WO2017198102A1 - Substituted macrocyclic quinoxaline compound and pharmaceutical composition and use thereof - Google Patents

Abstract

Provided are a substituted macrocyclic quinoxaline compound and a pharmaceutical composition and use thereof, wherein the macrocyclic quinoxaline compound is the compound as shown in formula (I), or a polymorph, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant, an hydrate, or a solvate thereof. The compound of the present invention can be used as a hepatitis C virus inhibitor, and has a better hepatitis C virus protein NS3A inhibitory activity and better pharmacodynamic/pharmacokinetic performances. The compound has good applicability and high safety, can be used to prepare drugs for treating hepatitis C virus infections, and has good prospects for market development.

Description

Substituted macrocyclic quinoxaline compound and pharmaceutical composition thereof and application thereof Technical field

The invention belongs to the technical field of medicine, and in particular relates to a hepatitis C virus inhibitor, a pharmaceutical composition and application thereof.

Background technique

HCV (Hepatitis C Virus) is an RNA virus belonging to the genus Hepacivirus genus in the Flaviviridae family. The encapsulated HCV virion contains a positive-stranded RNA genome that encodes all known virus-specific proteins in a single uninterrupted open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of approximately 3000 amino acids. Polyproteins include core proteins, envelope proteins E1 and E2, membrane-bound protein P7, and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B.

Sofabru is the first medicine in the world that can completely cure hepatitis C in the short term. It takes the oral route directly to the lesion, and the method has simple side effects and is highly sought after by patients. Sofibuvir is produced by Gilead, USA, and is marketed in the United States in 2013. It has been clinically proven to be effective in treating hepatitis C, type 1, 2, 3, and 4, including liver transplantation, liver cancer, and HCV/HIV-1 co-infection. Clinical Trials. This breakthrough has brought the gospel to hepatitis C patients around the world.

HCV infection is associated with progressive liver disease, including cirrhosis and hepatocellular carcinoma. Grazoprevir is an NS3 inhibitor developed by Merck. In January 2016, the United States Food and Drug Administration (FDA) approved Merck & Co's combination drug elbasvir/grazoprevir (Zepatier) for the treatment of chronic hepatitis C (HCV) genotype 1 and 4 infections. The combination does not require the use of interferon at the same time, avoiding all serious adverse events of interferon therapy.

Therefore, there is still a need in the art to develop compounds having inhibitory activity or better pharmacodynamic properties against the hepatitis C virus protein NS3.

Summary of the invention

In view of the above technical problems, the present invention discloses a hepatitis C virus inhibitor, a pharmaceutical composition and use thereof, which have better hepatitis C virus protein NS5A inhibitory activity and/or have better pharmacodynamics/pharmacokinetics. performance.

In this regard, the technical solution adopted by the present invention is:

A hepatitis C virus inhibitor, such as a macrocyclic quinoxaline compound of formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydration thereof Compound or solvent compound,

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ And R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ⁴⁷ are each independently hydrogen. , hydrazine, halogen or trifluoromethyl;

Additional conditions are R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ And R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , at least one of R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ⁴⁷ Modern or awkward.

With this technical solution, the shape and volume of the ruthenium in the drug molecule are substantially the same as those of the hydrogen. If the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug generally retains the original biological activity and selectivity. At the same time, the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.

Preferably, the strontium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95. %, more preferably greater than 99%.

Specifically, in the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ And R ³² , R ³³ , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ^The strontium isotope content of each of the ⁴⁷ generations is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, and even more preferably greater than 30%. Preferably more than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably The ground is greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, and even more preferably greater than 99%.

Preferably, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R of the compound of formula (I) ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ And R ⁴⁷ , at least one of R contains ruthenium, more preferably two R 氘, more preferably three R 氘, more preferably four R 氘, more preferably five R 氘, more preferably The six Rs contain ruthenium, more preferably seven R 氘, more preferably eight R 氘, more preferably nine R 氘, more preferably ten R 氘, more preferably eleven R氘, more preferably twelve R 氘, more preferably thirteen R 氘, more preferably fourteen R 氘, more preferably fifteen R 氘, more preferably sixteen R氘, preferably seventeen R 氘, more preferably eighteen R 氘, more preferably nineteen R 氘, more preferably twenty R 氘, more preferably twenty one R Containing bismuth, better twenty-two R containing 氘More preferably, twenty-three R contains 氘, more preferably twenty-four R contains 氘, more preferably twenty-five R contains 氘, more preferably twenty-six R contains 氘, more preferably twenty The seven Rs contain ruthenium, more preferably twenty-eight R 氘, more preferably twenty-nine R 氘, more preferably thirty R 氘, more preferably thirty-one R 氘, more Good place thirty-two R containing 氘, more preferably thirty-three R containing 氘, more preferably thirty-four R containing 氘, more preferably thirty-five R containing 氘, more preferably thirty-six R contains 氘, more preferably thirty-seven R contains 氘, more preferably thirty-eight R contains 氘, more preferably thirty-nine R contains 氘, more preferably forty R contains 氘, more preferably Forty-one R contains 氘, more preferably forty-two R contains 氘, more preferably forty-three R contains 氘, more preferably forty-four R contains 氘, more preferably forty-five R氘, preferably, forty-six R 氘, more preferably forty-seven 氘.

As a further improvement of the present invention, R ¹ , R ² and R ³ are each independently hydrazine or hydrogen.

In another preferred embodiment, R ¹ , R ² , and R ³ are deuterium.

As a further improvement of the present invention, R ⁴ , R ⁵ and R ⁶ are each independently hydrazine or hydrogen.

In another preferred embodiment, R ⁴ , R ⁵ and R ⁶ are deuterium.

As a further improvement of the present invention, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently The ground is helium or hydrogen.

In another preferred embodiment, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ are 氘.

As a further improvement of the present invention, R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ and R ³⁰ are each independently hydrazine or hydrogen.

In another preferred embodiment, R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ and R ³⁰ are 氘.

As a further improvement of the present invention, R ³¹ , R ³² , R ³³ , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently hydrazine or hydrogen.

In another preferred embodiment, R ³¹ , R ³² , R ³³ , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are 氘.

As a further improvement of the present invention, R ³⁷ , R ³⁸ and R ³⁹ are each independently hydrazine or hydrogen.

In another preferred embodiment, R ³⁷ , R ³⁸ , and R ³⁹ are deuterium.

As a further improvement of the present invention, R ⁴⁰ , R ⁴¹ and R ⁴² are each independently hydrazine or hydrogen.

In another preferred embodiment, R ⁴⁰ , R ⁴¹ , and R ⁴² are 氘.

As a further improvement of the present invention, R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ⁴⁷ are each independently hydrazine or hydrogen.

In another preferred embodiment, R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ⁴⁷ are 氘.

As a further improvement of the present invention, the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

In another preferred embodiment, the compound does not include a non-deuterated compound.

The invention also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the hepatitis C virus inhibitor as described above, or a polymorphic form thereof, a pharmaceutically acceptable salt, a prodrug, Stereoisomers, isotopic variations, hydrates or solvates.

As a further improvement of the present invention, it further comprises other active compounds including, but not limited to, others HCV antiviral, anti-infective, immunomodulatory, antibiotic or vaccine combination.

As a further improvement of the present invention, the immunomodulator is an interferon drug compound.

