Compound and use thereof

Abstract

The present invention relates to a compound and a use thereof. The compound may be used for treating diseases which inhibit TLR7 and / or TLR8 or dependent immune responses. The compound has the general formula as shown in formula (I).

Description

A compound and uses thereof

[0001] This application claims priority to Chinese patent application PCT / CN2024 / 101586 with a filing date of 2024 / 6 / 26, and Chinese patent application PCT / CN2024 / 136275 with a filing date of 2024 / 12 / 3. This application incorporates the full text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the field of medicinal chemistry, and relates to a compound and uses thereof. BACKGROUND

[0003] Toll-like receptors (TLRs) are a conserved class of type I transmembrane proteins in the immune system that recognize conserved molecular patterns (pathogen-associated molecular patterns, PAMPs) present in pathogen proteins, lipids, and nucleic acids. Activation of TLRs can trigger host defense mechanisms, such as secretion of inflammatory cytokines, induction of interferon pathways, and activation of B cells and neutrophils. Endosomal TLRs, including TLR3, TLR7 / 8, and TLR9, can recognize double-stranded RNA (dsRNA), GU-rich single-stranded RNA (ssRNA), and non-methylated single-stranded DNA (ssDNA), respectively. Abnormal activation of these nucleic acid-sensing endosomal TLRs is believed to be a potential driving factor for autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjogren's syndrome (SjS).

[0004] Genetic and functional evidence suggests that chronic over-activation of TLR7 / 8 by endogenous single-stranded RNA is a driving factor for several systemic autoimmune diseases. For example, gain-of-function mutations in TLR7 were found to exist in children with severe autoimmune disease, and expression of this mutation in mice led to a fatal lupus-like disease. Overexpression of TLR7 or TLR8 also triggered similar lupus-like diseases.

[0005] ​Enhanced activation of TLR7 and TLR8 contributes to the cellular mechanisms of multiple systemic autoimmune diseases. For example, patient autoantibodies form RNA-containing immune complexes (ICs) with ribonucleoproteins (RNPs) that drive type I interferon (IFN) release from plasmacytoid dendritic cells (pDCs) in a TLR7-dependent manner. IFNs, as well as an elevated IFN-stimulated gene signature, are characteristic features of SLE patients. Neutrophils are activated through TLR8, autoreactive B cells internalize RNA-containing autoantigens to activate TLR7, and autoantigens containing complex RNA are phagocytosed by monocytes / dendritic cells (DCs) to activate TLR8. In summary, enhanced activation of TLR7 / 8 increases the secretion of antinuclear antibodies (ANAs) by autoreactive B cells, pDCs, and monocytes / DCs and sustains a self-sustaining feedback loop of inflammation and tissue damage.

[0006] Accordingly, TLR7 / 8 antagonists can help break this vicious cycle in patients, and the development of small molecule inhibitors is an attractive approach to treat such autoimmune diseases. SUMMARY

[0007] In one aspect, the present application provides a compound. Specifically as follows:

[0008] a compound of Formula (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a deuterated derivative thereof,

[0009] wherein,

[0010] R1is H, Cl, -CN, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxy-fluoroalkyl, -CR z =CH2, C 3-6 cycloalkyl, -CH2(C 3- 6cycloalkyl), -C(O)O(C 1-3 alkyl), or tetrahydropyranyl;

[0011] each R2is independently halogen, -CN, -OH, -NO2 + , C 1-3 alkyl, C 1-2 fluoroalkyl, C 1-2 cyanoalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 alkyl), C 1-3fluoroalkyl, -(CH2) 1-4 O(C 1-3 alkyl), -O(CH2) 1- 2OC(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -C(O)NR y R y , -NR y R y , -NR y (C 1-3 fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x (CH2-cyclopropyl), C 3-6 cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl);

[0012] p is 0, 1, 2, or 3;

[0013] each R x is independently H or -CH3;

[0014] each R y is independently H or C 1-6 alkyl;

[0015] R z is H, C 1-2 alkyl or C 1-2 fluoroalkyl;

[0016] R3, R4are independently selected from H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally substituted with 1, 2, 3, 4, 5, or 6 R5, each R5is independently selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -C(=O)C(=O)NH2, -(C 1-6 alkylene)C(=O)NH2, -C(=O)NH(C 1-6 haloalkyl, -C(=O)NH2, -C(=O)OH, -C(=O)(C 1-6 haloalkyl), -C(=O)(C 1-6 alkyl); R5is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C 1-6 haloalkyl, -C(=O)NH2, -C(=O)OH, -C(=O)(C 1-6 haloalkyl), -C(=O)(C 1-6 alkyl); R5is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of C

[0017] or R3, R4, and the atoms to which they are attached together form a 5-10 membered heterocyclyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each independently selected from the group consisting of halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups are substituted.

[0018] In some schemes, R3 and R4 are independently selected from H, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, optionally surrounded by 1, 2, 3, 4, 5, or 6 independently selected from halogen, oxo, C1-6 alkyl, C1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1- 6-alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Substitution of alkyl groups;

[0019] Alternatively, R3, R4, and the atoms they are attached to form a 5-10 membered heterocyclic group, which may be selected independently by one, two, three, four, five, or six atoms from halogen, oxo, C, and D atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2NH(C 1-6 alkyl), -S(=O)2NH(C 1-6 alkyl), -S(=O)2NH(C

[0020] In some embodiments, each R5is independently selected from the group consisting of H, F, Cl, -CN, -OH, -NO2, -NH2, -N(C 6-10 aryl includes, but is not limited to, phenyl, naphthyl, anthryl, and the like, which can also be optionally substituted with one or more substituents each independently selected from the group consisting of -CF3, -CH2CF3, -C(=O)NH2, -C(=O)OH, -C(=O)CH3, -C(=O)CF3.

[0021] In some embodiments, each R5is independently selected from the group consisting of H, F, Cl, -CN, -OH, -NO2, -NH2, -N(C

[0022] In some embodiments, each R5is independently selected from the group consisting of H, F, Cl, -CN, -OH, -NO2, -NH2, -N(C 3-10 cycloalkyl includes, but is not limited to, cyclohexyl, cyclopentyl, and the like, which can also be optionally substituted with one or more substituents each independently selected from the group consisting of -CF3, -CH2CF3, -C(=O)NH2, -C(=O)OH, -C(=O)CH3, -C(=O)CF3.

[0023] In some embodiments, each R5is independently selected from the group consisting of H, F, Cl, -CN, -OH, -NO2, -NH2, -N(C

[0024] In some embodiments, R1is H, Cl, -CN, methyl, ethyl, propyl, isopropyl, -CF3, -CH2CF3, -CR z =CH2, C 3-6 cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)O(C 1-3 alkyl), or tetrahydropyranyl.

[0025] In some embodiments, R1is isopropyl.

[0026] In some embodiments, each R2is independently F, Cl, -CN, -OH, -NO2 + , methyl, ethyl, propyl, isopropyl, -CF3, -CH2CF3, C1-2 cyanoalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, -0(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 alkyl), C 1-3 fluoroalkoxy, -(CH2) 1-4 O(C 1-3 alkyl), -0(CH2) 1-2 OC(O)(C 1-3 alkyl), -0(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -C(O)NR y R y , -NR y R y , -NR y (C 1-3 fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x (CH2-cyclopropyl), C 3-6 cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl).

[0027] In some embodiments, each R2is independently methyl.

[0028] In some embodiments, each R x is independently H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl;

[0029] each R y is independently H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, or 2-methylbutyl;

[0030] R z is H, methyl, ethyl, -CF3, or -CH2CF3.

[0031] In some embodiments, R3, R4are independently selected from H, CN, C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, pyridinyl, pyranyl, furanyl, imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, quinolinyl, morpholinyl, dioxothiomorpholinyl, or C 6-10 aryl, optionally substituted with 1, 2, 3, 4, 5, or 6 R5, each R5 is independently selected from F, Cl, oxo, C1-6alkyl, C1-6haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -NH2, -CN, -COOH, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)C(=O)NH2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1- 6alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1- 6alkyl)2, -NHS(=O)2(C 1-6 alkyl).

[0032] In some aspects, R5is optionally substituted with 1, 2, or 3 each independently selected from C 1-6 haloalkyl, -C(=O)NH2, -C(=O)OH, -C(=O)(C 1-6 haloalkyl), -C(=O)(C 1-6Alkyl groups are substituted.

[0033] In some schemes, R3, R4, and the atoms they are bonded to together form tetrahydropyrrole, piperazinyl, piperidinyl, oxohexylcycloyl, tetrahydrofuranyl, morpholinyl, or dioxothiomorpholinyl, which are optionally selected by one, two, three, four, five, or six independently from halogen, oxo, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1- 6-alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups are substituted.

[0034] In some embodiments, R3, R4are independently selected from H, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl or 2-methylbutyl, -CH2C(CH3)3, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)2, -CH=CH2, -CH2CH=CH2, -C=C(CH3)2, -CH2C≡CH, -CH2CH2C≡CH, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, pyridinyl, pyranyl, furanyl, imidazolyl, thiazolyl, pyrazolyl, isopyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, quinolinyl, morpholinyl or dioxothiomorpholinyl, optionally substituted with 1, 2, 3, 4, 5 or 6 R5, each R5is independently selected from F, Cl, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)2, -CH=CH2, -CH2CH=CH2, -CH2C≡CH, -CH2CH2C≡CH, cyclopropanyl, cyclobutanyl, cyclopentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, biphenyl, naphthyl, pyrrolyl, pyrazolyl, isopyrazolyl, pyridinyl, pyrazinyl, thiophenyl, morpholinyl, dioxothiomorpholinyl, -NH2, -CN, -COOH, -NH(CH3), -NH(CH2H3), -N(CH3)2, -N(CH2H3)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -C(=O)O(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6alkyl)2、-NHS(=O)2(C 1-6 Substitution of alkyl groups;

[0035] Alternatively, R3, R4, and the atoms they are connected to can form tetrahydropyrrolidinyl, piperazinyl, piperidinyl, oxohexylcycloyl, tetrahydrofuranyl, morpholinyl, or dioxothiomorpholinyl, which may be selected independently by one, two, three, four, five, or six atoms from F, Cl, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)2, -CH=CH2, or -CH2CH=CH2. -CH2C≡CH, -CH2CH2C≡CH, cyclopropane, cyclobutane, cyclopentane, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazine, morpholinyl, phenyl, biphenyl, naphthyl, pyrrolyl, pyrazolyl, isopyrazolyl, pyridinyl, pyrazine, thiophene, morpholinyl, dioxothiomorpholinyl, -NH2, -CN, -COOH, -NH(CH3), -NH(CH2H3), -N(CH3)2, -N(CH2H3)2, -OH, -O(C 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups are substituted.

[0036] In some schemes, C in R5 is defined 1-6 The alkyl group is methyl, ethyl, propyl or isopropyl.

