Antifungal compounds, pharmaceutical compositions and formulations comprising the same, and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and particularly relates to an antifungal compound, a pharmaceutical composition and preparation containing the same, and application thereof. The present application provides a compound having the structure of formula (I), and a pharmaceutical composition and a pharmaceutical preparation containing the same, and the like, which can be used for preventing and / or treating diseases (such as invasive fungal infection and the like) caused at least in part by fungal infection.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to antifungal compounds, pharmaceutical compositions and formulations containing them, and their applications. Background Technology

[0002] Pathogenic microorganisms have always been a threat to our health. With the widespread use of antibiotics, the drug resistance of pathogenic microorganisms is constantly increasing. In recent years, multidrug-resistant bacteria, extensively drug-resistant bacteria, and pan-drug-resistant bacteria have emerged, posing a huge challenge to global public health and clinical medicine.

[0003] Fungal diseases in humans are classified into superficial and invasive fungal infections. Invasive fungal infections, often called "hidden killers," are caused by pathogens such as Aspergillus and spore-forming organisms, and are a significant cause of death in patients with cancer, AIDS, or organ transplants. Currently, the use of broad-spectrum antibiotics and other potent drugs has led to a substantial increase in the number of patients with invasive fungal infections. The medical community has yet to find a satisfactory solution for combating drug-resistant and refractory pathogen infections.

[0004] A breakthrough in antifungal treatment has been achieved, with F2G Inc. announcing that the FDA has granted Breakthrough Therapy Designation to its first-in-line drug candidate, olorofim (F901318). olorofim is currently in an open-label Phase 2b clinical trial and is indicated for the treatment of rare and drug-resistant invasive fungal infections, such as invasive aspergillosis (including azole-resistant strains), sclerosing fungal infections, omentosporidiosis, fusarium infections, cysticercosis, and coccidioidomycosis (valley fever).

[0005] However, considering factors such as patient medication choices and the economic burden of medication, there is still a need to develop a new type of antibacterial drug with effects comparable to or better than olorofim. Summary of the Invention

[0006] The problem the invention aims to solve

[0007] The present invention aims to provide a series of novel compounds with antifungal activity, pharmaceutical compositions and formulations containing the compounds, and the pharmaceutical uses of the series of compounds.

[0008] Solution for solving the problem

[0009] <First Aspect>

[0010] This invention provides compounds of formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, chelates, non-covalent complexes, or prodrugs thereof, wherein the general structural formula of the compounds of formula (I) is:

[0011]

[0012] in:

[0013] X1 is CR1 or N, X2 is NR2, X3 is CR3 or N, and X4 is CR4 or N;

[0014] m is 0 or 1;

[0015] Y is either O or NR5;

[0016] R1, R2, R3, R4, and R5 are each independently H, CN, and C. 1-4 Alkyl, C 2-4 alkenyl or C 6-10 Aryl, or R5 together with R1 or R2 and the atoms to which they are attached, forms a 5 to 8-membered heterocycle, the 5 to 8-membered heterocycle containing 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0017] Z is CH or N;

[0018] A and B are each independently C 6-10 Aromatic rings or 5- to 10-membered heteroaromatic rings, wherein the 5- to 10-membered heteroaromatic rings contain 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0019] R6, R7, and R8 are each independently H and C. 1-8 Alkyl, C 2-8 alkenyl or C 2-8 The alkynyl group, or R7 together with R6 or R8 and the atoms to which they are attached, forms a 5 to 8-membered heterocycle, the 5 to 8-membered heterocycle containing 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0020] R9 is H, halogen, or -P(=O)(CH3)2;

[0021] Where R1 is phenyl, R2 and R3 are both methyl, R4, R6, R7 and R8 are all H, Y is O, Z is N, m is 1, and A is... and for When R9 is not F.

[0022] Preferably, the compound has the structure shown in formula (I-1):

[0023]

[0024] Where W is R1, R2, R3, and R4 are defined as above.

[0025] Preferably, the compound has the structure shown in formula (I-2):

[0026]

[0027] Where m, Z, A, B, R6, R7, R8, and R9 are defined as above, and when R6, R7, and R8 are all H, Z is N, m is 1, and A is... and for When R9 is not F.

[0028] More preferably, the compound has the structure shown in formula (I-2-1):

[0029]

[0030] Wherein, Z, A, B, R6, R7, R8, and R9 are defined as above; more preferably, the compound has the structure shown in formula (I-2-1-1):

[0031]

[0032] Z, B, R7, and R8 are defined as described above.

[0033] More preferably, the compound has the structure shown in formula (I-2-2):

[0034]

[0035] Wherein, B is defined above, R7 together with R6 or R8 and the atoms to which they are attached form a 5 to 8-membered heterocycle, the 5 to 8-membered heterocycle containing 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0036] More preferably, the compound has the structure shown in formula (I-2-3):

[0037]

[0038] R7 and R9 are defined as described above.

[0039] More preferably, the compound has the structure shown in formula (I-2-4):

[0040]

[0041] R9 is -P(=O)(CH3)2.

[0042] Preferably, the compound has the structure shown in formula (I′):

[0043]

[0044] in:

[0045] R3 is CH3 or CN, and X4 is CH or N;

[0046] Z is CH or N;

[0047] for

[0048] R6, R7, and R8 are each independently H, or R7 together with R6 or R8 and the atoms to which it is attached forms a 6 or 7-membered heterocycle, wherein the 6 or 7-membered heterocycle contains one or two cyclic heteroatoms, wherein each heteroatom is independently N or O.

[0049] Where R3 is CH3, X4 is CH, R6, R7, and R8 are all H, and Z is N, Not for

[0050] <Second aspect>

[0051] This invention provides the following compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, chelates, non-covalent complexes, or prodrugs:

[0052]

[0053]

[0054] <Third aspect>

[0055] The present invention provides a pharmaceutical composition comprising the compound according to the first aspect and the second aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof.

[0056] <Fourth Aspect>

[0057] This invention provides a pharmaceutical formulation comprising a compound according to the first aspect or the second aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug thereof, or a pharmaceutical composition according to the third aspect, wherein the pharmaceutical formulation is any one of tablets, capsules, granules, powders, suppositories, pills, gels, creams, ointments, powders, films, patches, lotions, pastes, oral solutions, inhalants, suspensions, dry suspensions, or injections.

[0058] <Fifth Aspect>

[0059] The present invention provides the use of the compounds according to the first aspect, the second aspect, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof, or pharmaceutical compositions according to the third aspect, or pharmaceutical formulations according to the fourth aspect, in the preparation of medicaments for the prevention and / or treatment of diseases at least partially caused by fungal infections.

[0060] <Sixth Aspect>

[0061] The present invention provides compounds according to the first aspect and the second aspect, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof, or pharmaceutical compositions according to the third aspect, or pharmaceutical preparations according to the fourth aspect, for the prevention and / or treatment of diseases at least partially caused by fungal infections.

[0062] <Seventh Aspect>

[0063] The present invention provides a method for preventing and / or treating diseases at least partially caused by fungal infection, comprising the steps of administering a therapeutically effective amount of the compound according to the first aspect, the second aspect, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug thereof, or a pharmaceutical composition according to the third aspect, or a pharmaceutical preparation according to the fourth aspect, to a patient in need of it.

[0064] <Eighth Aspect>

[0065] The present invention provides a pharmaceutical combination comprising a compound according to the first aspect, the second aspect or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition according to the third aspect, or a pharmaceutical formulation according to the fourth aspect, and at least one additional antibacterial agent.

