A condensed ring compound, a method for preparing the same, and a use thereof

Abstract

The application belongs to the technical field of chemical medicines, and provides a fused ring compound, a preparation method and application thereof. The compound provided by the application can effectively regulate the activity of human TNF alpha, and can be used for treating or preventing rheumatoid arthritis and psoriasis.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a fused-ring compound, its preparation method, and its uses. Background Technology

[0002] TNFα is a pleiotropic cytokine produced by activated macrophages, monocytes, and lymphocytes. It is a typical member of the tumor necrosis factor (TNF) protein superfamily, and its main function is to regulate cell survival and cell death. A common structural feature of all known members of the TNF superfamily is the formation and activation of a trimeric complex that binds to specific TNF superfamily receptors. TNFα exists in a soluble and transmembrane form and signals through two receptors with different functional endpoints (TNFR1 and TNFR2).

[0003] TNFα is a potent mediator of inflammatory and immune responses, including recruiting leukocytes to damaged tissues during bacterial and other microbial infections and after stimulation by inflammatory substances. When present in excess, TNFα is known to cause tissue damage and is associated with pathologies related to inflammation and autoimmune diseases. The pathological effects of TNFα can be mitigated by administration of soluble TNFR fragments or anti-TNFα antibodies. Typical macromolecular inhibitors of TNFα include anti-TNFα antibodies and soluble TNFR fusion proteins. Examples of commercially available anti-TNFα antibodies include fully human antibodies (e.g., adalimumab). and golimumab ), chimeric antibodies (e.g., infliximab) ) and PEGylated Fab' fragments (e.g., cetrus zucchini pegol) An example of a commercially available soluble TNFR fusion protein is etanercept. These drugs bind to circulating TNF-α, thereby preventing TNF-α from binding to TNFR and reducing TNF-α signaling, thus effectively treating TNF-α-mediated conditions. However, the aforementioned drugs are expensive to produce, and these protein drugs need to be administered intravenously.

[0004] Most reported TNFα activity modulators are macromolecules, with very few small-molecule TNFα activity modulators. For example, patents WO2013186229A1 and WO2018197503A1 disclose a small-molecule TNFα activity modulator. However, there are currently no commercially available small-molecule TNFα activity modulators. Therefore, there is an urgent need to provide more small-molecule drugs for the treatment of TNFα-mediated diseases. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a fused ring compound that can effectively regulate the activity of human TNFα.

[0006] This invention is achieved through the following technical solution: This invention provides a fused-ring compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, the structure of which is shown in general formula (I):

[0007]

[0008] in:

[0009] X is selected from: substituted or unsubstituted. The m is selected from an integer of 1, 2, 3, or 4; the R4 or R5 is independently selected from: H, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0010] The R3 is selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C5-C 12 Spirocycloalkyl, substituted or unsubstituted 5-12 membered spiroheterocycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C 12 Aryl;

[0011] The Y is selected from: carbonyl, sulfone, or sulfoxide;

[0012] The R1 is selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C5-C 12 Spirocycloalkyl, substituted or unsubstituted 5-12 membered spiroheterocycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C 12 Aryl;

[0013] The Q is independently selected from: N or CR6;

[0014] The U is independently selected from: N or CR7;

[0015] The W is independently selected from: N or CR8;

[0016] Each of R6, R7, or R8 is independently selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0017] The R2 is selected from: substituted or unsubstituted C5-C. 12 Spirocycloalkyl, substituted or unsubstituted 5-12 membered spiroheterocycloalkyl;

[0018] The substituents referred to as "substitution" are all independently selected from: -OH, oxo, halogen, -NH2, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino, -CN, -COOH, -SO3H, aminoC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups.

[0019] Furthermore, as a preferred embodiment of the present invention, the fused-ring compound has the structure shown in general formula (II):

[0020]

[0021] R9 is independently selected from: -OH, C1-C6 hydroxyalkyl, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino or -CN;

[0022] The R 10 R 11 Together with the attached carbon atom, they form substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted 3-8 membered heterocyclic alkyl groups;

[0023] The definitions of R1, R3, Q, X, Y, U, and W are the same as those in general formula (I).

[0024] Furthermore, as a preferred embodiment of the present invention, the fused ring compound of the present invention has a structure shown in general formula (IIA) or general formula (IIB): Among them, R1, R3, R9, R 10 R 11 The definitions of Q, X, Y, U and W are the same as those in general formula (II).

[0025] Furthermore, as a preferred embodiment of the present invention, X is independently selected from: -CH2-, -CH2CH2-, -CH(CH3)-;

[0026] R3 is selected from: H, C 1-6 alkyl;

[0027] The Y is selected from: carbonyl;

[0028] R1 is selected from: H, halogens;

[0029] The Q is independently selected from: CH;

[0030] The U is independently selected from: N;

[0031] The W is independently selected from: N;

[0032] R9 is independently selected from: -OH, -NH2, or -CN;

[0033] The R 10 R 11 Together with the attached carbon atom, they form substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted 3-8 membered heterocyclic alkyl groups.

[0034] Furthermore, as a preferred embodiment of the present invention, the C3-C8 cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0035] The 3-8 membered heterocyclic alkyl group is selected from: oxobutyranyl, azaheptacyclic alkyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydroimidazoyl, tetrahydropyrazoleyl, tetrahydrothiazoyl, tetrahydroisothiazoyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazine, morpholinyl, hexahydropyrimidinyl, or thiomorpholinyl; the substituent group of the "substituted" group is selected from: oxo, halogen, -OH, -CN, -NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino, and aminoC1-C6 alkyl.

[0036] Preferably, the substituted 3-8 membered heterocyclic alkyl group is selected from: substituted or unsubstituted γ-butyrolactone group, substituted or unsubstituted γ-butyrolactam group, substituted or unsubstituted δ-valerolactone group or substituted or unsubstituted δ-valerolactone group;

[0037] Furthermore, as a preferred embodiment of the present invention, the substituted or unsubstituted C3-C8 cycloalkyl group is selected from: The R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Or R 21All are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0038] The substituted or unsubstituted 3-8 membered heterocyclic alkyl groups are selected from:

[0039]

[0040] The V is independently selected from: -O-, -S-, -C(O)-, or -N(R). 22 )-;

[0041] The Z is independently selected from: -O-, -S-, -C(O)-, -N(R)-. 23 - or -C(R) 24 (R) 25 )-;

[0042] The R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 Or R 25 All are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0043] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0044]

[0045] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0046]

[0047] The V is independently selected from: -O-, -S-, -C(O)-, or -N(R)-. 22 )-;

[0048] The Z is independently selected from: -O-, -S-, -C(O)-, -N(R)-. 23 - or -C(R) 24 (R) 25 )-;

[0049] The R 22 R 23 R 24 Or R 25 All are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0050] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0051]

[0052] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0053]

[0054] The V is independently selected from: -O-, -S-, -C(O)-, or -N(R)-. 22 )-;

[0055] The R 22 Independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0056] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0057]

[0058] The V is independently selected from: -O-, -S-, -C(O)-, or -N(R)-. 22 )-;

[0059] The R 22 Independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0060] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0061]

[0062] Furthermore, as a preferred embodiment of the present invention, the R... 10 R 11 It forms together with the carbon atoms it is attached to:

[0063]

[0064] Furthermore, as a preferred embodiment of the present invention, the fused ring compound is selected from:

[0065]

[0066] Furthermore, as a preferred embodiment of the present invention, the fused ring compound is selected from:

[0067]

[0068]

[0069] Furthermore, the present invention also provides a pharmaceutical composition comprising a fused-ring compound of formula (I), formula (II), formula (IIA) or formula (IIB), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0070] Furthermore, the present invention also provides the use of a fused-ring compound comprising formula (I), formula (II), formula (IIA) or formula (IIB), or an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), formula (II), formula (IIA) or formula (IIB) in the preparation of a compound for the prevention or treatment of TNFα-related diseases.

[0071] Furthermore, as a preferred embodiment of the present invention, the TNFα-related diseases are selected from: rheumatoid arthritis and psoriasis.

[0072] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations;

[0073] In the chemical structure of the compound described in this invention, the bond... This indicates that the key can be a single key. or double bond

[0074] In the chemical structure of the compounds described in this disclosure, the bonds... The configuration is not specified, meaning it can be either Z configuration or E configuration, or both configurations can be included simultaneously;

[0075] In the chemical structure of the compound described in this invention, the bond... Indicates a connection key;

[0076] The compounds and intermediates of the present invention may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibrium are between A and B as shown below.

[0077]

[0078] All compounds in this invention may be designated as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0079] For clarity, this article defines the general terminology used in the description of compounds.

[0080] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0081] The term "alkyl" refers to a branched, unbranched, or cyclic saturated hydrocarbon chain containing a specified number (1-20) of carbon atoms. The alkyl group is preferably C16-20. 1- C6 alkyl, the C 1- The number of carbon atoms in a C6 alkyl group is selected from 1, 2, 3, 4, 5, or 6, wherein the C... 1-C6 alkyl groups are preferably C1-C2, C1-C3, C1-C4, or C1-C5 alkyl groups; examples of such alkyl groups include: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0082] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above, and non-limiting examples of hydroxyalkyl groups include: -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)2, -CHOHCH2OH, etc.

