a yield of 32.0%.

Example 7: Preparation of 4-trifluoromethyl-N-(5-bromothiazol-2-yl)benzamide (Compound 28)

Using p-trifluoromethyl benzoic acid and 2-amino-5-bromothiazole as raw materials, weigh 4-trifluoromethyl benzoic acid (4.0 mmol, 0.76 g) into a 50 mL round-bottomed flask containing 10 mL of DMF, and add in turn PyBoP (4 mmol, 2.10 g), K ₂ CO ₃ (8 mmol, 1.10 g), 2-amino-5-bromothiazole (1 mmol, 0.18 g), transferred to 60° C. to react for 24 h. After monitoring by TLC until the reaction no longer occurred, water (25 mL) was added to the reaction system to quench the reaction, extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (40 mL*2), and dried over anhydrous sodium sulfate. , filtered and concentrated under reduced pressure. After separation by column chromatography, the product was collected as a white solid with a yield of 54%.

Characterization of the compounds of the present invention. The melting points of the compounds involved in the present invention were all determined, and characterized by hydrogen nuclear magnetic spectrum, carbon spectrum and high-resolution mass spectrometry.

2-Hydroxy-N-(5-nitrothiazol-2-yl)benzamide (TIZ). Pale yellow solid. Yield: 92%. mp: 209-210°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (br, 1H, OH), 8.70 (s, 1H, 4'-H), 7.91 (dd, J=7.9, 1.7 Hz, 1H, ArH), 7.54-7.47 (m, 1H, ArH), 7.08-6.98 (m, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.43, 161.45, 157.32, 142.35, 142.01, 135.12, 130.57, 119.87, 117.20, 116.42.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₆ N ₃ O ₄ S[MH] ^- , 264.0079; found 264.0081.

3-Hydroxy-N-(5-nitrothiazol-2-yl)benzamide (Compound 1). Pale yellow solid. Yield: 35%. mp: 245-246°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H, NH), 9.94 (s, 1H, OH), 8.71 (s, 1H, 4'-H), 7.58 (dt, J=7.8, 1.2Hz, 1H, ArH), 7.46 (t, J=2.1Hz, 1H, ArH), 7.37 (t, J=7.8Hz, 1H, ArH), 7.07 (ddd, J= 8.1, 2.5, 0.9 Hz, 1H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 166.44, 162.59, 157.59, 142.60, 142.00, 132.07, 129.86, 120.51, 119.03, 115.16.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₆ N ₃ O ₄ S[MH] ^- , 264.0079; found 264.0081.

4-Hydroxy-N-(5-nitrothiazol-2-yl)benzamide (compound 2). Pale yellow solid. Yield: 69%. mp: 213-214°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.31 (s, 1H, NH), 10.52 (s, 1H, OH), 8.70 (s, 1H, 4'-H), 8.05 (d, J=8.2Hz, 2H, ArH), 6.91 (d, J=8.2Hz, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.65, 162.95 , 162.40, 142.74, 141.81, 130.99, 121.13, 115.46.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₆ N ₃ O ₄ S[MH] ^- , 264.0079; found 264.0082.

N-(5-Nitrothiazol-2-yl)benzamide (compound 3). Pale yellow solid. Yield: 81%. mp: 218-219°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.60 (s, 1H, NH), 8.72 (s, 1H, 4'-H), 8.13 (d, J=7.8 Hz, 2H, ArH), 7.70 (t, J=7.3Hz, 1H, ArH), 7.59 (t, J=7.4Hz, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 166.43, 162.60, 142.61, 142.07, 133.50, 130.79, 128.79, 128.55.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₆ N ₃ O ₃ S[MH] ^- , 248.0130; found 248.0131.

2-Methyl-N-(5-nitrothiazol-2-yl)benzamide (compound 4). Pale yellow solid. Yield: 68%. mp: 182-183°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (s, 1H, NH), 8.69 (s, 1H, 4'-H), 7.64 (d, J=7.5 Hz, 1H, ArH), 7.49 (t, J=7.5Hz, 1H, ArH), 7.39-7.32 (m, 2H, ArH), 2143 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ168.55, 162.03, 142.65, 142.00, 137.03, 132.26, 131.55, 131.05, 128.50, 125.78, 19.66.m/z(ES ^- ), HRMS calcd for C ₁₁ H ₈ N ₃ O ₃ S[MH] ^- , 262.0286; found 262.0285.

