Fused ring derivative

Abstract

Disclosed are a compound as represented by general formula (I) and a pharmaceutically acceptable salt thereof: wherein R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined in the present disclosure.

Description

fused ring derivatives

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the Chinese invention patent application with application number 202410340495.6, filed with the State Intellectual Property Office of the People's Republic of China on March 22, 2024, and entitled "Condensed Ring Derivatives", and incorporates the entire contents thereof into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the field of medicinal chemistry, and more particularly, to fused ring derivatives.

[0005] background

[0006] Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). THF is essential for cell growth because it is involved in the synthesis of thymidine, purines, and some amino acids. By inhibiting DHFR, cells are unable to produce THF, and their growth is inhibited.

[0007] The metabolic pathway involved in DHFR includes the following steps: 1. Folic acid is first converted to dihydrofolate (DHF) by dihydrofolate synthase; 2. DHF is then reduced to THF by DHFR. THF is the biologically active form of folic acid; 3. THF is a cofactor used to synthesize thymidine, purines, and amino acids such as methionine and glycine, all of which are essential for cell growth and DNA synthesis; 4. THF can also be converted back to DHF by thymidylate synthase and other enzymes. The cycle then continues. Inhibition of DHFR blocks the conversion of DHF to THF, depleting the cells of THF. This deprives cells of precursors for thymidine, purines, and amino acids, inhibiting cell growth and proliferation.

[0008] DHFR inhibitors such as methotrexate and pemetrexed work by competing with DHF for binding to the DHFR enzyme. They inhibit DHFR activity and THF production. These drugs are used in chemotherapy to target rapidly dividing cells, such as cancer cells. Bacterial DHFR can also be targeted by antibiotics such as trimethoprim. By inhibiting bacterial DHFR, trimethoprim blocks the production of THF and other metabolites, preventing bacterial growth. Overall, DHFR and its inhibitors are important tools for chemotherapy and antibacterial therapy. By targeting DHFR, these drugs can disrupt metabolism, depriving cells or bacteria of important nutrients needed for growth and proliferation.

[0009] Overview

[0010] In one aspect, the present disclosure relates to compounds represented by general formula (I), and pharmaceutically acceptable salts thereof:

[0011] in:

[0012] R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0013] R3 is selected from hydroxy and optionally substituted amino;

[0014] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0015] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0016] R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl;

[0017] R9 and R 10 are each independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; and

[0018] X is selected from CH or N.

[0019] In another aspect, the present disclosure relates to compounds, and pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0020] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0021] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ia),

[0022] It involves carrying out the reaction shown below:

[0023] in:

[0024] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0025] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0026] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0027] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0028] X is selected from CH or N;

[0029] Y is hydrogen or absent; and

[0030] LG is selected from the group consisting of O, OH, halogen, diarylphosphono, OTs, OMs and OTf.

[0031] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ib),

[0032] It involves carrying out the reaction shown below:

[0033] in:

[0034] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0035] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0036] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0037] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0038] X is selected from CH or N; and

[0039] Y is hydrogen or absent.

[0040] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ic),

[0041] It involves reacting a compound represented by general formula (Ib):

[0042] in:

[0043] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0044] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0045] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0046] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0047] X is selected from CH or N;

[0048] Y is hydrogen or absent; and

[0049] M is selected from alkali metals.

[0050] In another aspect, the present disclosure relates to a method for preparing a compound of formula (Id),

[0051] It comprises reacting a compound represented by general formula (Ic):

[0052] in:

[0053] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0054] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0055] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0056] R9 and R 10Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0057] X is selected from CH or N; and

[0058] Y is hydrogen or absent.

[0059] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ie),

[0060] It involves reacting a compound represented by general formula (Id):

[0061] in:

[0062] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0063] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0064] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0065] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0066] X is selected from CH or N; and

[0067] Y is hydrogen or absent.

[0068] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (I),

[0069] It comprises reacting a compound represented by general formula (Ie):

[0070] in:

[0071] R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0072] R3 is selected from hydroxy and optionally substituted amino;

[0073] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0074] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0075] R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl;

[0076] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0077] X is selected from CH or N;

[0078] Y is hydrogen or absent; and

[0079] FC is selected from O, OH, halogen, diarylphosphono, OTs, OMs and OTf.

[0080] In another aspect, the present disclosure relates to a method for preparing a compound of formula (I),

[0081] It involves reacting a compound represented by the general formula (If):

[0082] in:

[0083] R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0084] R3 is selected from hydroxy and optionally substituted amino;

[0085] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0086] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0087] R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10, optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl;

[0088] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0089] X is selected from CH or N; and

[0090] LG' is selected from OH, halogen, diarylphosphono, OTs, OMs and OTf.

[0091] On the other hand, the present disclosure relates to a method for inhibiting dihydrofolate reductase (DHFR), comprising contacting dihydrofolate reductase with an effective inhibitory amount of a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0092] In another aspect, the present disclosure relates to a method for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR), comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0093] In another aspect, the present disclosure relates to the compound represented by general formula (I) of the present disclosure and its pharmaceutically acceptable salt for inhibiting dihydrofolate reductase (DHFR).

[0094] On the other hand, the present disclosure relates to the use of the compounds represented by general formula (I) of the present disclosure and pharmaceutically acceptable salts thereof, or the compounds of the present disclosure and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating or preventing diseases or disease states mediated by dihydrofolate reductase (DHFR).

[0095] BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 shows the -1 The blood concentration-time curve of Compound 5 in Example 4 of the present disclosure in ICR mice after intravenous administration of a dose of ; and

[0097] Figure 2 shows the -1The blood concentration-time curve of compound 5 in Example 4 of the present disclosure in ICR mice after intravenous administration of a dose of .

[0098] Details

[0099] In the following description, certain specific details are included to provide a thorough understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0100] Unless otherwise required by this disclosure, throughout this specification and the claims that follow, the words "include" and "comprising" should be construed in an open, inclusive sense, ie, "including, but not limited to."

[0101] Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "one embodiment" or "an embodiment" or "another embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0102] It should be understood that the singular article "a", "an" and "the" used in the specification of the present disclosure and the appended claims include plural objects unless the context clearly provides otherwise. Therefore, for example, a pharmaceutical composition comprising "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes one compound of formula (I) or a pharmaceutically acceptable salt thereof, or two or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0103] definition

[0104] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0105] Certain chemical groups named in this disclosure are preceded by abbreviations indicating the total number of carbon atoms present in the indicated chemical group. For example, C1-C4 alkyl describes an alkyl group as defined below having a total of 1 to 4 carbon atoms, while C3-C4 alkyl describes an alkyl group ... 10 Cycloalkyl describes a cycloalkyl group as defined below having a total of 3 to 10 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0106] In this disclosure, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0107] In this disclosure, the term "hydroxyl" refers to an -OH group.

[0108] In this disclosure, the term "amino" refers to a -NH2 group.

[0109] In this disclosure, the term "cyano" refers to a -CN group.

[0110] In the present disclosure, the term "hydrocarbyl" refers to an aliphatic hydrocarbon group. The hydrocarbyl portion can be a "saturated hydrocarbyl" group, meaning that it does not contain any alkene or alkyne moieties. The hydrocarbyl portion can also be an "unsaturated hydrocarbyl" portion, meaning that it contains at least one alkene or alkyne moiety. The "alkene" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and connected to the rest of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc., and the "alkyne" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight carbon atoms and at least one carbon-carbon triple bond, and connected to the rest of the molecule by a single bond. The hydrocarbyl portion, whether saturated or unsaturated, can be branched or straight-chain.

[0111] The hydrocarbyl group can have from 1 to 8 carbon atoms (each occurrence in this disclosure of a numerical range such as "1 to 8" refers to each integer in the given range; e.g., "1 to 8" means that the hydrocarbyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 8 carbon atoms, although this definition also covers occurrences of the term "hydrocarbyl" without specifying a numerical range).

[0112] The hydrocarbyl group may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are individually and independently selected from one or more of the following: cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined herein), or amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Typical hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl and butynyl. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0113] In certain embodiments, "C1-C4 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to four carbon atoms. The C1-C4 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0114] In certain embodiments, "C1-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to six carbon atoms. The C1-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0115] In certain embodiments, "C1-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing from one to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0116] In certain embodiments, "C2-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing two to six carbon atoms. The C2-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0117] In certain embodiments, "C3-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing three to six carbon atoms. A C3-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0118] In certain embodiments, "C3-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing three to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0119] In certain embodiments, "C6-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing six to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0120] In certain embodiments, "C7-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing seven to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0121] In the present disclosure, the term "alkyloxy" refers to the general formula -O-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and tert-pentoxy.

[0122] In the present disclosure, the term "aryl" refers to a carbocyclic ring (all carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a completely delocalized pi electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aryl groups can, for example, have five to twelve carbon atoms. The aryl groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0123] In the present disclosure, the term "heteroaryl" refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Illustrative examples of heteroaryl groups include, but are not limited to, azaquinolyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, diphenyl The heteroaryl groups of the present disclosure may be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0124] In the present disclosure, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, in certain embodiments from three to twelve carbon atoms, and which is saturated or unsaturated and is attached to the rest of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, and the like. Unless otherwise expressly stated in the present disclosure, the term "cycloalkyl" is intended to include cycloalkyl as defined above optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfinylamino, N-sulfinylamino, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl as defined in the present disclosure), or amino including mono- and di-substituted amino groups, and protected derivatives thereof.

[0125] In certain embodiments, "C3-C6 cycloalkyl" refers to a cycloalkyl group as defined above having three to six carbon atoms. The C3-C6 cycloalkyl group may be optionally substituted as defined above for cycloalkyl.

[0126] In certain embodiments, "C3-C 10 "Cycloalkyl" refers to a cycloalkyl group as defined above having three to ten carbon atoms. 10 The cycloalkyl group may be optionally substituted as defined above for a cycloalkyl group.

[0127] In certain embodiments, "C3-C 12 "Cycloalkyl" refers to a cycloalkyl group as defined above having three to twelve carbon atoms. 12 The cycloalkyl group may be optionally substituted as defined above for a cycloalkyl group.

[0128] In the present disclosure, the term "heterocycloalkyl" refers to a stable three- to twelve-membered non-aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of such heterocyclyl groups include, but are not limited to, dioxolane, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0129] In the present disclosure, the term "compound of the present disclosure or a pharmaceutically acceptable salt thereof" refers to the compound represented by the general formula (I) of the present disclosure and a pharmaceutically acceptable salt thereof, as well as any specific compound falling within the general formula (I) and a pharmaceutically acceptable salt thereof.

[0130] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0131] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In certain embodiments, the patient is a mammal, including males and females. In certain embodiments, the patient is a human.

[0132] In this disclosure, the term "pharmaceutically acceptable" refers to carriers, vehicles, diluents, excipients and / or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0133] In this disclosure, the terms “optional” or “optionally” mean that the subsequently described event or circumstance can or cannot occur, and the description includes instances where the event or circumstance occurs and instances where it does not.

[0134] In the present disclosure, the term "pharmaceutically acceptable excipients" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0135] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0136] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0137] In this disclosure, the term "acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0138] In this disclosure, the term "acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids, and the base addition salts are biologically or otherwise suitable. These salts are prepared by adding inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0139] As used herein, the term "pharmaceutical composition" refers to a formulation of a compound described herein and a medium generally accepted in the art for delivering the bioactive compound to mammals, such as humans. Such a medium includes any pharmaceutically acceptable carrier, diluent, or excipient.

[0140] In the present disclosure, the term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that ameliorates, reduces, or eliminates a particular disease or condition and symptoms of a particular disease or condition, or prevents or delays the onset of a particular disease or condition or symptoms of a particular disease or condition. The amount of a compound described in the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but the amount of a compound described in the present disclosure can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0141] As used herein, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, suffering from the relevant disease or condition, and includes:

[0142] (i) preventing a disease or disease state from occurring in a mammal, particularly where the mammal is susceptible to said disease state but has not yet been diagnosed with such disease state;

[0143] (ii) inhibiting the disease or disease state, i.e., preventing its occurrence; or

[0144] (iii) ameliorating the disease or condition, even if the disease or condition regresses or does not progress.

[0145] As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific constellation of symptoms. DETAILED DESCRIPTION

[0146] In one aspect, the present disclosure relates to compounds represented by general formula (I), and pharmaceutically acceptable salts thereof:

[0147] in:

[0148] R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0149] R3 is selected from hydroxy and optionally substituted amino;

[0150] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0151] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0152] R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl;

[0153] R9 and R 10 are each independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; and

[0154] X is selected from CH or N.

[0155] In certain embodiments, R1 and R2 are each independently selected from hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl.

[0156] In certain embodiments, R1 and R2 are each independently selected from hydrogen, optionally substituted aryl-substituted alkyl, optionally substituted heteroaryl-substituted alkyl, and optionally substituted cycloalkyl.

[0157] In certain embodiments, R1 and R2 are each independently selected from hydrogen, optionally substituted phenyl substituted alkyl, optionally substituted pyridyl substituted alkyl, and optionally substituted cycloalkyl.

[0158] In certain embodiments, R1 and R2 are each independently selected from hydrogen, optionally substituted aryl-substituted alkyl, optionally substituted heteroaryl-substituted alkyl, and optionally substituted cycloalkyl.

[0159] In certain embodiments, R1 and R2 are each independently selected from hydrogen, optionally substituted phenyl substituted alkyl, optionally substituted pyridyl substituted alkyl, and optionally substituted cycloalkyl.

[0160] In certain embodiments, R1 and R2 are each independently selected from hydrogen, benzyl, aminopyridinylmethyl, and cyclopropyl.

[0161] In certain embodiments, R3 is selected from hydroxy, amino, and optionally substituted hydrocarbyl-substituted amino.

[0162] In certain embodiments, R3 is selected from hydroxy, amino, and hydroxy-substituted alkyl-substituted amino.

[0163] In certain embodiments, R3 is selected from hydroxy, amino, and optionally substituted alkyl-substituted amino.

[0164] In certain embodiments, R3 is selected from hydroxy, amino, and hydroxy-substituted alkyl-substituted amino.

[0165] In certain embodiments, R3 is selected from hydroxy, amino, and hydroxyethylamino.

[0166] In certain embodiments, R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, aryl, halogen-substituted aryl, optionally substituted alkoxy-substituted aryl, heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted cycloalkyl-substituted heteroaryl, and optionally substituted heterocyclyl-substituted heteroaryl.

[0167] In certain embodiments, R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, phenyl, halogen-substituted phenyl, optionally substituted alkoxy-substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted cycloalkyl-substituted heteroaryl, and optionally substituted heterocycloalkyl-substituted heteroaryl.

[0168] In certain embodiments, R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, phenyl, fluoro-substituted aryl, optionally substituted alkyloxy-substituted phenyl, heteroaryl, optionally substituted alkyl-substituted pyrazolyl, optionally substituted cyclohexyl-substituted heteroaryl, and optionally substituted oxacycloalkyl-substituted heteroaryl.

[0169] In certain embodiments, R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, phenyl, fluorophenyl, optionally substituted alkoxy-substituted phenyl, heteroaryl, optionally substituted alkyl-substituted pyrazolyl, optionally substituted cyclohexyl-substituted heteroaryl, optionally substituted oxolanyl-substituted heteroaryl, and optionally substituted azacyclohexyl-substituted heteroaryl.

[0170] In certain embodiments, R4 and R5 are each independently selected from hydrogen, halogen, methyl, phenylvinyl, cyclopropyl, phenyl, fluorophenyl, methoxyphenyl, pyridinyl, methylpyrazolyl, pyrrolo[1,2-b]pyrazolyl, cyclohexylpyrazolyl, oxolanylpyrazolyl, piperidinylpyrazolyl, and Boc-piperidinylpyrazolyl.

[0171] In certain embodiments, R6 is selected from hydrogen and optionally substituted alkyl.

[0172] In certain embodiments, R6 is selected from hydrogen and methyl.

[0173] In certain embodiments, R7 and R8 are each independently selected from hydrogen, optionally substituted alkoxy-substituted alkoxy, optionally substituted aryl-substituted alkoxy, heterocyclyl, aryl, halogen-substituted aryl, nitro-substituted aryl, optionally substituted alkoxy-substituted aryl, optionally substituted alkoxycarbonyl-substituted aryl, optionally substituted alkoxy-substituted aminocarbonyl-substituted aryl, optionally substituted aminocarbonyl-substituted aryl, optionally substituted aryl-substituted aryl, optionally substituted heteroaryl-substituted aryl, heteroaryl, halogen-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted alkoxy-substituted heteroaryl, optionally substituted aryl-substituted heteroaryl, and optionally substituted heteroaryl-substituted heteroaryl.

[0174] In certain embodiments, R7 and R8 are each independently selected from hydrogen, optionally substituted alkoxy-substituted alkyl, optionally substituted phenyl-substituted alkyl, heterocyclyl, aryl, halogen-substituted phenyl, nitro-substituted phenyl, optionally substituted alkyl-substituted aryl, optionally substituted alkenyl-substituted aryl, optionally substituted alkynyl-substituted aryl, optionally substituted alkoxy-substituted aryl, optionally substituted alkoxycarbonyl-substituted aryl, optionally substituted alkoxy-substituted aminocarbonylaryl, optionally substituted benzyl-substituted aminocarbonylaryl, optionally substituted benzylpyrazolyl-substituted aminocarbonylaryl, optionally substituted phenyl-substituted aryl, optionally substituted pyridyl-substituted aryl, heteroaryl, fluoro-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted alkoxy-substituted heteroaryl, optionally substituted phenyl-substituted heteroaryl, and optionally substituted pyridyl-substituted heteroaryl.

[0175] In certain embodiments, R7 and R8 are each independently selected from hydrogen, optionally substituted alkyl substituted by alkoxy, optionally substituted aryl substituted alkyl, heterocyclyl, aryl, halogen substituted phenyl, nitro substituted phenyl, optionally substituted alkyl substituted phenyl, optionally substituted alkoxy substituted phenyl, optionally substituted alkoxy substituted phenyl, optionally substituted alkoxy substituted aminocarbonylphenyl, optionally substituted aminocarbonyl substituted phenyl, optionally substituted aryl substituted phenyl, optionally substituted heteroaryl substituted phenyl, heteroaryl, fluoro substituted heteroaryl, cyano substituted heteroaryl, optionally substituted alkyl substituted phenyl, optionally substituted alkyl substituted pyridyl, optionally substituted alkoxy substituted pyridyl, optionally substituted alkyl substituted pyrazolyl, optionally substituted quinolyl, optionally substituted aryl substituted pyridyl, optionally substituted heteroaryl substituted pyridyl, and optionally substituted alkyl substituted thiazolyl.

[0176] In certain embodiments, R7 and R8 are each independently selected from hydrogen, optionally substituted alkoxy-substituted alkyl, optionally substituted phenyl-substituted alkyl, heterocyclyl, aryl, optionally substituted alkyl-substituted phenyl, optionally substituted alkenyl-substituted phenyl, optionally substituted alkoxy-substituted phenyl, optionally substituted benzyl-substituted aminocarbonylphenyl, optionally substituted benzyloxyaminocarbonylphenyl, optionally substituted benzylpyrazolyl-substituted aminocarbonylphenyl, optionally substituted phenyl-substituted phenyl, optionally substituted pyridyl-substituted phenyl, heteroaryl, fluoro-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted alkyl-substituted phenyl, optionally substituted alkyl-substituted pyridyl, optionally substituted alkoxy-substituted pyridyl, optionally substituted alkyl-substituted pyrazolyl, optionally substituted quinolyl, optionally substituted phenyl-substituted pyridyl, optionally substituted pyridyl-substituted pyridyl, cyano-substituted thienyl, and optionally substituted alkyl-substituted pyrazolyl.