As a further improvement of the invention, the quinoxaline macrocycles of the invention may be used in combination therapies involving one or more additional therapeutic agents. Additional therapeutic agents include those that also target HCV, target different pathogenic agents, or enhance the immune system. Agents that enhance the immune system include those that normally enhance the function of the immune system and those that produce a specific immune response against HCV. Additional therapeutic agents that target HCV include agents that target NS3 and agents that target other HCV activities, such as NS5A and NS5B, and agents that target host cell activity involved in HCV replication.

Other examples of therapeutic agents that may be present in the combination include ribavirin, levovirin, viramidine, thymosin alpha-1, interferon-beta, interferon-alpha, PEGylated interferon-alpha (peg interferon-alpha) a combination of interferon-[alpha] and ribavirin, a combination of peg interferon-[alpha] and ribavirin, a combination of interferon-[alpha] and levovirin, and a combination of peg interferon-[alpha] and levovirin. Interferon-α includes recombinant interferon-α2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, NJ), PEGylated interferon-α2a (Pegasys), interferon-α2b (eg available from Schering Corp) .Kenilworth, NJ's Intron-A interferon), PEGylated interferon-α2b (PegIntron), recombinant complex interferon (such as interferon alphacon-1), and purified interferon-α product. The individual components of the combination may be administered separately at different times during the course of the treatment or simultaneously in separate or individual combinations.

For the treatment of HCV infection, the compounds of the invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane). For a full description of the agent, see J. Kirschbaum, 12 Anal. Profiles Drug Subs. 1-36 (1983).

For the treatment of HCV infection, the compounds of the invention may also be administered in combination with the antiviral polymerase inhibitor R7128 (Roche).

For the treatment of HCV infection, the compounds of the invention may also be administered in combination with an HCV NS5B polymerase inhibitor. Such HCV NS5B polymerase inhibitors that can be used as a combination therapy include, but are not limited to, International Patent Application Publication No. WO 02/057287, WO 02/057425, WO 03/068244, WO 2004/000858, WO 04/003138, and WO 2004 /007512; those disclosed in U.S. Patent No. 6,777,392, and U.S. Patent Application Publication No. 2004/0067901, the entire contents of each of which are hereby incorporated by reference. Other such HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147).

As a further improvement of the present invention, the pharmaceutically acceptable carrier includes a glidant, a sweetener, a diluent, a preservative, a dye/colorant, a flavor enhancer, a surfactant, a wetting agent, a dispersant At least one of a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.

As a further improvement of the present invention, the pharmaceutical composition is a tablet, a pill, a capsule, a powder, a granule, an ointment, an emulsion, a suspension, a solution, a suppository, an injection, an inhalant, a gel, a microsphere or Aerosol.

Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.

The pharmaceutical compositions of the present invention can be produced by methods well known in the art, such as conventional mixing methods, dissolution methods, Granulation method, sugar-coated pellet method, grinding method, emulsification method, freeze-drying method, and the like.

The present invention also provides a method of preparing a pharmaceutical composition comprising the steps of: administering a pharmaceutically acceptable carrier to a hepatitis C virus inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, or a hydrate thereof Or the solvate is mixed to form a pharmaceutical composition.

The invention also discloses the use of a hepatitis C virus inhibitor as described above, characterized in that it is used for the preparation of a medicament for the treatment of hepatitis C virus infection.

NS3 inhibitors can also be used in the preparation and implementation of screening assays for antiviral compounds. For example, such compounds can be used to isolate enzyme mutants, which are excellent screening tools for more potent antiviral compounds. In addition, these compounds can be used to establish or measure binding sites for other antiviral agents to HCV protease, for example by competitive inhibition.

To inhibit the HCV NS3 protease and to treat HCV infection and/or reduce the likelihood or severity of HCV infection symptoms, the compounds of the invention, optionally in salt form, can be administered by contacting the active agent with the site of action of the drug. They can be administered as a separate therapeutic or combination of therapeutic agents by conventional means which can be used in combination with the drug. They can be administered alone, but are usually administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.

The HCV includes a plurality of genotypes thereof and a plurality of gene subtypes, such as 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a, 6a.

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

Herein, "halogen" means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.

As used herein, unless otherwise specified, "deuterated" means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted. The terms "one or more deuterated" are used interchangeably with "one or more deuterated".

As used herein, unless otherwise specified, "non-deuterated compound" means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).

The invention also includes isotopically labeled compounds (also referred to as "isotopic variants"), equivalent to the original compounds disclosed herein. Examples of isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, respectively. , ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. A compound of the formula (I) of the present invention containing the above isotope or other isotopic atom, or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvate thereof It is within the scope of the invention. Certain isotopically-labeled compounds of the present invention, such as the radioisotopes of ³ H and ¹⁴ C, are also among them, useful in tissue distribution experiments of drugs and substrates.氚, ie ³ H and carbon-14, ie ¹⁴ C, are easier to prepare and detect and are preferred in isotopes. In addition, heavier isotopic substitutions such as guanidine, or ² H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.

Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are the salts of the compounds of the invention with bases, such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium). Salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl A base amine salt, an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.

The term "polymorph" refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state. A drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.

The term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio. "Hydrate" means a complex formed by the coordination of a compound of the invention with water.

The term "prodrug" refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood. A prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo. Prodrugs are typically prepared by modifying functional groups that cleave the prodrug in vivo to yield the parent compound. Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group. Thus, representative examples of prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid. Further, in the case of a carboxylic acid (-COOH), an ester such as a methyl ester, an ethyl ester or the like can be used. The ester itself may be active and/or may hydrolyze under conditions in humans. Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.

The compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included. The isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.

The beneficial effects of the present invention compared to the prior art are: First, the compound of the present invention has excellent inhibitory effect on the hepatitis C virus protein NS3. Second, by deuteration this technique changes the metabolism of the compound in the organism, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, replace it with 氘 The hydrogen atom in the compound, due to its strontium isotope effect, increases the drug concentration of the compound in the animal and improves the drug efficacy. Fourth, replacing the hydrogen atom in the compound with hydrazine can inhibit certain metabolites and improve the safety of the compound.

detailed description

The preparation of the structural compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.

Usually, in the preparation scheme, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C). The reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.

Example 1 Preparation of a substituted macrocyclic quinoxaline compound G-1 having the following formula:

Use the following route for synthesis:

Step 1. Synthesis of diethyl [2-(dimethylamino)-2-oxoethyl]phosphate (Compound 3).

Compound 2 (10.5 g, 63.65 mmol) was added to a three-necked flask under nitrogen and heated to 110 °C. After dropwise addition of Compound 1 (10 g, 82.65 mmol), the reaction was carried out at 110 ° C for 3-4 hours, and concentrated at 65 ° C to give a crude product which was purified by column chromatography to give 7.7 g of Compound 3, yield 54. -MS(APCI): m/z = 224 (M + 1) ⁺ , ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.22-4.08 (m, 4H), 3.11 (s, 3H), 3.08 (d, J) = 2.4 Hz, 2H), 2.99 - 2.91 (m, 3H), 1.32 (t, J = 7.1 Hz, 6H).

Step 2. Synthesis of chloro-2-hydroxy-1-heptene (Compound 6).