[0037] In some schemes, R3 is H.

[0038] R4 is C1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, or 6 R5,

[0039] each R5is independently oxo, 3-10 membered heterocyclyl, -S(=O)2(C 1-6 alkyl), -C(=O)NH2, -NHC(=O)(C 1-6 alkyl), -NHS(=O)2(C 1-6 alkyl), -C(=O)C(=O)NH2, -(C 1-6 alkylene)C(=O)NH2; R5is optionally substituted with 1, 2, or 3 substituents each independently C 1-6 haloalkyl, -C(=O)NH2, -C(=O)(C 1-6 haloalkyl), -C(=O)(C 1-6 alkyl);

[0040] or R3, R4and the atom to which they are attached together form a 5-10 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently oxo, C 1-6 haloalkyl, or -NHS(=O)2(C 1-6 alkyl).

[0041] In some embodiments, R3is independently H; R4is independently -CH2CF3, -CH(CH3)CF3, -CH(CH2CH3)CF3, tetrahydropyrrolyl, piperidinyl, cyclopentyl, -CH2-cyclohexyl, -CH2-piperidinyl, tetrahydropyrrolyl, piperidinyl, cyclopentyl, -CH2-cyclohexyl, -CH2-piperidinyl is substituted with one or more R5, each R5is independently selected from -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -(C 1- 6alkylene)C(=O)NH2, -NHS(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 haloalkyl), -C(=O)C(=O)NH2;

[0042] or R3, R4and the atom to which they are attached together form a tetrahydropyrrolyl, piperidinyl, substituted with a substituent C 1-6 haloalkyl.

[0043] In some embodiments, R3is independently H; R4is independently -CH2CF3, -CH(CH3)CF3, -CH(CH2CH3)CF3, tetrahydropyrrolyl, piperidinyl, cyclopentyl, -CH2-cyclohexyl, tetrahydropyrrolyl, piperidinyl, cyclopentyl, -CH2-cyclohexyl is substituted with R5, R5is independently selected from -S(=0)2(C 1-6 alkyl), -C(=0)(C 1-6 alkyl).

[0044] In some embodiments, R3is independently H; R4is independently C 3-6 halo branched alkyl.

[0045] In some embodiments, the compound has the structure of Formula (I-1):

[0046] In some embodiments, the compound is any one of the following formulae:

[0047] In some embodiments, the compound is any one of the following formulae:

[0048] In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a deuterated derivative thereof; and at least one pharmaceutically acceptable excipient, according to any of the above embodiments.

[0049] In yet another aspect, the present application provides a use of a compound of Formula (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a deuterated derivative thereof; or a pharmaceutical composition according to any of the above embodiments, in the manufacture of a medicament for treating a disease, which is a TLR7 and / or TLR8 mediated disease or an immune disease, such as a disease caused by over-activation of TLR7 and / or TLR8, etc. In some embodiments, the disease is a (immune) disease mediated by TLR7 and / or TLR8.

[0050] In some embodiments, the disease comprises systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, hidradenitis suppurativa, dermatomyositis, polymyositis, Sjogren’s syndrome, arthritis, rheumatoid arthritis, or psoriasis.

[0051] In yet another aspect, the present application provides a method of treating a subject having a disease that inhibits a TLR7 and / or TLR8 or dependent immune response, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof; or a pharmaceutical composition as described in any of the preceding aspects.

[0052] In some aspects, the disease comprises systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, hidradenitis suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome, arthritis, rheumatoid arthritis, or psoriasis.

[0053] In yet another aspect, the present application provides a compound of Formula (I), a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof; or a pharmaceutical composition as described in any of the preceding aspects for use in the treatment of a disease that inhibits a TLR7 and / or TLR8 or dependent immune response.

[0054] In some aspects, the disease comprises systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, hidradenitis suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome, arthritis, rheumatoid arthritis, or psoriasis.

[0055] Definitions

[0056] The term "halogen" or "halo" as used interchangeably herein, means fluorine, chlorine, bromine, or iodine, unless otherwise indicated. Preferred halogen groups include -F, -Cl, and -Br.

[0057] The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl, and the like. Similarly, C 1-6 C 1-6 C The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl, and the like. Similarly, C

[0058] The term "haloalkyl" as used herein, unless otherwise indicated, means an alkyl group as defined above substituted with one or more (1, 2, 3, 4, 5, or 6) halogen (-F, -Cl, or -Br). In some embodiments, haloalkyl is interchangeable with -C 1-6 haloalkyl or halo-C 1-6 alkyl, wherein -C 1-6 haloalkyl or halo-C 1-6 alkyl, wherein -C 1-6 represents the total number of carbon atoms in the alkyl group is 1 to 6. In some embodiments, -C 1- 6haloalkyl is -C 1-3 haloalkyl. In some embodiments, -C 1-3 haloalkyl is (methyl, ethyl, propyl, or isopropyl) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, -C 1-3 haloalkyl is -CF3.

[0059] The term "alkylene" refers to a bi-functional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0060] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length. For example, "-C 2- 6alkenyl" contains 2 to 6 carbon atoms. For example, alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hexenyl, heptenyl, octenyl, and the like.

[0061] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds, typically 2 to 20 carbon atoms in length. For example, "-C 2- 6alkynyl" contains 2 to 6 carbon atoms. For example, representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, heptynyl, octynyl, and the like.

[0062] The term "alkoxy" is an oxygen ether formed from a preceeding alkyl group, including, but not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2OCH3, -CH2CH2OCH3.

[0063] The term "haloalkoxy" as used herein, unless otherwise indicated, refers to the above-mentioned alkoxy groups substituted with one or more (1, 2, 3, 4, 5, or 6) halogen (-F, -Cl, or -Br). In certain embodiments, haloalkoxy is interchangeable with -C 1-6 haloalkoxy or halo-C 1-6 alkoxy, wherein -C 1-6 haloalkoxy or halo-C 1-6 alkoxy, wherein -C 1-6 indicates that the total carbon atoms of the alkoxy group is 1 to 6. In certain embodiments, -C 1-6 haloalkoxy can be (methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy) substituted with 1, 2, 3, 4, 5, or 6 -F, -Cl, or -Br; preferred -C 1-3 haloalkoxy is -OCF3.

[0064] The term "alkylhydroxy-fluoroalkyl" is an alkyl group substituted with both a hydroxyl and a fluorine, such as -CHFOH, -CH2CHFOH, -CH2CH2CHFOH, -CH2CH2CH2CHFOH. In certain embodiments, alkylhydroxy-fluoroalkyl can be C 1-3 hydroxy-fluoroalkyl, such as -CHFOH, -CH2CHFOH, -CH2CH2CHFOH.

[0065] The term "aryl" or "aromatic ring" as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

[0066] The term "heterocyclyl" or "heterocycle" as used herein, unless otherwise indicated, refers to an unsubstituted and substituted monocyclic or polycyclic non-aromatic ring system containing one or more ring heteroatoms, including monocyclic heterocyclic (group), bicyclic heterocyclic (group), bridged heterocyclic (group), fused heterocyclic (group), and spirocyclic heterocyclic (group). Preferred heteroatoms include N, O, and S, including N-oxides, S-oxides, and dioxides. Preferably, the heterocyclic (group) is fully saturated or has one or more degrees of unsaturation in a three to ten membered ring. The current definition of heterocyclic (group) includes multiple degrees of substitution (preferably one, two, or three degrees of substitution). Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0067] The term "heteroaryl" as used herein, unless otherwise indicated, denotes an aromatic ring system containing carbon and at least one heteroatom (e.g., N, O, or S, etc.). The heteroaryl or heteroaromatic ring can be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl can have from 1 to 4 heteroatoms in its ring, while a polycyclic heteroaryl can include from 1 to 10 heteroatoms. The polycyclic heteroaryl ring can contain fused, spiro, or bridged ring connections, for example, a bicyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring can contain from 8 to 12 ring atoms. A monocyclic heteroaryl ring can contain from 5 to 8 ring atoms (carbon atoms and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.

[0068] The term "carbocyclyl" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, spiro non-aromatic ring system containing only carbon atoms. Preferably, the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included within the present definition. Carbocyclyl includes, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0069] The term "one or more" means one or more. In some embodiments, "one or more" means 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" means 1, 2, 3, or 4. In some embodiments, "one or more" means 1, 2, or 3. In some embodiments, "one or more" means 1 or 2. In some embodiments, "one or more" means 1. In some embodiments, "one or more" means 2. In some embodiments, "one or more" means 3. In some embodiments, "one or more" means 4. In some embodiments, "one or more" means 5. In some embodiments, "one or more" means up to 6.

[0070] In the present application, when a ring is substituted with one or more substituents, it means that each substituent can independently substitute on each ring atom of the ring, including but not limited to ring carbon atoms or ring hetero (e.g., nitrogen, sulfur, etc.) atoms, respectively. In addition, when the ring is polycyclic, such as fused, bridged, or spiro, each substituent can independently substitute on each ring atom of the polycyclic ring, respectively.

[0071] The term "oxo" refers to an oxygen and the carbon atom to which it is attached collectively forming a group.

[0072] In the present application, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present application as an active ingredient, as well as methods of preparing compounds of the present application, are part of the present application. Also, some crystalline forms of the compounds can exist as polymorphs and as such are intended to be included in the present application. In addition, some of the compounds can form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this application.

[0073] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present application is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. When the compound of the present application is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic acids and organic acids. Since the compounds of the present application are intended for pharmaceutical use, they are preferably provided in substantially pure form, e.g., at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).

[0074] The present application includes within its scope prodrugs of the compounds of this application. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present application, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which can not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and

[0075] The definition of any substituent or variable at a particular location in a molecule herein includes substitution at that position with any of the specified radicals. It is understood that a skilled artisan can select substituents and substitution patterns on the compounds of the present application to provide compounds that are chemically stable, and can be readily synthesized by techniques known in the art and methods set forth herein.

[0076] The compounds described herein can contain one or more asymmetric centers and thus can exist in various stereoisomeric forms. The present application includes all such possible stereoisomers as well as mixtures thereof, including racemic mixtures, as well as their substantially pure resolved or enriched enantiomeric forms. Isomers can be separated from mixtures by known techniques including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis.

[0077] The present application includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and separate individual stereoisomers are also included. The products of the synthetic steps can be a mixture of stereoisomers, during the processes used to produce the compounds or when using racemization or epimerization methods known to those skilled in the art.

[0078] The term "stereoisomers" as used herein refers to isomers that have the same sequence of atoms but differ in the spatial arrangement of their atoms, including geometric isomers and conformational isomers, and wherein geometric isomers include enantiomers and diastereomers, and enantiomers include mirror-image forms that are non-superimposable. The present application includes all possible stereoisomers of the compounds.

[0079] Certain compounds provided herein can exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is hindered or greatly slowed due to steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, including pure individual atropisomers, atropisomers enriched in each, or non-specific mixtures of each. Isolation of atropisomers can be permitted if the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow.