[0177] In certain embodiments, R7 and R8 are each independently selected from hydrogen, trimethylsilylethoxymethyl, p-methoxybenzyl, oxacyclohexyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, 2-bromo-3-fluorophenyl, iodophenyl, nitrophenyl, isopropylphenyl, trifluoromethylphenyl, 3,5-difluoro-4-methoxyphenyl, vinylphenyl, ethynylphenyl, methoxyphenyl, 5-bromo-2-methoxyphenyl, methoxycarbonylphenyl, benzylaminocarbonylphenyl, benzylpyrazolylaminocarbonylphenyl, benzyloxyaminocarbonylphenyl, pyridylphenyl , fluoropyridylphenyl, biphenyl, 3,5-difluoro-4-methoxybiphenyl, naphthyl, pyridyl, fluoropyridyl, bromopyridinyl, methylpyridyl, trifluoromethylpyridyl, methoxypyridyl, trifluoromethylpyridyl, quinolyl, phenylpyridyl, 3,5-difluoro-4-methoxyphenylpyridyl, pyridylpyridyl, 1,3-benzodioxolan-5-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, methylpyrazolyl, 1-methyl-5-cyano-pyrazol-4-yl, cyanothienyl and trifluoromethylthiazolyl.

[0178] In certain embodiments, R7 and R8 are each independently selected from hydrogen,

[0179] In certain embodiments, R7 and R8, together with the nitrogen atom to which they are attached, form an optionally substituted 1,3-dioxoisoindolyl.

[0180] In certain embodiments, R9 and R 10Each is independently selected from the group consisting of hydrocarbon groups, optionally substituted aryl-substituted hydrocarbon groups, optionally substituted aryl-substituted hydrocarbonoxy groups, optionally substituted hydrocarbonoxy groups, cycloalkyl groups, aryl groups, halogen-substituted aryl groups, optionally substituted alkyl-substituted aryl groups, optionally substituted hydrocarbonoxy-substituted aryl groups, and heteroaryl groups.

[0181] In certain embodiments, R9 and R 10 Each is independently selected from a hydrocarbon group, an optionally substituted phenyl-substituted hydrocarbon group, an optionally substituted fluorenyl-substituted hydrocarbonoxy group, an optionally substituted alkyl-substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an aryl group, a fluorine-substituted aryl group, an optionally substituted alkyl-substituted aryl group, an optionally substituted alkoxy-substituted aryl group, and a heteroaryl group.

[0182] In certain embodiments, R9 and R 10 Each is independently selected from optionally substituted alkyl, optionally substituted aryl-substituted alkyl, optionally substituted alkenyl, optionally substituted aryl-substituted alkoxy, optionally substituted alkyl-substituted alkoxy, cycloalkyl, optionally substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkyloxy-substituted phenyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyridyl and optionally substituted benzofuranyl.

[0183] In certain embodiments, R9 and R 10 Each is independently selected from alkyl, optionally substituted phenyl-substituted alkoxy, optionally substituted fluorenyl-substituted alkoxy, optionally substituted phenyl-substituted alkyl, alkenyl, optionally substituted phenyl-substituted alkenyl, optionally substituted alkyl-substituted alkoxy, optionally substituted fluorenyl-substituted alkoxy, optionally substituted cyclopropyl, optionally substituted cyclohexyl, halogen-substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkoxy-substituted phenyl, furyl, chlorothienyl, thienyl, pyridyl and benzofuranyl.

[0184] In certain embodiments, R9 and R 10 Each is independently selected from methyl, benzyl, benzyloxy, vinyl, fluorenylmethoxy, tert-butoxy, styryl, propenyl, cyclopropyl, cyclohexyl, phenyl, fluorophenyl, tolyl, methoxyphenyl, furyl, thienyl, chlorothienyl, pyridyl and benzofuranyl.

[0185] In certain embodiments, X is CH.

[0186] In another aspect, the present disclosure relates to compounds, and pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0187] In certain embodiments, the compounds of the present disclosure bind to dihydrofolate reductase (DHFR) in a novel manner, thereby avoiding cross-resistance.

[0188] In certain embodiments, the compounds of the present disclosure have the activity of inhibiting dihydrofolate reductase (DHFR).

[0189] In certain embodiments, the compounds of the present disclosure are capable of minimizing toxic effects, particularly long-term organ damage.

[0190] In certain embodiments, the compounds of the present disclosure are selective for cancer cells as compared to normal cells.

[0191] In certain embodiments, the compounds of the present disclosure have improved selectivity without necessarily inhibiting related enzymes involved in normal cellular metabolism, such as thymidylate synthase (TS).

[0192] In certain embodiments, the compounds of the present disclosure possess excellent pharmacokinetic properties.

[0193] In certain embodiments, the compounds of the present disclosure have enhanced bioavailability.

[0194] In certain embodiments, the compounds of the present disclosure have excellent pharmaceutical efficacy.

[0195] In certain embodiments, compounds of the present disclosure have the ability to inhibit mutant dihydrofolate reductase (DHFR).

[0196] In certain embodiments, the compounds of the present disclosure are capable of effectively inhibiting wild-type and common mutant forms of dihydrofolate reductase (DHFR).

[0197] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0198] Pharmaceutical composition

[0199] In certain embodiments, the pharmaceutical composition comprises a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0200] In certain embodiments, the compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof, or the compound of the present invention or a pharmaceutically acceptable salt thereof for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR) when administered to a mammal can be administered by an enteral route or a parenteral route.

[0201] In certain embodiments, the compound of the present invention represented by general formula (I) or its pharmaceutically acceptable salt, or the compound of the present invention or its pharmaceutically acceptable salt for use in a dihydrofolate reductase (DHFR)-mediated disease or disease state when administered to a mammal can be administered orally.

[0202] In certain embodiments, the compound of the present invention represented by general formula (I) or its pharmaceutically acceptable salt, or the compound of the present invention or its pharmaceutically acceptable salt for use in a dihydrofolate reductase (DHFR)-mediated disease or condition when administered to a mammal can be administered via the rectal route.

[0203] The compounds described in the present disclosure can be obtained in any suitable form, such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories, etc. Illustrative examples of the tablets include, but are not limited to, plain tablets, sugar-coated tablets, and film-coated tablets.

[0204] Examples of pharmaceutically acceptable excipients that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers approved by the U.S. Food and Drug Administration for use in humans or animals, and any carriers that have no side effects on the composition of the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.

[0205] The pharmaceutical composition of the present disclosure can be applied by any method that realizes its intended purpose.For example, application can be carried out by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intraspinal, transtracheal, per ocular, subcutaneous, intraperitoneal, transdermal or buccal routes.The route of administration can be parenteral, oral and rectal routes.The dosage applied will depend on the age, health status and weight of the recipient, and if concurrent treatment is provided, also depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0206] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, dragees, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be prepared according to methods known in the art.

[0207] Particularly suitable for oral administration are ordinary tablets (plain tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, also can be oil-based solutions or aqueous solutions, in addition there are also suspensions, emulsions or implants, suitable for topical use are ointments, creams or powders. The product in the present disclosure can also be lyophilized, and the lyophilized material generated is used for example to prepare injections. The given preparation can be sterilized and / or comprise adjuvants (assistant), such as wetting agents, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for changing osmotic pressure, buffer substances, dyes, flavorings and / or numerous other active ingredients, such as one or more vitamins.

[0208] In certain embodiments, the pharmaceutical compositions of the present disclosure are prepared as tablets, solutions, granules, patches, ointments, capsules, aerosols, or suppositories for parenteral, transdermal, mucosal, nasal, buccal, sublingual, or oral use.

[0209] Preservatives, stabilizers, dyes, sweeteners, aromatics, spices, etc. can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used.

[0210] In different embodiments, alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethylcellulose calcium, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspending agents or lubricants; cellulose acetate phthalate, which is a derivative of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, can be used as a suspending agent; and plasticizers such as phthalates can be used as suspending agents.

[0211] Suitable routes of administration may include, for example, oral administration, rectal administration, transmembrane administration, parenteral delivery, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection. The compound can also be extended and / or timed, pulsed at a predetermined rate in a sustained-release or controlled-release dosage form including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, etc.

[0212] The pharmaceutical compositions of the present disclosure can be manufactured in a known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting operations.

[0213] Therefore, according to the present disclosure, the pharmaceutical composition used can be prepared in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate processing of the active compound into a pharmaceutically useful preparation. Suitable formulations depend on the selected route of administration. Any known techniques, carriers, and excipients can be used as is suitable and understood in the art.

[0214] Injection can be prepared into the following conventional forms: as a solution or suspension, a solid dosage form suitable for making a solution or suspension before injection, or as an emulsion. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, etc. In addition, if necessary, the injection pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include but are not limited to Hank's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancing preparations (such as liposomes) can be used.

[0215] For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of the present disclosure to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, pastes, suspensions, solutions, powders, and the like for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral administration can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture, if necessary, after adding suitable adjuvants, to obtain tablets or lozenge cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or alginates such as sodium alginate may be added if necessary. The dragee core is carried out to suitable coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally comprise gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel (carbopol gel), polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to identify or characterize the different combinations of active compound dosage, dyestuff or pigment can be added in tablet or dragee coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally comprise gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.

[0216] Pharmaceutical formulations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0217] In certain embodiments, the pharmaceutical compositions of the present disclosure may contain 0.1%-95% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0218] In certain embodiments, the pharmaceutical compositions of the present disclosure may contain 1%-70% of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0219] In any case, the composition or formulation to be administered will contain an amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, that is effective to treat the disease / condition in the subject being treated.

[0220] Dosage

[0221] At least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be administered to a patient by any method suitable for systemic and / or local delivery of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Non-limiting examples of methods of administration include (a) oral administration, including administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) non-oral administration, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraaural, including administration in the form of aqueous suspensions, oily preparations, etc. or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including delivery by infusion pump; (d) local administration, such as injection directly in the kidney area or heart area, for example, by reservoir implantation; and (e) topical administration; as recognized by those skilled in the art, an appropriate mode of administration is contact of the compounds described in the present disclosure with living tissue.

[0222] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients and other matters related to delivering the compound, its stereoisomer or its pharmaceutically acceptable salt to a subject in need.

[0223] Pharmaceutical compositions suitable for administration include compositions containing an effective amount of an active ingredient to achieve their desired effect. The dosage required for a therapeutically effective amount of the pharmaceutical compositions described in this disclosure depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal being considered. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medications, and other factors recognized by those skilled in the art of medicine. More specifically, a therapeutically effective amount refers to an amount of a compound that effectively prevents, alleviates, or ameliorates symptoms of a disease, or prolongs the lifespan of the individual being treated. A therapeutically effective amount is well within the skill of those skilled in the art, particularly in light of the detailed disclosure provided herein.

[0224] As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight, and type of mammal being treated, the specific compound being used, and the specific purpose of the compound being used. Conventional pharmacological methods can be used by those skilled in the art to determine effective dosage levels, i.e., dosage levels necessary for the desired effect. Typically, clinical use of the product in humans is initiated at lower dosage levels, with the dosage levels increasing until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective dosages and routes of administration for the compositions identified by the present method.

[0225] In non-human animal studies, the use of potential products is initiated at higher dose levels, with the dose being reduced until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the desired effect and the therapeutic indication, the dosage range can be relatively wide. Typically, the dosage can be from about 10 μg / kg body weight to 1000 mg / kg body weight, and in certain embodiments, from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dosage can be based on and calculated according to the patient's body surface area.

[0226] Each physician will be able to select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described herein based on the patient's condition. Typically, the composition administered to a patient may be administered in a dosage range of about 0.5 mg / kg to 1000 mg / kg of the patient's body weight. Depending on the patient's needs, the dosage may be administered once alone or twice or more frequently over a day or several days. In cases where human dosages for a compound have been established for at least some conditions, the present disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosage, and in certain embodiments, from 25% to 250% of the established human dosage. In cases where there is no established human dosage, such as in the case of a newly discovered pharmaceutical compound, an appropriate human dosage can be inferred from the median effective dose or infective dose, or other appropriate values ​​from in vitro or in vivo studies, as quantified in animal toxicity studies and efficacy studies.

[0227] It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust the administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The size of the dosage in the treatment of the disease being paid attention to will change with the severity of the disease state to be treated and the change of the route of administration. For example, the severity of the disease state can be evaluated in part by a standard prognostic evaluation method. In addition, the dosage and possible dosage frequency will also change according to the age, body weight, and reaction of the individual patient. A scheme comparable to the above-mentioned discussion scheme can be used in veterinary medicine.

[0228] Although the exact dosage can be determined based on a drug-by-drug analysis, in most cases, it is possible to make certain generalizations about the medicament. The daily dosing regimen for adult patients is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, in certain embodiments 1 mg to 2000 mg of each active ingredient, for example 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, in certain embodiments 0.1 mg to 1000 mg, for example 1 mg to 800 mg. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the composition described in the present disclosure can be administered by continuous intravenous infusion, in certain embodiments administered at a dosage of up to 2000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in some cases, it may be necessary to administer the compounds described herein in amounts exceeding or far exceeding the above dosage ranges in order to effectively and rapidly treat rapidly developing diseases or infections. In certain embodiments, the compounds are administered over a continuous treatment period, such as one or several weeks, or several months or years.

[0229] Dosage and dosing interval can be adjusted individually to provide a plasma level of the active moiety sufficient to maintain the adjustment effect or minimum effective concentration (MEC). The MEC of each compound is different, but it is possible to estimate the MEC from in vitro data. The required dosage to reach the MEC depends on individual characteristics and route of administration. However, plasma concentration can be determined using HPLC (high performance liquid chromatography) assays or bioassays.

[0230] Dosage intervals can also be determined using the MEC. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, in certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time.

[0231] In cases of local administration or selective uptake, the effective local concentration of the drug is independent of plasma concentration.

[0232] The amount of composition administered will, of course, be dependent on the individual being treated, on the individual's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0233] The efficacy and toxicity of the compounds described herein can be assessed using known methods. For example, the toxicology of a specific compound, or a subset of compounds sharing certain chemical moieties, can be established by in vitro toxicity assays in cell lines, such as mammalian cell lines, and in certain embodiments, human cell lines. The results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, in humans. Alternatively, the toxicity of a specific compound can be assessed in animal models such as mice, rats, rabbits, or monkeys using known methods. The efficacy of a specific compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents used to treat these disease states. When selecting a model to determine efficacy, the skilled artisan can select an appropriate model, dosage, route of administration, and treatment regimen, guided by existing knowledge in the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0234] If desired, the composition can be placed in a package or dispensing device that can contain one or more unit dosage forms containing the active ingredient. The package can, for example, include metal or plastic foil, such as a blister pack. The package or dispensing device can carry instructions for administration. The package or dispensing device can also carry notes associated with the container, which are prescribed by a government agency that manages drug production, use, or sales, reflecting that the drug form has been approved by the agency for human or veterinary administration. Such notes, for example, can be a label approved for prescription drugs by the State Food and Drug Administration or the U.S. Food and Drug Administration, or an approved product instruction sheet. Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can also be prepared in a suitable container and placed in a compatible pharmaceutical carrier and labeled for use in the treatment of a specified disease state.

[0235] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ia),

[0236] It involves carrying out the reaction shown below:

[0237] in:

[0238] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0239] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0240] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0241] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0242] X is selected from CH or N;

[0243] Y is hydrogen or absent;

[0244] LG is selected from the group consisting of O, OH, halogen, diarylphosphono, OTs, OMs and OTf.

[0245] In certain embodiments, LG is selected from O, and the method for preparing the compound represented by formula (Ia) is carried out under mild conditions.

[0246] In certain embodiments, LG is selected from OH, and the method for preparing the compound represented by formula (Ia) is carried out under Mitsunobu reaction conditions. The reagent used in the Mitsunobu reaction conditions is selected from organophosphorus compounds and Mitsunobu reagents.

[0247] In certain embodiments, illustrative examples of organophosphorus compounds that can be used in the present disclosure include, but are not limited to, triphenylphosphine.

[0248] In certain embodiments, illustrative examples of Mitsunobu reagents that can be used in the present disclosure include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or any mixture thereof.

[0249] In certain embodiments, LG is selected from halogen, diarylphosphono, OTs, OMs and OTf, and the method for preparing the compound represented by formula (Ia) is carried out in the presence of a base.

[0250] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0251] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0252] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, or any mixture thereof.

[0253] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0254] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ib),

[0255] It involves carrying out the reaction shown below:

[0256] in:

[0257] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0258] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0259] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0260] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0261] X is selected from CH or N; and

[0262] Y is hydrogen or absent.

[0263] In certain embodiments, the method for preparing the compound represented by formula (Ib) is carried out in the presence of a metal and an acidic substance.

[0264] In certain embodiments, the method for preparing the compound represented by formula (Ib) is carried out in the presence of a metal and hydrogen.

[0265] In certain embodiments, illustrative examples of metals that can be used in the present disclosure include, but are not limited to, iron, cobalt, nickel, palladium, rhodium, or any mixture thereof.

[0266] In certain embodiments, illustrative examples of acidic substances that can be used in the present disclosure include, but are not limited to, inorganic acids, organic acids, acidic salts, or any mixtures thereof.

[0267] In certain embodiments, illustrative examples of inorganic acids that can be used in the present disclosure include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, or any mixture thereof.

[0268] In certain embodiments, illustrative examples of organic acids that can be used in the present disclosure include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, or any mixture thereof.

[0269] In certain embodiments, illustrative examples of acidic salts that can be used in the present disclosure include, but are not limited to, ammonium chloride, ammonium acetate, ammonium phosphate, or any mixture thereof.

[0270] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ic),

[0271] It involves reacting a compound represented by general formula (Ib):

[0272] in:

[0273] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0274] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0275] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0276] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0277] X is selected from CH or N;

[0278] Y is hydrogen or absent; and

[0279] M is selected from alkali metals.

[0280] In certain embodiments, the method for preparing the compound represented by formula (Ic) is carried out in the presence of a base.

[0281] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0282] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0283] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, or any mixture thereof.

[0284] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0285] In another aspect, the present disclosure relates to a method for preparing a compound of formula (Id),

[0286] It comprises reacting a compound represented by general formula (Ic):

[0287] in:

[0288] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0289] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0290] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0291] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0292] X is selected from CH or N; and

[0293] Y is hydrogen or absent.

[0294] In certain embodiments, the method for preparing the compound represented by formula (Id) is carried out in the presence of an acid.

[0295] In certain embodiments, illustrative examples of acids that can be used in the present disclosure include, but are not limited to, inorganic acids, organic acids, Lewis acids, or any mixture thereof.

[0296] In certain embodiments, illustrative examples of inorganic acids that can be used in the present disclosure include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, or any mixture thereof.

[0297] In certain embodiments, illustrative examples of organic acids that can be used in the present disclosure include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, optionally substituted benzenesulfonic acid, or any mixture thereof.

[0298] In certain embodiments, illustrative examples of Lewis acids that can be used in the present disclosure include, but are not limited to, boron trifluoride ethyl etherate, boron trichloride, boron tribromide, titanium tetrachloride, tetraisopropyl titanate, aluminum chloride, zinc chloride, ferric chloride, or any mixture thereof.

[0299] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (Ie),

[0300] It involves reacting a compound represented by general formula (Id):

[0301] in:

[0302] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0303] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0304] R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl;

[0305] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0306] X is selected from CH or N; and

[0307] Y is hydrogen or absent.

[0308] In certain embodiments, the method for preparing the compound represented by formula (Ie) is carried out with an alkyl halide in the presence of a base.

[0309] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0310] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0311] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, or any mixture thereof.

[0312] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0313] In certain embodiments, illustrative examples of halogens that can be used in the alkyl halides of the present disclosure include, but are not limited to, fluorine, chlorine, bromine, and iodine.

