Oxazolo- or thiazolo-indole compound or derivative thereof, and use thereof

Abstract

Provided in the present invention are an oxazolo- or thiazolo-indole compound having a structure as represented by formula I or a derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug molecule thereof, a deuterated compound thereof or a tritiated compound thereof, and the use thereof. The oxazolo or thiazolo-indole compound or derivative thereof provided in the present invention is a compound with a new structure. The compound exhibits a relatively good inhibitory activity against both xanthine oxidases and uric acid transporters, XOR / URAT1 dual inhibition, and good uric acid-lowering effects. Moreover, the compound has high safety, desirable pharmacokinetic properties, and high druggability, and can be used in the preparation of uric acid-lowering drugs for preventing and / or treating gout or hyperuricemia.

Description

Oxazole or thiazole indole compounds or derivatives thereof and applications thereof

[0001] The present application claims priority to the Chinese patent application No. 2024110326519, filed on July 30, 2024, and entitled "Oxazole or thiazole indole compounds or derivatives thereof and applications thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of medicinal chemistry, and relates to uric acid-lowering drugs, in particular to a class of oxazole or thiazole indole compounds or derivatives thereof and applications thereof in lowering uric acid. BACKGROUND

[0003] Uric acid is the final product of purine metabolism in humans and non-human primates, which is formed by the catalysis of xanthine oxidase. Humans do not have uricase, and uric acid can only be excreted out of the body through the intestines and the kidneys. Due to the popularity of Western diets, excessive intake of purines through diet, a large number of cell deaths in a short period of time (tumor lysis syndrome), and genetic or environmental factors that cause low efficiency of uric acid excretion pathways, all of which can lead to hyperuricemia. A large amount of basic and clinical medical data shows that, whether or not uric acid crystals are formed, hyperuricemia itself is an independent high-risk factor, and is related to the pathogenesis of many diseases of the body (such as diabetic nephropathy, other chronic kidney diseases, and cardiovascular and cerebrovascular diseases). The normal value range of human blood uric acid is 3-6.0 mg / dl (180-360 umol), and the solubility of uric acid is <6.5 mg / dl (37℃, pH 7.0). When the concentration exceeds this value, crystals may be formed, and the pH value and temperature decrease promote the formation of crystals, which are deposited in the joints of the distal extremities or other parts of the body (such as blood vessels and kidneys), causing cell damage and inflammation, and causing great pain to patients and seriously affecting the quality of life of patients. Hyperuricemia accounts for 8% of the total population, and gout patients account for 4% of the total population. Among people over 60 years old, more than 10% of them will have gout attacks.

[0004] Currently, the drugs used for lowering uric acid mainly include the following: allopurinol or febuxostat inhibits xanthine oxidase to reduce the generation of uric acid; benzbromarone interferes with the reabsorption of uric acid in the kidneys to promote the excretion of uric acid; or for patients with refractory hyperuricemia, exogenous recombinant, modified uricase (even combined with immunosuppressants) is used to degrade uric acid; or some single-target drugs targeting uric acid transport proteins, such as Lesinurad approved in the United States in 2015 and withdrawn from the market in 2019, and Dotinurad approved in Japan.

[0005] Current drugs and treatment methods have their limitations, and there is a huge unmet clinical need for hyperuricemia and gout patients, so it is necessary to develop safe and effective new uric acid-lowering drugs. From the mechanism of action and pharmacokinetics, the strategy of simultaneously attacking the pathways of uric acid generation (xanthine oxidase) and uric acid reabsorption (urate transporter URAT1, gene name SLC22A12) with a single molecule is more advantageous than the strategy of attacking them separately. Pfizer developed a XOR / URAT1 dual inhibitor, a dual-target molecule PF-06743649, but it stopped at the clinical phase I because a few patients developed acute kidney injury. Therefore, it is necessary to develop a new dual-target uric acid-lowering drug to benefit hyperuricemia patients and reduce the burden of national medical payment. SUMMARY

[0006] In view of the above problems, the present application provides an oxazole or thiazole indole compound or its derivative, which has good inhibitory activity on xanthine oxidase (XOR) and uric acid transporter (URAT1), is a XOR / URAT1 dual inhibitor, and has good uric acid-lowering effect.

[0007] The present application comprises the following technical solutions:

[0008] The oxazole or thiazole indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritium, having the structure shown in Formula I,

[0009] wherein M is selected from: N, O, CR 1 , S;

[0010] X is selected from: CR 1 , N;

[0011] Y is selected from: N, O, CR 1 , S;

[0012] M, X and Y together with the carbon atoms connected thereto form a heteroaromatic ring;

[0013] Z is selected from: CR 3 , N;

[0014] W is selected from: CR 4 , N;

[0015] Q is selected from: halogen, cyano;

[0016] L is selected from: R 5 substituted or unsubstituted C6-C10 aryl, R 5 substituted or unsubstituted 5-10 membered heteroaryl,

[0017] X 1 , X 2 are each independently selected from the group consisting of: O, S, CH2, NH;

[0018] Z 1 , Z 2 , and Z 3 are each independently selected from the group consisting of: CH, N;

[0019] each R 1 is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, halogen-substituted C1-C6 alkyl, C6-C10 aryl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkylthio, (C1-C6 alkyl)2N-C(=O)-substituted C1-C6 alkyl, (C1-C6 alkyl)N(H)-C(=O)-substituted C1-C6 alkyl; 14 aryl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkylthio, (C1-C6 alkyl)2N-C(=O)-substituted C1-C6 alkyl, (C1-C6 alkyl)N(H)-C(=O)-substituted C1-C6 alkyl;

[0020] R 3 and R 4 are each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkylthio;

[0021] each R 5 is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 6 substituted or unsubstituted C6-C10 aryl, R 10 aryl, R 6 substituted or unsubstituted 5-10 membered heteroaryl;

[0022] each R 6 is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehydo, carboxy, nitro, hydroxy;

[0023] each R is independently selected from the group consisting of: hydrogen, hydroxy, hydroxylamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino.

[0024] In some embodiments, only one of M, X, Y is CR 1 .

[0025] In some embodiments, the oxazoles or thiazoloindoles have a structure according to Formula II-1, II-2, II-3, or II-4:

[0026] wherein M is selected from the group consisting of: O, S;

[0027] Y is selected from the group consisting of: O, S.

[0028] In some embodiments, the oxazoles or thiazoloindoles have a structure according to Formula III-1, III-2, III-3, or III-4:

[0029] In some embodiments, the oxazoles or thiazoloindoles have a structure according to Formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV-11, or IV-12:

[0030] In some embodiments, each R 1 is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkylthio, halogen, halogen-substituted C1-C3 alkyl, C6-C10 aryl-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylthio, (C1-C3 alkyl)2N-C(=O)-substituted C1-C3 alkyl, (C1-C3 alkyl)N(H)-C(=O)-substituted C1-C3 alkyl. 10 is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkylthio, halogen, halogen-substituted C1-C3 alkyl, C6-C10 aryl-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylthio, (C1-C3 alkyl)2N-C(=O)-substituted C1-C3 alkyl, (C1-C3 alkyl)N(H)-C(=O)-substituted C1-C3 alkyl.

[0031] In some embodiments, each R 1 is independently selected from the group consisting of: hydrogen, methyl, ethyl, n-propyl, i-propyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoroethyl,

[0032] In some embodiments, R 3 and R 4 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylthio.

[0033] In some embodiments, R 4 is hydrogen.

[0034] In some embodiments, R 3 is selected from: hydrogen, C1-C3 alkyl, halogen.

[0035] In some embodiments, R 3 and R 4 are each independently selected from: hydrogen, methyl, fluoro, chloro, trifluoromethyl, methoxy.

[0036] In some embodiments, R 3 is selected from: hydrogen, methyl, fluoro, chloro.

[0037] In some embodiments, Q is selected from: cyano, bromo, chloro.

[0038] In some embodiments, Q is cyano.

[0039] In some embodiments, X 1 is selected from: O, S, X 2 is NH; Z 1 , Z 2 , and Z 3 are each independently selected from: CH, N.

[0040] In some embodiments, each R 5 is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, thiol, amino, R 6 substituted or unsubstituted phenyl, R 6 substituted or unsubstituted naphthyl, R 6 substituted or unsubstituted 5-6 membered heteroaryl;

[0041] each R is independently selected from: hydrogen, hydroxy, hydroxylamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

[0042] In some embodiments, each R 6 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy.

[0043] In some embodiments, each R 5independently selected from the group consisting of: hydrogen, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehydo, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxy, mercapto, amino, methoxysubstituted methyl, methoxysubstituted ethyl, methoxysubstituted propyl, methoxysubstituted methoxy, methoxysubstituted ethoxy, methoxysubstituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl.

[0044] In some embodiments, L is selected from the group consisting of: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl,

[0045] X 1 , X 2 are independently selected from the group consisting of: O, S, CH2, NH;

[0046] Z 1 , Z 2 , and Z 3 are independently selected from the group consisting of: CH, N.

[0047] In some embodiments, L is selected from the group consisting of: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 6 membered nitrogen heteroaryl.

[0048] In some embodiments, L is selected from the group consisting of: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted pyridyl, R 5 substituted or unsubstituted pyrazinyl, R 5 substituted or unsubstituted pyridazinyl, R 5 substituted or unsubstituted pyrimidinyl,

[0049] In some embodiments, L is selected from the group consisting of:

[0050] In some embodiments, L is selected from the group consisting of:

[0051] In some embodiments, the oxazoles or thiazoloindoles have a structure as shown in Formula V-1 or Formula V-2:

[0052] In some embodiments, R 1 is selected from: hydrogen, C1-C6 alkyl.

[0053] In some embodiments, R 1 is selected from: hydrogen, methyl, ethyl, isopropyl.

[0054] In some embodiments, R 1 is selected from: methyl, ethyl.

[0055] In some embodiments, R 3 is selected from: hydrogen, C1-C6 alkyl, halogen.

[0056] In some embodiments, R 3 is selected from: hydrogen, methyl, fluorine.

[0057] In some embodiments, L is selected from: 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 6-membered nitrogen heteroaryl; R 5 is selected from: hydrogen, carboxyl, hydroxyl.

[0058] In some embodiments, L is selected from:

[0059] In some embodiments, L is selected from:

[0060] The present application also provides uses of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, including the following technical solutions:

[0061] The present application also provides uses of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof in the preparation of xanthine oxidase inhibitors and / or URAT1 inhibitors.

[0062] The present application also provides uses of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof in the preparation of xanthine oxidase inhibitors and / or URAT1 inhibitors.

[0063] The oxazole or thiazoloindole compound or derivative thereof, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug molecule thereof, or deuteride thereof, or tritide thereof described in the present application is used for preparing a drug for preventing and / or treating gout or hyperuricemia.

[0064] The present application also provides an XOR / URAT1 dual inhibitor, which contains the active ingredient of the oxazole or thiazoloindole compound or derivative thereof, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug molecule thereof, or deuteride thereof, or tritide thereof described in the present application.

[0065] The present application also provides a uric acid-lowering drug, which is prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, wherein the active ingredient comprises the oxazole or thiazoloindole compound or derivative thereof, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug molecule thereof, or deuteride thereof, or tritide thereof described in the present application.

[0066] The present application also provides a method for preventing and / or treating gout or hyperuricemia, which comprises:

[0067] administering a safe and effective amount of the oxazole or thiazoloindole compound or derivative thereof, or stereoisomer thereof, or pharmaceutically acceptable salt thereof, or solvate thereof, or prodrug molecule thereof, or deuteride thereof, or tritide thereof described in the present application to a patient with gout or hyperuricemia; and / or,

[0068] administering a safe and effective amount of the uric acid-lowering drug described in the present application to a patient with gout or hyperuricemia.

[0069] The oxazole or thiazoloindole compound or derivative thereof provided by the present application is a novel compound, which has good inhibitory activity on xanthine oxidase and urate transporter, is an XOR / URAT1 dual inhibitor, has good uric acid-lowering effect, good safety, good pharmacokinetic properties, high drug-making property, good in vivo efficacy, and can be used for preparing a uric acid-lowering drug, for preventing and / or treating gout or hyperuricemia. DETAILED DESCRIPTION

[0070] In order to facilitate the understanding of the present application, the present application will be described more fully below. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0071] The experimental procedures in the following examples, where not otherwise specified, were carried out under conventional conditions or as suggested by the manufacturer. The various common chemical reagents used in the examples are commercially available.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0073] In addition, as used herein, the term "or" is the inclusive, not the exclusive, "or" and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for the inclusion of other factors based on the context, unless the context clearly dictates otherwise. Furthermore, throughout the specification, "one", "a", and "the" are used inclusively unless the context clearly dictates otherwise. "In" includes "in" and "on".