[0083] The term "halogenated alkyl" means that the hydrogen atom on the alkyl group can be replaced by one or more halogen atoms, preferably C16. 1- C6 haloalkane, wherein the C 1- The number of carbon atoms in the C6 haloalkyl group is selected from 1, 2, 3, 4, 5, or 6, wherein the C... 1- C6 haloalkyl groups are preferably C1-C2, C1-C3, C1-C4, or C1-C5 haloalkyl groups; examples of such haloalkyl groups include: -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF3, -CCl3, -CHFCH2F, -CHClCH2F, -CF2CHF2, -CH2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CH2CF2CHF2, -CCl2CHCl2, -CH2CH Cl2, -CH2CCl3, -CHClCH3, -CH2CH2Cl, -CCl2CH3, -CH2CCl2CHCl2, -CH2Br, -CHBr2, -CHBr2, -CBr3, -CHBrCH2Br, -CHClCH2F, -CBr2CHBr2, -CH2CHBr2, -CH2CBr3, -CHBrCH3, -CH2CH2Br, -CBr2CH3, -CH2CBr2CHBr2, etc., in one embodiment, C 1- C6 haloalkyl groups include C6 groups with fluorine substitution. 1- C6 alkyl, chlorinated C 1- C6 alkyl, bromine-substituted C 1- C6 alkyl, in one embodiment, C 1- C6 haloalkyl groups include C6 groups with fluorine substitution. 1- C6 alkyl; in another embodiment, C 1- C4 haloalkyl groups include C4 groups with fluorine substitution. 1-C4 alkyl; in another embodiment, C 1- C3 haloalkyl groups include C3 fluorinated alkyl groups. 1- C3 alkyl.

[0084] The term "aminoalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an amino group, wherein the definition of alkyl is as described above. Preferably, the aminoalkyl group is an aminoC1-C6 alkyl group, an aminoC1-C5 alkyl group, an aminoC1-C4 alkyl group, an aminoC1-C3 alkyl group, or an aminoC1-C2 alkyl group. Examples of the aminoalkyl group include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, -CH(NH2)2, -CHNH2CH2NH2, -CH2CH(NH2)2, -CH2CH2NH2CH3, -CH2CH(NH2)2CH3, -CH2CH2CH(NH2)2, -CHNHCHNHCH3, -CH2CHNHCH2NH2, etc.

[0085] The term "alkylamine" refers to a -NHR group, where R is an alkyl group as defined above, preferably, the alkylamine group is C. 1- C6 alkylamine group, C 1- C5 alkylamine group, C 1- C4 alkylamine group, C 1- C3 alkylamine group, C 1- C2 alkylamine, examples of which include, but are not limited to: methylamino, ethylamino, propylamino, 2-propylamino, tert-butylamino, n-butylamino, isobutylamino, sec-butylamino, n-pentanamino, sec-pentanamino, tert-pentanamino, isopentanamino, neopentanamino, n-hexylamino, isohexylamino, 1,1-dimethylbutylamino, 3,3-dimethylbutane-1-amino.

[0086] The term "dialkylamine" refers to a group having the structure -NRR', where R and R' are each independently an alkyl group as defined herein. R and R' may be the same or different in the dialkylamino moiety. Preferably, the dialkylamine is a bis(C1-C6)amine, bis(C1-C5)amine, bis(C1-C4)amine, bis(C1-C3)amine, or bis(C1-C2)amine. Examples of dialkylamines include, but are not limited to, dimethylamine, N-methylethylamine, diethylamine, N-methylpropyl-1-amine, di-n-propylamine, diisopropylamine, dicyclopropylamine, di-n-butylamine, di-tert-butylamine, di-neopentylamine, di-n-pentylamine, di-hexylamine, dicyclohexylamine, etc. In some embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0087] The term "alkoxy" refers to an alkyl group in which one or more carbon atoms are replaced by oxygen, such as -O-(alkyl), wherein the definition of alkyl is as described above. The number of carbon atoms in the C1-C6 alkoxy group is selected from 1, 2, 3, 4, 5 or 6, and the alkoxy group is preferably C1-C6 alkoxy. The C1-C6 alkoxy group is preferably C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy. Further, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0088] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are substituted by halogens; the haloalkoxy group is preferably C64-C ... 1- C6 haloalkoxy group, wherein the C 1- The number of carbon atoms in the C6 haloalkoxy group is selected from 1, 2, 3, 4, 5, or 6, wherein the C... 1- The preferred C6 haloalkoxy group is a C1-C2, C1-C3, C1-C4, or C1-C5 haloalkoxy group. Further, the haloalkoxy group is specifically selected from -OCHF2, -OCHCl2, -OCHBr2, -OCF3, -OCCl3, -OCBr3, -OCH2CH2F, -OCH2CH2Cl, -OCHFCH2F, -OCHClCH2F, -OCHBrCH2F, -OCF2CHF2, -OCH2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, - OCF2CH3, -OCH2CF2CHF2, -OCCl2CHCl2, -OCH2CHCl2, -OCH2CCl3, -OCHClCH3, -OCH2CH2Cl, -OCCl2CH3, -OCH2CCl2CHCl2, -OCH2CH2Br, -OCBr2CHBr2, -OCH2CHBr2, -OCH2CBr3, -OCHBrCH3, -OCH2CH2Br, -OCBr2CH3, -OCH2CBr2CHBr2, etc., in one embodiment, C 1- C6 haloalkoxy groups include C with fluorine substitution. 1- C6 alkoxy, chlorinated C 1- C6 alkoxy, bromine-substituted C 1- C6 alkoxy; in another embodiment, C 1- C4 haloalkyl groups include C4 groups with fluorine substitution. 1- C4 alkoxy; in yet another embodiment, C 1- C3 haloalkyl groups include C3 fluorinated alkyl groups. 1- C3 alkoxy group.

[0089] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic hydrocarbon ring structure having a specified number of ring atoms, wherein the cycloalkyl group is preferably C16. 3- C8 cycloalkyl, the C 3- C8 cycloalkyl groups are C3, C4, C5, C6, C7, or C8 cycloalkyl groups having 3 to 8 carbocyclic members, wherein the C 3- C8 cycloalkyl groups are preferably derived from: C 3- C7 cycloalkyl, C 3- C6 cycloalkyl, C 3- C5 cycloalkyl or C 3- In one embodiment, the cycloalkyl group is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0090] The term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms independently selected from N, O, and S; the number of heteroatoms is 1, 2, 3, or 4; the heterocyclic alkyl group is preferably a 3-10 membered heterocyclic alkyl group; the number of carbon atoms in the 3-10 membered heterocyclic alkyl group is selected from 2, 3, 4, 5, 6, 7, 8, or 9, and the 3-10 membered heterocyclic alkyl group is preferably selected from: 3-9 membered heterocyclic alkyl groups, 3-8 membered heterocyclic alkyl groups, 3-7 membered heterocyclic alkyl groups, 3-6 membered heterocyclic alkyl groups, 3-5 membered heterocyclic alkyl groups, or 3-4 membered heterocyclic alkyl groups. In one embodiment, examples of the heterocyclic alkyl group include, but are not limited to: aziridine propane, ethylene oxide, aziridine butane, oxadiazine, and pyrrolidine. Tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine, diazacycloheptyl, high-piperazinyl, oxaziridine, thiazoyl, 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,6-diaza-spiro[3.3]heptyl. More specific examples of heterocyclic alkyl groups are pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirheptanyl, diazaheptanyl, high-piperazinyl, oxazheptanyl, thiazolyl and 2,6-diaza-spiro[3.3]heptyl.

[0091] The term "oxoheterocyclic alkyl" refers to a heterocyclic alkyl group in which one or two carbon atoms are replaced by a bridging oxygen (C=O) group. Examples of such oxoheterocyclic alkyl groups include, but are not limited to: 2- or 3-oxopyrrolidone-1-yl, 2,3- or 4-oxopyridinyl-1-yl, 3-oxomorpholino-4-yl, 2-oxo-piperazinyl-1-yl, 2-oxotetrahydropyran-3-yl, 3-oxothiomorpholino-4-yl, and 2-imidazolidineone-1-yl.

[0092] The term "aryl" refers to a set of 6- to 14-membered monocyclic or polycyclic aromatic rings, in which all ring atoms are carbon atoms. Generally, aryl groups are 6-membered monocyclic, 10- to 12-membered bicyclic, or 14-membered fused tricyclic aromatic ring systems. The C4 group used in this paper... A Aryl and C A-B The aryl group indicates that A and B represent the number of carbon atoms in the ring system. The aryl group is preferably C6-C. 12 Aryl, further preferred: C6-C 10 Aryl, C6-C8 aryl, or C6-C7 aryl; in one embodiment, the aryl group is specifically selected from phenyl, naphthyl, anthraceneyl, phenanthrene, etc.

[0093] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure comprising one or more (preferably 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, and a specified number of carbon atoms. Specifically, the aromatic ring structure may have 5 to 12 ring members. The heteroaryl is preferably a 5- to 12-membered heteroaryl, more preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 8-membered heteroaryl, and most preferably a 5-, 6-, 7-, or 8-membered heteroaryl. The heteroaryl may be, for example, a five- or six-membered monocyclic ring or a fused bicyclic structure formed by fused five- and six-membered rings or two fused six-membered rings or, as another example, two fused five-membered rings. Each ring may contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. The heteroaryl ring typically contains up to four heteroatoms, more typically up to three heteroatoms, and more typically up to two heteroatoms, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl ring (including any amino substituents in the ring) will be less than five.

