Aryl alkyl ether compound and derivative thereof, preparation method, pharmaceutical composition and application

文档序号：627933 发布日期：2021-05-11 浏览：49次中文

阅读说明：本技术 芳基烷基醚化合物及其衍生物，制备方法、药物组合物和应用 (Aryl alkyl ether compound and derivative thereof, preparation method, pharmaceutical composition and application ) 是由赖宜生刘文斌马雪薇葛书山李月珍徐强郭文洁钟海清刘雯于 2021-01-18 设计创作，主要内容包括：本发明公开了一类芳基烷基醚化合物及其衍生物,制备方法、药物组合物和应用。该类芳基烷基醚化合物结构如式(I),该类芳基烷基醚化合物衍生物涉及所述芳基烷基醚化合物的立体异构体、互变异构体、代谢产物、代谢前体、前药、溶剂化物、溶剂化物的盐、结晶、药学上可接受的盐或它们的混合物。该类芳基烷基醚化合物及其衍生物对吲哚胺2,3-双加氧酶1抑制作用显著,可用于制备治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病的药物,所制备药物在分子水平即可发挥药效,应用广泛。。(The invention discloses aryl alkyl ether compounds and derivatives thereof, a preparation method, a pharmaceutical composition and application. The structure of the aryl alkyl ether compound is shown in formula (I), and the aryl alkyl ether compound derivative relates to a stereoisomer, a tautomer, a metabolite, a metabolic precursor, a prodrug, a solvate, a salt of the solvate, a crystal, a pharmaceutically acceptable salt or a mixture of the stereoisomer, the tautomer, the metabolite, the metabolic precursor, the prodrug, the solvate and the salt of the solvate. The aryl alkyl ether compound and the derivatives thereof have obvious inhibition effect on indoleamine 2, 3-dioxygenase 1, can be used for preparing medicines for treating indoleamine 2, 3-dioxygenase 1-mediated immunosuppression-related diseases, can exert the medicine effect at the molecular level, and are widely applied.)

1. An arylalkyl ether compound and derivatives thereof, wherein the arylalkyl ether compound and derivatives thereof have the structure of formula (I), and wherein the arylalkyl ether compound derivatives are stereoisomers, tautomers, metabolites, metabolic precursors, prodrugs, solvates, salts of solvates, crystals, pharmaceutically acceptable salts, or mixtures thereof, of the arylalkyl ether compound:

wherein:

x or Y is a C atom or a N atom;

R¹or R²Is hydrogen, halogen, C₁-C₆Alkyl radical, R¹And R²With adjacent carbon atoms forming C₃-C₈Cycloalkyl or R¹And R²With adjacent carbon atoms forming C₃-C₈Heterocycloalkyl containing one or more heteroatoms selected from O or N;

R³is aryl, heteroaryl, C₃-C₈Cycloalkyl or C₃-C₈A heterocycloalkyl group, said heteroaryl or heterocycloalkyl group containing one or more O, S or N atoms, said aryl, heteroaryl, cycloalkyl or heterocycloalkyl group containing one or more D group substituents;

the D group is hydrogen, halogen, cyano, hydroxyl, sulfydryl, carboxyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Or C containing one or more halogens₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆An alkylamino group;

R⁴is aryl, heteroaryl, C₃-C₈Cycloalkyl or C₃-C₈Heterocycloalkyl, said heteroaryl and heterocycloalkyl containing one or more atoms selected from O, S or N, said aryl, heteroaryl, cycloalkyl or heterocycloalkyl containing one or more E group substituents;

the E group is hydrogen, halogen, cyano, hydroxyl, sulfydryl, carboxyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylamino or C containing one or more halogens₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆An alkylamino group;

said C is₁-C₆Alkyl is straight chain alkyl, branched chain alkyl or cyclic alkyl;

said C is₁-C₆Alkoxy is linear alkoxy, branched alkoxy or cyclic alkoxy;

said C is₁-C₆The alkylamino group is a straight-chain alkylamino group, a branched-chain alkylamino group or a cyclic alkylamino group.

2. The arylalkyl ether compound of claim 1 wherein the arylalkyl ether compound and its derivatives have the structure:

x or Y is a C atom or a N atom;

R¹or R²Is hydrogen, C₁-C₆Alkyl or R¹And R²With adjacent carbon atoms forming C₃-C₈A cycloalkyl group;

R³is aryl or heteroaryl, said heteroaryl containing one or more N atoms, said aryl or heteroaryl containing one or more D group substituents;

the D group is hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylamino or C containing one or more halogens₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆An alkylamino group;

R⁴is aryl, heteroaryl, C₃-C₈Cycloalkyl or C₃-C₈Heterocycloalkyl, said heteroaryl and heterocyclyl containing one or more N atoms, said aryl, heteroaryl, cycloalkyl or heterocycloalkyl containing one or more E group substituents;

the E group is hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylamino or C containing one or more halogens₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆An alkylamino group;

the aryl group represents phenyl, benzyl, naphthyl, acenaphthyl or tetrahydronaphthyl;

the heteroaryl group represents a pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, quinazolinyl, isoquinolyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxinyl, or benzo [1,3] dioxolyl group.

3. The arylalkyl ether compound of claim 1 wherein the arylalkyl ether compound and its derivatives have the structure:

x or Y is a C atom or a N atom;

R¹or R²Is hydrogen, methyl, cyclopropyl or cyclobutyl;

R³is phenyl or pyridyl, said phenyl or pyridyl containing one or more D group substituents;

the D group is hydrogen, halogen or cyano;

R⁴is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl, said phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl containing one or more E group substituents;

the E group is hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, cyano or C₁-C₃An alkyl group.

4. The arylalkyl ether compound and its derivatives of claim 3 having the structure of formula (Ia):

wherein:

x or Y is a C atom or a N atom;

R³is phenyl or pyridyl, said phenyl or pyridyl containing one or more D group substituents;

the D group is hydrogen, halogen or cyano;

R⁴is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl, said phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl containing one or more E group substituents;

the E group is hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, cyano or C₁-C₃An alkyl group.

5. The arylalkyl ether compound and its derivatives of claim 3 having the structure of formula (Ib):

wherein:

x or Y is a C atom or a N atom;

R³is phenyl or pyridyl, said phenyl or pyridyl containing one or more D group substituents;

the D group is hydrogen, halogen or cyano;

R⁴is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl, said phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl containing one or more E group substituents;

the E group is hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, cyano or C₁-C₃An alkyl group.

6. The arylalkyl ether compound of claim 1 wherein the arylalkyl ether compound and its derivatives have the structure:

n- (2-ethoxyphenyl) -4- (2- ((4-bromophenyl) amino) -2-oxoethoxy) benzamide (1),

n- (2-ethoxyphenyl) -4- ((2-methyl-1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (2),

(S) -N- (2-ethoxyphenyl) -4- ((1- ((4-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (3),

(S) -N- (2-ethoxyphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (4),

n- (2-ethoxyphenyl) -4- ((1- ((3-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (5),

n- (2-ethoxyphenyl) -4- ((1- ((3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (6),

n- (2-ethoxyphenyl) -4- ((1- ((2-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (7),

n- (2-ethoxyphenyl) -4- ((1- ((2-fluoro-3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (8),

n- (2-ethoxyphenyl) -4- ((1- ((3-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (9),

n- (2-ethoxyphenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (10),

(S) -N- (2-methoxyphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (11),

n- (2-methylphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (12),

n-phenyl-4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (13),

n- (2-isopropylphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (14),

(R) -N- (2-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (15),

n- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (16),

(S) -N- (4-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (17),

n- (2-methyl-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (18),

(S) -N- (2-methyl-4-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (19),

n- (2-fluoro-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (20),

(S) -N- (2-fluoro-4-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (21),

n-cyclohexyl-4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (22),

n- (tetrahydro-2H-pyran) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (23),

n- (1-methylpiperidin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (24),

n- (1-tert-Butoxycarbonylpiperidin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (25),

n- (piperidin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (26),

(S) -N- (2-methylphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (27),

(R) -N- (2-methylphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (28),

(S) -N- (2-methylphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (29),

(R) -N- (2-methylphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (30),

(S) -N- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (31),

(R) -N- (3-chlorophenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (32),

n- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (33),

n- (2-fluoro-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (34),

n- (2-methyl-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (35),

(S) -N- (3-chlorophenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (36),

(S) -N- (2-methylphenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (37),

(S) -N- (2-fluoro-3-chlorophenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (38),

(S) -N-phenyl-4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (39),

(S) -N- (2-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (40),

(S) -N- (2-methyl-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (41),

(S) -N- (2-fluoro-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (42),

(S) -N- ((2-trifluoromethyl) phenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (43),

(S) -N- (2-fluoro-5-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (44),

n- (2-methylphenyl) -4- ((1- ((5-chloropyridin-2-yl) amino) -1-oxopropan-2-yl) oxy) benzamide (45),

(S) -N- (3-chlorophenyl) -4- ((1- ((6-chloropyridin-3-yl) amino) -1-oxopropan-2-yl) oxy) benzamide (46),

(S) -N- (6-chloropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (47),

(S) -N- (2-chloropyridin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (48),

(S) -N- (5-chloropyridin-3-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (49),

(S) -N- (4-chloropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (50),

(S) -N- (3-chlorophenyl) -6- (((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) nicotinamide (51),

(S) -N- (3-chlorophenyl) -5- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) pyridinamide (52),

(S) -N- ((3-trifluoromethyl) phenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (53),

(S) -N- (2-methyl-3-chlorophenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (54),

(S) -N- ((3-fluorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (55),

(S) -N- (3-chlorophenyl) -4- ((1- ((4-cyanophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (56),

(S) -N- (3-chlorophenyl) -4- ((1- ((4-cyanophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (57),

n- (3-chlorophenyl) -4- ((1- ((6-chloropyridin-3-yl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (58),

n- (6-chloropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (59),

n- (6-fluoropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (60),

(S) -N- (6-fluoropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (61),

(S) -N- (3-chlorophenyl) -4- ((1- ((5-chloropyridin-2-yl) amino) -1-oxopropan-2-yl) oxy) benzamide (62).

7. The arylalkyl ether compound and its derivatives according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt is a salt of the arylalkyl ether compound with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid and mandelic acid.

8. A method for preparing an arylalkyl ether compound or a derivative thereof according to any one of claims 1 to 7, wherein the method comprises any one of the following steps:

the method comprises the following steps: etherifying, hydrolyzing, acylating, hydrolyzing and acylating the compound I to obtain a compound (I);

the second method comprises the following steps: carrying out acylation reaction on the compound ii to obtain an intermediate a, carrying out acylation, acylation and hydrolysis reaction on the compound iii to obtain an intermediate d, and carrying out etherification reaction on the intermediate a and the intermediate d to obtain a compound (I);

wherein, X, Y, R¹、R²、R³And R⁴As defined in any one of claims 1 to 5;

and (3) adding a corresponding acid solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after salt formation is completed to obtain the pharmaceutically acceptable salt of the aryl alkyl ether compound.

9. A pharmaceutical composition comprising an arylalkyl ether compound and/or derivative thereof according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. An application of the aryl alkyl ether compound and the derivatives thereof as claimed in any one of claims 1 to 8 in preparation of indoleamine 2, 3-dioxygenase 1 inhibitor drugs.

11. The use according to claim 10, wherein the medicament is a medicament for the treatment of a disease associated with indoleamine 2, 3-dioxygenase 1 mediated immunosuppression.

Technical Field

The invention relates to aryl alkyl ether compounds and derivatives thereof, a preparation method, a pharmaceutical composition and application, in particular to aryl alkyl ether compounds and derivatives thereof which can be prepared into indoleamine 2, 3-dioxygenase 1 inhibitor drugs, a preparation method, a pharmaceutical composition and application.

Background

Indoleamine 2, 3-dioxygenase 1(IDO1) is the rate-limiting enzyme in the kynurenine metabolic pathway that catalyzes tryptophan outside the human liver. IDO1 is expressed in various tissues (e.g., lung, kidney, brain, placenta, thymus) and in various cells (e.g., macrophages and dendritic cells), and cytokines such as IFN- γ, TNF- α, IL-1 β and IL-6 induce IDO1 expression.

IDO1 can be involved in the regulation of innate and adaptive immunity of the body by catalyzing tryptophan oxidative metabolism. IDO1 primarily catalyzes local depletion of tryptophan by tryptophan and accumulation of its metabolites to achieve its regulatory role on the immune system: in one aspect, tryptophan depletion can inhibit T cell proliferation by activating the GCN2 pathway to induce T cell division cycle arrest at G1, while also inhibiting primary CD4⁺T cell differentiation into helper T cell 17(Th17) leading to immunosuppression; on the other hand, kynurenine and other tryptophan metabolites are cytotoxic and can kill T cells and Natural Killer (NK) cells, and these metabolites can induce CD4 by activating aromatic hydrocarbon receptor (AhR)⁺Differentiation of T cells into regulatory T cells (tregs) and promotion of Dendritic Cell (DC) conversion to tolerogenic DC; in addition, tryptophan metabolites can inhibit the function of NK cells by down-regulating the expression of NK cell receptors, which can further inhibit the immune response of the body.