[0080] The present application is intended to include all atom isotopes of atoms occurring in the compounds of the present application. Isotopes are atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be denoted as 1H (hydrogen), 2H (deuterium), and 3H (tritium). They are also commonly denoted as D (deuterium) and T (tritium). In the present application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.

[0081] The term "deuterated derivative" as used herein, unless otherwise indicated, refers to a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D"). It will be recognized that depending on the source of the chemical materials used in the synthesis, some variation in the natural isotopic abundance will occur in the synthesized compounds. The concentration of the naturally abundant stable hydrogen isotope, compared to the degree of stable isotope substitution of the deuterated derivatives described herein, notwithstanding such variation is small and immaterial. Thus, unless otherwise indicated, when reference is made to "deuterated derivatives" of the presently disclosed compounds, at least one hydrogen is replaced by deuterium in amounts substantially higher than its natural isotopic abundance (typically about 0.015%). In some embodiments, the presently disclosed deuterated derivatives have an isotopic enrichment factor of at least 3500 for each deuterium atom (containing 52.5% deuterium in each specified deuterium), at least 4500 (containing 67.5% deuterium), at least 5000 (containing 75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 (containing 97% deuterium), or at least 6600 (containing 99% deuterium).

[0082] When tautomers exist for the compounds of the present application, the present application includes any and all possible tautomers, and mixtures thereof, unless otherwise indicated.

[0083] The pharmaceutical compositions of this application contain a compound of the present application (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. While in any given case the most suitable route will depend on the particular host, and the nature and severity of the condition (for which the active ingredient is being administered), the compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0084] In practice, the compounds of the present application, or prodrugs or metabolites thereof, or pharmaceutically acceptable salts thereof, can be combined with a pharmaceutical carrier chosen on the basis of the intended route of administration, e.g., oral or parenteral (including intravenous), to provide a pharmaceutical composition in a form appropriate for that route of administration. Thus, for example, for oral administration, the pharmaceutical composition can be in the form of a tablet, capsule, or powder containing premeasured amounts of the active ingredient. For parenteral administration, the pharmaceutical composition can be in the form of a sterile solution, suspension, or emulsion. The composition can be prepared by any of the methods of pharmacy. In general, the compositions are prepared by uniformly and intimately bringing the active ingredient into association with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation. The active object compound or its pharmaceutically acceptable salt can be admixed with any conventional pharmaceutical carrier to produce a pharmaceutical composition suitable for the desired administration route.

[0085] Thus, the pharmaceutical compositions of the present application can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds of Formula I or a pharmaceutically acceptable salt thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0086] The pharmaceutical carrier employed can, for example, be a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sugar, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In making the compositions of the present application, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease in administration, tablets and capsules are the preferred oral dosage unit form, and the use of solid pharmaceutical carriers is preferred for the creation of these dosage forms. Alternatively, the tablets can be coated by standard aqueous or nonaqueous techniques.

[0087] Tablets containing the compositions of the present application can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient. Each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For instance, a formulation for oral administration to humans can contain from about 0.5 mg to about 5 g of active agent mixed with appropriate and convenient amounts of carriers, solvents, fillers, buffers, diluents, surface active or dispersing agents, etc. The carriers, solvents, fillers, buffers, diluents, surface active agents, dispersants etc. can make up from about 0.05 to about 95% of the total composition, more preferably from about 5 to about 25%. Unit dosage forms will generally contain between about 0.01 mg and about 2 g, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg of the active ingredient.

[0088] Pharmaceutical compositions of the present application suitable for parenteral administration can be formulated as solutions or suspensions of the active compounds in water. Suitable surfactants such as hydroxypropylcellulose can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Moreover, a preservative can be included to prevent the detrimental growth of microorganisms.

[0089] Pharmaceutical compositions of the present application suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycols), vegetable oils, and

[0090] The pharmaceutical compositions of the present application can be in a form suitable for local use, such as an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for transdermal delivery. These formulations can be prepared using a compound of Formula (I) or a pharmaceutically acceptable salt thereof of the present application by conventional processing methods. For example, a cream or ointment can be made by grinding the active compound(s) with a suitable amount of the fatty substance(s) and the water or other liquid to produce a smooth, even dispersion.

[0091] The pharmaceutical compositions of this application can be in a form suitable for rectal administration wherein the carrier is a solid. Preferably, the composition takes the form of suppositories for rectal administration of the drug. Suitable carriers include cocoa butter, other materials often used for making suppositories, and the like. Suppositories forms can be conveniently prepared by first forming a mixture of the composition with a soft, malleable, easily deformed carrier consisting of, for example, cocoa butter and / or other materials often used for making suppositories and then shaping the mixture into the desired shape and size.

[0092] In addition to the carrier ingredients, the pharmaceutical formulations described above can include one or more additional ingredients such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. Further, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing compounds or pharmaceutically acceptable salts thereof can also be prepared in powder or liquid concentrate form.

[0093] Generally, dosage levels of the order of from about 0.001 mg to about 150 mg / kg body weight per day are useful in the treatment of the above -indicated conditions, or about 0.05 mg to about 7 g per patient per day of the compounds. For example, dosage levels of the order of from about 0.001 to 50 mg per kg of body weight per day are useful in the treatment of inflammation, cancer, psoriasis, allergy / asthma, immune system diseases and disorders, central nervous system (CNS) diseases and disorders.

[0094] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease being treated.

[0095] Unless otherwise indicated, when a value is expressed as "about" X or "approximately" X, the stated value of X will be understood to be accurate to ±10%, preferably ±5%, ±2%. DETAILED DESCRIPTION

[0096] The compounds of the application can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes are intended to be illustrative only and those skilled in the art will readily understand that the solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be varied as necessary to perform the synthesis.

[0097] EXAMPLES

[0098] The following examples are provided to better illustrate the application. All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise indicated. Abbreviations used in the examples are listed in the table below.

[0099] Example 1

[0100] Preparation of

[0101] Into a three-necked flask, p-toluenesulfonylmethyl isocyanide (12.3 g, 1.05 eq.), NaH (60% content, 3.6 g, 1.5 eq.) were placed, and under N2 atmosphere, injected with ethyl ether (100 mL), cooled with ice water bath, slowly added (E)-methyl 4-methylpent-2-enoate (7.69 g, 1 eq.), and after dropwise addition was completed, dropwise injected with super dry DMSO (50 mL), during which a large amount of gas was released, after recovery to room temperature, stirred for 4 h, after the reaction was completed, slowly added 100 mL water to quench the reaction, and extracted with EtOAc (100 mL*2), the combined organic phase was concentrated under reduced pressure to obtain yellow solid INT1 (3.3 g, 33%). LCMS: m / z = 168.1 [M+H] + .

[0102] INT1 (4.27 g, 1 eq.) was dissolved in super dry THF (40 mL), and 5 drops of pyridine were added, the reaction system was cooled to -78 °C, then NBS (4.5 g, 1 eq.) was added, and the temperature was increased to -25 °C for 1 h, TLC monitoring showed that the reaction was complete, then 20 mL water was added to quench the reaction, extracted with DCM (20 mL*3), the combined organic phase was concentrated under reduced pressure, then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain white solid INT2 (1.9 g, 30%). LCMS: m / z = 246.0 [M+H] + .

[0103] 2-Amino-3,5-dibromo-4-methylpyridine (20 g, 1 eq.) was dissolved in super dry isopropanol (150 mL), then DMF-DMA (11.65 g, 13 mL, 1.3 eq.) was added, N2 was filled, and reacted at 80 °C for 4 h, after the reaction was completed, reduced to about 20 mL, then injected with acetonitrile (20 mL), cooled to 0 °C, and filtered while cold to obtain tan filter residue INT3 (22.4 g, 93%). LCMS: m / z = 319.9 [M+H] + .

[0104] INT3 (15.3 g, 1 eq.), (dppf)NiCl2(1.26 g, 0.05 eq.) and zinc bromide (10.74 g, 1 eq.) were added into a three-neck flask, dry THF (200 mL) was injected under N2atmosphere, the system was cooled to -5 °C and kept low temperature, methyl magnesium chloride THF solution (1 M, 95 mL, 2 eq.) was added dropwise into the system, the reaction temperature was kept below 0 °C. After the dropwise addition was completed, the temperature was raised to 0 °C and the reaction was carried out for 4 h. After the reaction was completed, potassium carbonate solution (0.5 M, 300 mL) was slowly added into the three-neck flask, the solid was removed by filtration, and the filter residue was washed with DCM (70 mL*2). After the filtrate was separated, the aqueous phase was extracted with DCM (100 mL), and the combined organic phase was concentrated under reduced pressure to obtain INT4, yellow solid (10.7 g, 88%). LCMS: m / z = 256.0 [M+H] + .

[0105] INT4 (10.7 g, 1 eq.) and NH2OSO3H (7.09 g, 1.5 eq.) were added into a three-neck flask, dry isopropanol (120 mL) was injected under N2atmosphere, then DMF-DMA (6.47 g, 1.3 e.q) was added, and the reaction was carried out at 60 °C for about 8 h. After the reaction was completed, it was concentrated under reduced pressure, followed by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain INT5 white solid (7.3 g, 77%). LCMS: m / z = 225.9 [M+H] + .

[0106] INT5 (4.3 g, 1 eq.), B2Pin2(7.3 g, 1.5 eq.), KOAc (5.6 g, 3 eq.) and Pd(dppf)Cl2(2 g, 0.15 eq.) were added into a three-neck flask, dry dioxane (150 mL) was injected under N2atmosphere, and the reaction was carried out at 80 °C for 12 h. After the reaction was completed, it was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain INT6 solid (7.3 g, 77%). LCMS: m / z = 274.1 [M+H] + .

[0107] INT6 (1.5 g, 1.1 eq.), INT2 (1.23 g, 1 eq.), K3PO4(3.18 g, 3 eq.) and Pd(dppf)Cl2(366 mg, 0.1 eq.) were added into a three-neck flask, dry dioxane (50 mL) was injected under N2atmosphere, and the reaction was carried out at 90 °C for 2 h. After the reaction was completed, it was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain INT7 yellow solid (920 mg, 59%). LCMS: m / z = 313.1 [M+H] + .

[0108] INT7 (890 mg, 1 eq.), LiOH (137 mg, 2 eq.) were dissolved in methanol (25 mL) and water (2.5 mL) was added, keeping 70 °C reflux for 2 d, after the reaction was complete, concentrated under reduced pressure, purified by C18 column (mobile phase: [water-acetonitrile]) to give INT8 yellow solid (660 mg, 78%). LCMS: m / z = 299.1 [M+H] + .