[0314] In certain embodiments, illustrative examples of alkyl groups that can be used in the alkyl halides of the present disclosure include, but are not limited to, optionally substituted hydrocarbyl, optionally substituted cyclohydrocarbyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0315] In another aspect, the present disclosure relates to a method for preparing a compound represented by formula (I),

[0316] It comprises reacting a compound represented by general formula (Ie):

[0317] in:

[0318] R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0319] R3 is selected from hydroxy and optionally substituted amino;

[0320] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0321] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0322] R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10, optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl;

[0323] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0324] X is selected from CH or N;

[0325] Y is hydrogen or absent; and

[0326] FC is selected from O, OH, halogen, diarylphosphono, OTs, OMs and OTf.

[0327] In certain embodiments, FC is selected from halogen, diarylphosphonyl, OTs, OMs, OTf, and the method for preparing the compound represented by formula (I) is carried out in the presence of a base.

[0328] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0329] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0330] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, or any mixture thereof.

[0331] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0332] In certain embodiments, FC is selected from OH, and the method for preparing the compound represented by general formula (I) is carried out under Mitsunobu reaction conditions. The reagent used in the Mitsunobu reaction conditions is selected from organophosphorus compounds and Mitsunobu reagents.

[0333] In certain embodiments, illustrative examples of organophosphorus compounds that can be used in the present disclosure include, but are not limited to, triphenylphosphine.

[0334] In certain embodiments, illustrative examples of Mitsunobu reagents that can be used in the present disclosure include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or any mixture thereof.

[0335] In certain embodiments, FC is selected from O, and the method for preparing the compound represented by formula (I) is carried out in the presence of an acid and a reducing substance.

[0336] In certain embodiments, illustrative examples of acidic substances that can be used in the present disclosure include, but are not limited to, inorganic acids, organic acids, acidic salts, or any mixtures thereof.

[0337] In certain embodiments, illustrative examples of inorganic acids that can be used in the present disclosure include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, or any mixture thereof.

[0338] In certain embodiments, illustrative examples of organic acids that can be used in the present disclosure include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, or any mixture thereof.

[0339] In certain embodiments, illustrative examples of acidic salts that can be used in the present disclosure include, but are not limited to, ammonium chloride, ammonium acetate, ammonium phosphate, or any mixture thereof.

[0340] In certain embodiments, illustrative examples of reducing substances that can be used in the present disclosure include, but are not limited to, inorganic salts, organic boron compounds, organic silicon compounds, or any mixture thereof.

[0341] In certain embodiments, illustrative examples of inorganic salts that can be used in the present disclosure include, but are not limited to, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triethoxyborohydride, or any mixture thereof.

[0342] In certain embodiments, illustrative examples of organoboron compounds that can be used in the present disclosure include, but are not limited to, borane dimethyl sulfide, borane tetrahydrofuran, N,N-diethylphenylborane, pinacol borane, catechol borane, 9-borabicyclo[3.3.1]nonane, or any mixture thereof.

[0343] In certain embodiments, illustrative examples of organosilicon compounds that can be used in the present disclosure include, but are not limited to, triethoxysilane, triethylsilane, phenyldimethylsilane, or any mixture thereof.

[0344] In another aspect, the present disclosure relates to a method for preparing a compound of formula (I),

[0345] It involves reacting a compound represented by the general formula (If):

[0346] in:

[0347] R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0348] R3 is selected from hydroxy and optionally substituted amino;

[0349] R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0350] R6 is selected from hydrogen and optionally substituted hydrocarbon groups;

[0351] R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl;

[0352] R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group;

[0353] X is selected from CH or N;

[0354] Y is hydrogen or absent;

[0355] LG' is selected from OH, halogen, diarylphosphono, OTs, OMs and OTf.

[0356] In certain embodiments, LG' is selected from OH, and the method for preparing the compound represented by formula (I) is carried out under Mitsunobu reaction conditions. The reagent used in the Mitsunobu reaction conditions is selected from organic phosphides and Mitsunobu reagents.

[0357] In certain embodiments, illustrative examples of organophosphorus compounds that can be used in the present disclosure include, but are not limited to, triphenylphosphine.

[0358] In certain embodiments, illustrative examples of Mitsunobu reagents that can be used in the present disclosure include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or any mixture thereof.

[0359] In certain embodiments, LG' is selected from halogen, diarylphosphonyl, OTs, OMs, OTf, and the method for preparing the compound represented by formula (I) is carried out in the presence of a base.

[0360] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, alkali metal salts, organic bases, or any mixture thereof.

[0361] In certain embodiments, illustrative examples of alkali metal salts that can be used in the present disclosure include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof.

[0362] In certain embodiments, illustrative examples of alcohols that can be used in the present disclosure include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, or any mixture thereof.

[0363] In certain embodiments, illustrative examples of organic bases that can be used in the present disclosure include, but are not limited to, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

[0364] On the other hand, the present disclosure relates to a method for inhibiting dihydrofolate reductase (DHFR), comprising contacting dihydrofolate reductase with an effective inhibitory amount of a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0365] In another aspect, the present disclosure relates to a method for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR), comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0366] In certain embodiments, illustrative examples of individuals that can be used in the disclosed methods of treating or preventing a dihydrofolate reductase (DHFR)-mediated disease or condition include, but are not limited to, mammals.

[0367] In certain embodiments, the subject is a human.

[0368] In certain embodiments, illustrative examples of diseases or conditions that can be used in the methods of treating or preventing dihydrofolate reductase (DHFR)-mediated diseases or conditions of the present disclosure include, but are not limited to, tumors, microbial infections, or mixed diseases or conditions thereof.

[0369] In certain embodiments, illustrative examples of dihydrofolate reductase (DHFR)-mediated tumors that can be used for the treatment or prevention of the present disclosure include, but are not limited to, lymphoma, blastoma, sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancies, lung cancer, squamous cell lung cancer, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancer, and hematological malignancies.

[0370] In certain embodiments, the methods of treating or preventing dihydrofolate reductase (DHFR)-mediated tumors of the present disclosure further comprise administering to the individual an additional active agent.

[0371] In certain embodiments, the present invention can be used to treat or prevent dihydrofolate reductase. Examples of active agents for the treatment of tumors mediated by DHFR (dehydrogenase) include, but are not limited to, nitrogen mustards, aziridines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors, anticancer vaccines, acivicin, aclarubicin, acodazole hydrochloride, aclonine, adolesin, aldesleukin, amblycins, amenanthrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, trilinomycin, azacitidine, azatepa, azotocin, batimastat, benzotepa, bicalutamide, bisantrene hydrochloride, binafadol mesylate, bisezole, bleomycin sulfate, busulfan, actinomycin C, captestosterone, caracetamide, carbenicillin, carboplatin, carmustine, carrubicin hydrochloride , chlorambucil, cilomycin, cladribine, clinatrol mesylate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, epirubicin hydrochloride, esorubicin hydrochloride, estramustine, etanercept, etoposide, floxuridine, fluorouracil, flucitabine, gemcitabine, idarubicin hydrochloride, ifosfamide , interleukin II, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, chlorpheniramine, selenomethoxazole, mitoxantrone, paclitaxel, procarbazine, thiotepa, vinblastine, vincristine, angiogenesis inhibitors, camptothecin, dexamethasone, aspirin, acetaminophen, indomethacin, ibuprofen, ketoprofen, meloxicam, corticosteroids and corticosteroids.

[0372] In certain embodiments, illustrative examples of microbial infections mediated by dihydrofolate reductase (DHFR) that can be used in the present disclosure include, but are not limited to, pathogenic bacteria, fungi, nematodes, and viruses, or mixed diseases or disease states thereof.

[0373] In certain embodiments, illustrative examples of pathogenic bacteria that can be used for the treatment or prevention of dihydrofolate reductase (DHFR)-mediated diseases in the present disclosure include, but are not limited to, Gram-positive bacteria, Gram-negative bacteria, and pathogenic bacteria that cannot be stained, or any mixed pathogenic bacteria thereof.

[0374] In certain embodiments, illustrative examples of Gram-positive bacteria that can be used for the treatment or prevention of dihydrofolate reductase (DHFR)-mediated gram-positive bacteria of the present disclosure include, but are not limited to, Bacillus, Clostridium, Corynebacterium, Enterococcus, Listeria, Staphylococcus, Streptococcus, or any mixed pathogenic bacterial genera thereof.

[0375] In certain embodiments, illustrative examples of Gram-positive bacteria that can be used for the treatment or prevention of dihydrofolate reductase (DHFR)-mediated gram-positive bacteria in the present disclosure include, but are not limited to, Bacillus anthracis, Bacillus cereus, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, and their corresponding drug-resistant strains, or any mixed pathogenic bacteria thereof.

[0376] In certain embodiments, illustrative examples of Gram-negative bacteria that can be used for the treatment or prevention of dihydrofolate reductase (DHFR)-mediated gram-negative bacteria of the present disclosure include, but are not limited to, Bartonella, Bordetella, Borrelia, Brucella, Campylobacter, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Treponema, Vibrio, Yersinia, or any mixed pathogenic bacterial genera thereof.

[0377] In certain embodiments, the present invention can be used to treat or prevent dihydrofolate reductase. Exemplary examples of Gram-negative bacteria mediated by DHFR include, but are not limited to, Bartonella henslera, Bartonella quinquefasciatus, Borrelia pertussis, Borrelia burgdorferi, Borrelia californica, Borrelia afzal, Borrelia relapsing fever, Brucella abortus, Brucella canis, Brucella malta, Brucella suis, Campylobacter jejuni, Escherichia coli, Francisella toulonis, Haemophilus influenzae, Helicobacter pylori, Legionella, Leptospira renalis, Leptospira santorum, Leptospira veseri, Leptospira noguchi, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, Treponema pallidum, Vibrio cholerae, Yersinia pestis, Yersinia colitis, Yersinia pseudotuberculosis and their corresponding drug-resistant strains or any mixed pathogenic bacteria thereof.

[0378] In certain embodiments, illustrative examples of pathogenic bacteria that can be used for the treatment or prevention of dihydrofolate reductase (DHFR)-mediated non-staining in the present disclosure include, but are not limited to, Chlamydia and Chlamydia, Mycobacterium, Mycoplasma, or any mixed pathogenic bacteria thereof.

[0379] In certain embodiments, illustrative examples of pathogenic bacteria that can be used for the treatment or prevention of dihydrofolate reductase (DHFR)-mediated non-staining in the present disclosure include, but are not limited to, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia felis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma pneumoniae, and their corresponding drug-resistant strains, or any mixed pathogenic bacteria thereof.

[0380] In certain embodiments, a method for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR) comprises administering to a subject in need thereof 1 mg to 10 g of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0381] In certain embodiments, a method for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR) comprises administering to a subject in need thereof 10 mg to 3000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0382] In certain embodiments, a method for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR) comprises administering to a subject in need thereof 100 mg to 1000 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0383] In certain embodiments, a method for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR) comprises administering to a subject in need thereof 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg or 1000 mg of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0384] In another aspect, the present disclosure relates to the compound represented by general formula (I) of the present disclosure and its pharmaceutically acceptable salt for inhibiting dihydrofolate reductase (DHFR).

[0385] In another aspect, the present disclosure relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in treating or preventing diseases or conditions mediated by dihydrofolate reductase (DHFR).

[0386] On the other hand, the present disclosure relates to the use of the compound represented by general formula (I) of the present disclosure and its pharmaceutically acceptable salt or the compound of the present disclosure and its pharmaceutically acceptable salt in the preparation of a medicament for inhibiting dihydrofolate reductase (DHFR).

[0387] In another aspect, the present disclosure relates to the compounds of general formula (I) of the present disclosure and pharmaceutically acceptable salts thereof, or the use of the compounds of the present disclosure and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating or preventing diseases or disease states mediated by dihydrofolate reductase (DHFR).

[0388] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0389] Example

[0390] The reagents and equipment used in the examples of this disclosure are conventional and commercially available. For example:

[0391] Preparation Example

[0392] Preparation Example 1

[0393] Preparation of 7-N-phenylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 1) Route 1: Step a

[0394] Step a: To a solution of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (199 mg, 1 mmol) in DMF (3 mL) was added NaH (60 mg, 1.5 mmol, 60%). The mixture was stirred at 0°C for 15 minutes, followed by the addition of O-(methylsulfonyl)-N-phenylhydroxylamine (205 mg, 1.2 mmol). Stirring was continued for 1 hour. After completion of the reaction, the reaction was monitored by TLC. Ice water was slowly added dropwise to quench the reaction, and 10 mL of water was added. The mixture was extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to yield compound 1 (6 mg, 5%).

[0395] 1 H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 7.77 (d, J = 3.2Hz, 1H), 7.67 (d, J = 9.0Hz, 1H), 7. 35(d,J=3.2Hz,1H),7.24-7.13(m,3H),6.82(t,J=8.0Hz,1H),6.37(d,J=8.0Hz,2H).

[0396] MS(ESI):[M+H + ]290.15.

[0397] Preparation Example 2

[0398] Preparation of 7-N-(4-methoxyphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 13) Route 2: Steps b and c

[0399] Step b: To a solution of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (199 mg, 2 mmol) in DMF (5 mL) was added NaH (120 mg, 3 mmol, 60%). The mixture was stirred at 0°C for 15 minutes, followed by the addition of diphenylphosphonic acid hydroxylamine (860 mg, 3.7 mmol). Stirring continued for 1 hour after the addition. After completion of the reaction, the reaction was monitored by TLC. Ice water was slowly added dropwise to quench the reaction, and 20 mL of water was added. The mixture was extracted with dichloromethane / methanol, concentrated, and purified by silica gel column chromatography to obtain 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (25 mg, 12%).

[0400] Step c: Palladium acetate (1 mg, 0.005 mmol), Binap (7.1 mg, 0.011 mmol), sodium methoxide (6 mg, 0.11 mmol), 4-methoxyiodobenzene (28 mg, 0.12 mmol), and 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (21 mg, 0.1 mmol) were added in sequence, and then the argon atmosphere was quickly replaced three times. Toluene (3 mL) was added to the reaction flask. The reaction flask was placed at 110°C and reacted overnight. After completion of the reaction monitored by TLC, the reaction solution was cooled to room temperature, 5 mL of water was added, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound 13 (6 mg, 20%).

[0401] 1 H NMR (400MHz, Methanol-d4) δ7.70 (dd, J=8.9, 0.9Hz, 1H), 7.53 (d, J=3.3Hz, 1H), 7.17 (d, J= 9.0Hz,1H),7.06(dd,J=3.3,0.9Hz,1H),6.82-6.73(m,2H),6.52-6.40(m,2H),3.72(s,3H).

[0402] MS(ESI):[M+H + ]320.16.

[0403] Preparation Example 3

[0404] Preparation of 7-N-phenylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 2) Route 3: Steps b, d, c, and e

[0405] Step b: Same as step b in route 2.

[0406] Step d: To a solution of 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (105 mg, 0.5 mmol) in DMF (2 mL) was added cesium carbonate (195 mg, 0.6 mmol) and benzyl bromide (103 mg, 0.6 mmol). After completion of the reaction, monitored by TLC, 10 mL of water was added. The product was extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to afford N-benzyl-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (91 mg, 60%).

[0407] Step c: Same as step c in route 2, replace 4-methoxyiodobenzene and N- 77H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine was replaced with 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (60 mg, 0.2 mmol) to give N7-benzyl-N7-(4-fluorophenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (46 mg, 58%).

[0408] Step e: Under argon, methanol (5 mL) was added to a reaction flask containing N7-benzyl-N7-(4-fluorophenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (40 mg, 0.1 mmol) and Pd / C (12 mg, 0.01 mmol, 10%). The atmosphere was replaced with hydrogen and allowed to react at room temperature. After completion of the reaction, monitored by TLC, the reaction mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to yield compound 2 (24 mg, 78%).

[0409] 1 H NMR (400MHz, DMSO-d6) δ12.30 (s, 1H), 9.63 (s, 1H), 7.87 (d, J = 3.3Hz, 1H), 7.79-7.72 (m, 1H),7.45-7.41(m,1H),7.28(d,J=8.8Hz,1H),7.04(t,J=8.8Hz,2H),6.47-6.29(m,2H).

[0410] MS(ESI):[M+H + ]308.14.

[0411] Preparation Example 4

[0412] Preparation of 7-N-(4-iodophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 4) Route 4: Steps b, f, g, and e

[0413] Step b: Same as step b in route 2.

[0414] Step f: Add 1,4-dioxane (3 mL) to a reaction flask containing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (105 mg, 0.5 mmol), triphenylphosphine (157 mg, 0.6 mmol), and p-methoxybenzyl alcohol (83 mg, 0.6 mmol), and add diisopropyl azodicarboxylate (120 μL, 0.6 mmol) dropwise under reflux, and then continue to reflux until the reaction is completed as monitored by TLC. The reaction solution was cooled to room temperature, slightly concentrated, and then purified by silica gel column chromatography to obtain N 7-(4-methoxybenzyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (45 mg, 27%).

[0415] Step g: Towards N 7 To a solution of -(4-methoxybenzyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (40 mg, 0.12 mmol) in DMSO (1 mL) were added 4-iodophenylboronic acid (35 mg, 0.14 mmol), copper acetate (11 mg, 0.06 mmol), and potassium carbonate (28 mg, 0.2 mmol). The reaction was allowed to proceed overnight at room temperature. After completion of the reaction monitored by TLC, the reaction solution was poured into 2 mL of water and extracted with ethyl acetate. The organic phases were combined and washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain N7-(4-iodophenyl)-N 7 -(4-methoxybenzyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (31 mg, 48%).

[0416] Step e: Same as step e of route 3, react at 15°C for 2 hours to obtain compound 4 (8 mg, 38%).

[0417] 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 7.87 (d, J = 3.3Hz, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.51-7.47(m,2H),7.44(d,J=3.3Hz,1H),7.28(d,J=8.8Hz,1H),6.24-6.14(m,2H).

[0418] MS(ESI):[M+H + ]416.04.

[0419] Preparation Example 5

[0420] N 7 Preparation of -(4-methylpyridin-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 49)

[0421] Route 5: Steps b, h, g, and i

[0422] Step b: Same as step b in route 2.

[0423] Step h: To a solution of 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (215 mg, 1 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) in ethanol (3 mL) was added Boc2O (255 μL, 1.1 mmol). After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography to afford tert-butyl (1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-7-yl)carbamate (104 mg, 33%).

[0424] Step g: As in step g of route 4, replace 4-iodophenylboronic acid with (4-methylpyridin-2-yl)boronic acid (33 mg, 0.24 mmol) and 7H-pyrrolo[3,2-f]quinazolin-7-yl)carbamic acid tert-butyl ester (62 mg, 0.2 mmol) with (1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-1,3,7-triamine) to obtain tert-butyl (1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-7-yl)(4-methylpyridin-2-yl)carbamate (36 mg, 44%).

[0425] Step i: To a solution of tert-butyl (1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-7-yl)carbamate (20 mg, 0.05 mmol) in dichloromethane / methanol (1 mL, v / v = 9 / 1) was added trifluoroacetic acid (8 μL, 0.1 mmol). The reaction was allowed to proceed. After TLC monitoring, the reaction mixture was concentrated and purified by silica gel column chromatography to afford compound 49 (5 mg, 33%).

[0426] 1 H NMR (400MHz, MeOD-d4) δ7.97(d,J=5.3Hz,1H),7.67(d,J=8.9Hz,1H),7.56(d,J=3.4Hz,1H),7 .21(d,J=8.9Hz,1H),7.14(d,J=3.3Hz,1H),6.75(d,J=5.1Hz,1H),5.99(s,1H),2.19(s,3H).

[0427] MS(ESI):[M+H + ]306.28.