[0066] The effects of the invention

[0067] This invention provides a series of novel compounds of formula (I) that can be used to prepare pharmaceutical compositions and pharmaceutical preparations for the prevention and / or treatment of diseases at least partially caused by fungal infections (such as invasive fungal infections), providing patients with more medication options and reducing their economic burden. Detailed Implementation

[0068] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for description only and not for limiting specific embodiments.

[0069] [Terminology Definition]

[0070] Unless otherwise stated, the following terms have the following meanings:

[0071] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compounds of this invention with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases; such salts are also known as acid addition salts or base addition salts. Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; common organic acids include (but are not limited to) trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; common inorganic bases include (but are not limited to) sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc.; and common organic bases include (but are not limited to) diethylamine, triethylamine, ethylaminobutanol, etc.

[0072] The term "ester" is used to refer to organic esters, including monoesters, diesters, triesters, and more commonly polyesters.

[0073] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetric plane due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), thereby enabling the rotation of plane-polarized light. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Because the compounds of this invention and their salts include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched with single stereoisomers (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). The single stereoisomer of a compound is prepared by synthesis from an optically active starting material containing the desired chiral center, or by separation or resolution of a mixture of enantiomers, for example, by conversion to a mixture of diastereomers followed by separation, chromatographic processing, use of chiral resolving reagents, or direct separation of enantiomers on a chiral chromatographic column. Starting compounds with specific stereochemistry are commercially available or can be prepared according to the methods described below and then resolved by methods well known in the art.

[0074] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0075] The term "solvent" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates, ethanol compounds, acetone compounds, etc.

[0076] The term "chelate" refers to a complex with a cyclic structure, obtained through the chelation of two or more ligands with the same metal ion to form a chelate ring.

[0077] The term "non-covalent complex" refers to a complex formed through the interaction of a compound with another molecule, where no covalent bond is formed between the two molecules. Complexation can occur, for example, through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding).

[0078] The term "prodrug" refers to a derived compound that, when administered to a patient, can directly or indirectly provide the compounds of the present invention. Particularly preferred derived compounds or prodrugs are those that, when administered to a patient, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise stated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0079] The term "independently" means that at least two groups (or ring systems) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0080] The term "halogen" refers to four atoms: fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0081] The term "alkyl" includes straight-chain, branched, or cyclic saturated alkyl groups. In this invention, alkyl groups include (but are not limited to) methyl, ethyl, propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclohexyl, and similar groups, for example, "C 1-4 The "C" in "alkyl" 1-4 "" refers to a group consisting of 1, 2, 3, or 4 carbon atoms arranged in a straight chain, branched chain, or ring.

[0082] The term "alkenyl" herein refers to a group having and having at least one alkenyl unsaturated site. In this invention, alkenyl includes (but is not limited to) vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and other groups, such as "C 2-4 "Alkenyl" refers to alkenyl groups containing 2, 3, or 4 carbon atoms arranged in a straight chain, branched chain, or cyclic form.

[0083] The term "alkynyl" refers to a group having and having at least one alkynyl unsaturated site. In this invention, alkynyl includes (but is not limited to) ethynyl, propyn-1-yl, propyn-2-yl, and other groups, for example, "C 2-8"Alkyne" refers to an alkynyl group containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight chain, branched chain, or cyclic form.

[0084] The terms “aryl” and “aromatic ring” refer to an aromatic carbocyclic group consisting of a monocyclic or fused ring, whether unsubstituted or substituted, and are used interchangeably herein, such as (but not limited to) phenyl, naphthyl, phenanthryl and biphenyl.

[0085] The term "heterocycle" refers to an unsubstituted or substituted stable 5- to 8-membered monocyclic or 8- to 14-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more heteroatoms (i.e., atoms different from carbon or hydrogen, such as N, S, O, P, Se, Te, preferably N, S, O, P).

[0086] The term "heteroaromatic ring" refers to an aromatic group that contains at least one heteroatom (i.e., an atom different from carbon or hydrogen, such as N, S, O, P, Se, Te, preferably N, S, O, P) as a ring member.

[0087] The term “prevention” refers to the complete or near-complete prevention of the occurrence of a disease or condition (e.g., infection, ischemia, or reperfusion injury) when a patient or subject is susceptible to or at risk of the disease or condition; prevention may also include suppression, i.e., preventing the development of the condition.

[0088] The term “treatment” means: 1) suppressing the disease; for example, suppressing the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom of the disease (i.e., preventing further development of the pathology and / or symptom); or 2) improving the disease; for example, improving the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom (i.e., reversing the pathology and / or symptom).

[0089] The term "therapeutic effective amount" refers to the amount of an active compound or agent that researchers, veterinarians, physicians, or other clinicians seek to elicit a biological or medical response in an tissue, system, animal, individual, or human.

[0090] [General Formula Compound]

[0091] This invention provides (I) a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug thereof, wherein the general structural formula of the compound (I) is:

[0092]

[0093] in:

[0094] X1 is CR1 or N, X2 is NR2, X3 is CR3 or N, and X4 is CR4 or N;

[0095] m is 0 or 1;

[0096] Y is either O or NR5;

[0097] R1, R2, R3, R4, and R5 are each independently H, CN, and C. 1-4 Alkyl, C 2-4 alkenyl or C 6-10 Aryl, or R5 together with R1 or R2 and the atoms to which they are attached, forms a 5 to 8-membered heterocycle, the 5 to 8-membered heterocycle containing 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0098] Z is CH or N;

[0099] A and B are each independently C 6-10 Aromatic rings or 5- to 10-membered heteroaromatic rings, wherein the 5- to 10-membered heteroaromatic rings contain 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0100] R6, R7, and R8 are each independently H and C. 1-8 Alkyl, C 2-8 alkenyl or C 2-8 The alkynyl group, or R7 together with R6 or R8 and the atoms to which they are attached, forms a 5 to 8-membered heterocycle, the 5 to 8-membered heterocycle containing 1 to 3 cyclic heteroatoms, each of which is independently N, O or S;

[0101] R9 is H, halogen, or -P(=O)(CH3)2;

[0102] Where R1 is phenyl, R2 and R3 are both methyl, R4, R6, R7 and R8 are all H, Y is O, Z is N, m is 1, and A is... and for When R9 is not F.

[0103] In some specific embodiments of the present invention, in the compound of formula (I) above, X1 is CR1 or N, X2 is NR2, X3 is CR3 or N, X4 is CR4 or N, wherein R1, R2, R3 and R4 are each independently H, CN, methyl, vinyl or phenyl, and m, Y, Z, A, B, R6, R7, R8 and R9 are defined as defined in the general structural formula of the compound of formula (I), and when R1 is phenyl, R2 and R3 are both methyl, R4, R6, R7 and R8 are all H, Y is O, Z is N, m is 1, and A is and for When R9 is not F.

[0104] In some specific embodiments of the present invention, in the compound of formula (I) above, when R1 is methyl, X2 can be NH, N(CH3) or N(C6H6), X3 can be N, CH, C(CH3) or C(C6H6), X4 can be N, CH, C(CH3) or C(C6H6), and the definitions of m, Y, Z, A, B, R6, R7, R8 and R9 are as defined in the general structural formula of the compound of formula (I).

[0105] In some specific embodiments of the present invention, in the compound of formula (I) above, when R2 is phenyl, X1 can be N, CH, C(CH3) or C(C6H6), X3 can be N, CH, C(CH3) or C(C6H6), X4 can be N, CH, C(CH3) or C(C6H6), and the definitions of m, Y, Z, A, B, R6, R7, R8 and R9 are as defined in the general structural formula of the compound of formula (I).