2-Nitro-N-(5-nitrothiazol-2-yl)benzamide (compound 5). Pale yellow solid. Yield: 62%. mp: 227-228°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.83 (s, 1H, NH), 8.70 (s, 1H, 4'-H), 8.25 (d, J=8.1 Hz, 1H, ArH), 7.95 (t, J=7.5Hz, 1H, ArH), 7.90-7.83 (m, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.91, 161.41, 146.12, 142.53 , 142.36, 134.58, 132.36, 129.81, 129.21, 124.59.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₅ N ₄ O ₅ S[MH] ^- , 292.9981; found 292.9981.

2-Fluoro-N-(5-nitrothiazol-2-yl)benzamide (compound 6). Pale yellow solid. Yield: 86%. mp: 188-189°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (s, 1H, NH), 8.71 (s, 1H, 4'-H), 7.81 (td, J=7.5, 1.7 Hz, 1H, ArH), 7.73-7.66 (m, 1H, ArH), 7.46-7.35 (m, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 164.09, 161.64, 159.50 (d, J=252.7Hz), 142.59, 142.19, 134.61 (d, J=8.7Hz), 130.58, 124.74 (d, J=3.6Hz), 120.94 (d, J=12.6Hz), 116.53 (d, J=21.3Hz) ).m/z(ES ^- ), HRMS calcd for C ₁₀ H ₅ FN ₃ O ₃ S[MH] ^- , 266.0036; found 266.0031.

2-Bromo-N-(5-nitrothiazol-2-yl)benzamide (compound 7). Pale yellow solid. Yield: 70%. mp: 198-199°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.73 (s, 1H, NH), 8.70 (s, 1H, 4'-H), 7.78 (d, J=7.5 Hz, 1H, ArH), 7.69 (d, J=7.5Hz, 1H, ArH), 7.58-7.48 (m, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 167.01, 161.39, 142.57, 142.37 , 135.10, 133.03, 132.69, 129.67, 127.78, 119.18.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₅ BrN ₃ O ₃ S[MH] ^- , 325.9235, 327.9215; found 325.9233, 327.9213.

2-Chloro-N-(5-nitrothiazol-2-yl)benzamide (compound 8). Pale yellow solid. Yield: 64%. mp: 191-192°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.73 (s, 1H, NH), 8.70 (s, 1H, 4'-H), 7.72 (d, J=7.4 Hz, 1H, ArH), 7.66-7.58 (m, 2H, Ar-H), 7.54-7.48 (m, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 166.15, 161.39, 142.56, 142.35, 132.86, 132.71, 130.43, 129.98, 129.80, 127.35.m/z (ES ⁻ ), HRMS calcd for C ₁₀ H ₅ ClN ₃ O ₃ S[MH] ⁻ , 281.9740; found 281.9743.

2-Hydroxy-3-methyl-N-(5-nitrothiazol-2-yl)benzamide (compound 9). Pale yellow solid. Yield: 31%. mp: 181-182°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (br, 1H, OH) 8.76 (s, 1H, 4'-H), 7.92 (d, J=6.9Hz, 1H, ArH), 7.42 (d, J=6.9Hz, 1H, ArH), 6.90 (t, J=7.7Hz, 1H, ArH), 2.22 (s, 3H, _CH3 ). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 169.36, 162.71, 158.00, 141.32, 141.14, 136.18, 126.91, 126.41, 118.90, 114.87, 15.77.m/z (ES ^- ), HRMS calcd for C ₁₁₁ _H8N3O4S _[ MH] ^- , _278.0236 ; found 278.0238.

2-Hydroxy-4-methyl-N-(5-nitrothiazol-2-yl)benzamide (compound 10). Pale yellow solid. Yield: 28%. mp: 216-217°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (br, 1H, OH), 8.69 (s, 1H, 4'-H), 7.85 (d, J=8.0 Hz, 1H, ArH), 6.89-6.81 (m, 2H, ArH), 2.32 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.38, 161.59, 157.52, 146.09, 142.37, 141.85 , 130.44, 121.01, 117.35, 113.43, 21.23.m/z(ES ^- ), HRMS calcd for C ₁₁ H ₈ N ₃ O ₄ S[MH] ^- , 278.0236; found 278.0242.

