Micromolecule inhibitor targeting EB virus nuclear antigen protein, preparation method and application thereof

文档序号：1931849 发布日期：2021-12-07 浏览：13次中文

阅读说明：本技术 靶向eb病毒核抗原蛋白的小分子抑制剂、制备方法及其应用 (Micromolecule inhibitor targeting EB virus nuclear antigen protein, preparation method and application thereof ) 是由朱振东许正双黎婷车超张庆舟陈思贵陈煌灿向德虎杨震于 2020-06-02 设计创作，主要内容包括：本发明提供靶向EB病毒核抗原蛋白的小分子抑制剂,和/或包含其的药物组合物,其可用于治疗由EBNA1活性引起的疾病,如,但不限于,癌症、感染性单核细胞增多症、慢性疲乏综合征、多发性硬化、系统性红斑性狼疮和/或类风湿性关节炎。本发明进一步提供靶向EB病毒核抗原蛋白的小分子抑制剂,和/或包含其的药物组合物,其可用于治疗处于裂解期和/或潜伏期的EBV感染引起的疾病。(The present invention provides small molecule inhibitors targeting epstein barr virus nuclear antigen protein, and/or pharmaceutical compositions comprising the same, which are useful for treating diseases caused by EBNA1 activity, such as, but not limited to, cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, and/or rheumatoid arthritis. The invention further provides small molecule inhibitors targeting epstein-barr virus nuclear antigen protein, and/or pharmaceutical compositions comprising the same, which can be used for treating diseases caused by EBV infection in lytic and/or latent phase.)

1. A compound of general formula (I), or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof:

Wherein: x¹、X²、X³Are identical or different and are selected independently of one another from CR^xaOr a nitrogen atom;

R^xaselected from hydrogen, halogen; the halogen is selected from fluorine, chlorine, bromine and iodine;

R¹selected from-COOH, -C (═ O) -O-R^1a、-C(＝O)-NH₂、-C(＝O)-NHR^1b、-C(＝O)-NR^1bR^1c、-C(＝O)-NH-S(＝O)₂-R^1b、

-C(＝O)-NH-(CH₂)_q-R^1d、-S(＝O)₂OH、-B(OH)₂、-S(＝O)₂-NH₂、-S(＝O)₂-NHR^1b、-S(＝O)₂-NR^1bR^1c，

q is 0, 1, 2 or 3;

wherein R is^1aIndependently selected from: li;

or R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl;

or R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

the heterocyclic group is selected from: a 4-7 membered oxygen, nitrogen, and/or sulfur containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, indazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzotriazolyl, benzothiazolyl;

Said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

or, R^1bAnd R^1cForm a cyclic group together with the atoms to which they are attached; the cyclic group is selected from: optionally substitutedMorpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl;

R^1dselected from: hydrogen, hydroxy, amino, cyano, -O-C (═ O) -R¹⁷、-O-R¹²、-NR⁹R¹⁰Optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

R²Selected from the following groups:

hydrogen, amino, halogen, nitro, optionally substituted C1-C4 alkyl,

Wherein the dotsRepresents said R²The point of attachment of the group to other groups of the compound molecule of formula (I);

X⁴selected from O, S, NR^2d；

Wherein R is^2a、R^2b、R^2cAre identical or different and are selected, independently of one another, from:

hydrogen, halogen, amino, nitro,Hydroxy, C1-C8 hydroxyalkyl, cyano, - (CH)₂)_q-COOH、-(CH₂)_q-C(＝O)-O-R⁸、-(CH₂)_q-C(＝O)-NH-R⁸、-N(H)C(＝O)-R⁸、-N(H)S(＝O)₂-R⁸、-O-R⁸、-NH-R⁸、-S(＝O)₂NH-R⁸、-S(＝O)₂-R⁸、-C(＝O)-R⁸、-O-C(＝O)-R⁸Optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy, phenyl, said phenyl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

q is 0, 1, 2 or 3;

or, R^2aSelected from aryl, heterocyclyl, heteroaryl:

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

or, adjacent R^2aForm a fused ring structure with each other and with the atoms to which they are attached, or adjacent R^2bForm a fused ring structure with each other and with the atoms to which they are attached, saidThe ring structure is selected from: phenyl, heteroaryl, said heteroaryl being selected from: thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, indazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzotriazolyl, benzothiazolyl; said phenyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

R^2dselected from hydrogen, optionally halogenated or non-halogenated C1-C3 linear alkyl, isopropyl, cyclopropyl;

Or, R^2dSelected from: -C (═ O) -R⁵、-S(＝O)₂-R⁵；

Or, R^2dSelected from aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

l is selected from the following groups:

wherein the dotsRepresents the point of attachment of L to the right fragment of the compound of formula (I);

wherein the asterisks indicate L and R³A connection point to which it is connected;

X⁵selected from: o, NH, S;

Y¹selected from: o, NR^L2；

Said L being substituted by a substituent R^L1One or more substitutions at the same or different sites;

R^L1Selected from: a hydrogen or fluorine atom;

R^L2selected from: hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl;

or, R^L2Selected from: - (CH)₂)_q-R⁷、-C(＝O)-N(H)-R¹⁹、-C(＝S)-N(H)-R¹⁹、-C(＝O)-R²⁰、-S(＝O)₂-R²⁰；

Or, R^L2Selected from: aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

Or R^L2And R³Together with the atoms to which they are attached, form a 5-10 membered nitrogenous and/or thiacyclic group, said 5-10 membered nitrogenous and/or thiacyclic group comprising-C (═ O) -, -S (═ O)₂-a group;

R^L3、R^L4are identical or different and are selected, independently of one another, from: a hydrogen or fluorine atom;

or R^L3And R^L4Together with the atoms to which they are attached form a carbonyl, thiocarbonyl;

or R^L3And R^L4Together with the atoms to which they are attached form a nitrogen-and/or sulfur-containing heterocyclic group, wherein R^L3And R^L4The C atom to which it is attached is replaced by-S (═ O)₂-；

m, n are identical or different and are selected, independently of one another, from: 1. 2 or 3 to form ring systems of different atomic numbers;

q is 0, 1, 2 or 3;

R³selected from the following groups:

C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, and halogenated C3-C8 cycloalkyl; the C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl and halogenated C3-C8 cycloalkyl are optionally substituted by a substituent R⁶One or more substitutions, which may be the same or different;

or, R³Selected from the following groups:

(1)or

(2) Or

(3) Or

(4)Or

(5) Or

(6)Or

(7)Or

(8)

Wherein the dotsRepresents the point of attachment to the right fragment of the compound of formula (I);

X⁶Selected from O, S, NR^3g；

X⁷Selected from O, S, NR^3g、CHR^3a；

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring;

Z¹selected from O, S, NR^3h；

Wherein R is^3aSelected from: hydrogen, halogen, nitro, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, hydroxy, C1-C8 hydroxyalkyl, - (CH-N-O-C-N-O-C-N-O-C-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C8 hydroxyalkyl is hydroxy-substituted C1-C8 alkyl;

p and q are each independently 0, 1, 2 or 3;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

Said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

or adjacent R^3aForm a cyclic structure with the atoms to which they are attached, or R^3aAnd R adjacent thereto^3cAnd together with the atoms to which they are attached form a cyclic structure, or R^3aAnd R adjacent thereto^3dAnd together with the atoms to which they are attached form a cyclic structure, including saturated or aromatic cyclic structures, selected from: cycloalkanes, aryl, heterocyclyl, heteroaryl;

preferably, the cyclic structure is selected from: phenyl, pyridyl, pyrrolyl, thienyl, furyl, oxazolyl, thiazolyl, isoxazolyl, indazolyl, a 5-7 membered nitrogen/oxygen containing saturated heterocyclic group selected from the group consisting of: tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl;

said cyclic structure being optionally substituted with a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3bselected from:

hydrogen, optionally substituted C1-C8 straight chain alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 straight chain alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, -C (═ O) -R ²⁰、-C(＝O)N(H)-R¹⁹、-C(＝S)N(H)-R¹⁹、-C(＝O)O-R¹⁹、-S(＝O)₂-R²⁰；

q is 0, 1, 2 or 3;

or, R^3bSelected from: aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: optionally substituted phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

Or when L is selected from When R is^3cAnd R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl, hydroxy, C1-C8 hydroxyalkyl, -O-C (═ O) -R ²⁰Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: optionally substituted phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

or R^3cAnd R^3dAnd together with the atoms to which they are attached form a carbonyl, thiocarbonyl, imino group;

R^3eand R^3fAre identical or different and are selected, independently of one another, from:

Or, R^3eAnd R^3fAnd together with the atoms to which they are attached form a carbonyl, thiocarbonyl group;

or, R^3eAnd R^3fAre identical or different and are selected, independently of one another, from: aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: optionally substituted phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3hselected from: hydrogen, nitro, cyano;

the R is⁴Selected from: hydrogen, fluorine, chlorine, hydroxy, C1-C3Hydroxyalkyl, optionally substituted C1-C3 alkyl, optionally substituted halogenated C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted halogenated C1-C3 alkoxy, nitro, cyano, amino, acetyl, methylsulfonyl, acetamido, methylsulfonamido;

The R is⁵Selected from: hydrogen, optionally substituted C1-C3 alkyl, optionally substituted halo C1-C3 alkyl;

the R is⁶Selected from: hydroxy, C1-C8 straight chain alkoxy, C3-C8 branched chain alkoxy, C3-C8 cycloalkoxy, -O-C (═ O) -R²⁰Amino, -NH-C (═ O) -R²⁰、-NH-S(＝O)₂-R²⁰、-NH-C(＝O)-O-R²⁰、-NH-C(＝O)-NH-R²⁰、-NH-C(＝S)-NH-R²⁰；

The R is⁷Selected from: phenyl, naphthyl, heterocyclyl, heteroaryl, the heterocyclyl being selected from: a 4-7 membered oxygen, nitrogen, and/or sulfur containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl; the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, indazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzotriazolyl, benzothiazolyl, said phenyl, naphthyl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is⁸Selected from: optionally substituted C1-C3 alkyl, optionally substituted halogenated C1-C3 alkyl;

The R is⁹、R¹⁰Identical or different and independently of one another selected from: hydrogen, optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy;

or, R⁹、R¹⁰Identical or different and independently of one another selected from: optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