[0428] Preparation Example 6

[0429] Preparation of 7-N-(6-methoxypyridin-2-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 34)

[0430] Route 6: Steps b, j, c, and e

[0431] Step b: Same as step b in route 2.

[0432] Step j: To a DMF solution (3 mL) containing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (215 mg, 1 mmol) and cesium carbonate (390 mg, 1.2 mmol) was added benzyl chloroformate (187 mg, 1.1 mmol). After completion of the reaction, monitored by TLC, 10 mL of water was added. The product was extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to yield benzyl (1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-7-yl)carbamate (275 mg, 79%).

[0433] Step c: As in step c of route 2, replace 4-methoxyiodobenzene with 2-bromo-6-methoxypyridine (28 mg, 0.15 mmol), and replace 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine with (benzyl(1,3-diamino-7H-pyrrolo[3,2-f]quinazoline-7-yl)carbamate (35 mg, 0.1 mmol). Benzyl(1,3-diamino-7H-pyrrolo[3,2-f]quinazoline-7-yl)(6-methoxypyridin-2-yl)carbamate (10 mg, 22%) was obtained.

[0434] Step e: The same as step e of route 3 to obtain compound 34 (2 mg, 29%).

[0435] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,3H),7.88(d,J=7.6Hz,3H),7.80(d,J=7.0Hz,3H),7.64(d,J=7.8Hz,3H),7.56(dd,J=7.6,6.9Hz,3H),7.39(d ,J=5.3Hz,3H),6.59(d,J=7.6Hz,3H),6.51(dd,J=7.6,1.2Hz,3H),6.37-6. 31(m,3H),6.25(d,J=7.6Hz,3H),5.65(dd,J=6.9,1.2Hz,3H),5.40(s,3H).

[0436] MS(ESI):[M+H + ]322.35.

[0437] Preparation Example 7

[0438] Preparation of 7-N-(oxan-4-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 40) Route 7: Steps b and k

[0439] Step b: Same as step b in route 2.

[0440] Step k: To a DCE solution (0.5 mL) containing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (21 mg, 0.1 mmol), tetrahydropyrone (11 μL, 0.12 mmol), and sodium triacetoxyborohydride (23 mg, 0.12 mmol) was added acetic acid (9 μL, 0.15 mmol). After completion of the reaction, monitored by TLC, 10 mL of water was added. The product was extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to yield compound 40 (7 mg, 23%).

[0441] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J= 7.8Hz,1H),7.39(d,J=5.6Hz,1H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.6Hz,1H),6.25(d,J=7.6Hz,1H), 3.78(ddd,J=12.4,5.2,2.5Hz,2H),3.34(ddd,J=12.3,5.2,2.5Hz,2H),2.73(dt,J=5.0,4.5Hz,1H),1. 95(dddd,J=12.3,5.2,4.6,2.5Hz,2H),1.70(dddd,J=12.3,5.1,4.5,2.4Hz,2H),1.50(d,J=5.1Hz,1H).

[0442] MS(ESI):[M+H + ]298.27.

[0443] Preparation Example 8

[0444] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)benzamide (Compound 21) Scheme 8: Steps b and j

[0445] Step b: Same as step b in route 2.

[0446] Step j: Same as step j in route 6, except that benzyl chloroformate was replaced by benzoyl chloride (35 μL, 0.3 mmol), to obtain compound 21 (49 mg, 62%).

[0447] 1 H NMR (400MHz, DMSO-d6) δ8.06(d,J=7.6Hz,2H),7.77-7.65(m,3H),7.61(t,J=7.6Hz,2H),7.31(d,J=3.4Hz,1H),7.22(d,J=8.9Hz,1H).

[0448] MS(ESI):[M+H + ]318.25.

[0449] Preparation Example 9

[0450] Preparation of 7-N-(4-iodophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 4)

[0451] Route 9: Steps b, g, k, l, and m

[0452] Step b: To a mixture of 5-nitrodihydroindole (5.0 g, 30.84 mmol) in DMF (50 mL) was added NaH (2.47 g, 61.67 mmol), stirred at 0°C for 5 minutes, and diphenylphosphonic acid hydroxylamine (8.6 g, 37 mmol) was added. After the addition, stirring was continued for 1 hour. After the reaction was complete by TLC, ice water was slowly added dropwise to quench the reaction, and 100 mL of water was added to precipitate a yellow solid. The solution was filtered, washed with water, and the filter cake was dried in vacuo at 60°C to obtain the desired compound 5-nitro-1H-indole-1-amine (4.5 g, 82.4).

[0453] Step g: To a mixture of compound 5-nitro-1H-indole-1-amine (4.5 g, 25.4 mmol) in DMSO (50 mL) were added 4-iodophenylboronic acid (7.55 g, 30.48 mmol), anhydrous copper acetate (2.31 g, 12.7 mmol), and anhydrous potassium carbonate (7.02 g, 50.08 mmol). The reaction was stirred at rt for 12 hours. After completion of the reaction by TLC, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography to obtain the desired product N-(4-iodophenyl)-5-nitro-1H-indole-1-amine (5.5 g, 57.1%).

[0454] Step k: To a mixture of N-(4-iodophenyl)-5-nitro-1H-indole-1-amine (5.5 g, 14.51 mmol) in ethanol (60 mL) was added iron powder (4.05 g, 72.5 mmol), and saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was heated to 90 ° C for 2 hours. After the reaction was completed by TLC, the mixture was cooled, passed through celite, and the filter cake was washed with ethyl acetate (200 mL). The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with 100 mL of water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography to obtain N 1 -(4-iodophenyl)-1H-indole-1,5-diamine (4.2 g, 82.9%).

[0455] Step 1. To N 1 To a mixed solution of -(4-iodophenyl)-1H-indole-1,5-diamine (4.2 g, 12.03 mmol) in DMF (50 mL) were added sodium dicyanamide (1.29 g, 14.43 mmol) and methylbenzenesulfonic acid (3.11 g, 18.04 mmol), and the mixture was heated to 60°C for 2 hours. After completion of the reaction by TLC, the mixture was cooled and poured into 100 mL of water. 100 mL of ethyl acetate was added for separation. The aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography to obtain (E)-2-cyano-1-(1-((4-iodophenyl)amino)-1H-indol-5-yl)guanidine (4.1 g, 81.9%).

[0456] Step m: To a mixed solution of (E)-2-cyano-1-(1-((4-iodophenyl)amino)-1H-indol-5-yl)guanidine (4.1 g, 9.081 mmol) in DME (50 mL) was added boron trifluoride etherate (6.13 mL, 49.25 mmol), heated to 80°C for 2 hours. After the reaction was completed by TLC, the mixture was concentrated under reduced pressure and dissolved in 30 mL of methanol. Aqueous ammonia was slowly added dropwise in an ice-water bath until pH = 8, and stirring was continued for 2 hours. The mixture was concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography to give compound 4 (3.3 g, 80.5%).

[0457] 1H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 7.87 (d, J = 3.3Hz, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.51-7.47(m,2H),7.44(d,J=3.3Hz,1H),7.28(d,J=8.8Hz,1H),6.24-6.14(m,2H).

[0458] MS(ESI):[M+H + ]416.04.

[0459] Preparation Example 10

[0460] Preparation of 7-N-(4-ethynylphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 5)

[0461] Route 10: Steps n and o

[0462] Step n: To a solution of compound 4 (0.5 g, 1.2 mmol) in DMF (5 mL) were added trimethylsilylacetylene (0.44 g, 4.46 mmol), Pd(dppf)Cl2 (87.9 mg, 0.3 mmol), CuI (56.7 mg, 0.3 mmol), and triethylamine (242.7 mg, 2.4 mmol) in sequence. The atmosphere was replaced with nitrogen three times and the reaction was stirred at room temperature for 4 hours. After completion of the reaction by TLC, the reaction solution was poured into 50 mL of water, and 50 mL of ethyl acetate was added for separation. The aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was further purified by silica gel column chromatography to give N7-(4-((trimethylsilyl)ethynyl)phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (300 mg, 64.7%).

[0463] Step o: To a solution of N7-(4-((trimethylsilyl)ethynyl)phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (300 mg, 0.78 mmol) in THF (2 mL) was added TBAF (1.5 mL, 1 M), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed by TLC, the reaction solution was poured into 50 mL of water, and 50 mL of ethyl acetate was added for separation. The aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed with 100 mL of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography to obtain compound 5 (150 mg, 61.5%).

[0464] 1 H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 7.77 (d, J = 3.3Hz, 1H), 7.63 (d, J = 8.9Hz, 1H), 7.35 (d ,J=3.4Hz,1H),7.32-7.27(m,2H),7.20(d,J=8.9Hz,1H),6.35-6.29(m,2H),3.96(s,1H).

[0465] MS(ESI):[M+H + ]314.25.

[0466] Preparation Example 11

[0467] Preparation of 7-N-[(4-fluorophenyl)methyl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 3)

[0468] Using a similar method to Example 3, replacing benzyl bromide with 4-fluorobenzyl bromide, compound 3 was prepared via Route 3 (steps b and d).

[0469] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.9Hz,1H),7.64(d,J=3.3Hz,1H),7.33(dd,J=8.9,5.7Hz,2H),7.17-7.06(m,4H),4.24(d,J=4.6Hz,2H).

[0470] MS(ESI):[M+H + ]322.13

[0471] Preparation Example 12

[0472] Preparation of 7-N-[4-(6-fluoropyridin-3-yl)phenyl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 6)

[0473] Using a method similar to Example 2, replacing 4-fluorophenylboronic acid with (4-(6-fluoropyridin-3-yl)phenyl)boronic acid, compound 6 was prepared via Scheme 2 (steps b and c).

[0474] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.9Hz,1H),7.64(d,J=3.3Hz,1H),7.33(dd,J=8.9,5.7Hz,2H),7.17-7.06(m,4H),4.24(d,J=4.6Hz,2H).

[0475] MS(ESI):[M+H + ]322.13.

[0476] Preparation Example 13

[0477] Preparation of N-benzyl-4-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]benzamide (Compound 7)

[0478] Using a method similar to Example 6, substituting N-benzyl-4-bromobenzamide for 2-bromo-6-methoxypyridine, compound 7 was prepared via Scheme 6 (steps b, j, c, and e).

[0479] 1 H NMR(400MHz,MeOD-d4)δ7.78(dd,J=8.9,0.7Hz,1H),7.75(d,J=1.9Hz,1H),7.73(d,J=1.9Hz,1H ),7.67(d,J=3.4Hz,1H),7.35-7.28(m,4H),7.26-7.19(m,3H),6.52-6.47(m,2H),4.55(s,2H).

[0480] MS(ESI):[M+H + ]444.28.

[0481] Preparation Example 14

[0482] Preparation of 4-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]-N'-phenylbenzohydrazide (Compound 8)

[0483] Using a method similar to Example 6, replacing 2-bromo-6-methoxypyridine with 4-bromo-N'-phenylbenzohydrazide, compound 8 was prepared via Scheme 6 (steps b, j, c, and e).

[0484] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J =7.0Hz,1H),7.72-7.64(m,2H),7.67-7.57(m,2H),7.39(d,J=5.3Hz,1H),7.29 -7.20(m,2H),7.10-7.02(m,2H),6.99-6.91(m,2H),6.78(tt,J=6.8,1.1Hz,1H ),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0485] MS(ESI):[M+H + ]425.46.

[0486] Preparation Example 15

[0487] Preparation of N-(1-benzylpyrazol-4-yl)-4-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]benzamide (Compound 9)

[0488] Using a method similar to Example 6, substituting N-(1-benzyl-1H-pyrazol-4-yl)-4-bromobenzamide for 2-bromo-6-methoxypyridine, compound 9 was prepared via Route 6 (steps b, j, c, and e).

[0489] 1 H NMR (400MHz, MeOD-d4) δ = 8.07 (s, 1H), 7.86-7.76 (m, 3H), 7.72-7.64 (m, 2H), 7 .33(dd,J=13.4,7.2,3H),7.29-7.19(m,4H),6.52(d,J=8.6,2H),5.33(s,2H).

[0490] MS(ESI):[M+H + ]490.28.

[0491] Preparation Example 16

[0492] Preparation of 4-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]-N-phenylmethoxybenzamide (Compound 10)

[0493] Using a method similar to Example 5, compound 10 was prepared using N-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4-methylpyridin-2-yl)boronic acid via Route 5 (steps b, h, g, and i).

[0494] 1 H NMR (400MHz, MeOD-d4) δ7.73(d,J=8.8Hz,1H),7.63(d,J=3.4Hz,1H),7.59(d,J=8.8Hz,2H),7.47(d,J=6.1H z,2H),7.38(d,J=7.2Hz,3H),7.26-7.18(m,2H),6.47(d,J=8.7Hz,2H),5.36(t,J=4.6Hz,1H),4.95(s,3H).

[0495] MS(ESI):[M+H + ]440.25.

[0496] Preparation Example 17

[0497] Preparation of methyl 4-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]benzoate (Compound 11)

[0498] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with methyl 4-iodobenzoate, compound 11 was prepared via Route 2 (steps b and c).

[0499] 1 H NMR(400MHz,MeOD-d4)δ7.86(d,J=8.7Hz,2H),7.68(d,J=8.9Hz,1H),7.58(d,J=3.3Hz ,1H),7.22(d,J=9.1Hz,1H),7.17(d,J=3.2Hz,1H),6.48(d,J=8.7Hz,2H),3.85(s,3H).

[0500] MS(ESI):[M+H + ]349.20.

[0501] Preparation Example 18

[0502] Preparation of benzyl N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)carbamate (Compound 12)

[0503] Using the method of Example 6, compound 12 was prepared via Scheme 6 (steps b and j).

[0504] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H ),7.32(s,3H),7.37-7.25(m,2H),7.00(s,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.02(d,J=0.9Hz,2H).

[0505] MS(ESI):[M+H + ]349.41.

[0506] Preparation Example 19

[0507] Preparation of 7-N-[4-(trifluoromethyl)phenyl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 14)

[0508] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with 4-iodotrifluorotoluene, compound 14 was prepared via Route 2 (steps b and c).

[0509] 1 H NMR (400MHz, methanol-d4) δ7.68 (dd, J=8.9, 0.9Hz, 1H), 7.58 (d, J=3.4Hz, 1H), 7.51-7.4 2(m,2H),7.22(d,J=8.9Hz,1H),7.16(dd,J=3.4,0.9Hz,1H),6.56(d,J=8.5Hz,2H).

[0510] MS(ESI):[M+H + ]358.22.

[0511] Preparation Example 20

[0512] Preparation of 7-N-(6-fluoropyridin-3-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 15)

[0513] Using a method similar to Example 5, substituting 2-fluoro-5-pyridineboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 15 was prepared via Scheme 5 (steps b, h, g, and i).

[0514] 1 H NMR (400MHz, methanol-d4) δ7.71(dd,J=9.0,0.9Hz,1H),7.58(d,J=3.4Hz,1H),7.36(dd,J=3.0,1.6Hz,1H),7.22( d,J=8.9Hz,1H),7.14(dd,J=3.4,0.9Hz,1H),7.01(ddd,J=9.3,6.5,3.0Hz,1H),6.93(dd,J=8.8,2.6Hz,1H).

[0515] MS(ESI):[M+H + ]309.17.

[0516] Preparation Example 21

[0517] Preparation of 7-N-pyridin-3-ylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 16)

[0518] Using a method similar to Example 5, substituting 3-pyridineboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 16 was prepared via Scheme 5 (steps b, h, g, and i).

[0519] 1 H NMR (400MHz, methanol-d4) δ8.05(dd,J=4.7,1.4Hz,1H),7.82(d,J=2.7Hz,1H),7.66(dd,J=9.0,0.9Hz,1H),7.55(d,J=3.4Hz, 1H), 7.25 (dd, J=8.4, 4.7Hz, 1H), 7.21 (d, J=9.0Hz, 1H), 7.13 (dd, J=3.4, 0.9Hz, 1H), 6.80 (ddd, J=8.4, 2.8, 1.4Hz, 1H).

[0520] MS(ESI):[M+H + ]291.24.

[0521] Preparation Example 22

[0522] Preparation of 2-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)isoindole-1,3-dione (Compound 17)

[0523] Using a method similar to Example 1, replacing O-(methylsulfonyl)-N-phenylhydroxylamine with 1,3-dioxoisoindolin-2-yl methanesulfonate, compound 17 was prepared via Route 1 (step a).

[0524] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=6.0Hz,1H),7.88(d,J=7.6Hz,1H),7.85(s,4H),7.83-7.77(m,1H),7.64( d,J=7.8Hz,1H),7.39(d,J=3.8Hz,1H),6.59(d,J=7.6Hz,1H),6.34(d,J=3.8Hz,1H),6.25(d,J=7.6Hz,1H).

[0525] MS(ESI):[M+H + ]345.21.

[0526] Preparation Example 23

[0527] Preparation of 7-N-(2-methoxypyridin-4-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 18)

[0528] Using a method similar to Example 5, substituting 2-methoxypyridine-4-boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 18 was prepared via Scheme 5 (steps b, h, g, and i).

[0529] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.46-7.36(m,2H ),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),6.13(d,J=2.2Hz,1H),5.71(dd,J=3.7,2.3Hz,1H),3.83(s,3H).

[0530] MS(ESI):[M+H + ]322.39.

[0531] Preparation Example 24

[0532] Preparation of 7-N-[6-(trifluoromethyl)pyridin-3-yl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 19)

[0533] Using a method similar to Example 5, substituting 2-trifluoromethyl-5-pyridineboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 19 was prepared via Scheme 5 (steps b, h, g, and i).

[0534] 1 H NMR(400MHz,MeOD-d4)δ9.18(s,1H),8.64(d,J=8.2Hz,1H),8.02(d,J=8.1Hz,1H),7.8 6(d,J=8.6Hz,1H),7.53(d,J=2.8Hz,1H),7.29(d,J=7.6Hz,1H),7.04(d,J=2.5Hz,1H).

[0535] MS(ESI):[M+H + ]360.17.

[0536] Preparation Example 25

[0537] Preparation of 7-N-(6-fluoropyridin-2-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 20)

[0538] Using a method similar to Example 6, substituting 2-bromo-6-fluoropyridine for 2-bromo-6-methoxypyridine, compound 20 was prepared via Scheme 6 (steps b, j, c, and e).

[0539] 1 H NMR (400MHz, DMSO-d6) δ8.01-7.91(m,2H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H), 6.77(dd,J=6.7,1.1Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),6.14(td,J=7.7,1.2Hz,1H),5.40(s,1H).

[0540] MS(ESI):[M+H + ]310.37.

[0541] Preparation Example 26

[0542] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)cyclopropanecarboxamide (Compound 22)

[0543] Using a method similar to Example 8, substituting cyclopropylcarbonyl chloride for benzoyl chloride, compound 22 was prepared via Scheme 8 (steps b and j).

[0544] 1 H NMR (400MHz, DMSO-d6) δ11.67 (s, 1H), 7.69-7.53 (m, 2H), 7.21 (d, J = 9.0Hz, 2H) ,6.69(s,2H),1.24(d,J=6.3Hz,1H),0.93(d,J=8.0Hz,2H),0.90-0.83(m,2H).

[0545] MS(ESI):[M+H + ]282.08.

[0546] Preparation Example 27

[0547] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)furan-2-carboxamide (Compound 23)

[0548] Using a method similar to Example 8, replacing benzoyl chloride with furoyl chloride, compound 23 was prepared via Scheme 8 (steps b and j).

[0549] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.78(s,1H),7.65-7.59(m,2H),7.42(d,J=3.5Hz,1H),7.23(d, J=3.5Hz,1H),7.17(d,J=8.9Hz,1H),7.01(s,1H),6.78(d,J=3.4Hz,1H),6.57(dd,J=3.4,1.7Hz,1H).

[0550] MS(ESI):[M+H + ]308.20.