[0074] In the compounds described herein, when any variable (e.g. R 5 If any variable occurs more than one time, for example, in a substituent group, its definition on each occurrence is independent of its definition at any other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in chemically sensible compounds. A line drawn to a ring indicates that the bond can be attached to any available carbon atom of the ring. If the ring system is polycyclic, it means that the bond is attached to any appropriate carbon atom of the adjacent ring. It is understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the application which result in a stable compound and which are easily synthesized from readily available starting materials by the methods described and hereafter presented. If a substituent is itself substituted with more than one group, it is understood that the groups can be on the same carbon atom or on different carbon atoms, as long as the structure is stable.

[0075] The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6alkyl" as defined includes groups with 1, 2, 3, 4, 5, or 6 carbon atoms in linear or branched arrangements. For example, "C1-C6alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl.

[0076] As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, and the like.

[0077] As used herein, the term "heteroaryl" or "heteroaromatic" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S, which aromatic ring can be monocyclic, bicyclic, or polycyclic, for example including, but not limited to, quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, and the like; "heteroaryl" is also understood to include N-oxide derivatives of any nitrogen-containing heteroaryl group. Attachment of a heteroaryl group can be through a carbon atom or through a heteroatom.

[0078] As used herein, "halo" or "halogen" means chlorine, fluorine, bromine, and iodine, as understood by those skilled in the art.

[0079] The present application includes the free form of the compounds of Formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Included are pharmaceutically acceptable salts not only of the specific compounds described herein, but also of all the free forms of the compounds of Formula I. The free form of a particular salt of a compound can be isolated using techniques known in the art. The pharmaceutically acceptable salts of the present application can be synthesized from the compounds of the present application which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared by reacting the free base with a chemically acceptable inorganic or organic acid by conventional means. Similarly, the salts of the acidic compounds are prepared by reacting the free acid with a chemically acceptable inorganic or organic base by conventional means.

[0080] Thus, pharmaceutically acceptable salts of the compounds of this application include the conventional nontoxic salts of the compounds of the present application as formed by reaction with inorganic or organic acids. For example, conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, and organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic, and the like.

[0081] If the compound of the present application is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyldiamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0082] Metabolites of the compounds of the present application and pharmaceutically acceptable salts thereof, and prodrugs that can be converted to the structures of the compounds of the present application and pharmaceutically acceptable salts thereof in vivo, are also within the scope of the present application.

[0083] The present application provides a pharmaceutical for lowering uric acid, and a pharmaceutical or a method for preventing and / or treating gout or hyperuricemia, which comprises (administering to a patient or a subject) a safe and effective amount of an active ingredient (i.e., an oxazolyl or thiazolyl indole compound or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof, as described herein) and a pharmaceutically acceptable excipient. The pharmaceutical is administered by administering a safe and effective amount of the active ingredient to a mammal (e.g., a human) in need of treatment, wherein the amount is administered in a pharmaceutically effective amount. Of course, the specific amount will depend on the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.

[0084] A "safe and effective amount" means an amount of the active ingredient sufficient to significantly induce a positive improvement in the condition and not cause significant adverse side effects.

[0085] A "pharmaceutically acceptable excipient" means one or more compatible solid or liquid filler diluents or gel materials which are suitable for use in manufacturing drugs, and which are acceptable to the U.S. Food and Drug Administration as well as to the drug regulatory authorities of the countries in which they are to be distributed and used.

[0086] "Compatible" means that the components of the composition are capable of being commingled with the active ingredients of the present application, and with each other, in the particular preparation herein without any chemical incompatibility resulting in, for example, an undesirable chemical reaction or degradation.

[0087] Pharmaceutically acceptable examples of carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0088] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0089] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0090] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components:

[0091] (a) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silica;

[0092] (b) Adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0093] (c) Moisturizers, such as glycerin;

[0094] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginate, certain complex silicates, and sodium carbonate;

[0095] (e) Slow solvents, such as paraffin;

[0096] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0097] (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0098] (h) Adsorbents, such as kaolin; and

[0099] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0100] The solid dosage forms can also be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the digestive tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0101] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, or combinations thereof. In addition, if desired, the compositions can contain minor amounts of wetting or emulsifying agents, or

[0102] Suspensions, in addition to the active ingredient, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, agar-agar, and the like. Oils, in particular, cottonseed oil, sesame oil, olive oil, corn oil, and the like, or mixtures thereof, can also be used.

[0103] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0104] The compounds of the present application can be administered alone, or in combination with known treatments or other drugs that improve the same conditions. When administered in combination, the previously known drugs are administered at their usual dose, while the compound of Formula I is administered simultaneously or sequentially. When the compound of Formula I is administered simultaneously with the other drug(s), the use of a pharmaceutical composition containing both the known drug(s) and the compound of Formula I is preferred. The combination of drugs also includes the administration of the compound of Formula I and the other known drug(s) within a time period that will allow the combination of the two drugs to have a therapeutic effect. When the compound of Formula I is administered in combination with the other drug(s), the dose of the compound of Formula I or the known drug(s) can be lower than when they are administered alone.

[0105] The present application is further illustrated by the following examples. It is to be understood that these examples are merely illustrative of the present application and do not in any way limit the scope of the application. The following examples do not describe specific conditions unless otherwise noted. The methods used in the following examples were generally carried out according to routine conditions, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0106] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this application belongs. Also, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The methods and materials described herein are illustrative only and not intended to be limiting.

[0107] The starting materials used in the following examples can be obtained commercially, or prepared by known methods in the art, or prepared according to the methods described herein.

[0108] The following abbreviations are used for the reagents used in the following examples:

[0109] NIS: N-iodosuccinimide;

[0110] TEA: triethylamine;

[0111] DMF: N,N-dimethylformamide;

[0112] DCM: dichloromethane;

[0113] THF: tetrahydrofuran;

[0114] TFA: trifluoroacetic acid;

[0115] DMSO: dimethylsulfoxide;

[0116] NMP: N-methylpyrrolidinone;

[0117] NBS: N-bromosuccinimide;

[0118] NCS: N-chlorosuccinimide;

[0119] DMAc: N,N-dimethylacetamide.

[0120] Example 1 Preparation of Compound 1

[0121] Step 1: Synthesis of 4-iodo-2-methyl-5-aminobenzoxazole (Intermediate 1-1)

[0122] To 2-methyl-5-aminobenzoxazole (200 mg, 1.35 mmol) in acetonitrile (7 ml) was added NIS (334 mg, 1.48 mmol) and the reaction was stirred at 0 °C for 4 hours. The reaction was concentrated and treated with water, extracted with dichloromethane, and the organic phase was dried, concentrated under reduced pressure and column purified to give the product as a yellow oil (87 mg, 24%).

[0123] 1H NMR (400 MHz, CDC13) δ 7.21 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.11 (s, 2H), 2.62 (s, 3H).

[0124] Step 2: Synthesis of 4-trimethylsilanylyl-2-methyl-5-aminobenzoxazole (Intermediate 1-2)

[0125] In triethylamine (3.5 ml), was added 4-iodo-2-methyl-5-aminobenzoxazole (176 mg, 0.64 mmol), trimethylsilanylyl (95 mg, 0.96 mmol), CuI (13 mg, 0.06 mmol), Pd(dppf)Cl2(47 mg, 0.06 mmol). Then the reaction was stirred at 80 °C for 12 h, treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and the residue was dried and then columned to give the product as a brown solid (138 mg, 81%).

[0126] 1 H NMR (400 MHz, CDC13) δ 7.21 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.11 (s, 2H), 2.62 (s, 3H).

[0127] Step 3: Synthesis of 2-methyl-6H-oxazolo[4,5-e]indole (Intermediate 1-3)

[0128] In DMF (3 ml), was added 4-trimethylsilanylyl-2-methyl-5-aminobenzoxazole (125 mg, 0.51 mmol), CuI (195 mg, 1.02 mmol). Then the reaction was stirred at 120 °C for 2 h, treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and the residue was dried and then columned to give the product as a white solid (26 mg, 30%).

[0129] 1 H NMR (400 MHz, CDC13) δ 7.21 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.11 (s, 2H), 2.62 (s, 3H).

[0130] Step 4: Synthesis of 8-formyl-2-methyl-6H-oxazolo[4,5-e]indole (Intermediate 1-4)

[0131] In DMF (2.5 ml) was added 2-methyl-6H-oxazolo[4,5-e]indole (80 mg, 0.46 mmol), POCl3(75 mg, 0.49 mmol). Then the reaction was stirred at room temperature for 12 hours. Then NaOH aqueous solution (2.0 M) was added and heated to 70 °C for 1 hour. DCM was added to extract the product. The organic phase was dried, concentrated under reduced pressure and then column purified to give the product as yellow oil (33 mg, 36%).

[0132] 1 HNMR (400 MHz, CDC13) δ 10.49 (s, 1H), 9.24 (br s, 1H), 8.01 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 2.74 (s, 3H).

[0133] Step 5: Synthesis of 8-cyano-2-methyl-6H-oxazolo[4,5-e]indole (Intermediate 1-5)

[0134] In THF (12 ml) was added 8-formyl-2-methyl-6H-oxazolo[4,5-e]indole (410 mg, 2.05 mmol), hydroxylamine hydrochloride (285 mg, 4.10 mmol) and pyridine (650 mg, 8.20 mmol). Then the reaction was stirred at 80 °C for 7 hours. Acetic anhydride (2.0 ml) was then added and stirred for 12 hours. Then NaOH aqueous solution (2.0 M) was added to basify the reaction at room temperature and stirred for half an hour. DCM was added to extract the product. The organic phase was dried, concentrated under reduced pressure and then column purified to give the product as white solid (142 mg, 35%).

[0135] MS (ESI) calcd for C 11 H7N3O: 197.1; found: 198.0 [M + 1].

[0136] Step 6: Synthesis of 4-(8-cyano-2-methyl-6H-oxazolo[4,5-e]indol-6-yl)- benzoic acid tert-butyl ester (Intermediate 1-6)

[0137] In DMF (2 ml) was added 8-cyano-2-methyl-6H-oxazolo[4,5-e]indole (80 mg, 0.41 mmol), Cs2CO3(198 mg, 0.61 mmol), 4-fluoro-benzoic acid tert-butyl ester (96 mg, 0.49 mmol). Then the reaction was stirred at 80 °C for 12 hours and cooled to room temperature. Water was then added to the reaction and DCM was added to extract the product. The organic phase was dried, concentrated under reduced pressure and then column purified to give the product as yellow oil (65 mg, 42%).

[0138] MS (ESI) calcd for C 22 H 19 N3O3: 373.14; found: 374.15 [M + 1].

[0139] 1 H NMR (400 MHz, CDC13) δ 8.21 (d, J = 8.4 Hz, 2H), 7.88 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 2.75 (s, 3H), 1.64 (s, 9H).

[0140] Step 7: Synthesis of 4-(8-cyano-2-methyl-6H-oxazolo[4,5- e]indol-6-yl)-benzoic acid (Compound 1)

[0141] In TFA (1 ml), add tert-butyl 4-(8-cyano-2-methyl-6H-oxazolo[4,5- e]indol-6-yl)-benzoate (60 mg, 0.16 mmol). Then react at 60 °C for 2 hours, then concentrate under reduced pressure and dry, add ethyl acetate, filter, dry to obtain the target product (23 mg, 45%).

[0142] MS (ESI) calcd for C 18 H 11 N3O3: 317.1; found: 318.1 [M + 1].

[0143] 1 H NMR (400 MHz, DMSO-D6) δ 8.75 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 2.72 (s, 3H)

[0144] Preparation of Example 2 Compound 6

[0145] Step 1: Synthesis of ethyl 4-(8-cyano-2-methyl-6H-oxazolo[4,5- e]indol-6-yl)-2-(methoxymethylideneoxy)benzoate (Intermediate 6-1)

[0146] To 8-cyano-2-methyl-6H-oxazolo[4,5-e]indole (120 mg, 0.61 mmol), Cs2CO3(290 mg, 0.91 mmol), ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (209 mg, 0.91 mmol) in DMF (3.5 ml) was added. Then react at 85 °C for 12 h, cool to room temperature. Then treat the reaction with water, extract with dichloromethane, dry the organic phase and concentrate under reduced pressure. Dryness followed by column chromatography gave the product as a white solid (86 mg, 34%).