[0094] Examples of five-membered monocyclic heteroaryl groups include (but are not limited to) pyrrole, furanyl, thiophene, imidazolyl, furazonyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl. Examples of six-membered monocyclic heteroaryl groups include (but are not limited to) pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include (but are not limited to) imidazothiazolyl and imidazothiazolyl. Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include (but are not limited to) benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, purine (e.g., adenine, guanine), indazoleyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl. Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include (but are not limited to) quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cenolinyl, phthalazinyl, naphthidyl, and pteridinyl. The specific heteroaryl group is those heteroaryl groups derived from thienyl, pyrroleyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.

[0095] The term "halogen" is selected from F, Cl, Br, or I;

[0096] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which the rings are linked by a common carbon atom (called the spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spirocycloalkyl group is 5- to 12-membered, and more preferably 5- to 10-membered. Depending on the number of shared spiro atoms, spirocycloalkyl groups are classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or dispirocycloalkyl. Representative examples of monospirocycloalkyl groups include, but are not limited to, the following substituents:

[0097]

[0098] The term "heterospirocycloalkyl" refers to the aforementioned spirocycloalkyl containing at least one heteroatom selected from O, NH, and S, preferably containing at least one heteroatom of O or N. Preferably, the heterospirocycloalkyl is a 5-12-membered heterospirocycloalkyl, more preferably, the heterospirocycloalkyl is a 5-9-membered heterospirocycloalkyl. In some embodiments, the heterospirocycloalkyl is selected from 5-12-membered nitrogen-containing heterospirocycloalkyls, and in other embodiments, the heterospirocycloalkyl is selected from 5-9-membered nitrogen-containing heterospirocycloalkyls. Representative examples of nitrogen-containing heterospirocycloalkyls include, but are not limited to, the following substituents:

[0099]

[0100] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0101] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0102] The term "stereoisomer" refers to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0103] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0104] The term "racemate" refers to a mixture of two equimolar enantiomers that lack optical activity.

[0105] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0106] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0107] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0108] The term "one or more" means that there can be one or more substituents, preferably one, two, three, four, five or six; more preferably one, two or three.

[0109] The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the in vivo environment via chemical or biochemical methods.

[0110] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0111] The atoms in the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, stabilize metabolism, and enhance in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0112] For example, the compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0113] Furthermore, one or more hydrogen atoms in the compound of the present invention are coated with the isotope deuterium ( 2 The compounds of this invention, after being substituted with H), have the effects of prolonged half-life, reduced clearance rate, metabolic stabilization, and increased in vivo activity.

[0114] The preparation methods of the isotope derivatives typically include phase-transfer catalysis. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in the introduction of higher levels of deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0115] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0116] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0117] The advantages of this invention over the prior art include, but are not limited to:

[0118] The TNFα activity modulator of the present invention has a lower IC50 value compared with the prior art. 50 Values ​​and / or better pharmacokinetic characteristics. Detailed Implementation

[0119] The present invention will be further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0120] Example 1

[0121] Synthesis of (7R,14R)-11-(2-(2-aminospiro[3.3]heptane-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0122] The specific synthesis route is as follows:

[0123]

[0124] Step A: Synthesis of 2-bromo-6-(difluoromethoxy)benzaldehyde

[0125] The reaction is accomplished using fluid chemistry, with a two-phase feed, as detailed below:

[0126] Solution 1: At room temperature, 190 g (945 mmol) of 2-bromo-6-hydroxybenzaldehyde and 403 g (1.51 mmol) of diethyl bromodifluoromethylphosphonate were dissolved in 1.9 L of ethylene glycol dimethyl ether. The solution was injected into the reaction coil at a rate of 6 mL per minute using a syringe pump.

[0127] Solution 2: Dissolve 583 g (10.4 mol) of potassium hydroxide in 2.09 L of ice water at 10°C. Inject the solution into the reaction coil at a rate of 6 mL per minute using a pump.

[0128] The reaction mixture was collected after reacting in a coil for 8 minutes, and this process was continued until the reaction was complete. The reaction mixture was extracted with ethyl acetate (1000 mL × 3), the organic phases were combined, washed with saturated brine (1500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to give 143 g of 2-bromo-6-(difluoromethoxy)benzaldehyde. LCMS: RT = 0.490 min. 1 HNMR (400MHz, CDCl3) δ10.33(s,1H),7.56(dd,J=8.1,1.1Hz,1H),7.40(t,J=8.2Hz,1H),7.24(dd,J=8.3,1.2Hz,1H),6.60(t,J=73.4Hz,1H).

[0129] Step B: Synthesis of (S)-N-[(E)-[2-bromo-6-(difluoromethoxy)phenyl]methylethylene]-2-methylpropane-2-sulfinamide

[0130] At 0°C, 370 g (1.47 mol) of 2-bromo-6-(difluoromethoxy)benzaldehyde was dissolved in 2.59 L of tetrahydrofuran, and (S)-tert-butylsulfinamide (188 g, 1.55 mmol), potassium phosphate (939 g, 4.42 mol), and potassium dihydrogen phosphate (602 g, 4.42 mol) were added. The reaction mixture was stirred mechanically at room temperature for 16 h, and the reaction was monitored by LC-MS until complete. The reaction mixture was filtered, and the filter cake was washed twice with ethyl acetate (500 mL). The organic phases were combined and washed once each with water (1 L) and saturated saline solution (1 L). The organic phase was concentrated to give 512 g (S)-N-[(E)-[2-bromo-6-(difluoromethoxy)phenyl]methylethylene]-2-methylpropane-2-sulfinamide (512 g), which was used directly in the next reaction without further purification. LCMS:RT = 0.575 min, [M+H] + =353.9. 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),7.58(d,J=8.0Hz,1H),7.30-7.37(m,1H),7.21-7.27(m,1H),6.57(t,J=73.6Hz,1H),1.30(s,9H).

[0131] Step C: Synthesis of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propionate

[0132] Six batches were run in parallel. At room temperature, zinc powder (81.2 g, 1.24 mmol) was suspended in tetrahydrofuran (770 mL), and trimethylchlorosilane (6.75 g, 62.1 mmol) was added with stirring. The mixture was purged with nitrogen three times, heated to 50°C, and stirred for 30 minutes. After cooling to room temperature, cuprous chloride (36.9 g, 373 mmol) was added, and the mixture was heated to reflux and stirred for 30 minutes. The mixture was then cooled to 50°C. Ethyl bromoacetate (130 g, 776 mmol) was dissolved in tetrahydrofuran (440 mL) and slowly added dropwise to the mixture while maintaining the temperature below 55°C. After the addition was complete, the mixture was stirred for 30 minutes and then cooled to 0°C. (S)-N-[(E)-[2-bromo-6-(difluoromethoxy)phenyl]methylethylene]-2-methylpropane-2-sulfinamide (110 g, 311 mmol) was dissolved in tetrahydrofuran (440 mL) and added dropwise to the reaction solution. The mixture was allowed to warm naturally to room temperature and stirred for 8 hours, monitored by LC-MS until the reaction was complete. The reaction solution was diluted with water (1000 mL) and ethyl acetate (300 mL), filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (300 mL × 3), the organic phases were combined, washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propionate (491 g). LCMS:RT = 1.212 min, [M+H] + =442.1. 1 HNMR (400MHz, CDCl3) δ7.44(d,J=8.8Hz,1H),7.00-7.20(m,2H),6.61(t,J=73.2Hz,1H),5.59(brd,J=8 .0Hz,1H),4.21-4.46(m,1H),4.09-4.15(m,2H),2.88-3.35(m,2H),1.20(t,J=7.2Hz,3H),1.14(s,9H).

[0133] Step D: Synthesis of ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propionate

[0134] Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-{[(S)-2-methylpropane-2-sulfinyl]amino}propionate (491 g, 1.11 mol) was dissolved in ethanol (330 mL) and petroleum ether (660 mL) at room temperature, and dioxane hydrochloride solution (980 mL, 2 mol / L) was added. The reaction was carried out at room temperature for 2 hours. LCMS was monitored until the reaction was complete. The reaction solution was concentrated under vacuum to give ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propionate (472 g). This compound was used directly in the next reaction without further purification. LCMS: RT = 0.393 min, [M+H] + =337.9.

[0135] Step E: Synthesis of ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionate

[0136] Two batches were performed in parallel. Ethyl (3R)-3-amino-3-[2-bromo-6-(difluoromethoxy)phenyl]propionate (230 g, 614 mmol) was dissolved in acetonitrile (1840 mL) at room temperature, followed by the sequential addition of 4-chloro-2-fluoro-1-nitrobenzene (129 g, 737 mmol) and potassium carbonate (255 g, 1.84 mol). The mixture was heated to 80°C and reacted for 12 hours. After the reaction was monitored by LCMS until complete, the reaction solution was filtered, concentrated, and the residue was diluted with water (2000 mL) and ethyl acetate (1000 mL). The residue was extracted with ethyl acetate (1000 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to give ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionate (468 g). LCMS: RT = 2.29 min, [M+H] + =492.85.