IDO1 is involved in many pathophysiological processes. Research shows that IDO1 plays an important role in physiological stress processes such as host immune defense, maternal and fetal immune tolerance and the like, and cytokines such as IFN-gamma secretion is remarkably increased in the process, so that IDO1 expression is induced, tryptophan depletion and accumulation of metabolites such as kynurenine and the like are caused, T cell reaction of a mother body is inhibited, maternal immune tolerance is induced, and the fetus is ensured not to be rejected by an immune system of the mother body. Depletion of tryptophan in the host microenvironment renders it unable to provide the tryptophan necessary for replication of pathogenic microorganisms, thereby leading to death of the pathogenic microorganisms, while IDO 1-mediated immunosuppression prevents over-activation of the body's immune system. IDO1 also exerts an immunosuppressive effect on the survival of transplanted tissue in new hosts. These findings indicate that IDO1 is an immunomodulatory enzyme involved in immune tolerance in the body.

Numerous studies have shown that IDO 1-mediated immune tolerance is closely related to tumor immune escape, viral infection, neurodegenerative diseases, organ transplant rejection, autoimmune diseases, neuropsychiatric diseases, and cataract. In these diseases, local depletion of tryptophan mediated by over-expressed IDO1 and accumulation of its metabolites may inhibit T cell activation, resulting in immune tolerance in the body.

In addition, tryptophan metabolites catalyzed by IDO1, such as kynurenine and quinolinic acid, etc., have neurotoxicity, and these metabolites are closely related to the occurrence of neurodegenerative diseases such as memory disorder, Alzheimer's Disease (AD), cognitive disorder, senile dementia, parkinson's disease, and dyskinetic disease. Neuropsychiatric disorders such as depression, schizophrenia, anxiety are also associated with an overexpression of IDO1 and an elevated level of metabolic products such as kynurenine. Overexpression of IDO1 results in depletion of tryptophan, thereby reducing the amount of tryptophan used to synthesize the neurotransmitter 5-hydroxytryptamine, resulting in 5-hydroxytryptamine deficiency, coupled with accumulation of neurotoxic metabolites such as kynurenine and quinolinic acid, contributes to the development of neuropsychiatric disorders and is a factor of various mood disorders.

Tryptophan depletion mediated by IDO1 overexpression is also present in various autoimmune diseases. IDO1 is highly expressed in DCs of synovial joint tissues of patients with rheumatoid arthritis, the concentration of tryptophan in serum of the patients is reduced, and the concentration of kynurenine and the ratio of kynurenine/tryptophan are obviously increased.

IDO 1-induced immunosuppression plays an important role in tumor immune escape. IDO1 is over-expressed in various tumors and cells in the microenvironment thereof such as DC cells and stromal cells, resulting in local tryptophan depletion and accumulation of tryptophan metabolites in the tumors, thereby inducing tumor immune escape and helping tumor cells escape from the attack of the body immune system.

The IDO1 inhibitor can reduce accumulation of metabolites such as tryptophan metabolism and kynurenine, thereby reversing the immunosuppressive action mediated by IDO1, restoring the proliferation and functions of T cells and NK cells, and inhibiting the proliferation of Treg cells, thereby enhancing the immune response of the body, so that the IDO1 inhibitor can be used for treating or preventing the above-mentioned related diseases caused by the IDO 1-mediated immunosuppression, including cancer, viral infection, neurodegenerative diseases, cataract, organ transplantation rejection, depression, autoimmune diseases, and the like. In addition, IDO1 inhibitors may also be used in combination with other chemotherapeutic agents, targeted antineoplastic agents, immune checkpoint inhibitors, immune checkpoint agonists, anti-tumor vaccines, antiviral agents, antiviral vaccines, cytokine therapy, adoptive cellular immunotherapy and radiation therapy to achieve synergistic or enhanced therapy.

Furthermore, it is worth noting that since the 4-month-old default of phase iii clinical trials (ECHO-301) by the 4-month-old morshadong company of the IDO1 inhibitor epacadostat in combination with the PD-1 mab pembrolizumab for the treatment of metastatic melanoma, clinical emphasis has been placed on developing a new generation of apo-IDO1 inhibitors that bind to heme-free IDO 1. It is expected that a breakthrough in clinical trials will be obtained by developing a first generation IDO1 inhibitor (holo-IDO 1 inhibitor in combination with heme-containing IDO1) that is distinct from earlier findings. Therefore, a new generation of apo-IDO1 inhibitors may be the mainstream direction for the development of future IDO1 inhibitors.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide an aryl alkyl ether compound and a derivative thereof, a preparation method of the aryl alkyl ether compound and the derivative thereof, a third purpose of a pharmaceutical composition containing the aryl alkyl ether compound and/or the derivative thereof, and a fourth purpose of an application of the aryl alkyl ether compound and the derivative thereof in preparation of indoleamine 2, 3-dioxygenase 1 inhibitor drugs.

The technical scheme is as follows: the aryl alkyl ether compound and the derivatives thereof have the structure of formula (I), and the aryl alkyl ether compound derivatives are stereoisomers, tautomers, metabolites, metabolic precursors, prodrugs, solvates, salts of solvates, crystals, pharmaceutically acceptable salts of the aryl alkyl ether compound, or mixtures thereof:

wherein:

x or Y is a C atom or a N atom;

said C is₁-C₆Alkyl is straight chain alkyl, branched chain alkyl or cyclic alkyl;

said C is₁-C₆Alkoxy is linear alkoxy, branched alkoxy or cyclic alkoxy;

said C is₁-C₆The alkylamino group is a straight-chain alkylamino group, a branched-chain alkylamino group or a cyclic alkylamino group.

Preferably, the aryl alkyl ether compound and the derivative thereof have the following structures:

x or Y is a C atom or a N atom;

R¹or R²Is hydrogen, C₁-C₆Alkyl or R¹And R²With adjacent carbon atoms forming C₃-C₈A cycloalkyl group;

R³is aryl or heteroaryl, said heteroaryl containing one or more N atoms, said aryl or heteroaryl containing one or more D group substituents;

the aryl group represents phenyl, benzyl, naphthyl, acenaphthyl or tetrahydronaphthyl;

Preferably, the aryl alkyl ether compound and the derivative thereof have the following structures:

x or Y is a C atom or a N atom;

R¹or R²Is hydrogen, methyl, cyclopropyl or cyclobutyl;

R³is phenyl or pyridyl, said phenyl or pyridyl containing one or more D group substituents;

the D group is hydrogen, halogen or cyano;

R⁴is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl, said phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl containing one or more E group substituents;

the E group is hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, cyano or C₁-C₃An alkyl group.

Further preferably, the arylalkyl ether compound and its derivatives have the structure of formula (Ia):

wherein:

x or Y is a C atom or a N atom;

R³is phenyl or pyridyl, said phenyl or pyridyl containing one or more D group substituents;

the D group is hydrogen, halogen or cyano;

R⁴is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl, said phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl containing one or more E group substituents;

the E group is hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, cyano or C₁-C₃An alkyl group.

Further preferably, the arylalkyl ether compound and its derivatives have the structure of formula (Ib):

wherein:

x or Y is a C atom or a N atom;

R³is phenyl or pyridyl, said phenyl or pyridyl containing one or more D group substituents;

the D group is hydrogen, halogen or cyano;

R⁴is phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl, said phenyl, pyridyl, cyclohexyl, tetrahydropyranyl or piperidinyl containing one or more E group substituents;

the E group is hydrogen, halogen, methoxy, ethoxy, trifluoromethyl, cyano or C₁-C₃An alkyl group.

More specifically, the aryl alkyl ether compound is any one of the following compounds:

preferably, the pharmaceutically acceptable salt is a salt of the arylalkyl ether compound with an acid, the acid being hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, malic acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid.

The preparation method of the aryl alkyl ether compound and the derivative thereof is any one of the following methods:

the method comprises the following steps: etherifying, hydrolyzing, acylating, hydrolyzing and acylating the compound I to obtain a compound (I);

wherein, X, Y, R¹、R²、R³And R⁴As defined above;

More specifically, the etherification reaction is carried out in an anhydrous solvent, wherein the solvent is dichloromethane, dioxane, toluene or tetrahydrofuran; the acylation reaction is carried out under the action of alkali and/or a condensing agent, wherein the alkali is triethylamine, diisopropylethylamine, pyridine and K₂CO₃Or Cs₂CO₃The condensing agent is HATU, HOBT or EDCI; the hydrolysis reaction is carried out under the action of a base selected from LiOH, NaOH or KOH.

The pharmaceutical composition of the present invention comprises the arylalkyl ether compound and/or its derivative and a pharmaceutically acceptable carrier.

The pharmaceutical composition may be formulated into various types of administration unit dosage forms according to the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably tablets, capsules, liquids, suspensions, and injections (solutions and suspensions).

For shaping the pharmaceutical composition in the form of tablets, pills or suppositories, any excipient known and widely used in the art can be used.

For preparing the pharmaceutical composition in the form of injection, the solution or suspension may be sterilized (preferably by adding appropriate amount of sodium chloride, glucose or glycerol) and made into injection with blood isotonic pressure. In the preparation of injection, any carrier commonly used in the art may also be used. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, usual dissolving agents, buffers and the like may be added.

The content of the arylalkyl ether compound and/or its derivative in the pharmaceutical composition according to the invention can be selected within a wide range, generally from 5% to 95%, preferably from 30% to 85%.

The method of administration of the pharmaceutical composition of the present invention is not particularly limited, and various dosage forms of the preparation may be selected for administration according to the age, sex, and other conditions and symptoms of the patient.

The aryl alkyl ether compound and the derivative thereof are applied to the preparation of indoleamine 2, 3-dioxygenase 1 inhibitor drugs; the medicine is used for treating indoleamine 2, 3-dioxygenase 1 mediated immunosuppression related diseases, specifically cancer, virus infection, neurodegenerative diseases, cataract, organ transplantation rejection, depression or autoimmune diseases. Wherein the cancer is one or more of malignant melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymph cancer, leukemia, prostate cancer, testicular cancer, renal cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, endometrial cancer, mesothelial cancer, thyroid tumor, liver cancer, and esophageal cancer; the virus infection is infection caused by one or more of human immunodeficiency virus, hepatitis B virus, hepatitis C virus, influenza virus, poliovirus, cytomegalovirus, coxsackievirus, human papilloma virus, Epstein-Barr virus and varicella-zoster virus; the neurodegenerative disease is one or more of dysmnesia, Alzheimer disease, cognitive disorder, senile dementia, Parkinson disease and dyskinesia; the autoimmune disease is one or more of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, nodular vasculitis, multiple sclerosis, myasthenia gravis, mixed connective tissue disease, psoriasis, and autoimmune response due to infection.

Further, the arylalkyl ether compounds and derivatives thereof can be used in combination with one or more other types of therapeutic agents and/or methods of treatment for the treatment of related diseases mediated by IDO 1. Such other classes of therapeutic agents and/or methods of treatment include, but are not limited to, one or more chemotherapeutic agents, targeted antineoplastic agents, immune checkpoint inhibitors, immune checkpoint agonists, anti-tumor vaccines, antiviral agents, antiviral vaccines, cytokine therapy, adoptive cellular immunotherapy, or radiation therapy. Wherein the chemotherapeutic agent is not limited to alkylating agents, tubulin inhibitors, topoisomerase inhibitors, platinum-based drugs, antimetabolite drugs, or hormonal antineoplastic drugs; the targeted antineoplastic agent is not limited to a protein kinase inhibitor, a protease inhibitor, a proteasome inhibitor, an isocitrate dehydrogenase inhibitor, an epigenetic-based antineoplastic agent or a cell cycle signaling pathway inhibitor; the immune checkpoint inhibitor is not limited to a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a TIM-3 inhibitor, a VISTA inhibitor, a LAG3 inhibitor, a TIGIT inhibitor, an A2AR inhibitor, or a VTCN1 inhibitor; the immune checkpoint agonist is not limited to a STING agonist, a 4-1BB agonist, an OX40 agonist, a ROR γ agonist, or an ICOS agonist.

Has the advantages that: compared with the prior art, the invention has the following remarkable advantages:

(1) the aryl alkyl ether compound, the derivative and the pharmaceutical composition thereof can effectively inhibit the activity (IC) of indoleamine 2, 3-dioxygenase 1₅₀Optimally to picomolar levels);

(2) the aryl alkyl ether compound, the derivative thereof and the pharmaceutical composition thereof have wide application, and can be prepared into the drugs for treating indoleamine 2, 3-dioxygenase 1-mediated immunosuppression-related diseases; the medicine can exert the drug effect at molecular level, cellular level and in vivo by activating host immune response, has more excellent treatment effect and can optimally reach the level;

(3) the preparation method of the aryl alkyl ether compound is simple and convenient and easy to operate.

Detailed Description

The technical solution of the present invention is further illustrated by the following examples.

Reagents and materials: all reagents required for the experiments are, without particular mention, commercially available, chemically pure or analytically pure products.

The instrument comprises the following steps:¹HNMR were measured using a Bruker AV-300 and 400MHz NMR spectrometer with chemical shift values (. delta.) in ppm, coupling constants (J) in Hz and TMS as internal standard. The Mass Spectrometry (MS) analysis instrument is a Shimadzu LCMS-2020 mass spectrometer; thin Layer Chromatography (TLC) adopts HG/T2354-92 model GF254 thin layer chromatography silica gel produced by Qingdao ocean chemistry Co., Ltd, and ZF7 model three-purpose ultraviolet analyzer 254nm color development; the column chromatography uses 300-400 mesh column chromatography silica gel of Qingdao ocean chemical plant coarse pore (ZCX-II).