Or said R is⁹、R¹⁰And together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group selected from: azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, said nitrogen-containing heterocyclyl being substituted one or more times, identically or differently, with: hydroxyl, C1-C8 hydroxyalkyl, C1-C8 linear alkyl or alkoxy, C3-C8 branched alkyl or alkoxy, C3-C8 cycloalkyl or alkoxy, halogenated C1-C8 linear alkyl or alkoxy, halogenated C3-C8 branched alkyl or alkoxy, halogenated C3-C8 cycloalkyl or alkoxy, amino, optionally substituted amido, optionally substituted sulfonamido;

the R is¹¹Selected from: hydrogen, optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy;

or, R¹¹Selected from: aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

the aryl, heterocyclyl and heteroaryl groups are substituted, one or more times, identically or differently, with: halogen, hydroxy, C1-C8 hydroxyalkyl, C1-C8 straight-chain alkyl or alkoxy, C3-C8 branched-chain alkyl or alkoxy, C3-C8 cycloalkyl or alkoxy, halogenated C1-C8 straight-chain alkyl or alkoxy, halogenated C3-C8 branched-chain alkyl or alkoxy, halogenated C3-C8 cycloalkyl or alkoxy, amino, optionally substituted amido, optionally substituted sulfonamide, cyano, nitro, sulfonic acid, optionally substituted ureido, guanidino;

the R is¹²Selected from: hydrogen, C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, halogenated C3-C8 cycloalkyl, aryl, heterocyclic and heteroaromatic radical; the C1-C8 alkyl group is substituted, one or more times, identically or differently, with: -O-R²⁰、-OH、-N(H)C(＝O)-R²⁰、-NR⁹R¹⁰；

The aryl group is selected from: phenyl, naphthyl, anthracenyl;

The heterocyclic group is selected from: a 4-7 membered oxygen, nitrogen, and/or sulfur containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is¹³Selected from: hydrogen, optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy;

or, said R¹³Selected from: - (CH)₂)_q-phenyl, - (CH) ₂)_q-halophenyl, - (CH)₂)_q-naphthyl, - (CH)₂)_q-halonaphthyl, - (CH)₂)_q-anthracenyl, - (CH)₂)_q-halogenated anthracenyl, - (CH)₂)_q-heterocyclyl, - (CH)₂)_q-halogenated heterocyclyl, - (CH)₂)_q-heteroaryl, - (CH)₂)_q-a halogenated heteroaryl group;

q is 0, 1, 2 or 3;

said phenyl, naphthyl, anthracenyl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸Is identical at one or more timesOr substituted differently;

the R is¹⁴Selected from: a heteroaryl group selected from: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, indazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzotriazolyl, benzothiazolyl; said heteroaryl being optionally substituted by a substituent R ¹⁸One or more substitutions, which may be the same or different;

the R is¹⁵Selected from: a 4-7 membered oxygen, nitrogen, and/or sulfur containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl; said saturated heterocyclic group being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is¹⁶Selected from: hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched or cyclic alkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched or cyclic alkyl, optionally substituted acyl, optionally substituted sulfonyl;

or, R¹⁶Selected from: a 4-7 membered oxygen, nitrogen, and/or sulfur containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl; said saturated heterocyclic group being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

or, R¹⁶Selected from: aryl- (CH)₂)_q-, heteroaryl- (CH) ₂)_q-; the aryl group is selected from: phenyl, naphthyl, anthracenyl; the aromatic hetero group is selected from: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, indazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzotriazolyl, benzothienyl, thienyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, oxazolyl, pyridyl, and the likeA thiazolyl group; said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

q is 0, 1, 2 or 3;

the R is¹⁷Selected from: optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

the R is¹⁸Selected from: hydrogen, halogen, optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy, nitro, optionally substituted amino, hydroxy, C1-C8 hydroxyalkyl, aryloxy, heterocyclyloxy, heteroaryloxy, - (CH-H-8 cycloalkyl or alkoxy, aryl-oxy, heterocyclyloxy, heteroaryl-oxy, or a salt thereof₂)_q-COOH、-O-C(＝O)-R²⁰Optionally substituted amido, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted acyl, optionally substituted sulfonyl, aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

the R is¹⁹Selected from: hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

Said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is²⁰Selected from: hydrogen, optionally substituted C1-C8 linear alkylOptionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R ¹⁸One or more substitutions, which may be the same or different;

wherein p and q are each independently 0, 1, 2 or 3;

m, n are identical or different and are selected, independently of one another, from: 1. 2 or 3 to form ring systems of different atomic numbers.

2. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, which is at least one compound selected from the following formulae:

3. the compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

R²selected from the following groups:

hydrogen, amino, nitro,

Wherein the dotsRepresents said R²The point of attachment of the group to the other fragment of the compound of formula (I);

X⁴selected from O, S, NR^2d；

Wherein R is^2a、R^2b、R^2cAre identical or different and are selected, independently of one another, from:

hydrogen, halogen, amino, nitro, hydroxy, C1-C8 hydroxyalkyl, cyano, - (CH)₂)_q-COOH、-(CH₂)_q-C(＝O)-O-R⁸、-(CH₂)_q-C(＝O)-NH-R⁸、-N(H)C(＝O)-R⁸、-N(H)S(＝O)₂-R⁸、-O-R⁸、-NH-R⁸、-S(＝O)₂NH-R⁸、-S(＝O)₂-R⁸、-C(＝O)-R⁸Optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy, phenyl, said phenyl being optionally substituted by a substituent R ⁴One or more substitutions, which may be the same or different;

q is 0, 1, 2 or 3;

R^2dselected from: hydrogen, optionally fluorinated or non-fluorinated C1-C3Alkyl, isopropyl, cyclopropyl, -C (═ O) -R⁵、-S(＝O)₂-R⁵。

4. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from the following groups:

wherein the dotsRepresents the point of attachment of L to the right fragment of the compound of formula (I);

wherein the asterisks indicate L and R³A connection point to which it is connected;

said L being substituted by a substituent R^L1One or more substitutions at the same or different sites;

R^L1selected from: a hydrogen or fluorine atom;

or, R^L2Selected from: - (CH)₂)_q-R⁷、-C(＝O)N(H)-R¹⁹、-C(＝S)N(H)-R¹⁹、-C(＝O)-R²⁰、-S(＝O)₂-R²⁰；

q is 0, 1, 2 or 3;

The R is⁷Selected from: phenyl, heterocyclyl, heteroarylAnd (b) a heterocyclyl selected from: a 4-7 membered oxygen, nitrogen containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl; the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, said phenyl, heterocyclyl, heteroaryl being optionally substituted with a substituent R¹⁸One or more substitutions, which may be the same or different;

preferably, R¹⁸Selected from: hydrogen, F, Cl, optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy, nitro, optionally substituted amino, hydroxy, C1-C8 hydroxyalkyl, phenyloxy, heteroaryloxy, - (CH 3-C8 cycloalkyl or alkoxy₂)_q-COOH、-O-C(＝O)-R²⁰Optionally substituted amido, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted acyl, optionally substituted sulfonyl, aryl, heterocyclyl, heteroaryl;

The aryl group is selected from: a phenyl group;

the heterocyclic group is selected from: a 4-7 membered oxygen, nitrogen containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different.

5. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

R³selected from the following groups:

(1)or

(2) Or

(5) Or

(6)Or

(7)Or

(8)

Wherein the dotsRepresents the point of attachment to the right fragment of the compound of formula (I);

X⁶selected from O, S, NR^3g；

X⁷Selected from O, S, NR^3g、CHR^3a；

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring;

Z¹selected from O, S, NR^3h；

Wherein R is^3aSelected from:

hydrogen, halogen, nitro, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl, - (CH-N-O-C-N-O-C-N-O-C-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N- ₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

p and q are each independently 0, 1, 2 or 3;

R^3bselected from:

hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

q is 0, 1, 2 or 3;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl;

or when L is selected fromWhen R is^3cAnd R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl, hydroxy, C1-C8 hydroxyalkyl, -O-C (═ O) -R²⁰；

Preferably, R^3cAnd R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl, hydroxy, C1-C8 hydroxyalkyl, -O-C (═ O) -R⁸；

Or R^3cAnd R^3dTogether with the atoms to which they are attachedCarbonyl, thiocarbonyl and imino groups;

R^3eand R^3fAre identical or different and are selected, independently of one another, from:

hydrogen, C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, halogenated C3-C8 cycloalkyl, aryl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

Said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more of the same or different substitutions,

or, R^3eAnd R^3fAnd together with the atoms to which they are attached form a carbonyl group, a thiocarbonyl group.

6. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein: r¹Selected from-COOH, -C (═ O) -O-R ^1a、-C(＝O)-NH-S(＝O)₂-R^1b、-C(＝O)-NH-(CH₂)_q-R^1d、

Wherein R is^1aSelected from: li;

or R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: hydrogen, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched or cyclic alkyl, optionally substituted halogenated C1-C4 linear alkyl, optionally substituted halogenated C3-C4 branched or cyclic alkyl;

R^1dselected from hydroxy, amino, cyano, -O-R¹²、-NR⁹R¹⁰Aryl, heterocyclyl, heteroaryl;

preferably, the aryl group is selected from: a phenyl group;

the heterocyclic group is selected from: azetidinyl, pyrrolidinyl;

the heteroaryl group is selected from: thienyl, furyl;

the R is⁹、R¹⁰Identical or different and independently of one another selected from: hydrogen, optionally substituted C1-C4 alkyl, optionally substituted halogenated C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted halogenated C1-C4 alkoxy;

or, R⁹、R¹⁰Identical or different and independently of one another selected from: optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

the aryl group is selected from: a phenyl group;

The heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

or said R is⁹、R¹⁰And together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group selected from: azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl.

7. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein: r²Selected from: hydrogen, amino, nitro, optionally substituted pyrrolyl, optionally substituted benzofuranyl, optionally substituted indolyl, optionally substituted benzothiophenyl, optionally substituted phenyl, optionally substituted benzothiadiazolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted indazolyl, optionally substituted benzothiazolyl, optionally substituted pyridyl, optionally substituted imidazolyl, optionally substituted thienyl.

8. The compound of claim 7, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

R²Selected from: hydrogen, amino, nitro, pyrrolyl, benzofuranyl, indolyl, benzo [ b ]]Thienyl, phenyl, halophenyl, cyanophenyl, cyanohalophenyl, carboxyphenyl, haloC 1-C4 alkylphenyl, biphenyl, methylsulphonamidophenyl, acetylphenyl, methylsulphonylphenyl, aminosulphonylphenyl, C1-C4 alkoxyphenyl, benzo [ C][1,2,5]Thiadiazolyl, furyl, pyrazolyl, indazolyl, benzo [ d ]]A thiazolyl group.

9. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R²selected from: hydrogen, hydrogen, X⁴Selected from NR^2d；

Wherein R is^2a、R^2b、R^2cAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, optionally substituted C1-C4 linear alkyl or alkoxy, optionally substituted C3-C4 branched alkyl or alkoxy, optionally substituted C3-C4 cycloalkyl or alkoxy, optionally substituted halogenated C1-C4 linear alkyl or alkoxy, optionally substituted halogenated C3-C4 branched alkyl or alkoxy, optionally substituted halogenated C3-C4 cycloalkyl or alkoxy;

R³selected from:wherein R is^3aSelected from: hydrogen, halogen, orOptionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, - (CH) ₂)_q-O-R¹²Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

or R³Selected from:wherein

R^3aSelected from: hydrogen, halogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, - (CH)₂)_q-O-R¹²Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; said phenyl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, hydroxy, C1-C8 hydroxyalkyl, -O-C (═ O) -R²⁰；

Or R³Selected from:wherein

R^3aSelected from: hydrogen, halogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, - (CH)₂)_q-O-R¹²Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; said phenyl, heterocyclyl, heteroaryl being optionally substituted by a substituent R ⁴One or more substitutions, which may be the same or different;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, hydroxy, C1-C8 hydroxyalkyl, -O-C (═ O) -R²⁰。

10. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R²selected from: hydrogen, amino, nitro, X⁴Selected from NR^2d；

R³selected from:wherein the content of the first and second substances,

R^3aselected from: hydrogen, - (CH)₂)_q-NR⁹R¹⁰Nitro, C1-C8 straight chain alkyl, C3-C8 branched chainAlkyl, halogenated C1-C8 straight-chain alkyl, halogenated C3-C8 branched-chain alkyl, - (CH)₂)_q-COOH、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷。

11. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

L is selected from:

R²selected from: hydrogen, amino, halogen, optionally substituted C1-C4 alkyl,

X⁴Selected from O, S, NR^2d；

Wherein R is^2a、R^2b、R^2cAre identical or different and are selected, independently of one another, from:

hydrogen, halogen, cyano, - (CH)₂)_q-COOH、-O-R⁸、-N(H)S(＝O)₂-R⁸、-S(＝O)₂-R⁸、-C(＝O)-R⁸、-O-C(＝O)-R⁸C1-C4 linear alkyl or alkoxy, C3-C4 branched alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halogenated C1-C4 linear alkyl or alkoxy, halogenated C3-C4 branched alkyl or alkoxy, halogenated C3-C4 cycloalkyl or alkoxy, phenyl, said phenyl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

R²selected from: hydrogen, amino, halogen, pyrrolyl, benzofuranyl, indolyl, benzothienyl, phenyl, benzothiadiazolyl, furanyl, pyrazolylIndazolyl, benzothiazolyl, thiazolyl, imidazolyl, thienyl, oxazolyl, C1-C4 alkyl; said pyrrolyl, benzofuranyl, indolyl, benzothienyl, phenyl, benzothiadiazolyl, furanyl, pyrazolyl, indazolyl, benzothiazolyl, thiazolyl, imidazolyl, thienyl, oxazolyl, C1-C4 alkyl is optionally substituted, identically or differently, one or more times, with a substituent selected from the group consisting of: hydrogen, halogen, cyano, - (CH) ₂)_q-COOH、-O-C(＝O)-R⁸C1-C4 straight chain alkyl or alkoxy, C3-C4 branched chain alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halogenated C1-C4 straight chain alkyl or alkoxy, halogenated C3-C4 branched chain alkyl or alkoxy, halogenated C3-C4 cycloalkyl or alkoxy, phenyl, methylsulfonamido, acetyl, methylsulfonyl;

R³selected from:wherein

R^3aSelected from:

hydrogen, halogen, nitro, cyano, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl, - (CH-H-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl;

or, R⁹、R¹⁰Identical or different and independently of one another selected from: optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

the aryl group is selected from: a phenyl group;

The heterocyclic group is selected from: a 4-7 membered oxygen, nitrogen containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

the R is¹¹Selected from: hydrogen, optionally substituted C1-C6 linear alkyl or alkoxy, optionally substituted C3-C6 branched alkyl or alkoxy, optionally substituted C3-C6 cycloalkyl orAlkoxy, optionally substituted halogenated C1-C6 linear alkyl or alkoxy, optionally substituted halogenated C3-C6 branched alkyl or alkoxy, optionally substituted halogenated C3-C6 cycloalkyl or alkoxy;

or, R¹¹Selected from: aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: a phenyl group;

The heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

the aryl, heterocyclyl and heteroaryl groups are substituted, one or more times, identically or differently, with: halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or alkoxy, amino, acetyl, acetamido, methylsulfonamido, methylphenylsulfonamido, cyano, nitro, sulfonic, ureido, guanidino;

the R is¹²Selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl, heterocyclic group, and heteroaryl; the C1-C6 alkyl group is substituted, one or more times, identically or differently, with: -O-R²⁰、-OH、-N(H)C(＝O)-R²⁰、-NR⁹R¹⁰；

The aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

Said phenyl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is¹³Selected from: hydrogen, optionally substituted C1-C6 linear alkyl or alkoxy, optionally substituted C3-C6 branched alkyl or alkoxy, optionally substituted C3-C6 cycloalkyl or alkoxy, optionally substituted halogenated C1-C6 linear alkyl or alkoxy, optionally substituted halogenated C3-C6 branched alkyl or alkoxy, optionally substituted halogenated C3-C6 cycloalkyl or alkoxy; or, said R¹³Selected from: - (CH)₂)_q-phenyl, - (CH)₂)_q-halophenyl, - (CH)₂)_q-heterocyclyl, - (CH)₂)_q-halogenated heterocyclyl, - (CH)₂)_q-heteroaryl, - (CH)₂)_q-a halogenated heteroaryl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said phenyl, heterocyclyl, heteroaryl being optionally substituted one or more times with: methyl, ethyl, Cl, F, cyano;

The R is¹⁵Selected from: a 4-7 membered oxygen, nitrogen containing saturated heterocyclic group selected from: oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl;

the R is¹⁷Selected from: optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaromateA group;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

more preferably, said R¹⁷Selected from: methyl, cyclopropane, phenyl, thienyl, indolyl; said phenyl, thienyl, indolyl being optionally substituted one or more times with: methyl, ethyl, Cl, F, cyano;

The R is¹⁸Selected from: hydrogen, F, Cl, optionally substituted C1-C6 linear alkyl or alkoxy, optionally substituted C3-C6 branched alkyl or alkoxy, optionally substituted C3-C6 cycloalkyl or alkoxy, optionally substituted halogenated C1-C6 linear alkyl or alkoxy, optionally substituted halogenated C3-C6 branched alkyl or alkoxy, optionally substituted halogenated C3-C6 cycloalkyl or alkoxy, nitro, optionally substituted amino, hydroxy, C1-C6 hydroxyalkyl, phenyloxy, heteroaryloxy, - (CH 3-C6 cycloalkyl or alkoxy₂)_q-COOH、-O-C(＝O)-R²⁰Optionally substituted amido, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted acyl, optionally substituted sulfonyl;

the R is²⁰Selected from: hydrogen, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, phenyl, morpholinyl; said phenyl group being substituted one or more times with the following substituents: methyl, ethyl, Cl, F, cyano;

p and q are each independently 0, 1, 2 or 3;

or, R³Selected from:wherein R is^3aSelected from:

hydrogen, halogen, nitro, cyano, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl, - (CH-H-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl ₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C6 alkyl;

or R^3cAnd R^3dAnd together with the atoms to which they are attachedCarbonyl, thiocarbonyl and imino;

or, R³Selected from:wherein

X⁶Selected from O, S, NR^3g，

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring,

R^3aselected from:

hydrogen, halogen, nitro, cyano, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl, - (CH-H-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclic ringRadical- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl; r^3gSelected from: hydrogen, C1-C6 linear alkyl, C3-C6 branched alkyl, halogenated C1-C6 linear alkyl, halogenated C3-C6 branched alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-, optionally substituted sulfonyl, optionally substituted acyl; said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R ⁴One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

the sulfonyl group is selected from: methylsulfonyl, optionally substituted phenylsulfonyl;

the acyl group is selected from: acetyl, optionally substituted benzoyl;

the benzenesulfonyl group and benzoyl group are optionally substituted one or more times by the following substituents: methyl, ethyl, methoxy, Cl, F, cyano; the methyl, ethyl, methoxy groups are optionally substituted one or more times with the following substituents: cl, F;

or, R³Selected from:

wherein Y is²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring,

R^3aselected from:

hydrogen, halogen, nitro, cyano, optionally substitutedC1-C6 linear alkyl group, optionally substituted C3-C6 branched alkyl group, optionally substituted C3-C6 cycloalkyl group, optionally substituted halogenated C1-C6 linear alkyl group, optionally substituted halogenated C3-C6 branched alkyl group, optionally substituted halogenated C3-C6 cycloalkyl group, hydroxy group, C1-C6 hydroxyalkyl group, - (CH) ₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl;

or, R³Selected from:

wherein

X⁶Selected from O, S, NR^3g，

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring,

R^3aselected from:

R^3gselected from: hydrogen, C1-C6 linear alkyl, C3-C6 branched alkyl, halogenated C1-C6 linear alkyl, halogenated C3-C6 branched alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-, optionally substituted sulfonyl, optionally substituted acyl; the aromatic hydrocarbonOptionally substituted by radicals R, heterocyclyl, heteroaryl⁴One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

The heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

the sulfonyl group is selected from: methylsulfonyl, optionally substituted phenylsulfonyl;

the acyl group is selected from: acetyl, optionally substituted benzoyl;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C6 alkyl;

or R^3cAnd R^3dAnd together with the atoms to which they are attached form a carbonyl, thiocarbonyl, imino group;

or, R³Selected from:wherein

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring;

R^3aselected from:

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C6 alkyl;

or R^3cAnd R^3dAnd together with the atoms to which they are attached form a carbonyl, thiocarbonyl, imino group;

or, R³Selected from:wherein

X⁷Selected from O, NR^3g，

Z¹Is selected from the group consisting of O, S,

R^3bselected from:

optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH-H-C-8 cycloalkyl₂)_q-, heteroaryl- (CH)₂)_q-; said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is¹⁸Selected from: hydrogen, halogen, optionally substituted C1-C6 linear alkyl or alkoxy, optionally substituted C3-C6 branched alkyl or alkoxy, optionally substituted C3-C6 cycloalkyl or alkoxy, optionally substituted halogenated C1-C6 linear alkyl or alkoxy, optionally substituted halogenated C3-C6 branched alkyl or alkoxy, optionally substituted halogenated C3-C6 cycloalkyl or alkoxy, nitro, optionally substituted amino, hydroxy, C1-C6 hydroxyalkyl, aryloxy, heterocyclyloxy, heteroaryloxy, - (CH-H-6 cycloalkyl or alkoxy, aryl-oxy, heterocyclyloxy, heteroaryl-oxy, or a salt thereof ₂)_q-COOH、-O-C(＝O)-R²⁰Optionally substituted amido, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted acyl, optionally substituted sulfonyl, aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

q is 0, 1, 2 or 3;

R^3gselected from: hydrogen, C1-C8 straight chain alkylC3-C8 branched alkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C6 alkyl;

or, R³Selected from: wherein

X⁶Selected from O, S, NR^3g；

X⁷Selected from O, S, NR^3g；

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring;

R^3aselected from:

R^3bSelected from:

hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-、-C(＝O)-R²⁰、-C(＝O)N(H)-R¹⁹、-C(＝S)N(H)-R¹⁹、-C(＝O)O-R¹⁹(ii) a Said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3gselected from: hydrogen, C1-C8 straight chain alkyl, C3-C8 branched chain alkyl, haloC1-C8 straight chain alkyl, halogenated C3-C8 branched chain alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-, optionally substituted sulfonyl, optionally substituted acyl; said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

The sulfonyl group is selected from: methylsulfonyl, optionally substituted phenylsulfonyl;

the acyl group is selected from: acetyl, optionally substituted benzoyl;

or, R³Selected from:

X⁷selected from O, NR^3g，

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring; wherein R is^3aSelected from:

hydrogen, halogen, nitro, cyano, optionally substituted C1-C6 straight chain alkylOptionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 straight chain alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl, - (CH) C₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl;

R^3bselected from: hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH) ₂)_q-, heteroaryl- (CH)₂)_q-、-C(＝O)-R²⁰、-C(＝O)N(H)-R¹⁹、-C(＝S)N(H)-R¹⁹、-C(＝O)O-R¹⁹(ii) a The phenyl group,Aryl, heteroaryl optionally substituted by R¹⁸One or more substitutions, which may be the same or different;

R^3gselected from: hydrogen, C1-C8 linear alkyl, C3-C8 branched alkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-, optionally substituted sulfonyl, optionally substituted acyl; said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

the sulfonyl group is selected from: methylsulfonyl, optionally substituted phenylsulfonyl;

the acyl group is selected from: acetyl, optionally substituted benzoyl;

R^3eAnd R^3fAre identical or different and are selected, independently of one another, from:

hydrogen, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-、-C(＝O)-R²⁰、-C(＝O)N(H)-R¹⁹、-C(＝O)O-R¹⁹、-S(＝O)₂-R²⁰；

Or, R^3eAnd R^3fAnd together with the atoms to which they are attached form a carbonyl group;

or, R^3eAnd R^3fAre identical or different and are selected, independently of one another, from: aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different.

12. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R²selected from: hydrogen, hydrogen,

X⁴Selected from NR^2d；

Wherein R is^2a、R^2b、R^2cAre identical or different and are selected independently of one another: hydrogen, fluorine, optionally substituted C1-C4 linear alkyl or alkoxy, optionally substituted C3-C4 branched alkyl or alkoxy, optionally substituted C3-C4 cycloalkyl or alkoxy, optionally substituted halogenated C1-C4 linear alkyl or alkoxy, optionally substituted halogenated C3-C4 branched alkyl or alkoxy, optionally substituted halogenated C3-C4 cycloalkyl or alkoxy;

R³selected from: optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl;

or R³Is selected fromR^3aSelected from: hydrogen, halogen, nitro, cyano, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted halogenated C1-C4 linear alkyl, optionally substituted halogenated C3-C4 branched alkyl, optionally substituted halogenated C3-C4 cycloalkyl, -C (═ O) -NHR ¹³；

The R is¹³Selected from: hydrogen, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl;

or, said R¹³Selected from: - (CH)₂)_q-phenyl, - (CH)₂)_q-a halophenyl group.

13. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R^L1selected from: hydrogen and a gas having a molecular weight of F,

R^L2selected from: the presence of hydrogen in the presence of hydrogen,

R²selected from: hydrogen, hydrogen, X⁴Selected from NR^2d；

R³selected from: C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, and halogenated C3-C8 cycloalkyl; the C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl and halogenated C3-C8 cycloalkyl are optionally substituted by a substituent R ⁶One or more substitutions, which may be the same or different;

or, R³Selected from:wherein

X⁷Selected from: NR (nitrogen to noise ratio)^3g，

Z¹Selected from: o, S the flow of the air in the air conditioner,

q is 0, 1, 2 or 3;

R^3bselected from:

optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH-H-C-8 cycloalkyl₂)_q-、Heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3gselected from: hydrogen;

or, R³Selected from:

wherein R is^3bSelected from:

optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH-H-C-8 cycloalkyl ₂)_q-, heteroaryl- (CH)₂)_q-; said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

preferably, said R is¹⁸Selected from: F. cl, C1-C8 linear alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, halogenated C1-C8 linear alkyl, halogenated C3-C8 branched alkyl, halogenated C3-C38 cycloalkyl;

R^3gselected from: hydrogen, aryl- (CH)₂)_q-; said aryl group being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different; the aryl group is selected from: a phenyl group; preferably, R^3gSelected from: hydrogen, phenylmethyl;

or, R³Selected from:wherein

R^3aSelected from:

hydrogen, halogen, nitro, cyano, optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl, - (CH-H-C6 cycloalkyl, hydroxy, C1-C6 hydroxyalkyl₂)_q-COOH、-(CH₂)_q-O-R¹²、-(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、-(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、-NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、-(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH) ₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C6 hydroxyalkyl is hydroxy-substituted C1-C6 alkyl;

R^3cand R^3dTogether with the atoms to which they are attached form a carbonyl group;

or L is selected from:

R^L1is hydrogen, R^L2Is aryl- (CH)₂)_q-; the aryl group is selected from: a phenyl group;

R²selected from: hydrogen, hydrogen, X⁴Selected from NR^2d；

R³selected from:wherein

R^3bSelected from:

The aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

Said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different.

14. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R²selected from: X⁴selected from NR^2d；

R³selected from:wherein

R^3bSelected from:

The aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the R is¹⁸Selected from: F. cl, nitro, C1-C4 linear alkyl or alkoxy, C3-C4 branched alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halogenated C1-C4 linear alkyl or alkoxy, halogenated C3-C4 branched alkyl or alkoxy, halogenated C3-C4 cycloalkyl or alkoxy, phenoxy;

or, L is selected from:

R^L2selected from: aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-, said aryl group- (CH)₂)_q-is selected from: phenyl-CH₂-; said heterocyclyl- (CH)₂)_q-is selected from: piperidinyl-CH₂-; said heteroaryl- (CH)₂)_q-is selected from: indolyl-CH₂-, thienyl-CH₂-, benzothienyl-CH₂-, furyl-CH₂-, benzofuranyl-CH₂-, pyridinyl-CH₂-, in which phenyl group,Indolyl, thienyl, benzothienyl, furyl, benzofuryl, pyridyl-, piperidyl-substituted one or more times with substituents selected from the group consisting of: halogen, cyano, -NR ⁹R¹⁰A hydroxyl group, a C1-C8 hydroxyalkyl group, a C1-C8 linear alkyl or alkoxy group, a C3-C8 branched alkyl or alkoxy group, a C3-C8 cycloalkyl or alkoxy group, a halogenated C1-C8 linear alkyl or alkoxy group, a halogenated C3-C8 branched alkyl or alkoxy group, a halogenated C3-C8 cycloalkyl or alkoxy group, an optionally substituted amide group, an optionally substituted sulfonamide group;

R²selected from: X⁴selected from NR^2d；

R³selected from:wherein

R^3bSelected from: optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, aryl- (CH-H-C-8 cycloalkyl₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

Said aryl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

preferably, said R is¹⁸Selected from: hydrogen, halogen, optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy, aryl, heteroaryl, heterocyclyl; the aryl group is selected from: a phenyl group;

or, L is selected from:

R²selected from: X⁴selected from NR^2d；

R^L2and R³Together with the atoms to which they are attached, form a 5-10 membered nitrogenous and/or thiacyclic group, said 5-10 membered nitrogenous and/or thiacyclic group comprising-C (═ O) -, -S (═ O) ₂-a group.

15. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R^L1selected from: hydrogen, fluorine;

R²selected from: hydrogen, halogen, amino, X⁴Selected from NR^2d；

R³selected from:

R^3aselected from: hydrogen, halogen, nitro, cyano, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted halogenated C1-C4 linear alkyl, optionally substituted halogenated C3-C4 branched alkyl, optionally substituted halogenated C3-C4 cycloalkyl.

16. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

L is selected from:wherein

R^L1Selected from: hydrogen, fluorine;

R²selected from: hydrogen, halogen, amino, X⁴Selected from NR^2d；

R³selected from:wherein

X⁷Selected from: o, NR^3g；

Z¹Selected from: o;

R^3bselected from:

q is 0, 1, 2 or 3;

the aryl group is selected from: a phenyl group;

The heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3gselected from: hydrogen, C1-C6 linear alkyl, C3-C6 branched alkyl, halogenated C1-C6 linear alkyl, halogenated C3-C6 branched alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-, optionally substituted sulfonyl, optionally substituted acyl; said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

The sulfonyl group is selected from: methylsulfonyl, optionally substituted phenylsulfonyl;

the acyl group is selected from: acetyl, optionally substituted benzoyl;

17. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

R^L1selected from: hydrogen, fluorine;

R²selected from: hydrogen, halogen, amino, X⁴Selected from O, S, NR^2d；

R³selected from:

R^3aselected from: hydrogen, halogen, nitro, cyano, hydroxyl, C1-C6 hydroxyalkyl, optionally substituted C1-C6 straight chain alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 straight chain alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl.

18. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

l is selected from:

1, 3-substituted-bicyclo [1.1.1] pentyl, 2, 6-substituted-diazacyclo [3.3] heptyl, oxy-azetidinyl, 3-amino-azetidin-1-yl, 3-amino (benzyl) -azetidin-1-yl, aminoethynyl, 1, 2-substituted cyclopropane, 3-alkenylazetidin-1-yl, 3-thio-azetidin-1-yl, 3-sulfinylazetidin-1-yl, 3-sulfonylazetidin-1-yl, 1H-1,2, 3-triazol-4-yl;

wherein the oxy-azetidinyl is selected from: 3-oxy-azetidin-1-yl, azetidinyl-3-oxy;

the aminoethynyl group is selected from:

aminoethynyl, amino (alkyl) ethynyl, amino (aryl-CH)₂-) ethynyl, amino (heterocyclyl-CH₂-) ethynyl, amino (heteroaryl-CH₂-) ethynyl, amino (sulfonyl) ethynyl;

the alkyl group is selected from: optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl;

Preferably, the alkyl group is selected from: optionally substituted C1-C6 linear alkyl, optionally substituted C3-C6 branched alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted halogenated C1-C6 linear alkyl, optionally substituted halogenated C3-C6 branched alkyl, optionally substituted halogenated C3-C6 cycloalkyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

the aryl group is selected from: phenyl, naphthyl; preferably from phenyl;

the heteroaryl group is selected from: thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl;

the sulfonyl group is selected from: methylsulfonyl, optionally substituted phenylsulfonyl;

the acyl group is selected from: acetyl, optionally substituted benzoyl;

More preferably, the amino (alkyl) ethynyl group is selected from: amino (methyl) ethynyl;

said amino group (aryl-CH)₂-) ethynyl selected from: amino (benzyl) ethynyl, amino (4-fluorobenzyl) ethynyl, amino (4-methylbenzyl) ethynyl, amino (4-trifluoromethylbenzyl) ethynyl, amino (methoxybenzyl) ethynyl, amino (2-fluorobenzyl) ethynyl, amino (4- (hydroxymethyl) benzyl) ethynyl;

said amino group (heterocyclyl-CH)₂-) ethynyl selected from: amino ((1-methylpiperidin-4-yl) methyl) ethynyl;

said amino group (heteroaryl-CH)₂-) ethynyl selected from: amino (pyridin-3-ylmethyl) ethynyl, amino (furan-2-ylmethyl) ethynyl, amino (1-methyl-1H-indol-5-yl) methylacetylyl, amino (thiophen-2-ylmethyl) ethynyl;

said amino (sulfonyl) ethynyl group is selected from: amino (methylsulfonyl) ethynyl, amino (cyclopropylalkylsulfonyl) ethynyl, amino (phenylsulfonyl) ethynyl, amino ((4-methylphenyl) sulfonyl) ethynyl, amino (benzo [ b ] thiophene-3-sulfonyl) ethynyl, amino (thiophene-2-sulfonyl) ethynyl, amino (benzofuran-5-sulfonyl) ethynyl.

19. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

R³Selected from:

20. a compound according to claim 1, or an enantiomer, diastereomer, tautomer, salt, crystal, solvate, and/or isotopically substituted derivative thereof, selected from the group consisting of: 3- (3- (acetoxy (4-methoxyphenyl) methyl) bicyclo [1.1.1] pentan-1-yl) benzoic acid, 3- (3- (acetoxy (6- (trifluoromethyl) pyridin-3-yl) methyl) bicyclo [1.1.1] pentan-1-yl) benzoic acid, 3- (3- (hydroxy (6- (trifluoromethyl) pyridin-3-yl) methyl) bicyclo [1.1.1] pentan-1-yl) benzoic acid, 3- (3-phenylbicyclo [1.1.1] pentan-1-yl) benzoic acid, methyl 3- (3-phenylbicyclo [1.1.1] pentan-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3-phenylbicyclo [1.1.1] pentan-1-yl) -2- (1H-pyrrol-1-yl) benzoate -pyrrol-1-yl) benzoic acid, methyl 3- (3- (4-methoxyphenyl) bicyclo [1.1.1] pentan-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 2-amino-3- (6-phenyl-2, 6-diazaspiro [3.3] heptan-2-yl) benzoate, 2-amino-3- (6-phenyl-2, 6-diazaspiro [3.3] heptan-2-yl) benzoic acid, 3- (6-phenyl-2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 2-amino-3- (6- (2-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoic acid, methyl 2-amino-3- (6- (4-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoate, 2-amino-3- (6- (4-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoic acid, 2-amino-3- (6- (3- (methoxycarbonyl) phenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoic acid methyl ester, 2-amino-3- (6- (3-carboxyphenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoic acid, 3- (6- (3- (methoxycarbonyl) phenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (6- (3-carboxyphenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (6- (2-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (6- (2-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (6- (2-nitrophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (6- (2-nitrophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (6- (4- (methoxycarbonyl) phenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (6- (4-carboxyphenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (6- (3-nitrophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-nitrobenzoic acid methyl ester, 3- (6- (3-nitrophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-nitrobenzoic acid, methyl ester, 3- (6- (3- (methylsulfonylamino) phenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-nitrobenzoic acid methyl ester, 3- (6- (3- (methylsulfonylamino) phenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-nitrobenzoic acid, methyl 3- (6- (3-acetamidophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-aminobenzoate, 3- (6- (3-acetamidophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) -2-aminobenzoic acid, methyl ester, Methyl 2-amino-3- (6- (3- (cyclopropylalkylsulfonylamino) phenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoate, methyl 2-amino-3- (6- (3-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoate, methyl, 3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid, 2-amino-3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid, methyl 3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-indol-6-yl) benzoate 3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-indol-6-yl) benzoic acid, methyl 6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, methyl 2- (benzo [ b ] thiophen-6-yl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) benzoate, and mixtures thereof, 2- (benzo [ b ] thiophen-6-yl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid, methyl 2- (benzo [ c ] [1,2,5] thiadiazol-5-yl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) benzoate, 2- (benzo [ c ] [1,2,5] thiadiazol-5-yl) -3- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid, methyl 2- (furan-2-yl) -3- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) benzoate, methyl ester of benzoic acid, and mixtures thereof, Methyl 2- (furan-3-yl) -3- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) benzoate, methyl 3 '-fluoro-6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, benzoic acid, or mixtures thereof, 2- (benzofuran-6-yl) -3- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid, methyl 3 '-chloro-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, methyl 3 '-chloro-6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, 3 '-cyano-6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, and mixtures thereof, 6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2,3' -dicarboxylic acid, methyl 4' -chloro-6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, 4' -chloro-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid, 3' - (trifluoromethyl) -6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid methyl ester, 3' - (trifluoromethyl) -6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid, 3',5' -difluoro-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid methyl ester, 3',5' -difluoro-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid, 6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1, 4',1 "-terphenyl ] -2-carboxylic acid methyl ester, 6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1':4', 1" -terphenyl ] -2-carboxylic acid, 3' - (methylsulfonylamino) -6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid methyl ester, 3' -methoxy-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -3' -methoxy-6- (3- (4- (hydroxymethyl) phenoxy) azetidin- 1-yl) - [1,1 '-biphenyl ] -2-carboxylic acid, methyl 3' -cyano-4 '-fluoro-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylate, methyl 3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrazol-1-yl) benzoate, 3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrazol-1-yl) benzoic acid, 3- ((1- (3- (benzylcarbamoyl) phenyl) azetidin-3-yl) oxy) Benzoic acid, 3- (3- (3-carboxyphenoxy) azetidin-1-yl) -2-aminobenzoic acid, 3- (3- (3-carboxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (acetoxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- ((octanoyloxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (acetamidomethyl) phenoxy) azetidine- 1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (acetamidomethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (cyclopropylsulfonamidomethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (3-methoxyphenoxy) azetidin-1-yl) -2- (1H- Pyrrol-1-yl) benzoic acid, methyl 2- (1H-pyrrol-1-yl) -3- (3- (4- (trifluoromethyl) phenoxy) azetidin-1-yl) benzoate, methyl 2- (1H-pyrrol-1-yl) -3- (3- (4- (trifluoromethoxy) phenoxy) azetidin-1-yl) benzoate, 2- (1H-pyrrol-1-yl) -3- (3- (4- (trifluoromethoxy) phenoxy) azetidin-1-yl) benzoic acid, or combinations thereof, Methyl 3- (3- ((6-chloropyridin-3-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4-acetylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4-acetylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, or mixtures thereof, Methyl 3- (3- (4- (1-hydroxyethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- ((2, 6-dichloropyridin-4-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzene Formic acid, methyl 3- (3- (4-cyanophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4-chlorophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4-chlorophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (dimethylamino) phenoxy) azetidin-1-yl) benzoate Methyl yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (dimethylamino) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4-ethoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3-phenoxyazetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl N-propylphenyl-N-ethyl-N-propylphenyl-2- (1H-pyrrol-1-yl) benzoate, N-propylphenyl-2-propylphenyl-azetidin-1-yl-ethyl-2-ethyl-phenyl-ethyl-phenyl-3- (4-ethoxy-phenoxy) benzoate, and N-propylphenyl-1-ethyl-phenyl-ethyl-benzoate, 3- (3-phenoxyazetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- ((1H-indol-6-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- ((1H-indol-6-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4-propoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, 3- (3- (4-propoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4-butoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4-isopropoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, 3- (3- (4-Isopropoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 2- (1H-pyrrol-1-yl) -3- (3- (4- (((tetrahydro-2H-pyran-4-yl) oxy) methyl) phenoxy) azetidin-1-yl) benzoate, methods of making and using the same, Methyl 3- (3- (4- (phenoxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (phenoxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4-nitrophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (3-propylthioureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, Methyl 2- (1H-pyrrol-1-yl) -3- (3- (4- (3- (4- (trifluoromethyl) phenyl) thioureido) phenoxy) azetidin-1-yl) benzoate, methyl 3- (3- (4- (3- (2-methoxyphenyl) thioureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4-acetaminophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4-acetaminophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate -yl) benzoic acid, methyl 2- (1H-pyrrol-1-yl) -3- (3- (4- (thiophene-2-carboxamido) phenoxy) azetidin-1-yl) benzoate, methyl 3- (3- (4- (N- (methylsulfonyl) methylsulfonamido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (methylsulfonamido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (cyclopropylalkylsulfonylamino) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (3- (4-chlorophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (3- (4-chlorophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (3-cyclohexylureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (3-hexylureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (3- (3-chlorophenyl) ureido) phenoxy) azetidin-1-yl) benzoate -yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (3- (3-chlorophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (3- (2-chlorophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (3- (2-chlorophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, and mixtures thereof, 3- (3- (4- (3- (3-cyanophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (3- (3-cyanophenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- ((4-methoxybenzyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 2- (1H-pyrrol-1-yl) -3- (3- (thiazol-4-yl) methoxy) azetidin-1-yl) Methyl benzoate, 2- (1H-pyrrol-1-yl) -3- (3- (thiazol-4-yl) methoxy) azetidin-1-yl) benzoic acid, methyl 3- (3- (pyrazin-2-yl) methoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (2-oxo-2- (phenylamino) ethoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl N-methyl-N-ethyl-azetidin-1-yl) benzoate, N-methyl-N-ethyl-phenyl-ethyl-2- (1H-pyrrol-1-yl) benzoate, N-methyl-ethyl-methyl-N-ethyl-azetidin-1-yl-2- (3- (2-pyrazin-yl) benzoate, N-ethyl-azetidin-1-yl) benzoate, N-methyl-ethyl-azetidin-1-yl-ethyl-benzoate, N-ethyl-phenyl-ethyl-azetidin-1-benzoate, N-ethyl-phenyl-ethyl-phenyl-ethyl-benzoate, and N-ethyl, 3- (3- (2-oxo-2- (phenylamino) ethoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (((2, 4-dimethoxyphenyl) carbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (((4-chlorophenyl) thiocarbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (((4-chlorophenyl) thiocarbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-yl) 1-yl) benzoic acid, methyl 3- (3- ((cyclohexylcarbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (((3-fluoro-4- (morpholin-2-yl) phenyl) carbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (((4-phenoxyphenyl) carbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate -pyrrol-1-yl) benzoic acid methyl ester, 2- (1H-pyrrol-1-yl) -3- (3- (((4- (trifluoromethoxy) phenyl) carbamoyl) oxy) azetidin-1-yl) benzoic acid methyl ester, 2- (1H-pyrrol-1-yl) -3- (3- (((4- (trifluoromethyl) benzyl) carbamoyl) oxy) azetidin-1-yl) benzoic acid methyl ester, 3- (3- ((cyclopropylcarbamoyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (((4-bromophenyl) thiocarbamoyl) oxy) azetidin-1-yl) -methyl 2- (1H-pyrrol-1-yl) benzoate, 3- (3- (((4-bromophenyl) carbothioformyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (((4-methoxyphenyl) carbothioformyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (((4-methoxyphenyl) carbothioformyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- ((ethylcarbothioformyl) oxy) azetidin-1-yl) benzoic acid Methyl 3- (3- ((ethylcarbamothioyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (((2, 4-dichlorophenyl) carbamothioyl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (3-cyclopropylureido) azetidin-1-yl) -benzoic acid Methyl 2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (3- (4-phenoxyphenyl) ureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 2- (1H-pyrrol-1-yl) -3- (3- (3- (4- (trifluoromethoxy) phenyl) ureido) azetidin-1-yl) benzoate, methyl 3- (3- (3- (4-phenoxyphenyl) ureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 2- (1H-pyrrol-1-yl) -3- (3- (3- (4- (trifluoromethoxy) phenyl) ureido) azetidin-1-yl) benzoic acid, 3- (3- (3-cyclopropylureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (3- (3, 5-dimethoxyphenyl) ureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (3- (3, 5-dimethoxyphenyl) ureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (3-ethylthioureido) azetidin-1-yl) -2- (1H-pir-inyl) benzoic acid Pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (3-ethylthioureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (3- (4-chlorophenyl) thioureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (3- (4-chlorophenyl) thioureido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- ((4-methylphenyl) sulfonamido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, methyl ester, 3- (3- ((4-methylphenyl) sulfonamido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3-benzoylaminoazetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3-benzoylaminoazetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (2-nitrobenzamido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (2-nitrobenzamido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (cyclopropylalkylsulfonamido) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- ((N-benzyl-4-methylphenyl) sulfonamide) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- ((N-benzyl-4-methylphenyl) sulfonamide) azetidin-1-yl) -2- (1H-pyrrol-1-) 1-yl) benzoic acid, 3- (1- (4- (hydroxymethyl) phenyl) -1H-1,2, 3-triazol-4-yl) -2- (1H-indol-6-yl) benzoic acid, methyl 3- (3- (4-hydroxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4-hydroxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (2- (tert-butoxy) -2-oxovinyl) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate Esters, methyl 2- (1H-pyrrol-1-yl) -3- (3- (p-tolylthio) azetidin-1-yl) benzoate, methyl 2- (1H-pyrrol-1-yl) -3- (3- (p-tolylsulfinyl) azetidin-1-yl) benzoate, methyl 2- (1H-pyrrol-1-yl) -3- (3- (p-tolylsulfonyl) azetidin-1-yl) benzoate, 2- (1H-pyrrol-1-yl) -3- (3-p-tolylsulfinyl) azetidin-1-yl) benzoate, and the like, Methyl 3- (3- (4- (4-chlorophenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (3-methoxyphenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, Methyl 3- (3- (3-chloro-4-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (3-fluoro-4-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (3-fluoro-4-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, and mixtures thereof, 3- (3- (4- (4-fluorophenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (4-fluorophenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (3, 5-difluoro-4-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (3, 5-difluoro-4-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzene Formic acid, methyl 3- (3- (4- (4-acetylphenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (phenylthio) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, benzoic acid, or mixtures thereof, 