CN105541828B - Amide imidazole derivative and application thereof - Google Patents

Amide imidazole derivative and application thereof Download PDF

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Publication number
CN105541828B
CN105541828B CN201510895760.8A CN201510895760A CN105541828B CN 105541828 B CN105541828 B CN 105541828B CN 201510895760 A CN201510895760 A CN 201510895760A CN 105541828 B CN105541828 B CN 105541828B
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imidazol
carboxamido
methyl
propionic acid
ester
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CN105541828A (en
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赵冬梅
赵世振
孙彬
程卯生
李凤荣
赵立雨
郝晨洲
刘春池
任金红
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention belongs to pharmaceutical technology field, it is related to amide imidazole derivative shown in general formula I, stereoisomer and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein substituent R, R1, Ar, M, X there is the definition that provides in the description.The invention further relates to the method for preparing compound of formula I, the Pharmaceutical composition containing above compound and above compounds and Pharmaceutical composition to be used to prepare the purposes in treatment and/or pre- anti-cancer and the drug of other skin hyperplasia diseases.The compounds of this invention also finds there is stronger antibacterial effect to various superficial parts and deep fungal through antimycotic experiment, can be used for preparing the purposes in treatment antifungal drug.

Description

Amide imidazole derivative and application thereof
Technical Field
The invention relates to novel imidazole derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method thereof and a pharmaceutical composition containing the compounds. The invention relates to an imidazole derivative, and an application of a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof in preparing a medicament for treating transretinoic acid (ATRA) metabolism caused by abnormal high expression of CYP26A1 so as to weaken the pharmacological activity of the transretinoic acid, in particular to an application in preparing a medicament for treating and/or preventing cancer. The invention also relates to application of the imidazole derivative and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicines for treating various diseases caused by fungal infection.
Background
Cancer is one of the important diseases that currently seriously threaten human health, and the treatment and prevention thereof draws extensive attention. The current treatment methods include surgical excision, radiotherapy, chemical drug therapy and the like, but mainly include chemical drug therapy. The latest data of the world health organization show that the incidence rate of cancer will increase by 50% every year in the world by 2020, i.e. 1500 ten thousand cancer patients will be newly added every year.
Retinoic Acid (RA), also known as retinoic acid or retinoic acid, is a derivative of vitamin A and has a structure consisting of a cyclohexene ring, a side chain and a polar group. The retinoic acid includes various isomers due to differences of polar groups and side chain portions, and of which 13-cis retinoic acid (3-cis retinic acid,13-cis-RA), 9-cis retinoic acid (9-cis retinic acid,9-cis-RA) and all-trans retinoic acid (ATRA) are more important. The retinoic acid in a certain concentration in the body can regulate the proliferation, differentiation and maturation of cells, and is an essential important factor for normal growth and development and physiological activities of the body. Meanwhile, retinoic acid plays an important role in the treatment of malignant tumors. The research shows that: retinoid compounds play an important role in cell differentiation, proliferation and apoptosis, and have a variety of applications in the treatment of tumors, skin diseases and various diseases. All-trans retinoic acid (ATRA), the metabolite of vitamin A with the strongest biological activity, plays an important role in the differentiation and proliferation of epithelial cells, and has been successfully applied to the treatment of Acute Promyelocytic Leukemia (APL).
The action mechanism is that ATRA and Cytoplasmic Retinoic Acid Binding Protein (CRABP) are combined in cells, two specific cytoplasmic retinoic acid binding proteins CRABP I and CRABP II are found to be involved in the intracellular transport of retinoic acid, and two directions are found after ATRA and CRABP are combined: firstly, CRABP I is responsible for transferring ATRA in cytoplasm to endoplasmic reticulum, and then is oxidized and metabolized by cytochrome P450 enzyme (CYPs) in the corpuscle; secondly, CRABP II is combined with unmetabolized ATRA and 9-cis-RA in cytoplasm and is transported to nucleus, so that ATRA and 9-cis-RA are combined with nuclear receptors RARs (receptor receptors), RXRs (receptor receptors), ATRA is a natural ligand of RARs, 9-cis-RA is a ligand of RXRs, but 9-cis-RA has higher affinity to RARs, and after being activated, the receptors interact with Retinoic Acid Response Elements (RARE) in target gene DNA in the form of RXRs/RXRs homodimers or RARs/RXRs heterodimers to promote transcription of target genes together, regulate expression of different genes or enzymes in cells, activate or inhibit the genes, thereby generating a series of biological effects including tumor resistance.
However, patients treated by ATRA can obtain complete remission in a short period, but relapse is easily caused by long-term application, and exogenous ATRA is rapidly metabolized by cytochrome P450 enzyme after entering a human body, so that researches show that CYP26, a new member of CYP450 family, is expressed in liver, heart, pituitary, adrenal gland, testis, duodenum, colon, brain and placenta. CYP26 has four subtypes, CYP26A1, CYP26B1, CYP26C1, CYP26D1, CYP26A1 are expressed in tissues of zebrafish, human and mouse [33-38 ]. CYP26B1 was 44% similar to CYP26a 1. CYP26A1 and CYP26B1 are induced by ATRA to be produced in large quantity, and contribute most to ATRA 4-hydroxylation, CYP26A1 and CYP26B1 do not hydroxylate 9-cis-RA and 13-cis-RA, and the enzymes show high selectivity to ATRA and play an important role in regulating the intracellular ARTA level. Retinoic Acid Metabolism Blocking Agents (RAMBAs) can inhibit the metabolism of trans-retinoic acid, temporarily increase the ATRA level in tissues, increase the concentration of ATRA in tumor cells, and locally generate the effect of ATRA drugs, thereby showing anticancer activity. Therefore, many pharmaceutical workers are engaged in the research of tretinoin metabolism blockers.
Fungal infections are common diseases and can cause fungal infections of superficial parts such as skin, hair and nails, and also can cause fungal infections of deep tissues such as subcutaneous tissues and intima, and are mainly classified into superficial fungal infections and systemic fungal infections. In recent years, with the wide development of organ transplantation, the use of immunosuppressive agents is greatly increased, and the radiotherapy and chemotherapy of malignant tumor patients damage the normal immune function of human bodies, so that fungal infection becomes a more and more common problem in clinic and seriously threatens the health of human beings, and therefore, the search for new and more ideal antifungal drugs becomes a research hotspot.
CYP51 is monooxygenase, catalyzes sterol precursor 14 α -methyl hydroxylation reaction in the sterol synthesis pathway of organisms, the process comprises 3 steps, each step needs one molecule of oxygen and one molecule of NADPH, the first 2 steps follow the general formula of the cytochrome P450 superfamily protein monooxygenation cycle, 14 α -methyl is monooxygenated into 14 α -hydroxymethyl and 14 α -aldehyde group in sequence, the last step 14 α -aldehyde group is released in the form of formic acid, and △ 14,15 double bonds are generated, the activity of CYP51 is inhibited in fungi, the synthesis of ergosterol can be reduced, the synthesis of cell membranes in the fungi is blocked, and the purpose of inhibiting the growth of the fungi is achieved.
Lanosterol 14 α -demethylase is the most active target for antifungal drug research, especially for some azole drugs, azoles are developed from plant antifungal agents in pesticides in the 20 th 70 th generation, azole antifungal drugs are the more numerous drugs currently used clinically due to their broad antibacterial spectrum, good antifungal activity and low toxicity, azole compounds such as triazoles, imidazoles, benzimidazoles and the like have broad biological activity and play an important role in clinical application, such as imidazole drugs Miconazole (Miconazole), Clotrimazole (Clotrimazole), Econazole (Econazole), Ketoconazole (Ketoconazole) and the like and triazole drugs such as Fluconazole (Fluconazole), Itraconazole (Voriconazole), Voriconazole (Voriconazole) and Posaconazole (Posaconazole) and the like, which are widely used in clinical field.
The inventor designs and synthesizes a series of novel imidazole derivatives on the basis of the reference. In vitro activity screening shows that the compound has the activity of enhancing the tumor inhibition and differentiation induction of ATRA after being combined with ATRA. The compounds are proved to have stronger antifungal activity through in vitro antifungal activity tests, and have larger research value in treating fungal infection diseases.