[0109] INT8 (100 mg, 1 eq.), 2,2,2-trifluoroethylamine hydrochloride (45 mg, 1 eq.) and HATU (260 mg, 2 eq.) were placed in a three-necked flask, super dry DMF (6 mL) was added, followed by the addition of DIEA (219 mg, 5 eq.), the reaction was carried out at room temperature for 4 h, after the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate (10 mL*3), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by C18 column (mobile phase: [water-acetonitrile]) to give compound 1, white solid (4.7 mg, 4%). 1 HNMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 8.29 (t, J = 6.0 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.06 (m, 1H), 2.56 (s, 3H), 2.09 (s, 3H), 1.11 (brs, 6H). LCMS: m / z = 380.3 [M+H] + .

[0110] Example 2

[0111] Preparation of

[0112] INT8 (200 mg, 1 eq.) was added to super dry DCM (6 mL), stirred into a turbid liquid at 0 °C, oxalyl chloride (111 mg, 1.3 eq.) was added at 0 °C, and 2 drops of DMF were added dropwise, the system released a large amount of gas, and then returned to room temperature and stirred for about 1.5 h, after the reaction was complete, the INT9 DCM solution was used directly in the next step without purification. LCMS: m / z = 313.1 [M+H] + This data was measured after quenching with methanol.

[0113] To the solution of INT9 in DCM was added thiomorpholine-1,1-dioxide hydrochloride (114.6 mg, 1 eq.) and triethylamine (270 mg, 4 eq.) dropwise. After 2 h of reaction at room temperature, the reaction was complete. The reaction was concentrated under reduced pressure, and then purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give compound 2 as a brown solid (16.3 mg, 5.8%). 1 HNMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.10 (d, J = 2.8 Hz, 1H), 3.97 (s, 4H), 3.23-3.21 (m, 4H), 2.72 (m, 1H), 2.56 (s, 3H), 2.10 (s, 3H), 1.07 (d, J = 6.8 Hz, 6H). LCMS: m / z = 416.5 [M+H] + .

[0114] Example 3

[0115] Preparation of

[0116] To the solution of INT9 in DCM was added thiomorpholine-1,1-dioxide hydrochloride (114.6 mg, 1 eq.) and triethylamine (270 mg, 4 eq.) dropwise. After 2 h of reaction at room temperature, the reaction was complete. The reaction was concentrated under reduced pressure, and then purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give compound 2 as a brown solid (16.3 mg, 5.8%).

[0117] To the solution of INT9 in DCM was added thiomorpholine-1,1-dioxide hydrochloride (114.6 mg, 1 eq.) and triethylamine (270 mg, 4 eq.) dropwise. After 2 h of reaction at room temperature, the reaction was complete. The reaction was concentrated under reduced pressure, and then purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give compound 2 as a brown solid (16.3 mg, 5.8%). 1HNMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 3.2 Hz, 1H), 4.56 - 4.48 (m, 1H), 3.56 (dd, J = 9.6, 7.2 Hz, 1H), 3.13 (dd, J = 8.8, 4.4 Hz, 1H), 3.06 (m, 1H), 2.55 (s, 3H), 2.47 (d, J = 8.8 Hz, 1H), 2.22 (dd, J = 16.8, 5.6 Hz, 1H), 2.09 (s, 3H), 1.11 (s, 6H). LCMS: m / z = 381.7 [M+H] + .

[0118] Example 4

[0119] Preparation of

[0120] INT 11 was prepared by dissolving 1-Boc-2-oxopiperazine (65 mg, 1 eq.) in HCl in dioxane (4 M, 4 mL) and reacting at room temperature for 2 h, then concentrating under reduced pressure to give INT 11 as a white solid (78 mg, 100%).

[0121] INT 8 (100 mg, 1 eq.), INT 11 (57 mg, 1 eq.) and HATU (190 mg, 1.5 eq.) were added to super dry DMF (5 mL), followed by the addition of DIEA (170 mg, 4 eq.) and the reaction was allowed to proceed at room temperature for about 2 h. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate (10 mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The compound 4 was purified by preparative high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to give compound 4 as a white solid (11.2 mg, 9%). 1 HNMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 3.2 Hz, 1H), 4.56 - 4.48 (m, 1H), 3.56 (dd, J = 9.6, 7.2 Hz, 1H), 3.13 (dd, J = 8.8, 4.4 Hz, 1H), 3.06 (m, 1H), 2.55 (s, 3H), 2.47 (d, J = 8.8 Hz, 1H), 2.22 (dd, J = 16.8, 5.6 Hz, 1H), 2.09 (s, 3H), 1.11 (s, 6H). LCMS: m / z = 381.7 [M+H] + .

[0122] Example 5

[0123] Preparation

[0124] INT8 (300 mg, 1 eq.), 1-Boc-3-aminopyrrolidine (279 mg, 1.5 eq.), and HATU (570 mg, 1.5 eq.) were added to ultra-dry DMF (8 mL), followed by DIEA (387 mg, 4 eq.). The mixture was reacted at 55 °C for approximately 2 h. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain INT12 as a white solid (70 mg, 15%). LCMS: m / z = 467.5 [M + H]. + .

[0125] INT12 (70 mg, 1 eq.) was dissolved in a dioxane solution of HCl (4 M, 6 mL), reacted at room temperature for 2 h, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 5 as a white solid (53.9 mg, 98%). 1 HNMR (400MHz, DMSO-d6): δ11.04(s,1H),8.61(s,1H),8.43(s,1H),7.65(d,J=7. 2Hz,1H),7.36(d,J=3.2Hz,1H),4.30–4.23(m,1H),3.05(m,1H),2.98–2.91(m,2H ),2.80–2.74(m,1H),2.67(dd,J=10.8,4.4Hz,1H),2.54(d,J=10.8Hz,3H),2.09( s,3H),2.01–1.91(m,1H),1.68–4.60(m,1H),1.11(s,6H).LCMS:m / z=367.5[M+H] + .

[0126] Example 6

[0127] Preparation

[0128] Compound 5 (30 mg, 1 eq.) and methanesulfonic anhydride (15 mg, 1 eq.) were dissolved in methanol (1.5 mL), and triethylamine (16 mg, 2 eq.) was added dropwise. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 6 as a white solid (24.1 mg, 67%). 1HNMR (400 MHz, DMSO-d6): δ 11.12 (d, J = 2.0 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 3.54 (dd, J = 10.0, 6.8 Hz, 1H), 3.44 (ddd, J = 10.0, 7.6, 6.4 Hz, 1H), 3.31 - 3.27 (m, 1H), 3.16 (dd, J = 10.2, 5.6 Hz, 1H), 3.04 (m, 1H), 2.93 (s, 3H), 2.56 (s, 3H), 2.20 - 2.12 (m, 1H), 2.09 (s, 3H), 2.01 - 1.91 (m, 1H), 1.12 (s, 6H). LCMS: m / z = 446.2 [M+H] + .

[0129] Example 7

[0130] Preparation of

[0131] INT8 (1 g, 1 eq.), (S)-1-tert-butoxycarbonyl-3-aminopyrrolidine (750 mg, 1.5 eq.) and HATU (1.9 g, 1.5 eq.) were added to super dry DMF (20 mL), followed by the addition of DIEA (1.7 g, 4 eq.) and the reaction was allowed to proceed at 60 °C for about 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to give INT13 as a white solid (450 mg, 29%). LCMS: m / z = 467.1 [M+H] + .

[0132] INT13 (450 mg, 1 eq.) was dissolved in a solution of HCI in dioxane (4 M, 10 mL) and the reaction was allowed to proceed at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and redissolved in 10 mL of MeOH. Ammonia was added dropwise until the reaction mixture became basic. The reaction mixture was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 7 as a purple solid (287.4 mg, 81%). 1HNMR (400 MHz, DMSO-d6): δ 11.21 (d, J = 2.4 Hz, 1H), 9.30 (br, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.14 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.56 - 4.49 (m, 1H), 3.35 - 3.31 (m, 2H), 3.26 - 3.19 (m, 1H), 3.16 (dd, J = 12.4, 8.4 Hz, 1H), 3.07 (dq, J = 13.9, 6.9 Hz, 1H), 2.55 (s, 3H), 2.21 - 2.12 (m, 1H), 2.09 (s, 3H), 2.02 - 1.93 (m, 1H), 1.12 (d, J = 10.8 Hz, 6H). LCMS: m / z = 367.4 [M+H] + .

[0133] Example 8

[0134] Preparation of

[0135] Compound 7 (73 mg, 1 eq.) was dissolved in methanol (2.5 mL) with methanesulfonic anhydride (140 mg, 4 eq.), triethylamine (80 mg, 4 eq.) was added dropwise, and the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 8 as a white solid (57.8 mg, 65%). 1 HNMR (400 MHz, DMSO-d6): δ 11.21 (d, J = 2.4 Hz, 1H), 9.30 (br, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.14 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.56 - 4.49 (m, 1H), 3.35 - 3.31 (m, 2H), 3.26 - 3.19 (m, 1H), 3.16 (dd, J = 12.4, 8.4 Hz, 1H), 3.07 (dq, J = 13.9, 6.9 Hz, 1H), 2.55 (s, 3H), 2.21 - 2.12 (m, 1H), 2.09 (s, 3H), 2.02 - 1.93 (m, 1H), 1.12 (d, J = 10.8 Hz, 6H). LCMS: m / z = 367.4 [M+H] + .

[0136] Example 9

[0137] Preparation of

[0138] Compound 7 (36.6 mg, 1 eq.) was dissolved in methanol (1.5 mL) with 2-bromoacetamide (17 mg, 1.2 eq.), and triethylamine (40 mg, 4 eq.) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h, and after the reaction was complete, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (DCM / MeOH = 10 / 1) gave compound 9 as a white solid (27.5 mg, 65%). 1 HNMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 4.50-4.45 (m, 1H), 3.81 (br, 2H), 3.48-3.41 (m, 1H), 3.10-3.02 (m, 5H), 2.56 (s, 3H), 2.32-2.23 (m, 1H), 2.09 (s, 3H), 2.05-1.96 (m, 2H), 1.12 (s, 6H). LCMS: m / z = 424.7 [M+H] + .

[0139] Example 10

[0140] Preparation of

[0141] INT8 (685 mg, 1 eq.), (S)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (691 mg, 1.5 eq.), and HATU (1.3 g, 1.5 eq.) were added to super dry DMF (12 mL), followed by the addition of DIEA (1.2 g, 4 eq.). The reaction was allowed to proceed at 60 °C for about 2 h, and after the reaction was complete, the reaction mixture was concentrated under reduced pressure. Purification by preparative HPLC (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) gave INT14 as a yellow solid (350 mg, 32%). LCMS: m / z = 481.4 [M+H] + .