Example 1

Synthesis of methyl 4- (2-methoxy-2-oxoethoxy) benzoate (1A)

Dissolving methyl 4-hydroxybenzoate (2g,13.15mmol), methyl 2-glycolate (1.30g,14.46mmol) and triphenylphosphine (3.79g,14.46mmol) in anhydrous toluene (10mL), cooling with ice salt bath, slowly adding DEAD (3.43g,19.72mmol) dropwise, reacting at low temperature for 2h, removing ice salt bath, reacting at room temperature for 5h, removing solvent under reduced pressure, slowly adding 30mL water, extracting with ethyl acetate (3 × 15mL), mixing organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with silica gel column chromatography (PE: EA 20:1) to obtain white solid 2.05g with yield of 69%。MS(ESI)m/z:223.1[M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)7.91(d,J＝8.6Hz,2H),7.05(d,J＝8.6Hz,2H),4.91(s,2H),3.82(s,3H),3.71(s,3H)。

Synthesis of 2- (4- (methoxycarbonyl) phenoxy) acetic acid (1B)

Dissolving compound 1A (1.71g,7.63mmol) in a mixed solvent of 5mL methanol and 5mL THF, adding lithium hydroxide (0.2g,8.41mmol) in portions under ice bath condition, removing ice bath, reacting at room temperature for 2d, evaporating the solvent under reduced pressure, adding 10mL water, adjusting pH to 4 with dilute hydrochloric acid, extracting with ethyl acetate (3X 15mL), washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 1.50g of white solid with yield of 93.8%, MS (ESI) M/z 209.1[ M-H ESI ]]^-。

Synthesis of methyl 4- (2- ((4-bromophenyl) amino) -2-oxoethoxy) benzoate (1C)

Compound 1B (1.30g,6.19mmol) was dissolved in 4mL of anhydrous dichloromethane, oxalyl chloride (2.36g,18.59mmol) was slowly added dropwise under ice bath, 2 drops of DMF were added, the ice bath was removed, reaction was carried out at room temperature for 3h, the solvent and excess oxalyl chloride were removed under reduced pressure, dissolved by adding 3mL of anhydrous dichloromethane, slowly added dropwise to a dichloromethane (4mL) solution of a mixture of 4-bromoaniline (1.06g,6.17mmol) and triethylamine (2.50g,24.67mmol) under ice bath, the ice bath was removed, and reaction was carried out at room temperature for 5 h. The solvent was removed by evaporation, 20mL of water was added, extraction was performed with ethyl acetate (3 × 15mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA ═ 15:1) to give 1.5g of a white solid with a yield of 66.7%. MS (ESI) M/z 362.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.23(s,1H),7.91(d,J＝8.9Hz,2H),7.69(d,J＝9.0Hz,2H),7.50(d,J＝9.0Hz,2H),7.05(d,J＝9.0Hz,2H),4.91(s,2H),3.79(s,3H)。

Synthesis of 4- (2- ((4-bromophenyl) amino) -2-oxoethoxy) benzoic acid (1D)

Dissolving compound 1C (1g,2.75mmol) in a mixed solvent of 3mL methanol and 3mL THF, adding LiOH (131.51mg,5.49mmol), reacting at 45 deg.C for 2d, removing solvent under reduced pressure, adding 15mL water, adjusting pH to 4 with dilute hydrochloric acid, filtering, drying to obtain 630mg white solid with yield of 65%, MS (ESI) M/z:348.0[ M-H)]^-。

Synthesis of N- (2-ethoxyphenyl) -4- (2- ((4-bromophenyl) amino) -2-oxoethoxy) benzamide (1)

Compound 1D (0.23g,656.83 μmol) was dissolved in 3mL DMF, DIPEA (169.79mg,1.31mmol), HOBT (133.13mg,985.24 μmol) and EDCI (188.87mg,985.24 μmol) were added under ice bath, ice bath was removed, reaction was performed at room temperature for 1.5h, 2-ethoxyaniline (90.10mg,656.83 μmol) was added, reaction was performed at room temperature for 8h, 10mL of water was added, ethyl acetate extraction (3 × 15mL) was performed, organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and silica gel column chromatography purification was performed (PE: EA ═ 10:1) to obtain 150mg of white solid with a yield of 49%. MS (ESI) M/z 467.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.30(s,1H),9.95(s,1H),8.00-7.91(m,2H),7.83(dd,J＝7.8,1.6Hz,1H),7.69-7.59(m,2H),7.58-7.49(m,2H),7.20-7.05(m,4H),6.95(t,J＝7.6Hz,1H),4.82(s,2H),4.10(q,J＝6.9Hz,2H),1.36(t,J＝6.9Hz,3H)。

Example 2

Synthesis of methyl 4- ((1-methoxy-2-methyl-1-oxopropan-2-yl) oxy) benzoate (2A)

Methyl 4-hydroxybenzoate (2g,13.15mmol), methyl 2-hydroxy-2-methylpropionate (1.71g,14.46mmol) and triphenylphosphine (3.79g,14.46mmol) were dissolved in anhydrous toluene (10mL), cooled in an ice-salt bath, DEAD (3.43g,19.72mmol) was slowly added dropwise, the reaction was kept at low temperature for 2h after completion of the dropwise addition, the ice-salt bath was removed, the reaction was carried out at room temperature for 5h, the solvent was removed under reduced pressure, 30mL of water was slowly added, ethyl acetate extraction (3 × 15mL) was carried out, the organic phases were combined, washed with saturated common salt water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA ═ 20:1) to obtain 2.50g of a white solid with a yield of 75.3%. MS (ESI) M/z 251.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)7.87(dd,J＝8.8,7.1Hz,2H),6.87(dd,J＝8.8,7.3Hz,2H),3.65(s,3H),1.57(s,6H)。

Synthesis of 2- (4- (methoxycarbonyl) phenoxy) -2-methylpropanoic acid (2B)

Dissolving compound 2A (2g,7.93mmol) in a mixed solvent of 5mL methanol and 5mL THF, adding lithium hydroxide (0.2g,8.41mmol) in portions under ice bath conditions, removing the ice bath, reacting at room temperature for 2d, removing the solvent under reduced pressure, adding 10mL water, adjusting pH to 4 with dilute hydrochloric acid, extracting with ethyl acetate (3X 15mL), washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 1.73g of white solid with a yield of 91.5%. MS (ESI) M/z 237.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)12.98(s,1H),7.85(dd,J＝8.5,7.1Hz,2H),6.85(dd,J＝8.6,7.3Hz,2H),3.89(s,3H),1.57(s,6H)。

Synthesis of methyl 4- ((2-methyl-1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (2C)

Dissolving compound 2B (1.30g,5.46mmol) in 4mL of anhydrous dichloromethane, slowly dropping oxalyl chloride (2.08g,16.37mmol) under ice bath conditions, then adding 2 drops of DMF, removing ice bath, reacting at room temperature for 3h, removing solvent and excess oxalyl chloride under reduced pressure, adding 3mL of anhydrous dichloromethane for dissolving, slowly dropping 4-bromoaniline (0.95g,5.49mmol) and triethylamine (2.22g,21.97mmol) mixed dichloromethane (4mL) under ice bath conditions, removing ice bath, reacting at room temperature for 5h, removing solvent under reduced pressure, adding 20mL of water, extracting with ethyl acetate (3 × 15mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography (PE: EA ═ 15:1), obtaining 1.70g of white solid, yield 79%. MS (ESI) M/z 390.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.15(s,1H),7.95-7.89(m,2H),7.66-7.57(m,2H),7.55-7.43(m,2H),7.04-6.92(m,2H),3.79(s,3H),1.60(s,6H)。

Synthesis of 4- ((2-methyl-1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (2D)

Dissolving compound 2C (1g,2.55mmol) in a mixed solvent of 3mL methanol and 3mL THF, adding LiOH (122.10mg,5.10mmol), reacting at 45 deg.C for 2d, removing solvent under reduced pressure, adding 15mL water, adjusting pH to 4 with dilute hydrochloric acid, filtering, drying to obtain white solid 730mg, yield 75%, MS (ESI) M/z 376.0[ M-H ] M/z]^-。

Synthesis of N- (2-ethoxyphenyl) -4- ((2-methyl-1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (2)

Compound 2D (150mg,396.59 μmol) was dissolved in 3mL DMF, DIPEA (102.52mg,793.18 μmol), HOBT (80.38mg,594.89 μmol) and EDCI (114.04mg,594.89 μmol) were added while cooling on ice, the ice bath was removed, reaction was performed at room temperature for 1.5h, 2-ethoxyaniline (90mg,656.83 μmol) was added, reaction was performed at room temperature for 8h, 10mL of water was added, ethyl acetate extraction (3 × 15mL) was performed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA 10:1) to obtain 105mg of a white solid with a yield of 53%. MS (ESI) M/z 495.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.20(s,1H),9.22(s,1H),8.00-7.93(m,2H),7.83(dd,J＝7.9,1.6Hz,1H),7.70-7.59(m,2H),7.58-7.49(m,2H),7.20-7.05(m,4H),6.95(t,J＝7.7Hz,1H),4.15(q,J＝6.9Hz,2H),1.65(s,6H),1.36(t,J＝6.9Hz,3H)。

Example 3

Synthesis of methyl (S) -4- ((1-methoxy-1-oxopropan-2-yl) oxy) benzoate (3A)

Methyl 4-hydroxybenzoate (2g,13.15mmol), methyl D-lactate (1.51g,14.46mmol) and triphenylphosphine (3.79g,14.46mmol) were dissolved in anhydrous toluene (10mL), cooled in an ice-salt bath, DEAD (3.43g,19.72mmol) was slowly added dropwise, the reaction was kept at a low temperature for 2h after completion of the dropwise addition, the ice-salt bath was removed, the reaction was carried out at room temperature for 5h, the solvent was removed under reduced pressure, 30mL of water was slowly added, ethyl acetate was extracted (3X 15mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA 20:1) to obtain 2.25g of a colorless oily liquid with a yield of 72%. MS (ESI) M/z 237.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)7.94-7.87(m,2H),7.02-6.96(m,2H),5.14(q,J＝6.7Hz,1H),3.82(s,3H),3.69(s,3H),1.54(d,J＝6.8Hz,3H)。

Synthesis of (S) -2- (4- (methoxycarbonyl) phenoxy) propionic acid (3B)

Reacting the compound 3A(2g,8.39mmol) was dissolved in a mixed solvent of 5mL methanol and 5mL THF, lithium hydroxide (0.2g,8.39mmol) was added in portions under ice bath conditions, the ice bath was removed, the reaction was carried out at room temperature for 2d, the solvent was removed under reduced pressure, 10mL water was added, the pH was adjusted to 4 with dilute hydrochloric acid, ethyl acetate was extracted (3X 15mL), the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.80g of a colorless oily liquid with a yield of 95.7%. MS (ESI) M/z 224.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)12.99(s,1H),7.87(dd,J＝8.8,7.1Hz,2H),6.87(dd,J＝8.8,7.3Hz,2H),5.14(q,J＝6.7Hz,1H),3.82(s,3H),1.54(d,J＝6.8Hz,3H)。

Synthesis of methyl (S) -4- ((1- ((4-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (3C)

Compound 3B (1g,4.46mmol) was dissolved in 4mL of anhydrous dichloromethane, oxalyl chloride (1.70g,13.38mmol) was slowly added dropwise under ice bath, 2 drops of DMF were added, the ice bath was removed, reaction was carried out at room temperature for 3 hours, the solvent and excess oxalyl chloride were removed by rotary removal under reduced pressure, dissolved in 3mL of anhydrous dichloromethane, slowly added dropwise to a dichloromethane (4mL) solution of a mixture of 4-fluoroaniline (0.49g,4.45mmol) and triethylamine (1.80g,17.80mmol) under ice bath, the ice bath was removed, and reaction was carried out at room temperature for 5 hours. The solvent was removed by evaporation, 20mL of water was added, extraction was performed with ethyl acetate (3 × 15mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA ═ 15:1) to give 1.2g of a white solid in 85% yield. MS (ESI) M/z 316.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.30(s,1H),7.92(d,J＝8.9Hz,2H),7.59(d,J＝9.0Hz,2H),7.49(d,J＝9.0Hz,2H),7.02(d,J＝9.0Hz,2H),5.00(q,J＝6.8Hz,1H),3.80(s,3H),1.57(d,J＝6.7Hz,3H)。

Synthesis of (S) -4- ((1- ((4-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (3D)

Dissolving compound 3C (1g,3.15mmol) in a mixed solvent of 3mL methanol and 3mL THF, adding LiOH (159.93mg,6.30mmol), reacting at 45 deg.C for 2d, removing solvent under reduced pressure, adding 15mL water, adjusting pH to 4 with dilute hydrochloric acid, filtering, drying to obtain white solid 550mg, yield 57%, MS (ESI) M/z 362.0[ M-H ] M/z]^-。

Synthesis of (S) -N- (2-ethoxyphenyl) -4- ((1- ((4-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (3)

Compound 3D (300mg,989.15 μmol) was dissolved in 3mL DMF, DIPEA (255.7mg,1.98mmol), HOBT (0.2g,1.48 μmol) and EDCI (0.28g,1.48 μmol) were added under ice bath, ice bath was removed, reaction was performed at room temperature for 1.5h, 2-ethoxyaniline (135.7mg,989.15 μmol) was added, reaction was performed at room temperature for 8h, 10mL of water was added, ethyl acetate was extracted (3 × 15mL), organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA ═ 10:1) to give 205mg of white solid with a yield of 49%. MS (ESI) M/z 421.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.26(s,1H),9.21(s,1H),7.92(d,J＝8.4Hz,2H),7.83(dd,J＝7.8,1.6Hz,1H),7.66(dd,J＝9.0,5.0Hz,2H),7.27-7.01(m,6H),7.00-6.90(m,1H),5.00(q,J＝6.6Hz,1H),4.09(q,J＝6.9Hz,2H),1.60(d,J＝6.6Hz,3H),1.36(t,J＝6.9Hz,3H)。