3- (3- (4- (4-cyanophenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (4-cyanophenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (4- (methylsulfonyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester -yl) benzoic acid, methyl 3- (3- (4-propionylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4-isobutyrylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4-isobutyrylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl N-propylphenyl-ethyl-phenyl-ethyl-phenyl-ethyl, Methyl 3- (3- (3-methoxy-4- (2-methoxyethoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (2-acetamidoethoxy) -3-methoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (2-acetamidoethoxy) -3-methoxybenzene Oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (3-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (3-phenoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (2-methoxyethoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (2-methoxyethoxy) phenoxy) azetidin-1-yl) -1- Methyl 3- (3- (4- (3- (4-chlorophenyl) thioureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (3- (3-cyanophenyl) thioureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, Methyl 3- (3- (4- (3- (4- (trifluoromethyl) phenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (3- (4- (trifluoromethyl) phenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, N- (thien-2-ylmethyl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzamide, 3- (3- (4- (ethoxymethyl) phenoxy) azetidin-1-yl) Ethyl yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (ethoxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (((((tetrahydro-2H-pyran-4-yl) oxy) carbonyl) oxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (morpholinylmethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, Methyl 3- (3- (4- (((4-chlorophenyl) aminothiocarbonyl) oxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- ((((4-chlorophenyl) aminothiocarbonyl) oxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (((ethylamino thiocarboxamido) oxy) methyl) pyrrol-1-yl) benzoate ) Phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- ((4-chlorophenoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- ((3-cyclopropylureido) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, Methyl 3- (3- (4- ((pyridin-3-yloxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- ((4-fluorophenoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- ((4-fluorophenoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- ((3-fluorophenoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- ((3- (trifluoromethyl) phenoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- ((3- (trifluoromethyl) phenoxy) methyl) phenoxy) azepin-1-yl) benzoate, and mixtures thereof Cyclobutane-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (hydroxymethyl) -3-methylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (hydroxymethyl) -3-methylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4-aminophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4-aminophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (2-aminophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- ((3-phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- ((3-phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, and mixtures thereof, 3- (3- (pyridin-3-yloxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (pyridin-3-yloxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (2- (methylsulfonamido) thiazol-4-yl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester -1-yl) benzoic acid, methyl 3- (3- (4- (phenylcarbamoyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (ethylcarbamoyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (morpholine-4-carbonyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate -1-yl) benzoic acid, methyl 3- (3- (4- ((4-fluorophenyl) carbamoyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (1- (4- (hydroxymethyl) phenyl) -1H-1,2, 3-triazol-4-yl) -2- (1H-indol-6-yl) benzoate, 3- (1, 1-dioxadibenzo [ d ] isothiazol-2 (3H) -yl) acetylene) -2- Methyl (1H-pyrrol-1-yl) benzoate, methyl 3- (((N-benzyl-4-methylphenyl) sulfonylamino) acetylene) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (2-phenylcyclopropane) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (hydroxy (4-methoxyphenyl) methyl) bicyclo [1.1.1] pentan-1-yl) benzoate, methyl 3- (6-phenyl-2, 6-diazaspiro [3.3] heptan-2-yl) -2- (1H-pyrrol-1-yl) benzoate, 2-amino-3- (6- (2-aminophenyl) -2, 6-diazaspiro [3.3] heptan-2-yl) benzoic acid methyl ester, 2- (furan-2-yl) -3- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid, 2- (benzofuran-6-yl) -3- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) benzoic acid methyl ester, 3' -cyano-6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid, 3' -carboxy-6- (3- (4-hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1 '-biphenyl ] -2-carboxylic acid methyl ester, 6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -3' - (methylsulfonylamino) - [1,1 '-biphenyl ] -2-carboxylic acid, 3' -cyano-4 '-fluoro-6- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) - [1,1' -biphenyl ] -2-carboxylic acid, 2-amino-3- (3- (3-carboxyphenoxy) azetidin-1-yl) benzoic acid methyl ester, 3- (3- (4- (((4-methylphenyl) sulfonylamino) methyl) phenoxy) azetidin-1-yl) -2- (1H-sulfonylamino) azetidin-1-yl -pyrrol-1-yl) benzoic acid methyl ester, 3- (3- ((2, 6-difluoropyridin-4-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4-nitrophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (((N- (pyridin-3-ylmethyl) -N- (4-methylphenyl) sulfonamido) ethynyl) - Lithium 2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (3- (2- (methylsulfonylamino) thiazol-4-yl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (3- (2-methoxyphenyl) ureido) phenoxy) azetidin-1-yl) 2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (3-hexylureido) phenoxy) azetidin-1-yl) 2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (4- (trifluoromethyl) phenoxy) Azetidin-1-yl) 2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (4- (trifluoromethyl) phenoxy) azetidin-1-yl) 2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (3-acetylphenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (3-acetylphenoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, and mixtures thereof, Methyl 3- (3- (3- (3- (4- (trifluoromethoxy) phenyl) ureido) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (3- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (3- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1- 1-yl) benzoic acid, methyl 3- (3- (4- (hydroxymethyl) -2-methylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (hydroxymethyl) -2-methylphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4-nitrophenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (phenylcarbamoyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzene Formic acid, methyl 3- (3- (4- (ethylcarbamoyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- ((1-p-toluenesulfonyl-1H-indol-5-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- ((1-p-toluenesulfonyl-1H-indol-5-yl) oxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (3, 4-bis (2-methoxyethoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (3, 4-bis (2-methoxyethoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- ((tetrahydro-2H-pyran-2-yl) oxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (2- (methylamino) ethoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrazin-1-yl) benzoic acid methyl ester Pyrrole-1-yl) benzoic acid methyl ester, 3- (3- (4- (2-aminoethoxy) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (2-aminoethoxy) -3-methoxyphenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (2-acetamidoethoxy) phenoxy) azetidin-1-yl) benzoic acid methyl ester -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (((N- (furan-2-ylmethyl) -4-methylphenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium 3- (((N- (furan-2-ylmethyl) -4-methylphenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (((4-methyl-N- ((1-methyl-1H-indol-5-yl) methyl) phenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, Lithium 3- (((4-methyl-N- ((1-methyl-1H-indol-5-yl) methyl) phenyl) sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (((4-methyl-N- ((1-methylpiperidin-4-yl) methyl) phenyl) sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium 3- (((4-methyl-N- ((1-methylpiperidin-4-yl) methyl) phenyl) sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, 3- ((N-benzylbenzo [ b ] thiophene-3-sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- ((N-benzylbenzo [ b ] thiophene-3-sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid lithium, 3- ((N-benzylthiophene-2-sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- ((N-benzylthiophene-2-sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid lithium, 3- ((N- (2-fluorobenzyl) thiophene-2-sulfonamide) ethynyl) -2 Methyl (1H-pyrrol-1-yl) benzoate, lithium 3- ((N- (2-fluorobenzyl) thiophene-2-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- ((N- (4-fluorobenzyl) thiophene-2-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium 3- ((N- (4-fluorobenzyl) thiophene-2-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, 3- (((4-methyl-N- (thiophen-2-ylmethyl) phenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol- 1-yl) benzoic acid methyl ester, lithium 3- (((4-methyl-N- (thien-2-ylmethyl) phenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- ((N-benzylbenzofuran-5-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium 3- ((N-benzylbenzofuran-5-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (((N- (4- (hydroxymethyl) benzyl) -4-methylphenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium acetate, sodium chloride, and sodium chloride, Lithium 3- (((N- (4- (hydroxymethyl) benzyl) -4-methylphenyl) sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- ((N- ((1-methyl-1H-indol-5-yl) methyl) benzo [ b ] thiophene-3-sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium 3- ((N- ((1-methyl-1H-indol-5-yl) methyl) benzo [ b ] thiophene-3-sulfonamide) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, 3- ((N- (4- (trifluoromethyl) benzyl) thiophene-2-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- ((N- (4- (trifluoromethyl) benzyl) thiophene-2-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid lithium, 3- ((N- ((1-methyl-1H-indol-5-yl) methyl) benzofuran-5-sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- ((N- ((1-methyl-1H-indol-5-yl) methyl) benzofuran-5-sulfonylamino) Lithium ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- ((N-benzyl-N-benzenesulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (((N- (4-methylbenzyl) -N- (4-methylbenzylsulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, 3- (((N- (4-methylbenzyl) -N- (4-methylbenzylsulfonamido) ethynyl) -2- (1H-pyrrol-1-yl -yl) benzoic acid lithium salt, 3- (((N- (4-fluorobenzyl) -4-methylbenzenesulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (((N- (4-fluorobenzyl) -4-methylbenzenesulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid lithium salt, 3- (((N- (4- (trifluoromethyl) benzyl) -N- (4-methylbenzenesulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (((N- (4- (trifluoromethyl) benzyl) - (4-methylbenzenesulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester 1-yl) benzoic acid lithium salt, 3- (3- ((4-isopropylphenyl) thio) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- ((4-chlorophenyl) thio) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (cyclohexylthio) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (phenylthio) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, sodium benzoate, potassium benzoate, sodium benzoate, and sodium benzoate, Methyl 3- (3- ((4- (hydroxymethyl) phenyl) thio) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- ((4-isopropylphenyl) sulfonyl) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- ((4-chlorophenyl) sulfonyl) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (cyclohexylsulfonyl) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl N-phenyl-3- (4-isopropylphenyl) sulfonyl) azetidin-1-yl) benzoate, N-phenyl-3- (4-isopropylphenyl) azetidin-1-yl) benzoate, N-phenyl-azetidin-1-yl-2- (1H-pyrrol-1-yl) benzoate, N-methyl-phenyl-azetidin-1-yl) benzoate, N-phenyl-azetidin-1-yl-phenyl-benzoate, N-azetidin-1-yl-benzoate, N-phenyl-benzoate, N-azetidin-1-phenyl-benzoate, N-phenyl-methyl-phenyl-2- (3- (1-phenyl) benzoate, N-phenyl-methyl-phenyl-2- (3- (2- (3-azetidin-phenyl) benzoate, N-2- (1-phenyl) benzoate, N-phenyl) benzoate, N-phenyl, N-phenyl) benzoate, N, Methyl 3- (3- (benzenesulfonyl) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- ((4- (hydroxymethyl) phenyl) sulfonyl) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (((5-fluoropyridin-3-yl) oxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (((5-fluoropyridin-3-yl) oxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate -1-yl) benzoic acid, methyl 3- (3- (4- ((pyrimidin-5-yloxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- ((pyrimidin-5-yloxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (phenylamino) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (phenylamino) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, methyl 3- (3- (4- (benzylamino) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (3- (2-methoxyethoxy) -4- ((2-methoxyethoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, and mixtures thereof, 3- (3- (3- (2-methoxyethoxy) -4- ((2-methoxyethoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, N- (2-cyanoethyl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzamide, N-methylsulfonyl- (3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl)) benzamide, and, Methyl 3- (3- (4- (2-methoxyethoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- (2-methoxyethoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (3- (4- (2-hydroxyethoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) -yl) benzoic acid, methyl 3- (3- (4- (2-acetamidoethoxy) methyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (3- (4- (tetrahydrofuran-3-yl) oxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoate, 3- (3- (4- ((oxetan-3-oxy) methyl) phenoxy) azetidin-1-yl) benzoate, and mixtures thereof -1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (3- (4- (1-acetylpiperidin-4-yl) oxymethyl) phenoxy (azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (1, 1-dioxadibenzo [ d ] isothiazol-2 (3H) -yl) acetylene) -2- (1H-pyrrol-1-yl) benzoic acid, 3- (((N-benzyl-4-methylphenyl) sulfonylamino) acetylene) -2- (1H-pyrrol-1-yl) benzoic acid, 3- ((N-benzylmethylsulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid 1-yl) benzoic acid methyl ester, 3- ((N-benzylmethylsulfonylamino) acetylene) -2- (1H-pyrrol-1-yl) benzoic acid lithium salt, 3- (((N-methyl-4-methylphenylsulfonamido) acetylene) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, 3- (((N- (4-methoxybenzyl) -4-methylphenylsulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoic acid methyl ester, and mixtures thereof, Lithium 3- (((N- (4-methoxybenzyl) -4-methylphenylsulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, methyl 3- (((N- (pyridin-3-ylmethyl) -N- (4-methylphenyl) sulfonamido) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, N- (furan-2-ylmethyl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzamide, 3- (((N- (pyridin-4-ylmethyl) -N- (4-methylphenyl) sulfonamido) ethynyl) acetylene Methyl 3- (((N- (pyridin-4-ylmethyl) -N- (4-methylphenyl) sulfonylamino) ethynyl) -2- (1H-pyrrol-1-yl) benzoate, lithium 2-amino-3- (2-phenylcyclopropanyl) benzoate, methyl 2-amino-3- (2-phenylcyclopropanyl) benzoate, 3- (2-phenylcyclopropanyl) -2- (1H-pyrrol-1-yl) benzoic acid, 2- (1H-pyrrol-1-yl) -3- (3- (4- (((tetrahydro-2H-pyran-4-yl) oxy) methyl) phenoxy) Azetidin-1-yl) benzoic acid, methyl 2- (benzo [ b ] thiophen-2-yl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) benzoate, N- (2-dimethylamino) ethyl) -3- (3- (4- (hydroxymethyl) phenoxy) azetidin-1-yl) -2- (1H-pyrrol-1-yl) benzamide.