[0137] Step F: Synthesis of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde

[0138] Ethyl (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionate (32.8 g, 66.4 mmol) was dissolved in toluene (328 mL) at room temperature, purged three times with nitrogen. The mixture was cooled to -70°C, and a toluene solution of diisobutylaluminum hydride (133 mL, 133 mmol, 1.0 M) was slowly added dropwise, maintaining this temperature with stirring for 2 hours. After the reaction was monitored by LCMS until complete, a saturated aqueous solution of ammonium chloride (500 mL) was added dropwise to quench the reaction completely. The mixture was extracted with ethyl acetate (300 mL × 3), and the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde (27 g). LCMS:RT = 2.21 min, [M+H] + =448.89.

[0139] Step G: Synthesis of (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxo]butyronitrile

[0140] At room temperature, the crude product of (3R)-3-[2-bromo-6-(difluoromethoxy)phenyl]-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde (27.0 g, 60.1 mmol) was dissolved in dichloromethane (500 mL), followed by the sequential addition of triethylamine (0.608 g, 6.00 mmol) and zinc iodide (1.92 g, 6.00 mmol), and finally the slow dropwise addition of trimethylcyanosilane (11.9 g, 120 mmol). The reaction was carried out at room temperature for 12 hours. LCMS was used to monitor the reaction until it was complete. The reaction was quenched with water (500 mL), and the aqueous phase was extracted with dichloromethane (300 mL × 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxo]butyronitrile (28 g). This compound was used directly in the next reaction without further purification. LCMS: RT = 2.29 min, [M+H] + =475.80.

[0141] Step H: Synthesis of (1R,3S)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol

[0142] At room temperature, crude (4R)-4-[2-bromo-6-(difluoromethoxy)phenyl]-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxo]butyronitrile (28.0 g, 51.0 mmol) was dissolved in ethanol (450 mL), and stannous chloride (48.4 g, 255 mmol) was added. The mixture was heated to 80 °C and reacted for 12 h. After the reaction was monitored by LCMS until complete, the reaction mixture was diluted with water (500 mL), and the pH of the system was adjusted to 9 with 1 M potassium hydroxide aqueous solution. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed successively with water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give (1R,3S)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (5.00 g). LCMS: RT = 1.067 min, [M+H] + =429.1.

[0143] Step I: Synthesis of (1R,3R)-3-azido-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium

[0144] At room temperature, (1R,3S)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (5.00 g, 11.6 mmol) was dissolved in toluene (25 mL), cooled to 0°C, and diphenyl azidophosphate (4.16 g, 15.1 mmol) and 1,8-diazabicyclo[5.4.0]undecane-7-ene (2.48 g, 16.3 mmol) were added. The mixture was heated to room temperature and stirred for 2 hours, then heated to 50°C and reacted for 12 hours. After the reaction was monitored by LCMS until complete, the reaction mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude product (5.3 g) of (1R,3R)-3-azido-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole. This crude product was used directly in the next reaction without further purification. LCMS: RT = 0.561 min, [M+H] + =453.9.

[0145] Step J: Synthesis of (1R,3R)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine

[0146] At room temperature, crude (11.6 mmol) product of (1R,3R)-3-azido-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole was dissolved in toluene (53 mL) and water (26 mL), and triphenylphosphine (9.17 g, 35.0 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction was monitored by LCMS until complete. The reaction was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give (1R,3R)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (3.1 g). LCMS: RT = 0.452 min, [M+H] + =427.9.

[0147] Step K: Synthesis of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0148] At room temperature, (1R,3R)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (2.5 g, 5.85 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of phenyl formate (2.14 g, 17.5 mmol), triethylamine (2.95 g, 29.2 mmol), and dichloro[9,9-dimethyl-4,5-di(diphenylphosphino)oxanthracene]palladium(II) (441 mg, 0.583 mmol). The mixture was purged with nitrogen three times and stirred in an oil bath at 100°C for 20 hours. The reaction was monitored by LCMS until complete. The reaction was quenched with water (200 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give compound (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (1.9 g, crude). This compound was used directly in the next reaction without further purification. LCMS: RT = 0.491 min, [M+H] + =376.0.

[0149] Step L: Synthesis of (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0150] At room temperature, crude (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (1.9 g, 5.06 mmol) was dissolved in tetrahydrofuran (38 mL), and after purging under a nitrogen atmosphere, the mixture was cooled to -78°C, and a tetrahydrofuran solution of potassium di(trimethylsilyl)amino (5.7 mL, 5.7 mmol, 1 M in THF) was slowly added dropwise. After maintaining this temperature for 1 hour, methyl iodide (1.08 g, 7.58 mmol) was added, and the mixture was heated to room temperature and stirred for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was quenched at 5°C by adding 50 mL of saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 1.2 g of compound (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (1.2 g). LC-MS: RT = 0.5 × 10 min, [M + H] + =390.0. 1 H NMR(400MHz,Chloroform-d)δ8.33–8.25(m,1H),7.42(d,J=8.7Hz,1H),7.23(dd,J=8.2,0.9Hz,1H),7.15(d,J=8.1Hz,1H),7.07(d,J=0.9Hz,1H) ,7.02–6.99(m,1H),6.65(t,J=73.2Hz,1H),6.01(d,J=7.2Hz,1H),4.74( d,J=7.1Hz,1H),3.31(s,3H),3.26–3.21(m,1H),2.67(d,J=13.7Hz,1H).

[0151] Step M: Synthesis of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0152] At room temperature, (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (1.2 g, 3.08 mmol) was dissolved in 1,4-dioxane (30 mL), followed by the addition of pinacol diborate (0.94 g, 3.70 mmol), potassium acetate (0.76 g, 7.7 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.29 g, 0.62 mmol), and tridibenzylacetone dipalladium (0.28 g, 0.31 mmol). After replacing the atmosphere with nitrogen, the mixture was stirred in an oil bath at 100°C for 12 hours. The reaction was monitored by LCMS until complete, and then cooled to room temperature. A 0.1 M solution of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one was obtained (30 mL, 0.1 M, yield: 100%). LCMS: RT = 2.02 min, [M+H] + =482.03.

[0153] Step N: Synthesis of (R)-2-methyl-N-(spiro[3.3]heptane-2-yl)propane-2-sulfonamide

[0154] Spiro[3.3]heptan-2-one (1.0 g, 9.08 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.21 g, 9.99 mmol) were dissolved in tetrahydrofuran (30 mL) at room temperature, followed by the addition of tetraethyl titanate (4.14 g, 18.16 mmol). The reaction was stirred in an oil bath at 70 °C for 12 h. After the reaction was complete, 80 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to give compound (R)-2-methyl-N-(spiro[3.3]heptane-2-yl)propane-2-sulfonamide (1.27 g). LCMS: RT = 1.6 min, [M+H] + =214.07.

[0155] Step O: Synthesis of (R)-N-(2-(5-bromopyrimidin-2-yl)spiro[3.3]heptane-2-yl)-2-methylprop-2-sulfonamide`

[0156] 5-Bromo-2-iodopyrimidine (800.0 mg, 2.81 mmol) was dissolved in dichloromethane (30 mL), and a solution of n-butyllithium in n-hexane (1.12 mL, 2.5 mol / L) was slowly added dropwise at -78°C, with the system temperature not exceeding -70°C during the addition. After the addition was complete, the reaction was stirred at this temperature for half an hour, and then (R)-2-methyl-N-(spiro[3.3]heptane-2-yl)propane-2-sulfonamide (500.0 mg, 2.34 mmol) was added at -78°C. The reaction was stirred at this temperature for 2 hours, and then slowly increased to 20°C and continued to react for 1 hour. After the reaction was completed by LCMS, the reaction was quenched with saturated ammonium chloride aqueous solution (80 mL), extracted with dichloromethane (25 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 0 / 1) to give compound ((R)-N-(2-(5-bromopyrimidin-2-yl)spiro[3.3]heptane-2-yl)-2-methylprop-2-sulfonamide (270.0 mg). LCMS: RT = 2.00 min, [M+H) + =372.09.

[0157] Step P: Synthesis of N-(2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide

[0158] At room temperature, ((R)-N-(2-(5-bromopyrimidin-2-yl)spiro[3.3]heptane-2-yl)-2-methylprop-2-sulfonamide (90.0 mg, 0.29 mmol) was added to freshly prepared (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazolium A solution of zo[1,2-a][1,4]diazon-5(14H)-one (139.58 mg, 0.29 mmol, 3 mL, 0.1 M) in 1,4-dioxane was prepared by adding tris(dibenzylideneacetone)dipalladium (27.0 mg, 0.029 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (28.0 mg, 0.058 mmol), and potassium phosphate dissolved in water (1 mL) (7... 1.0 mg (0.72 mmol). The atmosphere was replaced with nitrogen, and the reaction was carried out in an oil bath at 110°C for 6 hours. After the reaction was complete as detected by LCMS, the mixture was cooled to room temperature, 15 mL of water was added, and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give compound N. -(2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide (91.0 mg). LCMS: RT = 2.05 min, [M+H] + =646.90.

[0159] Step Q: Synthesis of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(3-methylpyrazolo[1,5-a]pyrimidin-6-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0160] N-(2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide (91.0 mg, 0.14 mmol) was dissolved in dioxane (3 mL), and a dioxane solution of hydrogen chloride (0.18 mL, 4 mol / L) was added at room temperature. The reaction was carried out at room temperature for 1 hour.