Example 4

Synthesis of methyl (S) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (4C)

Referring to the synthesis of 3C, 3B was reacted with 4-chloroaniline to produce a white solid in 78% yield. MS (ESI) M/z 332.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆) δ (ppm)10.33(s,1H),7.90(d, J ═ 8.5Hz,2H),7.62(d, J ═ 8.6Hz,2H),7.35(d, J ═ 8.6Hz,2H),7.05(d, J ═ 9.0Hz,2H),5.01(q, J ═ 6.8Hz,1H),3.80(s,3H),1.57(d, J ═ 6.7Hz, 3H). Synthesis of (S) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (4D)

Referring to the 3D synthesis, a pale yellow solid was obtained in 56% yield from 4C, MS (ESI) M/z 318.1[ M-H ]]^-. Synthesis of (S) -N- (2-ethoxyphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (4)

Referring to the synthesis of example 3, a white solid was obtained from 4D in 51% yield. MS (ESI) M/z 437.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.34(s,1H),9.20(s,1H),8.05-7.89(m,2H),7.82(dd,J＝7.9,1.6Hz,1H),7.68(dd,J＝10.5,3.8Hz,2H),7.39(td,J＝7.3,6.6Hz,2H),7.21-7.04(m,4H),6.94(td,J＝7.6,1.4Hz,1H),5.01(q,J＝6.6Hz,1H),4.09(q,J＝7.1Hz,2H),1.59(d,J＝6.5Hz,3H),1.34(t,J＝7.0Hz,3H)。

Example 5

Synthesis of 2- (4- (methoxycarbonyl) phenoxy) propionic acid (5B)

Referring to the synthesis method of 3B, 4-hydroxybenzoic acid and methyl lactate were reacted and then hydrolyzed to obtain colorless oily liquid with yield of 87%, MS (ESI) M/z 224.1[ M-H ]]^-。

Synthesis of methyl 4- ((1- ((3-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (5C)

Referring to the synthesis of 3C, 5B was reacted with 3-fluoroaniline to give a white solid with a yield of 62%. MS (ESI) M/z 316.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.41(s,1H),7.90-7.80(m,2H),7.62(d,J＝8.6Hz,2H),7.33(d,J＝8.6Hz,2H),7.09-6.98(m,2H),5.01(q,J＝6.8Hz,1H),3.80(s,3H),1.57(d,J＝6.7Hz,3H)。

Synthesis of 4- ((1- ((3-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (5D)

Referring to the 3D synthesis, a white solid was prepared from 5C in 55% yield, MS (ESI) M/z 302.1[ M-H%]^-. Synthesis of N- (2-ethoxyphenyl) -4- ((1- ((3-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (5)

Referring to the synthesis of example 3, a white solid was obtained from 5D in 62% yield. MS (ESI) M/z 421.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.41(s,1H),9.20(s,1H),7.97-7.90(m,2H),7.82(dd,J＝7.9,1.7Hz,1H),7.64-7.59(m,1H),7.45-7.32(m,2H),7.17-7.05(m,4H),6.99-6.88(m,2H),5.02(q,J＝6.6Hz,1H),4.09(q,J＝6.9Hz,2H),1.60(d,J＝6.6Hz,3H),1.35(t,J＝6.9Hz,3H)。

Example 6

Synthesis of methyl 4- ((1- ((3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (6C)

Referring to the synthesis of 3C, 5B was reacted with 3-chloroaniline to produce a white solid with a yield of 60%. MS (ESI) M/z 332.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.39(s,1H),7.97-7.87(m,2H),7.57-7.49(m,2H),7.36(d,J＝8.6Hz,2H),7.09-6.98(m,2H),5.01(q,J＝6.9Hz,1H),3.82(s,3H),1.57(d,J＝6.9Hz,3H)。

Synthesis of 4- ((1- ((3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (6D)

Referring to the 3D synthesis, a white solid was prepared from 6C in 50% yield, MS (ESI) M/z 318.1[ M-H ]]^-. Synthesis of N- (2-ethoxyphenyl) -4- ((1- ((3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (6)

Referring to the synthesis of example 3, a white solid was obtained from 6D in 53% yield. MS (ESI) M/z 437.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.39(s,1H),9.21(s,1H),7.92(d,J＝8.3Hz,2H),7.88-7.79(m,2H),7.54(d,J＝8.2Hz,1H),7.36(t,J＝8.2Hz,1H),7.20-7.05(m,5H),6.94(t,J＝7.6Hz,1H),5.02(q,J＝6.5Hz,1H),4.09(q,J＝6.9Hz,2H),1.60(d,J＝6.5Hz,3H),1.35(t,J＝6.9Hz,3H)。

Example 7

Synthesis of methyl 4- ((1- ((2-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (7C)

Referring to the synthesis of 3C, 5B was reacted with 2-fluoroaniline to give a white solid in 60% yield. MS (ESI) M/z 316.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.04(s,1H),7.93(d,J＝8.7Hz,2H),7.78-7.75(m,1H),7.33-7.15(m,5H),5.20(q,J＝6.9Hz,1H),3.80(s,3H),1.59(d,J＝6.9Hz,3H)。

Synthesis of 4- ((1- ((2-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (7D)

Referring to the 3D synthesis, a white solid was prepared from 7C in 50% yield, MS (ESI) M/z 302.1[ M-H%]^-. Synthesis of N- (2-ethoxyphenyl) -4- ((1- ((2-fluorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (7)

Referring to the synthesis procedure of example 3, a white solid was obtained from 7D in 43% yield. MS (ESI) M/z 421.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.03(s,1H),9.25(s,1H),7.93(d,J＝8.8Hz,2H),7.85-7.82(m,1H),7.79-7.73(m,1H),7.35-7.05(m,7H),6.95(t,J＝7.7Hz,1H),5.21-5.13(m,1H),4.10(q,J＝6.8Hz,2H),1.64-1.53(m,3H),1.41-1.30(m,3H)。

Example 8

Synthesis of methyl 4- ((1- ((2-fluoro-3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (8C)

Referring to the synthesis of 3C, 5B was reacted with 2-fluoro-3-chloroaniline to produce a white solid with a yield of 60%. MS (ESI) M/z 350.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.23(s,1H),8.03-7.89(m,2H),7.78-7.75(m,1H),7.72-7.66(m,1H),7.42(t,J＝7.9Hz,1H),7.21(t,J＝8.2Hz,1H),6.94(t,J＝7.6Hz,1H),5.20(q,J＝6.9Hz,1H),3.70(s,3H),1.59(d,J＝6.9Hz,3H)。

Synthesis of 4- ((1- ((2-fluoro-3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (8D)

Referring to the 3D synthesis, a white solid was obtained from 8C in 52% yield, MS (ESI) M/z 336.1[ M-H ]]^-. Synthesis of N- (2-ethoxyphenyl) -4- ((1- ((2-fluoro-3-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (8)

Referring to the synthesis of example 3, a white solid was obtained from 8D in 50% yield. MS (ESI) M/z 455.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.22(s,1H),9.22(s,1H),8.05-7.90(m,2H),7.82(dd,J＝7.9,1.6Hz,1H),7.72-7.66(m,1H),7.40(t,J＝7.9Hz,1H),7.21(t,J＝8.2Hz,1H),7.18-7.05(m,4H),6.95(t,J＝7.6Hz,1H),5.17(t,J＝6.6Hz,1H),4.10(q,J＝6.9Hz,2H),1.60(d,J＝6.6Hz,3H),1.35(t,J＝6.9Hz,3H)。

Example 9

Synthesis of methyl 4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (9C)

Referring to the synthesis of 3C, 5B was reacted with 2-fluoro-4-chloroaniline to produce a white solid in 65% yield. MS (ESI) M/z 350.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.11(s,1H),8.00-7.85(m,2H),7.88-7.75(m,2H),7.72-7.65(m,2H),7.50(d,J＝10.6Hz,1H),5.15(q,J＝6.9Hz,1H),3.70(s,3H),1.59(d,J＝6.9Hz,3H)。

Synthesis of 4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (9D)

Referring to the 3D synthesis, a white solid was obtained from 9C in 52% yield, MS (ESI) M/z 336.1[ M-H ]]^-. Synthesis of N- (2-ethoxyphenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (9)

Referring to the synthesis of example 3, a white solid was obtained from 9D in 57% yield. MS (ESI) M/z 455.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.14(d,J＝4.1Hz,1H),9.22(d,J＝4.1Hz,1H),7.93(dd,J＝8.7,4.1Hz,2H),7.88-7.74(m,2H),7.52(dd,J＝10.6,4.1Hz,1H),7.33-7.24(m,1H),7.20-7.04(m,4H),7.00-6.91(m,1H),5.17(t,J＝6.7Hz,1H),4.09(q,J＝6.9Hz,2H),1.59(d,J＝6.6Hz,3H),1.35(t,J＝6.9Hz,3H)。

Example 10

Synthesis of methyl 4- ((1- ((3-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (10C)

Referring to the synthesis of 3C, 5B was reacted with 3-fluoro-4-chloroaniline to produce a white solid in 65% yield. MS (ESI) M/z 350.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.47(s,1H),8.00-7.86(m,2H),7.80(t,J＝11.8Hz,2H),7.49(t,J＝8.5Hz,1H),7.45(d,J＝8.9Hz,1H),7.39(d,J＝8.6Hz,1H),5.01(q,J＝6.5Hz,1H),3.68(s,3H),1.59(d,J＝6.5Hz,3H)。

Synthesis of 4- ((1- ((3-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (10D)

Referring to the 3D synthesis, a white solid was obtained from 10C in 52% yield, MS (ESI) M/z 336.1[ M-H ]]^-. Synthesis of N- (2-ethoxyphenyl) -4- ((1- ((3-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (10)

Referring to the synthesis of example 3, a white solid was obtained from 10D in 61% yield. MS (ESI) M/z 455.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.49(s,1H),9.18(s,1H),7.97-7.87(m,2H),7.81(t,J＝11.8Hz,2H),7.53(t,J＝8.5Hz,1H),7.45(d,J＝8.9Hz,1H),7.17-7.03(m,4H),6.94(t,J＝7.5Hz,1H),5.02(q,J＝6.5Hz,1H),4.10(q,J＝7.1Hz,2H),1.59(d,J＝6.6Hz,3H),1.35(t,J＝7.0Hz,3H)。

Example 11

Synthesis of methyl (S) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (11C)

Referring to the synthesis of 3C, 3B was reacted with 4-bromoaniline to give a white solid in 65% yield. MS (ESI) M/z 376.0[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.33(s,1H),8.01-7.90(m,2H),7.75(d,J＝7.9,Hz,1H),7.66-7.57(m,2H),7.55-7.49(m,2H),7.14(d,J＝8.9Hz,1H),5.01(q,J＝6.7Hz,1H),3.58(s,3H),1.59(d,J＝6.6Hz,3H)。

Synthesis of (S) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (11D)

Referring to the 3D synthesis, a white solid was obtained from 11C in 52% yield, MS (ESI) M/z 362.0[ M-H ]]^-。

Synthesis of (S) -N- (2-methoxyphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (11)

Referring to the synthesis procedure of example 3, a white solid was obtained from 11D in 53% yield. MS (ESI) M/z 467.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.35(s,1H),9.28(s,1H),7.93(dd,J＝9.0,2.2Hz,2H),7.77(dt,J＝7.9,2.2Hz,1H),7.66-7.59(m,2H),7.55-7.49(m,2H),7.16(dd,J＝8.9,7.4Hz,1H),7.07(d,J＝9.7Hz,3H),7.00-6.93(m,1H),5.01(d,J＝6.7Hz,1H),3.82(s,3H),1.59(d,J＝6.6Hz,3H)。

Example 12

Synthesis of methyl 4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (12C)

Referring to the synthesis of 3C, 5B was reacted with 4-bromoaniline to give a white solid in 65% yield. MS (ESI) M/z 376.0[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.32(s,1H),8.00-7.90(m,2H),7.75(d,J＝7.9,Hz,1H),7.67-7.57(m,2H),7.52-7.49(m,2H),7.14(d,J＝8.9Hz,1H),5.01(q,J＝6.7Hz,1H),3.58(s,3H),1.59(d,J＝6.6Hz,3H)。

Synthesis of 4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (12D)

Referring to the 3D synthesis, a white solid was obtained from 12C in 52% yield, MS (ESI) M/z 362.0[ M-H ]]^-. Synthesis of N- (2-methylphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (12)

Referring to the synthesis of example 3, a white solid was obtained from 12D in 50% yield. MS (ESI) M/z 451.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.35(s,1H),9.72(s,1H),8.00-7.92(m,2H),7.66-7.58(m,2H),7.51(d,J＝8.9Hz,2H),7.31(d,J＝7.8Hz,1H),7.26(d,J＝7.3Hz,1H),7.24-7.12(m,2H),7.11-7.04(m,2H),5.02(d,J＝7.0Hz,1H),2.21(s,3H),1.59(d,J＝6.9,Hz,3H)。

Example 13

Synthesis of methyl 4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (13C)

Referring to the synthesis of 3C, 5B was reacted with 4-chloroaniline to produce a white solid in 78% yield. MS (ESI) M/z 332.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.31(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝8.6Hz,2H),7.33(d,J＝8.6Hz,2H),7.05(d,J＝9.0Hz,2H),5.01(q,J＝6.8Hz,1H),3.80(s,3H),1.57(d,J＝6.7Hz,3H)。