[0106] In some specific embodiments of the present invention, in the compound of formula (I) above, when R3 is CN, X1 can be N, CH, C(CH3) or C(C6H6), X2 can be NH, N(CH3) or N(C6H6), X4 can be N, CH, C(CH3) or C(C6H6), and the definitions of m, Y, Z, A, B, R6, R7, R8 and R9 are as defined in the general structural formula of the compound of formula (I).

[0107] In some specific embodiments of the present invention, in the compound of formula (I) above, when X4 is N, X1 can be N, CH, C(CH3) or C(C6H6), X2 can be NH, CH2, C(CH3) or C(C6H6), X3 can be N, CH, C(CH3) or C(C6H6), and the definitions of m, Y, Z, A, B, R6, R7, R8 and R9 are as defined in the general structural formula of the compound of formula (I).

[0108] In some specific embodiments of the present invention, in the compound of formula (I) above, R5, together with R1 or R2 and the atoms to which they are attached, forms a 5- to 8-membered heterocycle, which contains 1 to 3 cyclic heteroatoms, each of which is independently N, O, or S; preferably R1 is phenyl, and R5, together with R2 and the atoms to which they are attached, forms a six-membered heterocycle, which contains 2 cyclic heteroatoms, both of which are N. The definitions of the others, such as X3, X4, m, Y, Z, A, B, R6, R7, R8, and R9, are as defined in the general structural formula of the compound of formula (I).

[0109] In some specific embodiments of the present invention, in the compound of formula (I) above, R7 together with R6 or R8 and the atoms to which they are attached forms a 5- to 8-membered heterocycle, the 5- to 8-membered heterocycle containing 1 to 3 cyclic heteroatoms, each heteroatom being independently N, O or S; preferably, R7 together with R6 and the atoms to which they are attached forms a 7-membered heterocycle, the 7-membered heterocycle containing 2 cyclic heteroatoms, the heteroatoms being N and O respectively; preferably, R7 together with R8 and the atoms to which they are attached forms a 6-membered heterocycle, the 6-membered heterocycle containing 2 cyclic heteroatoms, the heteroatoms being N and O respectively. The definitions of the others, such as X1, X2, X3, X4, m, Y, Z, A, B and R9, are as defined in the general structural formula of the compound of formula (I).

[0110] In some specific embodiments of the present invention, in the compound of formula (I) above, R9 is H, Cl, Br or -P(=O)(CH3)2, and the definitions of the others such as X1, X2, X3, X4, m, Y, Z, A, B, R6, R7 and R8 are as defined in the general structural formula of the compound of formula (I).

[0111] In the specific implementation plan described above, A and B are each independently...

[0112] In some specific embodiments of the present invention, the compound of formula (I) has the structure shown in formula (I-1):

[0113]

[0114] Where W is R1, R2, R3 and R4 are defined as in the general formula of compound structure (I).

[0115] In some specific embodiments of the present invention, the compound of formula (I) has the structure shown in formula (I-2):

[0116]

[0117] Wherein, m, Z, A, B, R6, R7, R8, and R9 are defined as in the general formula of compound structure (I), and when R6, R7, and R8 are all H, Z is N, m is 1, and A is... and for When R9 is not F.

[0118] In some preferred embodiments of the present invention, the compound of formula (I-2) has the structure shown in formula (I-2-1):

[0119]

[0120] The definitions of Z, A, B, R6, R7, R8 and R9 are as defined in the compound of formula (I-2).

[0121] In some preferred embodiments of the present invention, the compound of formula (I-2-1) has the structure shown in formula (I-2-1-1):

[0122]

[0123] Z, B, R7 and R8 are defined as in the compound of formula (I-2-1).

[0124] In some preferred embodiments of the present invention, the compound of formula (I-2) has the structure shown in formula (I-2-2):

[0125]

[0126] In this case, B is defined as in the compound of formula (I-2), where R7, together with R6 or R8 and the atoms to which they are attached, forms a 5 to 8-membered heterocycle, which contains 1 to 3 cyclic heteroatoms, each of which is independently N, O or S.

[0127] In some preferred embodiments of the present invention, in the compound of formula (I-2-2) above, R7 and R6 together with the atoms to which they are attached form a 7-membered heterocycle, which contains two cyclic heteroatoms, namely N and O; B is defined as defined in the compound of formula (I-2).

[0128] In some preferred embodiments of the present invention, in the compound of formula (I-2-2) above, R7 and R8 together with the atoms to which they are attached form a 6-membered heterocycle, which contains two cyclic heteroatoms, namely N and O; B is defined as defined in the compound of formula (I-2).

[0129] In some preferred embodiments of the present invention, the compound of formula (I-2) has the structure shown in formula (I-2-3):

[0130]

[0131] R7 and R9 are defined as in the compound of formula (I-2).

[0132] In some preferred embodiments of the present invention, the compound of formula (I-2) has the structure shown in formula (I-2-4):

[0133]

[0134] R9 is -P(=O)(CH3)2.

[0135] In some specific embodiments of the present invention, the compound of formula (I) has the structure shown in formula (I′):

[0136]

[0137] in:

[0138] R3 is CH3 or CN, and X4 is CH or N;

[0139] Z is CH or N;

[0140] for

[0141] R6, R7 and R8 are each independently H, or R7 together with R6 or R8 and the atoms to which it is attached to form a 6 or 7-membered heterocycle, the 6 or 7-membered heterocycle containing 1 or 2 cyclic heteroatoms, each heteroatom being independently N or O.

[0142] Where R3 is CH3, X4 is CH, R6, R7, and R8 are all H, and Z is N, Not for

[0143] In some specific embodiments of the present invention, the compound is any one of the following:

[0144]

[0145]

[0146]

[0147] [Pharmaceutical Composition]

[0148] The present invention also provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug thereof.

[0149] In some specific embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier or diluent.

[0150] In some preferred embodiments of the present invention, the pharmaceutical composition further includes:

[0151] - Pharmaceutically acceptable carriers; and / or

[0152] -excipient.

[0153] The term "pharmaceuticalally acceptable carrier" refers to pharmaceutical excipients that are compatible with the active ingredient of a drug and are harmless to the subjects, including (but not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, cosolvents, and surfactants.

[0154] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.

[0155] [Pharmaceutical Preparations]

[0156] The present invention provides a pharmaceutical formulation comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug or pharmaceutical composition thereof.

[0157] In some specific embodiments of the present invention, the pharmaceutical preparation is any one of tablets, capsules, granules, powders, suppositories, pills, gels, creams, ointments, powders, films, patches, lotions, pastes, oral solutions, inhalants, suspensions, dry suspensions, or injections.

[0158] [Medical Uses]

[0159] Whether it is the above-mentioned compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, or pharmaceutical composition or pharmaceutical preparation, all of which can exhibit antifungal activity, the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, or the above-mentioned pharmaceutical composition or pharmaceutical preparation, for the prevention and / or treatment of diseases at least partially caused by fungal infection.

[0160] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof, or the above-described pharmaceutical compositions, or the above-described pharmaceutical preparations in the preparation of medicaments for the prevention and / or treatment of diseases at least partially caused by fungal infections.

[0161] In some specific embodiments of the present invention, diseases caused by fungal infections include those caused by Aspergillus and Candida.

[0162] [Treatment methods]

[0163] The present invention also provides a method for preventing and / or treating diseases at least partially caused by fungal infection, comprising the steps of administering a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, or a pharmaceutical composition thereof, or a pharmaceutical formulation thereof, to a patient in need of it.