[0551] Preparation Example 28

[0552] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)thiophene-2-carboxamide (Compound 24)

[0553] Using a method similar to Example 8, substituting 2-thenoyl chloride for benzoyl chloride, compound 24 was prepared via Scheme 8 (steps b and j).

[0554] 1 H NMR (400MHz, DMSO-d6) δ8.06(d,J=3.8Hz,1H),8.00(d,J=5.0Hz,1H),7.78-7.65(m,3H),7.61(d,J=3.6H z,1H),7.32(t,J=4.4Hz,1H),7.28(d,J=3.8Hz,1H),7.21(d,J=8.9Hz,1H),7.13(dd,J=5.0,3.6Hz,1H).

[0555] MS(ESI):[M+H + ]324.18.

[0556] Preparation Example 29

[0557] Preparation of (E)-N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)but-2-enamide (Compound 25)

[0558] Using a method similar to Example 8, substituting crotonyl chloride for benzoyl chloride, compound 25 was prepared via Scheme 8 (steps b and j).

[0559] 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),7.65-7.58(m,2H),7.27-7.15(m,2H), 6.91(dd,J=15.3,7.0Hz,1H), 6.17(d,J=15.3Hz,1H), 1.93(d,J=6.8Hz,3H).

[0560] MS(ESI):[M+H + ]282.20.

[0561] Preparation Example 30

[0562] Preparation of (E)-N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)-3-phenylprop-2-enamide (Compound 26)

[0563] Using a method similar to Example 8, substituting cinnamoyl chloride for benzoyl chloride, compound 26 was prepared via Scheme 8 (steps b and j).

[0564] 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),7.79-7.74(m,2H),7.74-7.67(m,3H),7.54- 7.43(m,3H),7.35(d,J=3.4Hz,1H),7.27(d,J=8.9Hz,1H),6.89(d,J=16.0Hz,1H).

[0565] MS(ESI):[M+H + ]344.22.

[0566] Preparation Example 31

[0567] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)prop-2-enamide (Compound 27)

[0568] Using a method similar to Example 8, using acryloyl chloride instead of benzoyl chloride, compound 27 was prepared via Scheme 8 (steps b and j).

[0569] 1H NMR(400MHz,Chloroform-d)δ9.05(s,1H),8.01(d,J=7.5Hz,1H),7.90(d,J=7.5Hz,1H),7.39(d,J=7.5Hz,1H ),7.08(s,2H),6.55-6.43(m,2H),6.37(dd,J=13.9,10.1Hz,1H),5.78(dd,J=16.7,13.9Hz,1H),1.61(s,2H).

[0570] MS(ESI):[M+H + ]269.30.

[0571] Preparation Example 32

[0572] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)pyridine-2-carboxamide (Compound 28)

[0573] Using a method similar to Example 8, substituting pyridinyl chloride for benzoyl chloride, compound 28 was prepared via Scheme 8 (steps b and j).

[0574] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.80(dd,J=4.6,1.4Hz,1H),8.12(dd,J=5 .8,2.0Hz,2H),7.82-7.64(m,3H),7.33(d,J=3.4Hz,1H),7.22(d,J=8.9Hz,1H).

[0575] MS(ESI):[M+H + ]319.24.

[0576] Preparation Example 33

[0577] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)pyridine-3-carboxamide (Compound 29)

[0578] Using a method similar to Example 8, substituting nicotinoyl chloride for benzoyl chloride, compound 29 was prepared via Scheme 8 (steps b and j).

[0579] 1H NMR (400MHz, DMSO-d6) δ9.22(d,J=2.2Hz,1H),9.07(d,J=2.1Hz,1H),8.86(dd,J=4 .9,1.8Hz,1H),8.71(dd,J=4.8,1.8Hz,1H),8.39(dt,J=8.0,2.0Hz,1H),8.25(dt,J =7.9,2.0Hz,1H),7.82(d,J=8.9Hz,1H),7.75(d,J=3.4Hz,1H),7.66(dd,J=8.0,4. 8Hz,1H),7.49(dd,J=7.9,4.8Hz,1H),7.31(d,J=3.4Hz,1H),7.24(d,J=8.9Hz,1H).

[0580] MS(ESI):[M+H + ]319.24.

[0581] Preparation Example 34

[0582] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)-1-benzofuran-2-carboxamide (Compound 30)

[0583] Using a method similar to Example 8, substituting 1-benzofuran-2-carbonyl chloride for benzoyl chloride, compound 30 was prepared via Scheme 8 (steps b and j).

[0584] 1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.06(d,J=7.3Hz,1H),7.96(d,J=7.5Hz,1H),7.62(dt,J=7.5,1.6Hz,1H),7.52-7.43(m,2 H),7.39(d,J=7.5Hz,1H),7.28(td,J=7.4,1.6Hz,1H),7.22(td,J=7.4,1.6Hz,1H),7.08(s,2H),6.61(d,J=7.5Hz,1H),1.89(s,2H).

[0585] MS(ESI):[M+H + ]359.41.

[0586] Preparation Example 35

[0587] Preparation of 5-chloro-N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)thiophene-2-carboxamide (Compound 31)

[0588] Using a method similar to Example 8, substituting 5-chlorothiophene-2-carbonyl chloride for benzoyl chloride, compound 31 was prepared via Scheme 8 (steps b and j).

[0589] 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=4.1Hz,1H),7.75(d,J=8.0Hz,2H),7.36(d,J=4.0Hz,1H),7.32-7.19(m,3H),7.04(d,J=3.9Hz,1H).

[0590] MS(ESI):[M+H + ]358.06.

[0591] Preparation Example 36

[0592] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)cyclohexanecarboxamide (Compound 32)

[0593] Using a method similar to Example 8, substituting cyclohexanecarbonyl chloride for benzoyl chloride, compound 32 was prepared via Scheme 8 (steps b and j).

[0594] 1 H NMR (400MHz, DMSO-d6) δ11.39 (s, 1H), 7.63 (d, J = 8.0Hz, 2H), 7.32-7.17 (m, 2H), 2.47-2.38 ( m,1H),1.99-1.89(m,2H),1.79(d,J=12.4Hz,2H),1.47(d,J=12.0Hz,2H),1.39-1.26(m,4H).

[0595] MS(ESI):[M+H + ]324.05.

[0596] Preparation Example 37

[0597] Preparation of 7-N-(5-bromo-2-methoxyphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 33)

[0598] Using a method similar to Example 5, substituting 5-bromo-2-methoxyphenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 33 was prepared via Scheme 5 (steps b, h, g, and i).

[0599] 1H NMR (400MHz, chloroform-d) δ8.07-7.97(m,2H),7.39(d,J=7.5Hz,1H),7.08(s,2H),6.86(dd,J=7.5,2.0Hz ,1H),6.54(dd,J=22.9,7.5Hz,2H),6.37(d,J=2.0Hz,1H),3.94(s,3H),3.42(s,1H),1.87(s,2H).

[0600] MS(ESI):[M+H+]400.25.

[0601] Preparation Example 38

[0602] Preparation of 7-N-(2-bromophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 35)

[0603] Using a method similar to Example 5, substituting 2-bromophenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 35 was prepared via Scheme 5 (steps b, h, g, and i).

[0604] H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.70(s,1H),7.58(dd,J=7.8,1.4Hz,1H),7.50(s,1H),7.3 0(s,1H),7.15(d,J=8.9Hz,1H),7.06(t,J=7.8Hz,1H),6.77(t,J=7.3Hz,1H),5.72-5.60(m,1H).

[0605] MS(ESI):[M+H + ]396.23

[0606] Preparation Example 39

[0607] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)pyridine-3-sulfonamide (Compound 36)

[0608] Using a method similar to Example 8, substituting pyridine-3-sulfonyl chloride for benzoyl chloride, compound 36 was prepared via Scheme 8 (steps b and j).

[0609] 1H NMR(400MHz, DMSO-d6)δ8.50(dd,J=4.4,1.8Hz,2H),7.81(d,J=8.0Hz,1H),7.53(d,J=8.8Hz,1H) ,7.34(dd,J=8.0,4.8Hz,1H),7.19(d,J=3.2Hz,1H),6.97(d,J=3.2Hz,1H),6.91(d,J=8.8Hz,1H).

[0610] MS(ESI):[M+H + ]355.15.

[0611] Preparation Example 40

[0612] Preparation of 7-N-(3-nitrophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 37)

[0613] Using a method similar to Example 5, substituting 3-nitrophenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 37 was prepared via Scheme 5 (steps b, h, g, and i).

[0614] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),7.71(s,1H),7.67(dd,J=7.8,2.3Hz,1H),7.58(d,J=9. 0Hz,1H),7.48(t,J=8.2Hz,1H),7.31(s,1H),7.17-7.08(m,2H),6.80(dd,J=7.8,2.3Hz,1H).

[0615] MS(ESI):[M+H + ]335.23

[0616] Preparation Example 41

[0617] Preparation of 7-N-(2-bromo-3-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 38)

[0618] Using a method similar to Example 5, substituting 2-bromo-3-fluorophenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 38 was prepared via Scheme 5 (steps b, h, g, and i).

[0619] 1H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.71(d,J=3.3Hz,1H),7.52(d,J=8.9Hz,1H),7.31(d,J=3.4Hz,1H) ,7.16(d,J=8.9Hz,1H),7.09(td,J=8.3,6.2Hz,1H),6.81(td,J=8.4,1.3Hz,1H),5.47(d,J=8.4Hz,1H).

[0620] MS(ESI):[M+H + ]386.23.

[0621] Preparation Example 42

[0622] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)-4-fluorobenzenesulfonamide (Compound 39)

[0623] Using a method similar to Example 8, substituting 4-fluorobenzenesulfonyl chloride for benzoyl chloride, compound 39 was prepared via Scheme 8 (steps b and j).

[0624] 1 H NMR (400MHz, chloroform-d) δ8.01(d,J=7.5Hz,1H),7.83(d,J=7.5Hz,1H),7.80-7.72(m,2H),7.39(d,J =7.5Hz,1H),7.20-7.12(m,2H),7.08(s,2H),6.31(d,J=7.5Hz,1H),5.20(s,1H),3.00(s,2H).

[0625] MS(ESI):[M+H + ]373.69.

[0626] Preparation Example 43

[0627] Preparation of 7-N-(4-propan-2-ylphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 41)

[0628] Using a method similar to Example 5, substituting 4-isopropylphenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 41 was prepared via Scheme 5 (steps b, h, g, and i).

[0629] 1H NMR (400MHz, Methanol-d4) δ10.29(s,1H),8.57(d,J=3.3Hz,1H),8.52(d,J=8.8Hz,1H),8.16(d,J=3.3Hz,1H) ,8.03(d,J=8.8Hz,1H),7.85(d,J=8.6Hz,2H),7.11(d,J=8.6Hz,2H),3.62-3.49(m,1H),1.93(d,J=6.9Hz,6H).

[0630] MS(ESI):[M+H + ]332.09.

[0631] Preparation Example 44

[0632] N 7 Preparation of -(3,5-difluoro-4-methoxyphenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 42)

[0633] Using a method similar to Example 5, substituting 3,5-difluoro-4-methoxy-phenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 42 was prepared via Scheme 5 (steps b, h, g, and i).

[0634] 1 H NMR(400MHz,Chloroform-d)δ8.07-7.97(m,2H),7.39(d,J=7.5Hz,1H),7.08(s,2H),6. 57(d,J=7.4Hz,1H),5.72(dt,J=9.3,1.2Hz,2H),4.00(s,3H),3.44(s,1H),1.92(s,2H).

[0635] MS(ESI):[M+H + ]357.74.

[0636] Preparation Example 45

[0637] Preparation of N-(1,3-diamino-7H-pyrrolo[3,2-f]quinazolin-7-yl)-4-methoxybenzenesulfonamide (Compound 43)

[0638] Using a method similar to Example 8, substituting p-methoxybenzenesulfonyl chloride for benzoyl chloride, compound 43 was prepared via Scheme 8 (steps b and j).

[0639] 1H NMR(400MHz,DMSO-d6)δ7.98(d,J=7.5Hz,1H),7.83-7.70(m,3H),7.39(d,J=7 .5Hz,1H),7.12-7.02(m,3H),6.39(d,J=7.7Hz,3H),6.19(s,2H),3.79(s,3H).

[0640] MS(ESI):[M+H + ]385.22.

[0641] Preparation Example 46

[0642] N 7 ,N 7 Preparation of -bis(quinolin-8-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 44)

[0643] Using a method similar to Example 2, substituting 8-bromoquinoline for 4-methoxyiodobenzene, compound 44 was prepared via Scheme 2 (steps b and c).

[0644] 1 H NMR (400MHz, DMSO-d6) δ9.04(dd,J=7.4,1.5Hz,2H),8.47(dt,J=7.6,1.6Hz,2H),8.22(d,J=7.4Hz,1H),8.09(d,J=7.5Hz,1H),8.02(dd,J= 7.5,1.6Hz,2H),7.81(dt,J=7.6,1.6Hz,2H),7.63(q,J=7.6Hz,4H),7.39(d,J=7.4Hz,1H),6.64(d,J=7.4Hz,1H),5.11(s,2H),4.45(s,2H).

[0645] MS(ESI):[M+H + ]469.74.

[0646] Preparation Example 47

[0647] N 7 Preparation of -(3',5'-difluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 45)

[0648] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with 3,5-difluoro-4'-iodo-4-methoxy-1,1'-biphenyl, compound 45 was prepared via route 2 (steps b and c).

[0649] 1 H NMR (400MHz, DMSO-d6) δ8.19-8.10(m,2H),7.57-7.49(m,2H),7.39(d,J=7.5Hz,1H),7.05 -6.91(m,4H),6.67(d,J=7.5Hz,1H),5.09(s,2H),4.46(s,2H),4.35(s,1H),4.00(s,3H).

[0650] MS(ESI):[M+H + ]432.66.

[0651] Preparation Example 48

[0652] N 7 Preparation of -(5-bromopyridin-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 46)

[0653] Using a method similar to Example 5, substituting 5-bromopyridine-2-boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 46 was prepared via Scheme 5 (steps b, h, g, and i).

[0654] 1 H NMR (400MHz, DMSO-d6) δ8.40(d,J=1.4Hz,1H),8.12(s,2H),7.70(dd,J=8.0,1.3Hz,1H),7.39(d,J =7.5Hz,1H),7.07(d,J=8.1Hz,1H),6.65(d,J=7.5Hz,1H),4.73(s,2H),4.47(s,2H),4.40(s,1H).

[0655] MS(ESI):[M+H + ]371.36.

[0656] Preparation Example 49

[0657] N 7 Preparation of -(5-phenylpyridin-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 47)

[0658] Using a method similar to Example 5, substituting (5-phenylpyridin-2-yl)boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 47 was prepared via Scheme 5 (steps b, h, g, and i).

[0659] 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.92-7.85(m,2H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.58-7.44(m,4H),7.48-7. 36(m,2H),7.30(dd,J=7.3,2.3Hz,1H),6.84(d,J=7.2Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.40(s,1H).

[0660] MS(ESI):[M+H + ]368.41.

[0661] Preparation Example 50

[0662] N 7 Preparation of -(5-(3,5-difluoro-4-methoxyphenyl)pyridin-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 48)

[0663] Using a method similar to Example 5, substituting (5-(3,5-difluoro-4-methoxyphenyl)pyridin-2-yl)boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 48 was prepared via Route 5 (steps b, h, g, and i).

[0664] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.92-7.85(m,2H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.43(dt,J=7.9,0.7Hz,2H),7.39( d,J=5.3Hz,1H),7.30(dd,J=7.2,2.3Hz,1H),6.84(d,J=7.2Hz,1H),6.59 (d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.40(s,1H).

[0665] MS(ESI):[M+H + ]434.85.

[0666] Preparation Example 51

[0667] N 7Preparation of -(quinolin-8-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 50)

[0668] Using a method similar to Example 2, substituting 8-bromoquinoline for 4-methoxyiodobenzene, compound 50 was prepared via Scheme 2 (steps b and c).

[0669] 1 H NMR (400MHz, DMSO-d6) δ9.07 (dd, J=7.5, 1.5Hz, 1H), 8.41 (dt, J=7.5, 1.5Hz, 1H), 8.20-8.09 (m, 2H), 7.64-7.52 (m,2H),7.54-7.44(m,2H),7.39(d,J=7.5Hz,1H),6.67(d,J=7.5Hz,1H),5.46(s,1H),5.10(s,2H),4.45(s,2H).

[0670] MS(ESI):[M+H + ]342.82.

[0671] Preparation Example 52

[0672] Preparation of 7-N-(4-chlorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 51)

[0673] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with 4-chlorophenylboronic acid, compound 51 was prepared via Scheme 2 (steps b and c).

[0674] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5 .3Hz,1H),7.15-7.07(m,2H),6.75-6.67(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0675] MS(ESI):[M+H + ]325.63.

[0676] Preparation Example 53

[0677] Preparation of 7-N-(4-bromophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 52)

[0678] Using a method similar to Example 5, substituting 4-bromophenylboronic acid for (4-methylpyridin-2-yl)boronic acid, compound 52 was prepared via Scheme 5 (steps b, h, g, and i).

[0679] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5 .3Hz,1H),7.30-7.22(m,2H),6.70-6.62(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0680] MS(ESI):[M+H + ]370.29.

[0681] Preparation Example 54

[0682] Preparation of 7-naphthylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 53)

[0683] Using a method similar to Example 2, substituting 1-naphthaleneboronic acid for 4-methoxyiodobenzene, compound 53 was prepared via Route 2 (steps b and c).

[0684] 1 H NMR(400MHz,DMSO-d6)δ8.04-7.95(m,4H),7.88(d,J=7.6Hz,2H),7.80(d,J=7.0Hz,2 H),7.74-7.67(m,2H),7.64(d,J=7.8Hz,2H),7.59-7.51(m,2H),7.42(ddd,J=8.2,7.1 ,1.2Hz,2H),7.39(d,J=5.3Hz,2H),7.33-7.25(m,2H),6.96-6.90(m,2H),6.77-6.69 (m,2H),6.59(d,J=7.6Hz,2H),6.37-6.31(m,2H),6.25(d,J=7.6Hz,2H),4.90(s,2H).

[0685] MS(ESI):[M+H +]341.36.

[0686] Preparation Example 55

[0687] Preparation of 7-naphthyl-2-pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 54)

[0688] Using a method similar to Example 2, substituting 2-naphthaleneboronic acid for 4-methoxyiodobenzene, compound 54 was prepared via Route 2 (steps b and c).

[0689] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.84-7.77(m,2H),7.75-7.67(m,1H),7.64(d,J=7.8Hz ,1H),7.58-7.36(m,5H),7.11(t,J=2.0Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0690] MS(ESI):[M+H + ]341.39.

[0691] Preparation Example 56

[0692] Preparation of 7-N-(4-vinylphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 55)

[0693] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with 4-vinylbenzeneboronic acid, compound 55 was prepared via Scheme 2 (steps b and c).

[0694] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.70-7.61(m,3H),7.39(d,J=5.3Hz,1H), 6.82-6.70(m,2H),6.71(s,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.59(d,J=16.3Hz,2H),4.90(s,1H).

[0695] MS(ESI):[M+H +]317.72.

[0696] Preparation Example 57

[0697] Preparation of 7-N-(1,3-benzodioxazol-5-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 56)

[0698] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with benzo[d][1,3]dihydroxy-5-ylboronic acid, compound 56 was prepared via Route 2 (steps b and c).

[0699] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6. 64(d,J=8.4Hz,1H),6.59(d,J=7.6Hz,1H),6.45(dq,J=4.2,1.9Hz,2H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.97(s,2H),4.90(s,1H).

[0700] MS(ESI):[M+H + ]335.42.