Synthesis of 4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (13D)

Referring to the 3D synthesis, a pale yellow solid was obtained in 56% yield from 13C, MS (ESI) M/z 318.1[ M-H ]]^-。

Synthesis of N-phenyl-4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (13)

Referring to the synthesis of example 3, a white solid was obtained from 13D in 65% yield. MS (ESI) M/z 393.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.35(s,1H),10.09(s,1H),7.99-7.90(m,2H),7.82-7.72(m,2H),7.71-7.64(m,2H),7.42-7.30(m,4H),7.11-7.04(m,3H),5.02(q,J＝6.5Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 14

Synthesis of N- (2-isopropylphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (14)

Referring to the synthesis of example 3, a white solid was obtained in 55% yield from the reaction of 13D and 2-isopropylaniline. MS (ESI) M/z 435.2[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.31(s,1H),9.74(s,1H),8.01-7.88(m,2H),7.73-7.61(m,2H),7.45-7.30(m,3H),7.23(d,J＝11.0Hz,3H),7.13-7.00(m,2H),5.01(t,J＝6.7Hz,1H),3.17(d,J＝6.9Hz,1H),1.60(d,J＝6.7Hz,3H),1.14(d,J＝6.9Hz,6H)。

Example 15

Synthesis of methyl (R) -4- ((1-methoxy-1-oxopropan-2-yl) oxy) benzoate (15A)

Referring to the synthesis method of 3A, methyl 4-hydroxybenzoate was reacted with methyl L-lactate to obtain a colorless oily liquid with a yield of 68%, MS (ESI) M/z 237.1[ M-H ]]^-。

Synthesis of (R) -2- (4- (methoxycarbonyl) phenoxy) propanoic acid (15B)

Referring to the synthesis of 3B, hydrolysis of 15A gave a colorless oily liquid in 87% yield, MS (ESI) M/z:223.1[ M-H ]]^-. Synthesis of methyl (R) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (15C)

Referring to the synthesis of 3C, 15B was reacted with 4-chloroaniline to produce a white solid in 75% yield. MS (ESI) M/z 332.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.31(s,1H),7.92(d,J＝8.5Hz,2H),7.62(d,J＝8.5Hz,2H),7.33(d,J＝8.6Hz,2H),7.07(d,J＝9.0Hz,2H),5.00(q,J＝6.8Hz,1H),3.85(s,3H),1.57(d,J＝6.7Hz,3H)。

Synthesis of (R) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (15D)

Referring to the 3D synthesis, a light yellow solid was obtained from 15C in 54% yield, MS (ESI))m/z:318.1[M-H]^-。

Synthesis of (R) -N- (2-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (15)

15D (150mg, 469.13. mu. mol) was dissolved in 2mL of anhydrous dichloromethane, oxalyl chloride (178.63mg,1.41mmol) was slowly added dropwise under ice bath, 2 drops of DMF were added, the ice bath was removed, reaction was carried out at room temperature for 3 hours, the solvent and excess oxalyl chloride were removed under reduced pressure, 3mL of anhydrous dichloromethane was added and dissolved, 2-chloroaniline (59.85mg,0.47mmol) and triethylamine (189.89mg,1.88mmol) were slowly added dropwise under ice bath, the ice bath was removed, reaction was carried out at 40 ℃ for 5 hours, the solvent was removed, 20mL of water was added, ethyl acetate was extracted (3X 15mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (PE: EA: 4:1) to obtain 130mg of a white solid with a yield of 65%. MS (ESI) M/z 427.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),9.89(s,1H),8.07-7.92(m,2H),7.76-7.63(m,2H),7.55(d,J＝8.6Hz,2H),7.47-7.33(m,2H),7.27(d,J＝8.6Hz,2H),7.18-7.05(m,2H),5.05(q,J＝6.5Hz,1H),1.60(d,J＝6.6Hz,3H)。

Example 16

Synthesis of N- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (16)

Referring to the synthesis of example 15, a white solid was prepared in 55% yield from 13D and 3-chloroaniline. MS (ESI) M/z 427.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),10.24(s,1H),8.00-7.90(m,3H),7.72-7.64(m,3H),7.42-7.33(m,3H),7.14(d,J＝8.1Hz,1H),7.11-7.06(m,2H),5.03(q,J＝6.5Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 17

Synthesis of (S) -N- (4-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (17)

Referring to the synthesis of example 15, a white solid was obtained in 58% yield from the reaction of 4D and 4-chloroaniline. MS (ESI) M/z 427.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.36(s,1H),10.22(s,1H),7.98-7.89(m,2H),7.86-7.75(m,2H),7.71-7.62(m,2H),7.45-7.32(m,4H),7.13-7.01(m,2H),5.02(q,J＝6.5Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 18

Synthesis of N- (2-methyl-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (18)

Referring to the synthesis of example 15, a white solid was obtained in 60% yield from the reaction of 13D and 2-methyl-3-chloroaniline. MS (ESI) M/z 441.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.36(s,1H),9.97(s,1H),7.99-7.91(m,2H),7.68(d,J＝1.9Hz,1H),7.42-7.31(m,3H),7.31-7.27(m,2H),7.24(t,J＝7.9Hz,1H),7.10(d,J＝1.8Hz,1H),7.07(d,J＝1.8Hz,1H),5.06-4.99(m,1H),2.21(d,J＝5.7Hz,3H),1.59(dd,J＝6.8,1.7Hz,3H)。

Example 19

Synthesis of (S) -N- (2-methyl-4-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (19)

Referring to the synthesis of example 15, a white solid was obtained in 57% yield from the reaction of 4D and 2-methyl-4-chloroaniline. MS (ESI) M/z 441.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.34(s,1H),9.76(s,1H),7.99-7.90(m,2H),7.71-7.62(m,2H),7.44-7.33(m,4H),7.26(dd,J＝8.5,2.5Hz,1H),7.12-7.04(m,2H),5.02(q,J＝6.5Hz,1H),2.21(s,3H),1.59(d,J＝6.6Hz,3H)。

Example 20

Synthesis of N- (2-fluoro-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (20)

Referring to the synthesis of example 15, a white solid was prepared in 55% yield from 13D and 2-fluoro-3-chloroaniline. MS (ESI) M/z 445.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.34(s,1H),10.13(s,1H),7.95(d,J＝8.8Hz,2H),7.66(d,J＝8.7Hz,2H),7.55(dd,J＝8.4,5.1Hz,1H),7.44(dd,J＝8.4,6.7Hz,1H),7.38(d,J＝9.0,2.5Hz,2H),7.24(td,J＝8.2,7.5Hz,1H),7.09(d,J＝9.0Hz,2H),5.04(q,J＝6.6Hz,1H),1.59(dd,J＝6.6,2.2Hz,3H)。

Example 21

Synthesis of (S) -N- (2-fluoro-4-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (21)

Referring to the synthesis of example 15, a white solid was obtained in 52% yield from the reaction of 4D and 2-fluoro-4-chloroaniline. MS (ESI) M/z 445.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.31(s,1H),10.00(s,1H),7.95(t,J＝5.7Hz,2H),7.65(dd,J＝8.6,6.3Hz,2H),7.55-7.45(m,1H),7.47-7.35(m,2H),7.30(d,J＝8.6Hz,1H),7.09(d,J＝8.4Hz,3H),5.02(q,J＝6.6Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 22

Synthesis of N-cyclohexyl-4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (22)

Referring to the synthesis of example 15, a white solid was obtained in 82% yield from the reaction of 13D and cyclohexylamine. MS (ESI) M/z 399.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.27(s,1H),7.98(d,J＝7.9Hz,1H),7.80(dd,J＝8.9,4.5Hz,2H),7.66(t,J＝6.7Hz,2H),7.51-7.31(m,2H),7.15-6.93(m,2H),5.10-4.92(m,1H),3.73(s,1H),1.76(d,J＝21.9Hz,6H),1.57(t,J＝5.8Hz,3H),1.29(s,4H)。

Example 23

Synthesis of N- (tetrahydro-2H-pyran) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (23)

Referring to the synthesis of example 15, a white solid was obtained in 75% yield from the reaction of 13D and 4-aminotetrahydropyran. MS (ESI) M/z 401.1[ M-H]^-；¹H NMR(300MHz,Chloroform-d)δ(ppm)8.10(s,1H),7.78(d,J＝8.4Hz,2H),7.50(d,J＝8.5Hz,2H),7.31(d,J＝8.5Hz,2H),7.02(d,J＝8.4Hz,2H),5.92(d,J＝7.7Hz,1H),4.86(q,J＝6.7Hz,1H),4.30-4.13(m,1H),4.02(dd,J＝11.7,3.7Hz,2H),3.55(t,J＝11.8Hz,2H),2.02(dd,J＝11.8,3.7Hz,2H),1.69(d,J＝6.7Hz,3H),1.66-1.58(m,2H)。

Example 24

Synthesis of N- (1-methylpiperidin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (24)

Referring to the synthesis of example 15, a white solid was obtained in 69% yield from the reaction of 13D and 4-amino-1-methylpiperidine. MS (ESI) M/z 414.2[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.29(s,1H),8.05(d,J＝7.8Hz,1H),7.80(d,J＝8.4Hz,2H),7.65(d,J＝8.4Hz,2H),7.37(d,J＝8.5Hz,2H),6.99(d,J＝8.4Hz,2H),4.97(q,J＝6.7Hz,1H),3.67(s,1H),2.74(d,J＝11.3Hz,2H),2.15(s,3H),1.92(t,J＝11.5Hz,2H),1.72(d,J＝12.5Hz,2H),1.62-1.48(m,5H)。

Example 25

Synthesis of N- (1-tert-Butoxycarbonylpiperidin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (25)

Referring to the synthesis of example 15, a white solid was prepared in 65% yield from 13D and 1-Boc-4-aminopiperidine. MS (ESI) M/z 500.2[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.27(s,1H),8.07(d,J＝7.7Hz,1H),7.80(d,J＝8.6Hz,2H),7.65(d,J＝8.3Hz,2H),7.37(t,J＝6.0Hz,2H),7.01(d,J＝8.6Hz,2H),4.97(q,J＝6.5Hz,1H),4.07-3.85(m,3H),2.84(s,2H),1.85-1.69(m,4H),1.56(d,J＝6.6Hz,3H),1.41(s,9H)。

Example 26

Synthesis of N- (piperidin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (26)

Dissolving the compound 25(150mg,298.80 mu mol) in dichloromethane, slowly adding trifluoroacetic acid (102.21mg,896.40 mu mol) dropwise at room temperature, continuing to react for 30min at room temperature, removing the solvent by rotary evaporation under reduced pressure, adding 10mL of water for dissolving, adjusting the pH to 8 by using a 3M NaOH aqueous solution, performing suction filtration, and drying to obtain 110mg of a white solid with the yield of 92%. MS (ESI) M/z 400.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.32(s,1H),8.06(d,J＝7.8Hz,1H),7.91-7.74(m,3H),7.65(dd,J＝8.9,2.6Hz,2H),7.36(dd,J＝8.9,2.5Hz,2H),7.09-6.92(m,2H),4.97(q,J＝5.7Hz,1H),3.79(s,1H),2.94(d,J＝11.0Hz,2H),2.05-1.92(m,3H),1.70(d,J＝12.3Hz,2H),1.56(d,J＝5.9Hz,3H),1.38(d,J＝12.1Hz,2H)。

Example 27

Synthesis of (R) -N- (4-bromophenyl) -2-hydroxypropionamide (27A)

4-bromoaniline (1g,5.81mmol) was dissolved in D-lactic acid (785.45mg,8.72mmol), heated to 75 deg.C, reacted for 8h, 10mL water was added, ethyl acetate (3X 15mL) was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE: EA ═ 4:1) to give 850mg of a white solid, yield 59.8%. MS (ESI) M/z 242.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)9.79(s,1H),7.77-7.66(m,2H),7.48(dd,J＝8.9,2.0Hz,2H),5.75(d,J＝5.0Hz,1H),1.30(dd,J＝6.7,1.7Hz,3H)。

Synthesis of 4-acetoxybenzoic acid (27B)

Dissolving p-hydroxybenzoic acid (1g,7.24mmol) in 2mL of acetic anhydride, heating to 80 deg.C, reacting for 2H, cooling to room temperature, adding 5mL of water, stirring at room temperature for 30min, filtering, drying to obtain 1.1g of white solid with yield of 85%, MS (ESI) M/z:179.0[ M-H%]^-。

Synthesis of phenyl 4- (2-methylphenylcarbamoyl) acetate (27C)

Compound 27B (1g,5.15mmol) was dissolved in 5mL of anhydrous dichloromethane, oxalyl chloride (1.96g,15.45mmol) was slowly added dropwise under ice bath, 2 drops of DMF were added, the ice bath was removed, reaction was carried out at room temperature for 2h, the solvent and excess oxalyl chloride were removed under reduced pressure, dissolved in 3mL of anhydrous dichloromethane, slowly added dropwise to a dichloromethane (4mL) solution of a mixture of 2-methylaniline (549.31mg,5.13mmol) and triethylamine (2.07g,20.51mmol) under ice bath, the ice bath was removed, and reaction was carried out at room temperature for 5 h. Removing solvent, adding 20mL water, extracting with ethyl acetate (3 × 15mL), mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography (PE: EA is 4:1) to obtain white solid 1.2g, yield 82.7%, MS (ESI) M/z:268.1[ M-H ESI ]]^-。

Synthesis of N- (2-methylphenyl) -4-hydroxybenzamide (27D)