[0164] The amount of compound, pharmaceutical composition, or pharmaceutical preparation administered to a patient will vary depending on the drug being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, and the method of administration. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially suppress the symptoms and complications of the disease. The therapeutically effective amount will depend on the symptoms of the disease being treated and, by the judgment of the attending clinician, on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0165] [Combination therapy]

[0166] The present invention provides a pharmaceutical combination comprising the above-described compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition comprising the above-described compound, or a pharmaceutical formulation comprising the above-described compound, and at least one additional antibacterial agent.

[0167] In some specific embodiments of the present invention, additional antimicrobial agents refer to pharmaceutical compositions or formulations capable of effectively controlling and / or combating fungi. Common antimicrobial agents include (but are not limited to) azole antimicrobial agents, polyene antimicrobial agents, purine nucleotide inhibitors, pyrimidine nucleotide inhibitors, mannan inhibitors, protein elongation factor inhibitors, echinocandins, allylamine antimicrobial agents, anti-HSP90 antibodies, bactericidal / permeability-inducing protein products, polyoxin, compound AN2690, compound AN2718, and icofungipen, or one or more of these.

[0168] [Preparation Method]

[0169] This invention provides a method for preparing the above-mentioned compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent compound or prodrug. The following describes a typical synthetic route for several specific compounds to further illustrate the technical solution of this invention.

[0170] The following abbreviations may be used in this invention: DIEA (N,N-diisopropylethylamine); DMSO (dimethyl sulfoxide); NaBH4 (sodium borohydride); MeOH (methanol); Pd / C (palladium on carbon); HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate); K2CO3 (potassium carbonate); dioxane (1,4-dioxane); DCM (dichloromethane); NaH (sodium hydride); MeI, CH3I (iodomethane); DMF (N,N-dimethylformamide); Pd(dcpf)Cl2 (dichloro[1,1'-bis(di(di)-dimethylformamide)); Cyclohexylphosphine]ferrocene]palladium(II)); Cs2CO3 (cesium carbonate); KOH (potassium hydroxide); N2H4·H2O (hydrazine hydrate); EtOH (ethanol); NBS (N-bromosuccinimide); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride); AlCl3 (aluminum chloride); EA or EtOAc (ethyl acetate); water; LCMS or LC-MS (liquid chromatography-mass spectrometry); TLC (thin-layer chromatography); Rt, rt or RT (room temperature); h, hr or hrs (hours); min (minutes).

[0171] The raw materials used in this invention are sourced from: methyl 2-fluoro-5-nitrobenzene (Leyan); (4-benzyl-piperazin-2-yl)methanol (Bide); DIEA (Example 1, Leyan; Examples 2, 3 and 5, Shanghai Yishi); DMSO (Tianjin Damao); sodium borohydride (Shanghai Yishi); methanol (Tianjin Damao); palladium on carbon (Example 1, Shanghai Yishi; Examples 2, 3 and 5, Kaida); 2-chloro-5-fluoropyrimidine (Leyan); HAT U (Leyan); DCM (Tianjin Damao); 2,3,5-Trifluoropyridine (Bide); 1-BOC-3-hydroxymethylpiperazine (Bide); K2CO3 (Tianjin Damao); HCl / dioxane (Shanghai Yishi); 1-Fluoro-4-nitrobenzene (Bide); 4-Bromo-1H-pyrrole-2-carboxaldehyde (Leyan); DMF (Tianjin Damao); NaH (Shaoyuan); CH3I (Shaoyuan); Phenylboronic acid (Leyan); Cs2C O3 (Shaoyuan); Pd(dppf)Cl2 (Example 3, Leyan; Examples 4 and 5, Rock); dioxane / H2O (Tianjin Damao); KOH (Tianjin Damao); N2H4·H2O (Shaoyuan); diethylene glycol (Shaoyuan); oxaloyl chloride (Leyan); 1-Boc-4-methanesulfonyloxypiperidine (Bide); 4-fluoropyridin-2-ol (Bide); 1-fluoro-4-nitrobenzene (Bide); 4-bromo-1 2-Dimethyl-1H-imidazolium (Leyan); 1,4-Dioxane (Tianjin Damao); ethyl 2-chloro-2-oxoacetate (Shanghai Yishi); NaOH (Tianjin Damao); ethanol (Tianjin Damao); 2-chloro-5-fluoropyrimidine (Bide); piperazine-1-carboxylic acid tert-butyl ester (Bide); 1-fluoro-4-nitrobenzene (Bide); N-methyl-2-pyrrolidone (Leyan); NBS (Leyan); AlCl3 (Shangfu).

[0172] Unless otherwise specified, commercially available solvents and reagents used in this experiment can be used directly without further purification or treatment after purchase. When referring to other examples or synthetic methods, reaction conditions (reaction temperature, reaction solvent, reactant molar ratio, and / or reaction duration) may differ. Generally, the reaction progress can be monitored by TLC, and the appropriate time to terminate the reaction and perform post-processing can be selected accordingly. Purification conditions for compounds may also vary; generally, a suitable column chromatography eluent is selected based on the Rf value of the TLC, or the corresponding compound is purified by preparative TLC.

[0173] Example 1 2-(1,5-dimethyl-3-phenyl-1H-pyrrolo-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-2,3,4,4a,5,7-hexahydro-1H-benzo[e]pyrazino[2,1-c][1,4]oxazine Synthesis of 9-yl)-2-oxoacetamide (compound 1)

[0174] The synthesis route is as follows:

[0175]

[0176]

[0177] Step 1: Synthesis of Compounds 1-2

[0178] 4-Bromo-1H-pyrrole-2-carboxaldehyde (compound 1-1, 10 g, 0.057 mol) was added to DMF (200 mL), cooled to 0 °C, and NaH (2.74 g, 0.114 mmol) was added and reacted for 1 h. Then CH3I (24.27 g, 0.171 mmol) was added and reacted for 3 h. The reaction solution was then quenched with 200 mL of saturated Na2CO3 solution, and 200 mL of water was added to dilute the reaction solution. The solution was extracted with EA (100 mL * 4) to obtain an organic phase. The organic phase was washed with saturated brine (100 mL * 2), dried, evaporated to dryness, mixed, and purified by column chromatography (PE:EA = 20:1). After purification, compound 1-2 was obtained as a purple solid, 8.3 g.

[0179] Step 2: Synthesis of compounds 1-4

[0180] Compounds 1-2 (3.5 g, 0.0186 mol), phenylboronic acid (compound 1-3, 2.7 g, 0.022 mol), and Cs₂CO₃ (13.44 g, 0.041 mol) were added to a 250 mL single-necked flask containing dioxane / H₂O (50 mL, volume ratio 10:1). Pd(dppf)Cl₂ (1.5 g, 0.0019 mol) was then added for venting. The mixture was heated to 95 °C under N₂ protection for 5 h, and monitored by TLC. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with EA. The filtrate was evaporated to dryness, mixed, and purified by column chromatography (PE / EA = 10 / 1) to obtain compounds 1-4, a white solid, 3.0 g.

[0181] Step 3: Synthesis of compounds 1-5

[0182] Compounds 1-4 (1.5 g, 0.008 mol), KOH (1.36 g, 0.024 mol), and N₂H₄·H₂O (1.21 g, 0.024 mol) were added to a 100 mL single-necked flask containing 15 mL of diethylene glycol. The mixture was gradually heated to 130 °C and maintained at this temperature for 3 h. The reaction solution was diluted with 100 mL of water and then extracted with EA (100 mL * 4). The organic phases were combined, washed with 200 mL of saturated brine, dried, mixed, and purified by column chromatography (PE / EA = 20:1) to obtain compound 1-5, a yellow oil, 900 mg.