[0701] Preparation Example 58

[0702] Preparation of 7-N-(4-phenylphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 57)

[0703] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with 4-biphenylboronic acid, compound 57 was prepared via Scheme 2 (steps b and c).

[0704] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.77-7.69(m,2H),7.64(d,J=7.8Hz,1H), 7.55-7.46(m,2H),7.46-7.36(m,4H),7.00-6.92(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0705] MS(ESI):[M+H + ]367.22.

[0706] Preparation Example 59

[0707] Preparation of 7-N-(4-pyridin-2-ylphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 58)

[0708] Using a method similar to Example 2, substituting 4-(2-pyridyl)phenylboronic acid for 4-methoxyiodobenzene, compound 58 was prepared via Scheme 2 (steps b and c).

[0709] 1 H NMR(400MHz, DMSO-d6)δ8.69(dd,J=4.1,1.7Hz,1H),8.32-8.24(m,2H),8.01-7.85(m,3H),7.80(d,J=7.0Hz,1H),7.71-7.61 (m,2H),7.47-7.36(m,2H),7.00-6.92(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0710] MS(ESI):[M+H + ]368.53.

[0711] Preparation Example 60

[0712] Preparation of 7-N-(6-phenylpyridin-3-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 59)

[0713] Using a method similar to Example 2, substituting 2-phenylpyridine-5-boronic acid for 4-methoxyiodobenzene, compound 59 was prepared via Scheme 2 (steps b and c).

[0714] 1H NMR (400MHz, DMSO-d6) δ8.12-8.05(m,2H),8.02(d,J=1.9Hz,1H),7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.79(t,J=7.5Hz,2H),7.64 (d,J=7.8Hz,1H),7.59-7.49(m,2H),7.46-7.38(m,1H),7.39(d,J=5.3Hz,1H),6.66-6.56(m,2H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H).

[0715] MS(ESI):[M+H + ]368.38.

[0716] Preparation Example 61

[0717] Preparation of 7-N-(5-pyridin-2-ylpyridin-2-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 60)

[0718] Using a method similar to Example 5, replacing (4-methylpyridin-2-yl)boronic acid with [2,3'-bipyridyl]-6'-ylboronic acid, compound 60 was prepared via Scheme 5 (steps b, h, g, and i).

[0719] 1 H NMR(400MHz,DMSO-d6)δ9.42(d,J=2.2Hz,1H),8.80(dd,J=4.0,1.7Hz,1H),8.61(dd, J=7.6,2.2Hz,1H),8.22(td,J=7.2,1.8Hz,1H),7.98(d,J=7.0Hz,1H),7.96-7.85(m, 2H),7.80(d,J=7.0Hz,1H),7.71-7.61(m,2H),7.39(d,J=5.3Hz,1H),6.84(d,J=7.6H z,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.40(s,1H).

[0720] MS(ESI):[M+H + ]369.59.

[0721] Preparation Example 62

[0722] Preparation of 7-N-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 61)

[0723] Using a method similar to Example 2, replacing 4-methoxyiodobenzene with 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, compound 61 was prepared via Scheme 2 (steps b and c).

[0724] 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.85-7.77( m,2H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6 .31(m,1H),6.25(d,J=7.6Hz,1H),3.71(dd,J=5.7,2.9Hz,2H),2.77-2.59(m,2H) ,2.09(dddd,J=7.3,5.7,4.5,2.9Hz,2H),1.82(dddd,J=7.9,7.2,5.5,4.5Hz,2H).

[0725] MS(ESI):[M+H + ]335.26.

[0726] Preparation Example 63

[0727] Preparation of 7-N-(1-methylpyrazol-4-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 62)

[0728] Using a method similar to Example 2, substituting 1-methyl-4-bromopyrazole for 4-methoxyiodobenzene, compound 62 was prepared via Scheme 2 (steps b and c).

[0729] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.91-7.83(m,2H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39( d,J=5.3Hz,1H),7.29(d,J=1.7Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),3.94(s,3H).

[0730] MS(ESI):[M+H + ]295.44.

[0731] Preparation Example 64

[0732] Preparation of 4-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]-2-methylpyrazole-3-carbonitrile (Compound 63)

[0733] Using a method similar to Example 5, substituting (5-cyano-1-methyl-1H-pyrazol-4-yl)boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 63 was prepared via Scheme 5 (steps b, h, g, and i).

[0734] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.91-7.83(m,2H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz ,1H),7.39(d,J=5.3Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),3.81(s,3H).

[0735] MS(ESI):[M+H + ]320.51.

[0736] Preparation Example 65

[0737] Preparation of 5-[(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)amino]thiophene-2-carbonitrile (Compound 64)

[0738] Using a method similar to Example 5, substituting 5-cyanothiophene-2-boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 64 was prepared via Scheme 5 (steps b, h, g, and i).

[0739] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,2H),7.88(d,J=7.6Hz,2H),7.80(d,J=7.0Hz,2H),7.64(d,J=7.8Hz,2H),7.39(d, J=5.3Hz,2H),7.03(d,J=5.8Hz,2H),6.59(d,J=7.6Hz,2H),6.37-6.31(m,2H),6.25(d,J=7.6Hz,2H),6.01(d,J=6.0Hz,2H).

[0740] MS(ESI):[M+H + ]322.17.

[0741] Preparation Example 66

[0742] Preparation of 7-N-[2-(trifluoromethyl)-1,3-thiazol-4-yl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 65)

[0743] Using a method analogous to Example 5, substituting (2-(trifluoromethyl)thiazol-4-yl)boronic acid for (4-methylpyridin-2-yl)boronic acid, compound 65 was prepared via Scheme 5 (steps b, h, g, and i).

[0744] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,2H),7.88(d,J=7.6Hz,2H),7.80(d,J=7.0Hz,2H),7.64(d,J=7.8H z,2H),7.39(d,J=5.3Hz,2H),6.59(d,J=7.6Hz,2H),6.37-6.31(m,2H),6.25(d,J=7.6Hz,2H),6.18(s,2H).

[0745] MS(ESI):[M+H + ]366.34.

[0746] Preparation Example 67

[0747] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)-4-methylbenzenesulfonamide (Compound 66)

[0748] Using a method similar to Example 8, substituting p-toluenesulfonyl chloride for benzoyl chloride, compound 66 was prepared via Scheme 8 (steps b and j).

[0749] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7 .39(d,J=5.3Hz,1H),7.37(s,4H),7.20(s,1H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.3Hz,1H),6.25(d,J=7.6Hz,1H).

[0750] MS(ESI):[M+H+ ]369.44.

[0751] Preparation Example 68

[0752] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)methanesulfonamide (Compound 67)

[0753] Using a method similar to Example 8, substituting methanesulfonyl chloride for benzoyl chloride, compound 67 was prepared via Scheme 8 (steps b and j).

[0754] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,2H),7.88(d,J=7.6Hz,2H),7.80(d,J=7.0Hz,2H),7.64(d,J=7.8Hz ,2H),7.39(d,J=5.3Hz,2H),6.80(s,2H),6.59(d,J=7.6Hz,2H),6.34(d,J=5.3Hz,2H),6.25(d,J=7.6Hz,2H).

[0755] MS(ESI):[M+H + ]293.31.

[0756] Preparation Example 69

[0757] Preparation of 9H-fluoren-9-ylmethyl N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)carbamate (Compound 68)

[0758] Using a method similar to Example 8, substituting 9-fluorenylmethyl chloroformate for benzoyl chloride, compound 68 was prepared via Scheme 8 (steps b and j).

[0759] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.83-7.75(m,3H),7.67-7.58(m,3H),7.49(td,J=7.7,1.3Hz,2H),7. 45-7.36(m,3H),7.00(s,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.40(d,J=4.9Hz,2H),4.28(d,J=5.0Hz,1H).

[0760] MS(ESI):[M+H +]437.40.

[0761] Preparation Example 70

[0762] Preparation of tert-butyl N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)carbamate (Compound 69)

[0763] Using the method of Example 5, compound 69 was prepared via Route 5 (steps b and h).

[0764] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H) ,7.39(d,J=5.3Hz,1H),7.00(s,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),1.38(s,8H).

[0765] MS(ESI):[M+H + ]315.41.

[0766] Preparation Example 71

[0767] Preparation of N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)benzamide (Compound 70)

[0768] Using the method of Example 3, compound 70 was prepared via Route 3 (steps b and d).

[0769] 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=7.0Hz,1H),7.94-7.85(m,3H),7.80(d,J=7.0Hz,1H),7.70(s,1H),7.64(d,J=7.8Hz,1H), 7.61-7.53(m,1H),7.53-7.44(m,2H),7.39(d,J=5.3Hz,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H).

[0770] MS(ESI):[M+H + ]319.29.

[0771] Preparation Example 72

[0772] Preparation of 7-N-[(4-methoxyphenyl)methyl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 71)

[0773] Using the method of Example 4, compound 71 was prepared via Route 4 (steps b and f).

[0774] 1 H NMR(400MHz,DMSO-d6)δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80( d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),7.20(dt,J=8. 3,1.0Hz,2H),7.01(t,J=3.3Hz,1H),6.95-6.87(m,2H),6.59(d,J=7.6Hz,1H ), 6.34 (d, J = 5.3Hz, 1H), 6.25 (d, J = 7.6Hz, 1H), 4.28 (dt, J = 3.2, 0.9Hz, 2H).

[0775] MS(ESI):[M+H + ]335.31.

[0776] Preparation Example 73

[0777] Preparation of benzyl N-(1,3-diaminopyrrolo[3,2-f]quinazolin-7-yl)carbamate (Compound 72)

[0778] Using the method of Example 6, compound 72 was prepared via Scheme 6 (steps b and j).

[0779] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H ),7.32(s,3H),7.37-7.25(m,2H),7.00(s,1H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),5.02(d,J=0.9Hz,2H).

[0780] MS(ESI):[M+H + ]349.51.

[0781] Preparation Example 74

[0782] Preparation of 7-N-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 73)

[0783] Using a method similar to Example 3, substituting 2-(trimethylsilyl)ethoxymethyl chloride for benzyl bromide, compound 73 was prepared via Scheme 3 (steps b and d).

[0784] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.59(d,J= 7.6Hz,1H),6.34(d,J=5.3Hz,1H),6.25(d,J=7.6Hz,1H),4.73(d,J=1.3Hz ,2H),3.60(d,J=16.7Hz,1H),1.50(t,J=1.4Hz,1H),0.85(t,J=8.3Hz,2H).

[0785] MS(ESI):[M+H + ]345.53.

[0786] Preparation Example 75

[0787] Preparation of 6-chloro-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 74)

[0788] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-chloro-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 74 was prepared via Route 5 (steps b, h, g, and i).

[0789] 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J= 7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0790] MS(ESI):[M+H + ]343.82.

[0791] Preparation Example 76

[0792] Preparation of 6-bromo-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 75)

[0793] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-bromo-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 75 was prepared via Route 5 (steps b, h, g, and i).

[0794] 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J= 7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0795] MS(ESI):[M+H + ]388.31.

[0796] Preparation Example 77

[0797] Preparation of 7-N-(4-fluorophenyl)-6-iodopyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 76)

[0798] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 76 was prepared via Route 5 (steps b, h, g, and i).

[0799] 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J= 7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0800] MS(ESI):[M+H + ]435.22.

[0801] Preparation Example 78

[0802] Preparation of 7-N-(4-fluorophenyl)-6-[(E)-2-phenylvinyl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 77)

[0803] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with (E)-6-phenylvinyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 77 was prepared via Route 5 (steps b, h, g, and i).

[0804] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.59-7 .51(m,2H),7.44(ddt,J=7.5,6.8,0.7Hz,2H),7.39(d,J=5.1Hz,1H),7.37-7.28(m,1H),7. 07(dt,J=14.9,0.7Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.89(d,J=15.1Hz,1H),6.79-6.7 1(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0805] MS(ESI):[M+H + ]411.43.

[0806] Preparation Example 79

[0807] Preparation of 7-N-(4-fluorophenyl)-6-phenylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 78)

[0808] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-phenyl-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 78 was prepared via Route 5 (steps b, h, g, and i).

[0809] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.46-7.36(m,2H),7.35-7.27(m,2H),7.26-7.17(m ,2H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0810] MS(ESI):[M+H + ]385.20.

[0811] Preparation Example 80

[0812] Preparation of 7-N,6-bis(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 79)

[0813] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(4-fluorophenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 79 was prepared via Route 5 (steps b, h, g, and i).

[0814] 1H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),7.33-7.19(m,4H),6. 98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0815] MS(ESI):[M+H + ]403.49.

[0816] Preparation Example 81

[0817] Preparation of 7-N-(4-fluorophenyl)-6-(4-methoxyphenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 80)

[0818] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(4-methoxyphenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 80 was prepared via Route 5 (steps b, h, g, and i).

[0819] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),7.25-7.17(m,2H),6.98(tt,J= 7.8,1.5Hz,2H),6.88-6.80(m,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0820] MS(ESI):[M+H + ]415.55.

[0821] Preparation Example 82

[0822] Preparation of 7-N-(4-fluorophenyl)-6-pyridin-2-ylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 81)

[0823] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(pyridin-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 81 was prepared via Route 5 (steps b, h, g, and i).

[0824] 1 H NMR(400MHz, DMSO-d6)δ8.58(dd,J=4.0,1.7Hz,1H),8.49(s,1H),7.88(d,J=7.6 Hz,1H),7.75(ddd,J=8.1,7.2,1.7Hz,1H),7.64(d,J=7.8Hz,1H),7.50(dd,J=8.1 ,1.4Hz,1H),7.47-7.36(m,2H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H), 6.59(d,J=7.6Hz,1H), 6.34(d,J=5.1Hz,1H), 6.25(d,J=7.6Hz,1H), 4.90(s,1H).

[0825] MS(ESI):[M+H + ]386.45.

[0826] Preparation Example 83

[0827] Preparation of 7-N-(4-fluorophenyl)-6-pyridin-4-ylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 82)

[0828] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(pyridin-4-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 82 was prepared via Route 5 (steps b, h, g, and i).

[0829] 1H NMR (400MHz, DMSO-d6) δ8.71-8.65(m,2H),8.10(s,1H),7.88(d,J=7.6Hz,1H),7.70-7.61(m,3H),7.39(d,J=5.1Hz,1H),6.9 8(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0830] MS(ESI):[M+H + ]386.40.

[0831] Preparation Example 84

[0832] Preparation of 7-N-(4-fluorophenyl)-6-(2-methylpyrazol-3-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 83)

[0833] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 83 was prepared via Route 5 (steps b, h, g, and i).

[0834] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.50(d,J=3.4Hz,1H),7.39(d,J=5.1Hz,1H), 6.98(tt,J=7.8,1.5Hz,2H),6.79-6.69(m,3H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0835] MS(ESI):[M+H + ]389.40.

[0836] Preparation Example 85

[0837] Preparation of 6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 84)

[0838] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 84 was prepared via Route 5 (steps b, h, g, and i).

[0839] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.10(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7 .8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.5 9(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H),3.71(t ,J=3.8Hz,2H),2.87(ddd,J=8.1,6.2,0.6Hz,2H),2.58(ddt,J=7.9,6.2,3.8Hz,2H).

[0840] MS(ESI):[M+H + ]415.50.

[0841] Preparation Example 86

[0842] Preparation of 7-N-(4-fluorophenyl)-6-[1-(oxoalkyl-3-yl)pyrazol-4-yl]pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 85)

[0843] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 85 was prepared via Route 5 (steps b, h, g, and i).

[0844] 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=1.6Hz,1H),8.23(dd,J=1.7,0.6Hz,1H),8.10(s,1H),7.88( d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79 -6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H), 4.36-4.28(m,1H),4.11-3.97(m,2H),3.93-3.83(m,1H),2.47-2.37(m,1H),2.22-2.12(m,1H).

[0845] MS(ESI):[M+H + ]445.53.

[0846] Preparation Example 87

[0847] Preparation of 6-(1-cyclohexylpyrazol-4-yl)-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 86)

[0848] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(1-cyclohexyl-1H-pyrazol-4-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 86 was prepared via Route 5 (steps b, h, g, and i).

[0849] 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=1.6Hz,1H),8.23(dd,J=1.6,0.6Hz,1H),8.10(s,1H),7.88(d,J=7.6 Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6. 59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H),3.64(pd,J=3.5,0.6Hz, 1H),2.00(dddd,J=12.2,7.9,5.0,3.5Hz,2H),1.81-1.56(m,4H),1.56-1.40(m,3H),1.26-1.12(m,1H).

[0850] MS(ESI):[M+H + ]457.59.

[0851] Preparation Example 88

[0852] Preparation of 7-N-(4-fluorophenyl)-6-(1-piperidin-4-ylpyrazol-4-yl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 87)

[0853] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 87 was prepared via Route 5 (steps b, h, g, and i).

[0854] 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=1.6Hz,1H),8.23(dd,J=1.6,0.6Hz,1H),8.10(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7 .8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.34(d,J=5.1Hz,1 H),6.25(d,J=7.6Hz,1H),4.90(s,1H),4.40(qd,J=3.8,0.7Hz,1H),3.04(ddt,J=12.3,5.6,2.9Hz,2H),2.74(ddt,J=12.5, 5.8,2.9Hz,2H),2.44(p,J=3.1Hz,1H),1.93(dddd,J=12.1,5.4,3.7,2.8Hz,2H),1.79(dddd,J=12.3,5.6,3.7,2.8Hz,2H).

[0855] MS(ESI):[M+H + ]458.66.

[0856] Preparation Example 89

[0857] Preparation of tert-butyl 4-[4-[1,3-diamino-7-(4-fluoroanilino)pyrrolo[3,2-f]quinazolin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate (Compound 88)

[0858] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine with tert-butyl 4-(4-(1,3-diamino-7H-pyrrolo[3,2-f]quinazoline-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 88 was prepared via route 5 (steps b, h, g, and i).

[0859] 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=1.6Hz,1H),8.23(dd,J=1.7,0.7Hz,1H),8.10(s,1H),7.88(d,J=7.6Hz,1H),7.6 4(d,J=7.8Hz,1H),7.39(d,J=5.1Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6. 34(d,J=5.1Hz,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H),4.45(pd,J=3.3,0.7Hz,1H),3.78(ddd,J=12.3,8.0,5.3Hz ,2H),2.76(ddd,J=12.3,8.1,5.3Hz,2H),2.13(dddd,J=12.4,8.4,5.4,3.3Hz,2H),1.94-1.82(m,2H),1.39(s,7H).

[0860] MS(ESI):[M+H + ]558.60.

[0861] Preparation Example 90

[0862] Preparation of 5-chloro-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 89)

[0863] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 5-chloro-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 89 was prepared via Route 5 (steps b, h, g, and i).

[0864] 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=7.6Hz,1H),7.84(s,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.98(tt, J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0865] MS(ESI):[M+H + ]343.76.

[0866] Preparation Example 91

[0867] Preparation of 5-bromo-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 90)

[0868] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 5-bromo-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 90 was prepared via Route 5 (steps b, h, g, and i).

[0869] 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.88(d,J=7.6Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.98(tt, J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0870] MS(ESI):[M+H + ]388.15.

[0871] Preparation Example 92

[0872] Preparation of 7-N-(4-fluorophenyl)-5-methylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 91)

[0873] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 5-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 91 was prepared via Route 5 (steps b, h, g, and i).

[0874] 1H NMR (400MHz, DMSO-d6) δ7.88(d,J=7.6Hz,1H),7.71(d,J=0.8Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.98 (tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0875] MS(ESI):[M+H + ]323.41.

[0876] Preparation Example 93

[0877] Preparation of 5-cyclopropyl-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 92)

[0878] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 5-cyclopropyl-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 92 was prepared via Route 5 (steps b, h, g, and i).