Compound 27C (1.2g,4.24mmol) was dissolved in 3mL of methanol and 3mL of tetrahydrofuranAnd adding LiOH (101.42mg,4.24mmol) into the mixed solution in batches under ice bath, removing the ice bath, reacting at room temperature for 2h, removing the solvent by rotary evaporation under reduced pressure, adding 5mL of water for dissolving, adjusting the pH value to 4 by using dilute hydrochloric acid, performing suction filtration and drying to obtain 0.89g of white solid with the yield of 92.5%. MS (ESI) M/z 226.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.05(s,1H),9.59(s,1H),7.91-7.79(m,2H),7.37-7.08(m,4H),6.90-6.80(m,2H),2.22(s,3H)。

Synthesis of (S) -N- (2-methylphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (27)

Dissolving compound 27D (100mg,440.02 μmol) and 27A (107.40mg,440.02 μmol) in anhydrous toluene, adding triphenylphosphine (138.50mg,528.02 μmol), slowly adding DIAD (133.46mg,660.03 μmol) dropwise under ice salt bath, reacting for 2h, transferring to room temperature to react for 8h, precipitating white solid, slowly adding 1mL methanol dropwise to quench, removing solvent under reduced pressure, adding 20mL water, adding ethyl acetate (3 × 15mL) to extract, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying by silica gel column chromatography (PE: EA ═ 3:1) to obtain 105mg of white solid with 52.8% yield. MS (ESI) M/z 451.1[ M-H ]]^-；¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.35(s,1H),9.72(s,1H),8.00-7.92(m,2H),7.66-7.58(m,2H),7.51(d,J＝8.9Hz,2H),7.31(d,J＝7.8Hz,1H),7.26(d,J＝7.3Hz,1H),7.24-7.12(m,2H),7.11-7.04(m,2H),5.02(d,J＝7.0Hz,1H),2.21(s,3H),1.59(d,J＝6.9,Hz,3H)。

Example 28

Synthesis of (S) -N- (4-bromophenyl) -2-hydroxypropionamide (28A)

Referring to the synthesis of 27A, a white solid was prepared in 55% yield from L-lactic acid reacted with 4-bromoaniline. MS (ESI) M/z 242.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)9.72(s,1H),7.75-7.68(m,2H),7.48(d,J＝8.9Hz,2H),5.73(d,J＝6.5Hz,1H),1.30(dd,J＝6.7,1.7Hz,3H)。

Synthesis of (R) -N- (2-methylphenyl) -4- ((1- ((4-bromophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (28)

Referring to the synthesis of example 27, from the reaction of 28A and 27D a white solid was obtained in 65% yield. MS (ESI) M/z 451.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.33(s,1H),9.72(s,1H),8.00-7.92(m,2H),7.66-7.58(m,2H),7.50(d,J＝8.9Hz,2H),7.31(d,J＝7.8Hz,1H),7.26(d,J＝7.3Hz,1H),7.22-7.12(m,2H),7.11-7.04(m,2H),5.02(d,J＝7.0Hz,1H),2.21(s,3H),1.59(d,J＝6.9,Hz,3H)。

Example 29

Synthesis of (R) -N- (4-chlorophenyl) -2-hydroxypropionamide (29A)

Referring to the synthesis of 27A, a white solid was prepared from D-lactic acid and 4-chloroaniline in 55% yield. MS (ESI) M/z 198.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)9.82(s,1H),7.75-7.66(m,2H),7.48(dd,J＝8.9,2.5Hz,2H),5.75(d,J＝6.5Hz,1H),1.30(dd,J＝6.7,1.7Hz,3H)。

Synthesis of (S) -N- (2-methylphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (29)

Referring to the synthesis procedure of example 27, a white solid was obtained in 60% yield from the reaction of 29A and 27D. MS (ESI) M/z 407.1[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.39(s,1H),9.70(s,1H),8.03-7.95(m,2H),7.66-7.58(m,2H),7.50(d,J＝8.9Hz,2H),7.31(d,J＝7.8Hz,1H),7.26(d,J＝7.3Hz,1H),7.20-7.10(m,2H),7.11-7.04(m,2H),5.00(d,J＝7.0Hz,1H),2.19(s,3H),1.59(d,J＝6.9,Hz,3H).

Example 30

Synthesis of (S) -N- (4-chlorophenyl) -2-hydroxypropionamide (30A)

Referring to the synthesis of 27A, a white solid was prepared in 55% yield from L-lactic acid reacted with 4-chloroaniline. MS (ESI) M/z 198.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)9.82(s,1H),7.75-7.66(m,2H),7.48(dd,J＝8.9,2.5Hz,2H),5.75(d,J＝6.5Hz,1H),1.30(dd,J＝6.7,1.7Hz,3H)。

Synthesis of (R) -N- (2-methylphenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (30)

Referring to the synthesis of example 27, a white solid was obtained in 58% yield from the reaction of 27D and 30A. MS (ESI) M/z 407.1[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.39(s,1H),9.70(s,1H),8.03-7.95(m,2H),7.66-7.58(m,2H),7.50(d,J＝8.9Hz,2H),7.31(d,J＝7.8Hz,1H),7.26(d,J＝7.3Hz,1H),7.20-7.10(m,2H),7.11-7.04(m,2H),5.00(d,J＝7.0Hz,1H),2.19(s,3H),1.59(d,J＝6.9,Hz,3H)。

Example 31

Synthesis of phenyl 4- (3-chlorophenylcarbamoyl) acetate (31C)

Referring to the synthesis of 27C, 27B was reacted with 3-chloroaniline to give a pale yellow solid in 80.6% yield, MS (ESI) M/z 288.0[ M-H ]]^-。

Synthesis of N- (3-chlorophenyl) -4-hydroxybenzamide (31D)

Reference to the synthesis of 27D, hydrolysis from 31C gave 89% yield of a white solid, MS (ESI) M/z 246.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.15(s,1H),7.96(t,J＝2.1Hz,1H),7.94-7.81(m,2H),7.69(dd,J＝8.3,1.9Hz,1H),7.36(t,J＝8.1Hz,1H),7.13(dd,J＝7.9,2.1Hz,1H),6.97-6.83(m,2H)。

Synthesis of (S) -N- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (31)

Referring to the synthesis of example 27, a white solid was obtained in 58% yield from the reaction of 29A and 31D. MS (ESI))m/z:427.1[M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),10.24(s,1H),8.00-7.90(m,3H),7.72-7.64(m,3H),7.42-7.33(m,3H),7.14(d,J＝8.1Hz,1H),7.10-7.06(m,2H),5.00(q,J＝6.5Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 32

Synthesis of (R) -N- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (32)

Referring to the synthesis of example 27, a white solid was obtained in 55% yield from the reaction of 30A and 31D. MS (ESI) M/z 427.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.33(s,1H),10.22(s,1H),8.00-7.90(m,3H),7.72-7.64(m,3H),7.42-7.33(m,3H),7.14(d,J＝8.1Hz,1H),7.10-7.06(m,2H),5.00(q,J＝6.5Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 33

Synthesis of methyl 4- ((2-methyl-1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoate (33C)

2B was condensed with 4-chloroaniline according to the synthesis procedure of example 2C to give a white solid with a yield of 65%. MS (ESI) M/z 346.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.12(s,1H),7.98-7.89(m,2H),7.65-7.57(m,2H),7.55-7.43(m,2H),7.04-6.92(m,2H),3.79(s,3H),1.50(s,6H)。

Synthesis of 4- ((2-methyl-1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (33D)

Referring to the synthesis of example 2D, hydrolysis of 33C gave a white solid in 68% yield, MS (ESI) M/z 332.1[ M-H ]]^-。

Synthesis of N- (3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (33)

Referring to the synthesis of example 2, a white solid was obtained from 33D in 50% yield. MS (ESI) M/z 441.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.22(s,1H),10.17(s,1H),7.95-7.83(m,3H),7.67(dd,J＝14.5,8.6Hz,3H),7.34(d,J＝7.6Hz,3H),7.11(d,J＝8.0Hz,1H),6.99(d,J＝8.4Hz,2H),1.60(s,6H)。

Example 34

Synthesis of N- (2-fluoro-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (34)

Referring to the synthesis of example 2, a white solid was obtained in 52% yield from the reaction of 33D and 2-fluoro-3-chloroaniline. MS (ESI) M/z 459.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.19(s,1H),10.13(s,1H),7.92(d,J＝8.7Hz,2H),7.78-7.67(m,2H),7.60-7.49(m,1H),7.49-7.33(m,3H),7.29-7.19(m,1H),7.10-6.98(m,2H),1.62(s,6H)。

Example 35

Synthesis of N- (2-methyl-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (35)

Referring to the synthesis of example 2, a white solid was prepared in 56% yield from 33D and 2-methyl-3-chloroaniline. MS (ESI) M/z 455.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.20(s,1H),9.97(s,1H),8.00-7.89(m,2H),7.79-7.68(m,2H),7.36(d,J＝9.4Hz,3H),7.31-7.19(m,2H),7.08-6.97(m,2H),2.22(s,3H),1.62(s,6H)。

Example 36

Synthesis of (R) -N- (2-fluoro-4-chlorophenyl) -2-hydroxypropionamide (36A)

Referring to the synthesis of 27A, a white solid was prepared from D-lactic acid and 2-fluoro-4-chloroaniline with a yield of 60%. MS (ESI) M/z 216.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)9.88(s,1H),7.73-7.66(m,1H),7.52(d,J＝8.9Hz,2H),5.60(d,J＝6.5Hz,1H),1.30(d,J＝6.7Hz,3H)。

Synthesis of (S) -N- (3-chlorophenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (36)

Referring to the synthesis of example 27, a white solid was obtained in 65% yield from the reaction of 36A and 31D. MS (ESI) M/z 445.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)δ10.24(s,1H),10.11(s,1H),7.99-7.91(m,3H),7.77(t,J＝8.6Hz,1H),7.69(d,J＝8.2Hz,1H),7.51(dd,J＝10.5,2.3Hz,1H),7.37(t,J＝8.1Hz,1H),7.28(dd,J＝8.7,2.1Hz,1H),7.13(d,J＝10.8Hz,1H),7.09(d,J＝8.6Hz,2H),5.17(q,J＝6.5Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 37

Synthesis of (S) -N- (2-methylphenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (37)

Referring to the synthesis of example 27, from 36A and 27D a white solid was obtained in 65% yield. MS (ESI) M/z 425.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.10(s,1H),9.70(s,1H),8.03-7.89(m,2H),7.77(q,J＝7.8Hz,1H),7.51(dt,J＝9.9,5.1Hz,1H),7.37-7.12(m,5H),7.11-7.01(m,2H),5.16(q,J＝6.7Hz,1H),2.21(d,J＝6.8Hz,3H),1.59(d,J＝6.7Hz,3H)。

Example 38

Synthesis of phenyl 4- (2-fluoro-3-chlorophenylcarbamoyl) acetate (38C)

Referring to the synthesis of 27C, 27B was reacted with 2-fluoro-3-chloroaniline to give a pale yellow solid in 85% yield, MS (ESI) M/z 306.0[ M-H ]]^-。

Synthesis of N- (2-fluoro-3-chlorophenyl) -4-hydroxybenzamide (38D)

Reference to the synthesis of 27D, hydrolysis of 38C gave 89% yield of a white solid, MS (ESI) M/z 246.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.19(s,1H),10.01(s,1H),7.86(d,J＝8.4Hz,2H),7.63-7.50(m,1H),7.49-7.38(m,1H),7.29-7.17(m,1H),6.87(d,J＝8.4Hz,2H)。

Synthesis of (S) -N- (2-fluoro-3-chlorophenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (38)

Referring to the synthesis of example 27, from 36A and 38D a white solid was obtained in 56% yield. MS (ESI) M/z 463.1[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.12(s,2H),7.96(d,J＝8.4Hz,2H),7.77(t,J＝8.5Hz,1H),7.54(q,J＝10.2,8.8Hz,2H),7.44(t,J＝7.4Hz,1H),7.25(q,J＝8.0Hz,2H),7.09(d,J＝8.3Hz,2H),5.17(q,J＝6.9Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 39

Synthesis of phenyl 4- (phenylcarbamoyl) acetate (39C)

Referring to the synthesis of 27C, 27B was reacted with aniline to produce a white solid in 85% yield, MS (ESI) M/z 254.1[ M-H ]]^-。

Synthesis of N-phenyl-4-hydroxybenzamide (39D)

According to the synthesis of 27D, a white solid was obtained by hydrolysis of 39C in 95% yield, MS (ESI) M/z 212.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.12(s,1H),10.00(s,1H)7.87(dd, J ═ 10.0,3.8Hz,2H),7.76(d, J ═ 8.0Hz,2H),7.33(t, J ═ 7.9Hz,2H),7.08(q, J ═ 7.5Hz,1H),6.98-6.82(m, 2H). Synthesis of (S) -N-phenyl-4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (39)

Referring to the synthesis procedure of example 27, from the reaction of 29A and 39D, a white solid was obtained in 63% yield. MS (ESI) M/z 393.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.35(s,1H),10.09(s,1H),7.99-7.90(m,2H),7.82-7.72(m,2H),7.71-7.64(m,2H),7.42-7.30(m,4H),7.10-7.04(m,3H),5.02(q,J＝6.5Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 40

Synthesis of phenyl 4- (2-chlorophenylcarbamoyl) acetate (40C)

Referring to the synthesis of 27C, 27B was reacted with 2-chloroaniline to give a white solid in 83% yield, MS (ESI) M/z 288.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.11(s,1H),8.04(d,J＝8.4Hz,2H),7.63-7.53(m,2H),7.41(t,J＝7.3Hz,1H),7.36-7.27(m,3H),2.32(s,3H)。