[0147] MS (ESI) calcd for C 22 H 19 N3O5: 405.13; found: 406.15 [M+1].

[0148] 1 H NMR (400 MHz, CDC13) δ 8.00 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.4 and 2.0 Hz, 1H), 5.32 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.55 (s, 3H), 2.76 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0149] Step 2: Synthesis of ethyl 4-(8-cyano-2-methyl-6H-oxazolo[4,5-e]indol-6-yl)-2- hydroxybenzoate (Intermediate 6-2)

[0150] To ethyl 4-(8-cyano-2-methyl-6H-oxazolo[4,5-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (85 mg, 0.21 mmol), EtOH (1.0 ml), HCl ethanolic solution (2.0 M, 1.0 ml) in THF (2 ml) was added. Then react at 70 °C for 12 h, cool to room temperature. Then concentrate under reduced pressure and dryness followed by column chromatography gave the product as a yellow solid (60 mg, 76%).

[0151] MS (ESI) calcd for C 20 H 15 N3O4: 361.11; found: 362.00 [M+1].

[0152] Step 3: Synthesis of 4-(8-cyano-2-methyl-6H-oxazolo[4,5-e]indol-6-yl)-2- hydroxybenzoic acid (Compound 6)

[0153] In THF (1.2 ml), add 4-(8-cyano-2-methyl-6H-oxazol[4,5-e]indol-6-yl)-2- hydroxybenzoic acid ethyl ester (60 mg, 0.16 mmol), H2O (0.6 ml), LiOH (140 mg) and ethanol (0.3 ml). Then react at room temperature for 72 hours, then add HCl (2.0 M) to acidify, filter to get the product as a white solid, wash with H2O and EtOH, dry to get the target product (13 mg, 25%).

[0154] MS (ESI) calcd for C 18 H 11 N3O4: 333.07; found: 333.70 [M+1].

[0155] 1 H NMR (400 MHz, DMSO-D6) δ 8.74 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 8.4 and 2.0 Hz, 1H), 2.72 (s, 3H).

[0156] Preparation of compound 13 of Example 3

[0157] Step 1: Synthesis of 7-iodo-2-methyl-6-aminobenzoxazole (Intermediate 13-1)

[0158] In a mixed solvent of dichloromethane (20 ml) and water (20 ml), add 2-methyl-6- aminobenzoxazole (2.0 g, 13.5 mmol), I2 (3.58 g, 14.17 mmol), NaHCO3 (1.7 g, 20.25 mmol), then stir the reaction at 25 °C for 12 hours, extract with ethyl acetate, dry the organic phase, concentrate under reduced pressure, dry to get the product as a yellow solid (1.08 g, 29%) after column.

[0159] MS (ESI) calcd for C8H7IN2O: 273.96; found: 274.90 [M+1].

[0160] 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 3.75 (br s, 2H), 2.61 (s, 3H).

[0161] Step 2: Synthesis of 7-trimethylsilany-2-methyl-6-aminobenzoxazole (Intermediate 13-2)

[0162] In triethylamine (13 ml) was added 7-iodo-2-methyl-6-aminobenzoxazole (1.08 g, 3.94 mmol), trimethylsilane (968 mg, 9.85 mmol), CuI (1.5 g, 0.78 mmol), Pd(dppf)Cl2(288 mg, 0.39 mmol). The reaction was then treated with water after 12 hours at 100 °C, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried to give a yellowish solid product (772 mg, 80%).

[0163] MS (ESI) calcd for C 13 H 16 N2OSi: 244.10; found: 245.00 [M+1].

[0164] 1 H NMR (400 MHz, CDC13) δ 7.36 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.31 (br s, 2H), 2.60 (s, 3H), 0.31 (s, 9H).

[0165] Step 3: Synthesis of 2-methyl-6H-oxazolo[5,4-e]indole (Intermediate 13-3)

[0166] In DMF (85 ml) was added 7-trimethylsilany-2-methyl-6-aminobenzoxazole (5.35 g, 21.9 mmol), CuI (8.34 g, 43.8 mmol). The reaction was then treated with water after 2 hours at 120 °C, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried to give a yellowish solid product (1.29 g, 34%).

[0167] MS (ESI) calcd for C 10 H8N2O: 172.06; found: 173.00 [M+1].

[0168] 1 H NMR (400 MHz, CDC13) δ 8.57 (br s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 3.2 Hz, 1H), 6.76-6.75 (m, 1H), 2.68 (s, 3H).

[0169] Step 4: Synthesis of 8-formyl-2-methyl-6H-oxazol[5,4-e]indole (Intermediate 13-4)

[0170] In DMF (12 ml) was added 2-methyl-6H-oxazol[5,4-e]indole (1.0 g, 5.81 mmol), POCl3(0.64 ml, 6.97 mmol). Then the reaction was stirred at room temperature for 12 hours. Then NaOH aqueous solution (2.0 M) was added and heated to 70 °C for 1 hour. Then ethyl acetate was added at room temperature and the organic phase was dried, concentrated under reduced pressure and dried to give a yellow solid product (820 mg, 71%).

[0171] MS (ESI) calcd for C 11 H8N2O2: 200.06; found: 201.00 [M+1].

[0172] 1 H NMR (400 MHz, CDC13) δ 10.21 (s, 1H), 9.70 (br s, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 2.73 (s, 3H).

[0173] Step 5: Synthesis of 8-cyano-2-methyl-6H-oxazol[5,4-e]indole (Intermediate 13-5)

[0174] In THF (3 ml) was added 8-formyl-2-methyl-6H-oxazol[5,4-e]indole (80 mg, 0.55 mmol), hydroxylamine hydrochloride (76 mg, 1.10 mmol) and pyridine (0.18 ml, 2.20 mmol). Then the reaction was stirred at 80 °C for 12 hours. Then acetic anhydride (0.51 ml) was added and stirred for 12 hours. Then NaOH aqueous solution (2.0 M) was added at room temperature and stirred for half an hour. Ethyl acetate was added and the organic phase was dried, concentrated under reduced pressure and dried to give a yellow solid product (34 mg, 31%).

[0175] MS (ESI) calcd for C 11 H7N3O: 197.06; found: 198.0 [M+1].

[0176] 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.42 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 2.73 (s, 3H).

[0177] Step 6: Synthesis of 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)- benzoic acid ethyl ester (Intermediate 13-6)

[0178] To 8-cyano-2-methyl-6H-oxazol[5,4-e]indole (50 mg, 0.25 mmol), Cs2C03(124 mg) and 4-fluoro-benzoic acid ethyl ester (64 mg, 0.38 mmol) in DMF (3 ml) was added. Then the reaction was stirred at 80 °C for 12 h, cooled to room temperature. The reaction was then treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried to give the product as a yellow oil (60 mg, 70%).

[0179] MS (ESI) calcd for C 20 H 15 N3O3: 345.11; found: 346.00 [M+1].

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.72 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0181] Step 7: Synthesis of 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)- benzoic acid (Compound 13)

[0182] To 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)-benzoic acid ethyl ester (55 mg, 0.16 mmol), H20 (0.5 ml), LiOH (40 mg) and ethanol (0.5 ml) in THF (1.5 ml) was added. Then the reaction was stirred at room temperature for 12 h, then acidified with HC1 (2.0 M), extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried to give the target product (25 mg, 50%).

[0183] MS (ESI) calcd for C 18 H 11 N3O3: 317.08; found: 317.95 [M+1].

[0184] 1H NMR (400 MHz, DMSO-d6) δ 13.28 (br s, 1H), 8.79 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 2.72 (s, 3H).

[0185] Preparation of compound 18 of Example 4

[0186] Step 1 : Synthesis of methyl 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)-2- (benzyloxy)benzoate (Intermediate 18-1)

[0187] In DMF (6.0 ml) was added 8-cyano-2-methyl-6H-oxazol[5,4-e]indole (197 mg, 1.0 mmol), Cs2C03(489 mg, 1.5 mmol), methyl 4-fluoro-2-(benzyloxy)benzoate (390 mg, 1.5 mmol). Then react at 85 °C for 12 hours, cool to room temperature. Then treat the reaction with water, extract with ethyl acetate, dry the organic phase and concentrate under reduced pressure to dryness then pass through a column to give the product as a white solid (110 mg, 25%).

[0188] MS (ESI) calcd for C 26 H 19 N3O4: 437.14; found: 438.15 [M+1].

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.47-7.45 (m, 2H), 7.39-7.35 (m, 3H), 5.36 (s, 2H), 3.87 (s, 3H), 2.72 (s, 3H).

[0190] Step 2: Synthesis of methyl 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)-2- hydroxybenzoate (Intermediate 18-2)

[0191] In THF (7 ml), add 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)-2- (benzyloxy)benzoic acid methyl ester (100 mg, 0.23 mmol), MeOH (0.5 ml), Pd / C (15 mg), Pd(OH)2(15 mg). Then hydrogenate at 20 °C for 12 h, filter and concentrate under reduced pressure to dryness, add ethyl acetate and stir for half an hour, filter to get the product as a white solid (63 mg, 80%).

[0192] MS (ESI) calcd for C 19 H 13 N3O4: 347.09; found: 348.05 [M+1].

[0193] Step 3: Synthesis of 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)-2- hydroxybenzoic acid (Compound 18)

[0194] In THF (5.0 ml), add 4-(8-cyano-2-methyl-6H-oxazol[5,4-e]indol-6-yl)-2- hydroxybenzoic acid methyl ester (58 mg, 0.17 mmol), LiOH (0.65 ml, 2.0 M), then react at room temperature for 60 h, then acidify by adding HC1 (2.0 M), extract with ethyl acetate, wash the organic phase with H2O and saturated brine, dry and concentrate under reduced pressure to dryness to get the product as a white solid (16 mg, 28%).

[0195] MS (ESI) calcd for C 18 H 11 N3O4: 333.07; found: 334.10 [M+1].

[0196] 1 H NMR (400 MHz, DMSO-D6) δ 8.67 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 6.87 (s, 1H), 6.84 (d, J = 8.4, 1H), 2.72 (s, 3H).

[0197] Preparation of Example 5 Compound 10

[0198] Step 1: Synthesis of 4-(8-formyl-2-methyl-6H-oxazol[4,5-e]indol-6-yl)-2- (methoxymethyleneoxy)benzonitrile (Intermediate 10-1)

[0199] To 8-formyl-2-methyl-6H-thiazolo[4,5-e]indole (166 mg, 0.83 mmol), Cs2C03(405 mg, 1.24 mmol), 4-fluoro-2-(methoxymethyleneoxy)benzonitrile (225 mg, 1.24 mmol) in DMF (4.5 ml) was added. Then reacted at 80 °C for 12 h, cooled to room temperature. The reaction was then treated with water, extracted with dichloromethane, the organic phase was dried and concentrated under reduced pressure. The residue was then columned to give the product as a yellow oil (282 mg, 94%).

[0200] MS (ESI) calcd for C 20 H 15 N3O4: 361.11; found: 362.05 [M+1].

[0201] Step 2: Synthesis of 5-(8-formyl-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)-2-(lH- tetrazol-5-yl)phenol (Intermediate 10-2)

[0202] To 4-(8-formyl-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)-2-(methoxymethyleneoxy)benzonitrile (282 mg, 0.78 mmol), NaN3(178 mg), Et3N hydrochloride (215 mg) in NMP (4 ml) was added. Then reacted at 120 °C for 12 h, cooled to room temperature. After the addition of hydrochloric acid (2.0 M) and filtration, the product was obtained as a brown solid after drying under reduced pressure (131 mg, 47%).

[0203] MS (ESI) calcd for C 18 H 12 N6O3: 360.10; found: 361.10 [M+1].

[0204] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 2.71 (s, 3H).