2-Hydroxy-5-methyl-N-(5-nitrothiazol-2-yl)benzamide (compound 11). Pale yellow solid. Yield: 22%. mp: 209-210°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.01 (br, 1H, OH), 8.67 (s, 1H, 4'-H ), 7.74-7.70 (m, 1H, ArH), 7.31 (dd, J=8.4, 2.4Hz, 1H, ArH), 6.94 (d, J=8.3Hz, 1H, ArH), 2.26 (s, 3H, CH) ₃ ). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 165.44, 161.51, 155.21, 142.40, 141.92, 135.83, 130.25, 128.65, 117.11, 115.85, 19.86.m/z (ES ^- ), HRMS calcd for C _11H8N3O4S _[ MH] ^- , _278.0236 ; found _278.0243 .

2,4-Dihydroxy-N-(5-nitrothiazol-2-yl)benzamide (compound 12). Pale yellow solid. Yield: 45%. mp: 243-244°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.07 (s, 2H, NH+OH), 10.53 (s, 1H, OH), 8.68 (s, 1H, 4'-H ), 7.86 (d, J=9.3 Hz, 1H, ArH), 6.45 (m, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 164.73, 164.12, 161.59, 159.84, 142.52, 141.96, 132.56, 108.95, 107.02, 102.8.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₆ N ₃ O ₅ S[MH] ^- , 280.0028; found 280.0031.

3-Chloro-N-(5-nitrothiazol-2-yl)benzamide (compound 13). Pale yellow solid. Yield: 62%. mp: 192-193°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.66 (s, 1H, NH), 8.70 (s, 1H, 4'-H), 8.17 (t, J=1.8 Hz, 1H, ArH), 8.08-8.03 (m, 1H, ArH), 7.78-7.72 (m, 1H, ArH), 7.60 (t, J=7.9Hz, 1H, ArH). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ165.17, 162.36, 142.44, 142.15, 133.53, 133.14, 132.81, 130.70, 128.26, 127.28.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₅ ClN ₃ O ₃ S[MH] ^- , 281.9740 ; found 281.9749.

4-Chloro-N-(5-nitrothiazol-2-yl)benzamide (compound 14). Pale yellow solid. Yield: 72%. mp: 244-245°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.66 (s, 1H, NH), 8.71 (s, 1H, 4'-H), 8.12 (d, J=8.6 Hz, 2H, ArH), 7.65 (d, J=8.6Hz, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.48, 162.50, 142.53, 142.14, 138.46, 130.48, 129.62, 128.91.m/ z(ES ⁻ ), HRMS calcd for C ₁₀ H ₅ ClN ₃ O ₃ S [MH] ⁻ , 281.9740; found 281.9745.

N-(5-Nitrothiazol-2-yl)-4-(trifluoromethyl)benzamide (compound 15). Pale yellow solid. Yield: 76%. mp: 227-228°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.80 (s, 1H, NH), 8.71 (s, 1H, 4'-H), 8.29 (d, J=8.2 Hz, 2H, ArH), 7.94 (d, J=8.2 Hz, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.52, 162.36, 142.33, 142.17, 134.70, 132.74 (q, J _CF = 32.2 Hz), 129.47, 125.63 (q, J _CF = 3.4 Hz), 123.66 (q, J _CF = 272.9 Hz). m/z (ES ⁻ ), HRMS calcd for C ₁₁ H ₅ F ₃ N ₃ O ₃ S[ MH] ^- , 316.0004; found 316.0008.

4-Azido-N-(5-nitrothiazol-2-yl)benzamide (compound 16). Pale yellow solid. Yield: 54%. mp: 172-173°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.56 (s, 1H, NH), 8.71 (s, 1H, 4'-H), 8.18 (d, J=7.7 Hz, 2H, ArH), 7.31 (d, J=7.7Hz, 2H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.38, 162.60, 144.72, 142.56, 142.02, 130.57, 127.07, 119.37.m/ z(ES ^- ), HRMS calcd for C ₁₀ H ₅ N ₆ O ₃ S[MH] ^- , 289.0144; found 289.0148.