Synthesis of N- (2-chlorophenyl) -4-hydroxybenzamide (40D)

According to the synthesis of 27D, a white solid was obtained by hydrolysis of 40C in 95% yield, MS (ESI) M/z 246.0[ M-H ]]^-. Synthesis of (S) -N- (2-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (40)

Referring to the synthesis of example 27, a white solid was obtained in 65% yield from the reaction of 29A and 40D. MS (ESI) M/z 427.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),9.89(s,1H),8.07-7.92(m,2H),7.76-7.63(m,2H),7.55(d,J＝8.6Hz,2H),7.47-7.33(m,2H),7.27(d,J＝8.6Hz,2H),7.18-7.05(m,2H),5.05(q,J＝6.5Hz,1H),1.60(d,J＝6.6Hz,3H)。

EXAMPLE 41

Synthesis of phenyl 4- (2-methyl-3-chlorophenylcarbamoyl) acetate (41C)

Referring to the synthesis of 27C, 27B was reacted with 2-methyl-3-chloroaniline to give a white solid in 83% yield, MS (ESI) M/z 302.1[ M-H ]]^-。

Synthesis of N- (2-methyl-3-chlorophenyl) -4-hydroxybenzamide (41D)

According to the synthesis of 27D, white solid was obtained by hydrolysis of 41C in 95% yield and MS (ESI) M/z 260.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.13(s,1H),9.88(s,1H),7.87(dd,J＝8.6,1.8Hz,2H),7.35(dd,J＝7.6,1.7Hz,1H),7.32-7.20(m,2H),6.92-6.83(m,2H),2.23(s,3H)。

Synthesis of (S) -N- (2-methyl-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (41)

Referring to the synthesis procedure of example 27, a white solid was obtained in 60% yield from the reaction of 29A and 41D. MS (ESI) M/z 441.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.36(s,1H),9.97(s,1H),7.98-7.90(m,2H),7.68(d,J＝1.9Hz,1H),7.42-7.31(m,3H),7.31-7.27(m,2H),7.24(t,J＝7.9Hz,1H),7.10(d,J＝1.8Hz,1H),7.07(d,J＝1.8Hz,1H),5.06-4.99(m,1H),2.21(d,J＝5.7Hz,3H),1.59(d,J＝6.8Hz,3H)。

Example 42

Synthesis of (S) -N- (2-fluoro-3-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (42)

Referring to the synthesis of example 27, from the reaction of 29A and 38D, a white solid was obtained in 67% yield. MS (ESI) M/z 445.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),10.13(s,1H),7.95(d,J＝8.8Hz,2H),7.66(d,J＝8.7Hz,2H),7.55(dd,J＝8.4,5.1Hz,1H),7.44(dd,J＝8.4,6.7Hz,1H),7.38(d,J＝9.0,2.5Hz,2H),7.24(td,J＝8.2,7.5Hz,1H),7.09(d,J＝9.0Hz,2H),5.04(q,J＝6.6Hz,1H),1.59(dd,J＝6.6,2.2Hz,3H)。

Example 43

Synthesis of phenyl 4- (2- (trifluoromethyl) phenylcarbamoyl) acetate (43C)

Referring to the synthesis of 27C, 27B was reacted with 2- (trifluoromethyl) aniline to produce a white solid in 84% yield, MS (ESI) M/z 322.1[ M-H ]]^-。

Synthesis of N- (2- (trifluoromethyl) phenyl) -4-hydroxybenzamide (43D)

According to the synthesis of 27D, hydrolysis of 43C gave a white solid in 95% yield, MS (ESI) M/z 280.1[ M-H ]]^-.¹H NMR(300MHz,Chloroform-d)δ(ppm)8.43(d,J＝8.3Hz,1H),8.20(s,1H),7.93(dd,J＝9.0,2.4Hz,2H),7.78-7.59(m,2H),7.41-7.23(m,4H)。

Synthesis of (S) -N- ((2-trifluoromethyl) phenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (43)

Referring to the synthesis of example 27, the reaction of 29A and 43D gave a white solid in 65% yield. MS (ESI) M/z 461.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.32(s,1H),9.95(s,1H),7.93(d,J＝8.3Hz,2H),7.78(d,J＝7.9Hz,2H),7.67(d,J＝8.5Hz,2H),7.51(d,J＝7.7Hz,2H),7.38(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),5.02(q,J＝6.5Hz,1H),1.59(d,J＝6.4Hz,3H)。

Example 44

Synthesis of phenyl 4- (2-fluoro-5-chlorophenylcarbamoyl) acetate (44C)

Referring to the synthesis of 27C, 27B was reacted with 2-fluoro-5-chloroaniline to give a white solid with a yield of 80%，MS(ESI)m/z:322.1[M-H]^-。

Synthesis of N- (2-fluoro-5-chlorophenyl) -4-hydroxybenzamide (44D)

According to the synthesis of 27D, hydrolysis of 44C gave a white solid in 95% yield, MS (ESI) M/z 280.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.16(s,1H),9.98-9.86(m,1H),7.84(dq,J＝11.0,6.4Hz,2H),7.73(dd,J＝9.2,6.4Hz,1H),7.31(d,J＝6.7Hz,2H),6.86(d,J＝10.4Hz,2H)。

Synthesis of (S) -N- (2-fluoro-5-chlorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (44)

Referring to the synthesis of example 27, from the reaction of 29A and 44D, a white solid was obtained in 60% yield. MS (ESI) M/z 445.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.32(s,1H),10.05(s,1H),7.94(d,J＝8.5Hz,2H),7.75(dd,J＝6.6,2.4Hz,1H),7.66(d,J＝8.5Hz,2H),7.44-7.27(m,4H),7.09(d,J＝8.5Hz,2H),5.02(q,J＝6.5Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 45

Synthesis of methyl 4- ((1- ((5-chloropyridin-2-yl) amino) -1-oxopropan-2-yl) oxy) benzoate (45C)

Referring to the synthesis of 3C, 5B was reacted with 2-amino-5-chloropyridine to give a white solid in 60% yield. MS (ESI) M/z 333.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.90(s,1H),8.06-7.98(m,1H),7.57-7.49(m,2H),7.38(d,J＝8.6Hz,2H),7.06-6.97(m,2H),5.01(q,J＝6.9Hz,1H),3.83(s,3H),1.56(d,J＝6.9Hz,3H).

Synthesis of 4- ((1- ((5-chloropyridin-2-yl) amino) -1-oxopropan-2-yl) oxy) benzoic acid (45D)

Referring to the 3D synthesis, a white solid was prepared from 45C in 50% yield, MS (ESI) M/z 319.1[ M-H%]^-. N- (2-methylphenyl) -4- ((1- ((5-chloropyridin-2-yl) amino) -1-oxopropan-2-yl) oxy) phenylmethylSynthesis of amide (45)

Referring to the synthesis of example 3, a white solid was obtained from 45D in 32% yield. MS (ESI) M/z 408.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.98(s,1H),9.61(s,1H),8.06(d,J＝8.8Hz,1H),7.94(d,J＝9.0Hz,2H),7.51-7.25(m,4H),7.25-6.98(m,4H),5.05(q,J＝6.4Hz,1H),2.09(d,J＝4.5Hz,3H),1.53(d,J＝6.5Hz,3H)。

Example 46

Synthesis of (S) -N- (3-chlorophenyl) -4- ((1- ((6-chloropyridin-3-yl) amino) -1-oxopropan-2-yl) oxy) benzamide (46)

Referring to the synthesis of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 2-chloro-5-aminopyridine and 3-chloroaniline, respectively, to obtain a white solid in 58% yield. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),10.14(s,1H),8.80(t,J＝2.7Hz,1H),8.26(dt,J＝8.9,2.7Hz,1H),7.72-7.64(m,3H),7.50(d,J＝8.7Hz,1H),7.42-7.33(m,2H),7.14(d,J＝8.1Hz,1H),7.10-7.06(m,2H),5.00(q,J＝6.5Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 47

Synthesis of phenyl 4- (6-chloropyridin-2-ylcarbamoyl) acetate (47C)

Referring to the synthesis of 27C, 27B was reacted with 2-amino-6-chloropyridine to give a white solid in 73% yield, MS (ESI) M/z 289.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)11.13(s,1H),8.19(d,J＝7.9Hz,1H),8.14-8.05(m,2H),7.91(t,J＝7.8Hz,1H),7.36-7.24(m,3H),2.37-2.26(m,3H)。

Synthesis of N- (6-chloropyridin-2-yl) -4-hydroxybenzamide (47D)

According to the synthesis of 27D, hydrolysis of 47C gave a white solid in 95% yield, MS (ESI) M/z 247.0[ M-H ]]^-. Synthesis of (S) -N- (6-chloropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (47)

Referring to the synthesis of example 27, 29A and 47D reacted to give a white solid in 50% yield. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.90(s,1H),10.31(s,1H),8.19(d,J＝7.9Hz,1H),8.14-8.05(m,2H),7.91(t,J＝7.8Hz,1H),7.77(d,J＝8.1Hz,2H),7.43-7.33(m,3H),7.23(d,J＝8.1Hz,2H),5.02(q,J＝6.4Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 48

Synthesis of phenyl 4- (2-chloropyridin-4-ylcarbamoyl) acetate (48C)

Referring to the synthesis of 27C, 27B was reacted with 2-chloro-4-aminopyridine to give a white solid in 55% yield, MS (ESI) M/z 289.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.82(s,1H),8.33(d,J＝5.7Hz,1H),8.07-7.99(m,2H),7.95(d,J＝1.8Hz,1H),7.74(dd,J＝5.7,1.9Hz,1H),7.35(d,J＝8.7Hz,2H),2.32(s,3H)。

Synthesis of N- (2-chloropyridin-4-yl) -4-hydroxybenzamide (48D)

According to the synthesis of 27D, hydrolysis of 48C gave a white solid in 93% yield, MS (ESI) M/z 247.0[ M-H ]]^-. Synthesis of (S) -N- (2-chloropyridin-4-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (48)

Referring to the synthesis procedure of example 27, the reactions of 29A and 48D produced white solids with 53% yield. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.82(s,1H),10.33(s,1H),8.33(d,J＝5.7Hz,1H),8.07-7.98(m,2H),7.95(d,J＝1.8Hz,1H),7.79(d,J＝8.0Hz,2H),7.74(dd,J＝5.7,1.9Hz,1H),7.40-7.31(m,2H),7.23(d,J＝8.0Hz,2H),5.00(q,J＝6.4Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 49

Synthesis of phenyl 4- (5-chloropyridin-3-ylcarbamoyl) acetate (49C)

Referring to the synthesis of 27C, 27B was reacted with 3-chloro-5-aminopyridine to give a white solid in 54% yield, MS (ESI) M/z 289.1[ M-H ]]^-。

Synthesis of N- (5-chloropyridin-3-yl) -4-hydroxybenzamide (49D)

According to the synthesis of 27D, hydrolysis of 49C gave a white solid in 95% yield, MS (ESI) M/z 247.0[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.36(s,1H),10.21(s,1H),8.86(d,J＝2.1Hz,1H),8.43-8.30(m,2H),7.95-7.81(m,2H),6.99-6.83(m,2H)。

Synthesis of (S) -N- (5-chloropyridin-3-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (49)

Referring to the synthesis of example 27, from the reaction of 29A and 49D, a white solid was obtained in 53% yield. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.95(s,1H),10.35(s,1H),8.35-8.27(m,1H),8.07-7.98(m,2H),7.96-7.90(m,1H),7.79(d,J＝8.0Hz,2H),7.67(dd,J＝5.0,1.9Hz,1H),7.40-7.31(m,2H),7.23(d,J＝8.0Hz,2H),5.10(q,J＝6.4Hz,1H),1.65(d,J＝6.5Hz,3H)。

Example 50

Synthesis of phenyl 4- (4-chloropyridin-2-ylcarbamoyl) acetate (50C)

Referring to the synthesis of 27C, 27B was reacted with 2-amino-4-chloropyridine to give a pale yellow solid in 34% yield, MS (ESI) M/z 289.1[ M-H ]]^-；¹H NMR(300MHz,Chloroform-d)δ(ppm)8.61(s,1H),8.50(d,J＝1.9Hz,1H),8.20(d,J＝5.3Hz,1H),8.05-7.93(m,2H),7.28(dd,J＝6.3,2.3Hz,2H),7.11(dd,J＝5.4,2.0Hz,1H),2.36(s,3H)。

Synthesis of N- (4-chloropyridin-2-yl) -4-hydroxybenzamide (50D)

According to the synthesis of 27D, white solid was obtained by hydrolysis at 50C, yield 91%, MS (ESI) M/z 247.0[ M-H ]]^-. Synthesis of (S) -N- (4-chloropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (50)

Referring to the synthesis of example 27, a white solid was obtained in 55% yield from the reaction of 29A and 50D. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.75(s,1H),9.79(s,1H),8.36(d,J＝5.4Hz,1H),8.29(d,J＝2.0Hz,1H),7.94(d,J＝8.2Hz,2H),7.76(d,J＝8.4Hz,3H),7.35(d,J＝8.4Hz,2H),7.27(dd,J＝5.3,1.9Hz,1H),6.84(d,J＝8.3Hz,3H),5.75(q,J＝6.4Hz,1H),1.30(d,J＝6.5Hz,3H).