[0142] INT14 (350 mg, 1 eq.) was dissolved in a solution of HCl in dioxane (4 M, 10 mL), and 3 mL of MeOH was added to aid dissolution. The reaction was allowed to proceed at room temperature for 2 h, and after the reaction was complete, the reaction mixture was concentrated under reduced pressure. The system was redissolved in 10 mL of MeOH, and ammonia water was added dropwise until the system became basic. Purification by silica gel column chromatography (DCM / MeOH = 10 / 1) gave compound 10 as a purple solid (254.0 mg, 92%). 1HNMR (400 MHz, DMSO-d6): δ 11.18 (d, J = 2.4 Hz, 1H), 9.20 (br, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 4.23 - 4.06 (m, 1H), 3.26 (dd, J = 12.0, 3.2 Hz, 1H), 3.13 - 3.05 (m, 2H), 2.92 - 2.78 (m, 2H), 2.56 (s, 3H), 2.10 (s, 3H), 1.93 - 1.86 (m, 2H), 1.76 - 1.56 (m, 2H), 1.12 (s, 6H). LCMS: m / z = 381.5 [M+H] + .

[0143] Example 11

[0144] Preparation of

[0145] N-(piperidin-4-ylmethyl)neopentanamide (750 mg, 1.0 eq) was dissolved in anhydrous dichloromethane (4 mL), 4-dimethylaminopyridine (21 mg, 0.05), triethylamine (531 mg, 1.5 eq) and trifluoroacetic anhydride (955 mg, 1.3 eq) were added, then stirred at 25 °C for 4 hours, the reaction solution was directly concentrated to obtain crude INT15 as an oily liquid. LCMS: m / z = 333.1 [M+23] + .

[0146] 4M hydrogen chloride-dioxane solution (5 mL, 7.0 eq) was added to INT15, then stirred at 25 °C for 2 hours. The reaction solution was directly concentrated to obtain crude INT16 as a solid. LCMS: m / z = 211.1 [M+1] + .

[0147] INT8 (150 mg, 1.0 eq) was dissolved in anhydrous dichloromethane (4 mL) and anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (267 mg, 1.4 eq) and triethylamine (127 mg, 2.5 eq) were added, and stirred at 25 °C for 15 minutes. Then INT16 (148 mg, 1.2 eq) was added, and stirred at 25 °C for 5 hours. Extraction was performed with ethyl acetate (5 mL*3), and the combined organic solution was dried over sodium sulfate and filtered. After the filtrate was concentrated, the crude product was separated by preparative high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product compound 11 (22 mg, 8.9%) as a solid.1 H NMR (400 MHz, Chloroform-d) δ 12.06 (s, 1H), 7.27 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.99 (s, 1H), 4.29 - 4.17 (m, 4H), 3.80 - 3.70 (m, 4H), 3.51 - 3.41 (m, 1H), 2.42 - 2.34 (m, 1H), 2.27 (m, 3H), 1.62 (s, 2H), 1.39 - 1.18 (m, 9H). LCMS: m / z = 491.3 [M+H] + .

[0148] Example 12

[0149] Preparation of

[0150] INT8 (300 mg, 1.0 eq) was dissolved in anhydrous dichloromethane (8 mL) and anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (535 mg, 1.4 eq) and triethylamine (254 mg, 2.5 eq) were added, and stirred at 25 °C for 15 min. Then 4-(aminomethyl)cyclohexane-l-carboxylic acid methyl ester hydrochloride (250 mg, 1.2 eq) was added, and stirred at 25 °C for 5 h. The mixture was extracted with ethyl acetate (10 mL*3), and the combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated to give crude INT17 as a solid. LCMS: m / z = 452.3 [M+1] + .

[0151] INT17 (226 mg, 1 eq) was dissolved in water (1 mL) and methanol (5 mL), and lithium hydroxide monohydrate (63 mg, 3 eq) was added, and then stirred at 25 °C for 5 h. The filtrate was concentrated, and the crude was separated by preparative HPLC (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to give compound 12 as a solid. The order of elution of the cis / trans isomers 12A (33 mg, 30.0%) and 12B (40 mg, 36.3%) was as follows: 12A eluted first, and 12B eluted later. 12A: 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.14 - 10.88 (m, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 3.07 (s, 1H), 3.02 (s, 2H), 2.55 (s, 3H), 2.19 - 2.12 (m, 1H), 2.09 (s, 3H), 1.95 - 1.87 (m, 2H), 1.85 - 1.73 (m, 2H), 1.46 (ddt, J = 11.4, 7.7, 3.8 Hz, 1H), 1.30 - 1.21 (m, 2H), 1.11 (s, 6H), 0.96 (td, J = 12.7, 3.3 Hz, 2H). LCMS: m / z = 436.2 [M-H] - .12B: 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.14 - 10.88 (m, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 3.07 (s, 1H), 3.02 (s, 2H), 2.55 (s, 3H), 2.19 - 2.12 (m, 1H), 2.09 (s, 3H), 1.95 - 1.87 (m, 2H), 1.85 - 1.73 (m, 2H), 1.46 (ddt, J = 11.4, 7.7, 3.8 Hz, 1H), 1.30 - 1.21 (m, 2H), 1.11 (s, 6H), 0.96 (td, J = 12.7, 3.3 Hz, 2H). LCMS: m / z = 436.2 [M-H] + .

[0152] Example 13

[0153] Preparation of

[0154] INT8 (150 mg, 1.0 eq) was dissolved in anhydrous dichloromethane (4 mL) and anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (267 mg, 1.4 eq) and triethylamine (127 mg, 2.5 eq) were added, the reaction was stirred at 25 °C for 15 min. Then 1-(4- (aminomethyl)piperidin-1-yl)ethanone hydrochloride (116 mg, 1.2 eq) was added, stirred at 25 °C for 5 h. After the reaction was completed, extracted with ethyl acetate (5 mL*3), the combined organic solution was dried over sodium sulfate, filtered. The filtrate was concentrated, the crude product was separated by high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product compound 13 (41 mg, 17.0%) as a solid. 1 H NMR (400 MHz, DMSO-d6) d 11.03 (d, J = 3.0 Hz, 1H), 8.62 (s, 1H), 8.43 (s, 1H), 7.75 (t, J = 5.9 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H), 3.08 (dd, J = 12.5, 6.3 Hz, 2H), 3.02 - 2.93 (m, 1H), 2.55 (s, 3H), 2.09 (s, 3H), 1.98 (s, 2H), 1.72 (m, 4H), 1.45 (t, J = 7.1 Hz, 1H), 1.24 (d, J = 3.3 Hz, 4H), 1.16 - 1.05 (m, 6H). LCMS: m / z = 437.3 [M+H] + .

[0155] Example 14

[0156] Preparation of

[0157] Compound 12 (219 mg, 1 eq) was dissolved in anhydrous dichloromethane (4 mL) and anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (267 mg, 1.4 eq) and N,N- diisopropylethylamine (127 mg, 3 eq) were added, followed by stirring at 25 °C for 15 min. Ammonium chloride (81 mg, 3 eq) was then added, followed by stirring at 25 °C overnight. Extraction was performed with ethyl acetate (5 mL*3), and the combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated, and the crude product was separated by preparative high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain compound 14 as cis / trans isomers 14A (21 mg, 19.1%) and 14B (18 mg, 16.3%) as solids. During the preparative separation, compound 14A eluted first, and 14B eluted later. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 3.1 Hz, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.32 (d, J = 3.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.68 - 6.60 (m, 1H), 3.02 (d, J = 6.4 Hz, 2H), 2.55 (s, 3H), 2.09 (s, 3H), 2.02 (m, 1H), 1.78 (m, 4H), 1.46 (d, J = 17.0 Hz, 1H), 1.31 - 1.23 (m, 2H), 1.11 (s, 6H), 0.91 (m, 2H). LCMS: m / z = 437.2 [M+1] + .14B: 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 3.1 Hz, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.32 (d, J = 3.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.68 - 6.60 (m, 1H), 3.02 (d, J = 6.4 Hz, 2H), 2.55 (s, 3H), 2.09 (s, 3H), 2.02 (m, 1H), 1.78 (m, 4H), 1.46 (d, J = 17.0 Hz, 1H), 1.31 - 1.23 (m, 2H), 1.11 (s, 6H), 0.91 (m, 2H). LCMS: m / z = 437.2 [M+1] + .

[0158] Example 15

[0159] Preparation

[0160] INT8 (60 mg, 1 eq.), (R)-1,1,1-trifluoroisopropylamine hydrochloride (45 mg, 1.5 eq.), and HATU (114 mg, 1.5 eq.) were added to ultra-dry DMF (1.5 mL), followed by DIEA (103 mg, 4 eq.). The mixture was reacted at 80 °C for approximately 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain compound 15 as a white solid (18.6 mg, 24%). 1 HNMR (400MHz, DMSO-d6): δ 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),8.64(s,1H),8.44(s,1H),8.06(d,J=8.8Hz,1H),7.48(d,J=2.8Hz,1H),4.86– 4.76(m,1H),3.15–2.97(m,1H),2.56(s,3H),2.09(s,3H),1.33(d,J=6.8Hz,3H),1.11(s,6H).LCMS:m / z=394.5[M+H] + .

[0161] Example 16

[0162] Preparation

[0163] INT8 (60 mg, 1 eq.), (S)-1,1,1-trifluoroisopropylamine hydrochloride (45 mg, 1.5 eq.), and HATU (114 mg, 1.5 eq.) were added to ultra-dry DMF (1.5 mL), followed by DIEA (103 mg, 4 eq.). The mixture was reacted at 80 °C for approximately 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain compound 16 as a white solid (16.2 mg, 21%). 1 HNMR (400MHz, DMSO-d6): δ 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 3.2 Hz, 1H), 4.82 (q, J = 7.6 Hz, 1H), 3.12 - 2.97 (m, 1H), 2.56 (s, 3H), 2.10 (s, 3H), 1.33 (d, J = 7.2 Hz, 3H), 1.12 (s, 6H). LCMS: m / z = 394.5 [M+H] + .

[0164] Example 17

[0165] Preparation of

[0166] INT8 (60 mg, 1 eq.), (S)-2-(trifluoromethyl)pyrrolidine (42 mg, 1.5 eq.) and HATU (114 mg, 1.5 eq.) were added to super dry DMF (1.5 mL), followed by DIEA (103 mg, 4 eq.) and the reaction was allowed to proceed at 80 °C for about 4 h. After completion of the reaction, it was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to give compound 17 as a white solid (16.8 mg, 20%). 1 H NMR (400 MHz, DMSO-d6): δ 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.16 (d, J = 3.2 Hz, 1H), 5.13 - 5.04 (d, J = 10.7 Hz, 1H), 3.72 - 3.56 (m, 2H), 2.56 (s, 3H), 2.23 - 2.15 (m, 1H), 2.09 (s, 3H), 2.05 - 1.83 (m, 4H), 1.11 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.0 Hz, 3H). LCMS: m / z = 420.6 [M+H] + .