[0183] Step 4: Synthesis of compounds 1-7

[0184] Compounds 1-5 (900 mg, 5.26 mmol) were added to a 50 mL single-necked flask containing 10 mL of DCM. Oxaloyl chloride (compounds 1-6, 1.5 g, 10.51 mmol) was added dropwise at 0 °C, and the reaction was carried out at room temperature under N2 protection for 40 min. The reaction was quenched dropwise in methanol to obtain methyl ester. The sample was stirred and purified at low temperature (to prevent damage from excessive temperature). The purified methyl ester was hydrolyzed with NaOH. The pH of the hydrolyzed reaction solution was adjusted to weakly acidic with 1 mol / L hydrochloric acid (10 mL). The solution was extracted with EA (200 mL * 2) to obtain the organic phase. The organic phase was evaporated to dryness at low temperature, and then lyophilized with a small amount of water to obtain compounds 1-7, a grayish-yellow solid, 700 mg.

[0185] Step 5: Synthesis of compound 1-10-1

[0186] Methyl 2-fluoro-5-nitrobenzoate (compounds 1-8, 270 mg, 1.36 mmol), (4-benzyl-piperazin-2-yl)methanol (compounds 1-9, 350.7 mg, 1.70 mmol), and DIEA (877 mg, 6.80 mmol) were added to DMSO (5 mL). The mixture was heated to 80 °C and reacted for 16 hours. Then, it was cooled to room temperature, and 20 mL of ethyl acetate was added. The mixture was washed with saturated ammonium chloride aqueous solution (10 mL * 2), and then extracted with EA (20 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 1 / 1) to obtain compound 1-10-1, totaling 350 mg (containing trace amounts of compound 1-10-2, which can be ignored).

[0187] Step 6: Synthesis of compounds 1-11

[0188] Compound 1-10-1 (containing trace amounts of compound 1-10-2, which can be disregarded) (350 mg, 0.991 mmol) was added to methanol (10 mL), cooled to 0 °C, and sodium borohydride (188 mg, 4.955 mmol) was added in portions. The mixture was allowed to rise naturally to room temperature and stirred for 4 hours. The reaction solution was then evaporated to dryness and purified by column chromatography (PE / EA = 1 / 3) to obtain compound 1-11, 340 mg.

[0189] Step 7: Synthesis of compounds 1-12

[0190] Compound 1-11 (340 mg, 0.95 mmol) was added to 50 wt% sulfuric acid (10 mL) and reacted at 120 °C for 1 hour. The mixture was then cooled to room temperature, water (30 mL) was added, and sodium hydroxide was added to adjust the pH to alkaline. The mixture was then extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 1-12, a yellow solid, 230 mg.

[0191] Step 8: Synthesis of compounds 1-13

[0192] Compound 1-12 (230 mg, 0.680 mmol) was added to MeOH (10 mL). Under nitrogen protection, wet palladium on carbon (50 mg) was added. After hydrogen purging, hydrogen was introduced and the reaction was carried out at room temperature for 3 hours. The mixture was then filtered, and the filtrate was evaporated to dryness to obtain compound 1-13, a yellow solid, 140 mg.

[0193] Step 9: Synthesis of compounds 1-15

[0194] Compounds 1-13 (140 mg, 0.630 mmol), 2-chloro-5-fluoropyrimidine (compound 1-14, 99 mg, 0.756 mmol), and DIEA (244 mg, 1.89 mmol) were added to DMSO (5 mL), purged with nitrogen, and reacted at 80 °C for 16 h. After cooling to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with saturated ammonium chloride aqueous solution (20 mL * 3). The mixture was then purified by column chromatography (MeOH / DCM = 1 / 20) to give compound 1-15, 90 mg.

[0195] Step 10: Synthesis of Compound 1

[0196] Compounds 1-7 (72.9 mg, 0.300 mmol), HATU (114 mg, 0.300 mmol), and DIEA (73.8 mg, 0.572 mmol) were added to DCM (5 mL) and stirred at room temperature for 10 min. Then, compound 1-15 (90 mg, 0.286 mmol) was added and stirred at room temperature for 2 h. The reaction was quenched with water (50 mL), and the aqueous phase was extracted with DCM (25 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by Prep-TLC (PE / EA = 1 / 2) to give compound 1, a yellow solid, 25.0 mg.

[0197] The results of proton nuclear magnetic resonance (NMR) and mass spectrometry (MS) measurements on compound 1 are as follows:

[0198] 1H NMR (300MHz, CDCl3): δ2.33(3H,s), δ3.00(1H,m), δ3.37(2H,m), δ3.62(1H,m), δ3.71(2H,m), δ3.82(3H,s), δ3.85(1H,m), δ4.2 6(2H,m), δ4.55(1H,d,J=12Hz), δ4.84(1H,d,J=12Hz), δ6.13(1H,s), δ6.96(2H,m), δ7.13(1H,s), δ7.23(5H,m), δ8.19(3H,m).

[0199] LC / MS (m / z): 541 [M+H] + (Calculated value: 540.59, C) 30 H 29 FN6O3).

[0200] Example 2 Synthesis of 2-(1,5-dimethyl-3-phenyl-1H-pyrrolo-2-yl)-N-(4-(3-fluoro-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazin-8-yl)phenyl)-2-oxoacetamide (compound 2)

[0201] The synthesis route is as follows:

[0202]

[0203] Step 1: Synthesis of compound 2-3-2

[0204] 2,3,5-trifluoropyridine (compound 2-1, 4.0 mL), 1-BOC-3-hydroxymethylpiperazine (compound 2-2, 3.0 g, 13.8 mmol), and K₂CO₃ (6.0 g, 43.2 mmol) were added to a 40 mL flask, and the system was reacted in a sealed container at 160 °C for 8 h. Since the reaction was incomplete, it was stopped when the system became viscous. The reaction solution was diluted with methanol and then directly passed through a reverse-phase column (mobile phase: 0.1% formic acid aqueous solution-acetonitrile) to obtain the crude product. The crude product was then purified again by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 2-3-2, a white solid, 202 mg (purity 90%, containing 10% compound 2-3-1).

[0205] Step 2: Synthesis of compounds 2-4

[0206] Compound 2-3-2 (182 mg, 0.59 mmol), a solution of 1,4-dioxane hydrogen chloride (HCl / dioxane, 0.5 mL), and DCM (5 mL) were added to a 50 mL single-necked flask. The system was reacted at rt for 5 h. The reaction solution was concentrated to dryness to obtain crude compound 2-4, a white solid, 195 mg, which was used directly in the next step.

[0207] Step 3: Synthesis of compounds 2-6

[0208] Crude compound 2-4 (195 mg), 1-fluoro-4-nitrobenzene (compound 2-5, 83 mg, 0.59 mmol), K₂CO₃ (164 mg, 1.17 mmol), and DMSO (3 mL) were added to a 40 mL flask. The system was reacted at 100 °C for 16 h. The reaction solution was added to water, and a solid precipitated. The mixture was filtered, and the resulting filter cake was evaporated to dryness to give compound 2-6, a yellow solid, 104 mg.