Disclosure of Invention
The invention relates to an imidazole compound shown in a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein:
x is N, C;
n is an integer between 0 and 2; selected from 0, 1,2, preferably 1;
r is (C)1-C5) Alkyl, (C)1-C4) Alkoxy radical, C6-C10Aryl, carboxyl, (C)1-C5) Ester group, (C)1-C5) Amide, N- (C)6-C10) An aryl amide; said C is6-C10Aryl may be substituted by 1-3 substituents selected from hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio groups.
Ar is C6-C10Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1-4, the same or different M;
m is hydrogen or 1-3 groups selected from hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group; m may also be 6-10 membered aryl, 5-10 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from O, N and S, said aryl and heteroaryl optionally containing 1-3R1Substitution;
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably relates to imidazole compounds shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
x is N, C;
n is an integer between 0 and 1;
r is (C)1-C5) Alkyl, (C)1-C4) Alkoxy radical, C6-C10Aryl, carboxyl, (C)1-C5) Ester group, (C)1-C5) Amide, N- (C)6-C10) An aryl amide; said C is6-C10Aryl may be substituted by 1-3 substituents selected from hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio groups.
Ar is phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyrimidinyl, benzopyrazinyl, thienopyrimidinyl, thienopyridinyl, and Ar is optionally substituted with 1 to 4 identical or different M;
m is hydrogen or 1-3 groups selected from hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group; m may also be 6-10 membered aryl, 5-10 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from O, N and S, aryl and heteroaryl may optionally have 1-3R1Substitution;
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably relates to imidazole compounds shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein
X is N, C;
n is an integer of 0 or 1;
r is phenyl, (C)1-C5) Ester group, (C)1-C5) An amide;
ar is phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, Ar is optionally substituted with 1 to 4 identical or different M;
m is hydrogen or 1-3 groups selected from hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, amino substituted by mono-or di (C1-C6 alkyl), (C1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted aminoFormyl, (C)1-C3) An alkylenedioxy group; m may also be 6-10 membered aryl, 5-10 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from O, N and S, said aryl and heteroaryl optionally containing 1-3R1Substitution;
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl substituted by mono-or di (C1-C6 alkyl), (C1-C3) alkylenedioxy.
The invention preferably relates to imidazole compounds shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein
X is C;
n is an integer of 1;
r is phenyl, (C)1-C5) Ester group, (C)1-C5) An amide;
ar is phenyl, pyrrolyl, pyrazolyl, benzothiazolyl, Ar is optionally substituted by 1-4 same or different M;
m is hydrogen or 1-3 groups selected from hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, optionallySubstituted by hydroxy, amino or halogen1-C6) Alkyl or (C)1-C6) Alkoxy or (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group; m may also be 6-10 membered aryl, 5-10 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms selected from O, N and S, said aryl and heteroaryl optionally containing 1-3R1Substitution;
R1is hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
The invention preferably relates to imidazole compounds shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein
X is C;
n is an integer of 1;
r is benzyl, methyl ester, ethyl ester, propyl ester, isopropyl ester, isobutyl ester group, N-phenylamide;
ar is phenyl, pyrrolyl, pyrazolyl, benzothiazolyl, Ar is optionally substituted by 1-4 same or different M;
m is hydrogen or 1-3 selected from hydroxyl, halogen, nitro, trifluoromethyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, phenyl, said phenyl optionally having 1 to 3R1Substitution;
R1is hydrogen or 1-3 substituents optionally selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl and trifluoromethoxy;
the compounds of formula I according to the invention and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs are preferably the following compounds, but these compounds are not meant to limit the invention in any way:
(S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phend-2-yl) benzo [ d ] thiazole-2-carboxamide
(S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-methyl-benzo [ d ] thiazole-2-carboxamide
(S) -2- (6-Bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-bromo-benzo [ d ] thiazole-2-carboxamide
(S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (6-chlorobenzo [ d ] thiazole-2-carboxamide) -3- (1H-imidazol-1-yl) propionate
(S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-chloro-benzo [ d ] thiazole-2-carboxamide
(S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-methoxy-benzo [ d ] thiazole-2-carboxamide
(S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-trifluoromethyl-benzo [ d ] thiazole-2-carboxamide
(S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-methyl-benzo [ d ] thiazole-2-carboxamide
(S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-methoxy-benzo [ d ] thiazole-2-carboxamide
(S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamide) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-trifluoromethyl-benzo [ d ] thiazole-2-carboxamide
(S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- (4-chlorobenzo [ d ] thiazole-2-carboxamide) -3- (1H-imidazol-1-yl) propionate
(S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-Cl-benzo [ d ] thiazole-2-carboxamide
(S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -ethyl 2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -propyl 2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamide
(S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2,4, 5-dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -2- [ (1,1' -Biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) - (1,1' -biphenyl) -4-carboxamide
(S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4 '-fluoro- (1,1' -biphenyl) -4-carboxamido
(S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4 '-methyl- (1,1' -biphenyl) -4-carboxamido
(S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2 '-fluoro- (1,1' -biphenyl) -4-carboxamido
(S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2 '-methyl- (1,1' -biphenyl) -4-carboxamido
(S) -N-methyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propanamide
(S) -N-ethyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propanamide
(S) -N-phenyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propanamide
Furthermore, the derivatives of formula I above may form pharmaceutically acceptable salts with acids according to some conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "aryl" refers to an organic group derived from an aromatic hydrocarbon by removal of two hydrogen atoms at one or different positions, such as phenyl, naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which refers to an organic group having aromatic character and obtained by removing two hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, and the like.
The invention can contain the derivative of the formula I, and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as active ingredients, and the derivative is mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
In vitro antitumor activity tests show that the derivative of the general formula I has antitumor activity when being combined with ATRA (all-trans retinoic acid), so that the compound can be used for preparing medicaments for treating and/or preventing various cancers, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophagus, leukemia, neuroblastoma and the like. In particular for the preparation of a medicament for the treatment and/or prevention of promyelocytic leukemia.
In-vitro antifungal activity experiments show that the derivatives shown in the general formula I have good antifungal activity, so that the derivatives can be used for preparing various antifungal medicines, such as medicines for resisting candida albicans, candida parapsilosis, candida glabrata, cryptococcus neoformans, microsporum gypseum, trichophyton rubrum, aspergillus fumigatus and the like.
The active compound or the medicinal salt and the solvate thereof can be used as an anti-tumor medicament combined with ATRA. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way. The compounds of formula I according to the invention can be prepared according to the method of scheme 1 from the corresponding intermediates a and B by acylation and nucleophilic substitution with imidazole or triazole, all variables used in these schemes being as defined in the claims.
The derivatives of formula I according to the present invention can be prepared by the method of scheme 1 by adding catalytic amount of EDCI, HOBt to the corresponding intermediate A, stirring at room temperature for 2h, adding intermediate B and DIEA, refluxing for about 5h, preparing intermediate C by acylation reaction, adding N, N '-carboxyldiidazole, imidazole or N, N' -carboxyldiidazole, and triazole in acetonitrile solvent, and refluxing for 5h to obtain the target product I. Wherein Ar, M, R and n in the compound are as defined in the claims.
When Ar is benzothiazolyl and n is 1, the synthesis of intermediate A-1 is as follows (scheme 2).
The synthesis of intermediate A-2 when Ar is pyrrolyl and n is 1 and M is phenyl is as follows (scheme 3).
The synthesis of intermediate A-2 when Ar is pyrazolyl and n is 1 and M is phenyl is as follows (scheme 4).
The synthesis of intermediate A-2 when Ar is phenyl and n is 1 and M is phenyl is as follows (scheme 5).
The synthesis of intermediate A-2 when n is 1 and M is phenyl is as follows (scheme 5).
When R is an ester group, the synthesis method of the intermediate B-1 is as follows:
when R is benzyl, the synthesis method of the intermediate B-2 is as follows:
substituents R of all intermediates in the above 7 routes1R, M, Ar and n are as defined in the claims.