[0167] Example 18

[0168] Preparation of

[0169] INT8 (129 mg, 1 eq.) was added to super dry DCM (4 mL) and stirred to a slurry at 0 °C, oxalyl chloride (71 mg, 1.3 eq.) was added and 2 drops of DMF was added dropwise, the system released a lot of gas, then it was returned to room temperature and stirred for about 4 h, after the reaction was completed, the INT18 DCM solution was used directly in the next step without purification. LCMS: m / z = 313.1 [M+H] + , this data was measured after quenching with methanol.

[0170] To the DCM solution of INT18, triethylamine (173 mg, 4 eq.) was added, and (S)-1,1,1- trifluorobutan-2-amine hydrochloride (80 mg, 1.5 eq.) was added, and the reaction was carried out at room temperature for 2 h, after the reaction was completed, it was concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to give compound 18 as a white solid (5.4 mg, 3%). 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 4.64-4.57 (m, 1H), 3.04 (dt, J = 9.6, 6.4 Hz, 1H), 2.56 (s, 3H), 2.11 (s, 3H), 1.82-1.66 (m, 2H), 1.12 (s, 6H), 0.95 (t, J = 7.2 Hz, 3H). LCMS: m / z = 408.5 [M+H] + .

[0171] Example 19

[0172] Preparation of

[0173] Compound 10 (38 mg, 1 eq.) was dissolved in DMF (1 mL), triethylamine (20 mg, 2 eq.) was added, and 2-propane sulfonyl chloride (14 mg, 1 eq.) was added, and the reaction was carried out at room temperature for 3 h, after the reaction was completed, it was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 19 as a white solid (24.4 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 2.8 Hz, 1H), 3.86 - 3.78 (m, 1H), 3.72 (dd, J = 11.6, 3.6 Hz, 1H), 3.57 - 3.51 (m, 1H), 3.10 - 3.03 (m, 1H), 2.90 - 2.85 (m, 1H), 2.76 (dd, J = 11.6, 9.6 Hz, 1H), 2.54 (s, 3H), 2.09 (s, 3H), 2.04 - 1.96 (m, 1H), 1.91 - 1.77 (m, 2H), 1.56 - 1.45 (m, 2H), 1.25 (s, 6H), 1.12 (s, 6H). LCMS: m / z = 487.5 [M+H] + .

[0174] Example 20

[0175] Preparation of

[0176] Compound 10 (73 mg, 1 eq.) was dissolved in methanol (2.5 mL) with methanesulfonic anhydride (55 mg, 2 eq.), triethylamine (48 mg, 3 eq.) was added dropwise, and the reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 20 as a white solid (14.8 mg, 20%). 1 H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 2.8 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.66 (dd, J = 10.4, 2.8 Hz, 1H), 3.46 (d, J = 12.0 Hz, 1H), 3.09 - 3.02 (m, 1H), 2.89 (s, 3H), 2.71 (t, J = 10.4 Hz, 1H), 2.55 (s, 3H), 2.10 (s, 3H), 2.04 - 1.95 (m, 1H), 1.87 - 1.84 (m, 2H), 1.60 - 1.44 (m, 2H), 1.12 (s, 6H). LCMS: m / z = 459.8 [M+H] + .

[0177] Example 21

[0178] Preparation of

[0179] Compound 7 (36.6 mg, 1 eq.), HATU (57 mg, 1.5 eq.) and 2-amino-2-oxoacetic acid (9 mg, 1 eq.) were dissolved in DMF (1.5 mL), DIEA (39 mg, 3 eq.) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 21 as a white solid (32.6 mg, 75%). 1 HNMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.66 (s, 1H), 7.41 (dd, J = 8.4, 2.8 Hz, 1H), 4.44 - 4.34 (m, 1H), 3.67 - 3.50 (m, 4H), 3.18 - 3.00 (m, 3H), 2.56 (s, 3H), 2.10 (s, 3H), 1.12 (s, 6H).. LCMS: m / z = 438.5 [M+H] + .

[0180] Example 22

[0181] Preparation of

[0182] INT8 (385 mg, 1 eq.), tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate (284.7 mg, 1.1 eq.) and HATU (0.74 g, 1.5 eq.) were added to super dry DMF (6 mL), followed by the addition of DIEA (0.5 g, 3 eq.), and the reaction was allowed to proceed at 60 °C for about 1.5 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain INT19 as a white solid (240 mg, 39%). LCMS: m / z = 481.4 [M+H] + .

[0183] INT19 (240 mg, 1 eq.) was dissolved in a hydrochloric acid solution in dioxane (4 M, 8 mL), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain INT20 as a solid (190 mg, 100%).

[0184] INT20 (95 mg, 1 eq.) was dissolved in methanol (3 mL) with methanesulfonic anhydride (65 mg, 1.5 eq.), and triethylamine (126 mg, 5 eq.) was added dropwise. The reaction was allowed to proceed at room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 22 as a white solid (20.4 mg, 18%). 1 HNMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 4.20 - 4.11 (m, 1H), 3.68 - 3.60 (m, 1H), 3.10 - 2.97 (m, 1H), 2.92 (s, 3H), 2.56 (s, 3H), 2.37 - 2.23 (m, 1H), 2.10 (s, 3H), 1.95 - 1.82 (m, 2H), 1.69 - 1.57 (m, 2H), 1.49 (dt, J = 12.8, 8.4 Hz, 1H), 1.12 (s, 6H). LCMS: m / z = 459.6 [M+H] + .

[0185] Example 23

[0186] Preparation of

[0187] INT20 (95 mg, 1 eq.), acetic acid (15 mg, 1 eq.), and HATU (144 mg, 1.5 eq.) were added to super dry DMF (3 mL), followed by the addition of DIEA (161 mg, 3 eq.). The reaction was allowed to proceed at room temperature for about 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 23 as a white solid (88.8 mg, 84%). 1HNMR (400MHz, DMSO-d6): δ11.05(d,J=2.0Hz,1H),8.61(s,1H),8.44(s,1H),7.93(d,J=7.2Hz ,1H),7.68(d,J=7.2Hz,1H),7.33(d,J=3.2Hz,1H),4.20–4.07(m,1H),4.03–3.91(m,1H),3.10 –2.98(m,1H),2.56(s,3H),2.23(dt,J=13.2,7.6Hz,1H),2.10(s,3H),1.91–1.82(m,2H),1.8 1(s,3H),1.69–1.51(m,2H),1.40(dt,J=16.0,8.0Hz,1H),1.12(s,6H).LCMS:m / z=423.6[M+H] + .

[0188] Example 24

[0189] Preparation

[0190] INT8 (298 mg, 1 eq.), (R)-3-tert-butoxycarbonylaminopyrrolidine (205 mg, 1.1 eq.), and HATU (0.6 g, 1.5 eq.) were added to ultradry DMF (5 mL), followed by DIEA (0.4 g, 3 eq.). The reaction was carried out at 60 °C for approximately 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure, redissolved in MeOH, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain INT21, a white solid (120 mg, 26%). LCMS: m / z = 467.3 [M+H] + .

[0191] INT21 (120 mg, 1 eq.) was dissolved in a dioxane solution of HCl (4 M, 8 mL), reacted at room temperature for 1 h, and then concentrated under reduced pressure. The system was then redissolved with 10 mL of MeOH, and ammonia was added dropwise until the system became alkaline. After concentration under reduced pressure, solid INT22 (80 mg, 100%) was obtained.

[0192] INT22 (80 mg, 1 eq.) and methanesulfonic anhydride (114 mg, 3 eq.) were dissolved in methanol (3 mL), and triethylamine (89 mg, 4 eq.) was added dropwise. The mixture was reacted at room temperature for 16 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 24 as a white solid (15.8 mg, 16%). 1HNMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.40 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 3.92 (s, 1H), 3.74 (dd, J = 11.8, 6.4 Hz, 1H), 3.63 - 3.55 (m, 1H), 3.52 - 3.38 (m, 2H), 2.97 (s, 3H), 2.89 - 2.82 (m, 1H), 2.56 (s, 3H), 2.19 - 2.13 (m, 1H), 2.09 (s, 3H), 1.92 - 1.79 (m, 1H), 1.09 - 1.07 (m, 6H). LCMS: m / z = 445.5 [M+H] + .

[0193] Example 25

[0194] Preparation of

[0195] INT8 (551 mg, 1 eq.), (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (556 mg, 1.5 eq.) and HATU (1.1 g, 1.5 eq.) were added to super dry DMF (10 mL), followed by DIEA (0.7 g, 3 eq.) and the reaction was stirred at 60 °C for about 2 h. After completion of the reaction, it was concentrated under reduced pressure, re-dissolved in MeOH and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to give INT23 as a solid (350 mg, 39%). LCMS: m / z = 481.3 [M+H] + .

[0196] INT23 (350 mg, 1 eq.) was dissolved in HCl in dioxane (4 M, 10 mL) and stirred at room temperature for 2 h. After completion of the reaction, it was concentrated under reduced pressure, re-dissolved in 10 mL MeOH and ammonia was added dropwise until the system became basic. It was purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to give compound 25 as a white solid (29.4 mg, 60%). 1HNMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.72 (dd, J = 11.6, 3.3 Hz, 1H), 3.54 (dt, J = 6.3, 3.5 Hz, 1H), 3.06 (dt, J = 13.9, 6.9 Hz, 1H), 2.88 (t, J = 10.1 Hz, 1H), 2.76 (dd, J = 11.6, 9.7 Hz, 1H), 2.56 (s, 3H), 2.09 (s, 3H), 1.94 - 1.75 (m, 2H), 1.52 (dd, J = 19.6, 13.4 Hz, 2H), 1.27 - 1.22 (m, 7H), 1.12 (s, 6H). LCMS: m / z = 381.5 [M+H] + .

[0197] Example 26

[0198] Preparation of

[0199] Compound 25 (38 mg, 1 eq.) was dissolved in DMF (1.3 mL), triethylamine (20 mg, 2 eq.) was added, and 2-propane sulfonyl chloride (14 mg, 1 eq.) was added. After the reaction was completed at room temperature for 2 h, the reaction was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 26 as a white solid (24.4 mg, 50%). 1 H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.72 (dd, J = 12.0, 3.6 Hz, 1H), 3.54 (dt, J = 13.2, 3.6 Hz, 1H), 3.10 - 3.03 (m, 1H), 2.91 - 2.86 (m, 1H), 2.76 (dd, J = 11.6, 9.6 Hz, 1H), 2.56 (s, 3H), 2.09 (s, 3H), 1.94 - 1.75 (m, 2H), 1.56 - 1.48 (m, 2H), 1.27 - 1.22 (m, 7H), 1.12 (s, 6H). LCMS: m / z = 487.56 [M+H] + .LCMS: m / z = 487.6 [M+H] + .