[0205] Step 3: Synthesis of 5-(8-cyano-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)-2-(lH- tetrazol-5-yl)phenol (Compound 10)

[0206] To 5-(8-formyl-2-methyl-6H-oxazolo[4,5-e]indol-6-yl)-2-(1H-tetrazol-5- yl)phenol (60 mg, 0.17 mmol) in formic acid (2 ml) was added sodium formate (34 mg), NH2OH hydrochloride (18 mg). The reaction was then heated at 120 °C for 3 h, cooled to room temperature, then treated with ice water and filtered to give the product as a off-white solid which was washed with water and dried to give the target product (42 mg, 70%).

[0207] MS (ESI) calcd for C 18 H 11 N7O2: 357.10; found: 358.10 [M+1].

[0208] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.35 - 7.32 (m, 2H), 2.73 (s, 3H).

[0209] Preparation of compound 73 of example 6

[0210] Step 1: Synthesis of 3-methyl-5-nitrobenzo[d]isoxazole (Intermediate 73-1)

[0211] To 2-hydroxy-5-nitroacetophenone (23.0 g, 0.127 mol) in methanolic ammonia (7.0 M, 100 ml) was added portionwise at room temperature, then the reaction was stirred at 25 °C for 4 h, concentrated, then THF (150 ml) was added, followed by NCS (25.4 g, 0.19 mol), K2CO3 (35.1 g, 0.254 mol). The reaction was then continued at 40 °C for 12 h. The reaction was treated with water (300 ml), filtered to give the filter cake which was washed with water and dried to give the product as a light yellow solid (15.1 g, 65%).

[0212] 1 H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 2.4 and 0.8 Hz, 1H), 8.48 (dd, J = 9.2 and 2.4 Hz, 1H), 7.66 (dd, J = 8.8 and 0.8 Hz, 1H), 2.67 (s, 3H).

[0213] Step 2: Synthesis of 3-methyl-5-amino-benzo[d]isoxazole (Intermediate 73-2)

[0214] To 3-methyl-5-nitrobenzo[d]isoxazole (20.0 g, 0.112 mol) in MeOH (200 ml) was added SnCl2.2H2O (88.5 g) at room temperature and heated to reflux for 3 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous K3PO4solution to pH = 10 and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give the product as off-white solid (9.7 g, 58%).

[0215] MS (ESI) calcd for C8H8N2O: 148.06; found: 149.35 [M + 1].

[0216] 1 HNMR (400 MHz, CDC13) δ 7.34 (dd, J = 8.8 and 0.8 Hz, 1H), 6.93 (ddd, J = 8.8 and 2.4 Hz, 1H), 6.81 (dd, J = 2.4 and 0.8 Hz, 1H), 3.71 (br s, 2H), 2.50 (s, 3H).

[0217] Step 3: Synthesis of 3-methyl-4-iodo-5-amino-benzo[d]isoxazole (Intermediate 73-3)

[0218] To 3-methyl-5-amino-benzo[d]isoxazole (9.7 g, 65.51 mmol) in acetonitrile (150 ml) was added NIS (15.5 g, 68.78 mmol) and stirred at 25 °C for 2 h. The reaction mixture was concentrated and treated with water. The reaction mixture was extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give the product as off-white solid (7.4 g, 41%).

[0219] 1 HNMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.33 (br s, 2H), 2.59 (s, 3H).

[0220] Step 4: Synthesis of 4-trimethylsilanediyl-3-methyl-5-amino-benzo[d]isoxazole (Intermediate 73-4)

[0221] To 3-methyl-4-iodo-5-amino-benzo[d]isoxazole (7.4 g, 26.89 mmol) in triethylamine (75 ml) was added trimethylsilanediyl (7.9 g, 80.67 mmol), CuI (250 mg), Pd(dppf)Cl2(640 mg) and stirred at 80 °C for 12 h. The reaction mixture was filtered with dichloromethane (200 ml) after cooling to room temperature to give the filtrate which was concentrated under reduced pressure and purified by column chromatography to give the product as brown solid (5.0 g, 74%).

[0222] 1 HNMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 5.53 (s, 2H), 2.57 (s, 3H), 0.27 (s, 9H).

[0223] Step 5: Synthesis of 1 -methyl-6H-isoxazol[4,5-e]indole (Intermediate 73-5)

[0224] In DMF (20 ml), add 4-trimethylsilanyl-3-methyl-5-aminobenzisoxazole (2.0 g, 8.18 mmol), CuI (3.1 g, 16.36 mmol). Then treat the reaction with water after 1 hour at 110 °C, add ethyl acetate to extract, dry the organic phase, concentrate under reduced pressure and dry under vacuum, then pass through a column to obtain the product as a light brown solid (0.86 g, 61%).

[0225] MS (ESI) calcd for C 10 H8N2O: 172.06; found: 173.35 [M + 1].

[0226] 1 HNMR (400 MHz, DMSO-d6) δ 11.66 (br s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.57 (t, J = 2.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.82-6.79 (m, 1H), 2.69 (s, 3H).

[0227] Step 6: Synthesis of 8-formyl-1 -methyl-6H-isoxazol[4,5-e]indole (Intermediate 73-6)

[0228] In DMF (10 ml), add 1 -methyl-6H-isoxazol[4,5-e]indole (760 mg, 4.42 mmol), POCl3(0.81 g). Then treat the reaction with NaOH aqueous solution (2.0 M) to pH > 10, at 25 °C for 0.5 hours. Add ethyl acetate to extract, dry the organic phase, concentrate under reduced pressure and dry under vacuum, then pass through a column to obtain the product as a light brown solid (790 mg, 89%).

[0229] 1 HNMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.43 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 2.86 (s, 3H).

[0230] Step 7: Synthesis of 8-cyano-l-methyl-6H-isoxazolo[4,5- e]indole (Intermediate 73-7)

[0231] To 8-formyl-l-methyl-6H-isoxazolo[4,5-e]indole (510 mg, 2.50 mmol) in THF (10 ml) was added hydroxylamine hydrochloride (350 mg, 5.0 mmol) and pyridine (800 mg). The reaction was then heated at 80 °C for 6 hours. Acetic anhydride (2.5 ml) was then added and the reaction was allowed to proceed for 12 hours. The reaction was then basified to pH > 10 with aqueous NaOH (2.0 M) and stirred for half an hour. Ethyl acetate was added and the organic phase was dried, concentrated under reduced pressure and dried in vacuo. The product was then purified by column chromatography to give a light brown solid (190 mg, 38%).

[0232] MS (ESI) calcd for C 11 H7N3O: 197.06; found: 198.30 [M + 1].

[0233] 1 HNMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 2.83 (s, 3H).

[0234] Step 8: Synthesis of 4-(8-cyano-l-methyl-6H-isoxazolo[4,5- e]indol-6-yl)-benzoic acid tert-butyl ester (Intermediate 73-8)

[0235] To 8-cyano-l-methyl-6H-isoxazolo[4,5-e]indole (100 mg, 0.51 mmol) in DMF (2 ml) was added Cs2C03(330 mg, 1.02 mmol) and 4-fluorobenzoic acid tert-butyl ester (200 mg, 1.02 mmol). The reaction was then heated at 100 °C for 12 hours and allowed to cool to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure and dried in vacuo. The product was then purified by column chromatography to give a brown solid (35 mg, 18%).

[0236] MS (ESI) calcd for C 22 H 19 N3O3: 373.14; found: 374.25 [M + 1].

[0237] 1HNMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 9.2 Hz, 1H), 2.88 (s, 3H), 1.59 (s, 9H).

[0238] Step 9: Synthesis of 4-(8-cyano-l-methyl-6H-isoxazolo[4,5- e]indol-6-yl)-benzoic acid (Compound 73)

[0239] In TFA (1 ml), add tert-butyl 4-(8-cyano-l-methyl-6H-isoxazolo[4,5- e]indol-6-yl)-benzoate (37 mg, 0.1 mmol). Then react at 25 °C for 1 hour, then concentrate under reduced pressure and dryness, then add methanol to slurry, filter and dry to get the product as a white solid (22 mg, 70%).

[0240] MS (ESI) calcd for C 18 H 11 N3O3: 317.08; found: 318.20 [M+l].

[0241] 1 HNMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.19 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 9.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 9.6 Hz, 1H), 2.89 (s, 3H).

[0242] Preparation of Example 7 Compound 121

[0243] Step 1: Synthesis of tert-butyl 4-(3-cyano-5-benzyloxy-lH-indol-l-yl)- benzoate (Intermediate 121-1)

[0244] In DMAc (85 ml), add 3-cyano-5-benzyloxy-lH-indole (12.7 g, 51.2 mmol), Cs2CO3(25.1 g, 76.81 mmol), tert-butyl 4-fluoro-benzoate (15.1 g, 76.81 mmol). Then react at 100 °C for 4 hours, cool to room temperature. Then treat the reaction with water (85 ml), filter to get the filter cake, wash with water, then dry at 50 °C, then slurry with ethyl acetate / petroleum ether (1 / 5, 72 ml) to get the product as a brown solid (18.9 g, 85%).

[0245] 1HNMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.12-8.09 (m, 2H), 7.81-7.78 (m, 2H), 7.62 (d, J = 9.2 Hz, 1H), 7.52-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.37-7.33 (m, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 5.23 (s, 2H), 1.58 (s, 9H).

[0246] Step 2: Synthesis of 4-(4-bromo-3-cyano-5-benzyloxy-lH-indol-l-yl)- benzoic acid tert-butyl ester (Intermediate 121-2)

[0247] To 4-(3-cyano-5-benzyloxy-lH-indol-l-yl)-benzoic acid tert-butyl ester (16.3 g, 38.39 mmol) in acetonitrile (240 ml) was added NBS (7.5 g, 42.23 mmol) and the reaction stirred at 70 °C for 4 hours. The reaction was concentrated and treated with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure and the residue taken up in acetonitrile (120 ml) and filtered to give the product as a brown solid (15.7 g, 81 %)

[0248] 1 HNMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.12-8.09 (m, 2H), 7.81-7.78 (m, 2H), 7.62 (d, J = 9.2 Hz, 1H), 7.52-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.37-7.33 (m, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 5.23 (s, 2H), 1.58 (s, 9H).

[0249] Step 3: Synthesis of 4-(4-benzylamino-3-cyano-5-benzyloxy-lH-indol-l-yl)- benzoic acid tert-butyl ester (Intermediate 121-3)

[0250] To 4-(4-bromo-3-cyano-5-benzyloxy-lH-indol-l-yl)-benzoic acid tert-butyl ester (19.4 g, 38.56 mmol) in toluene (190 ml) was added CS2CO3 (25.1 g, 77.13 mmol), benzylamine (8.3 g, 77.13 mmol), Pd(OAc)2 (870 mg, 3.85 mmol) and Ruphos (1.8 g). The reaction was then stirred at 100 °C for 12 hours, filtered and the filtrate concentrated under reduced pressure and taken up in hot acetonitrile (100 ml) and filtered to give the product as a yellow solid (11.4 g, 56 %).

[0251] MS(ESI)calcd for C 34 H 31 N3O3:529.24; found:530.25[M+1].

[0252] 1 HNMR(400MHz, CDCl3)δ8.15(d,J=8.4Hz,2H),7.77(s,1H),7.53(d,J=8.4Hz,2H),7.38-7.21( m,10H),7.02(d,J=9.2Hz,1H),6.98(d,J=9.2Hz,1H),5.00(s,2H),4.57(s,2H),1.58(s,9H).

[0253] Step 4: Synthesis of tert-butyl 4-(4-amino-3-cyano-5-hydroxy-1H-indole-1-yl)benzoate (intermediate 121-4)

[0254] In THF (3 ml), tert-butyl 4-(4-benzylamino-3-cyano-5-benzyloxy-1H-indol-1-yl)benzoate (300 mg, 0.56 mmol), 10% Pd / C (30 mg) and 10% Pd(OH)2 / C (30 mg), and acetic acid (70 mg) were added. The mixture was then hydrogenated at 40 °C for 4 hours. After filtration, the filtrate was concentrated under reduced pressure and evaporated to dryness before being used directly in the next step of the reaction.

[0255] Step 5: Synthesis of tert-butyl 4-(4-propionamido-3-cyano-5-hydroxy-1H-indole-1-yl)benzoate (intermediate 121-5)

[0256] In dichloromethane (2 ml), tert-butyl 4-(4-amino-3-cyano-5-hydroxy-1H-indol-1-yl)benzoate (130 mg) and pyridine (80 mg) were added, followed by the addition of propionyl chloride (42 mg, 0.32 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours, treated with water, extracted with dichloromethane, dried the organic phase, concentrated under reduced pressure, evaporated to dryness, and then passed through a column to obtain a light brown solid product (27 mg, 23%).