The specific implementation mode is as follows:
the examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the compounds was measured using BrukeraRx-400 and Mass Spectroscopy was measured using Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
TABLE 1 structural formulae of examples 1 to 60
TABLE 2 structural formulae of examples 61 to 130
TABLE 3 structural formulas of examples 131 to 202
TABLE 4 structural formulas of examples 203 to 241
Example 1: preparation of (S) -methyl 2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
Step A preparation of Ethyl 12-oxo-2-phenylaminoacetate (1)
Aniline 5.00g (53.8mmol) was added to 20mL diethyl oxalate, the temperature was controlled at 150 ℃ and the reaction was monitored by TLC for completion after 5 h. The reaction solution was cooled, 100mL of petroleum ether was added, and stirring was carried out for 10min to generate a large amount of white solid, which was filtered under suction to obtain 8.52g of white solid with a yield of 82.1%. MS [ M + H ]]++(m/z)：194。
Step A preparation of Ethyl 22-thio-2-phenylaminoacetate (2)
2.00g (10.4mmol) of intermediate 1 (ethyl 2-oxo-2-phenylamino acetate) and 2.10g (5.2mmol) of Lawson's reagent were added to 30mL of toluene, reacted at 70 ℃ for 3h, and the completion of the reaction was monitored by TLC. The solvent was concentrated under reduced pressure, and column chromatography gave 1.59g of a red oil in 73.6% yield. MS [ M + H ]]+(m/z)：210。
Step A preparation of 32-thio-2-phenylaminoacetic acid (3)
Intermediate 2 (ethyl thio-2-phenylaminoacetate) 1.5g (7.2mmol) was dissolved in 15mL of dichloromethane, 30mL of 2N NaOH was added, the mixture was stirred at room temperature for 2h, and the reaction was monitored by TLC for completion. The dichloromethane was distilled off under reduced pressure.
Step A-preparation of 4 benzo [ d ] thiazole-2-carboxylic acid (4)
Potassium ferricyanide 7.08g (21.6mmol) was dissolved in 21mL of water, added dropwise to the above reaction solution of 3 (2-thio-2-phenylamino acetic acid) at room temperature, and the completion of the reaction was monitored by TLC after 3 hours. Adjusting pH to 1 with concentrated hydrochloric acid to precipitate a large amount of solid, stirring for 30min, vacuum filtering, and drying to obtain off-white solid 0.93g with yield of 72.1%. MS [ M + H ]]-(m/z)：178。
Step A-5L-preparation of serine methyl ester hydrochloride (5)
L-serine 4.00g (38.10 mmo)l) into 40mL of methanol, SOCl was added dropwise28.3mL (114.30mmol), after dropping, the temperature was raised to reflux (65 ℃ C.), and the mixture was stirred until the reaction solution was clear. The reaction solution was concentrated under reduced pressure to obtain 5.67g of a white solid, yield 96.1%. MS [ M + H ]]-(m/z)：120。
Step A-preparation of methyl 6(S) -2- (benzo [ d ] thiazole-2-carboxamido) -3-hydroxypropionate (6)
Intermediate 4 benzo [ d ]]Thiazole-2-carboxylic acid 0.70g (3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) were dissolved in 30mL of DMF and stirred at room temperature for 2h, intermediate 5L-serine methyl ester hydrochloride 0.67g (4.30mmol) and DIEA 2mL were added, reacted at 70 ℃ for 5h and the reaction was monitored by TLC for completion. To the reaction solution, 100mL of water was added, 56mL of EA was extracted, and the obtained mixture was washed with saturated brine and Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 0.56g of a brown oil in 51.4% yield. MS [ M + H ]]-(m/z)：281。
Step A preparation of methyl 7 (S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate (7)
Intermediate 6(S) -2- (benzo [ d ]]Methyl thiazole-2-carboxamido) -3-hydroxypropionate 0.50g (1.79mmol), CDI 0.44g (2.69mmol) and imidazole 0.18g (2.69mmol) were dissolved in 10mL acetonitrile and reacted at 70 ℃ for 4h, and the reaction was monitored by TLC for completion. The reaction mixture was concentrated under pressure, and the residue was dissolved in ethyl acetate, washed with water, washed with saturated brine and then with Na2SO4Dry overnight. The drying agent was filtered off, concentrated under reduced pressure to give a reddish brown oil, which was subjected to column chromatography to give 0.38g of a white solid in 64.4% yield. m.p.147.0-147.3 deg.C;1H-NMR(CDCl3,400MHz):δ:8.16-8.14(d,1H,J＝7.24hz),8.11-8.09(d,1H,J＝7.84hz),7.99-7.97(m,1H),7.73(s,1H),7.56-7.50(m,2H),7.10(s,1H),6.95(s,1H),5.17-5.09(m,1H),4.66-4.64(d,2H,J＝4.52hz),3.86(s,3H)；ESI-MS m/z:331.0[M+H]+。
according to the method of the embodiment 1, substituted aniline is used as a raw material to react with diethyl oxalate to prepare an intermediate 1, then, the intermediate 1 is subjected to a thio reaction to obtain an intermediate 2, the intermediate 2 is subjected to a hydrolytic cyclization reaction to obtain an intermediate 4, the intermediate 4 is subjected to a reaction with L-serine ester to obtain an intermediate 6, and the intermediate 6 is subjected to a nucleophilic substitution reaction of an imidazole group to prepare the embodiments 2-50.
Example 2 Ethyl (S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):345；
EXAMPLE 3 propyl (S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):359；
Example 4 (S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):359；
Example 5 isobutyl (S) -2- (benzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):373；
Example 6 methyl (S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[[M+H]+(m/z):345；
Example 7 Ethyl (S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):359；
Example 8 propyl (S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):373；
Example 9 isopropyl (S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):373；
Example 10 isobutyl (S) -2- (6-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):387；
Example 11 methyl (S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):409；
Example 12 Ethyl (S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H](m/z):423；
Example 13 propyl (S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
Example 14 isopropyl (S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
Example 15 isobutyl (S) -2- (6-bromobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):451；
Example 16 methyl (S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):365；
Example 17 Ethyl (S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):379；
Example 18 propyl (S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):393；
Example 19 isopropyl (S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):393；
Example 20 isobutyl (S) -2- (6-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):407；
Example 21 methyl (S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):361；
Example 22 Ethyl (S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):375；
Example 23 propyl (S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):389；
Example 24 isopropyl (S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):389；
Example 25 isobutyl (S) -2- (6-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):403；
Example 26 methyl (S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):399；
Example 27 Ethyl (S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):413；
Example 28 propyl (S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):427；
Example 29 isopropyl (S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):427；
Example 30 isobutyl (S) -2- (6-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):441；
Example 31 methyl (S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):345；
Example 32 Ethyl (S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):359；
Example 33 propyl (S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):373；
Example 34 isopropyl (S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):373；
Example 35 isobutyl (S) -2- (4-methylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):441；
Example 36 methyl (S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):361；
Example 37 Ethyl (S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):375；
Example 38 propyl (S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):389；
Example 39 isopropyl (S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):389；
Example 40 isobutyl (S) -2- (4-methoxybenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):403；
Example 41 methyl (S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):399；
Example 42 Ethyl (S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):413；
Example 43 propyl (S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):427；
Example 44 isopropyl (S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):427；
Example 45 isobutyl (S) -2- (4-trifluoromethylbenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):441；
Example 46 methyl (S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):365；
Example 47 Ethyl (S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):379；
EXAMPLE 48 propyl (S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):393；
Example 49 isopropyl (S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):393；
Example 50 isobutyl (S) -2- (4-chlorobenzo [ d ] thiazole-2-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):407；
Example 51 preparation of (S) -N- (1- (1H-imidazol-1-yl) -3-phen-2-yl) benzo [ d ] thiazole-2-carboxamide;
firstly, reacting a compound 1 with borane, reducing to obtain an intermediate 2, then reacting with Baker anhydride to obtain an intermediate 3, then brominating to obtain an intermediate 4, carrying out nucleophilic substitution reaction with imidazole to obtain an intermediate 5, finally removing Baker protection to obtain an important intermediate 6, and finally carrying out acylation reaction with A-1, as shown in a synthetic route 8.