4-Methoxy-N-(5-nitrothiazol-2-yl)benzamide (compound 17). Pale yellow solid. Yield: 41%. mp: 231-232°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H, NH), 8.70 (s, 1H, 4'-H), 8.15 (d , J=8.9Hz, 2H, ArH), 7.11 (d, J=8.9Hz, 2H, ArH), 3.87 (s, 3H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ165.56, 163.40, 162.82 , 142.63, 141.87, 130.74, 122.72, 114.11, 55.62.m/z (ES ^- ), HRMS calcd for C ₁₁ H ₈ N ₃ O ₄ S[MH] ^- , 278.0236; found 278.0235.

4-(4-Methylpiperazin-1-yl)-N-(5-nitrothiazol-2-yl)benzamide (Compound 18). Pale yellow solid. Yield: 17%. mp: 210-211°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.87 (s, 1H, NH), 8.61 (s, 1H, 4'-H), 8.04 (d , J=8.6Hz, 2H, ArH), 7.02 (d, J=8.6Hz, 2H), 3.43 (t, J=5.0Hz, 4H, CH ₂ ), 2.76 (t, J=5.0Hz, 4H, CH ₂ ), 2.45 (s, 3H, CH ₃ ). m/z (ES ⁻ ), HRMS calcd for C ₁₅ H ₁₆ N ₅ O ₃ S[MH] ⁻ , 346.0974; found 346.0972.

4-Morpholinyl-N-(5-nitrothiazol-2-yl)benzamide (compound 19). Pale yellow solid. Yield: 33%. mp: 186-187°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.24 (s, 1H, NH), 8.69 (s, 1H, 4'-H), 8.05 (d, J=8.8 Hz, 2H, ArH), 7.05 (d, J=8.8Hz, 2H, ArH), 3.73 (t, J=4.7Hz, 4H, _CH2 ), 3.33 (t, J=4.7Hz, 4H, _CH2 ). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 165.39, 163.09, 154.28, 142.87, 141.74, 130.29, 118.97, 113.08, 65.86, 46.64.m/z (ES ^- ), HRMS calcd for C ₁₄ H ₁₃ N ₄ O ₄ S[MH] ^- , 333.0658; found 333.0658.

4-(tert-Butyl)-N-(5-nitrothiazol-2-yl)benzamide (compound 20). Pale yellow solid. Yield: 68%. mp: 179-180°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H, NH), 8.70 (s, 1H, 4'-H), 8.08 (d, J=8.1 Hz, 2H, ArH), 7.60 (d, J=8.1 Hz, 2H, ArH), 1.32 (s, 9H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 166.10, 162.63, 156.67, 142.60, 142.00, 128.47, 127.95, 125.63, 34.93, 30.77.m/z (ES ^- ), HRMS calcd for C ₁₄ H ₁₄ N ₃ O ₃ S[MH] ^- , 304.0756; found 304.0759.

4-(Methylsulfonyl)-N-(5-nitrothiazol-2-yl)benzamide (compound 21). Pale yellow solid. Yield: 56%. mp: 198-199°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.84 (s, 1H, NH), 8.75 (s, 1H, 4'-H), 8.34 (d, J=8.2 Hz, 2H, ArH), 8.13 (d, J=8.2Hz, 2H, ArH), 3.32 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.57, 162.42, 144.52, 142.39, 142.15, 135.42, 129.57, 127.22, 43.09.m/z (ES ^- ), HRMS calcd for C ₁₁ H ₈ N ₃ O ₅ S ₂ [MH] ^- , 325.9905; found 325.9910.

N-(5-Nitrothiazol-2-yl)-4-aminosulfonylbenzamide (compound 22). Pale yellow solid. Yield: 21%. mp: 193-194°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.78 (s, 1H, NH), 8.75 (s, 1H, 4'-H), 8.27 (d, J=8.3 Hz, 2H, ArH), 7.99 (d, J=8.3 Hz, 2H, ArH), 7.59 (s, 2H, NH ₂ ). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.68, 162.42, 147.89, 142.45, 142.15, 133.79, 129.33, 125.86.m/z (ES ^- ), HRMS calcd for C ₁₀ H ₇ N ₄ O ₅ S ₂ [MH] ^- , 326.9858; found 326.9872.