[0257] MS(ESI)calcd for C 23 H 23 N3O4:405.17; found:406.05[M+1].

[0258] Step 6: Synthesis of 4-(8-cyano-2-ethyl-6H-oxazol[4,5-e]indol-6-yl)-benzoic acid (compound 121)

[0259] In acetic acid (1 ml), add 4-(4-propionylamino-3-cyano-5-hydroxy-lH-indol-l- yl)-benzoic acid tert-butyl ester (27 mg). Then react at 100 °C for 8 hours, then concentrate under reduced pressure and dry over column to get the product as a light brown solid (15 mg, 68%).

[0260] MS (ESI) calcd for C 19 H 13 N3O3: 331.10; found: 332.20 [M + 1].

[0261] 1 HNMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.18 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 3.07 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H).

[0262] Preparation of compound 139 of example 8

[0263] Step 1 : Synthesis of 2-amino-5-nitrophenol isobutyrate (Intermediate 139-1)

[0264] In dichloromethane (230 ml), add 2-amino-5-nitrophenol (11.45 g, 74.29 mmol), TEA (11.3 g, 111.45 mmol), then isobutyryl chloride (8.71 g, 81.72 mmol) at 0 °C, react at room temperature for 1 hour, treat the reaction solution with saturated Na2CO3 to alkaline, then add dichloromethane to extract, dry the organic phase, concentrate under reduced pressure and dry over column to get the product as a light yellow solid (11.54 g, 69%).

[0265] 1 HNMR (400 MHz, DMSO-d6) δ 7.91 (dd, J = 8.8 Hz and 2.8 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.63 (br s, 2H), 2.94 (sept, J = 6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H).

[0266] Step 2: Synthesis of 2-isopropyl-6-nitrobenzoxazole (Intermediate 139-2)

[0267] In HOAc (170 ml) was added 2-amino-5-nitrophenol isobutyrate (11.54 g, 51.47 mmol) and the reaction was stirred at 100 °C for 12 h. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate and washed with saturated NaHCO3. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give the product as a white solid (5.45 g, 51%).

[0268] 1 HNMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 8.8 and 2.0

[0269] Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 3.37 (sept, J = 7.2 Hz, 1H), 1.40 (d, J = 7.2 Hz, 6H).

[0270] Step 3: Synthesis of 6-amino-2-isopropylbenzoxazole (Intermediate 139-3)

[0271] In methanol (160 ml) was added 2-isopropyl-6-nitrobenzoxazole (5.22 g, 25.32 mmol), 10% Pd / C (260 mg) and 10% Pd(OH)2 / C (260 mg) and the reaction was hydrogenated at 40 °C for 12 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the product as a yellow solid (4.27 g, 95%).

[0272] 1 HNMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.55 (dd, J = 8.8 and 2.0 Hz, 1H), 5.24 (s, 2H), 3.12 (sept, J = 7.2 Hz, 1H), 1.31 (d, J = 7.2 Hz, 6H).

[0273] Step 4: Synthesis of 6-amino-7-iodo-2-isopropylbenzoxazole (Intermediate 139-4)

[0274] In HOAc (80 ml) was added 6-amino-2-isopropylbenzoxazole (4.08 g, 23.25 mmol), NIS (5.73 g, 25.46 mmol) and the reaction was stirred at 25 °C for 2 h. The reaction was concentrated and taken up in water. Ethyl acetate was added and the reaction was washed with saturated NaHCO3. The organic phase was separated, dried, concentrated under reduced pressure and purified by column chromatography to give the product as a brown liquid (5.79 g, 82%).

[0275] 1HNMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 3.17 (sept, J = 7.2 Hz, 1H), 1.33 (d, J = 7.2 Hz, 6H).

[0276] Step 5: Synthesis of 6-amino-7-trimethylsilany-2-isopropylbenzoxazole (Intermediate 139-5)

[0277] In triethylamine (60 ml) was added 6-amino-7-iodo-2-isopropylbenzoxazole (5.79 g, 19.17 mmol), trimethylsilane (5.65 g, 57.51 mmol), CuI (183 mg, 0.96 mmol), Pd(dppf)Cl2(420 mg). After reaction at 80 °C for 12 h, dichloromethane was added, the filtrate was concentrated under reduced pressure and dried, then column chromatography gave the product as a brown liquid (4.97 g, 95%).

[0278] 1 HNMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 3.17 (sept, J = 7.2 Hz, 1H), 1.33 (d, J = 7.2 Hz, 6H).

[0279] Step 6: Synthesis of 2-isopropyl-6H-oxazolo[5,4-e]indole (Intermediate 139-6)

[0280] In DMF (50 ml) was added 6-amino-7-trimethylsilany-2-isopropylbenzoxazole (4.88 g, 17.91 mmol), CuI (6.8 g, 35.82 mmol). After reaction at 100 °C for 2 h, the reaction was treated with water, ethyl acetate was added and the organic phase was dried, concentrated under reduced pressure and dried, then column chromatography gave the product as a brown solid (2.14 g, 59%).

[0281] MS (ESI) calcd for C 12 H 12 N2O: 200.24; found: 201.35 [M + 1].

[0282] 1HNMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.47-7.45 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 3.27 (sept, J = 7.2 Hz, 1H), 1.39 (d, J = 7.2 Hz, 6H).

[0283] Step 7: Synthesis of 8-formyl-2-isopropyl-6H-oxazol[5,4-e]indole (Intermediate 139-7)

[0284] In DMF (7 ml), add 2-isopropyl-6H-oxazol[5,4-e]indole (720 mg, 3.59 mmol), POCl3(660 mg). Then react at room temperature for 12 hours. Then add NaOH aqueous solution (2.0 M) to the reaction solution to pH = 10, react at room temperature for 0.5 hours. Then add ethyl acetate to extract, dry the organic phase, concentrate under reduced pressure, and dry to give a brown solid product (658 mg, 80%).

[0285] MS (ESI) calcd for C 13 H 12 N2O2: 228.25; found: 229.30 [M + 1].

[0286] 1 HNMR (400 MHz, DMSO-d6) δ 12.54 (br s, 1H), 10.02 (s, 1H), 8.37 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 3.35-3.28 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[0287] Step 8: Synthesis of 8-cyano-2-isopropyl-6H-oxazol[5,4-e]indole (Intermediate 139-8)

[0288] In DMF (2 ml), add 8-formyl-2-isopropyl-6H-oxazol[5,4-e]indole (100 mg, 0.44 mmol), hydroxylamine hydrochloride (61 mg, 0.88 mmol), and pyridine (140 mg). Then react at 80 °C for 12 hours. Then add acetic anhydride (0.5 ml) and react for 4 hours. Then add NaOH aqueous solution (2.0 M) to the reaction solution to alkalize to pH > 10 at room temperature, stir for half an hour, add ethyl acetate to extract, dry the organic phase, concentrate under reduced pressure, and dry to give a light brown solid product (80 mg, 81%).

[0289] MS (ESI) calcd for C 13 H 11 N3O: 225.25; found: 226.30 [M + 1].

[0290] 1 HNMR (400 MHz, DMSO-d6) δ 12.58 (br s, 1H), 8.36 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.38-3.30 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[0291] Step 9: Synthesis of 4-(8-cyano-2-isopropyl-6H-oxazolo[5,4- e]indol-6-yl)-benzoic acid tert-butyl ester (Intermediate 139-9)

[0292] To 8-cyano-2-isopropyl-6H-oxazolo[5,4-e]indole (80 mg, 0.36 mmol), Cs2CO3(235 mg), 4-fluoro-benzoic acid tert-butyl ester (141 mg, 0.72 mmol) in DMF (3 ml) was added. Then react at 100 °C for 12 h, cool to room temperature. Then treat the reaction with water, extract with ethyl acetate, dry the organic phase, concentrate under reduced pressure and dryness, then column to give the product as a white solid (66 mg, 46%).

[0293] MS (ESI) calcd for C 24 H 23 N3O3: 401.47; found: 402.30 [M + 1].

[0294] 1 HNMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 3.37 (sept, J = 6.8 Hz, 1H), 1.59 (s, 9H), 1.44 (d, J = 6.8 Hz, 6H).

[0295] Step 10: Synthesis of 4-(8-cyano-2-isopropyl-6H-oxazolo[5,4- e]indol-6-yl)-benzoic acid (Compound 139)

[0296] To 4-(8-cyano-2-isopropyl-6H-oxazol[5,4-e]indol-6-yl)-benzoic acid tert-butyl ester (60 mg, 0.15 mmol) in TFA (1 ml) was added. Then reacted at 25 °C for 1 hour, then concentrated under reduced pressure and dried, then slurried with methanol, filtered and dried to give the product as a white solid (26 mg, 50%).

[0297] MS (ESI) calcd for C 20 H 15 N3O3: 345.36; found: 346.25 [M+1].

[0298] 1 HNMR (400MHz, DMSO-d6) δ 13.31 (brs, 1H), 8.80 (s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 3.42-3.35 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H).

[0299] Preparation of compound 169 of example 9

[0300] Step 1 : Synthesis of 8-bromo-2-methyl-6H-oxazol[4,5-e]indole (Intermediate 169-1)

[0301] To 2-methyl-6H-oxazol[4,5-e]indole (100 mg, 0.58 mmol), NBS (93 mg, 0.52 mmol) in MeCN (3 ml) was added. Then reacted at room temperature for 3 hours. Then treated the reaction with water, extracted with ethyl acetate, dried the organic phase, concentrated under reduced pressure and dried, then passed through a column to give the product as a white solid (116 mg, 79%).

[0302] MS (ESI) calcd for C 10 H7BrN2O: 249.97; found: 250.85, 252.85 [M+1].

[0303] 1 H NMR (400MHz, CDC13) δ 8.60 (brs, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 2.73 (s, 3H).

[0304] Step 2: Synthesis of 4-(8-bromo-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)- benzoic acid methyl ester (Intermediate 169-2)

[0305] In DMF (1.5 ml) was added 8-bromo-2-methyl-6H-thiazolo[4,5-e]indole (116 mg, 0.46 mmol), Cs2CO3(302 mg), 4-fluoro-benzoic acid methyl ester (107 mg, 0.7 mmol). Then react at 80 °C for 12 h, cool to room temperature. Then treat the reaction with water, extract with ethyl acetate, dry the organic phase, concentrate under reduced pressure and dryness, then column to get the yellow solid product (52 mg, 30%).

[0306] MS (ESI) calcd for C 18 H 13 BrN2O3: 384.01; found: 384.90, 386.90 [M+1].

[0307] 1 H NMR (400 MHz, CDC13) δ 8.22 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 2.75 (s, 3H).

[0308] Step 3: Synthesis of 4-(8-bromo-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)- benzoic acid (Compound 169)

[0309] In THF (1.5 ml) was added 4-(8-bromo-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)- benzoic acid methyl ester (52 mg, 0.14 mmol), LiOH (2.0 M, 0.7 ml). Then react at 25 °C for 72 h, add hydrochloric acid (2.0 M) to the reaction solution to pH = 2, filter to get the filter cake, wash with water and ethyl acetate, dry to get the yellow solid product (23 mg, 46%).

[0310] MS (ESI) calcd for C 17 H 11 BrN2O3: 370.00; found: 370.90, 372.90 [M+1].

[0311] 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.8 Hz, 2H), 8.08 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.60 (s, 2H), 2.69 (s, 3H).

[0312] Preparation of compound 265 of example 10

[0313] Step 1 : Synthesis of 4-iodo-2-methyl-5-amino-benzothiazole (intermediate 265-1)

[0314] In acetonitrile (9 ml), was added 2-methyl-5-amino-benzothiazole (500 mg, 3.0 mmol), NIS (685 mg, 3.0 mmol), then stirred at 25 °C for 5 hours, treated with saturated NaHC03(10 ml), extracted with ethyl acetate, dried the organic phase, concentrated under reduced pressure and dried, then columned to give the product as a brown solid (420 mg, 48%).

[0315] MS (ESI) calcd for C8H7IN2S: 289.94; found: 290.80 [M+1].