The preparation method comprises the following steps:
step B-1 β preparation of phenylalaninol 2
Dissolving borane (20ml, 0.12mol) in 30ml of THF solvent, cooling to 0 ℃, slowly adding the compound 1(5g, 30mmol), stirring for 15min, refluxing for 4h, cooling to 0 ℃ after the reaction is finished, adding anhydrous methanol for quenching until no bubbles are generated, stirring for 20min, evaporating to remove the solvent, dissolving DCM, washing with water, and drying to obtain 3.4g of colorless oily substance. The yield thereof was found to be 75%. MS [ M + H ]]+(m/z)：152。
Step B preparation of tert-butyl 2-tert-butyl (1-hydroxy-3-phenylprop-2-yl) carbamate 3
Intermediate 2(2.5g, 15.92mmol) was dissolved in 30ml MeOH and (Boc) was added2O(3.9，17.89mmol)，Na2CO3(7, 66.04mmol), stirring at room temperature for 10h, after the reaction is finished, evaporating the solvent, adding water, precipitating a solid, filtering, washing a filter cake with water, and drying. 3.04g of white solid is obtained with a yield of 76%, MS [ M + H%]+(m/z)：252。
Step B preparation of tert-butyl 3-tert-butyl (1-bromo-3-phenylpropan-2-yl) carbamate 4
Intermediate 3(0.4g, 1.59mmol) was dissolved in 15ml DCM and the ice salt bath brought to-5 ℃. PBr is prepared from3Dispersing in DCM, slowly dripping into the reaction system, keeping the temperature for 2.5h, after the reaction is completed, slowly adding water under ice bath for quenching, dissolving 30ml of DCM, washing with water, and drying. 034g of a colorless oil was obtained in 69% yield, MS [ M + H%]+(m/z)：314。
Step B preparation of tert-butyl (1- (1H-imidazol-1-yl) -3-phenylpropan-2-yl) carbamate 5
NaH (0.12g, 5.1mmol) was dissolved in 30ml DMF solvent under ice bath conditions, imidazole (0.18g, 2.82mmol) was added, stirring was carried out at room temperature for 30min, intermediate 4(0.8g, 2.56mmol) was added, reaction was carried out at 80 ℃ for 5h, after completion of the reaction, poured into water, extracted with EA and dried. 0.56g of colorless oil is obtained in 73% yield, MS [ M + H]+(m/z)：302。
Step B preparation of 51- (1H-imidazol-1-yl) -3-phenylpropan-2-amine 6
Dissolving intermediate 5(0.6g, 1.99mmol) in 15ml HCl. EA, stirring at room temperature for 10H, after reaction completely, precipitating solid, filtering, washing filter cake with water, drying to obtain white solid 0.54g, yield 86%, MS [ M + H ]]+(m/z)：314。
Step B preparation of 6(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) benzo [ d ] thiazole-2-carboxamide 7
Intermediate A-1 benzo [ d]Thiazole-2-carboxylic acid (0.70g,3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) were dissolved in 30mL of DMF and stirred at room temperature for 2h, intermediate 6(0.86g,4.30mmol) and DIEA 2mL were added and reacted at 70 ℃ for 5h, and the reaction was monitored by TLC for completion. 100mL of water was added to the reaction solution, 56mL of EA was extracted, and the obtained mixture was washed with saturated brine and Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 0.8g of a brown oil in 57% yield. MS [ M + H ]]-(m/z)：363。
According to the method of example 51, phenylalanine is used as a raw material, and the preparation method comprises the steps of reduction, Boc protection, bromination, nucleophilic substitution by imidazole, deprotection, and reaction with a substituted intermediate A-1 benzo [ d ] thiazole-2-carboxylic acid to obtain examples 52-60.
EXAMPLE 52 preparation of (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-methyl-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):377；
EXAMPLE 53 preparation of (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-bromo-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):441；
Example 54 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-chloro-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):397；
Example 55 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-methoxy-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):393；
Example 56 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -6-trifluoromethyl-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):431；
Example 57 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-methyl-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):377；
Example 58 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-methoxy-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):393；
Example 59 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-trifluoromethyl-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):431；
Example 60 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4-Cl-benzo [ d ] thiazole-2-carboxamide
ESI-MS[M+H]+(m/z):397；
EXAMPLE 61 preparation of methyl (S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
Step C-1 preparation of Ethyl acetoacetate sodium 1
Sodium (5.19g,225.6mmol) was cut into small pieces and added to 80mL of anhydrous ethanol in portions until the whole reaction, ethyl acetoacetate (28.7mL,225.6mmol) was added, the mixture was stirred at room temperature for 24 hours, and the mixture was concentrated under reduced pressure to obtain 33.70g of a pale yellow solid with a yield of 98.2%.
Step C-22-acetyl-3-methyl-4-oxopentanoic acid ethyl ester 2
2.00g (9.56mmol) of intermediate 1 ethyl acetoacetate sodium salt was dissolved in 20mL of acetone, 0.13g (0.96mmol) of NaI was added, 0.76mL (9.56mmol) of 3-chloro-2-butanone was added dropwise at 40 ℃ and the reaction was monitored by TCL for completion of the reaction after 5 hours at reflux (56 ℃). The reaction mixture was cooled, filtered and concentrated under reduced pressure to give a reddish brown oil. Column chromatography gave 1.46g of a pale yellow oil in 76.4% yield. ESI-MS [ M + H ]]+(m/z):201；
Step C preparation of 32, 4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid 3
Intermediate 2(1.00g, 5mmol) and aniline 0.49Ml (5.38mmol) were dissolved in 10mL ethanol, heated to reflux (78 deg.C) and the reaction was monitored by TLC for completion after 3 h. To the above reaction solution were added NaOH 0.86g (21.52mmol) and 10mL of water, and completion of the reaction was monitored by TLC after 7 h. The ethanol was evaporated under reduced pressure, the pH was adjusted to 2 with concentrated hydrochloric acid, and a solid precipitated, which was filtered and dried to give 0.85g of off-white solid with a yield of 74.4%. ESI-MS [ M + H ]]+(m/z):230；
Step C preparation of methyl 4 (S) -2- (2,4, 5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3-hydroxypropionate 4
Intermediate 3(0.53g,2.3mmol), EDC & HCl 0.50g (2.6mmol) and HOBt 0.35g (2.6mmol) were dissolved in 10mL DMF, stirred at room temperature for 3h, TLC monitored for reaction completion, L-serine methyl ester hydrochloride 0.40g (2.6mmol) and DIE were addedA0.79 mL (5.2mmol), stirring at room temperature for 5h, monitoring by TLC for completion of the reaction, adding 30mL of water, extracting with 40mL of ethyl acetate, washing the organic layer with saturated brine, Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 0.53g of a brown oil in 69.4% yield. ESI-MS [ M + H ]]+(m/z):331；
Step C preparation of methyl 5(S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate 5
Intermediate 4(0.52g,1.58mmol), CDI 0.38g (2.37mmol) and imidazole 0.16g (2.37mmol) were dissolved in 8mL acetonitrile and reacted at 50 ℃ for 9h with TLC monitoring of reaction completion. Concentrating the reaction solution under pressure, dissolving the residue in ethyl acetate, washing with water, washing with saturated saline, and washing with Na2SO4Dry overnight. The drying agent was filtered off, and concentrated under reduced pressure to give a reddish brown oil, which was subjected to column chromatography to give an off-white solid (0.31 g, yield 51.9%). m.p.79.6-81.0 deg.C;1H-NMR(CDCl3,400MHz):δ:7.55-7.44(m,3H),7.43(s,1H),7.20-7.15(d,2H,J＝6.68hz),7.05(s,1H),6.87(s,1H),6.38-6.33(d,1H,J＝5.96hz),5.07-5.01(m,1H),4.72-4.54(m,2H),3.86(s,3H),2.23(s,3H),2.17(s,3H),1.91(s,3H)；ESI-MS[M+H]+m/z:381.1。
according to the method of example 61, substituted anilines were used as raw materials, and reacted with ethyl 2-acetyl-3-methyl-4-oxopentanoate to prepare the key intermediate 2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid, which was then reacted with L-serine ester to obtain intermediate 4, which was subjected to nucleophilic substitution reaction with imidazole group to prepare examples 62-120.