Under a nitrogen atmosphere, 10 mL of dimethyltetrahydrofuran was added to a three-necked flask, magnesium (2 g, 82.29 mmol) was added, 90 mg of iodine was added, and compound 4 (10 g, 70.04 mmol) was slowly added dropwise, and the reaction was carried out at 70 ° C for 3-4 hours after completion of the dropwise addition. Cool to room temperature for use, add compound 3 (5.26 g, 56.82 mmol), CuI (530 mg, 2.78 mmol) and 28 mL of dimethyltetrahydrofuran to a three-necked flask under nitrogen, cool to -60 ° C, slowly add dropwise to the above. Format reagent, control reaction system does not exceed -50 ° C, stir reaction after completion of the addition for 1 hour, TLC detection of the raw material reaction is complete, quenched with ammonium chloride aqueous solution, rose to room temperature, stirred for 30 minutes, extracted with tert-butyl methyl ether three times The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate and evaporated. _{^{1 H NMR (300MHz, CDCl 3}} ) δ5.81 (m, J = 16.9,10.2,6.7Hz, 1H), 5.09-4.91 (m, 2H), 3.80 (t, J = 7.4Hz, 1H), 3.69- 3.61 (m, 1H), 3.49 (m, J = 11.1, 7.2 Hz, 1H), 2.16 (t, J = 5.2 Hz, 1H), 2.09 (t, J = 6.6 Hz, 2H), 1.58-1.49 (m) , 3H).

Step 3. Synthesis of (1R,2R)-2-pent-4-enyl-N,N-dimethylcyclopropylformamide (Compound 7).

Add compound 6 (3.579 g, 24.182 mmol), compound 3 (5.39 g, 24.18 mmol) to a three-reaction flask under nitrogen, add 70 mL of dimethyltetrahydrofuran, cool to -35 ° C, and slowly add n-butyllithium. (29 mL, 72.546 mmol), keeping the temperature of the reaction system not exceeding -20 ° C, about 1 hour dropwise, after 20 minutes of reaction, naturally warming to room temperature, heating to 72 ° C and reacting for 1 hour, the reaction solution turned pale yellow, TLC The reaction was confirmed to be complete, cooled to room temperature, and the reaction was quenched with a 10% sodium chloride solution, and extracted three times with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate Compound 8, yield 41.9%, ¹ H NMR (300MHz, CDCl ₃ ) δ 5.90-5.70 (m, 1H), 5.05 - 4.84 (m, 2H), 3.14 (d, J = 11.1 Hz, 3H), 2.99 -2.91(m,3H),2.14-2.02(m,2H),1.60-1.42(m,3H),1.41-1.25(m,3H), 1.15(m,J=6.4,4.5Hz,1H),0.95 -0.85 (m, 1H), 0.60 (m, J = 5.2, 3.7 Hz, 1H).

Step 4. Synthesis of (1R,2R)-2-pent-4-enylcyclopropylmethylketone (Compound 8).

Methyl magnesium chloride (16.9 mL, 50.94 mmol) was added to a three-necked reaction flask under nitrogen to heat to 60 ° C. At this temperature, a solution of compound 7 in dimethyltetrahydrofuran (4.16 g, 25.47 mmol, 20 mL) was slowly added dropwise. After the completion of the addition, the reaction was carried out at 60 ° C for 2 hours, and the reaction of the starting material was completed by TLC, quenched with aqueous ammonium chloride, extracted three times with n-hexane, and the organic phase was combined, washed with 1M hydrochloric acid, and washed with saturated aqueous sodium chloride, anhydrous sulfuric acid The sodium was dried and concentrated to give 4.37 g of Compound 8 in a yield -100%. Used directly in the next step.

Step 5. Synthesis of (1R,2R)-2-(4,5-dibromopentyl)cyclopropylmethyl ketone (Compound 9).

Add compound 8 (1.394 g, 9.96 mmol) to the reaction flask under nitrogen, dissolve in 12 mL of dichloromethane, cool to -45 ° C to -50 ° C, and add bromine (3.2 g, 19.92) at this temperature. After the completion of the dropwise addition, the reaction was carried out for 40 minutes, and the reaction of the material was purified by TLC. N,N-diisopropylethylamine (DIPEA, 321 mg, 2.49 mmol) was obtained. The organic phase was combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to give 1.01 g of compound 9 in a yield of 38.4%, LC-MS (APCI): m/z = 313 (M+ 1) ⁺ , ¹ H NMR (400MHz, CDCl ₃ ) δ 4.22-4.10 (m, 1H), 3.91-3.79 (m, 1H), 3.67-3.58 (m, 1H), 2.25 (d, J = 2.0 Hz) , 3H), 2.20-2.12 (m, 1H), 1.82 (m, J = 6.1, 5.1, 3.0 Hz, 1H), 1.77-1.67 (m, 2H), 1.53 (m, J = 18.6, 12.2, 6.4 Hz , 1H), 1.27 (m, J = 8.5, 4.2 Hz, 1H), 0.83 - 0.73 (m, 1H).

Step 6. Synthesis of (1R,2R)-2-(4,5-dibromopentyl)cyclopropyl acetate (Compound 10).

Compound 9 (963 mg, 3.086 mmol) was added to the reaction flask, and 10 mL of ethyl acetate was added to dissolve. After cooling to 0 ° C, urea hydrogen peroxide complex (UHP, 1.16 g, 12.346 mmol) was added in three portions, and trifluoroacetic anhydride was added dropwise. (TFAA, 2.673g, 12.73mmol) control temperature 0-3 ° C, about 1 hour dropwise, the reaction liquid became clear, heated reflux reaction for 16 hours, TLC detection of the raw material reaction was complete, cooled to room temperature, with 20% sodium bicarbonate The pH was adjusted to 7-9, and the mixture was extracted with EtOAc EtOAc (EtOAc). 41.4%. _{^{1 H NMR (300MHz, CDCl 3}} ) δ4.17 (m, J = 13.3,9.4,3.9Hz, 1H), 3.94-3.75 (m, 2H), 3.71-3.50 (m, 1H), 2.24-2.08 (m , 1H), 2.03 (s, 2H), 1.92-1.64 (m, 2H), 1.59-1.47 (m, 1H), 1.45-1.15 (m, 2H), 1.03 (m, J = 16.5, 6.9, 2.6 Hz , 1H), 0.91-0.79 (m, 1H), 0.66-0.47 (m, 1H).

Step 7. Synthesis of (1R,2R)-2-pent-4-ynylcyclopropanol (Compound 11).

Add diallyl phthalate (DAP, 18.11 mL) to a three-necked flask under nitrogen to cool to 0 ° C. N-butyl lithium (20.4 mL, 52 mmol, 2.5 M) was slowly added dropwise to the reaction flask to control the temperature. Below 5 ° C, after the completion of the dropwise addition, stirring at this temperature for 30 minutes, Compound 10 (2.84 g, 8.66 mmol) was dissolved in 5 mL of THF, slowly added dropwise to the reaction flask, controlled temperature 0-2 ° C, dropwise During the process, a yellow precipitate was formed. After the completion of the dropwise addition, the mixture was stirred at 0 ° C for 30 minutes. The reaction of the starting material was completely detected by TLC, quenched with aqueous ammonium chloride solution, extracted with methyl tert-butyl ether three times, and 1 M NaOH was added to the aqueous phase. To a basicity, the mixture was extracted twice with methyl tert-butyl ether. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under 30[deg.] C. to afford 730 mg of Compound 11. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.24 - 4.08 (m, 1H), 3.86 (m, J = 10.2, 4.3 Hz, 1H), 3.62 (t, J = 10.1 Hz, 1H), 2.24 (d, J = 1.3 Hz, 3H), 2.20-2.08 (m, 1H), 1.78 (m, J = 21.9, 18.2, 9.2, 6.2 Hz, 3H), 1.53 (m, J = 13.2, 6.3 Hz, 1H), 1.45 - 1.34 (m, 3H), 1.27 (m, J = 7.9, 3.5 Hz, 2H), 0.77 (m, J = 7.5, 4.9, 2.8 Hz, 1H).