[0879] 1 H NMR (400MHz, DMSO-d6) δ7.91-7.85 (m, 2H), 7.64 (d, J = 7.8Hz, 1H), 7.39 (d, J=5.3Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7. 6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H),3.50(qd,J =6.1,0.7Hz,1H),1.04-0.94(m,1H),0.98-0.88(m,1H),0.72-0.56(m,2H).

[0880] MS(ESI):[M+H + ]349.40.

[0881] Preparation Example 94

[0882] Preparation of 7-N-(4-fluorophenyl)-5-phenylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 93)

[0883] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 5-phenyl-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 93 was prepared via Route 5 (steps b, h, g, and i).

[0884] 1 H NMR(400MHz, DMSO-d6)δ7.94-7.85(m,2H),7.64(d,J=7.8Hz,1H),7.46-7.36(m,2H),7.35-7.27(m,2H),7.26-7.17(m,2H),6 .98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0885] MS(ESI):[M+H + ]385.42.

[0886] Preparation Example 95

[0887] Preparation of 3-N-cyclopropyl-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 94)

[0888] Using a method similar to Example 5, N 3 -cyclopropyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine instead of 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine, and 4-fluorophenylboronic acid instead of (4-methylpyridin-2-yl)boronic acid, and compound 94 were prepared via route 5 (steps b, h, g and i).

[0889] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.98( tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.37-6.31(m,1H),6.25(d,J= 6.4Hz, 1H), 4.90 (s, 1H), 3.02 (dp, J=6.6, 5.5Hz, 1H), 0.66-0.49 (m, 5H).

[0890] MS(ESI):[M+H + ]349.30.

[0891] Preparation Example 96

[0892] Preparation of 2-[[3-amino-7-(4-fluoroanilino)pyrrolo[3,2-f]quinazolin-1-yl]amino]ethanol (Compound 95)

[0893] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine with 2-((3-amino-7H-pyrrolo[3,2-f]quinazolin-1-yl)amino)ethane-1-ol and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 95 was prepared via Route 5 (steps b, h, g, and i).

[0894] 1 H NMR(400MHz, DMSO-d6)δ9.39(t,J=5.2Hz,1H),7.98(d,J=7.0Hz,1H),7.80(d ,J=7.0Hz,1H),7.39(d,J=5.3Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71 (m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.9 0(s,1H),4.75(t,J=5.5Hz,1H),3.62(q,J=5.1Hz,2H),3.48(q,J=5.1Hz,2H).

[0895] MS(ESI):[M+H + ]353.35.

[0896] Preparation Example 97

[0897] Preparation of 2-[[1-amino-7-(4-fluoroanilino)pyrrolo[3,2-f]quinazolin-3-yl]amino]ethanol (Compound 96)

[0898] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine with 2-((1-amino-7H-pyrrolo[3,2-f]quinazolin-3-yl)amino)ethane-1-ol and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 96 was prepared via Route 5 (steps b, h, g, and i).

[0899] 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.93-7.85(m,2H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz,1H),6.98(tt ,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6.37-6.31(m,1H),4.90(s,1H) ,4.81(t,J=5.4Hz,1H),3.54(qd,J=5.3,0.9Hz,2H),3.50-3.42(m,2H).

[0900] MS(ESI):[M+H + ]353.39.

[0901] Preparation Example 98

[0902] Preparation of 2-[[3-(cyclopropylamino)-7-(4-fluoroanilino)pyrrolo[3,2-f]quinazolin-1-yl]amino]ethanol (Compound 97)

[0903] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine with 2-((3-(cyclopropylamino)-7H-pyrrolo[3,2-f]quinazolin-1-yl)amino)ethane-1-ol and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 97 was prepared via Route 5 (steps b, h, g, and i).

[0904] 1 H NMR (400MHz, DMSO-d6) δ9.39(t,J=5.2Hz,1H),7.98(d,J=7.0Hz,1H),7.80(d,J=7. 0Hz,1H),7.39(d,J=5.3Hz,1H),6.98(tt,J=7.8,1.5Hz,2H),6.79-6.71(m,2H),6. 37-6.31(m,1H),6.25(d,J=6.4Hz,1H),4.90(s,1H),4.75(t,J=5.5Hz,1H),3.65-3 .58(m,2H),3.48(q,J=5.1Hz,2H),3.02(dp,J=6.6,5.5Hz,1H),0.66-0.49(m,4H).

[0905] MS(ESI):[M+H + ]393.41.

[0906] Preparation Example 99

[0907] Preparation of 3-N-benzyl-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 98)

[0908] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with N3-benzyl-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 98 was prepared via Route 5 (steps b, h, g, and i).

[0909] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.39(d,J=5.3Hz, 1H),7.37-7.22(m,5H),6.98(tt,J=7.8,1.5Hz,2H),6.81-6.71(m,3H),6.37-6.31(m,1H),4.90(s,1H),4.46(dt,J=5.2,1.0Hz,2H).

[0910] MS(ESI):[M+H + ]399.46.

[0911] Preparation Example 100

[0912] Preparation of 3-N-[(6-aminopyridin-2-yl)methyl]-7-N-(4-fluorophenyl)pyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 99)

[0913] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with N3-((6-aminopyridin-2-yl)methyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-triamine and replacing (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 99 was prepared via Route 5 (steps b, h, g, and i).

[0914] 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d, J=7.0Hz,1H),7.64(d,J=7.8Hz,1H),7.55-7.46(m,2H),7.39(d,J=5.3Hz,1H) ,6.98(tt,J=7.8,1.5Hz,2H),6.80-6.71(m,3H),6.58(dd,J=7.9,1.2Hz,1H), 6.41-6.31(m,2H),6.28(d,J=6.7Hz,1H),4.90(s,1H),4.73(d,J=5.1Hz,2H).

[0915] MS(ESI):[M+H + ]415.41.

[0916] Preparation Example 101

[0917] Preparation of 3-amino-7-(4-fluoroanilino)pyrrolo[3,2-f]quinazolin-1-ol (Compound 100)

[0918] Using a method similar to that of Example 5, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine with 3-amino-7H-pyrrolo[3,2-f]quinazoline-1-ol and (4-methylpyridin-2-yl)boronic acid with 4-fluorophenylboronic acid, compound 100 was prepared via Route 5 (steps b, h, g, and i).

[0919] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.0Hz,1H),7.80(d,J=7.0Hz,1H),7.39(d,J=5.3Hz,1H),6.98(tt,J=7.8, 1.5Hz,2H),6.79-6.71(m,2H),6.59(d,J=7.6Hz,1H),6.37-6.31(m,1H),6.25(d,J=7.6Hz,1H),4.90(s,1H).

[0920] MS(ESI):[M+H + ]310.35.

[0921] Preparation Example 102

[0922] Preparation of 8-methylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 101)

[0923] Using a method similar to Example 2, replacing 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine with 8-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3,7-triamine, compound 101 was prepared via route 2 (step b).

[0924] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=6.7Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=6.7Hz,1H),7.64( d,J=7.8Hz,1H),6.59(d,J=7.6Hz,1H),6.54(d,J=0.8Hz,1H),6.25(d,J=7.6Hz,1H),5.62(s,2H).

[0925] MS(ESI):[M+H + ]229.21.

[0926] Preparation Example 103

[0927] Preparation of 8-methylpyrrolo[3,2-f]quinazoline-1,3,7-triamine (Compound 102)

[0928] Using the method of Example 2, compound 102 was prepared via Route 2 (step b).

[0929] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=6.7Hz,1H),7.88(d,J=7.6Hz,1H),7.80(d,J=6.7Hz,1H),7.64(d,J=7.8Hz,1H ),7.39(d,J=5.1Hz,1H),6.59(d,J=7.6Hz,1H),6.34(dd,J=5.1,0.6Hz,1H),6.25(d,J=7.6Hz,1H),5.62(s,2H).

[0930] MS(ESI):[M+H + ]215.28.

[0931] Biological Examples

[0932] Biological Example 1

[0933] Tumor cell growth inhibitory activity

[0934] Cytotoxicity assay: Cells were cultured in the culture medium recommended by the supplier (containing 10% fetal bovine serum). 1×10 cells were added to a 96-well culture plate. 3 / well, culture overnight at 37°C and 5% CO2. Afterwards, culture medium containing different concentrations of the test compound (10 μM as the starting concentration, 3-fold dilution, 10 concentrations, duplicate wells) was added to each well and cultured for 72 hours. After trypan blue staining, the viable cells reached more than 95%. 4 hours before the end of the culture, 20 μL of MTT solution (5 mg / mL) was added to each well and incubated for another 4 hours. The culture medium was discarded, 150 μL of dimethyl sulfoxide was added, and the mixture was shaken for 15 minutes. The wavelength of 570 nm was selected, and the absorbance value (A value) was measured with an enzyme-labeled instrument, and the proliferation inhibition rate was calculated. Normal cells were selected from 293T, etc.; tumor cells were selected from HepG2, A549, Hela, etc.

[0935] Table 1. Half-maximal inhibitory concentration (IC) of the compounds disclosed herein against tumor cell growth 50 (μM)

[0936] Biological Example 2

[0937] Antibacterial growth inhibitory activity

[0938] Minimum inhibitory concentration (MIC) testing: Remove the corresponding strain from the -80°C glycerol stock and plate fresh CAMHB plates. To prepare CAMHB plates, dissolve 22 grams of powder per liter of purified water and autoclave at 121°C for 10 minutes (store at room temperature for no more than 1 week). For each test compound, aliquot the compound and DMSO into the corresponding wells of the master plate. Then, perform a 3x serial dilution, with the DMSO control in column 12. For vancomycin and meropenem, perform a similar procedure, but use a 2x dilution, also with the DMSO control in column 12. For the experimental plates (96-well plates), use a multichannel pipette to dispense 1 μL of the diluted compound into each well of the corresponding experimental plate. Remove 4-8 individual colonies from the agar plate and place them into a 14 mL Falcon conical tube containing 5 mL of saline. Adjust the turbidity to approximately 0.2 using an Ultrospec 10 cell density meter. The strain suspension was then diluted 200-fold in CAMHB medium and dispensed into a sterile reservoir. A multichannel pipette was then used to dispense 99 μL of the diluted inoculum onto the corresponding experimental plates. Finally, the experimental plates were incubated at 37°C and 85% humidity for 18-20 hours. Using a magnifying glass, the minimum inhibitory concentration (MIC) of each drug required to completely inhibit microbial growth was read, recorded, and photographed.

[0939] Table 2. Minimum inhibitory concentration (MIC) of the compounds of the present disclosure for inhibiting bacterial growth (μg / mL)

[0940] Biological Example 3

[0941] Anti-Mycobacterium tuberculosis growth inhibitory activity

[0942] THP-1 / U937 cells in the exponential growth phase (survival rate of more than 98%) were collected and counted. A portion of the cell suspension was added with 20 ng / mL PMA, resuspended in complete medium, and plated onto a sterile 96-well culture plate. Each well contained 100 μL of cell suspension at a cell density of 5 × 10 5 / mL. After PMA-induced cell differentiation for 48 hours, discard the old culture medium and add 100μL of complete culture medium to each well of cells and continue culturing for 24 hours. After 24 hours, discard the old culture medium and add 100μL of complete culture medium containing Mycobacterium tuberculosis to each well of cells and continue culturing for 4 hours. After 4 hours, discard the old culture medium, wash the cells three times with PBS, and then add 100μL of complete culture medium containing 50μM drug to each well of cells and continue culturing for 48 hours. After 48 hours, discard the old culture medium and add 100μL of complete culture medium containing 20ng / mL tetracycline inducer to the 96-well plate. After continuing culturing for 24 hours, centrifuge the cells in the 96-well plate, discard the supernatant, wash twice with PBS, and add 100μL of PBS. Finally, test the absorbance at wavelengths of 479 / 520nm and 555 / 591nm in a microplate reader.

[0943] MT WT The strain refers to the Mycobacterium tuberculosis H37Rv standard strain; MT 26-2 The strain came from Shenzhen Third People's Hospital. It was a clinical isolate from a pulmonary tuberculosis patient in the hospital and was dual-resistant to isoniazid and rifampicin. The hospital used the C26 (clinical) strain as its identifier.

[0944] Table 3. Minimum inhibitory concentration (MIC) (μg / mL) of the compounds of the present disclosure for inhibiting the growth of Mycobacterium tuberculosis

[0945] Biological Example 4

[0946] Pharmacokinetic property testing

[0947] The compounds disclosed in the present invention were tested for pharmacokinetic properties, and the test operation was as follows: the compound to be tested was dissolved and prepared into a stock solution of the required concentration for standby use. Then, male healthy mice were divided into groups of 3 mice per group. The mice were fasted for one night, allowed to drink water freely, and then fed and dosed 4 hours later. The dosage was as shown in the following table. Whole blood samples were collected through the orbital vein at designated time points (0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h), and 30 μL of the sample was flowed into a sodium heparin anticoagulant tube and centrifuged at 4000rcf / 4°C for 5 minutes, after which the upper plasma sample was taken. Finally, LC-MS / MS was used to collect data on the sample, and after data processing, the pharmacokinetic parameters of the compound to be tested were obtained.

[0948] Tables 4 and 5 show the plasma concentration-time data of Compound 5 of the present disclosure.

[0949] Table 4. Note: NA = Not Applicable

[0950] Table 5. Note: NA=Not Applicable NR=Not Reprotable

[0951] FIG1 and FIG2 show the blood concentration-time curves of compound 5 of the present disclosure.

[0952] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0953] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. Compounds represented by general formula (I), and pharmaceutically acceptable salts thereof: in: R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group; R3 is selected from hydroxy and optionally substituted amino; R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl; R9 and R 10 are each independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group; and X is selected from CH or N.

2. The compound of formula (I) according to claim 1, and a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from hydrogen, an optionally substituted alkyl group and a cycloalkyl group.

3. The compound of general formula (I) according to claim 1 or 2, and a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from hydrogen, an optionally substituted phenyl-substituted hydrocarbon group, an optionally substituted pyridyl-substituted hydrocarbon group, and an optionally substituted cycloalkyl group.

4. A compound of formula (I) according to any one of claims 1 to 3, and a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from hydrogen, an optionally substituted aryl-substituted alkyl, an optionally substituted heteroaryl-substituted alkyl and an optionally substituted cycloalkyl.

5. A compound of formula (I) according to any one of claims 1 to 4, and a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from hydrogen, an optionally substituted phenyl-substituted alkyl group, an optionally substituted pyridyl-substituted alkyl group, and an optionally substituted cycloalkyl group.

6. The compound of formula (I) according to any one of claims 1 to 5, and a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from hydrogen, benzyl, aminopyridylmethyl and cyclopropyl.

7. The compound of any one of claims 1 to 6, wherein R3 is selected from the group consisting of hydroxy, amino, and amino substituted with an optionally substituted hydrocarbon group, and a pharmaceutically acceptable salt thereof.

8. The compound of formula (I) according to any one of claims 1 to 7, and a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of hydroxy, amino, and amino substituted by a hydroxyl group.

9. The compound of formula (I) according to any one of claims 1 to 8, and a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of hydroxy, amino, and amino substituted with an optionally substituted alkyl group.

10. The compound of formula (I) according to any one of claims 1 to 9, and a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of hydroxy, amino, and amino substituted by an alkyl group substituted by a hydroxy.

11. The compound of general formula (I) according to any one of claims 1 to 10, and a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydroxyl, amino and hydroxyethylamino.

12. A compound of formula (I) as claimed in any one of claims 1 to 11, and a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, aryl, halogen-substituted aryl, optionally substituted alkyloxy-substituted aryl, heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted cycloalkyl-substituted heteroaryl and optionally substituted heterocyclyl-substituted heteroaryl.

13. A compound as shown in the general formula (I) according to any one of claims 1 to 12, and a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, phenyl, halogen-substituted phenyl, optionally substituted alkoxy-substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-substituted heteroaryl, optionally substituted cycloalkyl-substituted heteroaryl, and optionally substituted heterocycloalkyl-substituted heteroaryl.

14. A compound as shown in the general formula (I) according to any one of claims 1 to 13, and a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, phenyl, fluorine-substituted aryl, optionally substituted alkyloxy-substituted phenyl, heteroaryl, optionally substituted alkyl-substituted pyrazolyl, optionally substituted cyclohexyl-substituted heteroaryl, and optionally substituted oxacycloalkyl-substituted heteroaryl.

15. A compound as shown in the general formula (I) according to any one of claims 1 to 14, and a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from hydrogen, halogen, arbitrarily substituted alkyl, arbitrarily substituted cycloalkyl, phenyl, fluorophenyl, phenyl substituted by an alkoxy group, heteroaryl, pyrazolyl substituted by an arbitrarily substituted alkyl group, heteroaryl substituted by an arbitrarily substituted cyclohexyl group, heteroaryl substituted by an arbitrarily substituted oxacyclopentyl group, and heteroaryl substituted by an arbitrarily substituted azacyclohexyl group.

16. A compound of formula (I) according to any one of claims 1 to 15, and a pharmaceutically acceptable salt thereof, wherein R4 and R5 are each independently selected from hydrogen, halogen, methyl, phenylvinyl, cyclopropyl, phenyl, fluorophenyl, methoxyphenyl, pyridinyl, methylpyrazolyl, pyrrolo[1,2-b]pyrazolyl, cyclohexylpyrazolyl, oxolanylpyrazolyl, piperidinylpyrazolyl and Boc-piperidinylpyrazolyl.

17. The compound of formula (I) according to any one of claims 1 to 16, and a pharmaceutically acceptable salt thereof, wherein R6 is selected from hydrogen and an optionally substituted alkyl group.

18. The compound of formula (I) according to any one of claims 1 to 17, and a pharmaceutically acceptable salt thereof, wherein R6 is selected from hydrogen and methyl.

19. A compound of formula (I) as claimed in any one of claims 1 to 18, and a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently selected from hydrogen, an optionally substituted alkyl group substituted with an alkoxy group, an optionally substituted aryl group substituted with an alkyl group, a heterocyclic group, an aryl group, a halogen-substituted aryl group, a nitro-substituted aryl group, an optionally substituted alkyl group substituted with an aryl group, an optionally substituted alkyl group substituted with an aryl group, an optionally substituted alkyl group substituted with an aryl group, an optionally substituted alkyl group substituted with an aryl group, an optionally substituted alkyl group substituted with an aryl group, an optionally substituted alkyl group substituted with an aminocarbonyl group, an optionally substituted aminocarbonyl group substituted with an aryl group, an optionally substituted aryl group substituted with an aryl group, an optionally substituted heteroaryl group, a heteroaryl group, a halogen-substituted heteroaryl group, a cyano-substituted heteroaryl group, an optionally substituted alkyl group substituted with an heteroaryl group, an optionally substituted alkyl group substituted with an heteroaryl group, an optionally substituted aryl group substituted with an heteroaryl group, and an optionally substituted heteroaryl group substituted with an heteroaryl group.

20. The compound of any one of claims 1 to 19, and a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently selected from hydrogen, an optionally substituted alkoxy-substituted hydrocarbon group, an optionally substituted phenyl-substituted hydrocarbon group, a heterocyclic group, an aryl group, a halogen-substituted phenyl group, a nitro-substituted phenyl group, an optionally substituted alkyl-substituted aryl group, an optionally substituted alkenyl-substituted aryl group, an optionally substituted alkynyl-substituted aryl group, an optionally substituted alkoxy ... The invention also includes an optionally substituted aryl group, an optionally substituted aryl group substituted with alkylcarbonyl, an optionally substituted aminocarbonylaryl group, an optionally substituted benzylaminocarbonylaryl group, an optionally substituted benzylpyrazolylaminocarbonylaryl group, an optionally substituted phenyl-substituted aryl group, an optionally substituted pyridyl-substituted aryl group, a heteroaryl group, a fluorine-substituted heteroaryl group, a cyano-substituted heteroaryl group, an optionally substituted alkyl-substituted heteroaryl group, an optionally substituted alkoxy-substituted heteroaryl group, an optionally substituted phenyl-substituted heteroaryl group, and an optionally substituted pyridyl-substituted heteroaryl group.