Example 62 Ethyl (S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):395；
Example 63 propyl (S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):409；
Example 64 isopropyl (S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):409；
Example 65 isobutyl (S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):423；
Example 66 methyl (S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):395；
Example 67 Ethyl (S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):409；
EXAMPLE 68 propyl (S) -2- [2,4, 5-dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):423；
EXAMPLE 69 isopropyl (S) -2- [2,4, 5-dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):423；
Example 70 isobutyl (S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
Example 71 methyl (S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):459；
Example 72 Ethyl (S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):473；
EXAMPLE 73 propyl (S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):487；
Example 74 (S) -isopropyl 2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):487；
Example 75 isobutyl (S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):501；
EXAMPLE 76 methyl (S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):415；
Example 77 Ethyl (S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):429；
EXAMPLE 78 propyl (S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):443；
EXAMPLE 79 isopropyl (S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):443；
Example 80 isobutyl (S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):457；
Example 81 methyl (S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):411；
EXAMPLE 82 Ethyl (S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):425；
EXAMPLE 83 propyl (S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):439；
EXAMPLE 84 isopropyl (S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):439；
Example 85 isobutyl (S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):453；
Example 86 methyl (S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):449；
EXAMPLE 87 Ethyl (S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):463；
EXAMPLE 88 propyl (S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):477；
EXAMPLE 89 (S) -isopropyl 2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):477；
Example 90 isobutyl (S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):491；
Example 91 (S) -methyl 2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):409；
EXAMPLE 92 ethyl (S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):423；
Example 93 propyl (S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
EXAMPLE 94 isopropyl (S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
Example 95 isobutyl (S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):451；
Example 96 (S) -methyl 2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):426；
Example 97 (S) -ethyl 2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):440；
EXAMPLE 98 propyl (S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):454；
Example 99 (S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):454；
Example 100 isobutyl (S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):468；
Example 101 methyl (S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):395；
Example 102 Ethyl (S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):409；
Example 103 propyl (S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):423；
EXAMPLE 104 isopropyl (S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):423；
Example 105 isobutyl (S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
Example 106 methyl (S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):415；
Example 107 Ethyl (S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):429；
EXAMPLE 108 propyl (S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):443；
EXAMPLE 109 isopropyl (S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):437；
Example 110 isobutyl (S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):457；
Example 111 methyl (S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):411；
EXAMPLE 112 Ethyl (S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):425；
EXAMPLE 113 propyl (S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):439；
Example 114 (S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):439；
Example 115 isobutyl (S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):453；
Example 116 methyl (S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):449；
Example 117 Ethyl (S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):463；
Example 118 propyl (S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):477；
Example 119 (S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):477；
Example 120 isobutyl (S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):491；
EXAMPLE 121 preparation of (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamide
Step D preparation of 1 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamide
Intermediate A-22,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid (0.90g,3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) were dissolved in 30mL of DMF and stirred at room temperature for 2H, intermediate 6,1- (1H-imidazol-1-yl) -3-phenylpropan-2-amine (0.86g,4.30mmol) and DIEA 2mL were added and reacted at 70 ℃ for 5H, and TLC monitored for reaction completion. 100mL of water was added to the reaction solution, 56mL of EA was extracted, and the obtained mixture was washed with saturated brine and Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 0.9g of a brown oil in 56% yield. ESI-MS [ M + H ]]+(m/z):413。
Example 122-130 was obtained by amidation of 1- (1H-imidazol-1-yl) -3-phenylpropan-2-amine with the procedure of example 121, using variously substituted 2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid as starting material.
Example 122 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):427；
Example 123 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):491；
Example 124 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):447；
Example 125 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):443；
Example 126 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):481；
Example 127 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):427；
Example 128 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):413；
Example 129 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):443；
Example 130 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamide
ESI-MS[M+H]+(m/z):447；
EXAMPLE 131 preparation of methyl (S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
Step E-1 preparation of phenylhydrazine hydrochloride 1
Aniline (0.41g,4.4mmol) was dissolved in 5ml of concentrated hydrochloric acid, cooled to 0 with stirring, and NaNO was added dropwise22ml of an aqueous solution (0.33g,4.8mmo) was added dropwise thereto SnCl25ml of concentrated hydrochloric acid (2.36g,10mmol) is added dropwise, the reaction is carried out for 1h, the reaction is slowly raised to room temperature, the filtration is carried out, and the filter cake is washed by the concentrated hydrochloric acid, so that 0.42g of light yellow solid is obtained, and the yield is 65.2%.
Step preparation of E-23-methyl-1-phenyl-5-pyrazolone 2
Heating intermediate 1 phenylhydrazine (21.6g,200mmol) and 30mL of absolute ethyl alcohol to 50 ℃ while stirring, dropwise adding ethyl acetoacetate (26.0g,200mmol), controlling the temperature between 50 ℃ and 70 ℃ while dropwise adding, refluxing for 5h, cooling, concentrating the reaction solution to obtain red transparent liquid, standing overnight, precipitating yellow solid, suction filtering, drying, and recrystallizing with absolute ethyl alcohol29.3g of a pale yellow solid was obtained with a yield of 85.0%. mp 128.0-130.3 deg.C; ESI-MS M/z 175.1[ M + H ]]+；197.1[M+Na]+；172.9[M-H]-。
Preparation of step E-33-methyl-1-phenyl-5-chloro-4-pyrazolecarboxaldehyde 3
DMF (23mL,300mmol) was added to a 250mL three-necked flask, cooled to 0-5 ℃ in an ice water bath and POCl was added dropwise3(64mL,700mmol) and after dropping, adding the intermediate 2, 1-phenyl-3-methyl-5-pyrazolone (17.48g,100mmol) into the mixture, slowly heating to reflux, maintaining for 1h, cooling, slowly pouring the mixture into 600mL of ice-water mixture under stirring, separating out a solid, performing suction filtration, and drying to obtain 19.0g of a light yellow solid with the yield of 86.4%. mp 139.0-140.8 ℃; ESI-MS M/z 221.1[ M + H ]]+；243.1[M+Na]+。
Step E preparation of 43-methyl-1-phenyl-5-chloro-4-pyrazolecarboxylic acid 4
Adding an intermediate 3, 5-chloro-3-methyl-1-phenyl-4-pyrazolecarboxaldehyde (16.85g,76.4mmol), potassium permanganate (16.9g,106.96mmol) and 300mL of water into a 1000mL three-necked flask, stirring and heating to 90-95 ℃, keeping the temperature for reaction for 4h, stopping heating, stirring at room temperature for 2.5h, carrying out suction filtration, acidifying the filtrate with 2M HCl, precipitating a white solid, carrying out suction filtration, and drying to obtain 16.6g of a product, wherein the yield is 92.2%. mp 232.1-234.7 ℃;1H NMR(DMSO-d6,300MHz):δ2.41(s,3H),7.56(s,5H),12.88(s,1H)；ESI-MS m/z:237.1[M+H]+；259.1[M+Na]+。
step E preparation of 5- (S) -methyl 2- (5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido) -3-propanoate 5
Intermediate 4, 3-methyl-1-phenyl-5-chloro-4-pyrazolecarboxylic acid (0.92g,3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) were dissolved in 30mL of DMF, stirred at room temperature for 2h, intermediate 5L-serine methyl ester hydrochloride 0.67g (4.30mmol) and DIEA 2mL were added, reacted at 70 ℃ for 5h, and the reaction was monitored by TLC for completion. 100mL of water was added to the reaction solution, 56mL of EA was extracted, and the obtained mixture was washed with saturated brine and Na2SO4Dry overnight. Filtering and dryingThen, the mixture was concentrated under reduced pressure to obtain 0.70g of a brown oil in 53% yield. ESI-MS [ M + H ]]+(m/z)：338。
Step E-6 (S) -preparation of methyl 2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate 6
Intermediate 5(S) -methyl 2- (5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido) -3-propanoate 0.60g (1.79mmol), CDI 0.44g (2.69mmol) and imidazole 0.18g (2.69mmol) were dissolved in 10mL acetonitrile and reacted at 70 ℃ for 4H and TLC monitored for reaction completion. The reaction mixture was concentrated under pressure, and the residue was dissolved in ethyl acetate, washed with water, washed with saturated brine and then with Na2SO4Dry overnight. The drying agent was filtered off, concentrated under reduced pressure to give a reddish brown oil, which was subjected to column chromatography to give 0.46g of a white solid in 67% yield.
m.p.147.0-147.3℃；1H-NMR(CDCl3,400MHz):δ:8.47-8.42(d,1H,J＝7.92hz),7.62(s,1H),7.59-7.52(d,1H,J＝1.64hz),7.56(s,1H),7.55-7.53(d,1H,J＝2.8hz),7.53-7.51(m,1H),4.89-4.82(m,1H),4.54-4.34(m,2H),3.71(s,3H),2.23(s,3H)；ESI-MS[M+H]+(m/z)＝388。
According to the method of example 131, substituted anilines are respectively used as raw materials, the key intermediate 3-methyl-1-phenyl-5-chloro-4-pyrazolecarboxylic acid is prepared through diazo reduction, cyclization, hydroformylation and oxidation reaction, and then the key intermediate reacts with L-serine ester to obtain an intermediate 5, and the intermediate 5 is subjected to nucleophilic substitution reaction of imidazole groups to prepare the material of example 132-190-.