N-(5-Nitrothiazol-2-yl)-4-(N-phenylaminosulfonyl)benzamide (compound 23). Yield: 71%. Pale yellow solid. mp: 175-176°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.74 (s, 1H, CONH), 10.47 (s, 1H, SO ₂ NH), 8.72 (s, 1H, 4'-H ), 8.25-8.18(m, 2H, ArH), 7.94-7.88(m, 2H, ArH), 7.27-7.20(m, 2H, ArH), 7.16-7.07(m, 2H, ArH), 7.08-7.02( m, 1H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.58, 162.38, 143.30, 142.41, 142.13, 137.20, 134.86, 129.54, 129.27, 126.92, 124.49, 120.39.m/z (ES ^- ), HRMS calcd for C ₁₆ H ₁₁ N ₄ O ₅ S ₂ [MH] ⁻ , 403.0171; found 403.0173.

3,4-Dichloro-N-(5-nitrothiazol-2-yl)benzamide (compound 24). Pale yellow solid. Yield: 67%. mp: 202-203°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.73 (s, 1H, NH), 8.73 (s, 1H, 4'-H), 8.40-8.34 (m, 1H, ArH) ), 8.08-8.01 (m, 1H, ArH), 7.86 (d, J=8.4Hz, 1H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 164.59, 162.45, 142.55, 142.20, 136.31, 131.73, 131.40, 131.17, 130.51, 128.83.m/z (ES ⁻ ), HRMS calcd for C ₁₀ H ₄ Cl ₂ N ₃ O ₃ S [MH] ⁻ , 315.9350; found 315.9345.

3,4-Dihydroxy-N-(5-nitrothiazol-2-yl)benzamide (compound 25). Pale yellow solid. Yield: 48%.mp: 235-236°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.24 (s, 1H, NH), 10.07 (s, 1H, OH), 9.49 (s, 1H, OH), 8.67 (s, 1H, 4'-H), 7.58 (dd, J=8.3, 2.1 Hz, 1H, ArH), 7.52 (d, J=2.1 Hz, 1H, ArH), 6.85 (d, J =8.3Hz, 1H, ArH). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 165.81, 163.03, 151.10, 145.47, 142.86, 141.83, 121.48, 121.26, 116.02, 115.30.m/z (ES ⁻ ), HRMS calcd for C ₁₀ H ₆ N ₃ O ₅ S[MH] ⁻ , 280.0028; found 280.0023.

N-(5-Nitrothiazol-2-yl)-N-(propynyl)-4-(trifluoromethyl)benzamide (compound 26). Pale yellow solid. Yield: 72%. mp: 173-174°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H, 4'-H), 8.45 (d, J=8.2 Hz, 2H, ArH), 7.92 (d, J=8.2Hz, 2H, ArH), 5.23 (d, J=2.5Hz, 2H, CH ₂ ), 3.65 (t, J=2.5Hz, 1H, C≡CH). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ172.80, 165.12, 138.32, 134.57, 133.81, 132.38 (q, J=31.8Hz), 129.94, 125.61 (q, J=3.7Hz), 123.89 (q, J=272.7Hz), 77.50, 76.67, 38.91.rn/z (ES ⁻ ), HRMS calcd for C ₁₄ H ₇ F ₃ N ₃ O ₃ S [MH] ⁻ , 354.0160; found 354.0162.

2-Hydroxy-3-methyl-N-(thiazol-2-yl)benzamide (compound 27). mp: 176.9-177.2°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (bs, 1H), 12.81 (bs, 1H), 7.92 (m, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.33 (d, J=4.0Hz, 1H), 7.24 (m, 1H), 6.82 (m, 1H), 3.09 (s, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 159.08 , 135.44, 127.41, 126.26, 118.61, 113.42, 60.21, 16.17.HRMS(ESI)[M+H ⁺ ]calcd 235.0536 found 235.0545.