21. A compound of formula (I) as claimed in any one of claims 1 to 20, and a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently selected from hydrogen, an optionally substituted alkyl group substituted with a hydrocarbyloxy group, an optionally substituted alkyl group substituted with an aryl group, a heterocyclic group, an aryl group, a halogen-substituted phenyl group, a nitro-substituted phenyl group, an optionally substituted alkyl group substituted with a hydrocarbyloxy group, an optionally substituted phenyl group substituted with a hydrocarbyloxy group, an optionally substituted aminocarbonyl phenyl group, an optionally substituted aminocarbonyl substituted phenyl group, an optionally substituted phenyl group, an optionally substituted phenyl group, an optionally substituted heteroaryl substituted phenyl group, a heteroaryl group, a fluorine-substituted heteroaryl group, a cyano-substituted heteroaryl group, an optionally substituted alkyl-substituted phenyl group, an optionally substituted alkyl-substituted pyridyl group, an optionally substituted alkyl-substituted pyridyl group, an optionally substituted alkyloxy-substituted pyridyl group, an optionally substituted alkyl-substituted pyrazolyl group, an optionally substituted quinolyl group, an optionally substituted aryl-substituted pyridyl group, an optionally substituted heteroaryl-substituted pyridyl group and an optionally substituted alkyl-substituted thiazolyl group.

22. The compound of any one of claims 1 to 21, and a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently selected from hydrogen, an alkyl group substituted by an optionally substituted alkoxy group, an alkyl group substituted by an optionally substituted phenyl group, a heterocyclic group, an aryl group, a phenyl group substituted by an optionally substituted alkyl group, a phenyl group substituted by an optionally substituted alkenyl group, a phenyl group substituted by an optionally substituted alkoxy group, an aminocarbonylphenyl group substituted by an optionally substituted benzyl group, an optionally substituted benzyloxyaminocarbonylphenyl group, an optionally substituted benzylpyrrolidone group, an optionally substituted phenyl ... oxazolyl-substituted aminocarbonylphenyl, optionally substituted phenyl-substituted phenyl, optionally substituted pyridyl-substituted phenyl, heteroaryl, fluorine-substituted heteroaryl, cyano-substituted heteroaryl, optionally substituted alkyl-substituted phenyl, optionally substituted alkyl-substituted pyridyl, optionally substituted alkoxy-substituted pyridyl, optionally substituted alkyl-substituted pyrazolyl, optionally substituted quinolyl, optionally substituted phenyl-substituted pyridyl, optionally substituted pyridyl-substituted pyridyl, cyano-substituted thienyl and optionally substituted alkyl-substituted pyrazolyl.

23. The compound of any one of claims 1 to 22, and a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently selected from hydrogen, trimethylsilylethoxymethyl, p-methoxybenzyl, oxacyclohexyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, 2-bromo-3-fluorophenyl, iodophenyl, nitrophenyl, isopropylphenyl, trifluoromethylphenyl, 3,5-difluoro-4-methoxyphenyl, vinylphenyl, ethynylphenyl, methoxyphenyl, 5-bromo-2-methoxyphenyl, methoxycarbonylphenyl, benzylaminocarbonylphenyl, benzylpyrazolylaminocarbonylphenyl phenyl, 3,5-difluoro-4-methoxyphenyl, naphthyl, pyridyl, fluoropyridyl, bromopyridinyl, methylpyridyl, trifluoromethylpyridyl, methoxypyridyl, trifluoromethylpyridyl, quinolyl, phenylpyridyl, 3,5-difluoro-4-methoxyphenylpyridyl, pyridylpyridyl, 1,3-benzodioxolan-5-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, methylpyrazolyl, 1-methyl-5-cyano-pyrazol-4-yl, cyanothienyl, and trifluoromethylthiazolyl.

24. The compound of formula (I) according to any one of claims 1 to 23, and its pharmaceutically acceptable salt, wherein R7 and R8 are each independently selected from hydrogen, 25. The compound of formula (I) according to any one of claims 1 to 18, and a pharmaceutically acceptable salt thereof, wherein R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted 1,3-dioxoisoindolyl group.

26. The compound of formula (I) according to any one of claims 1 to 25, and its pharmaceutically acceptable salt, wherein R9 and R 10 Each is independently selected from the group consisting of hydrocarbon groups, optionally substituted aryl-substituted hydrocarbon groups, optionally substituted aryl-substituted hydrocarbonoxy groups, optionally substituted hydrocarbonoxy groups, cycloalkyl groups, aryl groups, halogen-substituted aryl groups, optionally substituted alkyl-substituted aryl groups, optionally substituted hydrocarbonoxy-substituted aryl groups, and heteroaryl groups.

27. The compound of formula (I) according to any one of claims 1 to 26, and its pharmaceutically acceptable salt, wherein R9 and R 10 Each is independently selected from a hydrocarbon group, an optionally substituted phenyl-substituted hydrocarbon group, an optionally substituted fluorenyl-substituted hydrocarbonoxy group, an optionally substituted alkyl-substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an aryl group, a fluorine-substituted aryl group, an optionally substituted alkyl-substituted aryl group, an optionally substituted alkoxy-substituted aryl group, and a heteroaryl group.

28. The compound of formula (I) according to any one of claims 1 to 27, and its pharmaceutically acceptable salt, wherein R9 and R 10 Each is independently selected from optionally substituted alkyl, optionally substituted aryl-substituted alkyl, optionally substituted alkenyl, optionally substituted aryl-substituted alkoxy, optionally substituted alkyl-substituted alkoxy, cycloalkyl, optionally substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkyloxy-substituted phenyl, optionally substituted furyl, optionally substituted thienyl, optionally substituted pyridyl and optionally substituted benzofuranyl.

29. The compound of any one of claims 1 to 28, and its pharmaceutically acceptable salt, wherein R9 and R 10 Each is independently selected from alkyl, optionally substituted phenyl-substituted alkoxy, optionally substituted fluorenyl-substituted alkoxy, optionally substituted phenyl-substituted alkyl, alkenyl, optionally substituted phenyl-substituted alkenyl, optionally substituted alkyl-substituted alkoxy, optionally substituted fluorenyl-substituted alkoxy, optionally substituted cyclopropyl, optionally substituted cyclohexyl, halogen-substituted phenyl, optionally substituted alkyl-substituted phenyl, optionally substituted alkoxy-substituted phenyl, furyl, chlorothienyl, thienyl, pyridyl and benzofuranyl.

30. The compound of formula (I) according to any one of claims 1 to 29, and its pharmaceutically acceptable salt, wherein R9 and R 10 Each is independently selected from methyl, benzyl, benzyloxy, vinyl, fluorenylmethoxy, tert-butoxy, styryl, propenyl, cyclopropyl, cyclohexyl, phenyl, fluorophenyl, tolyl, methoxyphenyl, furyl, thienyl, chlorothienyl, pyridyl and benzofuranyl.

31. The compound of formula (I) according to any one of claims 1 to 30, and a pharmaceutically acceptable salt thereof, wherein X is CH.

32. A compound, and a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

33. A pharmaceutical composition comprising the compound of general formula (I) according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or the compound according to claim 201 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

34. The pharmaceutical composition of claim 33, prepared as a tablet, solution, granule, patch, ointment, gel, capsule, aerosol or suppository for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral administration.

35. A method for preparing a compound represented by general formula (Ia), It involves carrying out the reaction shown below: in: R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; Y is hydrogen or absent; and LG is selected from O, OH, halogen, diarylphosphono, OTs, OMs, OTf.

36. The method of claim 35, when LG is selected from O, wherein the reaction is carried out under mild conditions.

37. The method of claim 35, when LG is selected from OH, wherein the reaction is carried out under Mitsunobu reaction conditions.

38. The method according to any one of claims 35 to 37, wherein the reagent used in the Mitsunobu reaction conditions is selected from the group consisting of organophosphides and Mitsunobu reagents.

39. The method of claim 38, wherein the organic phosphorus compound is triphenylphosphine.

40. The method of claim 38, wherein the Mitsunobu reagent is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or any mixture thereof.

41. The method according to any one of claims 35 to 40, wherein when LG is selected from halogen, diarylphosphono, OTs, OMs, OTf, the reaction is carried out in the presence of a base, wherein the base is selected from an alkali metal salt, an organic base, or any mixture thereof; the alkali metal salt is preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof; the alcohol is preferably methanol, ethanol, or tert-butanol; the organic base is preferably triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

42. A method for preparing a compound represented by general formula (Ib), It involves carrying out the reaction shown below: in: R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; and Y is hydrogen or absent.

43. The method of claim 42, wherein the reaction is carried out in the presence of a metal and an acidic substance.

44. The method of claim 42, wherein the reaction is carried out in the presence of a metal and hydrogen.

45. The method of claim 43 or 44, wherein the metal is selected from iron, cobalt, nickel, palladium, rhodium or any mixture thereof.

46. ​​The method according to claim 43 or 45, wherein the acidic substance is selected from an inorganic acid, an organic acid, an acid salt, or any mixture thereof. The inorganic acid is preferably hydrochloric acid, hydrobromic acid, phosphoric acid, or any mixture thereof; the organic acid is preferably formic acid, acetic acid, trifluoroacetic acid, or any mixture thereof; and the acid salt is preferably ammonium chloride, ammonium acetate, ammonium phosphate, or any mixture thereof.

47. A method for preparing a compound represented by general formula (Ic), It involves reacting a compound represented by general formula (Ib): in: R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; Y is hydrogen or absent; and M is selected from alkali metals.

48. The process of claim 47, wherein the process is performed in the presence of a base.

49. The method of claim 48, wherein the base is selected from an alkali metal salt, an organic base or any mixture thereof, preferably sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO) or any mixture thereof.

50. A method for preparing a compound represented by general formula (Id), It comprises reacting a compound represented by general formula (Ic): in: R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; and Y is hydrogen or absent.

51. The process of claim 50, wherein the process is performed in the presence of an acid.

52. The method of claim 51, wherein the acid is selected from an inorganic acid, an organic acid, a Lewis acid, or any mixture thereof. The inorganic acid is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, or any mixture thereof; the organic acid is preferably formic acid, acetic acid, trifluoroacetic acid, an optionally substituted benzenesulfonic acid, or any mixture thereof; and the Lewis acid is preferably boron trifluoride etherate, boron trichloride, boron tribromide, titanium tetrachloride, tetraisopropyl titanate, aluminum chloride, zinc chloride, ferric chloride, or any mixture thereof.

53. A method for preparing a compound represented by general formula (Ie), It involves reacting a compound represented by general formula (Id): in: R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 is selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; and Y hydrogen or not present.

54. The process of claim 53, wherein the process is performed with an alkyl halide in the presence of a base.

55. The method of claim 54, wherein the base is selected from an alkali metal salt, an organic base or any mixture thereof, preferably sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO) or any mixture thereof.

56. The method of claim 54 or 55, wherein the halogen on the alkyl halide is selected from fluorine, chlorine, bromine, and iodine; and the alkyl group on the alkyl halide is selected from optionally substituted hydrocarbon groups, optionally substituted cycloalkyl groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups.

57. A method for preparing a compound represented by general formula (I), It comprises reacting a compound represented by general formula (Ie): in: R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group; R3 is selected from hydroxy and optionally substituted amino; R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; Y is hydrogen or absent; and FC is selected from O, OH, halogen, diarylphosphono, OTs, OMs and OTf.

58. The process of claim 57, wherein FC is selected from halogen, diarylphosphono, OTs, OMs and OTf, wherein the reaction is carried out in the presence of a base.

59. The method of claim 58, wherein the base is selected from an alkali metal salt, an organic base, or any mixture thereof; the alkali metal salt is preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof, wherein the alcohol is preferably methanol, ethanol, or tert-butanol; the organic base is preferably triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

60. The method of claim 57, when FC is selected from OH, wherein the reaction is carried out under Mitsunobu reaction conditions.

61. The method of claim 60, wherein the reagent used in the Mitsunobu reaction conditions is selected from the group consisting of organic phosphides and Mitsunobu reagents.

62. The method of claim 61, wherein the organophosphorus compound is triphenylphosphine.

63. The method of claim 61, wherein the Mitsunobu reagent is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or any mixture thereof.

64. The method of claim 57, when LG is selected from O, wherein the reaction is carried out in the presence of an acid and a reducing substance.

65. The method of claim 64, wherein the acidic substance is selected from an inorganic acid, an organic acid, an acid salt or any mixture thereof; the inorganic acid is preferably hydrochloric acid, hydrobromic acid, phosphoric acid or any mixture thereof; the organic acid is preferably formic acid, acetic acid, trifluoroacetic acid or any mixture thereof; the acid salt is preferably ammonium chloride, ammonium acetate, ammonium phosphate or any mixture thereof.

66. The method of claim 64, wherein the reducing substance is selected from an inorganic salt, an organic boron compound, and an organic silicon compound; the inorganic salt is preferably lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triethoxyborohydride, or any mixture thereof; the organic boron compound is preferably borane dimethyl sulfide, borane tetrahydrofuran, N,N-diethylphenylborane, pinacol borane, catechol borane, 9-borabicyclo[3.3.1]nonane, or any mixture thereof; the organic silicon compound is preferably triethoxysilane, triethylsilane, phenyldimethylsilane, or any mixture thereof.

67. A method for preparing a compound represented by general formula (I), It involves reacting a compound represented by the general formula (If): in: R1 and R2 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group; R3 is selected from hydroxy and optionally substituted amino; R4 and R5 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R6 is selected from hydrogen and optionally substituted hydrocarbon groups; R7 and R8 are each independently selected from hydrogen, halogen, optionally substituted hydrocarbon, optionally substituted cycloalkyl, optionally substituted heterocyclic, -COR9, -SO2R 10 , optionally substituted aryl and optionally substituted heteroaryl; or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl; R9 and R 10 Each is independently selected from an optionally substituted hydrocarbon group, an optionally substituted hydrocarbonoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group and an optionally substituted heteroaryl group; X is selected from CH or N; and LG' is selected from OH, halogen, diarylphosphono, OTs, OMs and OTf.

68. The method of claim 67, when LG' is selected from OH, wherein the reaction is carried out under Mitsunobu reaction conditions.

69. The method of claim 68, wherein the reagent used in the Mitsunobu reaction conditions is selected from the group consisting of organic phosphides and Mitsunobu reagents.

70. The method of claim 69, wherein the organic phosphorus compound is triphenylphosphine.

71. The method of claim 69, wherein the Mitsunobu reagent is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or any mixture thereof.

72. The method of claim 67, wherein LG' is selected from halogen, diarylphosphono, OTs, OMs, or OTf, and the reaction is carried out in the presence of a base, wherein the base is selected from an alkali metal salt, an organic base, or any mixture thereof; the alkali metal salt is preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium alkoxide, sodium alkoxide, potassium alkoxide, or any mixture thereof; the alcohol is preferably methanol, ethanol, or tert-butanol; and the organic base is preferably triethylamine, N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), or any mixture thereof.

73. A method for treating or preventing a disease or disease state caused by a tumor, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, a compound according to claim 32 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33 or 34.

74. The method of claim 73, wherein the subject is a mammal, preferably a human.

75. The method of claim 73 or 74, wherein the tumor is selected from the group consisting of lymphoma, blastoma, sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, lymphoid malignancies, lung cancer, squamous cell lung cancer, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancer, and hematological malignancies.

76. The method of any one of claims 73 to 75, wherein a tumor-induced disease or condition is treated or prevented by inhibiting dihydrofolate reductase (DHFR).

77. The method of any one of claims 73-77, further comprising administering to the subject an additional active agent.

78. The method of claim 77, wherein the active agent is selected from the group consisting of nitrogen mustards, aziridines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors, anticancer vaccines, acivicin, aclarubicin, acodazole hydrochloride, aclonine, adolesin, aldesleukin, amblycins, amenanthrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, trilinomycin, azacitidine, azatepa, azotocin, batimastat, benzotepa, bicalutamide, bisantrene hydrochloride, binafadol mesylate, bisezole, bleomycin sulfate, busulfan, actinomycin C, captestosterone, caracetamide, carbetamol, carboplatin, carmustine, carrubicin hydrochloride, phenylbutyrate Mustard, cyromycin, cladribine, clinatol mesylate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, epirubicin hydrochloride, esorubicin hydrochloride, estramustine, etanercept, etoposide, floxuridine, fluorouracil, flucitabine, gemcitabine, idarubicin hydrochloride, ifosfamide, interleukin oxaliplatin, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, chlorpheniramine, selenomethoxazole, mitoxantrone, paclitaxel, procarbazine, thiotepa, vinblastine, vincristine, angiogenesis inhibitors, camptothecin, dexamethasone, aspirin, acetaminophen, indomethacin, ibuprofen, ketoprofen, meloxicam, corticosteroids, and adrenocortical steroids.

79. A method for treating or preventing a disease or condition caused by a microbial infection, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, a compound according to claim 32 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33 or 34.

80. The method of claim 79, wherein the subject is a mammal, preferably a human.

81. The method of claim 79 or 80, wherein the microorganism is selected from the group consisting of pathogenic bacteria, fungi, nematodes, and viruses.

82. The method of claim 81, wherein the pathogenic bacteria are selected from the group consisting of Gram-positive bacteria, Gram-negative bacteria, and pathogenic bacteria that cannot be stained.

83. The method of claim 82, wherein the Gram-positive bacteria is selected from the group consisting of Bacillus, Clostridium, Corynebacterium, Enterococcus, Listeria, Staphylococcus, and Streptococcus.

84. The method of claim 82, wherein the Gram-positive bacteria is selected from the group consisting of Bacillus anthracis, Bacillus cereus, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, and their corresponding drug-resistant strains.

85. The method of claim 82, wherein the Gram-negative bacteria is selected from the group consisting of Bartonella, Bordetella, Borrelia, Brucella, Campylobacter, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Treponema, Vibrio, and Yersinia.

86. The method of claim 82, wherein the Gram-negative bacteria is selected from the group consisting of Bartonella henslera, Bartonella quinquefasciatus, Borrelia pertussis, Borrelia burgdorferi, Borrelia californica, Borrelia afzalii, Borrelia relapsing fever, Brucella abortus, Brucella canis, Brucella malta, Brucella suis, Campylobacter jejuni, Escherichia coli, Francisella toulonis, Haemophilus influenzae, Helicobacter pylori, Legionella, Leptospira renalis, Leptospira santorum, Leptospira welchii, Leptospira noguchi, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, Treponema pallidum, Vibrio cholerae, Yersinia pestis, Yersinia colitis, Yersinia pseudotuberculosis, and their corresponding drug-resistant strains.

87. The method of claim 82, wherein the non-staining pathogenic bacteria are selected from the group consisting of Chlamydia and Chlamydia, Mycobacterium, and Mycoplasma.

88. The method of claim 82, wherein the pathogenic bacteria that will not be stained are selected from Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia felis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma pneumoniae, and corresponding drug-resistant strains thereof.

89. A compound of formula (I) according to any one of claims 1 to 31 and a pharmaceutically acceptable salt thereof, or a compound according to claim 32 and a pharmaceutically acceptable salt thereof, for use in inhibiting dihydrofolate reductase (DHFR).

90. Use of a compound of formula (I) according to any one of claims 1 to 31 and a pharmaceutically acceptable salt thereof, or a compound according to claim 32 and a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting dihydrofolate reductase (DHFR).

91. Use of a compound of formula (I) according to any one of claims 1 to 31 and a pharmaceutically acceptable salt thereof, or a compound according to claim 32 and a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or condition mediated by dihydrofolate reductase (DHFR).

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