Example 132 Ethyl (S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):402；
Example 133 (S) -propyl 2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):416；
Example 134 (S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):416；
Example 135 (S) -isobutyl 2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):444；
EXAMPLE 136 methyl (S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):402；
EXAMPLE 137 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):416；
EXAMPLE 138 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):430；
Example 139 (S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):430；
Example 140 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):458；
Example 141 methyl (S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):466；
EXAMPLE 142 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):495；
EXAMPLE 143 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):494；
Example 144 (S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):494；
Example 145 (S) -isobutyl 2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):522；
EXAMPLE 146 methyl (S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):422；
Example 147 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):436；
EXAMPLE 148 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):450；
EXAMPLE 149 (S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):450；
Example 150 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):478；
EXAMPLE 151 methyl (S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):418；
EXAMPLE 152 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):432；
EXAMPLE 153 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):446；
EXAMPLE 154 isopropyl (S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):446；
Example 155 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):474；
Example 156 methyl (S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):456；
Example 157 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):470；
EXAMPLE 158 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):484；
Example 159 (S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):484；
Example 160 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):512；
Example 161 (S) -methyl 2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):406；
Example 162 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):420；
Example 163 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):434；
Example 164 (S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):434；
Example 165 (S) -isobutyl 2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):462；
EXAMPLE 166 methyl (S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):433；
Example 167 (S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
ESI-MS[M+H]+(m/z):447；
EXAMPLE 168 propyl (S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):461；
Example 169 (S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):461；
Example 170 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):489；
Example 171 methyl (S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):402；
Example 172 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):416；
EXAMPLE 173 propyl (S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):430；
Example 174 (S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
ESI-MS[M+H]+(m/z):430；
Example 175 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):458；
Example 176 (S) -methyl 2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):422；
EXAMPLE 177 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):436；
EXAMPLE 178 propyl (S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):450；
EXAMPLE 179 (S) -isopropyl 2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):450；
Example 180 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):478；
Example 181 (S) -methyl 2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):418；
EXAMPLE 182 Ethyl (S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):432；
Example 183 (S) -propyl 2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):446；
EXAMPLE 184 isopropyl (S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):446；
Example 185 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):474；
EXAMPLE 186 (S) -methyl 2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):456；
Example 187 (S) -ethyl 2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):470；
EXAMPLE 188 propyl (S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):484；
Example 189 isopropyl (S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):484；
Example 190 isobutyl (S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):512；
EXAMPLE 191 preparation of (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide
Step F-1 intermediate A-33-methyl-1-phenyl-5-chloro-4-pyrazolecarboxylic acid (0.92g,3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) were dissolved in 30mL of DMF and stirred at room temperature for 2H, intermediate 6,1- (1H-imidazol-1-yl) -3-phenylpropan-2-amine (0.86g,4.30mmol) and DIEA 2mL were added and reacted at 70 ℃ for 5H, and TLC monitored for reaction completion. 100mL of water was added to the reaction solution, 56mL of EA was extracted, and the obtained mixture was washed with saturated brine and Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 0.9g of a brown oil in 55% yield. ESI-MS [ M + H ]]+(m/z):420。
EXAMPLE 192 Across 202 was obtained by amidation of 1- (1H-imidazol-1-yl) -3-phenylpropan-2-amine using the variously substituted 3-methyl-1-phenyl-5-chloro-4-pyrazolecarboxylic acid as starting material in the procedure of example 191.
Example 192 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):434；
Example 193 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):498；
Example 194 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):454；
Example 195 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):450；
Example 196 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):488；
Example 197 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):438；
Example 198 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):465；
Example 199 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):434；
Example 200 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):450；
Example 201 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):488；
Example 202 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamide
ESI-MS[M+H]+(m/z):454；
Example 203 preparation of methyl (S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
Step G-1 preparation of p-bromobenzoic acid 1
To bromobenzaldehyde 5.00g (27.17mmol), potassium permanganate 4.72(29.89mmol) was added to 30mL of 2N NaOH, the temperature was controlled at 70 ℃ and the reaction was monitored by TLC for completion after 5 h. The reaction solution was cooled, filtered, the pH was adjusted to 1, and a large amount of white solid was produced, and filtered to obtain 4.59g of white solid with a yield of 85.1%. MS [ M + H ]]+(m/z)：201。
Step G-21, 1' -Biphenylformic acid preparation 2
2.58g (11.9mmol) of bromobenzoic acid and 2g (16 mmol) of phenylboronic acid were added to the reaction solution.39mmol)K2CO34g of tetrakistriphenylphosphine palladium (0.2 g) was added to 30mL of dioxane solvent, the temperature was controlled at 75 ℃ and the reaction was monitored by TLC for 5h to be complete. The reaction solution was cooled, filtered, the pH was adjusted to 1, and a large amount of white solid was produced, and filtered to obtain 2.03g of white solid with a yield of 86.5%. MS [ M + H ]]+(m/z)：199。
Step G preparation of methyl 3 (S) -2- ([1,1' -biphenyl ] -4-ylcarboxamido) -3-hydroxypropionate 3
Intermediate 2(1g,5mmol), EDC & HCl 0.96g (5.5mmol) and HOBt 0.74g (5.5mmol) were dissolved in 30mL DMF and stirred at room temperature for 3h, TLC monitored reaction completion, L-serine methyl ester hydrochloride 0.83g (5.5mmol) and DIEA 1.58mL (11mmol) were added, stirring at room temperature for 5h, TLC monitored reaction completion, 30mL water was added, 40mL ethyl acetate was extracted, organic layer was washed with saturated brine, Na was added2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 1.08g of a brown oil in 66.2% yield. ESI-MS [ M + H ]]+(m/z):300；
Step G preparation of methyl 5(S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate 4
Intermediate 4(1.08g,3.61mmol), CDI 1.17g (7.22mmol) and imidazole 0.74g (10.83mmol) were dissolved in 20mL acetonitrile and reacted at 70 ℃ for 9h with TLC monitoring of reaction completion. Concentrating the reaction solution under pressure, dissolving the residue in ethyl acetate, washing with water, washing with saturated saline, and washing with Na2SO4Dry overnight. The drying agent was filtered off, and concentrated under reduced pressure to give a reddish brown oil, which was subjected to column chromatography to give an off-white solid (0.7 g, 56.2% yield). [ M + H ]]+(m/z):350.m.p.147.0-147.3℃；1H-NMR(DMSO,400MHz):δ:9.17-9.03(d,1H,J＝8hz),7.95-7.91(d,2H,J＝8hz),7.82-7.78(d,2H,J＝8hz),7.75-7.72(d,2H,J＝8hz),7.70(s,1H),7.52-7.48(m,2H),7.43-7.40(m,1H),7.24(s,1H)，6.89(s,1H),4.92-4.87(m,1H),4.60-4.41(m,2H),3.71(s,3H)。
According to the method of example 203, substituted phenylboronic acid is used as a raw material, and reacts with p-bromobenzoic acid to obtain a key intermediate 1,1' -bibenzoic acid, which reacts with L-serine ester to obtain an intermediate 3, and the intermediate 3 undergoes nucleophilic substitution reaction of imidazole group to obtain example 204-.