4-Trifluoromethyl-N-(5-bromothiazol-2-yl)benzamide (compound 28). mp: 184.3-184.6°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.17 (s, 1H), 8.27 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H) , 7.69(s, 1H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 135.83, 132.92, 132.60, 129.66, 126.08, 126.05, 126.01, 125.97, 125.57, 122.86, 102.96.HRMS (ESI) [M+ H ⁺ ]calcd 352.9389 found 352.9401.

biological example

1. Evaluation of the STAT3 pathway inhibitory activity of the compounds of the present invention. The present invention is carried out by the HEK-Blue IL-6 cell line that can stably express IL-6 receptor and secrete embryonic alkaline phosphatase reporter gene that can bind to STAT3.

Specifically, 20 μL of IL-6 cytokine (final concentration of 1 ng/mL), 20 μL of different concentrations of the test compound and HEK-Blue IL-6 cell suspension (5× per well) were added to each well of a 96-well plate for cell culture. 10 ⁴ ) 160 μL, a total of 200 μL liquid per well; the negative control group is 40 μL complete medium and 160 μL cell suspension; the positive control group is IL-6 cytokine (final concentration 1ng/mL) 20 μL, complete medium 20 μL and cells Suspension 160 μL. After the cells were incubated in a cell incubator at 37°C for 20 hours, 20 μL of the supernatant from each well was transferred to another 96-well plate, and 180 μL of QUANTI-Blue chromogenic solution pre-warmed at 37°C was added. After incubation at 37°C for 1 hour, Absorbance detection was performed at a wavelength of 655 nm. In order to exclude the false positive interference caused by the decrease in the number of cells caused by the toxicity of the compound, the activity of the treated HEK-Blue cells was tested using the tetramethylazolium salt microenzyme reaction colorimetric method (MTT method). MTT test The method is carried out according to the general test method.

2. Test method for the anti-cell proliferation activity of the compounds of the present invention. In the present invention, the anti-proliferative activity of the compound on different cell lines was tested by the tetramethylazolium salt micro-enzyme reaction colorimetric method (MTT method).

Specifically, 5000-6000 cells were seeded per well in a 96-well plate, and after culturing for 6 hours, the cells were treated with different concentrations of compounds or DMSO for different times, and three replicate wells were set in each group. After the incubation, the original drug-containing medium was removed by using a multi-channel pipette, and 100 μl of tetramethylazolium blue medium solution (5 mg/ml) was added to each well. Continue to incubate cells at 37 °C for 3-4 hours, remove the original medium with a multi-channel pipette, add 100 μL of dimethyl sulfoxide to each well, shake at room temperature for 15 minutes in the dark, and perform absorbance detection at 570 nm wavelength.

3. The method for culturing cells used in the present invention. Unless otherwise stated, the cell lines used in the present invention were purchased from Peking Union Medical College Cell Resource Center. Human cervical cancer cell line HeLa, human lung adenocarcinoma cell line A549, human malignant melanoma cell line A375 and human embryonic kidney cell line HEK293T were cultured in DMEM. Prostate cancer cell line PC3 was cultured in F12K medium. Colon adenocarcinoma cells Line HT29 was cultured in MCCOY's5a medium. Human glioblastoma cell line U87MG was cultured in MEM containing nonessential amino acids. 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 units/mL streptomycin were added to the above media. The human acute myeloid leukemia cell line HL60 was cultured in IMDM medium supplemented with 20% fetal bovine serum (FBS), 100 units/mL penicillin and 100 units/mL streptomycin. HEK-BlueTM-IL6 cells were purchased from Invivogen and supplemented with 10% heat-inactivated fetal bovine serum (FBS; heat-inactivated at 56°C for 30 minutes), 100 units/mL penicillin, 100 units/mL streptomycin, 100 μg /mL Normocin ^™ (Invivogen), 1x HEK Blue ^™ selective antibiotic (Invivogen) in DMEM medium. All cells were cultured at 37°C and 5% CO ₂ and were negative for mycoplasma contamination.