Step 8. Synthesis of Compound 13.

Compound 11 (630 mg, 5.08 mmol) was added to the reaction flask, DIPEA (2.35 g, 18.28 mmol) was added, and N'N-carbonyldiimidazole (CDI, 864 mg, 5.334 mmol) was added in two portions and allowed to react at room temperature for one hour. Compound 12 (800 mg, 6.1 mmol) was heated to 90 ° C, and reacted for 4 hours. The reaction of the starting material was completed by TLC, and water (20 mL) was added to the reaction mixture, and the pH was adjusted to 1.5-2.0 with 1 M hydrochloric acid. After extracting three times with methyl tert-butyl ether (MTBE), it was concentrated to give 1.56 g, Compound 12 yield - 100%, directly used for the next reaction.

Step 9.2, Synthesis of 3-dihydroxy-7-methoxyquinoxaline (Compound 15).

Add compound 14 (1 g, 7.24 mmol) to the reaction flask under nitrogen, add oxalyl chloride (1.2 g, 10.136 mmol), then add 10 mL of 3N hydrochloric acid, react at 90 ° C for 7 hours, cool to room temperature, and let stand at 0 ° C. After a few hours, a black solid precipitated, filtered, and the filter cake was washed with water, washed with a small amount of methanol, and dried under vacuum at 50 ° C for 18 hours to give 1.08 g, Compound 15, yield 77.6%, LC-MS (APCI): m/ z=193(M+1) ⁺ , ¹ H NMR (300MHz, DMSO) δ 11.80 (d, J = 13.7 Hz, 2H), 7.03 (d, J = 8.6 Hz, 1H), 6.68 (m, J = 4.6, 2.6 Hz, 2H), 3.70 (s, 3H).

Step 10.2, Synthesis of 3-dichloro-7-methoxyquinoxaline (Compound 16).

Add compound 15 (5.2 g, 27.06 mmol) to the reaction flask under nitrogen, add POCl ₃ (8 mL), heat to 98 ° C for 20 hours, cool to 80 ° C, add 25 mL of acetonitrile, then cool to 10-15 ° C, Add ice water to the reaction flask, make the reaction system below 25 ° C, precipitate a blue solid, filter, filter cake washed with water, wash with 5% sodium bicarbonate to pH ~ 8-9, vacuum drying below 50 ° C after 24 hours to give 4.65g of compound 16, yield 74.5%, LC-MS (APCI ): m / z = 230 (m + 1) +.

Step 11. Synthesis of Compound 19.

Glycine methyl ester hydrochloride (7.142 g, 0.057 mmol) was added to the reaction flask, anhydrous sodium sulfate (4.57 g, 0.032 mmol) was added, triethylamine (6 g, 0.059 mmol) was added, and methyl t-butyl ether was added. 100 mL, and reacted at room temperature for 18 hours, the reaction of the starting material was completely confirmed by TLC, and concentrated to give Intermediate 18 by filtration.

Add lithium t-butoxide (10.07 g, 0.125 mmol) to the reaction flask, add 100 mL of anhydrous toluene, and add the compound dropwise in an ice water bath. 50 mL of 18 and 1,4-dibromo-2-butene (8.57 g, 0.04 mmol) in toluene solution, after completion of the dropwise addition, the reaction was carried out at room temperature for 18 hours. The reaction of the starting material was completely confirmed by TLC, water (20 mL) was added, and 4N hydrochloric acid was added to adjust the pH. To 1-2, extract 3 times with water, combine the aqueous phase, extract three times with methyl tert-butyl ether, adjust the pH to 11-12 with 1N sodium hydroxide in water, extract 3 times with ethyl acetate, and combine the organic phase Washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated. Yield 19.25%

Step 12. Synthesis of Compound 20.

Add compound 19 (2g, 12.89mmol) to the reaction flask, add 10mL of dichloromethane to dissolve, add triethylamine (5g, 48mmol), add Boc anhydride (4.3g, 19.33mmol) for 3 hours at room temperature, complete the reaction of TNC , the reaction solution was concentrated, and column chromatography gave 2.2 g of compound 20 in a yield of 64.7%.

Step 13. Synthesis of Compound 21.

Add compound 20 (2.2 g, 9.12 mmol) to tetrahydrofuran: methanol = 1:1 40 mL, add lithium hydroxide (873 g, 36.47 mmol), and warm to 40 ° C for 18 hours. The reaction solution was concentrated, and 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate.

Step 14. Synthesis of Compound 22.

Compound 21 (678 mg, 2.986 mmol) was added to the reaction flask, and the mixture was dissolved in tetrahydrofuran (12 mL). CDI (628 mg, 3.88 mmol) was added, and the mixture was refluxed for 1 hour, cooled to room temperature, and hexanesulfonamide (469 mg, 3.88 mmol) was used in 2 mL. After the tetrahydrofuran was dissolved, it was added to the reaction flask, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 658 mg, 4.329 mmol) was added, and the reaction was carried out at room temperature for 18 hours, and the reaction of the starting material was completely confirmed by TLC. The pH was adjusted to 1-2 by the addition of 1 M hydrochloric acid, and the mixture was extracted with EtOAc EtOAc EtOAc. %

Step 15. Synthesis of Compound 23.

Add compound 22 (495mg, 1.39mmol) to the reaction flask, add 10mL of ethyl acetate to dissolve, add 5mL of methanolic acid (4M) solution, react at 40 °C for 4 hours, complete the reaction of TNC to detect the reaction, and concentrate the reaction solution to obtain 400mg of compound 23, directly Used for the next reaction.

Step 16. Synthesis of Compound 25.

Add compound 16 (2g, 8.73mmol), compound 24 (2.36g, 9.6mmol), add dimethylacetamide (DMAC) 10mL, add DBU (2g, 13.09mmol), heat to 50 The reaction was carried out for 20-30 hours, cooled to room temperature, 20 mL of water and 30 mL of MTBE were added, filtered, and the black insolubles were removed, and the mixture was extracted three times with MTBE. The organic phase was combined and dried over anhydrous sodium sulfate. Compound 25, recovered starting material, yield 31.4%, ¹ H NMR (300MHz, CDCl ₃ ) δ 7.81 (d, J = 9.1 Hz, 1H), 7.23 (m, J = 9.1, 2.6 Hz, 1H), 7.16 ( m, J = 7.7, 2.5 Hz, 1H), 5.73 (d, J = 20.8 Hz, 1H), 4.57 (m, J = 22.7, 7.8 Hz, 1H), 4.02-3.89 (m, 5H), 3.78 (d) , J = 9.0 Hz, 4H), 2.68 (d, J = 5.6 Hz, 1H), 2.51-2.35 (m, 1H), 1.46 (d, J = 8.6 Hz, 10H).

Step 17. Synthesis of Compound 26.