[0161] After the reaction was complete, the reaction solution was concentrated under vacuum, and the resulting residue was sent for preparation to obtain 27.0 mg of compound (7R,14R)-11-(2-(2-aminospiro[3.3]heptane-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one. LCMS: RT=1.73 min, [M+H] + =542.92. 1 H NMR (400MHz, DMSO-d6) δ9.02(s,2H),8.27(dd,J=5.9,3.6Hz,1H),7.86-7.49(m,6H),6.30(d,J=7.0Hz,1H),5.25(d,J=7.1Hz,1H),3.52(dt,J=14 .1,7.3Hz,1H),3.36(s,3H),2.84(d,J=13.8Hz,1H),2.78-2.71(m,2H),2 .32(s,2H),2.18-2.10(m,4H),1.90(t,J=7.4Hz,2H),1.84-1.72(m,2H).

[0162] Example 2

[0163] Synthesis of (7R,14R)-11-(2-(2-aminospiro[3.3]heptane-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0164] The specific synthesis route is as follows:

[0165] Step A: Synthesis of (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0166] At room temperature, crude (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (150 mg, 0.4 mmol) was dissolved in 1,4-dioxane (4 mL), followed by the addition of pinacol diborate (0.12 g, 0.48 mmol), potassium acetate (98 mg, 1.0 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (19 mg, 0.04 mmol), and tridibenzylacetone dipalladium (18 mg, 0.02 mmol). After purging to a nitrogen atmosphere, the mixture was stirred in an oil bath at 100°C for 8 hours. The reaction was monitored by LCMS until complete, and then cooled to room temperature for later use. A 0.1 M solution (30 mL, 0.1 M) of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one was obtained. LCMS: RT = 1.91 min, [M+H] + =468.21.

[0167] Step B: Synthesis of N-(2-(5-((7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide

[0168] At room temperature, ((R)-N-(2-(5-bromopyrimidin-2-yl)spiro[3.3]heptane-2-yl)-2-methylprop-2-sulfonamide (110.0 mg, 0.36 mmol) was added to freshly prepared (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-6,7-dihydro-7,14-toluene[f]benzo[] In the 1,4-dioxane of [4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (168.22 mg, 1.36 mmol), tris(dibenzylacetone)dipalladium (33.0 mg, 0.036 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (34.0 mg, 0.072 mmol), and potassium phosphate (88.0 mg, 0.90 mmol) were added sequentially. A 1 mL solution of water was prepared. The atmosphere was replaced with nitrogen, and the mixture was reacted in an oil bath at 110°C for 6 hours. After LCMS analysis, the reaction was quenched with 15 mL of water, extracted with dichloromethane (25 mL × 3), and the organic phases were combined. The mixture was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain the compound. N-(2-(5-((7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide (110 mg). LCMS: RT = 2.04 min, [M+H] + =632.93.

[0169] Step C: Synthesis of (7R,14R)-11-(2-(2-aminospiro[3.3]heptane-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0170] N-(2-(5-((7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide (110 mg, 0.19 mmol) was dissolved in 1,4-dioxane (3 mL). A solution of 1,4-dioxane in hydrogen chloride (0.18 mL, 4 mol / L) was added at room temperature, and the reaction was allowed to proceed for 1 hour at room temperature. After the reaction was completed by TLC, the reaction solution was concentrated under vacuum, and the residue was purified by preparative chromatography to obtain compound (7R,14R)-11-(2-(2-aminospiro[3.3]heptane-2-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (35.9 mg). LCMS: RT = 1.70 min, [M+H] + =528.95. 1 H NMR(400MHz, DMSO-d6)δ9.15(d,J=6.9Hz,1H),9.02(s,2H),8.22(dd,J=6.0,3.4Hz,1H),7.87-7.42(m,6H),6.36(d,J=7.1Hz,1H),4.90 (t,J=6.8Hz,1H),3.54-3.45(m,1H),2.78-2.70(m,3H),2.25(s,2H),2.18-2.10(m,4H),1.89(dd,J=8.5,5.8Hz,2H),1.84-1.72(m,2H).

[0171] Example 3

[0172] Synthesis of (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptane-6-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0173] The specific synthesis route is as follows:

[0174]

[0175] Step A: Synthesis of (R)-2-methyl-N-(2-oxaspiro[3.3]heptane-6-ylidene)propane-2-sulfonamide

[0176] Spiro[3.3]heptane-2-one (1.5 g, 13.38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.95 g, 16.06 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and tetraethyl titanate (6.1 g, 26.76 mmol) was added. The mixture was reacted in an oil bath at 45 °C for 12 h. After the reaction was detected by LCMS, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution (80 mL). The mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to give compound (R)-2-methyl-N-(2-oxaspiro[3.3]heptane-6-yl)propane-2-sulfonamide (1.9 g). LCMS: RT = 1.56 min, [M+H] + =216.07.

[0177] Step B: Synthesis of (R)-N-(6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptane-6-yl)-2-methylpropane-2-sulfonamide

[0178] 5-Bromo-2-iodopyrimidine (1.43 g, 5.02 mmol) was dissolved in dichloromethane (30 mL), and a solution of n-butyllithium in n-hexane (2.01 mL, 2.5 mol / L) was slowly added dropwise at -78°C, while controlling the system temperature to not exceed -70°C. After the addition was complete, the reaction was maintained at this temperature for half an hour, and then (R)-2-methyl-N-(2-oxaspiro[3.3]heptane-6-yl)propane-2-sulfonamide (900.0 mg, 4.18 mmol) was added at -78°C. The reaction was continued at this temperature for 2 hours, and then slowly increased to 20°C and reacted for 1 hour. After the reaction was completed by LCMS, a saturated ammonium chloride aqueous solution (80 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (25 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 0 / 1) to give compound (R)-N-(6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptane-6-yl)-2-methylpropane-2-sulfonamide (181.0 mg). LCMS: RT = 1.75 min, [M+H] + =373.89.

[0179] Step C: Synthesis of N-(6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)-2-oxaspiro[3,3]heptane-6-yl)-2-methylprop-2-sulfinamide

[0180] At room temperature, (R)-N-(6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptane-6-yl)-2-methylpropane-2-sulfonamide (181.0 mg, 0.48 mmol) was dissolved in a freshly prepared 1,4-dioxane solution of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one (230.0 mg, 0.48 mmol, 0.1 M). A solution of tris(dibenzylacetone)dipalladium (44.0 mg, 0.048 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (46.0 mg, 0.096 mmol), and potassium phosphate (310.0 mg, 1.44 mmol) in water (2 mL) was added sequentially. The atmosphere was replaced with nitrogen, and the mixture was reacted in an oil bath at 110°C for 6 hours. After the reaction was completed as detected by LCMS, the reaction was quenched with water (15 mL), the aqueous phase was extracted with dichloromethane (25 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give compound N-(6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)-2-oxaspiro[3,3]heptane-6-yl)-2-methylprop-2-sulfinamide (101.0 mg). LCMS: RT = 1.82 min, [M+H] + =649.04.

[0181] Step D: Synthesis of (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptane-6-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0182] N-(6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)-2-oxaspiro[3,3]heptane-6-yl)-2-methylprop-2-sulfinamide (81.0 mg, 0.12 mmol), iodine (76.0 mg, 0.30 mmol), sodium carbonate (38.0 mg, 0.36 mmol), and 4-dimethylaminopyridine (2.9 mg, 0.024 mmol) were dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL) and reacted at room temperature for 5 hours. After the reaction was completed by LCMS analysis, the system was extracted with a 10 mL / methanol (10:1) mixture (10 mL × 3 times), the organic phases were combined, washed with saturated brine (5 mL), filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatographic analysis to give compound (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (8.0 mg). LCMS: RT = 3.212 min, [M+H] + =545.2.

[0183] Example 4

[0184] Synthesis of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(3-methylpyrazolo[1,5-a]pyrimidin-6-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0185] The specific synthesis route is as follows:

[0186]

[0187] Step A: Synthesis of (R)-2-methyl-N-(spiro[2,3]hexane-5-yl)propane-2-sulfonamide

[0188] Spiro[2,3]hexane-5-one (500.0 mg, 5.2 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (690.0 mg, 5.72 mmol) were dissolved in tetrahydrofuran (30 mL) at room temperature, followed by the addition of tetraethyl titanate (2.37 g, 10.4 mmol). The reaction was stirred in an oil bath at 70 °C for 12 h. After the reaction was detected by LCMS, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution (80 mL). The mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to give compound (R)-2-methyl-N-(spiro[2,3]hexane-5-yl)propane-2-sulfonamide (877 mg). LCMS: RT = 1.81 min, [M+H] + =200.07.

[0189] Step B: Synthesis of (R)-N-(5-(5-bromopyrimidin-2-yl)spiro[2.3]hexane-5-yl)-2-methylprop-2-sulfonamide

[0190] 5-Bromo-2-iodopyrimidine (1.5 g, 5.28 mmol) was dissolved in dichloromethane (30 mL). A solution of n-butyllithium in n-hexane (3.3 mL, 1.6 mol / L) was slowly added dropwise at -78°C, while maintaining the system temperature below -70°C. After the addition was complete, the reaction was maintained at this temperature for half an hour. Then, (R)-2-methyl-N-(spiro[2.3]hexane-5-yl)propane-2-sulfonamide (877.0 mg, 4.4 mmol) was added at -78°C, and the reaction was maintained at this temperature for another 2 hours. The temperature was then slowly increased to 20°C, and the reaction was continued for 1 hour. After the reaction was completed by LCMS, a saturated ammonium chloride aqueous solution (80 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (25 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 0 / 1) to give compound (R)-N-(5-(5-bromopyrimidin-2-yl)spiro[2.3]hexane-5-yl)-2-methylprop-2-sulfonamide (310.0 mg). LCMS: RT = 1.98 min, [M+H] + =357.91.