4. The method for evaluating the pharmacokinetic properties of the present invention. The present invention tested the pharmacokinetic properties of compound NTZ and compound 15 using Sprague-Dawley rats. Specifically, 12 male SD rats (300-320 g) were divided into 4 groups of 3 rats each. After 1 day of adaptive feeding, all rats were fasted for 12 hours and then administered. Among them, NTZ test group was administered by tail vein injection at 5 mg/Kg (group A) or by gavage at 25 mg/Kg (group B); compound 15 test group was injected by tail vein, respectively, according to Administered at 5 mg/Kg (group C) or by gavage at 25 mg/Kg (group D). The administered drugs were dissolved in 10% dimethyl sulfoxide, 40% PEG-400 and 50% sterile saline. For the test animals, before administration, 5 minutes, 10 minutes, 20 minutes, 30 minutes after administration Minute, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 32 hours, and 48 hours, blood was collected from the orbital venous plexus, 100 μL of blood was collected each time, the blood was anticoagulated with heparin sodium, and the plasma was obtained by centrifugation and stored at -80°C. The obtained blood samples were analyzed by LC-MS/MS (Compound 14 (2ng/mL) as the internal standard

BEH C18 1.7 μm, ESI ⁺ , Waters) for quantitative analysis. The data were fitted with DAS version 2.1.1 software, and a two-compartment model was used for fitting.

5. Efficacy and safety in a mouse tumor-bearing model. 5-week-old female BALB/c-nu nude mice were subcutaneously inoculated with HeLa cells (5×10 ⁶ cells/mice) in the right axilla. After 28 days, the mean tumor-bearing volume reached 100 mm ³ . Mice were randomly divided into 5 groups of 6 mice each, and drug administration was started. Among them, the mice in the solvent group were intragastrically administered 100 μL of 0.5% sodium carboxymethylcellulose (CMC) aqueous solution once a day; the NTZ control group was intragastrically administered NTZ suspension (400 mg/kg) once a day; Compound 15 Divided into three groups of high, medium and low doses, the suspension of compound 15 was administered by gavage at 25, 5 and 1 mg/kg once a day, respectively. During the administration, the solvent group was administered on the 11th, 18th, and 21st days, the NTZ group was administered on the 18th day, the 15th high-dose group was administered on the 20th day, and the medium and low-dose groups were administered on the 27th day after administration. only mouse died. By the end of the 28th day of administration, the number of surviving mice in the solvent group was 2, and the number of mice in the NTZ group and the 15 high, medium and low dose groups was 5 each.

Table 1. Structures of compounds of the invention and their activity data.

^a Not tested, ^b Selectivity index: % inhibition of STAT3 pathway/% inhibition of cell viability of HEK-Blue ^™ IL-6 cells. All values are the mean of three independent experiments.

NTZ is nitazoxanide.

TIZ is tizoxanide.

Table 2. Growth inhibitory activity of compounds of the invention in HEK 293T and HeLa cell lines.

All values are the mean of three independent experiments.

WP1066 is (2E)-3-(6-bromopyridin-2-yl)-2-cyano-N-[(1S)-1-phenylethyl]-2-acrylamide.

Table 3. Growth inhibitory activity of NTZ and representative compounds of the invention on various cell lines.

All values are the mean of three independent experiments.

Table 4. Pharmacokinetic parameters of NTZ and Compound 15 (n=3 rats/group).

^a t _1/2α : the half-life of the distribution phase, ^b t _1/2β : the half-life of the elimination phase, ^c Vd/F: the apparent volume of the distribution, ^d Cl/F: the apparent clearance rate, clearance from the central chamber per unit time Apparent volume of drug, ^eAUC0 _-∞ : area under the curve of the concentration time curve, ^fTmax : time to _{peak concentration, gCmax} _: maximum plasma concentration, ^gF ^: absolute bioavailability.

The mean tumor volume-time curves of mice in each group within 28 days after administration are shown in Figure 1A. The results showed that the daily intragastric administration of compound 15 at 1 mg/kg could effectively inhibit the growth of tumor-bearing mice, and the effect was better than that of the 400 mg/kg NTZ control group. At the same time, with the increase of the dose of compound 15, the antitumor activity increased in a dose-dependent manner. At the end of the 28th day of administration, the average tumor-bearing volume of the mice in the high, medium and low doses of Compound 15 was smaller than that in the NTZ group, and there was a significant difference between the tumor volumes of the mice in the solvent group (Fig. 1B). . It indicated that the in vivo antitumor activity of compound 15 was better than that of NTZ.