21. A pharmaceutical composition comprising a compound of general formula (I), or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, according to any one of claims 1 to 20.

22. A pharmaceutical composition comprising a compound of general formula (I), or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, according to any one of claims 1 to 20, and a pharmaceutically acceptable carrier, excipient, or diluent.

23. A method for the treatment and/or prevention of a disease or disorder caused by EBNA1 activity, said method comprising administering to a subject an effective amount of at least one compound according to claims 1 to 20, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof.

24. A method for the treatment and/or prevention of a disease or disorder caused by EBNA1 activity, the method comprising administering to a subject an effective amount of at least one pharmaceutical composition according to claims 21 to 22.

25. The method of claim 23, 24, wherein the disease or disorder caused by EBNA1 activity is cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus or rheumatoid arthritis.

26. The method of claim 25, wherein the cancer is nasopharyngeal carcinoma, gastric carcinoma, non-hodgkin's lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, burkitt's lymphoma, reticuloendothelial proliferation, reticulocytosis, microglioma, diffuse large B-cell lymphoma, extranodal T/NK lymphoma/angiocentric lymphoma, follicular lymphoma, immunoblastic lymphoma, mucosa-associated lymphoid tissue lymphoma, B-cell chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal large B-cell lymphoma, lymphoplasmacytic lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphoma-like granuloma, Angioimmunoblastic lymphadenopathy, leiomyosarcoma, X-linked lymphoproliferative disorder, post-transplant lymphoproliferative disorder, Hodgkin's lymphoma, or breast cancer.

27. A method for the treatment and/or prevention of a disease or disorder infected by epstein-barr virus (EBV) and/or associated with EBV infection, said method comprising administering to a subject an effective amount of at least one compound according to claims 1 to 20, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof.

28. A method of treating and/or preventing a disease or disorder infected by epstein-barr virus (EBV) and/or associated with EBV infection, the method comprising administering to a subject an effective amount of at least one pharmaceutical composition according to claims 21 to 22.

29. A method for the treatment and/or prevention of EBV infections in lytic and/or latent phase, said method comprising administering to a subject an effective amount of at least one compound according to claims 1 to 20, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof.

30. A method of treating and/or preventing EBV infection in lytic and/or latent phase, the method comprising administering to a subject an effective amount of at least one pharmaceutical composition according to claims 21 to 22.

Technical Field

The invention provides a small molecule inhibitor targeting EB virus nuclear antigen protein, a preparation method and application for treating and/or preventing diseases caused by EBNA1 activity.

Background

Epstein-Barr Virus (EBV) is a Human Herpes Virus (Human Herpes Virus 4, HHV-4) belonging to the subfamily of gamma-Herpes viruses. EBV is a B-lymphotropic virus that is universally infected in humans. The primary EBV infection occurs in oropharyngeal squamous epithelial cells, which are then long-lived with B lymphocytes in a latent infection state. Latent infection EBV, once activated, can become a cause of disease associated with many diseases, including tumors, and EBV is therefore classified as a first class of human oncogenic viruses by IARC (1997).

EBV invades the human body through epithelial cells and naive B cells in a dormant state, and the gene products mainly expressed by EBV-infected B lymphocytes include: EBV nuclear antigen family (EBNA1, EBNA2, EBNA3a, EBNA3B, EBNA3c and LP), latent membrane proteins (LMP-1, LMP-2A and LMP-2B) and EBV-encoded RNA (EBER-1, EBER-2). EBV has two forms of infection in B cells: (1) proliferative infection: after EBV infects B cell, early gene products such as EA (early antigen) are firstly synthesized, then DNA replication, VCA (capsular protein) and MA (membrane antigen) are synthesized, finally complete virus particles are formed and released, and simultaneously the cell is dissolved and killed. (2) Non-proliferative infection: most viral genes are latent after EBV infection of B cells, when the cells synthesize only EBNA and LMP. The expression of EBV in different tumors can be divided into four types, with type I latency leading to Burkitt's lymphoma and gastric cancer; type II latent-induced hodgkin lymphoma, nasopharyngeal carcinoma and T/NK cell lymphoma; type III causes infectious mononucleosis; type IV refers to healthy carriers. The EBV nuclear antigen EBNA1 is one of the key proteins that the virus must express in all three pathogenic latent forms.

It was found that EBV has a relationship to Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, NK/T lymphocytoma, leiomyosarcoma, and malignant epithelial tumors of the stomach, breast and lung, in addition to Burkitt's lymphoma. Studies have shown that EBNA1 is a protein expressed by EBV virus and involved in important pathological processes such as viral DNA replication, maintenance of viral latency and mutation induced tumors, induction of tumor cell migration and induction of immune escape. Under the condition that the tumor cells detect the infected EBV, EBNA1 (virus nuclear antigen 1) is detected, so that the development of EBV early screening and prevention of tumorigenesis and development aiming at EBNA1 is fully paid attention to academic research and clinical medical research, and is particularly important for early clinical diagnosis of nasopharyngeal carcinoma.