[0191] Step C: Synthesis of N-(2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[3,3]heptane-2-yl)-2-methylpropane-2-sulfinamide

[0192] At room temperature, (R)-N-(5-(5-bromopyrimidin-2-yl)spiro[2.3]hexane-5-yl)-2-methylprop-2-sulfonamide (110.0 mg, 0.31 mmol) was dissolved in freshly prepared (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2] A solution of 1,4-dioxane containing 150.0 mg, 0.31 mmol, 0.1 M diazonium-5(14H)-one (150.0 mg, 0.31 mmol, 0.1 M) was added sequentially to tris(dibenzylacetone)dipalladium (28.0 mg, 0.031 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (30.0 mg, 0.062 mmol), and potassium phosphate (200.0 mg, 0.93 mmol) in water (1 mL). The atmosphere was replaced with nitrogen, and the reaction was carried out in an oil bath at 110 °C for 6 hours. After the reaction was completed as detected by LCMS, the mixture was cooled to room temperature, and 15 mL of water was added to quench the reaction. The aqueous phase was extracted with dichloromethane (25 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give compound N-(5-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[2,3]hexane-5-yl)-2-methylpropane-2-sulfinamide (76.0 mg). LCMS: RT = 2.02 min, [M+H] + =632.70.

[0193] Step D: Synthesis of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(3-methylpyrazolo[1,5-a]pyrimidin-6-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-5(14H)-one

[0194] At room temperature, N-(5-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)spiro[2,3]hexane-5-yl)-2-methylpropane-2-sulfinamide (76.0 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL), and a solution of dioxane in hydrogen chloride (0.15 mL, 4 mol / L) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed by LCMS analysis, the reaction solution was concentrated under vacuum, and the residue was purified by preparative chromatography to obtain compound (7R,14R)-11-(2-(5-aminospiro[2.3]hexane-5-yl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one (19.68 mg). LCMS: RT = 1.68 min, [M+H] +

[0195] =528.96.

[0196] 1 H NMR(400MHz, DMSO-d6)δ9.07(s,2H),8.27(dd,J=5.8,3.6Hz,1H),7.86–7.47(m,6H),6.31(d,J=7.1Hz,1H),5.25(d,J =7.1Hz,1H),3.52(dt,J=14.1,7.3Hz,1H),3.37(s,3H),2.84(d,J=12.0Hz,3H),2.25–2.22(m,2H),0.55–0.38(m,4H).

[0197] Example 5

[0198] Synthesis of 6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-11-yl)pyridin-2-yl)-2-aza[3,3]heptane-6-carbamate

[0199]

[0200] Step A: Synthesis of tert-butyl 6-(5-bromopyridin-2-yl)-6-cyano-2-aza[3.3]heptane-2-carboxylic acid

[0201] At room temperature, 0.79 g (4.49 mmol) of 5-bromo-2-fluoropyridine and 1 g (4.49 mmol) of 6-cyano-2-aza[3.3]heptane-2-carboxylic acid tert-butyl ester were dissolved in tetrahydrofuran (30 mL). After cooling to -15 °C, a THF solution of NaHMDS (2.5 mL, 2.0 M) was slowly added dropwise, and the mixture was stirred at this temperature for 12 hours. After the reaction was detected by TLC, saturated ammonium chloride was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to give compound 6-(5-bromopyridin-2-yl)-6-cyano-2-aza[3.3]heptane-2-carboxylic acid tert-butyl ester (1.3 g). LCMS: RT = 2.07 min, [M + H + =377.91.

[0202] Step B: Synthesis of 6-cyano-6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-11-yl)pyridin-2-yl)-2-azapyridine[3,3]heptane-2-carboxylic acid tert-butyl ester

[0203] At room temperature, 100 mg (0.21 mmol) of 6-(5-bromopyridin-2-yl)-6-cyano-2-aza[3.3]heptane-2-carboxylic acid tert-butyl ester was dissolved in freshly prepared (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-6,7-dihydro-7,14-methoxybenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one (100 mg, 0.21 mmol, 0.1 M) in a 1,4-dioxane solution. A solution of tris(dibenzylacetone)dipalladium (19 mg, 0.021 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (19 mg, 0.032 mmol), and potassium phosphate (89 mg, 0.42 mmol) in water (4 mL) was added sequentially, followed by 1,4-dioxane (10 mL). After purging with nitrogen three times, the mixture was stirred in an oil bath at 110°C for 3 hours. After the reaction was completed, the sample was filtered through diatomaceous earth, washed with dichloromethane, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 6-cyano-6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazin-11-yl)pyridin-2-yl)-2-azapyridine[3,3]heptane-2-carboxylic acid tert-butyl ester (120 mg). LCMS: RT = 2.04 min, [M+H] + =652.93.

[0204] Step C: Synthesis of 6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-11-yl)pyridin-2-yl)-2-aza[3,3]heptane-6-carbamate

[0205] 120 mg (0.18 mmol) of 6-cyano-6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazin-11-yl)pyridin-2-yl)-2-azapyridine[3,3]heptane-2-carboxylic acid tert-butyl ester was dissolved in dioxane (4 M, 10 mL) of hydrogen chloride and stirred at room temperature for 0.5 h. After the reaction was completed by LCMS, the solution was concentrated under reduced pressure. The crude product was purified by preparative chromatography to give compound 6-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazin-11-yl)pyridin-2-yl)-2-aza[3,3]heptane-6-carbamate (61 mg). LCMS: RT = 1.83 min, [M+H] + =553.

[0206] 1 H NMR (400MHz, DMSO-d6) δ9.39 (d, J=2.0Hz, 1H), 8.82 (dd, J=8.5, 2.0Hz, 1H), 8.28 (dd, J=6.6 ,2.9Hz,1H),8.20(d,J=8.4Hz,2H),8.18(brs,1H),7.91(d,J=8.5Hz,1H),7.80–7.78(m,1H) ,7.67(dd,J=8.5,1.9Hz,1H),7.54–7.43(m,2H),6.32(d,J=7.1Hz,1H),5.29(d,J=7.1Hz,1 H),4.92(s,2H),3.56–3.51(m,3H),3.36(s,3H),3.22–3.16(m,4H),2.87(d,J=13.8Hz,1H).

[0207] Example 6

[0208] Synthesis of (7R,14R)-1-(difluoromethoxy)-11-(2-(2-hydroxy-6-azacarbon[3,4]octan-2-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one

[0209]

[0210] Step A: Synthesis of tert-butyl 2-(5-bromopyrimidin-2-yl)-2-hydroxy-6-aza[3,4]octane-6-carboxylic acid

[0211] At room temperature, 1.5 g (5.27 mmol) of 5-bromo-2-iodopyrimidine was dissolved in 10 mL of toluene. After cooling to -70 °C and replacing the gas with nitrogen, a hexane solution of 3.3 mL (1.6 M) of n-butyllithium was slowly added dropwise. The reaction was maintained at this temperature for half an hour, and then 1.2 g (5.27 mmol) of 2-oxo-6-aza[3.4]octane-6-carboxylic acid tert-butyl ester was added. The reaction was continued at this temperature with stirring for 12 hours. After the reaction was completed by LCMS, a saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 10 / 1) to give 1 g of compound 2-(5-bromopyrimidin-2-yl)-2-hydroxy-6-aza[3.4]octane-6-carboxylic acid tert-butyl ester. LCMS:RT=1.97min,[M-56+H] + =328.

[0212] Step B: Synthesis of 2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-11-yl)pyrimidin-2-yl)-2-hydroxy-6-azapyridine[3,4]octane-6-carboxylic acid tert-butyl ester

[0213] At room temperature, 81 mg (0.21 mmol) of 2-(5-bromopyrimidin-2-yl)-2-hydroxy-6-aza[3,4]octane-6-carboxylic acid tert-butyl ester was dissolved in freshly prepared (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-6,7-dihydro-7,14-methoxybenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one was prepared. To a solution of 1,4-dioxane (100 mg, 0.21 mmol, 0.1 M), tris(dibenzylacetone)dipalladium (19 mg, 0.021 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (19 mg, 0.032 mmol), and potassium phosphate (89 mg, 0.42 mmol) in water (4 mL) were added sequentially. Then, 10 mL of 1,4-dioxane was added. After purging with nitrogen three times, the mixture was stirred in an oil bath at 110°C for 3 hours. After the reaction was completed, the solution was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazin-11-yl)pyrimidin-2-yl)-2-hydroxy-6-azapyridine[3,4]octane-6-carboxylic acid tert-butyl ester (50 mg). LCMS: RT = 2.04 min, [M+H] + =659.07.

[0214] Step C: Synthesis of (7R,14R)-1-(difluoromethoxy)-11-(2-(2-hydroxy-6-azacarbon[3,4]octan-2-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one

[0215] 2-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazin-11-yl)pyrimidin-2-yl)-2-hydroxy-6-azapyridine[3,4]octane-6-carboxylic acid tert-butyl ester (50 mg, 0.076 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was detected by LCMS, the crude product was concentrated under reduced pressure. The crude product was purified by preparative chromatography (Waters Xselect CSHC18, mobile phase A was 0.05% TFA aqueous solution, mobile phase B was acetonitrile, the stability gradient was 16% of phase B, and the flow rate was 20 mL / min) to obtain compound 6A (RT = 17.16 min, 10 mg) and compound 6B (RT = 19.32 min, 7 mg).