Example 51

Synthesis of (S) -N- (3-chlorophenyl) -6- (((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) nicotinamide (51)

Referring to the synthesis method of example 27, p-hydroxybenzoic acid, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 6-hydroxynicotinic acid, 4-chloroaniline and 3-chloroaniline, respectively, to obtain a white solid in a yield of 50%. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.75(s,1H),9.75(s,1H),8.56-8.45(m,1H),8.29-8.15(m,2H),7.74(d,J＝8.1Hz,2H),7.85(d,J＝8.4Hz,2H),7.46-7.32(m,3H),7.20(d,J＝7.7Hz,1H),5.73(q,J＝6.4Hz,1H),1.30(d,J＝6.5Hz,3H)。

Example 52

Synthesis of 5-acetoxypicolinic acid (52B)

Referring to the synthesis of 27B, a dark brown solid powder was prepared from 5-hydroxypicolinic acid in 89% yield, MS (ESI) M/z 180.0[ M-H ]]^-。

Synthesis of 6- ((3-chlorophenyl) carbamoyl) pyridin-3-yl acetate (52C)

With reference to the synthesis of 27C, a pale yellow solid powder was obtained from 52B in 56% yield, MS (ESI) M/z 289.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.82(s,1H),8.60(t,J＝2.7Hz,1H),8.29-8.19(m,1H),8.11(q,J＝2.5Hz,1H),7.89(d,J＝13.7Hz,2H),7.46-7.35(m,1H),7.18(dq,J＝7.4,2.1Hz,1H),2.37(d,J＝2.4Hz,3H)。

Synthesis of N- (3-chlorophenyl) -5-hydroxypyridine-carboxamide (53D)

With reference to the synthesis of 27D, a pale yellow solid powder was obtained from 52C in 89% yield, MS (ESI) M/z 247.0[ M-H ]]^-Synthesis of (S) -N- (3-chlorophenyl) -5- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) pyridinamide (52)

Referring to the synthesis of example 27, 29A and 53D reacted to give a white solid in 50% yield. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.82(s,1H),9.79(s,1H),8.60(t,J＝2.7Hz,1H),8.29-8.19(m,1H),8.11(q,J＝2.5Hz,1H),7.89(dd,J＝13.7,8.3Hz,2H),7.77(d,J＝8.1Hz,2H),7.46-7.30(m,3H),7.18(d,J＝7.4Hz,1H),5.78(q,J＝6.4Hz,1H),1.31(d,J＝6.5Hz,3H)。

Example 53

Synthesis of (S) -N- ((3-trifluoromethyl) phenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (53)

Referring to the synthesis of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 4-chloroaniline and 3- (trifluoromethyl) aniline, respectively, to obtain a white solid in 60% yield. MS (ESI) M/z 461.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.34(s,1H),10.21(s,1H),8.05-7.95(m,3H),7.72-7.65(m,3H),7.40-7.33(m,3H),7.14(d,J＝8.5Hz,1H),7.10-7.05(m,2H),5.00(q,J＝6.6Hz,1H),1.57(d,J＝6.6Hz,3H)。

Example 54

Synthesis of (S) -N- (2-methyl-3-chlorophenyl) -4- ((1- ((2-fluoro-4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (54)

Referring to the synthesis procedure of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 2-fluoro-4-chloroaniline and 2-methyl-3-chloroaniline, respectively, to obtain a white solid in a yield of 65%. MS (ESI) M/z 459.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)δ10.22(s,1H),10.01(s,1H),7.97-7.90(m,3H),7.74(t,J＝8.6Hz,1H),7.65(d,J＝8.2Hz,1H),7.51(d,J＝10.5Hz,1H),7.37(t,J＝8.1Hz,1H),7.28(dd,J＝8.7,2.1Hz,1H),7.15(d,J＝10.8Hz,1H),7.09(d,J＝8.6Hz,2H),5.17(q,J＝6.5Hz,1H),2.21(d,J＝6.8Hz,3H),1.59(d,J＝6.5Hz,3H)。

Example 55

Synthesis of (S) -N- (3-fluorophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (55)

Referring to the synthesis method of example 27, 4-bromoaniline and 2-methylaniline in example 27 were replaced with 4-chloroaniline and 3-fluoroaniline, respectively, to obtain a white solid in a yield of 57%. MS (ESI) M/z 411.1[ M-H]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.40(s,1H),10.25(s,1H),8.08-7.97(m,3H),7.75-7.67(m,3H),7.40-7.33(m,3H),7.14(d,J＝8.5Hz,1H),7.10-7.05(m,2H),5.11(q,J＝6.6Hz,1H),1.57(d,J＝6.6Hz,3H)。

Example 56

Synthesis of (S) -N- (3-chlorophenyl) -4- ((1- ((4-cyanophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (56)

Referring to the synthesis of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 4-cyanoaniline and 3-chloroaniline, respectively, to obtain a white solid in 55% yield. MS (ESI) M/z 418.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.33(s,1H),10.22(s,1H),8.00-7.90(m,3H),7.72-7.64(m,3H),7.42-7.33(m,3H),7.14(d,J＝8.1Hz,1H),7.10-7.06(m,2H),5.00(q,J＝6.5Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 57

Synthesis of (S) -N- (3-cyanophenyl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (57)

Referring to the synthesis of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 4-chloroaniline and 3-cyanoaniline, respectively, to obtain a white solid in 58% yield. MS (ESI) M/z 418.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.33(s,1H),10.22(s,1H),8.00-7.90(m,3H),7.73-7.64(m,3H),7.42-7.35(m,3H),7.14(d,J＝8.1Hz,1H),7.11-7.06(m,2H),5.00(q,J＝6.5Hz,1H),1.60(d,J＝6.6Hz,3H)。

Example 58

Synthesis of N- (3-chlorophenyl) -4- ((1- ((6-chloropyridin-3-yl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (58)

Referring to the synthesis of example 2, 4-bromoaniline and 2-ethoxyaniline of example 2 were replaced with 2-chloro-5-aminopyridinePyridine and 3-chloroaniline, a white solid was obtained in 43% yield. MS (ESI) M/z 442.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.22(s,1H),10.17(s,1H),8.05-7.95(m,2H),7.67(dd,J＝14.5,8.6Hz,3H),7.34(d,J＝7.6Hz,3H),7.11(d,J＝8.0Hz,1H),7.01(d,J＝8.4Hz,2H),1.60(s,6H)。

Example 59

Synthesis of N- (6-chloropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (59)

Referring to the synthesis of example 2, 4-bromoaniline and 2-ethoxyaniline of example 2 were replaced with 4-chloroaniline and 2-amino-6-chloropyridine, respectively, to prepare a white solid with a yield of 40%. MS (ESI) M/z 442.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.85(s,1H),10.25(s,1H),7.98-7.85(m,3H),7.67(d,J＝8.6Hz,3H),7.31(d,J＝7.6Hz,2H),7.11(d,J＝8.0Hz,1H),6.99(d,J＝8.4Hz,2H),1.60(s,6H)。

Example 60

Synthesis of N- (6-fluoropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -2-methyl-1-oxopropan-2-yl) oxy) benzamide (60)

Referring to the synthesis of example 2, 4-bromoaniline and 2-ethoxyaniline of example 2 were replaced with 4-chloroaniline and 2-amino-6-fluoropyridine, respectively, to obtain a white solid with a yield of 40%. MS (ESI) M/z 426.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.80(s,1H),10.05(s,1H),7.95-7.86(m,3H),7.77(d,J＝8.6Hz,3H),7.35(d,J＝7.6Hz,2H),7.11(d,J＝8.0Hz,1H),6.89(d,J＝8.4Hz,2H),1.60(s,6H)。

Example 61

Synthesis of (S) -N- (6-fluoropyridin-2-yl) -4- ((1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) oxy) benzamide (61)

Referring to the synthesis procedure of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 4-chloroaniline and 2-amino-6-fluoropyridine, respectively, to obtain a white solid in a yield of 50%. MS (ESI) M/z 412.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.91(s,1H),10.33(s,1H),8.25(d,J＝7.9Hz,1H),8.15-8.05(m,2H),7.91(t,J＝7.8Hz,1H),7.78(d,J＝8.1Hz,2H),7.43-7.33(m,3H),7.25(d,J＝8.1Hz,2H),5.05(q,J＝6.4Hz,1H),1.59(d,J＝6.5Hz,3H)。

Example 62

Synthesis of (S) -N- (3-chlorophenyl) -4- ((1- ((5-chloropyridin-2-yl) amino) -1-oxopropan-2-yl) oxy) benzamide (62)

Referring to the synthesis of example 27, 4-bromoaniline and 2-methylaniline from example 27 were replaced with 2-amino-5-chloropyridine and 3-chloroaniline, respectively, to obtain a white solid in 55% yield. MS (ESI) M/z 428.1[ M-H ]]^-；¹H NMR(300MHz,DMSO-d₆)δ(ppm)10.37(s,1H),10.15(s,1H),8.80(t,J＝2.7Hz,1H),8.28(d,J＝8.9Hz,1H),7.72-7.66(m,3H),7.50(d,J＝8.7Hz,1H),7.44-7.33(m,2H),7.14(d,J＝8.1Hz,1H),7.10-7.05(m,2H),5.00(q,J＝6.5Hz,1H),1.59(d,J＝6.6Hz,3H)。

Example 63 HeLa cell-based IDO1 inhibitory Activity test

1. Experimental materials and main instruments

HeLa cell line: ATCC, centrifuge: eppendorf (CHINA), electric heating constant temperature forced air drying oven (DHG-924385-III): shanghai New Miao medical device manufacturing Co., Ltd., acetic acid (glacial acetic acid): nanjing chemical reagents, Inc., trifluoroacetic acid: shanghai Linfeng Chemicals, ltd, electronic balance: sartorius, p-dimethylaminobenzaldehyde (CAS: 100-10-7): aladdin, Recombinant Human IFN-. gamma. (Catalog # AF-300-02): PEPROTECH.

2. Experimental methods

HeLa cells purchased from ATCC were stored in minimal basal medium (2mM L-glutamine and Earle's BSS adjusted to contain 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acids, 1mM sodium cuprate and 10% fetal bovine serum). HeLa cells were stored at 37 ℃ to provide 5% CO₂In a humidity-controlled incubator. The experiment was set up for a blank group, a model group (IFN-. gamma. + L-tryptophan) and an add group (IFN-. gamma. + L-tryptophan + test compound).

By 5X 10³Cell/well density HeLa cells were seeded in 96-well culture plates and cultured overnight. The next day, serial dilutions (total volume 200. mu.L of medium) containing IFN-. gamma. (final concentration 100ng/mL), L-tryptophan (final concentration 100. mu.M) and compound were added to the cells. After 24 hours of incubation, 140. mu.L of supernatant/well was transferred to a new 96-well plate, 10. mu.L of 6.1mol/L trichloroacetic acid was added, and incubated at 50 ℃ for 30min in a constant temperature oven to hydrolyze the produced N-formyl kynurenine to kynurenine. The reaction mixture was then centrifuged at 4000rpm for 10min to remove the precipitate. 100 μ L of supernatant/well was transferred to another 96-well plate and mixed with an equal volume of 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid. The absorbance was measured using a microplate reader at 490nm and the results were processed using GraphPad Prism software. Each concentration was plated in 3 duplicate wells and the experiment was repeated three times.

The inhibition rate (%) of the enzyme activity of IDO1 is [ (model group-adding medicine group)/(model group-blank group) ] × 100%

Furthermore, the survival rate of HeLa cells of each group was examined by the MTT method in order to investigate whether the compound inhibited IDO1 activity by inhibiting HeLa cell proliferation.

The method comprises the following specific operations: in the experiment based on the IDO1 inhibitory activity of HeLa cells, 140 μ L of supernatant per well was pipetted into a 96-well plate, 20 μ L of 4mg/mL MTT solution per well was added to the cell incubator, the incubation was terminated at 37 ℃ for 4 hours, and the culture solution in the wells was aspirated after centrifugation. Add 200. mu.L of dimethyl sulfoxide into each well, and shake for 10min at low speed on a shaking bed to dissolve the crystals sufficiently. The absorbance of each well was measured at 570nm in an enzyme linked immunosorbent assay.

Cell survival (%). group OD value/blank OD value X100%

3. Results of the experiment

The inhibition rate, IC, of the test compound is calculated according to the formula₅₀The percent inhibition and logarithmic concentration values were plotted and the results are shown in Table 1. The values indicated as "A" in Table 1 represent IC₅₀Less than 1 nM; the value indicated as "B" represents IC₅₀Between 1nM and 10 nM; the value indicated as "C" represents IC₅₀Greater than 10nM and less than 100 nM; the value indicated as "D" represents IC₅₀Between 100nM and 1 μ M; the value indicated as "E" represents IC₅₀Greater than 1 μ M.

TABLE 1 Effect of the Compounds of the present invention on HeLa cell proliferation and IDO1 Activity

^aIndicating the survival rate of HeLa cells at a concentration of 10 μ M;^bthe viability of HeLa cells at a concentration of 1. mu.M was shown.

The data in table 1 show that the compounds of the present invention have a significant inhibitory effect on the activity of IDO 1. Among them, IC of most compounds₅₀The value reaches the nanomolar level, and some values even reach the picomolar level. In addition, MTT test results show that the survival rate of HeLa cells in each group is kept above 90%, and the compounds do not inhibit the activity of IDO1 by inhibiting the proliferation of HeLa cells.

61页详细技术资料下载

上一篇：一种医用注射器针头装配设备

下一篇：妥卡雷琐衍生物及其用途

Aryl alkyl ether compound and derivative thereof, preparation method, pharmaceutical composition and application

相关技术

网友询问留言