[0209] Step 4: Synthesis of compounds 2-7

[0210] Compound 2-6 (94 mg, 0.28 mmol) and MeOH (10 mL) were added to a 50 mL single-necked flask. Under nitrogen protection, Pd / C (50 mg) was added. After purging with hydrogen, the system was purged with hydrogen and reacted at room temperature for 2 h. The reaction solution was filtered, and the filtrate was concentrated to dryness and passed through a silica gel column (PE / EA = 1 / 2) to give compound 2-7, a white solid, 72 mg.

[0211] Step 5: Synthesis of Compound 2

[0212] Compounds 2-8 (60 mg, 0.24 mmol, i.e., compounds 1-7 in Example 1), 2-7 (72 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), DIEA (93 mg, 0.72 mmol), and DCM (2 mL) were added to an 8 mL vial, and the system was reacted at room temperature for 2 h. The reaction solution was directly purified by Prep-TLC (DCM:MeOH = 20:1) to obtain a crude product, which was further purified by reverse-phase column chromatography (mobile phase: 0.1% formic acid aqueous solution-acetonitrile) to obtain compound 2, a yellow solid, 45 mg.

[0213] Compound 2 was subjected to proton nuclear magnetic resonance (NMR) and mass spectrometry tests, and the results are as follows:

[0214] 1H NMR (300MHz, CDCl3): δ2.33(3H,s), δ2.53(1H,t), δ2.90(2H,m), δ3.50(2H,m), δ3.63(1H,d,J=16Hz), δ3.82(3H,s), δ4.05(1H, m), δ4.28(1H,m), δ4.50(1H,d,J=12Hz), δ6.13(1H,s), δ6.83(3H,m), δ7.10(2H,m), δ7.25(5H,m), δ7.70(1H,m), δ8.21(1H,m).

[0215] LC / MS (m / z): 526 [M+H] + (Calculated value: 525.57, C) 31 H 28 FN5O3).

[0216] Example 3 Synthesis of 2-(1,5-dimethyl-3-phenyl-1H-pyrrolo-2-yl)-N-(4-(4-(4-(4-fluoro-2-oxopyridin-1(2H)-yl)piperidin-1-yl)phenyl)-2-oxoacetamide (compound 3)

[0217] The synthesis route is as follows:

[0218]

[0219] Step 1: Synthesis of compound 3-3

[0220] In a 100 mL single-necked flask, 4-fluoropyridine-2-ol (compound 3-1, 800 mg, 7.08 mmol), DME (40 mL), 1-Boc-4-methanesulfonyloxypiperidine (compound 3-2, 2.17 g, 7.78 mmol), and K₂CO₃ (2.93 g, 21.23 mmol) were added. The reaction mixture was reacted at 80 °C for 16 h, and the reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The crude product was passed through a normal-phase column (PE:EA = 3:1) to give compound 3-3, a colorless oil, 620 mg.

[0221] Step 2: Synthesis of compounds 3-4

[0222] Compound 3-3 (620 mg, 2.09 mmol) and DCM (10 mL) were added to a 100 mL single-necked flask, followed by the slow addition of TFA (2 mL). After the addition was complete, the mixture was allowed to react at room temperature for 1 h, and the reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was directly evaporated to dryness to obtain crude compound 3-4, a yellow oil, 600 mg, which was used directly in the next reaction.

[0223] Step 3: Synthesis of compounds 3-6

[0224] In a 100 mL single-necked flask, compound 3-4 (500 mg, 2.55 mmol), DMSO (25 mL), 1-fluoro-4-nitrobenzene (compound 3-5, 1.8 g, 12.76 mmol), and K₂CO₃ (1.76 g, 12.75 mmol) were added. The mixture was reacted at 80 °C for 16 h, and the reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was cooled to room temperature, diluted with EA (200 mL), and washed successively with water (200 mL) and brine (200 mL). The organic phase was collected, dried, and evaporated to dryness to obtain the crude product. The crude product was passed through a normal phase column (PE / EA = 1 / 3) to give compound 3-6, a yellow solid, 500 mg.

[0225] Step 4: Synthesis of compounds 3-7

[0226] In a 50 mL single-necked flask, compound 3-6 (200 mg, 0.63 mmol), EtOH (10 mL), and concentrated HCl (2 mL) were added. Then, SnCl2·2H2O (852.96 mg, 3.78 mmol) was added in portions. The reaction was carried out at room temperature for 1 h, and the reaction was monitored by liquid chromatography-mass spectrometry. The ethanol in the reaction solution was removed by rotary evaporation, diluted with water (100 mL), and the pH was adjusted to 9–10 with 2N NaOH aqueous solution. The solution was then extracted with DCM / MeOH at a ratio of 10:1 (100 mL * 3). The organic phase was collected, dried, and rotary evaporated to give compound 3-7 as a brown solid, 180 mg.

[0227] Step 5: Synthesis of Compound 3

[0228] In a 50 mL single-necked flask, compounds 3-8 (123 mg, 0.504 mmol, i.e., compounds 1-7 in Example 1), HATU (207 mg, 0.55 mmol), DIEA (431 mg, 3.36 mmol), and DCM (20 mL) were added and reacted at room temperature for 10 min. Compounds 3-7 (120 mg, 0.42 mmol) were added in portions, and the mixture was reacted at room temperature for 2 h after the addition was complete, with LC-MS monitoring. After the reaction was complete, the reaction solution was evaporated to dryness and purified by reverse-phase flash (mobile phase: 0.05% NH4HCO3 aqueous solution-acetonitrile) to obtain compound 3, a yellow solid, 90 mg.

[0229] The results of proton nuclear magnetic resonance (NMR) and mass spectrometry analysis of compound 3 are as follows:

[0230] 1H NMR (300MHz, DMSO-d6): δ1.84(2H,m), δ1.97(2H,m), δ2.33(3H,s), δ2.75(2H,m), δ3.75(2H,m), δ3.83(3H,s), δ4.78(1H,m), δ6 .11(1H,s),δ6.20(1H,m),δ6.30(1H,m),δ6.82(2H,m),δ7.05(2H,m),δ7.13(3H,m),δ7.24(2H,m),δ7.92(1H,m),δ10.19(1H,s).

[0231] LC / MS (m / z): 513 [M+H] + (Calculated value: 513.56, C) 30 H 29 FN4O3).

[0232] Example 4 Synthesis of 2-(1,2-dimethyl-4-phenyl-1H-imidazol-5-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide (compound 4)

[0233] The synthesis route is as follows:

[0234]

[0235] Step 1: Synthesis of Compound 4-3

[0236] 4-Bromo-1,2-dimethyl-1H-imidazole (compound 4-1, 1.0 g, 5.7 mmol), phenylboronic acid (compound 4-2, 1.4 g, 11.4 mmol), K₂CO₃ (1.6 g, 11.4 mmol), Pd(dppf)Cl₂ (100 mg), 1,4-dioxane (10 mL), and H₂O (1 mL) were added to a 40 mL reaction flask. The system was reacted at 100 °C for 3 h, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness and then passed through a silica gel column (PE / EA = 1 / 1) to obtain compound 4-3, a gray solid, 1.0 g.

[0237] Step 2: Synthesis of compounds 4-5

[0238] Compound 4-3 (100 mg, 0.578 mmol) and ethyl 2-chloro-2-oxoacetate (compound 4-4, 1.0 mL) were added to a 100 mL three-necked flask. Under nitrogen protection, the reaction was carried out at 120 °C for 16 h. Since the reactants could not react completely, the reaction endpoint was reached when the reactant concentration stopped decreasing. The system was then added dropwise to an aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the ethyl acetate phase was concentrated to dryness to give compound 4-5, a white solid, 125 mg.