Example 204 Ethyl (S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):364；
Example 205 propyl (S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):378；
Example 206 isopropyl (S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):378；
Example 207 isobutyl (S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):392；
Example 208 methyl (S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):368；
Example 209 Ethyl (S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):382；
Example 210 propyl (S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):396；
Example 211 isopropyl (S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):396；
Example 212 isobutyl (S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):410；
Example 213 methyl (S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):364；
Example 214 Ethyl (S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):378；
Example 215 propyl (S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):392；
Example 216 isopropyl (S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):392；
Example 217 (S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
ESI-MS[M+H]+(m/z):406；
Example 218 methyl (S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):368；
Example 219 Ethyl (S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):382；
Example 220 propyl (S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):396；
Example 221 (S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
ESI-MS[M+H]+(m/z):396；
Example 222 isobutyl (S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):410；
Example 223 methyl (S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):364；
Example 224 Ethyl (S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):378；
Example 225 propyl (S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):392；
Example 226 (S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
ESI-MS[M+H]+(m/z):392；
Example 227 isobutyl (S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):406；
EXAMPLE 228 methyl (S) -2- [2,4 '-dimethoxy- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):410；
EXAMPLE 229 (S) -ethyl 2- [2,4 '-dimethoxy- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):424；
EXAMPLE 230 propyl (S) -2- [2,4 '-dimethoxy- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):438；
EXAMPLE 231 (S) -isopropyl 2- [2,4 '-dimethoxy- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):438；
Example 232 isobutyl (S) -2- [2,4 '-dimethoxy- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
ESI-MS[M+H]+(m/z):452；
Example 233 preparation of (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) - (1,1' -biphenyl) -4-carboxamido
Step H-1 intermediate A-4 Bibenzoic acid (1g,5mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) were dissolved in 30mL DMF and stirred at room temperature for 2H, intermediate 6,1- (1H-imidazol-1-yl) -3-phenylpropan-2-amine (1.7g,5.5mmol) and DIEA 4mL were added and reacted at 70 ℃ for 5H, TLC monitored for reaction completion. 100mL of water was added to the reaction solution, 56mL of EA was extracted, and the obtained mixture was washed with saturated brine and Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 1.05g of a brown oil in 55% yield. ESI-MS [ M + H ]]+(m/z):382。
Example 234-238 was prepared by amidation of 1- (1H-imidazol-1-yl) -3-phenylpropan-2-amine with variously substituted diphenic acid as starting material in accordance with the procedure for example 233.
Example 234 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4 '-fluoro- (1,1' -biphenyl) -4-carboxamido
ESI-MS[M+H]+(m/z):400；
Example 235 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4 '-methyl- (1,1' -biphenyl) -4-carboxamido
ESI-MS[M+H]+(m/z):396；
Example 236 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2 '-fluoro- (1,1' -biphenyl) -4-carboxamido
ESI-MS[M+H]+(m/z):400；
Example 237 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2 '-methyl- (1,1' -biphenyl) -4-carboxamido
ESI-MS[M+H]+(m/z):396；
Example 238 (S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4 '-dimethoxy- (1,1' -biphenyl) -4-carboxamido
ESI-MS[M+H]+(m/z):442；
The compound 203 was obtained according to the method of example 203, and the compound 203 was hydrolyzed and then subjected to condensation reaction with various amines to obtain example 239-241.
Example 239 (S) -N-methyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionamide
ESI-MS[M+H]+(m/z):349；
Example 240 (S) -N-ethyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionamide
ESI-MS[M+H]+(m/z):363；
Example 241 (S) -N-phenyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionamide
ESI-MS[M+H]+(m/z):411。
Pharmacological study of a portion of the products of the invention
Cell culture in vitro antitumor cell and induced differentiation activity
Human APL cell line HL-60, suspension cultured in 10% fetal calf serum, 100U/mL penicillin, 100ug/mL streptomycin, 0.2% NaHCO3RPMI-1640 culture medium. The culture conditions were 37 ℃ and 5% CO2And saturation humidity. ATRA cell growth inhibitory Activity assay
1. Taking cells in logarithmic proliferation phase, blowing and beating the cells into uniform cell suspension, and making the cell suspension have a volume of 4X 10 per hole4cells/mL were plated at a density of 2mL/well in 24-well plates.
2. A blank control group without any reagent, a group administered with 1. mu.M ATRA alone, and a group administered with 1. mu.M ATRA in combination with 25. mu.M inhibitor were set up, respectively.
3. After 72h of drug incubation, 1.7mL of the 24-well plate supernatant was removed, and 1.8mL of fresh medium was added to continue incubating the cells for 24 h. 50 μ L of the suspended cell suspension was taken and added to 50 μ L of 0.4% trypan blue solution for staining.
4. The number of dead cells and the total number of cells in the control well and the drug-added well were counted using a hemocytometer. The cell growth inhibition rate was determined by the following formula (1-total number of cells in well/total number of cells in control well). times.100%.
The results of the compounds in combination with ATRA inhibiting HL-60 cell line activity are shown in Table 3.
Table 1 percentage inhibitory activity of the compounds of the examples against HL60 in vitro
Measurement of cell differentiation-inducing Activity
1. Embedded cells suspension cells were counted at 4X 105Add one/mL to a 24-well plate, 2 mL/well.
2. Adding medicine, namely adding the prepared medicine into the holes at a certain concentration, and setting up negative control holes and positive medicine control holes, wherein the medicine concentration is 25 mu M. After the medicine is added, the concentration of a medicine solvent DMSO is less than 0.1%, and the concentration of ethanol is less than 1%. And counting for 96 h.
3. And (3) developing, namely suspending the cells by using a 1mL pipette tip, adding 1mL of cell suspension into an ep tube, and centrifuging to collect the cells. 1mL of a color developing solution (14.7mL of 1640 medium, 300. mu.L of NBT and 15. mu.L of PMC) was added thereto and incubated at 37 ℃ for 20 minutes. Centrifuge at 2000r for 3 min, remove supernatant, leave 50. mu.L or add 50. mu.L PBS to resuspend cells.
4. Counting, 20 mul of cell suspension is added on the coated glass slide, the glass slide is covered, and the total cell number and the blue-violet cell number are counted under an objective lens multiplied by 20. The percentage of positive was determined.
5. The experiment was repeated 3 times independently, and the mean and variance were taken.
TABLE 2 percentage of differentiation-inducing activity of the compounds of the examples against HL60 in vitro
From the test results, it is clear that the compound of the general formula I to be protected has good in vitro anti-tumor and differentiation inducing activity after being used together with ATRA, so that the compound has good industrial application prospect.
In vitro antifungal Activity test
The experimental method comprises the following steps: conventional in vitro bacteriostatic assay methods were used (antimicrobial agents and chemotherapeutics, 1995,39(5): 1169).
Experimental materials and methods:
(1) experimental strains
The following 6 common human pathogenic standard fungal strains were selected as screening targets in the experiment, and the fungal strains were provided by Shenyang pharmaceutical university.
Bacterial species name Species Strain selection
Candida albicans Candida albicans SC5314
Candida albicans Candida albicans Y0109
Candida glabrata Candida glabrata 537
Trichophyton rubrum Trichophyton rubrum Cmccftla
Trichophyton verruciformis (Fr.) pers Trichophyton verrucosum
Microsporidian gypseum Microsporum gypseum Cmccfmza
(2) The experimental method comprises the following steps:
preparation of RPMI-1640 medium: RPMI1640(Gibco)10g, NaHCO32.0g of triazorphyrin propanesulfonic acid (sigma), 34.5g of triazorphyrin propanesulfonic acid (sigma), 800mL of sterile distilled water is added for dissolving, 1mol/L of NaOH is used for adjusting the pH value to 7.0, the volume is determined to 1000mL, and the solution is stored at 4 ℃ for standby after being filtered and sterilized by a 0.22 mu m microporous membrane.
Preparing filamentous fungus suspension: filamentous fungi (Trichophyton rubrum, Trichophyton verrucosum and Microsporum gypseum) are continuously subcultured twice on a Sasa medium plate, cultured in an incubator at 35 ℃ for 48h, and 5mL of 0.85% physiological saline is added to the bacterial colony to prepare a bacterial liquid. Adjusting the concentration of the bacterial liquid by using a spectrophotometer, and adjusting the value A to 0.3-0.5; then diluted 50 times with culture medium to obtain inoculum suspension.
Preparing a globular fungus suspension: coccoid (candida albicans, candida glabrata). Inoculating the activated strain on a solid Sha's medium plate by a partition-streaking method, culturing at a constant temperature of 32 ℃ for 2-3 days, taking a proper amount of single colony to a triangular flask containing 10 mL0.85% sterile physiological saline, shaking for 15 minutes, taking a small amount of bacterial liquid on a blood cell counting plate by using a sterilizing gun head, and counting under a microscope. Diluting with RPMI-1640 medium to obtain final bacterial suspension with concentration of 1 × 106one/mL.
Preparing a liquid medicine: 6.40mg of each of the above-mentioned chemical synthesis drugs was weighed, and 1.0mL of dimethyl sulfoxide (DMSO), 1.0mL of Tween 20 and 8.0mL of sterilized distilled water were sequentially added thereto and mixed well. The concentration of the prepared liquid medicine is 0.64 mg/mL. Positive control drugs fluconazole and voriconazole are prepared by the same method.