Compound 25 (1.866 g, 4.27 mmol) was added to the reaction flask 1 and dissolved in 10 mL of cyclopentyl methyl ether. Compound 13 (1.44 g, 5.124 mmol) was dissolved in 10 mL of cyclopentyl methyl ether and added to the reaction flask. Stir for 30 minutes. To the reaction flask 2, palladium acetate (32 mg, 0.145 mmol), P(t-Bu) ₃ BF ₄ (74 mg, 0.256 mmol), potassium carbonate (1.47 g, 1.067 mmol), 10 ml of acetonitrile was added, and stirred under nitrogen. In a minute, it was added to the reaction flask 1, stirred by nitrogen for 15 minutes, heated to 85 ° C for 3 hours, and the reaction of the starting material was completely detected by TLC. 30 mL of water was added, and the pH was adjusted to 1-2 with 2 M phosphoric acid. The ester was extracted three times, and the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated. LC-MS (APCI): m / z = 683 (M + 1) +. _{^{1 H NMR (300MHz, CDCl 3}} ) δ7.89-7.78 (m, 1H), 7.19 (d, J = 9.1Hz, 1H), 7.11 (d, J = 7.4Hz, 1H), 5.68 (s, 1H) , 5.31 (d, J = 7.5 Hz, 1H), 4.49 (t, J = 7.5 Hz, 1H), 4.02-3.89 (m, 4H), 3.79 (s, 6H), 2.60 (d, J = 6.4 Hz, 3H), 2.45 (m, J = 12.9, 6.7 Hz, 1H), 1.89-1.71 (m, 2H), 1.44 (d, J = 5.8 Hz, 11H), 1.26 (s, 1H), 1.01 (s, 11H) ), 0.89 (m, J = 10.6, 5.9 Hz, 3H), 0.56 (d, J = 6.3 Hz, 1H).

Step 18. Synthesis of Compound 27.

Adding compound 26 (445 mg, 0.651 mmol) to the reaction flask, adding 5 mL of deuterated methanol, dissolving, adding 10 mg of 10% palladium carbon, and reacting with helium at 40 ° C for 18 hours. The reaction of the raw materials was completely determined by LCMS, cooled to room temperature, and silicon was added. The algae was filtered, and the cake was washed with methanol, and concentrated to give 380 mg of compound 27, yield 84.4%

Step 19. Synthesis of Compound 28.

Compound 27 (380 mg, 0.55 mmol) was added to the reaction flask, dissolved in 3 mL of acetonitrile, trifluoroacetic acid (156 mg, 1.375 mmol) was added, the temperature was raised to 40 ° C, and the reaction was carried out for 18 hours. The reaction of the starting material was completely confirmed by TLC. Trifluoroacetic acid, the pH was adjusted to 8-9 with DIPEA, 3 mL of acetonitrile was added, and HATU (282 mg, 0.74 mmol) was added to react at room temperature for 8 hours. The reaction of the starting material was completed by TLC, and the reaction mixture was concentrated. Yield 66.9%

Step 20. Synthesis of Compound 29.

Compound 28 (211 mg, 0.368 mmol) was added to the reaction flask, and 5 mL of tetrahydrofuran was added. Lithium hydroxide (73 mg, 3.68 mmol) was dissolved in 2 mL of water, and then added to the reaction. The mixture was heated to 40 ° C for 1 hour, and the reaction of the starting material was completely confirmed by TLC. It was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and evaporated.

Step 21. Synthesis of Compound G-1.

Compound 29 (114 mg, 0.205 mmol), Compound 23 (61 mg, 0.266 mmol), was dissolved in 5 mL acetonitrile. Add pyridine (229 mg, 0.87 mmol), react at room temperature for 15 minutes, add EDCI (62.4 mg, 0.328 mmol), react at room temperature for 1.5 hours, the reaction solution becomes clear, add 2 mL of 2N hydrochloric acid solution, stir the reaction for 20 minutes, and determine the reaction of the raw materials by TLC. complete, the reaction solution was concentrated, to give 31mg compound G-1 was prepared by ^{TLC, 1 H NMR (400MHz, CDCl} 3) δ7.81 (d, J = 9.1Hz, 1H), 7.18 (m, J = 9.0,2.8Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H), 7.04 (s, 1H), 5.96 (s, 1H), 5.81 (s, 1H), 5.67 (s, 1H), 5.33 (m, J = 13.5) , 9.1 Hz, 1H), 5.12 (s, 1H), 4.51 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 9.8 Hz, 1H), 4.37 (s, 1H), 4.08 (d, J) = 6.7 Hz, 1H), 3.92 (d, J = 5.3 Hz, 2H), 3.80-3.73 (m, 1H), 2.93-2.84 (m, 1H), 2.93-2.83 (m, 1H), 2.74 (m, J = 13.3, 9.1 Hz, 1H), 2.57 (m, J = 13.8, 7.3 Hz, 1H), 2.41 (s, 1H), 2.22 - 2.15 (m, 1H), 1.83 (s, 1H), 1.53 (m) , J=36.0, 16.6 Hz, 3H), 1.28 (s, 3H), 1.06 (s, 9H), 1.00-0.88 (m, 2H), 0.67 (d, J = 6.8 Hz, 1H), 0.46 (q, J = 6.3 Hz, 1H).

Example 2 Preparation of a substituted macrocyclic quinoxaline compound G-2 having the following formula:

Synthesize using the following routes:

Step 1. Synthesis of 3-dichloro-7-hydroxyquinoxaline (Compound 30).

40 mL of toluene was added to the reaction flask at 0 ° C, aluminum trichloride (1.96 g, 14.67 mmol) was added, and compound 16 (1.4 g, 6.11 mmol) was added, and the mixture was heated to 80 ° C for 5 hours, and the reaction of the starting material was completely confirmed by TLC. To the room temperature, a solid precipitated, 40 mL of water was added to the reaction mixture, 50 mL of ethyl acetate was added, and the mixture was heated to dissolve in a solid. The phase was dried over anhydrous sodium sulfate and concentrated to give 1.3 g of Compound 30.

Step 2. Synthesis of 3-dichloro-7-d3-methoxyquinoxaline (Compound 31).

Compound 30 (1 g, 4.6 mmol) was added to a reaction flask, and potassium carbonate (1.6 g, 11.6 mmol) was added thereto, and dissolved in 30 mL of DMF, and deuterated iodomethane (1.65 g, 11.6 mmol) was added thereto, and the mixture was heated to 80 ° C for 3 hours. TLC was used to detect the reaction of the starting material, and the mixture was cooled to room temperature. 50 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate. 72.3%.

Step 3. Synthesis of Compound 32.

Add compound 31 (780 mg, 3.36 mmol), compound 24 (906 mg, 3.69 mmol), add 30 mL of DMAC, add DBU (664 g, 4.368 mmol), heat to 50 ° C for 18 hours, and measure the reaction of the material by TLC. After completion, it was cooled to room temperature, 40 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford 645 mg of compound 32, yield 45.3%, MS (APCI): m/z = 441 (M + 1) ⁺ .

Step 4. Synthesis of Compound 33.

Compound 32 (463 mg, 1.06 mmol) was added to the reaction flask 1 and dissolved in 1 mL of cyclopentyl methyl ether. Compound 13 (357 mg, 1.27 mmol) was dissolved in 1.5 mL of cyclopentyl methyl ether and added to the reaction flask, and stirred with nitrogen. 30 minutes. To the reaction flask 2, palladium acetate (8 mg, 0.036 mmol), P(t-Bu) ₃ BF ₄ (18 mg, 0.064 mmol), potassium carbonate (365 g, 2.65 mmol), 2 mL of acetonitrile, and stirred for 15 min. It was added to the reaction flask 1, stirred by nitrogen for 15 minutes, heated to 85 ° C for 2.5 hours, and the reaction of the starting material was completely detected by TLC. The pH was adjusted to 1-2 with 2M phosphoric acid, and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated. LC-MS (APCI): m / z = 686 (M + 1) +.