[0216] Compound 6A: HPLC: RT = 17.16 min, LCMS: [M+H] + =559.08.

[0217] Compound 6B: HPLC: RT = 19.32 min, LCMS: [M+H] + =559.02.

[0218] Example 7

[0219] Synthesis of (7R,14R)-1-(difluoromethoxy)-11-(2-(2-hydroxy-6-methyl-6-azacarbon[3,4]octan-2-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one

[0220] Step A: Synthesis of 2-(5-bromopyrimidin-2-yl)-6-aza[3,4]octane-2-ol

[0221]

[0222] At room temperature, 1 g (2.60 mmol) of tert-butyl 2-(5-bromopyrimidin-2-yl)-2-hydroxy-6-aza[3.4]octane-6-carboxylic acid was dissolved in 10 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed as determined by LCMS, the solution was concentrated under reduced pressure to obtain 800 mg of the crude compound 2-(5-bromopyrimidin-2-yl)-6-aza[3.4]octane-2-ol, which was used directly in the next reaction without further purification. LCMS: RT = 0.5 min, [M+H] + =284.

[0223] Step B: Synthesis of 2-(5-bromopyrimidin-2-yl)-6-methyl-6-aza[3,4]octane-2-ol

[0224] 2-(5-bromopyrimidin-2-yl)-6-aza[3.4]octane-2-ol (700 mg, 2.46 mmol) was dissolved in dichloromethane (10 mL), and 0.2 mL of 30% formaldehyde aqueous solution was added. After stirring at room temperature for 6 hours, sodium cyanoborohydride (460 mg, 7.38 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was detected by LCMS, saturated sodium chloride solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 2-(5-bromopyrimidin-2-yl)-6-methyl-6-aza[3.4]octane-2-ol (400 mg). LCMS: RT = 0.7 min, [M+H] + =298.

[0225] Step C: Synthesis of (7R,14R)-1-(difluoromethoxy)-11-(2-(2-hydroxy-6-methyl-6-azacarbon[3,4]octan-2-yl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one

[0226] At room temperature, 2-(5-bromopyrimidin-2-yl)-6-methyl-6-aza[3,4]octane-2-ol (63 mg, 0.21 mmol) was dissolved in a freshly prepared 1,4-dioxane solution of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-6,7-dihydro-7,14-methoxybenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazoazine-5(14H)-one (100 mg, 0.21 mmol, 0.1 M). A solution of tris(dibenzylacetone)dipalladium (19 mg, 0.021 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (19 mg, 0.032 mmol), and potassium phosphate (89 mg, 0.42 mmol) in water (4 mL) was added sequentially, followed by 10 mL of 1,4-dioxane. After purging with nitrogen three times, the mixture was stirred in an oil bath at 110°C for 3 hours. After the reaction was completed as determined by LCMS, the mixture was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the crude product, which was then purified by preparative chromatography (Agilent Poroshell 1204-HPH-C18, mobile phase A was 0.05% TFA aqueous solution, mobile phase B was acetonitrile, the stability gradient was 20% of phase B, and the flow rate was 15 mL / min) to obtain compound 7A (RT = 9.40 min, 4.611 mg) and compound 7B (RT = 9.93 min, 5.095 mg).

[0227] Compound 7A: HPLC: RT = 9.40 min, LCMS: [M+H] + =573.02.

[0228] Compound 7B: HPLC: RT = 9.93 min, LCMS: [M+H] + =573.02.

[0229] Example 8 Fluorescence Polarization Measurement

[0230] 8.1 Preparation of fluorescent conjugate compound A

[0231] Synthesis of N-(6-((1-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)cyclobutyl)amino)hexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthanene]-5-carboxamide

[0232]

[0233] The specific synthesis route is as follows:

[0234]

[0235] Step A: Synthesis of (6-((1-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidine-2)cyclobutyl)amino)hexyl)tert-butyl carbamate

[0236] At room temperature, tert-butyl 6-oxohexyl carbamate (237 mg, 1.1 mmol) was added to a methanol (20 mL) solution of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylaminobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diaza-5(14H)-one (0.5 g, 1.0 mmol). After stirring for 10 min, sodium triacetoxyborohydride (636 mg, 3 mmol) was added, and the reaction was continued at room temperature with stirring for 2 h. The reaction was monitored by LCMS to be essentially complete, and the crude product was obtained after concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19 / 1) to give compound (6-((1-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2)cyclobutyl)amino)hexyl)carbamate tert-butyl ester (359 mg). LCMS: RT = 1.75 min, [M+H]+ = 702.15.

[0237] Step B: Synthesis of N-(6-((1-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)cyclobutyl)amino)hexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthanene]-5-carboxamide

[0238] Hydrogen chloride (10 mL, 4 M in 1,4-dioxane) was added to a solution of 1,4-dioxane (359 mg, 0.51 mmol) of (6-((1-(5-(((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2)cyclobutyl)amino)hexyl)carbamate tert-butyl ester (10 mL, 4 M in 1,4-dioxane) at room temperature. The reaction was stirred at room temperature for 0.5 h. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure to obtain the crude product (7R,14R)-11-(2-(1-((6-aminohexyl)amino)cyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluene[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one. The crude product was used directly in the next reaction without further purification. LCMS: RT = 1.57 min, [M+H]+ = 602.08.

[0239] At room temperature, the crude product (0.51 mmol) of (7R,14R)-11-(2-(1-((6-aminohexyl)amino)cyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazon-5(14H)-one was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 5-carboxyfluorescein (210 mg, 0.56 mmol), N-methylimidazolium (210 mg, 2.55 mmol), and tetramethylchlorourea hexafluorophosphate (290 mg, 1.02 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was detected by LCMS, water (100 mL) was added to quench the reaction. The aqueous phase was extracted with a dichloromethane / ethanol (4:1) mixed solvent (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain N-(6-((1-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazo-11-yl)pyrimidin-2-yl)cyclobutyl)amino)hexyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthanene]-5-carboxamide (162.7 mg). LCMS: RT = 1.66 min, [M+H] + =960.39. 1H NMR (400MHz, DMSO-d6) δ10.19(brs,1H),9.46(d,J=6.2Hz,2H),9.25(s,2H),8.81(t,J=5.6Hz,1H),8.43(s,1H),8. 30–8.25(m,1H),8.21(d,J=8.0Hz,1H),7.85–7.80(m,2H),7.72–7.67(m,2H),7.49(d,J=5.9Hz,2H),7.36(d,J=8.0H z,1H),6.69(d,J=2.1Hz,2H),6.59–6.52(m,4H),6.31(d,J=7.1Hz,1H),5.27(d,J=7.1Hz,1H),3.36(s,3H),3.30(q ,J=6.6Hz,2H),2.85(d,J=13.8Hz,1H),2.78–2.73(m,7H),2.14–2.06(m,2H),1.66–1.53(m,4H),1.38–1.32(m,4H).

[0240] 8.2 Inhibition of TNFα binding by fluorescent conjugates

[0241] This invention relates to a fluorescence polarization (FP) assay method for evaluating the affinity of compounds for TNFα. The assay compound at final concentrations of 5 μM, 1.25 μM, 0.31 μM, 0.078 μM, 0.020 μM, 0.0049 μM, 0.0012 μM, 0.00031 μM, and 0.000076 μM, TNFα protein (Acro GMP-TNAH23) at a final concentration of 1 μg / mL, and probe molecules at a final concentration of 5 nM are mixed in an Assay Buffer (10 mM Tris-HCl, 1 mM HEPES, 1 M CaCl2, 20 mM HEPES) and incubated for 24 h. The results are obtained by reading the fluorescence polarization mode (FP 485520520). The inhibition rate was calculated using the following formula: Inhibition rate (%) = (mPNegative control - mPsample) / (mPNegative control - mPprobe control) * 100, where mP represents the measured fluorescence polarization value. Data analysis was performed using GraphPadPrism 9 software to calculate the IC50 value.

[0242] Table 1. FP-IC 50 data

[0243] Compound numbering <![CDATA[IC 50 (nM)]]> 1 A 2 A 3 A 4 A 6B A 7A A 7B A

[0244] Classification criteria: A(IC)50 ≤20nM), B(20nM) <IC 50 ≤50nM), C(IC) 50 >50nM).

[0245] As can be seen from the experimental results in Table 1, the compounds of this invention have a strong affinity for TNFα.