[0316] Step 2: Synthesis of 4-trimethylsilanylethynyl-2-methyl-5-amino-benzothiazole (intermediate 265-2)

[0317] In triethylamine (85 ml), was added 4-iodo-2-methyl-5-amino-benzothiazole (4.3 g, 14.82 mmol), trimethylsilanylethynyl (4.2 ml, 29.64 mmol), CuI (140 mg), Pd(dppf)Cl2(325 mg). Then reacted at 80 °C for 12 hours, cooled to room temperature, filtered, concentrated under reduced pressure and dried, then columned to give the product as a yellow solid (3.07 g, 80%).

[0318] 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 2.84 (s, 3H), 0.32 (s, 9H).

[0319] Step 3: Synthesis of 2-methyl-6H-thiazolo[4,5-e]indole (intermediate 265-3)

[0320] In DMSO (20 ml) was added 4-trimethylsilanyl-2-methyl-5-aminobenzothiazole (1.0 g, 3.8 mmol), t-BuOK (1.0 M in tetrahydrofuran, 7.6 ml). After reaction at 70 °C for 12 h, the reaction was treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure and dried to give a yellow solid (190 mg, 27%).

[0321] 1 H NMR (400 MHz, CDC13) δ 8.55 (br s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4 and 0.8 Hz, 1H), 7.33-7.26 (m, 1H), 7.15 (s, 1H), 2.94 (s, 3H).

[0322] Step 4: Synthesis of 8-formyl-2-methyl-6H-thiazolo[4,5-e]indole (Intermediate 265-4)

[0323] In DMF (1.5 ml) was added 2-methyl-6H-thiazolo[4,5-e]indole (100 mg, 0.53 mmol), POCl3(97 mg, 0.64 mmol). After reaction at room temperature for 12 h, NaOH aqueous solution (2.0 M) was added to the reaction until pH = 10, and heated to 70 °C for 0.5 h. After cooling to room temperature, ethyl acetate was added to extract the product. The organic phase was dried, concentrated under reduced pressure and dried to give a red solid (45 mg, 39%).

[0324] MS (ESI) calcd for C 11 H8N2OS: 216.04; found: 216.90 [M + 1].

[0325] Step 5: Synthesis of 8-cyano-2-methyl-6H-thiazolo[4,5-e]indole (Intermediate 265-5)

[0326] In THF (4 ml) was added 8-formyl-2-methyl-6H-thiazolo[4,5-e]indole (120 mg, 0.56 mmol), hydroxylamine hydrochloride (77 mg, 1.10 mmol) and pyridine (0.2 ml). After reaction at 80 °C for 5 h, acetic anhydride (0.4 ml) was added and the reaction continued for 12 h. After the reaction was alkalized to pH > 10 by adding NaOH aqueous solution (2.0 M) at room temperature, it was stirred for 0.5 h. Ethyl acetate was added to extract the product. The organic phase was dried, concentrated under reduced pressure and dried to give a white solid (64 mg, 54%).

[0327] MS (ESI) calcd for C11 H7N3S: 213.04; found: 213.90 [M+1].

[0328] Step 6: Synthesis of 4-(8-cyano-2-methyl-6H-thiazolo[4,5- e]indol-6-yl)-benzoic acid methyl ester (Intermediate 265-6)

[0329] To 8-cyano-2-methyl-6H-thiazolo[4,5-e]indole (60 mg, 0.28 mmol), Cs2CO3(180 mg), 4-fluoro-benzoic acid methyl ester (65 mg, 0.42 mmol) in DMF (1 ml) was added. Then react at 80 °C for 12 h, cool to room temperature. Then treat the reaction with water, filter to get the filter cake, wash with water and ethanol, dry to get the product as a light brown solid (29 mg, 30%).

[0330] 1 H NMR (400 MHz, DMSO-D6) δ 8.77 (s 1H), 8.21 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H), 2.92 (s, 3H).

[0331] Step 7: Synthesis of 4-(8-cyano-2-methyl-6H-thiazolo[4,5- e]indol-6-yl)-benzoic acid (Compound 265)

[0332] To 4-(8-cyano-2-methyl-6H-thiazolo[4,5-e]indol-6-yl)-benzoic acid methyl ester (25 mg, 0.07 mmol), LiOH (2.0 M, 0.6 ml) in THF (2 ml) was added. Then react at 25 °C for 12 h, treat the reaction with water (2.0 ml), add hydrochloric acid (2.0 M) to the reaction until pH = 3, filter to get the filter cake, wash with water and ethanol, dry to get the product as a light brown solid (15 mg, 64%).

[0333] MS (ESI) calcd for C 18 H 11 N3O2S: 333.06; found: 333.95 [M+1].

[0334] 1H NMR (400 MHz, DMSO-D6) δ 8.76 (s 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 2.92 (s, 3H).

[0335] Preparation of compound 382 of example 11

[0336] Step 1 : Synthesis of 5-bromo-2-methyl-7-fluorobenzoxazole (Intermediate 382-1 )

[0337] In the presence of triethyl orthoacetate (TEOA, 5 ml), 2-amino-4-bromo-6- fluorophenol (200 mg, 0.97 mmol) was added, then the reaction was stirred at 150 °C for 2 hours, then treated with saturated sodium bicarbonate at room temperature, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried, then columned to give the product as a white solid (201 mg, 91%).

[0338] 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.6 Hz, 1H), 7.23 (dd, J = 9.2 and 1.6 Hz, 1H), 2.67 (s, 3H).

[0339] Step 2: Synthesis of 5-benzylamino-2-methyl-7-fluorobenzoxazole (Intermediate 382-2)

[0340] In the presence of toluene (3 ml), 5-bromo-2-methyl-7-fluorobenzoxazole (200 mg, 0.87 mmol), CS2CO3 (854 mg, 2.62 mmol), benzylamine (187 mg, 1.75 mmol), Pd(OAc)2 (40 mg, 0.17 mmol) and Ruphos (79 mg, 0.17 mmol) were added. Then the reaction was stirred at 100 °C for 12 hours, then treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried, then columned to give the product as a white solid (25 mg, 11%).

[0341] MS (ESI) calcd for C 15 H 13 OFN2: 256.10; found: 257.01 [M + 1].

[0342] 1H NMR (400 MHz, CDC13) δ 7.35 - 7.25 (m, 5H), 6.60 (d, J = 2.4 Hz, 1H), 6.35 (dd, J = 12 and 2.4 Hz, 1H), 4.30 (s, 2H), 2.56 (s, 3H).

[0343] Step 3: Synthesis of 5-amino-2-methyl-7-fluorobenzoxazole (Intermediate 382-3)

[0344] To 5-benzylamino-2-methyl-7-fluorobenzoxazole (110 mg, 0.43 mmol) in methanol (3 ml) was added 10% Pd / C (11 mg) and 10% Pd(OH)2 / C (11 mg) and then hydrogenated at 40 °C for 2 hours. After filtration, the filtrate was concentrated under reduced pressure and dried in vacuo and then columned to give the product as a white solid (33 mg, 48%).

[0345] MS (ESI) calcd for C8H7OFN2: 166.05; found: 167.10 [M + 1].

[0346] 1 H NMR (400 MHz, CDC13) δ 6.70 (d, J = 1.6 Hz, 1H), 6.41 (dd, J = 11.2 and 2.0 Hz, 1H), 3.73 (br s, 2H), 2.60 (s, 3H).

[0347] Step 4: Synthesis of 2-methyl-7-fluoro-4-iodo-5-amino-benzoxazole (Intermediate 382-4)

[0348] To 5-amino-2-methyl-7-fluorobenzoxazole (30 mg, 0.18 mmol) in acetonitrile (1 ml) was added NIS (41 mg, 0.18 mmol) and then stirred at 0 °C for 4 hours. After concentration under reduced pressure and drying in vacuo, the residue was directly columned to give the product as a yellow liquid (40 mg, 76%).

[0349] MS (ESI) calcd for C8H6IOFN2: 291.95; found: 292.90 [M + 1].

[0350] 1 H NMR (400 MHz, CDC13) δ 6.56 (d, J = 11.2 Hz, 1H), 4.18 (br s, 2H), 2.65 (s, 3H).

[0351] Step 5: Synthesis of 4-trimethylsilanylyl-2-methyl-7-fluoro-5-amino-benzoxazole (Intermediate 382-5)

[0352] To a solution of 2-methyl-7-fluoro-4-iodo-5-amino-benzoxazole (40 mg, 0.14 mmol) in triethylamine (1 ml) was added trimethylsilyacetylene (34 mg, 0.34 mmol), CuI (3 mg), Pd(dppf)Cl2(5 mg). After reaction at 80 °C for 12 h, the mixture was cooled to room temperature and concentrated to dryness. The residue was directly purified by column to give the product (10 mg, 28%) as yellow liquid.

[0353] MS (ESI) calcd for C 13 H 15 OFN2Si: 262.09; found: 263.10 [M+1].

[0354] 1 H NMR (400 MHz, CDC13) δ 6.42 (d, J = 11.2 Hz, 1H), 4.32 (br s, 2H), 2.63 (s, 3H), 0.29 (s, 9H).

[0355] Step 6: Synthesis of 2-methyl-4-fluoro-6H-[l,3]oxazolo[4,5-e]indol (Intermediate 382-6)

[0356] To a solution of 4-trimethylsilany-2-methyl-7-fluoro-5-amino-benzoxazole (600 mg, 2.29 mmol) in DMF (10 ml) was added CuI (870 mg). After reaction at 120 °C for 3 h, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column to give the product (253 mg, 58%) as yellow solid.

[0357] MS (ESI) calcd for C 10 H7OFN2: 190.05; found: 191.05 [M+1].

[0358] 1 H NMR (400 MHz, CDC13) δ 8.43 (br s, 1H), 7.26 (s, 1H), 7.07 (d, J = 10.4 Hz, 1H), 6.86 (s, 1H), 2.70 (s, 3H).

[0359] Step 7: Synthesis of 8-formyl-2-methyl-4-fluoro-6H-[l,3]oxazolo[4,5-e]indol (Intermediate 382-7)

[0360] In DMF (7 ml) was added 2-methyl-4-fluoro-6H-[l,3]oxazolo[4,5- e]indole (253 mg, 1.31 mmol), POCl3(600 mg). Then the reaction was stirred at room temperature for 12 hours. Then NaOH aqueous solution (2.0 M) was added to the reaction until pH = 9, and heated to 70 °C for 0.5 hours. Then cooled to room temperature, ethyl acetate was added to extract, the organic phase was dried, concentrated under reduced pressure, and dried to give a brown solid product (200 mg, 70%).

[0361] MS (ESI) calcd for C 11 H7O2FN2: 218.05; found: 219.05 [M + 1].

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (br s, 1H), 10.29 (s, 1H), 8.27 (s, 1H), 7.42 (d, J = 10.8 Hz, 1H), 2.71 (s, 3H).

[0363] Step 8: Synthesis of 8-cyano-2-methyl-4-fluoro-6H-[l,3]oxazolo[4,5- e]indole (Intermediate 382-8)

[0364] In THF (5 ml) was added 8-formyl-2-methyl-4-fluoro-6H-[l,3]oxazolo[4,5- e]indole (80 mg, 0.37 mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and pyridine (115 mg). Then the reaction was stirred at 80 °C for 6 hours. Then acetic anhydride (300 mg) was added and the reaction was stirred at 80 °C for 12 hours. Then NaOH aqueous solution (2.0 M) was added to the reaction until pH = 10 at room temperature, and stirred for half an hour. Ethyl acetate was added to extract, the organic phase was dried, concentrated under reduced pressure, and dried to give a brown solid product (84 mg, 99%).

[0365] MS (ESI) calcd for C 11 H6NFO3: 215.05; found: 216.10 [M + 1].

[0366] Step 9: Synthesis of 4-(8-cyano-2-methyl-4-fluoro-[l,3]oxazolo[4,5- e]indol-6-yl)-benzoic acid tert-butyl ester (Intermediate 382-9)

[0367] To 8-cyano-2-methyl-4-fluoro-6H-[l,3]oxazolo[4,5-e]indole (80 mg, 0.37 mmol), Cs2CO3(242 mg, 0.74 mmol), 4-fluoro-benzoic acid tert-butyl ester (109 mg, 0.56 mmol) in DMF (2 ml) was added. Then reacted at 100 °C for 12 h, cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried to give a light yellow solid product (44 mg, 30%).

[0368] MS (ESI) calcd for C 22 H 18 O3FN3: 391.13; found: 392.20 [M+1].

[0369] Step 10: Synthesis of 4-(8-cyano-2-methyl-4-fluoro-[l,3]oxazolo[4,5- e]indol-6-yl)-benzoic acid (Compound 382)

[0370] To 4-(8-cyano-2-methyl-4-fluoro-[l,3]oxazolo[4,5-e]indol-6-yl)-benzoic acid tert- butyl ester (43 mg, 0.11 mmol) in TFA (1.5 ml) was added. Then reacted at 25 °C for 2 h, then concentrated under reduced pressure and dried, then added n-hexane, filtered and dried to give a white solid product (38 mg, 99%).

[0371] MS (ESI) calcd for C 18 H 10 O3FN3: 335.07; found: 336.05 [M+1].

[0372] 1 HNMR (400 MHz, DMSO-d6) δ 12.49 (br s, 1H), 8.77 (s, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 10.8 Hz, 1H), 2.77 (s, 3H).

[0373] Preparation of Example 12 Compound 455

[0374] Step 1: Synthesis of N-propionyl-4-bromo-2,6-difluoroaniline (Intermediate 455-1)

[0375] In dichloromethane (40 ml), was added 4-bromo-2,6-difluoroaniline (5.0 g, 24.16 mmol), TEA (3.7 g, 36.2 mmol) followed by propionyl chloride (2.5 g, 26.6 mmol) at -10 °C and the reaction stirred at room temperature for 6 h. The reaction was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure and the residue was dried under vacuum and column chromatography to give the product as a white solid (5.0 g, 79%).

[0376] 1 HNMR (400 MHz, CDC13) δ 7.13 (d, J = 9.6 Hz, 2H), 6.75 (br s, 1H), 2.44 (q, J = 7.6, 2H), 1.25 (t, J = 7.6, 3H).

[0377] Step 2: Synthesis of 6-bromo-2-ethyl-4-fluorobenzoxazole (Intermediate 455-2)

[0378] In NMP (150 ml), was added N-propionyl-4-bromo-2,6-difluoroaniline (14.0 g, 53.2 mmol), CS2CO3 (34.7 g, 106.5 mmol) and the reaction stirred at 130 °C for 4 h. The reaction was treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure and the residue was dried under vacuum and column chromatography to give the product as a yellow oil (4.4 g, 34%).

[0379] MS (ESI) calcd for C9H7OBrFN: 242.97; found: 244.25, 246.25 [M+l].

[0380] 1 HNMR (400 MHz, CDC13) δ 7.13 (d, J = 9.6 Hz, 2H), 6.75 (br s, 1H), 2.44 (q, J = 7.6, 2H), 1.25 (t, J = 7.6, 3H).

[0381] Step 3: Synthesis of 6-benzylamino-2-ethyl-4-fluorobenzoxazole (Intermediate 455-3)

[0382] To a solution of 6-bromo-2-ethyl-4-fluorobenzoxazole (8.3 g, 34.2 mmol) in toluene (90 ml) was added CS2CO3 (22.3 g, 68.3 mmol), benzylamine (7.3 g, 68.3 mmol), Pd(OAc)2(1.5 g, 6.8 mmol) and Ruphos (1.3 g, 6.8 mmol). The reaction was then stirred at 100 °C for 12 h, filtered, the filtrate was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and the residue was purified by column chromatography to give the product as a yellow oil (4.9 g, 53%).

[0383] 1 HNMR (400 MHz, CDC13) δ 7.37-7.28 (m, 5H), 6.48 (s, 1H), 6.35 (d, J = 11.6 Hz, 1H), 4.34 (s, 2H), 4.27 (br s, 1H), 2.87 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H).

[0384] Step 4: Synthesis of 6-amino-2-ethyl-4-fluorobenzoxazole (Intermediate 455-4)

[0385] To a solution of 6-benzylamino-2-ethyl-4-fluorobenzoxazole (4.9 g, 18.14 mmol) in methanol (80 ml) was added 10% Pd / C (490 mg) and 10% Pd(OH)2 / C (490 mg) and the reaction was hydrogenated at room temperature for 24 h, filtered and the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give the product as a yellow solid (3.1 g, 95%).

[0386] MS (ESI) calcd for C9H9OFN2: 180.07; found: 181.35 [M + 1].

[0387] 1 HNMR (400 MHz, CDC13) δ 7.37-7.28 (m, 5H), 6.48 (s, 1H), 6.35 (d, J = 11.6 Hz, 1H), 4.34 (s, 2H), 4.27 (br s, 1H), 2.87 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H).

[0388] Step 5: Synthesis of 2-ethyl-4-fluoro-7-iodo-6-aminobenzoxazole (Intermediate 455-5)

[0389] In acetonitrile (50 ml), was added 6-amino-2-ethyl-4-fluorobenzoxazole (3.1 g, 17.22 mmol), NIS (3.8 g, 17.22 mmol) and stirred at 25 °C for 4 h. After concentration, the reaction was treated with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was dried and purified by column to give the product (2.2 g, 42%) as yellow solid.

[0390] MS (ESI) calcd for C9H8OFIN2: 305.97; found: 307.10 [M+1].

[0391] 1 HNMR (400 MHz, CDC13) δ 6.51 (d, J = 11.2 Hz, 1H), 2.93 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H).

[0392] Step 6: Synthesis of 7-trimethylsilanylene-2-ethyl-4-fluoro-6-aminobenzoxazole (Intermediate 455-6)

[0393] In triethylamine (30 ml), was added 2-ethyl-4-fluoro-7-iodo-6-aminobenzoxazole (2.2 g, 7.2 mmol), trimethylsilane (1.4 g, 14.4 mmol), CuI (140 mg, 0.72 mmol), Pd(dppf)Cl2(500 mg). After reaction at 80 °C for 12 h, dichloromethane was added. The filtrate was concentrated under reduced pressure and dried. The residue was purified by column to give the product (1.9 g, 96%) as brown solid.

[0394] 1 HNMR (400 MHz, CDC13) δ 6.51 (d, J = 11.2 Hz, 1H), 2.93 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H).

[0395] Step 7: Synthesis of 2-ethyl-4-fluoro-6H-[l,3]oxazolo[5,4-e]indole (Intermediate 455-7)

[0396] In DMF (30 ml), was added 7-trimethylsilanylene-2-ethyl-4-fluoro-6-aminobenzoxazole (2.1 g, 7.61 mmol), CuI (2.9 g, 15.21 mmol). After reaction at 120 °C for 2 h, the mixture was filtered. The filtrate was concentrated under reduced pressure and dried. The residue was purified by column to give the product (500 mg, 32%) as yellow solid.

[0397] MS (ESI) calcd for C11 H9OFN2: 204.07; found: 205.30 [M + 1].

[0398] 1 HNMR (400 MHz, DMSO-D6) δ 11.54 (br s, 1H), 7.44 (t, J = 3.2 Hz, 1H), 7.22 (d, J = 10.8 Hz, 1H), 6.63 (t, J = 2.8 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H).

[0399] Step 8: Synthesis of 8-formyl-2-ethyl-4-fluoro-6H-[l,3]oxazol[5,4- e]indole (Intermediate 455-8)

[0400] In DMF (10 ml), add 2-ethyl-4-fluoro-6H-[l,3]oxazol[5,4-e]indole (500 mg, 2.45 mmol), POCl3(450 mg, 2.94 mmol). Then react at room temperature for 12 hours. Then add NaOH aqueous solution (2.0 M) to the reaction solution to pH = 11, heat to 70 °C for 0.5 hours. Then pour into hydrochloric acid (1.0 M) aqueous solution to pH = 1, add ethyl acetate extraction, dry the organic phase, concentrate under reduced pressure and dry to obtain brown solid product (410 mg, 72%).

[0401] MS (ESI) calcd for C 12 H9O2FN2: 232.06; found: 233.30 [M + 1].

[0402] Step 9: Synthesis of 8-cyano-2-ethyl-4-fluoro-6H-[l,3]oxazol[5,4- e]indole (Intermediate 455-9)

[0403] In THF (10 ml), add 8-formyl-2-ethyl-4-fluoro-6H-[l,3]oxazol[5,4-e]indole (400 mg, 1.72 mmol), hydroxylamine hydrochloride (240 mg, 3.45 mmol) and pyridine (545 mg). Then react at 80 °C for 8 hours. Then add acetic anhydride (0.85 ml) and react for 12 hours. Then add NaOH aqueous solution (2.0 M, 20 ml) to the reaction solution to alkalize at room temperature, then stir for half an hour, add ethyl acetate extraction, dry the organic phase, concentrate under reduced pressure and dry to obtain brown solid product (238 mg, 60%).

[0404] MS (ESI) calcd for C 12H8OFN3: 229.07; found: 230.30 [M + 1].

[0405] Step 10: Synthesis of 4-(8-cyano-2-ethyl-4-fluoro-[l,3]oxazol[5,4- e]indol-6-yl)-benzoic acid tert-butyl ester (Intermediate 455-10)

[0406] To 8-cyano-2-ethyl-4-fluoro-6H-[l,3]oxazol[5,4-e]indole (150 mg, 0.65 mmol), Cs2CO3(533 mg, 1.64 mmol), 4-fluoro-benzoic acid tert-butyl ester (193 mg, 0.98 mmol) in DMF (2 ml) was added. Then react at 100 °C for 12 h, cool to room temperature. Then treat the reaction with water, extract with ethyl acetate, dry the organic phase, concentrate under reduced pressure and dryness, then pass through a column to give the product as a white solid (94 mg, 41%).

[0407] MS (ESI) calcd for C 23 H 20 O3FN3: 405.15; found: 406.20 [M + 1].

[0408] 1 HNMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 10.8 Hz, 1H), 3.09 (q, J = 7.6 Hz, 2H), 1.59 (s, 9H), 1.41 (t, J = 7.6 Hz, 3H).

[0409] Step 11: Synthesis of 4-(8-cyano-2-ethyl-4-fluoro-[l,3]oxazol[5,4- e]indol-6-yl)-benzoic acid (Compound 455)

[0410] To 4-(8-cyano-2-ethyl-4-fluoro-[l,3]oxazol[5,4-e]indol-6-yl)-benzoic acid tert-butyl ester (50 mg, 0.12 mmol) in TFA (1 ml) was added. Then react at 25 °C for 2 h, then concentrate under reduced pressure and dryness, then add methanol, filter and dry to give the product as a white solid (36 mg, 83%).

[0411] MS (ESI) calcd for C 19 H 12 O3FN3: 349.09; found: 350.20 [M + 1].

[0412] 1HNMR (400 MHz, DMSO-d6) δ 13.28 (br s, 1H), 8.78 (s, 1H), 8.17 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 10.8 Hz, 1H), 3.09 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H).

[0413] Referring to the preparation method of Example 1-12, compounds 1- compound 692 were prepared, the preparation method of which was referred to the examples and the structural formula and characterization data thereof were shown in Table 1.

[0414] Table 1 Structural formula, characterization data and preparation method of compounds 1- compound 692

[0415] Inhibition of xanthine oxidase activity by compounds of Example 13

[0416] 3 mg of the compound to be tested, including the positive control febuxostat, was weighed and dissolved in DMSO to obtain a 10 mM stock solution, which was then diluted with 5% DMSO aqueous solution to obtain 8 concentration gradients (500 uM, 50 uM, 5 uM, 500 nM, 250 nM, 50 nM, 5 nM, 0.5 nM) containing the same concentration of DMSO.

[0417] Xanthine oxidase activity detection kit (MAK078-1KT) was purchased from the official website of reagent supplier Merck. Mouse liver tissue was homogenized with the detection buffer of the kit (500 ul / 30 mg) to obtain tissue homogenate containing mouse xanthine oxidase. After centrifugation at 10000 rpm x 10 min, 4℃, the supernatant was transferred to a new centrifuge tube and placed on ice for use.