Step 5. Synthesis of Compound 34.

Add compound 33 (0.185 mg, 0.219 mmol) to the reaction flask, add 2 mL of methanol to dissolve, dissolve 5 mL of isopropanol, add 20 mg of 10% palladium carbon, and react with hydrogen at 40 ° C for 18 hours. The reaction of the raw materials by LC-MS is complete. After cooling to room temperature, the mixture was filtered through Celite, and filtered, and filtered, and then evaporated to give 191 mg of Compound 34, yield 95.5% LC-MS (APCI): m/z = 690 (M+1) ⁺ .

Step 6. Synthesis of Compound 35.

Add compound 34 (191 mg, 0.29 mmol) to the reaction flask, add 3 mL of dichloromethane to dissolve, add 2 mL of trifluoroacetic acid, and react at room temperature for 18 hours. The reaction of the starting material is complete by TLC, and the dichloromethane and excess trifluoroacetic acid are concentrated to remove. DIPEA was adjusted to pH 8-9, 3 mL of acetonitrile was added, and HATU (148.9 mg, 0.39 mmol) was added to react at room temperature for 3 hours. The reaction of the starting material was completed by TLC. The reaction mixture was concentrated and purified by column chromatography to yield 54 mg of compound 35. , LC-MS (APCI): m/z = 572 (M + 1) ⁺ .

Step 7. Synthesis of Compound 36.

Compound 35 (54 mg, 0.094 mmol) was added to the reaction flask, and 4 mL of tetrahydrofuran was added. Lithium hydroxide (22 mg, 0.944 mmol) was dissolved in 2 mL of water and added to the reaction. The mixture was heated to 40 ° C for 1 hour, and the reaction of the starting material was completely confirmed by TLC. The mixture was extracted with EtOAc (3 mL). LC-MS (APCI): m / z = 556 (M + 1) -.

Step 8. Synthesis of Compound G-2.

Compound 36 (74 mg, 0.135 mmol), Compound 23 (40.6 mg, 0.177 mmol), was dissolved in 4 mL of acetonitrile. Add pyridine (152 mg, 1.902 mmol), react at room temperature for 15 minutes, add EDCI (41 mg, 0.217 mmol), react at room temperature for 1.5 hours, the reaction solution becomes clear, add 2 mL of 2N hydrochloric acid solution, stir the reaction for 20 minutes, and completely react with TLC. The reaction mixture was concentrated to give 27 mg of Compound G-2, LC-MS (APCI): m/z=770 (M+1) ⁺ , ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J = 9.0 Hz, 1H), 7.19 (m, J = 9.0, 2.8 Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H), 6.98 (s, 1H), 5.98 (s, 1H), 5.85-5.76 (m, 1H), 5.62 (d, J = 7.9 Hz, 1H), 5.41-5.32 (m, 1H), 5.14 (m, J = 23.0, 9.9 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 4.46 (d, J = 9.9 Hz, 1H), 4.35 (m, J = 25.6, 12.8 Hz, 1H), 4.07 (m, J = 11.6, 5.8 Hz, 1H), 3.83 - 3.71 (m, 1H) ), 2.91-2.84 (m, 2H), 2.62-2.53 (m, 2H), 2.46-2.36 (m, 1H), 2.19 (m, J = 16.1, 7.6 Hz, 2H), 2.06-1.96 (m, 1H) ), 1.84 (m, J = 8.3, 5.3 Hz, 1H), 1.76-1.65 (m, 3H), 1.57-1.42 (m, 3H), 1.36-1.30 (m, 4H), 1.08 (s, 9H), 0.95 (m, J = 10.1, 8.4, 3.0 Hz, 3H), 0.69 (s, 1H), 0.49 - 0.41 (m, 1H).

Example 3 Preparation of a substituted macrocyclic quinoxaline compound G-3 having the following formula:

Synthesize using the following routes:

Step 1. Synthesis of Compound 37.

Adding Compound 33 (0.185 mg, 0.219 mmol) to the reaction flask, adding 5 mL of deuterated methanol, dissolving, adding 10 mg of 10% palladium carbon, and reacting with helium at 40 ° C for 18 hours. The reaction of the raw materials was completely determined by LC-MS and cooled to room temperature. The mixture was filtered through Celite, and the filter cake was washed with methanol and concentrated to give 211 mg of Compound 37. LC-MS (APCI): m / z = 692 (M + 1) +.

Step 2. Synthesis of Compound 38.

Compound 37 (211 mg, 0.306 mmol) was added to the reaction flask, dissolved in 3 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was carried out for 18 hours at room temperature. The reaction of the starting material was completely confirmed by TLC, and dichloromethane and excess trifluoroacetic acid were concentrated to remove. The pH was adjusted to 8-9 by DIPEA, 3 mL of acetonitrile was added, and HATU (157 mg, 0.414 mmol) was added to react at room temperature for 3 hours. The reaction of the starting material was completed by TLC. The reaction mixture was concentrated and purified by column chromatography to give 63 mg of compound 38.

Step 3. Synthesis of Compound 39.

Compound 38 (63 mg, 0.109 mmol) was added to the reaction flask, and 4 mL of tetrahydrofuran was added. Lithium hydroxide (26 mg, 1.09 mmol) was dissolved in 2 mL of water and added to the reaction. The mixture was heated to 40 ° C for 1 hour, and the reaction of the starting material was completely confirmed by TLC. The mixture was extracted with EtOAc (3 mL).

Step 4. Synthesis of Compound G-3.

Compound 39 (74 mg, 0.135 mmol), compound 23 (40.6 mg, 0.177 mmol), was dissolved in 4 mL of acetonitrile. Add pyridine (152 mg, 1.902 mmol), react at room temperature for 15 minutes, add EDCI (41 mg, 0.22 mmol), react at room temperature for 1.5 hours, the reaction solution becomes clear, add 2 mL of 2N hydrochloric acid solution, stir the reaction for 20 minutes, and completely react with TLC. , the reaction solution was concentrated, to give 28mg compound by preparative TLC ^{G-3, 1 H NMR (} 500MHz, CDCl 3) δ7.82 (d, J = 9.0Hz, 1H), 7.19 (dd, J = 9.0,2.8Hz, 1H ), 7.12 (d, J = 2.7 Hz, 1H), 6.98 (s, 1H), 5.98 (s, 1H), 5.84-5.74 (m, 1H), 5.61 (d, J = 9.9 Hz, 1H), 5.38 – 5.32 (m, 1H), 5.16 (d, J = 11.3 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 4.46 (d, J = 9.9 Hz, 1H), 4.36 (m, J = 10.6, 6.6 Hz, 1H), 4.06 (m, J = 11.7, 4.1 Hz, 1H), 3.80-3.73 (m, 1H), 2.89 (m, J = 12.9, 8.2, 4.9 Hz, 2H), 2.70 (d , J = 19.5 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.44 (m, J = 10.6, 3.8 Hz, 1H), 2.19 (m, J = 16.1, 7.6 Hz, 2H), 1.84 (m, J = 8.3, 5.3 Hz, 1H), 1.78-1.65 (m, 4H), 1.52-1.42 (m, 3H), 1.38-1.31 (m, 3H), 1.08 (s, 8H), 0.94 (m, J = 13.6, 12.7, 7.8 Hz, 4H), 0.69 (s, 1H), 0.48-0.42 (m, 1H).