In terms of safety, administration of different concentrations of Compound 15 did not cause a significant decrease in the body weight of mice (Figure 1C). Indicates that the drug is well tolerated.

Claims

Use of a compound in the manufacture of a medicament for the treatment/prevention of cancer, wherein the compound is a compound of general formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

R 1 is selected from H, halogen, -CN, -NO 2 , -N 3 , -OR a , -NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

R 2 is selected from H, halogen, -CN, -NO 2 , -N 3 , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -S(O) R a , -S(O) 2 R a , -S(O)NR b R c , -S(O) 2 NR b R c , -S(O) 2 OR a , -P(O)R b R c , -P(O) 2 R a , -P(O)(NR b R c ) 2 , -P(O) 2 NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

R 3 is selected from H, halogen, -CN, -NO 2 , -N 3 , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -S(O) R a , -S(O) 2 R a , -S(O)NR b R c , -S(O) 2 NR b R c , -S(O) 2 OR a , -P(O)R b R c , -P(O) 2 R a , -P(O)(NR b R c ) 2 , -P(O) 2 NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

R 4 is selected from H, halogen, -CN, -NO 2 , -N 3 , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -S(O) R a , -S(O) 2 R a , -S(O)NR b R c , -S(O) 2 NR b R c , -S(O) 2 OR a , -P(O)R b R c , -P(O) 2 R a , -P(O)(NR b R c ) 2 , -P(O) 2 NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;

R 5 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R is selected from H, halogen, -CN or -NO2 ;

wherein R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkane radical, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; or R and R together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl or 5- to 10 -membered heterocyclyl 10-membered heteroaryl.
The use of claim 1 , wherein R1 is selected from H, halogen, -CN, -NO2 , -N3 or -OH, preferably H, halogen or -OH, more preferably H or -OH.
The use of claim 1 or 2, wherein R 2 is selected from H, halogen, -CN, -NO 2 , -N 3 , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -S(O) 2 OH, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, halogen, -CN, -NO 2 , -N 3 , C 1-6 alkyl or C 1-6 haloalkyl, more preferably H, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
The use of any one of claims 1-3, wherein R 3 is selected from H, halogen, -CN, -NO 2 , -N 3 , -C(O)R a , -C(O)OR a , -C (O)NR b R c , -S(O) 2 OH, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, halogen, -CN, -NO 2 , -N 3 , C 1- 6 alkyl or C 1-6 haloalkyl, more preferably H, halogen, -N 3 , C 1-6 alkyl or C 1-6 haloalkyl.
The use of any one of claims 1-4, wherein R 4 is selected from H, halogen, -CN, -NO 2 , -N 3 , -C(O)R a , -C(O)OR a , -C (O)NR b R c , -S(O) 2 OH, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, halogen, -CN, -NO 2 , -N 3 , C 1- 6 alkyl or C 1-6 haloalkyl, more preferably H, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
5. The use of any of claims 1-5, wherein R5 is H.
The use of any one of claims 1-6, wherein:

R 1 is H or -OH;

R 2 is H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 is H, halogen, -N 3 , C 1-6 alkyl or C 1-6 haloalkyl;

R 4 is H, C 1-6 alkyl or C 1-6 haloalkyl;

R5 is H.
7. The use of any of claims 1-7, wherein at least one of R2 and R3 is a non - hydrogen group.
8. Use according to any one of claims 1 to 8, wherein R is halogen, preferably Cl or Br, more preferably Br.
The use of any one of claims 1-8, wherein the compound has the structure of general formula (I-1):

wherein each group is as defined in any one of claims 1-8.
The purposes of claim 1, wherein said compound has following structure:

or a pharmaceutically acceptable salt, hydrate or solvate thereof.
The use of any one of claims 1-11, wherein the cancer is a STAT3 pathway mediated cancer, preferably glioma, colorectal cancer, gastric cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, head and neck cancer , breast cancer, leukemia or non-small cell lung cancer.
The purposes of claim 12, wherein said cancer is metastatic cancer that metastasizes to brain or bone tissue.
A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof: