CSF-1R inhibitors and uses thereof

Abstract

The present application relates to compounds of Formula (I) and Formula (I ') useful as CSF-1R inhibitors for the treatment of various diseases. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to International Patent Application No. PCT / CN2022 / 098943 filed on June 15, 2022 and International Patent Application No. PCT / CN2023 / 093222 filed on May 10, 2023. The entire contents of the above applications are incorporated herein by reference. Background Art

[0003] CSF-1R, i.e. CSF-1 receptor (colony stimulating factor 1 receptor), is encoded by the oncogene c-fms. The human c-fms gene is located at 5q33.3 of chromosome 5, downstream of the β-type platelet-derived growth factor receptor (PDGF_Rβ) gene, and the two genes are linked end to end. Human CSF-1R is a single-chain transmembrane receptor tyrosine kinase, a transmembrane glycoprotein composed of 972 amino acids with a molecular weight of 150Kd. It consists of an extracellular region with 512 amino acids, a transmembrane region with 25 amino acids, and an intracellular cytoplasmic region with 435 amino acids. The extracellular region has 5 disulfide bonds and 11 possible glycosylation sites, and the intracellular region has a Gly-X-Gly-XX-Gly motif. The lysine at position 616 is an ATP binding site, which is flanked by a kinase insertion region with 72 amino acids. It is speculated that it has the function of recognizing specific substrates (Cold Spring Harb Perspect Biol. 2014, 6 (6)).

[0004] CSF-1, also known as M-CSF (macrophage colony stimulating factor), is encoded by the CSF-1 gene. CSF-1 exerts its biological effects by binding to its only cell surface receptor CSF-1R. After binding to CSF-1, CSF-1R undergoes a change in its conformation and forms a dimer or polymer. After dimerization, the tyrosine kinase activity of the receptor is activated, and the tyrosines at positions 544, 559, 699, 708, 723, 809, 923, etc. are phosphorylated, and then interact with a variety of intracellular signal transduction pathways (such as Ras, MAPK, PI3K, JAK, etc.) to produce various biological effects in cells (J Cell Biochem. 1988, 38 (3): 179-87).

[0005] The tumor microenvironment is a complex ecosystem and provides support for the occurrence, growth and metastasis of tumors. Macrophages are particularly abundant in immune cells that migrate to the tumor site and are present in all stages of tumor development. Studies have shown that tumor-associated macrophages (TAMs) play an important role in the occurrence, growth and metastasis of tumors. For primary tumors, macrophages can stimulate new blood vessel formation, help the extravasation, survival and continuous growth of tumor cells, thereby promoting tumor cell metastasis. TAMs also play an immunosuppressive role, preventing natural killer cells and T cells from attacking tumor cells (Immunity.2014,41(1):49-61). CSF-1R is expressed in macrophages, and the survival and differentiation of macrophages depend on the CSF-1 / CSF-1R signal transduction pathway. The CSF-1 / CSF-1R signal transduction pathway interferes with tumor progression by regulating TAMs to reduce tumor invasiveness and proliferation. Therefore, the CSF1 / CSF1R signal transduction pathway is a potential target for cancer treatment. Overexpression of CSF-1 or CSF-1R is associated with tumor malignant invasiveness and poor prognosis. Studies have shown that the use of CSF-1R inhibitors can affect the exchange of inflammatory factors between TAMs and glioma cells, which significantly reduces the volume of glioblastoma and reduces tumor invasiveness and proliferation (Nat Med. 2013, 19 (10): 1264-72). In addition, abnormally high expression of CSF-1 is the main pathogenesis of giant cell tumor of the tendon sheath (a rare non-metastatic tumor accompanied by giant cell tumors in the tendon sheath and pigmented villonodular synovitis). Patients with giant cell tumor of the tendon sheath have significant clinical benefits after using CSF-1R inhibitors (N Engl J Med. 2015, 373 (5): 428-37).

[0006] In addition to tumors, the CSF-1R signaling pathway also plays an important role in autoimmune and inflammatory diseases (including systemic lupus erythematosus, arthritis, atherosclerosis and obesity) (Arthritis Res Ther. 2016, 18: 75; Nat Rev Immunol. 2008, 8 (7): 533-44; J Immunother Cancer. 2017, 5 (1): 53). Therefore, the development of CSF-1R inhibitors can also be used to treat such diseases.

[0007] In addition, more and more studies have shown that inflammation in the nervous system and abnormal activation of brain microglia are important pathogenic factors of related neurodegenerative diseases, especially Alzheimer's disease (Neurobiol Aging. 2000, 21: 383-421). Among them, the signal transduction pathway mediated by CSF-1R plays a leading role in the activation and proliferation of microglia in the brain. Studies have shown that the expression of CSF-1R in tissue samples from Alzheimer's patients is significantly upregulated, accompanied by abnormal activation and proliferation of microglia (Brain Res., 1994, 639: 171-4). Animal model studies have shown that blocking CSF-1R signal transduction can effectively inhibit microglial proliferation, thereby effectively alleviating disease progression in Alzheimer's mouse models (Brain. 2016, 139: 891-907). In models of other neurodegenerative diseases (such as amyotrophic lateral sclerosis), the therapeutic effect of targeting CSF-1R on the disease has been preliminarily confirmed in proof-of-concept studies (Sci Rep., 2016, 6: 25663). Currently, many CSF-1R inhibitor candidates are in clinical trials for neurodegenerative diseases.

[0008] Therefore, there remains a need to discover novel CSF-1R inhibitors for the treatment of diseases such as cancer, autoimmune diseases, inflammatory diseases or neurodegenerative diseases. Summary of the invention

[0009] Described herein are compounds of formula (I) (including subgenuses encompassed by formula (I)) or pharmaceutically acceptable salts thereof that inhibit CSF-1R activity. More specifically, the compounds disclosed herein not only effectively inhibit the activity of CSF-1R, but also selectively inhibit CSF-1R relative to cKit, FLT3, PDGFR-β (see Tables 2 and 3), have desirable pk characteristics (see Table 5), and have high brain exposure and high blood-brain barrier (BBB) ​​penetration compared to other known CSF-1R inhibitors (see Table 6).

[0010] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] wherein the variables shown in the formula are defined herein.

[0013] Also provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0014] The present disclosure further provides a method of inhibiting CSF-1R in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] The present disclosure also provides a method for treating a disease or condition mediated at least in part by CSF-1R in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or tautomer thereof. In certain embodiments, the disease is an autoimmune disease, an inflammatory disease, a neurodegenerative disease, cancer, a metabolic disease, obesity or an obesity-related disease.

[0016] The present disclosure further provides a method for treating Alzheimer's disease in a subject, the method comprising administering to the subject an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0017] The present disclosure further provides a method for treating progressive supranuclear palsy in a subject, the method comprising administering to the subject an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0018] The present disclosure further provides a method for treating a tau-mediated neurodegenerative disorder in a subject, the method comprising administering to the subject an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0019] The present disclosure further provides a method for treating a disease or condition involving microglia-mediated inflammation in a subject, the method comprising administering to the subject an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0020] The present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in any method described herein. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is provided for use in any method described herein. In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is provided for use in the manufacture of a medicament for use in any method described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 A- Figure 1 C shows the effect of CSF1R inhibitors on CSF1-induced CSF1R and ERK1 / 2 phosphorylation in BV2 cells. Figure 1 A), Comparison A( Figure 1 B) or Example 16 ( Figure 1 C) After pretreatment, BV2 cells were stimulated with recombinant mouse CSF1 (rmCSF1). Stimulation was terminated by cell lysis followed by SDS-PAGE, western blotting and immunoblotting of epitopes as described in the figure.

[0022] Figure 2 A- Figure 2 C: From Figure 1 Quantification of Western blots. Small molecule inhibitor of CSF1R (GW2580 ( Figure 2 A), Comparison A( Figure 2 B) and Example 16 ( Figure 2 C)) shows dose-dependent inhibition of CSF1-directed phosphorylation of CSF1R and ERK1 / 2. The corresponding values ​​represent the mean of two experimental replicates.

[0023] Figure 3 A- Figure 3 D shows the effect of CSF1R inhibitors on CSF1R phosphorylation in THP1 cells stimulated with CSF1. The graph shows the phosphorylation of CSF1R detected using a sandwich ELISA in GW2580 ( Figure 3 A) BLZ946( Figure 3 B), Comparison A ( Figure 3 C) and Example 16 ( Figure 3 D) Dose-dependent reduction of CSF1R phosphorylation induced by CSF1 in the presence of .

[0024] Figure 4 A- Figure 4D shows the effect of CSF1R inhibitor on CSF1-induced BV2 cell proliferation. The following experiments measured BV2 cell proliferation in response to CSF1 using the Cell Titer GLO assay. Figure 4 A shows that CSF1-induced cell proliferation was inhibited in the presence of 500 nM CSF1R inhibitors (GW2580 or BLZ945). The numbers above each bar indicate the percentage change (%) in proliferation. P values ​​were obtained from Dunnett's multiple comparison test. CSF1R inhibitors (GW2580 ( Figure 4 B) BLZ945( Figure 4 C) and Example 16 ( Figure 4 D)) shows dose-dependent inhibition of CSF1-directed cell proliferation.

[0025] Figure 5 A and Figure 5 B shows the effect of CSF1R inhibitors on the survival of primary rat microglial cells cultured in vitro. This experiment measured the efficacy of CSF1R inhibitors in vitro using primary brain glial cells from rat cortex. Figure 5 A shows that the CSF1R inhibitor (Example 16) exhibited a dose-dependent inhibition of primary rat microglial survival after 3 days of exposure. Figure 5 B shows that CSF1R inhibitors (Examples 73, 134 and 136) exhibited dose-dependent inhibition of primary rat microglial survival after 3 days of exposure.

[0026] Figure 6 The effects of CSF1R inhibitors on the levels of phosphorylated CSF1R (pCSF1R) in THP-1 cells, a human monocyte-like cell line, stimulated by CSF1R are shown. Figure 6 In Example 16, dose-dependent inhibition of CSF1R phosphorylation in CSF1R-stimulated THP-1 monocytes is shown.

[0027] Figure 7 A and Figure 7 B shows the effect of CSF1R inhibitor on the survival of human iPSC-derived microglia (hiPSC-MG). Figure 7 A shows that the CSF1R inhibitor (Example 16) exhibited a dose-dependent inhibition of hiPSC-MG survival (IC50=31.5 nM). Figure 7 B shows that CSF1R inhibitors (BLZ945, Example 73, Example 136, and Example 134) exhibited dose-dependent inhibition of hiPSC-MG survival.

[0028] Figure 8 A and Figure 8B shows the effect of Example 134 on the cortex of female C57BL / 6J mice after 7 days of oral gavage BID dosing regimen ( Figure 8 A) and hippocampus ( Figure 8 B) Effect of depletion of Iba1+ cell density (iba1 is a marker for microglia) in . DETAILED DESCRIPTION

[0029] 1. Compounds

[0030] In a first embodiment, the present disclosure provides a compound represented by formula (I):

[0031]

[0032] or a pharmaceutically acceptable salt or tautomer thereof, wherein:

[0033] Q is C or N;

[0034] When Q is N, QX 1 is a single bond and X 1 It is C=O;

[0035] When Q is C, QX 1 is a double bond and X 1 Is N or CR 1 ;

[0036] Z is CH or NH;

[0037] When Z is NH, ZX 3 is a single bond and X 3 is C=O;

[0038] When Z is CH, ZX 3 is a double bond and X 3 Is N or CR 3 ;

[0039] X 2 Is N or CR 2 ;

[0040] X 4 Is N or CR 4 ;

[0041] X 5 Is N or CR 5 ;

[0042] R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, -CN, -OH, C optionally substituted with one to three deuteriums1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0- 4C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R 1 , R 2 , R 3 , R 4 or R 5 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0043] A 1 , A 2 , A 3 and A 4 Each independently is N or CR A ; and A 1 , A 2 , A 3 and A 4 No more than two of them are N;

[0044] Each R A are independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R A The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0045] Ring B is phenyl, or a 5- or 6-membered monocyclic heteroaryl;

[0046] Each R B are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; or

[0047] Two R's B Together with the ring B atoms to which they are attached, they form a 5-7 membered monocyclic ring or a 6-9 membered bicyclic ring fused to ring B, wherein the 5-7 membered monocyclic ring or the 6-9 membered bicyclic ring is optionally substituted by one or two groups selected from the group consisting of CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and 3-6 membered cycloalkyl;

[0048] R C and R D are each independently selected from hydrogen, deuterium, F and methyl;

[0049] Each R * Independently selected from the group consisting of: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3-6 membered carbocyclyl or 4-6 membered heterocyclyl; and

[0050] m is 0, 1, 2, 3 or 4.

[0051] In a second embodiment, the present disclosure provides a compound according to the first embodiment, or a pharmaceutically acceptable salt thereof, wherein:

[0052] R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R1 , R 2 , R 3 , R 4 or R 5 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0053] Each R A are independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R A The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C1-6 Haloalkoxy;

[0054] Each R B are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; or

[0055] Two R's B Together with the ring B atoms to which they are attached, they form a 5,6-membered ring fused to ring B, wherein the 5,6-membered ring is optionally substituted with one or two groups selected from the group consisting of CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C1-6 haloalkoxy; and

[0056] R C and R D are each independently selected from hydrogen, F and methyl. Definitions of the remaining variables are provided in the first embodiment.

[0057] In a third embodiment, the present disclosure provides a compound according to the second embodiment, wherein the compound is represented by formula (II-A):

[0058]

[0059] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the second embodiment. Alternatively, definitions of the variables are provided in the first embodiment.

[0060] In a fourth embodiment, the present disclosure provides a compound according to the second embodiment, wherein the compound is represented by any one of Formula (III-A-1), Formula (III-A-2), Formula (III-A-3), Formula (III-A-4), Formula (III-A-5), Formula (III-A-6), or Formula (III-A-7):

[0061]

[0062]

[0063] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the second embodiment. Alternatively, definitions of the variables are provided in the first embodiment.

[0064] In a fifth embodiment, the present disclosure provides a compound according to the second embodiment, wherein the compound is represented by any one of Formula (III-B-1), Formula (III-B-2), Formula (III-C-1), Formula (III-C-2), or Formula (III-C-3):

[0065]

[0066]

[0067] or a pharmaceutically acceptable salt thereof. Definitions of the remaining variables are provided in the second embodiment. Alternatively, definitions of the variables are provided in the first embodiment.

[0068] In a sixth embodiment, the present disclosure provides a compound according to any one of the second to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein is phenyl or pyridyl, each of which is optionally substituted by one or two R AThe definitions of the remaining variables are provided in any of the second to fifth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment.

[0069] In a seventh embodiment, the present disclosure provides a compound according to any one of the second to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted by one or two R B Substituted phenyl, each R B are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-OR * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two halogen or C 1-6 Alkyl substituted. Definitions of the remaining variables are provided in any of the second through sixth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0070] In an eighth embodiment, the present disclosure provides a compound according to any one of the second to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted by one or two R B Substituted 5,6-membered monocyclic heteroaryl, each R B are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-OR * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two halogen or C 1-6 Alkyl substituted. Definitions of the remaining variables are provided in any of the second through sixth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0071] In a ninth embodiment, the present disclosure provides a compound according to any one of the second to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl or a 5,6-membered monocyclic heteroaryl, each of which is optionally substituted by one to four R BReplace, and the two R B Together with the ring B atoms to which they are attached, they form a 5,6-membered ring fused to ring B, wherein the 5,6-membered fused ring is optionally fused via one or two CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 The definitions of the remaining variables are provided in any of the second to sixth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment.

[0072] In the tenth embodiment, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof according to any one of the second to sixth embodiments, wherein Ring B is pyrazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl or benzo[d][1,3]dioxolyl. The definitions of the remaining variables are provided in any one of the second to sixth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment.

[0073] In an eleventh embodiment, the present disclosure provides a compound according to any one of the second to tenth embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * Definitions of the remaining variables are provided in any of the second to tenth embodiments.

[0074] In a twelfth embodiment, the present disclosure provides a compound according to any one of the second to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * Definitions of the remaining variables are provided in any of the second to eleventh embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0075] In a thirteenth embodiment, the present disclosure provides a compound according to any one of the second to twelfth embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, -(CH2) optionally substituted with one to three deuterium 0-2 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * Definitions of the remaining variables are provided in any of the second to twelfth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0076] In a fourteenth embodiment, the present disclosure provides a compound according to any one of the second to thirteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * Definitions of the remaining variables are provided in any of the second to thirteenth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0077] In a fifteenth embodiment, the present disclosure provides a compound according to any one of the second to fourteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 5 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-NR * R * 、-NR * C(O)R * and-NR * C(O)OR * Definitions of the remaining variables are provided in any of the second to fourteenth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0078] In a sixteenth embodiment, the present disclosure provides a compound according to any one of the second to fifteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein each RA are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * Definitions of the remaining variables are provided in any of the second to fifteenth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0079] In a seventeenth embodiment, the present disclosure provides compounds according to any one of the second to sixteenth embodiments, wherein each R B are independently selected from halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, -(CH2) optionally substituted with one to three deuterium 0-2 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * and -(CH2) optionally substituted by one or two halogens 0或1 -3-6 membered cycloalkyl. Definitions of the remaining variables are provided in any of the second through sixteenth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0080] In an eighteenth embodiment, the present disclosure provides compounds according to any one of the second to seventeenth embodiments, wherein each R *are independently H or C 1-4 Definitions of the remaining variables are provided in any of the second to seventeenth embodiments. In certain embodiments, each R * are independently H or C 1-2 Alkyl. Alternatively, definitions of the variables are provided in the first embodiment.

[0081] In a nineteenth embodiment, the present disclosure provides compounds according to any one of the second to eighteenth embodiments, wherein each R 1 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy (preferably H); and each R 2 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The definitions of the remaining variables are provided in any of the second to eighteenth embodiments. In certain embodiments, R 1 is H and R 2 is H. Alternatively, definitions of the variables are provided in the first embodiment.

[0082] In a twentieth embodiment, the present disclosure provides compounds according to any one of the second to nineteenth embodiments, wherein each R 3 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 haloalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy and C 1-4 The definitions of the remaining variables are provided in any of the second to nineteenth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment. In certain embodiments, each R 3 are independently H, CN, halogen, C 1-4 alkyl or C optionally substituted with one to three deuterium 1-4 In certain embodiments, R 3 It is H, CN, F, Cl, -CH3 or -OCH3.

[0083] In a twenty-first embodiment, the present disclosure provides compounds according to any one of the second to twentieth embodiments, wherein each R 4 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4The definitions of the remaining variables are provided in any of the second to twentieth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment. In certain embodiments, each R 4 is H, F or C 1-4 In certain embodiments, R 4 It is H, F or -OCH3.

[0084] In a twenty-second embodiment, the present disclosure provides compounds according to any one of the second to twenty-first embodiments, wherein each R 5 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The definitions of the remaining variables are provided in any of the second to twenty-first embodiments. Alternatively, the definitions of the variables are provided in the first embodiment. In certain embodiments, each R 5 It's H.

[0085] In a twenty-third embodiment, the present disclosure provides a compound according to any one of the second to twenty-second embodiments, wherein each R A Independently selected from H, C 1-2 alkyl or C optionally substituted with one to three deuterium 1-2 Alkoxy. Definitions of the remaining variables are provided in any of the second to twenty-second embodiments. Alternatively, definitions of the variables are provided in the first embodiment. In certain embodiments, each R A is H, -OCH3 or -OCD3. In certain embodiments, each R A It is H or -OCH3.

[0086] In a twenty-fourth embodiment, the present disclosure provides a compound according to any one of the second to twenty-third embodiments, wherein each R B independently selected from halogen, -OH, C 1-3 Alkyl, C 1-3 haloalkyl, -(CH2) optionally substituted with one to three deuterium 0-2 C 1-2 Alkoxy, C 1-2 Haloalkoxy, -(CH2) 0-2 NR * R * or 3-6 membered cycloalkyl optionally substituted with one or two halogens (preferred). Definitions of the remaining variables are provided in any of the second to twenty-third embodiments. Alternatively, definitions of the variables are provided in the first embodiment. In certain embodiments, each R BIn certain embodiments, each R is independently selected from F, Cl, -OH, -CH, -CHCH, -CH(CH), -CHF, -CF, -CHN(CH), -CHOCH, -OCH, -OCHF, -OCD, and cyclopropyl optionally substituted with one or two fluorine radicals. B Independently selected from F, Cl, -OH, -CH3, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -OCH3, -OCHF2 and cyclopropyl.

[0087] In a twenty-fifth embodiment, the present disclosure provides a compound according to any one of the second to twenty-fourth embodiments,

[0088] in yes Definitions of the remaining variables are provided in any of the second to twenty-fourth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0089] In a twenty-sixth embodiment, the present disclosure provides a compound according to any one of the second, thirteenth, fourteenth, sixteenth to eighteenth, twentieth, twenty-first, twenty-third, and twenty-fourth embodiments, wherein the compound is represented by formula (IV-A-1):

[0090]

[0091] or a pharmaceutically acceptable salt thereof. Definitions of the remaining variables are provided in any of the second, thirteenth, fourteenth, sixteenth to eighteenth, twentieth, twenty-first, twenty-third, and twenty-fourth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0092] In a twenty-seventh embodiment, the present disclosure provides a compound according to any one of the second, thirteenth, fourteenth, sixteenth to eighteenth, twentieth, twenty-first, twenty-third, and twenty-fourth embodiments, wherein the compound is represented by formula (IV-A-2):

[0093]

[0094] or a pharmaceutically acceptable salt thereof. Definitions of the remaining variables are provided in any of the second, thirteenth, fourteenth, sixteenth to eighteenth, twentieth, twenty-first, twenty-third, and twenty-fourth embodiments. Alternatively, definitions of the variables are provided in the first embodiment.