Inoculation: first, adding RPMI-1640 culture medium: the 1 st well of each row was filled with 180. mu.L of RPMI1640 medium, the 2-11 wells were filled with 100. mu.L of RPMI1640 medium, and the 12 wells were filled with 200. mu.L of RPMI1640 medium. Secondly, adding a medicine sample: adding 20 mu L of liquid medicine to be detected into the 1 st hole, uniformly mixing by using a liquid transfer gun, sucking 100 mu L to 2 holes, sequentially diluting by 2 times to the 10 th hole, uniformly mixing, and discarding 100 mu L. Step three, adding bacterial suspension: 100 mu L of inoculum suspension is added into each of 1-11 holes. Well 11 is growth control and well 12 is blank medium control. The positive control drug is not provided with a blank drug control, namely, the positive control drug is diluted from the 1 st hole by a multiple gradient until the 10 th hole, and the test concentration (mu g/mL) ranges from 256, 128, 64, 32, 16, 8, 4, 2, 1 and 0.5.
Culturing and detecting: and (4) taking the blank control aseptic growth and the positive control good growth as the standard for judging whether the test operation is qualified. Each plate tested 8 samples, and each bacteria was provided with a positive drug control. The test drug dilution method was as above.
TABLE 3 minimal inhibitory concentration (MIC, μ g/ml) of the exemplified compounds
Remarking: FCZ: fluconazole; VCZ: voriconazole.
From the test results, it is clear that the compound of the general formula I and the salts thereof to be protected have good antifungal activity, the antifungal activity of a plurality of compounds is stronger than that of a contrast drug, and compared with the existing antifungal drugs, the compound has the advantages of novel structure, high efficiency, broad spectrum and the like, so the compound has good application prospect.
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms of the compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, as appropriate.
Example 232: tablet formulation
10g of the compound of claim 1 (taking the compound of example 1 as an example) is mixed with 20g of auxiliary materials according to a general pharmaceutical tabletting method, and then the mixture is pressed into 100 tablets, wherein each tablet is 300 mg.
Example 233: capsule preparation
Mixing 10g of the compound of claim 1 (taking the compound in example 107 as an example) with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and filling the mixture into empty capsules, wherein each capsule weighs 300 mg.
Example 234: injection preparation
Using 10g of the compound of claim 1 (exemplified by the compound of example 206) as an active carbon adsorbent, filtering the mixture through a 0.65 μm microporous membrane, and filling the filtered product into nitrogen gas tanks to prepare water-injection preparations, each containing 2mL of the preparation and 100 bottles in total.
Example 235: aerosol formulation
Dissolving 10g of the compound of claim 1 (example 37) in propylene glycol, adding distilled water and other additives, and making into 500mL of clear solution.
Example 236: suppository
50 suppositories were prepared by grinding 10g of the compound of claim 1 (example 113) with the appropriate amount of glycerin, mixing well, adding molten glycerin gelatin, grinding well, pouring into lubricant-coated molds
Example 237: film agent
Using 10g of the compound containing the compound of claim 1 (in the case of the compound of example 117), polyvinyl alcohol, medicinal glycerin, water and the like were swelled under stirring and then dissolved by heating, and then the compound of example 18 was added to the filtrate and dissolved under stirring, and 100 sheets were formed on a film-forming machine.
Example 238: drop pills
10g of the compound containing the compound of claim 1 (taking the compound in example 147 as an example) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then the mixture is dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 239: external liniment
The compound of claim 1 (example 86) is 10g, mixed with 2.5g of emulsifier and other auxiliary materials according to conventional pharmacy method, ground, and added with distilled water to 200 mL.
Example 240: ointment formulation
Prepared by grinding 10g of the compound containing the compound of claim 1 (taking the compound in example 39 as an example), and then uniformly grinding the ground product with 500g of an oily base such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (12)

1. A compound shown in a general formula I or a pharmaceutically acceptable salt thereof,
x is N, C;
m is C6-C10Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S;
R1selected from H, hydroxy, halogen,Nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally substituted by hydroxy, amino or halogen (C)1-C6) Alkyl or (C)1-C6) Alkoxy or mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free carboxyl, salified carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group;
R2is (C)1-C4) Alkoxy group, (C)1-C5) Ester group, (C)1-C5) Amide, (C)6-C10) An aryl amide.
2. A compound of the general formula I according to claim 1,
wherein,
m is phenyl, pyrrolyl or pyrazolyl.
3. A compound of formula I according to claim 1,
wherein,
R1selected from H, hydroxyl, halogen, nitro, amino, cyano and (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) An alkoxy group.
4. A compound of formula I according to claim 1,
wherein,
R2is selected from (C)1-C5) Ester group, (C)1-C5) An amide.
5. A compound of formula I according to claim 1,
wherein,
x is C.
6. A compound or a pharmaceutically acceptable salt thereof,
selected from:
(S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -ethyl 2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -propyl 2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- (2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamido) -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1-phenyl-1H-pyrrole-3-carboxamide
(S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4,5 dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2,4, 5-dimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-methylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2,4, 5-dimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-bromophenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2, 5-dimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-chlorophenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-methoxyphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (4-trifluoromethylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-ethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (4-nitrophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-methylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -isobutyl 2- [2,4, 5-dimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-chlorophenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-methoxyphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [2,4, 5-dimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2,4, 5-trimethyl-1- (2-trifluoromethylphenyl) -1H-pyrrole-3-carboxamide
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-methylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-bromophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-chlorophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-methoxyphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (4-nitrophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-methylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-chlorophenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-methoxyphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propanoic acid isopropyl ester
(S) -2- [ 5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -5-chloro-3-methyl-1- (2-trifluoromethylphenyl) -1H-pyrazole-4-carboxamide
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid propyl ester
(S) -2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -2- [ (1,1' -Biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isobutyl ester
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) - (1,1' -biphenyl) -4-carboxamide
(S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [4 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4 '-fluoro- (1,1' -biphenyl) -4-carboxamido
(S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [4 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -4 '-methyl- (1,1' -biphenyl) -4-carboxamido
(S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [2 '-fluoro- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2 '-fluoro- (1,1' -biphenyl) -4-carboxamido
(S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid methyl ester
(S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid ethyl ester
(S) -propyl 2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionic acid isopropyl ester
(S) -isobutyl 2- [2 '-methyl- (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionate
(S) -N- (1- (1H-imidazol-1-yl) -3-phenylprop-2-yl) -2 '-methyl- (1,1' -biphenyl) -4-carboxamido
(S) -N-methyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propanamide
(S) -N-ethyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propanamide
(S) -N-phenyl-2- [ (1,1' -biphenyl) -4-carboxamido ] -3- (1H-imidazol-1-yl) propionamide.
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable excipient.
8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a composition of claim 7 in the manufacture of a medicament for the treatment and/or prevention of a proliferative disease.
9. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a composition according to claim 7 for the manufacture of a medicament for the combined treatment and/or prevention of cancer.
10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a composition according to claim 7 for the preparation of a medicament for the combined treatment and/or prophylaxis of lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer.
11. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the composition of claim 7 for the preparation of an antifungal medicament.
12. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the composition of claim 7 for the manufacture of a medicament against candida albicans, candida parapsilosis, candida glabrata, cryptococcus neoformans, microsporhium gypseum, trichophyton rubrum, aspergillus fumigatus.
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CN109485607B (en) * 2018-10-25 2020-11-17 沈阳药科大学 Beta-azole-phenyl ketone derivative and application thereof
CN109851560B (en) * 2019-01-09 2020-07-07 河南新天地药业股份有限公司 Biphenyl diazole derivative and preparation method and application thereof
CN110950845B (en) * 2019-11-21 2023-04-18 聊城大学 Formylacetamide azole derivative and application thereof
RU2730492C1 (en) * 2019-12-27 2020-08-24 Федеральное государственное бюджетное образовательное учреждение высшего образования "Российский химико-технологический университет имени Д.И. Менделеева" Method of producing alkyl 2-[([1,1'-biphenyl]-4-carbonyl)amino]-3-(1h-azol-1-yl) propanoates

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Inventor before: Hao Chenzhou

Inventor before: Liu Chunchi

Inventor before: Ren Jinhong

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