[0200] Example 27

[0201] Preparation of

[0202] Compound 25 (60 mg, 1 eq.) was dissolved in MeOH (2.5 mL), triethylamine (48 mg, 3 eq.) was added, and methanesulfonic anhydride (55 mg, 2 eq.) was added. After the reaction was completed at room temperature for 2 h, the reaction was concentrated under reduced pressure, and compound 27 was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain a white solid (65.2 mg, 89%). 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (d, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 3.95 - 3.81 (m, 1H), 3.66 (dd, J = 10.8, 3.2 Hz, 1H), 3.52 - 3.41 (m, 1H), 3.12 - 2.99 (m, 1H), 2.89 (s, 3H), 2.71 (td, J = 11.2, 2.0 Hz, 1H), 2.59 - 2.52 (m, 4H), 2.10 (s, 3H), 1.89 - 1.83 (m, 2H), 1.65 - 1.42 (m, 2H), 1.12 (s, 6H). LCMS: m / z = 459.5 [M+H] + .

[0203] Example 28

[0204] Preparation of

[0205] INT8 (298 mg, 1 eq.), (R)-1-tert-butoxycarbonyl-3-aminopyrrolidine (279 mg, 1.5 eq.), and HATU (0.6 g, 1.5 eq.) were added to super dry DMF (5 mL), followed by the addition of DIEA (0.4 g, 3 eq.), and the reaction was carried out at 60°C for about 2 h. After the reaction was completed, it was concentrated under reduced pressure, redissolved in MeOH, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain INT24 as a white solid (180 mg, 39%). LCMS: m / z = 467.3 [M+H] + .

[0206] INT24 (180 mg, 1 eq.) was dissolved in HCl solution in dioxane (4 M, 5 mL), after 1 h reaction at room temperature, it was concentrated under reduced pressure, then the system was redissolved with 10 mL MeOH, and ammonia water was added dropwise until the system became basic, and then concentrated under reduced pressure to obtain INT25 solid (142 mg, 100%).

[0207] INT25 (142 mg, 1 eq.) was dissolved in methanesulfonic anhydride (49 mg, 2 eq.) in methanol (2 mL), and triethylamine (41 mg, 4 eq.) was added dropwise, and the reaction was carried out at room temperature for 2 h, and then concentrated under reduced pressure after the reaction was completed, and then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 28, white solid (42.0 mg, 68%). 1 HNMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 4.41 (dq, J = 12.8, 6.4 Hz, 1H), 3.53 (dd, J = 10.0, 6.8 Hz, 1H), 3.45 (ddd, J = 10.0, 7.6, 6.4 Hz, 1H), 3.32-3.27 (m, 1H), 3.17 (dd, J = 10.4, 5.2 Hz, 1H), 3.04-3.00 (m, 1H), 2.93 (s, 3H), 2.56 (s, 3H), 2.20-2.12 (m, 1H), 2.09 (s, 3H), 2.00-1.92 (m, 1H), 1.12 (s, 6H). LCMS: m / z = 445.5 [M+H] + .

[0208] Example 29

[0209] Preparation of

[0210] INT25 (92 mg, 1 eq.) was dissolved in methanesulfonic anhydride (53 mg, 2 eq.) in methanol (3 mL), and triethylamine (75 mg, 3 eq.) was added dropwise, and the reaction was carried out at room temperature for 2 h, and then concentrated under reduced pressure after the reaction was completed, and then purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain INT26 white solid (78.0 mg, 80%). + .

[0211] INT26 (78 mg, 1 eq.) and K2CO3 (28 mg, 1 eq.) were added to DMSO (2.5 mL), and a 30% hydrogen peroxide solution (68 mg, 3 eq.) was added dropwise. The reaction was complete after stirring at room temperature for 2 h. The system was redissolved with 1 mL of H2O and 1 mL of MeOH after being concentrated under reduced pressure, and purified by C18 column chromatography (mobile phase: [water-acetonitrile]) to obtain compound 29 as a white solid (46.8 mg, 57%). 1 HNMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.40 (s, 1H), 5.72 (s, 2H), 4.38 (dq, J = 12.0, 6.4 Hz, 1H), 3.52 (dd, J = 10.4, 6.8 Hz, 1H), 3.29 - 3.23 (m, 2H), 3.16 - 3.01 (m, 2H), 2.56 (s, 3H), 2.14 - 1.99 (m, 4H), 1.91 - 1.83 (m, 1H), 1.12 (s, 6H). LCMS: m / z = 410.5 [M+H] + .

[0212] Example 30

[0213] Preparation of

[0214] INT8 (100 mg, 1.0 eq) was dissolved in anhydrous dichloromethane (3 mL) and anhydrous N,N-dimethylformamide (0.5 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (178 mg, 1.4 eq) and triethylamine (50 mg, 1.5 eq) were added, and stirred at 25 °C for 15 min. Then (4- (trifluoromethyl)phenyl)methanamine (76 mg, 1.3 eq) was added, and stirred at 25 °C for 3 h. Extraction was performed with ethyl acetate (5 mL*3), and the combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated, and the crude product was separated by high performance liquid chromatography (column: Phenomenex C18 packing; mobile phase: [water-acetonitrile]) to obtain the desired product compound 30 (0.112 g, 73.6%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (d, J = 3.2 Hz, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.35 (t, J = 6.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 3.1 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.03 (p, J = 7.0 Hz, 1H), 2.45 (p, J = 1.9 Hz, 3H), 2.04 (s, 3H), 1.06 (s, 6H). LCMS: m / z = 456.2 [M+H] + .

[0215] The pharmaceutical activity of the compounds obtained in each of the above examples was detected, in particular as follows.

[0216] Control compound 1:

[0217] Control compound 2:

[0218] I. TLR7 inhibitory activity screening test - HEK-Blue-TLR7 reporter assay

[0219] HEK-Blue TM hTLR7 cells are engineered from the HEK293 cell line for the study of the TLR7-dependent NF-κΒ pathway. These cells express the human TLR7 gene and an NF-κΒ / AP-1 inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene. HEK-Blue TM hTLR7 cells are able to respond strongly and stably to TLR7-specific ligands, allowing the screening of TLR7-specific agonists or inhibitors.

[0220] 1. Cell preparation: HEK-Blue TM hTLR7 cells were collected and resuspended in DMEM (11995065, Gibco) cell culture medium containing 10% FBS (#76294-180, Avantar). Cell density was determined using a cell counter. An appropriate amount of cell suspension was removed from the centrifuge tube to be sufficient to prepare 10000 cells / 40 μL of system. 40 μL of HEK-Blue™-TLR7 cell suspension was plated in each well of a 384-well plate (#3764, Corning).

[0221] 2. Compound preparation and addition: Compound powder was prepared into a 10 mM stock using DMSO, 3 ul of the stock was added to 6 ul of DMSO for a 3-fold dilution, test compounds were dispensed onto the cell plate using an Echo 650 Series acoustic liquid handler (Echo 650, Beckman Coulter), final test compound concentrations were: 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM and 1.52 nM. After 0.5 hours R848 (tlrl-r848, invivogen) was added to the well plate using an Echo 650 Series acoustic liquid handler. The well plate was incubated in a humidified tissue culture incubator (CLM-240B-8-TC, ESCO) for 24 hours.

[0222] 3. Detection and readout: To each well of a new 384 well plate 18 μΙ_ of prepared Quanti-Blue™ solution (rep-qbs3, InvivoGen) was added. 2 μΙ_ of supernatant was transferred to the Quanti-Blue™ solution and incubated for 60 minutes at room temperature. Data on the plate was read using a microplate reader in 384 well absorbance 620-655 mode (PHERAstar FSX, BMG).

[0223] 4. Data analysis: Data analysis, curve fitting and reporting was performed using the Dose-response one-site 205 model of IDBS XLfit.

[0224] Calculation formula Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L) (H = Ave(DMSO), L = Ave(Unstin))

[0225] IC50 fitting formula: IC50 values of compounds were fitted using a non-linear regression equation, formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0226] (X: cpd concentration, Y: inhibition%, Top and Bottom: Plateaus in same units as Y, logIC50: same log units as X)

[0227] 5. Results

[0228] Table 1 Half inhibitory concentration IC50 of different compounds on TLR7

[0229] II. Assessment of hERG potassium ion channel safety by automated patch clamp technology

[0230] This method is to apply SyncroPatch 384i automated patch clamp test system produced by Nanion Company to evaluate the inhibitory effect of the test compound on potassium ion voltage-gated channel hERG.

[0231] 1. Preparation of test compound solution: The test compound powder is dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM. The stock solution is diluted into other concentration solutions with a gradient of 1:3 ratio using DMSO as the solvent. Before the experiment, the test compound gradient solution is diluted into working solutions with corresponding concentrations by 1:500 ratio using extracellular fluid, and the final concentration is 20 μM, while the 60 μM working solution is diluted by 3:500 ratio from the 10 mM stock solution. Note: when dosing, the working solution will be added into the chip well containing the same volume of extracellular fluid with a volume ratio of 1:1, so the actual final gradient concentration of dosing should be: 30 μM, 10 μM.

[0232] 2. Cell culture and treatment: CHO cell strain stably expressing hERG ion channel is purchased from B'SYS GmbH Company in Switzerland. The cell strain is cultured in F-12 (HAM) medium containing 10% FBS buffer, 100 U / mL Penicillin-Streptomycin, 100 μg / mL Hygronycin and 100 μg / mL G418. The cells are digested and prepared into a final density of (5-7.5)*10 5 cells / mL into a 10 cm low adsorption cell culture dish, and incubated at 4-10°C for 10 minutes. Then the cells are transferred into a Teflon plate specially designed for SyncroPatch 384i system, and placed into the cell incubation tank of the automated patch clamp system, and incubated at 15°C, 200 rpm for 30 minutes before starting the experiment.

[0233] 3. Test of inhibitory effect of test compound on hERG current: First, the cells are perfused with extracellular fluid containing 0.1% DMSO for 6 times to determine the stable hERG current as the detection baseline, and the baseline current value is the average of 5 stable sampling points. After the hERG current remains stable, the solution containing the test compound is perfused around the cells, and 10 minutes are waited for the compound to fully act on the cells and record the hERG current synchronously. After the current tends to be stable, 5 stable hERG current values are read, and their average is taken as the final current value at a specific concentration.

[0234] 4. Data reading and analysis: Data were exported by Data control 384 software.

[0235] 1) After perfusion of blank solvent or compound gradient solution, the average of 5 consecutive current values was obtained as "tail current size 空白 " and "tail current size 化合物 ", respectively.

[0236] 2) The percentage of current inhibition was calculated by the following formula: tail current inhibition rate = (1 - tail current size 化合物 - tail current size 阳性对照 / tail current size 空白 - tail current size 阳性对照 ) x 100%

[0237] 5. Results

[0238] The results are shown in Table 2.