Example 4 Preparation of Substituted Macrocyclic Quinoxaline Compound G-4, the molecular formula is as follows:

Synthesize using the following routes:

Step 1. Synthesis of Compound 41.

3 mL of ethylene glycol dimethyl ether was added to the reaction flask, cyclopropanesulfonyl chloride (1.5 g, 1.07 mmol) was added, and the mixture was cooled with an ice water bath, and sodium cerium oxide (40%, 3 ml, 0.03 mol) was diluted with 3 mL of heavy water and added dropwise. In the reaction flask, after completion of the dropwise addition, the mixture was reacted at room temperature for 18 hours, cooled, and the pH was adjusted to acidic with deuterated hydrochloric acid. The solvent was evaporated to give a crude compound (yield: 3.19 g).

Step 2. Synthesis of Compound 42.

Compound 41 (1.6 g, 11.2 mmol) was added to the reaction flask, 10 mL of thionyl chloride was added, 5 drops of DMF were added, and the reaction was refluxed at 60 ° C for 4 hours, cooled to room temperature, and concentrated to remove excess thionyl chloride to obtain compound 42. The crude product 2.1 g was used directly in the next step without further purification.

Step 3. Synthesis of Compound 43.

2.1 g of crude product of compound 42 was added to the reaction flask, 100 mL of anhydrous tetrahydrofuran was added, and the mixture was cooled to -5 ° C under reduced temperature. Under stirring, ammonia gas was introduced for 20 minutes, and the reaction was carried out for 18 hours at room temperature. The tetrahydrofuran was removed by concentration, and 20 mL of water was added thereto. The ethyl ester was extracted 4 times, and the combined organic layers were washed with saturated sodium chloride and dried over anhydrous sodium sulfate.

Step 4. Synthesis of Compound 44.

Compound 21 (430 mg, 1.894 mmol) was added to the reaction mixture, and the mixture was dissolved in EtOAc (3 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc After adding to the reaction flask, DBU (417 mg, 2.48 mmol) was added, and the reaction was carried out for 17 hours at room temperature. The reaction of the starting material was completed by TLC. The pH was adjusted to 1-2 by adding 1 M hydrochloric acid, and extracted with ethyl acetate for 3 times. The extract was washed with saturated sodium chloride and dried over anhydrous sodium sulfate.

Step 5. Synthesis of Compound 45.

Compound 44 (710 mg, 2.14 mmol) was added to a reaction flask, and 10 mL of dichloromethane was added thereto, and 5 mL of a solution of dioxane (4M) hydrochloride was added thereto, and the reaction was carried out at 40 ° C for 4 hours. The reaction of the starting material was completely confirmed by TLC, and the reaction mixture was concentrated to give 338 mg of compound. 45, used directly in the next reaction.

Step 6. Synthesis of Compound 46.

Compound 26 (109 mg, 0.159 mmol) was added to the reaction flask, dissolved in 1 mL of methanol, dissolved in 2 mL of isopropanol, and 7 mg of palladium on carbon was added. The reaction was carried out under hydrogen at 40 ° C for 18 hours. The reaction of the starting material by LCMS was completed and cooled to room temperature. After filtration through celite, the cake was washed with methanol and concentrated to give 191 g of Compound 46 (yield: 63.5%, LC-MS (APCI): m/z = 687 (M+1) ⁺ .

Step 7. Synthesis of Compound 47.

Compound 46 (1 g, 1.45 mmol) was added to the reaction flask, dissolved in 10 mL of acetonitrile, trifluoroacetic acid (573 mg, 3.6 mmol) was added, the temperature was raised to 40 ° C, and the reaction was carried out for 18 hours. The reaction of the starting material was completely confirmed by TLC. Trifluoroacetic acid, the pH was adjusted to 8-9 with DIPEA, 3 mL of acetonitrile was added, and HATU (751 mg, 1.97 mmol) was added to react at room temperature for 4 hours. The reaction of the starting material was completed by TLC, and the reaction mixture was concentrated. The yield in two steps was 36.2%, LC-MS (APCI): m/z = 569 (M+1) ⁺ .

Step 8. Synthesis of Compound 48.

Compound 47 (100 mg, 0.152 mmol) was added to the reaction flask, and 1 mL of tetrahydrofuran was added. Lithium hydroxide (76 mg, 1.5 mmol) was dissolved in 2 mL of water and added to the reaction. The mixture was heated to 40 ° C for 1 hour, and the reaction of the starting material was completely confirmed by TLC. After cooling to room temperature, the pH was made acidic with 1N aqueous hydrochloric acid, and extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate.

Step 9. Synthesis of Compound G-4.

Compound 48 (100 mg, 0.18 mmol), compound 45 (53.8 mg, 0.23 mmol) was added to the reaction mixture at room temperature and dissolved in 5 mL of acetonitrile. Add pyridine (200 mg, 2.25 mmol), react at room temperature for 15 minutes, add EDCI (55 mg, 0.288 mmol), react at room temperature for 1.5 hours, the reaction solution becomes clear, add 2 mL of 2N hydrochloric acid solution, stir the reaction for 20 minutes, and completely react with TLC. , the reaction solution was concentrated, to give 10mg G-4, ¹ H NMR compound _{(500MHz, CDCl 3) δ7.83 (} d, J = 9.0Hz, 1H) using preparative TLC, 7.20 (m, J = 9.0,2.7Hz , 1H ), 7.14 (d, J = 2.7 Hz, 1H), 7.08 (s, 1H), 5.99 (s, 1H), 5.87-5.79 (m, 1H), 5.38 (s, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.09 (d, J = 10.1 Hz, 1H), 4.51 (d, J = 11.0 Hz, 1H), 4.42 (d, J = 9.9 Hz, 1H), 4.37 (s, 1H), 4.05 (d, J = 7.4 Hz, 1H), 3.94 (d, J = 8.4 Hz, 3H), 3.79 (d, J = 6.7 Hz, 1H), 2.98 (d, J = 6.6 Hz, 2H), 2.88 (s) , 1H), 2.57 (s, 1H), 2.47 (s, 1H), 2.07 (d, J = 8.5 Hz, 1H), 1.76 (d, J = 14.1 Hz, 2H), 1.66-1.61 (m, 2H) , 1.57-1.48 (m, 3H), 1.36-1.31 (m, 3H), 1.09 (d, J = 5.4 Hz, 9H), 0.89 (m, J = 13.3, 6.6 Hz, 4H), 0.68 (s, 1H) ), 0.48 (d, J = 6.5 Hz, 1H).