[0239] Step 3: Synthesis of compounds 4-6

[0240] Compound 4-5 (125.26 mg, 0.46 mmol), NaOH (40 mg), EtOH (2 mL), and H₂O (2 mL) were added to a 40 mL vial. After dissolution, the system was reacted at room temperature for 2 h, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was directly passed through a reversed-phase column (the binary mobile phase was 0.1% formic acid aqueous solution and acetonitrile; the elution method was isocratic elution, and the volume fraction of 0.1% formic acid aqueous solution was 65%) to obtain compound 4-6, a pale yellow solid, 62 mg.

[0241] Step 4: Synthesis of Compound 4

[0242] Compounds 4-6 (52 mg, 0.213 mmol), 4-7 (58 mg, 0.213 mmol), HATU (81 mg, 0.213 mmol), DIEA (82 mg, 0.64 mmol), and DCM (1 mL) were added to an 8 mL vial. The mixture was reacted at room temperature for 2 h, and the reaction was monitored by TLC until completion. The mixture was then directly concentrated and dried on a large plate (PE:EA = 1:2). The crude product was further purified by reverse-phase chromatography to give compound 4, a yellow solid, 40 mg.

[0243] Compound 4 was subjected to proton nuclear magnetic resonance (NMR) and mass spectrometry tests, and the results are as follows:

[0244] 1 H NMR (300MHz, DMSO-d6): δ2.47(3H,s), δ3.15(4H,m), δ3.82(7H,m), δ6.87(2H,m), δ7.20(5H,m), δ7.43(2H,m), δ8.49(2H,s), δ10.43(1H,s).

[0245] LC / MS (m / z): 500 [M+H] + (Calculated value: 499.54, C) 27 H 26 FN7O2).

[0246] Example 5 Synthesis of 2-(5-cyano-1-methyl-3-phenyl-1H-pyrrolo-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide (compound 5)

[0247] The synthesis route is as follows:

[0248]

[0249] Step 1: Synthesis of Compound 5-3

[0250] 2-Chloro-5-fluoropyrimidine (compound 5-1, 5.0 g, 37.8 mmol), piperazine-1-carboxylic acid tert-butyl ester (compound 5-2, 5.0 g, 26.9 mmol), DIEA (19.5 g, 151.2 mmol), and EtOH (50 mL) were added to a 250 mL three-necked flask, and the system was reacted at 80 °C for 16 h. The reaction solution was filtered, and the resulting filtrate was concentrated to dryness and then passed through a silica gel column (PE / EA = 2 / 1) to give compound 5-3, an off-white solid, 5.8 g.

[0251] Step 2: Synthesis of Compound 5-4

[0252] Compound 5-3 (5.0 g, 25.2 mmol), HCl / dioxane (10 mL), and DCM (100 mL) were added to a 250 mL single-necked flask. The system was reacted at room temperature for 2 h, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was concentrated to dryness, diluted with sodium bicarbonate aqueous solution, extracted with EA, and the EA phase was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 5-4, a yellow oil, 3.7 g.

[0253] Step 3: Synthesis of compounds 5-6

[0254] Compound 5-4 (3.7 g, 20.3 mmol), 1-fluoro-4-nitrobenzene (compound 5-5, 2.9 g, 20.3 mmol), K₂CO₃ (5.7 g, 40.7 mmol), and DMSO (50 mL) were added to a 100 mL three-necked flask, and the system was reacted at 100 °C for 16 h. The reaction solution was then added to water, resulting in the precipitation of a solid. The mixture was filtered, and the resulting filter cake was evaporated to dryness to give compound 5-6, a red solid, 3.6 g.

[0255] Step 4: Synthesis of compounds 5-7

[0256] Compound 5-6 (1.0 g, 3.3 mmol) and MeOH (50 mL) were added to a 100 mL single-necked flask. Under nitrogen protection, Pd / C (300 mg) was slowly added. After purging the system with hydrogen, the reaction was carried out at room temperature for 2 h under hydrogen purging. The reaction solution was filtered, and the filtrate was concentrated to dryness and passed through a silica gel column (PE / EA = 1 / 1) to give compound 5-7, a gray solid, 0.71 g.

[0257] Step 5: Synthesis of compounds 5-9

[0258] N-methyl-2-pyrrolidone (compound 5-8, 2.0 g, 18.8 mmol), NBS (3.35 g, 18.8 mmol), and DMF (20 mL) were added to a 40 mL vial, and the system was reacted at room temperature for 2 h. The reaction solution was then added to water, resulting in the precipitation of a solid. The mixture was filtered, and the filter cake was evaporated to dryness to obtain compound 5-9, a yellow solid, 1.6 g.

[0259] Step 6: Synthesis of Compounds 5-11

[0260] 4-Bromo-1-methyl-1H-pyrrolo-2-onitrile (compound 5-9, 1.5 g, 8.1 mmol), phenylboronic acid (compound 5-10, 3.0 g, 24.3 mmol), Pd(dppf)Cl2 (150 mg), K2CO3 (2.3 g, 16.3 mmol), 1,4-dioxane (30 mL), and H2O (3 mL) were added to a 40 mL vial. After nitrogen purging protection, the mixture was reacted at 80 °C for 2 h. The reaction solution was filtered, and the filtrate was concentrated to dryness. The crude product was passed through a silica gel column (PE / EA = 3 / 1) to give compound 5-11, a white solid, 1.1 g.

[0261] Step 7: Synthesis of compounds 5-13

[0262] Compound 5-11 (244 mg, 1.34 mmol), compound 5-12 (450 mg, 3.3 mmol), DCM (5 mL), and AlCl3 (432 mg, 3.3 mmol) were added to a 40 mL flask. The mixture was reacted at 50 °C for 2 h under nitrogen protection. The mixture was then added to an aqueous sodium bicarbonate solution and extracted with DCM. The DCM phase was concentrated to dryness, and the crude product was passed through a silica gel column (PE:EA = 1:1) to give compound 5-13, a white solid, 150 mg.

[0263] Step 8: Synthesis of compounds 5-14

[0264] Compound 5-13 (150 mg, 0.53 mmol), EtOH (2 mL), H₂O (2 mL), and NaOH (150 mg) were added to a 40 mL vial and dissolved. The system was then reacted at room temperature for 5 h. The reaction solution was directly passed through a reverse-phase column (mobile phase: 0.1% formic acid aqueous solution-acetonitrile) to give compound 5-14, a pale yellow solid, 140 mg.

[0265] Step 9: Synthesis of Compound 5

[0266] Compound 5-14 (100 mg, 0.39 mmol), DCM (2 mL), compound 5-7 (110 mg, 0.39 mmol), HATU (148 mg, 0.39 mmol), and DIEA (150 mg, 1.17 mmol) were added to an 8 mL vial, and the system was reacted at room temperature for 2 h. The system was directly filtered, and the filter cake was washed with DCM and then with MeOH. The resulting solid filter cake was dissolved in DMSO and then added dropwise to DCM, resulting in the precipitation of solid. The mixture was filtered, and the filter cake was evaporated to dryness to obtain compound 5, a yellow solid, 46 mg.

[0267] Compound 5 was subjected to proton NMR and mass spectrometry tests, and the results are as follows:

[0268] 1 H NMR (300MHz, DMSO-d6): δ3.21(4H,m), δ3.84(7H,m), δ7.03(2H,m), δ7.56(1H,m), δ7 .63(2H,m),δ7.80(2H,m),δ7.91(1H,m),δ8.03(2H,m),δ8.50(2H,s),δ10.72(1H,s).