[0239] Table 2 Percentage of current inhibition of different compounds

[0240] III. PK test

[0241] 1. Test method

[0242] Three ICR mice (male) were needed for each compound. The mice were treated with a single dose of 10 mg / kg (oral gavage). For each mouse, blood samples were collected at time points of 0.25, 0.5, 1, 2, 4 and 8 hours after administration. The whole blood samples were put into tubes containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm at 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma sample was determined using the LC-MS / MS method.

[0243] 2. Results

[0244] Table 3 Pharmacokinetic parameters of different compounds

[0245] As shown in the above table, the exposure levels of compound 1, compound 16 and compound 18 of the present application in vivo were significantly higher than those of the control compounds. Among them, the absolute bioavailability of compound 16 reached 76.6%, and the absorption was good.

[0246] IV. ADME test

[0247] 1. In vitro liver microsomal metabolic stability study

[0248] The compounds were incubated in duplicate with different species of liver microsomes containing co-factor in phosphate buffer (pH 7.4) for 60 minutes. Samples were taken at 0.5, 5, 10, 15, 30 and 60 minutes for termination. The samples were analyzed using UPLC-MS / MS to determine the concentration of the compound. The elimination rate constant (k) was determined by linear fitting of the natural logarithm of the percentage of parent drug remaining versus time. The intrinsic clearance (in vitro CLint) and half-life (t 1 / 2 ) were calculated. Where t 1 / 2 = 0.693 / k; in vitro CLint = kV / N, V = incubation volume per well, N = microsomal content per well.

[0249] Table 4. Results of liver microsomal stability

[0250] 2. Kinetic solubility

[0251] Simulated fasted state simulated intestinal fluid (FaSSIF), simulated fed state simulated intestinal fluid (FeSSIF), simulated fasted state simulated gastric fluid (FaSSGF) were prepared. Appropriate amount of 10 mM compound stock solution was taken and added into different buffer, final concentration was 0.3 mM, DMSO content was 3%, prepared in duplicate. After constant temperature shaking at 37 °C for 24 hours, the compound reached precipitation equilibrium, 0.45 um PVDF membrane filtration, take the filtrate, dilution after treatment, using UPLC-MS / MS to analyze the sample to determine the concentration of the compound, calculate the solubility (μM).

[0252] Calculation formula:

[0253] Table 5. Results of kinetic solubility

[0254] It will be understood that, if this application refers to any prior art publications; such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

[0255] All publications, patents, patent applications and published patent applications referred to herein are hereby incorporated by reference in their entirety.

[0256] While the foregoing application has been described in some detail for purposes of clarity and the specific embodiments, various changes and modifications can be made which will be apparent to one skilled in the art. It will be appreciated that the description and examples should not be construed as limiting the scope of the application.

Claims

Compounds of formula (I), their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of their stereoisomers, or acceptable salts of their deuterated derivatives, in, R1 is H, Cl, -CN, or C. 1-4 Alkyl, C 1-3 fluoroalkyl, C 1-3 Hydroxy-fluoroalkyl, -CR z =CH2,C 3-6 cycloalkyl, -CH2(C 3- 6-cycloalkyl), -C(O)O(C 1-3 alkyl) or tetrahydropyranyl; Each R2 is independently a halogen, -CN, -OH, or -NO2. + C 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 Alkyl), C 1-3 Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 Alkyl group), -O(CH2) 1- 2OC(O)(C 1-3 Alkyl group), -O(CH2) 1-2 NR x R x -C(O)O(C 1-3 Alkyl), -C(O)NR y R y -NR y R y -NR y (C 1-3 fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 cycloalkyl), -NR x C(O)(C 1-3 Alkyl), -NR x (CH2-cyclopropyl), C 3-6 Cycloalkyl, morpholino, dioxothiomorpholino, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or -C(O)(thiazolyl); p is 0, 1, 2 or 3; Each R x Independently, it can be H or -CH3; Each R y Independent of H or C 1-6 alkyl; R z For H, C 1-2 Alkyl or C 1-2 fluoroalkyl; R3 and R4 are independently selected from H, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl or 5-10 heteroaryl group is optionally substituted by 1, 2, 3, 4, 5, or 6 R5 groups, each R5 being independently selected from halogen, oxo, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl), -C(=O)C(=O)NH2, -(C 1-6 Alkylene)C(=O)NH2, -C(=O)NH(C 1-6 (Halogenated alkyl); R5 is optionally selected by one, two or three independently chosen from C1. 1-6 Halogenated alkyl groups, -C(=O)NH2, -C(=O)OH, -C(=O)(C 1-6 Halogenated alkyl groups), -C(=O)(C 1-6 Substitution of alkyl groups; Alternatively, R3, R4, and the atoms they are attached to form a 5-10 membered heterocyclic group, which may be selected independently by one, two, three, four, five, or six atoms from halogen, oxo, C, and D atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups are substituted. According to the compound described in 1, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt, its transisomer, or an acceptable salt of its deuterated derivative, wherein, R1 can be H, Cl, -CN, methyl, ethyl, propyl, isopropyl, -CF3, -CH2CF3, or -CR. z =CH2,C 3-6 cycloalkyl, -CH2(C 3- 6-cycloalkyl), -C(O)O(C 1-3 Alkyl group or tetrahydropyranyl group. The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of its stereoisomer, pharmaceutically acceptable salt of its transisomer, or an acceptable salt of its deuterated derivative according to any one of 1-2, wherein, Each R2 is independently F, Cl, -CN, -OH, -NO2 + , methyl, ethyl, propyl, isopropyl, -CF3, -CH2CF3, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 Alkyl), C 1-3 Fluoroalkoxy, -(CH2) 1- 4O(C 1-3 Alkyl group), -O(CH2) 1-2 OC(O)(C 1-3 Alkyl group), -O(CH2) 1-2 NR x R x -C(O)O(C 1-3 Alkyl), -C(O)NR y R y -NR y R y -NR y (C 1-3 fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 cycloalkyl), -NR x C(O)(C 1-3 Alkyl), -NR x (CH2-cyclopropyl), C 3-6 Cycloalkyl, morpholino, dioxothiomorpholino, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or -C(O)(thiazolyl). The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, or acceptable salt thereof of any one of claims 1-3, wherein, Each R x Independently, it can be H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, or 2-methylbutyl; Each R y Independently, it can be H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, or 2-methylbutyl; R z It can be H, methyl, ethyl, -CF3 or -CH2CF3. The compound, its stereoisomer, its transisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt, its transisomer, or an acceptable salt of its deuterated derivative according to any one of 1-4, wherein, R3 and R4 are independently selected from H, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, pyridinyl, pyranyl, furanyl, imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiophene, quinolinyl, morpholinyl, dioxothiomorpholinyl, or C 6-10 The aryl group is optionally substituted with one, two, three, four, five, or six R5s, each R5 being independently selected from F, C1, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 ... 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl groups, -C(=O)C(=O)NH2, -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Substitution of alkyl groups; Preferably, R5 is optionally selected by one, two, or three independently chosen from C. 1-6 Halogenated alkyl groups, -C(=O)NH2, -C(=O)OH, -C(=O)(C 1-6 Halogenated alkyl groups), -C(=O)(C 1-6 Alkyl groups are substituted. The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer, pharmaceutically acceptable salt of the transisomer, or an acceptable salt of the deuterated derivative thereof, according to any one of 1-5, wherein, R3, R4, and the atoms they are bonded to together form tetrahydropyrrole, piperazinyl, piperidinyl, oxohexylcycloyl, tetrahydrofuranyl, morpholinyl, or dioxothiomorpholinyl, which are optionally selected by one, two, three, four, five, or six independently from halogen, oxo, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NH2, -CN, -COOH, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups are substituted. The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer, pharmaceutically acceptable salt of the transisomer, or an acceptable salt of the deuterated derivative thereof, according to any one of 1-6, wherein, R3 and R4 are independently selected from H, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl or 2-methylbutyl, -CH2C(CH3)3, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)2, -CH=CH2, -CH2CH=CH2, -C=C(CH 3) 2, -CH2C≡CH, -CH2CH2C≡CH, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, pyridinyl, pyranyl, furanyl, imidazolyl, thiazolyl, pyrazolyl, isopyrazolyl, pyrimidinyl, pyrazinyl, thiopheneyl, quinolinyl, morpholinyl, or dioxothiomorpholinyl, optionally prefixed with one or two 3, 4, 5, or 6 R5 substitutions, each R5 independently selected from F, Cl, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)2, -CH=CH2, -CH2CH=CH2, -CH2C≡CH, -CH2CH2C≡CH, cyclopropane, Cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, biphenyl, naphthyl, pyrrolyl, pyrazolyl, isopyrazolyl, pyridinyl, pyrazinyl, thiophene, morpholinyl, dioxothiomorpholinyl, -NH2, -CN, -COOH, -NH(CH3), -NH(CH2H3), -N(CH3)2, -N(CH2H3)2, -OH, -O(C 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Substitution of alkyl groups; Alternatively, R3, R4, and the atoms they are connected to can form tetrahydropyrrolidinyl, piperazinyl, piperidinyl, oxohexylcycloyl, tetrahydrofuranyl, morpholinyl, or dioxothiomorpholinyl, which may be selected independently by one, two, three, four, five, or six atoms from F, Cl, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)2, -CH=CH2, or -CH2CH=CH2. -CH2C≡CH, -CH2CH2C≡CH, cyclopropane, cyclobutane, cyclopentane, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazine, morpholinyl, phenyl, biphenyl, naphthyl, pyrrolyl, pyrazolyl, isopyrazolyl, pyridinyl, pyrazine, thiophene, morpholinyl, dioxothiomorpholinyl, -NH2, -CN, -COOH, -NH(CH3), -NH(CH2H3), -N(CH3)2, -N(CH2H3)2, -OH, -O(C 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 Alkyl), -C(=O)O(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Substitution of alkyl groups; Preferably, C in R5 definition 1-6 The alkyl group is methyl, ethyl, propyl or isopropyl. The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer, pharmaceutically acceptable salt of the transisomer, or an acceptable salt of the deuterated derivative thereof, according to any one of 1-7, wherein, The compound has the structure of formula (I-1): The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, according to any one of 1-8, wherein the compound is any one of the following formulas: The compound, stereoisomer, transisomer, deuterated derivative, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of its stereoisomer, pharmaceutically acceptable salt of its transisomer, or an acceptable salt of its deuterated derivative according to any one of 1-9, wherein, The compound is any of the following formulas: A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or an acceptable salt of a deuterated derivative thereof; and at least one pharmaceutically acceptable excipient. A compound of formula (I) according to any one of claims 1 to 10, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer or an acceptable salt of its deuterated derivative; or the use of the pharmaceutical composition of claim 11 in the preparation of a medicament for treating a disease, said disease being a TLR7 and / or TLR8 mediated disease or a dependent immune disease. The use according to claim 12 is characterized in that, The diseases mentioned include systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, hidradenitis suppurativa, dermatomyositis, polymyositis, Sjögren's syndrome, arthritis, rheumatoid arthritis, or psoriasis.

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