Example 5 Preparation of a substituted macrocyclic quinoxaline compound G-5 having the following formula:

Synthesize using the following routes:

Compound 36 (77 mg, 0.138 mmol), compound 45 (41.4 mg, 0.179 mmol) was obtained. Add pyridine (153 mg, 0.192 mmol), react at room temperature for 15 minutes, add EDCI (43 mg, 0.219 mmol), react at room temperature for 1.5 hours, the reaction solution becomes clear, add 2 mL of 2N hydrochloric acid solution, stir the reaction for 20 minutes, and completely react with TLC. , the reaction solution was concentrated, to give 11mg compound G-5 by preparative ^{TLC, 1 H NMR (500MHz, CDCl} 3) δ7.83 (d, J = 9.1Hz, 1H), 7.20 (m, J = 9.1,2.8Hz, 1H ), 7.13 (d, J = 2.7 Hz, 1H), 6.85 (s, 1H), 6.00 (s, 1H), 5.79 (m, J = 17.4, 8.8 Hz, 1H), 5.43 (d, J = 9.7 Hz) , 1H), 5.22 (d, J = 17.3 Hz, 1H), 5.13 (d, J = 10.0 Hz, 1H), 4.65 (s, 1H), 4.53 (d, J = 11.3 Hz, 1H), 4.34 - 4.29 (m, 1H), 4.07-4.02 (m, 1H), 3.77 (d, J = 6.9 Hz, 1H), 2.87 (dd, J = 18.5, 11.2 Hz, 2H), 2.79 (d, J = 4.5 Hz, 1H), 2.58 (m, J = 12.8, 7.9 Hz, 1H), 2.46 (d, J = 10.4 Hz, 1H), 2.08 (d, J = 8.5 Hz, 1H), 1.75 (d, J = 15.1 Hz, 4H), 1.53-1.47 (m, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.09 (s, 9H), 0.89 (dd, J = 13.4, 6.6 Hz, 4H), 0.70 (d, J =18.8 Hz, 1H), 0.48 (m, J = 12.6, 6.1 Hz, 1H).

Evaluation of biological activity.

To verify the effect of the compounds described herein on HCV, the inventors used the HCV Replicon System as an evaluation model. Since its first report in Science in 1999, the HCV replication system has become one of the most important tools for studying HCV RNA replication, pathogenicity and viral persistence, for example, the use of replicons has successfully demonstrated the 5' required for HCV RNA replication. - NCR minimum region, and the HCV replication subsystem has been successfully used as an evaluation model for antiviral drugs. The inventors of the present invention verified according to the methods described in Science, 1999, 285 (5424), 110-3, and J. Virol, 2003, 77(5), 3007-19.

(1) Detection of compound anti-HCV 1a and 1b genotype replicon activity

The inhibitory activities of the recombinant hepatitis C virus genotype 1a and 1b replicons were detected by stable transfection of replicon cells with HCV-1a and HCV-1b. This experiment will use the NS3 inhibitor MK-5172 as a positive control compound.

Step 1: The compound was diluted 1:3 in 8 series points, double-replicated, and added to a 96-well plate. The DMSO was set to no compound control. The final concentration of DMSO in the cell culture was 0.5%.

Step 2: HCV-1a and 1b cells were separately suspended in a culture medium containing 10% FBS, and seeded into a 96-well plate containing the compound at a density of 8,000 cells per well. The cells were cultured for 3 days at 5% CO ₂ at 37 °C.

Step 3: The cytotoxicity of the compound against GT1b replicon was determined using CellTiter-Fluor (Promega).

Step 4: Detection of luciferase assay by Bright-Glo (Promega) for anti-hepatitis C virus activity.

Step Five: using GraphPad Prism data analysis software, the curve fitting and EC ₅₀ values _were calculated and the ₅₀ value CC.

Table 1 Comparison of anti-HCV genotype replicon activities of Examples 1-4 and control MK-5172

Numbering HCV GT1a EC ₅₀ (nM) HCV GT1b EC ₅₀ (nM) HCV CC ₅₀ (nM) MK-5172 0.967 0.98 >1000 G-1 2.188 1.863 >1000

G-2 1.172 0.963 >1000 G-3 1.404 0.884 >1000 G-4 3.370 2.613 >1000

As shown in Table 1, the compound of the present invention can be used for the inhibition of hepatitis C virus by inhibiting multiple genotypes of HCV.

(2) Metabolic stability evaluation

Microsomal experiments: human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).

Preparation of the stock solution: A certain amount of the powder of the compound examples 1-4 was accurately weighed and dissolved to 5 mM with DMSO, respectively.

Preparation of phosphate buffer (100 mM, pH 7.4): Mix 150 mL of pre-formed 0.5 M potassium dihydrogen phosphate and 700 mL of 0.5 M potassium dihydrogen phosphate solution, and adjust the mixture with 0.5 M potassium dihydrogen phosphate solution. The pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.

A solution of NADPH regeneration system (containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride) was prepared and placed on wet ice before use.

Formulation stop solution: acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 μL of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 μL of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.

Incubation of the sample: The stock solution of the corresponding compound was diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile as a working solution, and was used. 398 μL of human liver microsomes or rat liver microsome dilutions were added to 96-well incubation plates (N=2), and 2 μL of 0.25 mM working solution was added and mixed.

Determination of metabolic stability: 300 μL of pre-cooled stop solution was added to each well of a 96-well deep well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system were placed in a 37 ° C water bath, shaken at 100 rpm, and pre-incubated for 5 min. 80 μL of the incubation solution was taken from each well of the incubation plate, added to the stopper plate, and mixed, and 20 μL of the NADPH regeneration system solution was added as a sample of 0 min. Then, 80 μL of the NADPH regeneration system solution was added to each well of the incubation plate to start the reaction and start timing. The corresponding compound had a reaction concentration of 1 μM and a protein concentration of 0.5 mg/mL. 100 μL of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min. The plate was centrifuged at 5000 x g for 10 min at 4 °C. 100 μL of the supernatant was taken into a 96-well plate to which 100 μL of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.

Data analysis: The peak area of the corresponding compound and the internal standard was detected by LC-MS/MS system, and the ratio of the peak area of the compound to the internal standard was calculated. The slope is measured by the natural logarithm of the percentage of the remaining amount of the compound versus time, and t _1/2 and CL _{int are} calculated according to the following formula, where V/M is equal to 1/protein concentration.

The metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration. The half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 2. The undeuterated compound MK-5172 was used as a control sample in Table 2. As shown in Table 2, the compound of the present invention, particularly G-4, can significantly improve metabolic stability by comparison with the compound KK-5172 which has not been deuterated, and is thus more suitable as a hepatitis C virus inhibitor.

Table 2 Comparison of metabolic stability of Examples 1 to 4 and MK-5172 control

Claims (14)

A substituted macrocyclic quinoxaline compound characterized by a compound of formula (I), or a polymorph thereof, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant, Hydrate or solvent compound,

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ And R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ⁴⁷ are each independently hydrogen. , hydrazine, halogen or trifluoromethyl; Additional conditions are R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ And R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , at least one of R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ⁴⁷ Modern or awkward. The macrocyclic quinoxaline compound according to claim 1, wherein each of R ¹ , R ² and R ^{3 is} independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein each of R ⁴ , R ⁵ and R ^{6 is} independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ R ¹⁸ , R ¹⁹ and R ²⁰ are each independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ and R ³⁰ are each independently It is hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein R ³¹ , R ³² , R ³³ , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein each of R ³⁷ , R ³⁸ and R ^{39 is} independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein each of R ⁴⁰ , R ⁴¹ and R ^{42 is} independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein each of R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ^{47 is} independently hydrazine or hydrogen. The macrocyclic quinoxaline compound according to claim 1, wherein the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and according to any one of claims 1 to 10 A macrocyclic quinoxaline compound, or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvate thereof. The pharmaceutical composition according to claim 11, characterized in that it further comprises other active compounds which may be selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors. Use of a macrocyclic quinoxaline compound according to any one of claims 1 to 10 for use in the manufacture of a medicament for the treatment of hepatitis C virus infection. Use of a pharmaceutical composition according to any one of claims 11 and 12, characterized by the use of a medicament for the preparation of a medicament for inhibiting HCV NS3 protease activity in a subject in need thereof.