[0269] LC / MS (m / z): 510 [M+H] + (Calculated value: 509.53, C) 28 H 24 FN7O2).

[0270] [Antibacterial Test]

[0271] 1. Experimental Materials

[0272] 1.1 Instruments

[0273] name model supplier Biosafety cabinet BSC-1604IIA2 Shang Jing incubator B6120 Thermo Fisher Cell density meter Ultrospec 10 cypress Water purification system MILLI-Q DIRECT Millipore pH meter PB-10 Sartorius

[0274] 1.2 Reagents

[0275]

[0276] 1.3 Other Materials

[0277] Laboratory equipment supplier Item number / batch number 96–V orifice plate Aisjin WIPP02280 96-hole flat bottom plate Corning 3599 Sample addition tank Corning 4870 Sample addition tank BIOFIL LTT-011-050 Inoculation ring NEST Nest-717101 Disposable empty plate Alphaplus 704767-C100002 1.5ml centrifuge tube JET JET-CFT-001-015 50ml centrifuge tube JET JET-CFT-011-500 5ml pipette JET JET-GSP110005 25ml pipette JET JET-GSP110025 14ml round-bottom test tube BD Falcon 352001

[0278] 1.4 Test strains

[0279] No. strains Strain Information ATCC MYA-2876 Candida albicans ATCC ATCC MYA-4609 Aspergillus fumigatus ATCC

[0280] 2. Experimental Procedure

[0281] 2.1 Strain preparation

[0282] Inoculate one loop of Aspergillus fumigatus into a glycerol tube at -80℃ and incubate at 30±2℃ for 3 days.

[0283] Inoculate one loopful of Candida albicans into a glycerol tube at -80℃ and incubate at 30±2℃ for 1 day.

[0284] 2.2 Culture medium preparation

[0285] Weigh 10.4g of RMPI-1640 powder and 34.53g of MOPS, dissolve them in 900ml of distilled water, adjust the pH to 7.0 with sodium hydroxide, and bring the volume to 1L. Filter the solution through a 0.22μm filter membrane and store at 4℃ to obtain the test medium RPMI-1640 + 0.165MMOPS with a pH of 7.0.

[0286] 2.3 Preparation of compound plates

[0287] 2.3.1 Dissolve each compound according to the table below.

[0288]

[0289] 2.3.2 Preparation of Compound Masterbatch

[0290] Each compound was then subjected to a 2-fold serial dilution, as follows:

[0291] a) Prepare a 96-V type plate. Add 40 μL of the stock solution of compounds 1-4, olorofim, voriconazole and amphotericin B to column 1, and add 20 μL of the corresponding solvent to columns 2-12.

[0292] b) Transfer 20 μL from column 1 to column 2 and mix thoroughly by pipetting.

[0293] c) Transfer 20 μL from column 2 to column 3 and mix thoroughly by pipetting.

[0294] d) Repeat steps b to c until column 11;

[0295] e) The 12th column of the 96-V type plate contains only 20 μL of the corresponding solvent.

[0296] 2.3.2 Preparation of Compound Subplate

[0297] Transfer 2 μL of each compound solution, serially diluted 2-fold, from the compound master plate into a 96-well flat-bottom plate.

[0298] 2.4 Preparation of inoculum

[0299] 2.4.1 Preparation of Candida albicans inoculum

[0300] On the day of testing, a suitable amount of single colonies were picked and suspended in sterile physiological saline (0.9% NaCl). The turbidity of the bacterial solution was adjusted to OD600 = 0.2 (approximately 1 × 10⁻⁶) using a turbidimeter. 6 CFU / mL ~5×10 6 (CFU / mL). This bacterial suspension was first diluted 40-fold with test medium, then diluted 50-fold (total 2000-fold) to obtain the inoculum solution. The final inoculum concentration was 0.5–2.5 × 10⁻⁶ CFU / mL. 3 CFU / mL.

[0301] 2.4.2 Preparation of Aspergillus fumigatus inoculum

[0302] On the day of testing, add 5 ml of physiological saline containing 0.1% Tween 20 to a petri dish and cover with pili. Carefully squeeze and scrape the pili using an L-shaped applicator to release spores into the liquid. Collect the spore-containing physiological saline with a pipette, count the spores using a erythrocyte counter, and calculate the spore suspension concentration (spores / mL). Dilute the spore suspension to 0.2–2.5 × 10⁻⁶ ml with test medium (RPMI-1640 + 0.165 M MOPS, pH 7.0). 4 CFU / mL, this is the inoculum solution of Aspergillus fumigatus.

[0303] 2.5 Vaccination

[0304] Add 198 μL of Candida albicans and Aspergillus fumigatus inoculum to the compound subplate to obtain the MIC test plate. The total volume of each well of the test plate is 200 μL.

[0305] 2.6 Cultivation

[0306] The prepared MIC test plates were incubated at 35±2℃ for 24h (Candida albicans) and 48h (Aspergillus fumigatus), and the minimum inhibitory concentration (MIC) of each test compound against fungi was read.

[0307] Table 1. Minimum inhibitory concentrations (μg / mL) of each compound against Candida albicans and Aspergillus fumigatus.

[0308]

[0309] In Table 1, olorofim is a positive control. The results show that under the existing test conditions, compounds 1 and 2 have the same antibacterial activity as the positive control.

[0310] The above embodiments of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all possible implementations here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: X1 is CR1, X2 is NR2, X3 is CR3, and X4 is CR4; m is 1; Y is O; R1, R2, R3, and R4 are each independently H and C. 1-4 Alkyl or C 6-10 Aryl; Z is N; A is C 6-10 Aromatic rings; B is a 5- to 10-membered heteroaromatic ring, wherein the 5- to 10-membered heteroaromatic ring contains 1 to 3 cyclic heteroatoms, and the heteroatom is N; R8 is H or C 1-8 Alkyl groups, R7 and R6, and the atoms attached thereto form a 7-membered heterocycle, the 7-membered heterocycle containing two cyclic heteroatoms, namely N and O; or R6 is H or C 1-8 Alkyl groups, R7 and R8, together with the atoms attached thereto, form a 6-membered heterocycle, the 6-membered heterocycle containing two cyclic heteroatoms, namely N and O; R9 is a halogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound has the structure shown in formula (I-2): The definitions of m, Z, A, B, R6, R7, R8, and R9 are as defined in claim 1.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, The compound has the structure shown in formula (I-2-2): B, R6, R7 and R8 are as defined in claim 2.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound has the structure shown in formula (I′): in: R3 is CH3, X4 is CH; Z is N; for R8 is H, and R7, R6, and the atoms they are attached to form a 7-membered heterocycle, which contains two cyclic heteroatoms, namely N and O; or R6 is H, and R7, R8, and the atoms they are attached to form a 6-membered heterocycle. The 6-membered heterocycle contains two cyclic heteroatoms, namely N and O.

5. The following compounds or their pharmaceutically acceptable salts:

6. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

7. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, wherein the pharmaceutical preparation is any one of tablets, capsules, granules, powders, suppositories, pills, gels, creams, ointments, powders, films, patches, lotions, pastes, oral solutions, inhalers, suspensions, dry suspensions, or injections.

8. Use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, or the pharmaceutical preparation of claim 7, in the preparation of a medicament for the prevention and / or treatment of diseases at least partially caused by fungal infections.

9. A pharmaceutical combination comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6 or a pharmaceutical formulation according to claim 7, and at least one additional antibacterial agent.

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