[0246] Example 9 Reporter Gene Assay

[0247] Inhibition of TNFα-induced NF-κB activation

[0248] After resuscitation, HEK-Blue TNF-α (InvivoGen hkb-tnfdmyd) cells were cultured in growth medium without selection antibiotics. After two passages, they were transferred to medium containing selection antibiotics to cultivate stable cell lines. Cells with viability exceeding 90% in the selection medium were selected for subsequent experiments. Drug concentrations of 1 μM, 0.25 μM, 0.063 μM, 0.016 μM, 0.0039 μM, 0.00098 μM, 0.00024 μM, and 0.000061 μM were mixed with TNFα protein (AcroGMP-TNAH23) at a final concentration of 5 pg / mL in complete medium (90% DMEM + 10% FBS) and incubated for 1 hour. After incubation, 50 μL of the mixture was added to wells of a plate. After digestion and counting, cells were seeded at a density of 6.67 × 10^4 cells / mL and then incubated for 18 hours. After incubation, take 50 μL of the culture medium supernatant and use Phospha-Light... TM Fluorescence signals were detected using the SEAP Reporter GeneAssay System (Invitrogen T1017). The inhibition rate was calculated using the formula: Inhibition rate % = [1 - (Experimental group fluorescence value - Blank group fluorescence value) / (Positive control fluorescence value - Blank group fluorescence value)] × 100. Nonlinear fitting was performed on the compound concentration and inhibition rate to calculate the EC50. 50 The results are shown in Table 2.

[0249] Table 2. EC50 of the compounds of the present invention to HEK-Blue-293 50 value

[0250] Compound numbering <![CDATA[EC 50 (nM)]]> 1 A 2 A 3 A 4 A

[0251] Classification criteria: A(EC) 50 ≤10nM), B(10nM) <EC 50 ≤50nM), C(EC) 50 >50nM).

[0252] As can be seen from the experimental results in Table 2, the compounds of the present invention have a strong inhibitory effect on the TNFα-TNFR1 signaling pathway.

[0253] Example 10: Pharmacokinetic Study of Compound in Rat

[0254] 10.1 Experimental Materials

[0255] SD rats: male, 180-250g, purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0256] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, EDTA-2K anticoagulant, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0257] Instrument: AB SCIEX QTRAP 5500+.

[0258] 10.2 Experimental Methods

[0259] The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous or gavage administration to rats, 200 μL of venous blood was collected in EDTA-K2 anticoagulant tubes at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (an additional 5 min for the IV group). The blood was centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. 10 μL of each of the above standard solutions was accurately pipetted and added to 90 μL of blank plasma. The mixture was vortexed to prepare plasma samples with concentrations equivalent to 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL. Two samples were analyzed for each concentration to establish a standard curve. Take 30 μL of plasma (diluted 5-fold at 5 min, 15 min, and 30 min after intravenous administration), add 150 μL of propranolol (50 ng / mL) in acetonitrile-methanol (1:1) solution, vortex to mix, centrifuge at 4000 rpm for 5 min, take 100 μL of supernatant, add 100 μL of purified water, vortex again to mix, and analyze by LC-MS. LC-MS detection conditions are as follows:

[0260] Column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0261] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0262] Time (min) Water (containing 0.1% formic acid) Acetonitrile 0 80％ 20％ 0.4 80％ 20％ 1.2 15％ 85％ 2.6 15％ 85％ 2.61 80％ 20％ 3.2 80％ 20％

[0263] 10.3 Data Processing

[0264] After LC-MS was used to detect the blood drug concentration, the pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The test results are shown in Table 3.

[0265] Table 3: Pharmacokinetics of the compounds of this invention in rats

[0266]

[0267] As shown in Table 3, the compounds of the present invention all exhibit good pharmacokinetic characteristics in SD rats, with good absorption, high exposure, relatively long half-life, and high absolute bioavailability.

[0268] Example 11: In vitro hepatocyte stability experiment of the compound in different animal species

[0269] 11.1 Preparation of stock solution and working solution

[0270] The compound and positive control were dissolved in DMSO to obtain a 10 mM stock solution, which was then diluted with acetonitrile-water (1:1, v / v) to obtain a 100 μM solution.

[0271] 11.2 Hepatocyte stability assay

[0272] The compound was reacted with rat, dog, monkey, and human hepatocytes (0.5 × 10⁻⁶ cells, respectively). 6 The cells were incubated in duplicate using both William's E Medium and 1×GlutaMAX incubation media (cells / mL) and cell-free incubation media. The final drug concentration in the incubation system was 1 μM, and the total incubation time was 120 minutes. Samples were taken at time points of 0.0, 15, 30, 60, 90, and 120 minutes during incubation, and the reaction was terminated by adding acetonitrile solution containing an internal standard (0.5 μM tolbutamide). Verapamil (1 μM) was used as a positive control in the incubation system. The test samples were analyzed using UPLC-MS / MS to calculate the residual percentage, in vitro intrinsic clearance, and half-life.

[0273] 11.3 Data Analysis

[0274] The peak area ratio of the analyte to the internal standard was used to calculate the relative percentage content (residual percentage) of the compound after incubation and then fitted with an exponential function. The results are shown in Table 4, and the calculation formula is as follows:

[0275] t 1 / 2 =0.693 / k, k=rate constant(-slope value);

[0276] Scaled-up CL int = kV / N × scaling factor, V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1×10 6 cells).

[0277] CL invivo = (Q*F u / R B *Scale-up C lint ) / (Q + F u / R B *Scale-up C lint ) If F u = 1 & R B = 1 then CL = (Q*Scale-up C lint ) / (Q + Scale-up C lint )

[0278] ER (extraction rate) = CL invivo / hepatic blood flow

[0279] Physiological parameters

[0280]

[0281] Classification criteria: slow metabolism (ER < 0.3), medium metabolism (0.3 < ER < 0.7), fast metabolism (ER > 0.7).

[0282] Table 4 Stability of the compounds in human liver microsomes

[0283]

[0284] Note: " / " indicates not tested;

[0285] The experimental results in Table 4 show that the compounds of the present invention have good stability in human and rat liver microsomes.

[0286] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. For those of ordinary skill in the art, improvements or changes can be made according to the above description, and all such improvements and changes should fall within the protection scope of the appended claims of the present invention.

Claims

1. A fused-ring compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, The structure of the fused-ring compound is shown in general formula (I): in: X is selected from: substituted or unsubstituted. The m is selected from an integer of 1, 2, 3, or 4; the R4 or R5 is independently selected from: H, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; The R3 is selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C5-C 12 Spirocycloalkyl, substituted or unsubstituted 5-12 membered spiroheterocycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C 12 Aryl; The Y is selected from: carbonyl, sulfone, or sulfoxide; The R1 is selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C5-C 12 Spirocycloalkyl, substituted or unsubstituted 5-12 membered spiroheterocycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C 12 Aryl; The Q is independently selected from: N or CR6; The U is independently selected from: N or CR7; The W is independently selected from: N or CR8; Each of R6, R7, or R8 is independently selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C1-C6 alkoxy; The R2 is selected from: substituted or unsubstituted C5-C. 12 Spirocycloalkyl, substituted or unsubstituted 5-12 membered spiroheterocycloalkyl; The substituents referred to as "substituted" are all independently selected from: -OH, oxo, halogen, -NH2, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino, -CN, -COOH, -SO3H, aminoC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups.

2. The fused-ring compound according to claim 1, or its isomers, racemates, or pharmaceutically acceptable salts thereof, characterized in that, The fused-ring compound regulator has the structure shown in general formula (II): R9 is independently selected from: -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -NH2, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino or -CN; The R 10 R 11 Together with the attached carbon atom, it forms a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted 3-8 membered heterocyclic alkyl, wherein the substituents of the "substituted" group are independently selected from: -OH, oxo, halogen, -NH2, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino, -CN, -COOH, -SO3H, aminoC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups; The definitions of R1, R3, Q, X, Y, U, and W are the same as in claim 1.

3. The fused-ring compound according to claim 2, or its isomers, racemates, or pharmaceutically acceptable salts thereof, characterized in that, The fused-ring compound has the structure shown in general formula (IIA) or general formula (IIB): Among them, R1, R3, R9, R 10 R 11 The definitions of Q, X, Y, U, and W are the same as in claim 2.

4. The fused-ring compound according to any one of claims 2-3, or its isomers, racemates, or pharmaceutically acceptable salts thereof, characterized in that, The C3-C8 cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; The 3-8 membered heterocyclic alkyl group is selected from: oxobutyranyl, azaheptacyclic alkyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydroimidazoyl, tetrahydropyrazolyl, tetrahydrothiazoyl, tetrahydroisothiazoyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, or thiomorpholinyl; the substituent group of the "substituted" group is selected from: H, oxo, halogen, -OH, -CN, -NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, (C1-C6 alkyl)amino, bis(C1-C6 alkyl)amino, and aminoC1-C6 alkyl.

5. The fused-ring compound according to claim 4, or its isomers, racemates, or pharmaceutically acceptable salts thereof, characterized in that, The substituted or unsubstituted C3-C8 cycloalkyl group is selected from: The substituted or unsubstituted 3-8 membered heterocyclic alkyl groups are selected from: ； The V is independently selected from: -O-, -S-, -C(O)-, or -N(R)-. 22 )-; The Z is independently selected from: -O-, -S-, -C(O)-, -N(R)-. 23 - or -C(R) 24 (R) 25 )-; The R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 Or R 25 All are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl.

6. The fused-ring compound according to any one of claims 1-5, or its isomers, racemates, or pharmaceutically acceptable salts thereof, characterized in that, The fused ring compound is selected from:

7. The fused-ring compound according to any one of claims 1-6, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, The fused ring compound is selected from:

8. A pharmaceutical composition, characterized in that, It comprises the fused-ring compound of any one of claims 1-7, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

9. The use of the fused-ring compound of any one of claims 1-7, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation for the prevention or treatment of TNFα-related diseases; preferably, the TNFα-related diseases are selected from: rheumatoid arthritis and psoriasis.

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