[0418] In 96-well plates, 50ul of tissue homogenate was added, 2ul of the compound to be tested at a corresponding concentration was added, 48ul of a mixture containing other components of the kit was added, the total volume was 100ul / well, and incubation was carried out at 25°C for 3 minutes. The fluorescence intensity of the excited system was read at 587nm (the more superoxide free radicals generated by the oxidation of hypoxanthine and xanthine by xanthine oxidase in the reaction system, the more Resorufin generated by the chemical reaction of 10-acetyl-3,7-dihydroxyphenoxazine in the system, the higher the fluorescence intensity of the excited system, and the higher the activity of xanthine oxidase). Dynamic reading was carried out every 3 minutes within 15 minutes at 25°C. The well without the inhibitor was taken as 100% xanthine oxidase activity, and the well without the enzyme was taken as zero activity (background). After reading the plate, QC was performed to confirm that the 12-minute point was in the linear range, the inhibition efficiency at the 12-minute point was analyzed, and the IC50 of the compound to be tested was obtained 50 .

[0419] The test results are shown in Table 2: the oxazole or thiazoloindole compounds or derivatives thereof of the present application have strong inhibitory effect on the activity of xanthine oxidase, and the inhibitory activity of some compounds is better than that of the positive drug febuxostat.

[0420] Table 2. Inhibition results of compounds on xanthine oxidase activity

[0421] Example 14 Inhibition of uric acid transporter by the compound

[0422] The concentration gradient of the compound to be tested and the positive control (lesinurad) was prepared as in Example 13.

[0423] All cell culture media were purchased from Invitrogen, and plasticware was purchased from Corning. Because renal tubular epithelial cells express Urat1 as well as Glut9, this epithelial cell line can be used to detect urate transporter activity. Mouse renal tubular epithelial cells were seeded on cell culture transwell membranes with 0.4 um pore size, and cultured until the cells completely covered the transwell, forming a monolayer of cells on the membrane. Before testing the test compound, the cup of the transwell was changed to DMEM basal medium containing a specific concentration of the test compound and 4.5 mg / dL uric acid. The bottom layer of the multi-well plate was changed to DMEM basal medium without uric acid. Incubate at 37°C for 60 min, remove 100 ul of medium from the bottom layer of the multi-well plate, and read the uric acid concentration at 290 nm with a microplate reader. Take the well without uric acid as the blank control, and take the well without the compound as 100% transport. Compare the uric acid concentration of the well corresponding to the test compound with the concentration of the well with 100% transport to obtain the inhibition efficiency.

[0424] The results show that the inhibition rate of lesinurad on urate transporter is 23.63% at a concentration of 1000 nM; the inhibition rate of compound 6 on urate transporter is 55.6% at a concentration of 250 nM. It can be seen that the compound of the present application has good inhibition activity on urate transporter, and the inhibition activity on urate transporter at a concentration of 250 nM is higher than that of lesinurad at a concentration of 1000 nM.

[0425] Inhibition of compound of example 15 on urate transporter

[0426] Prepare different concentration dilutions of the test compound and the positive control (Dotinurad) as in example 13.

[0427] All cell culture media were purchased from Invitrogen, and plasticware was purchased from Corning. C14-labeled uric acid was from American Radiolabeled Chemicals, cat# ARC 0513-250 μCi). Human kidney proximal tubular epithelial cell line HK-2 (from ATCC.org) was used as a cell model to study uric acid transport. Cells were pre-plated in 96-well plates, with four replicates for each test condition. The next day, cells were washed with HBSS buffer without chloride, and then replaced with culture medium pre-mixed with 10 uM C14-labeled uric acid and different concentrations of positive control (Dotinurad) or other test compounds. After incubation at 37 °C in a carbon dioxide incubator for 30 minutes, the culture medium was removed, and cells were washed three times with 100 ul HBSS buffer without chloride, and then lysed with 100 ul 0.1 N NaOH. The cell lysate was mixed with 100 ul liquid scintillation cocktail (Ultima Gold CD), and then read with a Revvity liquid scintillation counter (Model MicroBeta TM ). 2 The reading of the wells with C14-labeled uric acid but without any compound was 100% uric acid transport, and the reading of the wells without C14-labeled uric acid was the background reading. Then the inhibition efficiency of uric acid transporters by different concentrations of positive control compounds or test compounds was calculated.

[0428] The inhibition rate of compound 454 of the present application on uric acid transporters at a concentration of 5 μM was 48.36%, which was slightly higher than that of the positive control drug Dotinurad. It can be seen that the compound of the present application has good inhibitory activity on uric acid transporters.

[0429] Table 3 Inhibition of uric acid transporters by compounds

[0430] Example 16 Pharmacodynamic test of compounds for reducing uric acid in vivo

[0431] In this embodiment, adult male Balb / c wild-type mice aged 8-12 weeks provided by Vital River were divided into a baseline group, a control group (vehicle), and nine compound administration groups (compounds 1, 6, 13, 139, 438, 454, 455, 683, and 687), with six animals in each group. The baseline group received no treatment. During gavage, the control group received 0.5 mL of a 1.2% 2-BP-β-CD (cyclodextrin) aqueous solution, while the treatment group received 0.5 mL (volume slightly adjusted according to the pre-administration weight of the mice) of a solution of the test compound prepared with a 1.2% 2-BP-β-CD (cyclodextrin) aqueous solution. Seven and 23 hours after administration, respectively, 0.5 mL of a mixed solution containing 60 mg / mL potassium oxonate (a uricase inhibitor) and 6.67 mg / mL hypoxanthine (a substrate of xanthine oxidase), prepared with a 0.5% methylcellulose aqueous solution, was administered orally to induce hyperuricemia. One hour later, 100 μL of peripheral blood was collected from the inner orbital cavity, and serum uric acid concentration was measured using the conventional phosphotungstic acid method. With the mean serum uric acid level in the control group as 100%, the percentage reduction in serum uric acid in the treatment group was calculated as: (1 - serum uric acid in the treatment group / serum uric acid in the control group) * 100.

[0432] The results are shown in Table 4. The compounds of the present invention, after 8 hours and 24 hours of administration, can more effectively reduce the concentration of uric acid in the body compared with the control compound (Kissei 194).

[0433] Table 4 shows the inhibitory effects of the compounds on serum uric acid.

[0434] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

An oxazolyl or thiazolyl indole compound or its derivative having a structure as shown in Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof, wherein M is selected from: N, O, CR 1 , S; X is selected from: CR 1 , N; Y is selected from: N, O, CR 1 , S; and M, X, Y and the carbon atom to which they are attached together form a heteroaromatic ring; Z is selected from: CR 3 , N; W is selected from: CR 4 , N; Q is selected from the group consisting of: halogen, cyano; L is selected from: R 5 substituted or unsubstituted C6-C 10 aryl, R 5 substituted or unsubstituted 5-10 membered heteroaryl, X 1 , X 2 are each independently selected from: O, S, CH2, NH; Z 1 , Z 2 , and Z 3 are each independently selected from: CH, N; Each R 1 Each of the following is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, halogen-substituted C1-C6 alkyl, C6-C 14 Aryl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkylthio, (C1-C6 alkyl)2N-C(=O)-substituted C1-C6 alkyl, (C1-C6 alkyl)N(H)-C(=O)-substituted C1-C6 alkyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, halogen, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, halogen-substituted C1-C6alkylthio; Each R 5 Each group is independently selected from: hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxyl, mercapto, amino, R 6 Replaced or not replaced C6-C 10 Aryl, R 6 Substituted or unsubstituted 5-10 heteroaryl groups; Each R 6 Each of the following is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. each R is independently selected from the group consisting of: hydrogen, hydroxyl, hydroxylamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino. The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to claim 1, characterized in that, M, X, Y have and only have one of them is CR 1 . The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 2, characterized in that, The oxazoles or thiazoloindoles have a structure as shown in Formula II-1, Formula II-2, Formula II-3, or Formula II-4: wherein M is selected from the group consisting of: O, S; Y is selected from the group consisting of: O, S. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 3, characterized in that, The oxazoles or thiazoloindoles have a structure as shown in Formula III-1, Formula III-2, Formula III-3, or Formula III-4: The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 3, characterized in that, The oxazoles or thiazoloindoles have a structure as shown in Formula IV-1, Formula IV-2, Formula IV-3, Formula IV-4, Formula IV-5, Formula IV-6, Formula IV-7, Formula IV-8, Formula IV-9, Formula IV-10, Formula IV-11, or Formula IV-12: The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 1-5, characterized in that, Each R 1 Each of the following is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkylthio, halogen, halogen-substituted C1-C3 alkyl, C6-C 10 Aryl-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylthio, (C1-C3 alkyl)2N-C(=O)-substituted C1-C3 alkyl, (C1-C3 alkyl)N(H)-C(=O)-substituted C1-C3 alkyl. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 6, characterized in that, each R is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, 1 each R is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, fluoro, chloro, bromo, trifluoromethyl, trifluoroethyl, The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 1-5, characterized in that, R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylthio, halogen, halogen-substituted C1-C3alkyl, halogen-substituted C1-C3alkoxy, halogen-substituted C1-C3alkylthio. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 8, characterized in that, R 3 and R 4 are each independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, trifluoromethyl, methoxy. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 8, characterized in that, R 4 is hydrogen; and / or, R 3 is selected from the group consisting of: hydrogen, C1-C3 alkyl, halogen; preferably, R 3 is selected from the group consisting of: hydrogen, methyl, fluorine, chlorine. The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 1-5, characterized in that, Q is selected from the group consisting of: cyano, bromo, chloro, preferably cyano. The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 1-5, characterized in that, X 1 is selected from: O, S, X 2 is NH; Z 1 , Z 2 and Z 3 is 0 or 1 is N, the others are CH. The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 1-5, characterized in that, Each R 5 Each group is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxyl, mercapto, amino, R 6 Substituted or unsubstituted phenyl, R 6 Substituted or unsubstituted naphthyl, R 6 Substituted or unsubstituted 5-6 membered heteroaryl groups; each R is independently selected from the group consisting of: hydrogen, hydroxyl, hydroxylamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino; Preferably, each R 6 Each of the following is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 13, characterized in that, Each R 5 Each of the following is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxy, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thiophene, pyrroleyl, imidazolyl. The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 1-5, characterized in that, L is selected from: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl, X 1 , X 2 are each independently selected from: O, S, CH2, NH; Z 1 , Z 2 , and Z 3 are each independently selected from: CH, N; Preferably, each R 5 Each of the following groups is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxyl, mercapto, amino, R 6 Substituted or unsubstituted phenyl, R 6 Substituted or unsubstituted naphthyl, R 6 Substituted or unsubstituted 5-6 membered heteroaryl groups; each R is independently selected from the group consisting of: hydrogen, hydroxyl, hydroxylamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino; Preferably, each R 6 Each of the following is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 15, characterized in that, L is selected from: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 6-membered nitrogen heteroaryl; Preferably, L is selected from: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted pyridyl, R 5 substituted or unsubstituted pyrazinyl, R 5 substituted or unsubstituted pyridazinyl, R 5 substituted or unsubstituted pyrimidinyl, Preferably, each R 5 Each of the following groups is independently selected: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyyl, ethoxyyl, carbamoyl, nitro, hydroxy, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thiophene, pyrroleyl, imidazolyl. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 16, characterized in that, L is selected from: Preferably, L is selected from: The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to claim 1, characterized in that, The oxazoles or thiazoloindoles have a structure as shown in Formula V-1 or Formula V-2: The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 18, characterized in that, R 1 selected from: hydrogen, C1-C6alkyl; and / or, R 3 selected from: hydrogen, C1-C6alkyl, halogen. The oxazoles or thiazoloindoles or derivatives thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof according to claim 19, characterized in that, R 1 is selected from: hydrogen, methyl, ethyl, isopropyl; and / or, R 3 is selected from: hydrogen, methyl, fluorine; Preferably, R 1 is selected from: methyl, ethyl. The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to any one of claims 18-20, characterized in that, L is selected from: R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 6-membered nitrogen heteroaryl; R 5 selected from: hydrogen, carboxyl, hydroxyl; Preferably, L is selected from: More preferably The oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritides thereof, according to claim 1, characterized in that, The oxazoles or thiazoloindoles are selected from the following compounds: The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of xanthine oxidase inhibitors and / or URAT1 inhibitors. The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of urate-lowering drugs. The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. An XOR / URAT1 dual inhibitor characterized in that, The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. A drug for reducing uric acid, characterized by The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. A method for preventing and / or treating gout or hyperuricemia, characterized by, The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia. The use of the oxazoles or thiazoloindoles or derivatives thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrug molecules thereof, or deuterides thereof, or tritium thereof of any one of claims 1-22 in the manufacture of drugs for the prevention and / or treatment of gout or hyperuricemia.

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