In recent years, research on targeted chemotherapy drugs for specific tumors developed by targeted EBNA1 has been advanced to a certain extent, which lays a foundation for target evaluation of EBNA1 protein, drug design of structural foundation, evaluation of small molecule activity and the like. For example, two world patents WO2016183534a1 and WO2015073864a1, filed 2015 and 2016 by mesrick TE et al, disclose the structures of compounds with two aromatic rings conjugated with alkynes, for inhibiting the binding of EBNA1 to DNA and blocking the replication of EBV-infected cells to play an antitumor role. In 2019, the group reports detailed research contents, the VK series molecules have good activity of inhibiting EBNA1, show good effects on cell level and mouse nasopharyngeal carcinoma models, and are in the clinical stage-I at present [ Sci. The result proves that the EBNA1 protein can be used as a new drug target for developing therapeutic drug researches of diseases related to EBV infection, including tumors.

The invention aims to optimize the molecular structure by improving bridging functional groups of two main fragments of a molecule aiming at a complexing site of the interaction of EBNA1 protein and DNA by utilizing a structure-based drug design method. The medicinal small molecular compound has activity of inhibiting the function of EBNA1 at a lower protein level, selectively inhibits the proliferation of an EBV positive tumor cell chain at a cell level, shows an excellent ADMET function as a medicament, and has better druggability.

Disclosure of Invention

The present invention provides compounds of general formula (I), or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates, and/or isotopically substituted derivatives thereof, as EBNA1 inhibitors:

the present invention further provides pharmaceutical compositions comprising at least one compound of the present invention, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof. The present invention further provides pharmaceutical compositions comprising at least one compound of the present invention, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, and at least one pharmaceutically acceptable carrier, excipient, or diluent. The invention further provides methods of treating and/or preventing diseases or disorders caused by the activity of EBNA 1. The invention further provides the use of the pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of a disease or disorder caused by the activity of EBNA 1. The invention further provides methods of treating and/or preventing an Epstein-Barr virus (EBV) infection and/or a disease or disorder associated with an EBV infection. The invention further provides the use of the pharmaceutical composition for the manufacture of a medicament for the treatment and/or prevention of an Epstein-Barr virus (EBV) infection and/or a disease associated with an EBV infection. The invention further provides methods of treating and/or preventing EBV infection in lytic and/or latent phase. The invention further provides the use of the pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of diseases caused by EBV infection in lytic and/or latent phase. The invention further provides processes for the preparation of the compounds of the general formula (I) according to the invention.

The present invention relates to compounds of general formula (I) or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and/or isotopically substituted derivatives thereof:

wherein:

X¹、X²、X³are identical or different and are selected independently of one another from CR^xaOr a nitrogen atom;

R^xaselected from hydrogen, halogen; the halogen is selected from fluorine, chlorine, bromine and iodine;

R¹selected from-COOH, -C (═ O) -O-R^1a、-C(＝O)-NH₂、-C(＝O)-NHR^1b、-C(＝O)-NR^1bR^1c、-C(＝O)-NH-S(＝O)₂-R^1b、 -C(＝O)-NH-(CH₂)_q-R^1d、-S(＝O)₂OH、-B(OH)₂、-S(＝O)₂-NH₂、-S(＝O)₂-NHR^1b、-S(＝O)₂-NR^1bR^1c，

q is 0, 1, 2 or 3;

wherein R is^1aIndependently selected from: li;

preferably, R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: hydrogen, optionally substituted C1-C3 straight chain alkyl, optionally substituted C1-C3 branched chain alkyl, optionally substituted C1-C3 cycloalkyl;

more preferably R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: hydrogen, methyl;

or R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

preferably, the aryl group is selected from: a phenyl group;

the heteroaryl group is selected from: thienyl, furyl, imidazolyl;

more preferably, R^1a、R^1b、R^1cAre identical or different and are selected, independently of one another, from: phenyl, thienyl, furyl;

or, R^1bAnd R^1cForm a cyclic group together with the atoms to which they are attached; the cyclic group is selected from: optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl;

R^1dSelected from: hydrogen, hydroxy, amino, cyano, -O-C (═ O) -R¹⁷、-O-R¹²、-NR⁹R¹⁰Optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

preferably, R^1dSelected from: hydrogen, hydroxy, amino, -O-R¹²、-NR⁹R¹⁰Optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted imidazolyl;

more preferably, R^1dSelected from: hydrogen, hydroxyl, methyl ether group, amino group, dimethylamino group, piperazinyl group, phenyl group, thienyl group, furyl group;

R²Selected from the following groups:

hydrogen, amino, halogen, nitro, optionally substituted C1-C4 alkyl,

Wherein the dotsRepresents said R²The point of attachment of the group to other groups of the compound molecule of formula (I);

X⁴selected from O, S, NR^2d；

Wherein R is^2a、R^2b、R^2cAre identical or different and are selected, independently of one another, from:

hydrogen, halogen, amino, nitro, hydroxy, C1-C8 hydroxyalkyl, cyano, - (CH)₂)_q-COOH、-(CH₂)_q-C(＝O)-O-R⁸、 -(CH₂)_q-C(＝O)-NH-R⁸、-N(H)C(＝O)-R⁸、-N(H)S(＝O)₂-R⁸、-O-R⁸、-NH-R⁸、-S(＝O)₂NH-R⁸、-S(＝O)₂-R⁸、-C(＝O)-R⁸、 -O-C(＝O)-R⁸Optionally substituted C1-C8 linear alkyl or alkoxy, optionally substituted C3-C8 branched alkyl or alkoxy, optionally substituted C3-C8 cycloalkyl or alkoxy, optionally substituted halogenated C1-C8 linear alkyl or alkoxy, optionally substituted halogenated C3-C8 branched alkyl or alkoxy, optionally substituted halogenated C3-C8 cycloalkyl or alkoxy, phenyl, said phenyl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

q is 0, 1, 2 or 3;

or, R^2aSelected from aryl, heterocyclyl, heteroaryl:

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

or, adjacent R^2aForm a fused ring structure with each other and with the atoms to which they are attached, or adjacent R^2bAnd together with the atoms to which they are attached form a fused ring structure selected from: phenyl, heteroaryl, said heteroaryl being selected from: thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, quinazolinyl, indazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzotriazolylA thiazolyl group; said phenyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

R^2dselected from hydrogen, optionally halogenated or non-halogenated C1-C3 linear alkyl, isopropyl, cyclopropyl; preferably, the halo is selected from fluoro;

Or, R^2dSelected from: -C (═ O) -R⁵、-S(＝O)₂-R⁵；

Or, R^2dSelected from aryl, heterocyclyl, heteroaryl;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R⁴One or more substitutions, which may be the same or different;

l is selected from the following groups:

wherein the dotsRepresenting L bound to the right-hand fragment of a compound of formula (I)A connection point;

wherein the asterisks indicate L and R³A connection point to which it is connected;

X⁵selected from: o, NH, S;

Y¹selected from: o, NR^L2；

Said L being substituted by a substituent R^L1One or more substitutions at the same or different sites;

R^L1Selected from: a hydrogen or fluorine atom;

or, R^L2Selected from: - (CH)₂)_q-R⁷、-C(＝O)-N(H)-R¹⁹、-C(＝S)-N(H)-R¹⁹、-C(＝O)-R²⁰、-S(＝O)₂-R²⁰；

Or, R^L2Selected from: aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^L3、R^L4are identical or different and are selected, independently of one another, from: a hydrogen or fluorine atom;

or R^L3And R^L4Together with the atoms to which they are attached form a carbonyl, thiocarbonyl;

m, n are identical or different and are selected, independently of one another, from: 1. 2 or 3 to form ring systems of different atomic numbers;

q is 0, 1, 2 or 3;

R³selected from the following groups:

or, R³Selected from the following groups:

wherein the dotsRepresents the point of attachment to the right fragment of the compound of formula (I);

X⁶selected from O, S, NR ^3g；

X⁷Selected from O, S, NR^3g、CHR^3a；

Y²Selected from CH, CR^3aN, and Y²A C atom that may be substituted at an optional position on the aromatic ring;

Z¹selected from O, S, NR^3h；

Wherein R is^3aSelected from: hydrogen, halogen, nitro, cyano, sulfonic acid, optionally substituted sulfonamide, optionally substituted C1-C8 linear alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 linear alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, hydroxy, C1-C8 hydroxyalkyl, - (CH-N-O-C-N-O-C-N-O-C-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-O-N-₂)_q-COOH、-(CH₂)_q-O-R¹²、 -(CH₂)_q-O-(CH₂)_p-R¹¹、-(CH₂)_q-NH-(CH₂)_p-R¹¹、-(CH₂)_q-S-(CH₂)_p-R¹¹、-C(＝O)-R²⁰、-C(＝O)-NHR¹³、 -(CH₂)_q-O-C(＝S)-NHR¹³、-(CH₂)_q-O-C(＝O)-R¹³、-C(＝O)-O-R²⁰、-(CH₂)_q-NH-C(＝O)-R¹¹、-(CH₂)_q-NH-C(＝O)-NH-R¹⁷、 -NH-C(＝S)-NH-R¹⁷、-(CH₂)_q-NR¹⁶-S(＝O)₂-R¹⁷、-N(SO₂R¹⁷)₂、-R¹⁴-NH-S(＝O)₂-R²⁰、-(CH₂)_q-R¹⁵、-NH-C(＝O)-O-R¹³、 -(CH₂)_q-C(＝O)NR⁹R¹⁰、-(CH₂)_q-NR⁹R¹⁰、-(CH₂)_q-S(＝O)₂-(CH₂)_p-R¹¹Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-; the C1-C8 hydroxyalkyl is hydroxy-substituted C1-C8 alkyl;

p and q are each independently 0, 1, 2 or 3;

the aryl group is selected from: phenyl, naphthyl, anthracenyl;

Said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

said cyclic structure being optionally substituted with a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3bselected from:

hydrogen, optionally substituted C1-C8 straight chain alkyl, optionally substituted C3-C8 branched alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted halogenated C1-C8 straight chain alkyl, optionally substituted halogenated C3-C8 branched alkyl, optionally substituted halogenated C3-C8 cycloalkyl, -C (═ O) -R ²⁰、 -C(＝O)N(H)-R¹⁹、-C(＝S)N(H)-R¹⁹、-C(＝O)O-R¹⁹、-S(＝O)₂-R²⁰；

q is 0, 1, 2 or 3;

or, R^3bSelected from: aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

The aryl group is selected from: optionally substituted phenyl, naphthyl, anthracenyl;

said aryl, heterocyclyl, heteroaryl being optionally substituted by a substituent R¹⁸One or more substitutions, which may be the same or different;

R^3cand R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl, aryl- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；

When L is selected from When R is^3cAnd R^3dAre identical or different and are selected, independently of one another, from: hydrogen, fluorine, C1-C8 alkyl, hydroxy, C1-C8 hydroxyalkyl, -O-C (═ O) -R ²⁰Aryl group- (CH)₂)_q-, heterocyclyl- (CH)₂)_q-, heteroaryl- (CH)₂)_q-；