[0095] In a twenty-eighth embodiment, the present disclosure provides a compound according to any one of the first to twelfth, fourteenth to nineteenth, and twenty-first to twenty-seventh embodiments, a pharmaceutically acceptable salt or a tautomer thereof, wherein each R3 are independently selected from H, halogen, -CN, C optionally substituted with one to three deuteriums 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 hydroxyalkyl, optionally substituted with one to three deuteriums -C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-NR * R * , 3-6 membered carbocyclic group, 3-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein R 3 The carbocyclic group, heterocyclic group, phenyl group or heteroaryl group in the group represented by is optionally substituted by one or two CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Definitions of the remaining variables are provided in any of the first through twelfth, fourteenth through nineteenth, and twenty-first through twenty-seventh embodiments.

[0096] In the twenty-ninth embodiment, the present disclosure provides a compound of the twenty-eighth embodiment, a pharmaceutically acceptable salt or a tautomer thereof, wherein each R 3 are independently selected from H, halogen, CN, C optionally substituted with one to three deuteriums 1-4 alkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, NR * R * 、-C(O)NR * R * , 3-6 membered cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-6 membered heteroaryl or 6-oxa-3-azabicyclo[3.1.1]heptyl, wherein R 3 The cycloalkyl, heterocyclic or heteroaryl groups in the groups represented by are optionally substituted by one or two halogens, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Definitions of the remaining variables are provided in a twenty-eighth embodiment.

[0097] In the thirtieth embodiment, the present disclosure provides a compound of the twenty-ninth embodiment, a pharmaceutically acceptable salt or a tautomer thereof, wherein each R 3Independently selected from H, F, Cl, CN, CH3, OCH3, OCD3, -N(CH3)2, -CON(CH3)2, cyclopropane, azetidinyl optionally substituted with one or two fluorine or OCH3, imidazole optionally substituted with CH3, morpholinyl, pyridinyl, piperazinyl optionally substituted with CH3, pyrrolidinyl optionally substituted with OCH3, pyrazolyl optionally substituted with CH3, thiazole or 6-oxa-3-azabicyclo[3.1.1]heptanyl optionally substituted with CH3. Definitions of the remaining variables are provided in the twenty-ninth embodiment.

[0098] In a thirty-first embodiment, the present disclosure provides a compound of the thirtieth embodiment, a pharmaceutically acceptable salt or a tautomer thereof, wherein each R 3 are independently selected from H or OCH3. Definitions of the remaining variables are provided in a thirtieth embodiment.

[0099] In the thirty-second embodiment, the present disclosure provides a compound of any one of the first to sixth, eleventh to twenty-fifth, and twenty-eighth to thirty-first embodiments, a pharmaceutically acceptable salt or a tautomer thereof, wherein Ring B is phenyl, a 5- or 6-membered monocyclic heteroaryl, optionally with one or two R B Replace, each R B independently selected from halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)NR * R * 、-(CH2) 0-1 NR * R * 、-NR * C(O)R * , -3-6 membered monocyclic carbocyclic group, -3-6 membered monocyclic heterocyclic group; wherein R B The carbocyclic or heterocyclic group in the group represented by is optionally substituted by one or two halogen or C 1-4 Definitions of the remaining variables are provided in the first through sixth, eleventh through twenty-fifth, and twenty-eighth through thirty-first embodiments.

[0100] In the thirty-third embodiment, the present disclosure provides a compound of the thirty-second embodiment, a pharmaceutically acceptable salt or a tautomer thereof, wherein each R B Independently selected from F, Cl, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxyalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)NR * R * 、-CH2NR * R * 、-NR * C(O)R * , -3-5 membered monocyclic cycloalkyl, -3-5 membered monocyclic heterocyclic group; wherein R B The cycloalkyl or heterocyclic group in the group represented by 1-2 Alkyl Substituted. Definitions of the remaining variables are provided in a thirty-second embodiment.

[0101] In the thirty-fourth embodiment, the present disclosure provides a compound of any one of the first to sixth, eleventh to twenty-fifth, and twenty-seventh to thirty-first embodiments, a pharmaceutically acceptable salt, or a tautomer thereof, wherein ring B is phenyl or a 5,6-membered monocyclic heteroaryl, each of which is optionally substituted by one to four R B Replace, and the two R B Together with the ring B atoms to which they are attached, they form a 5-7 membered monocyclic ring or a 6-9 membered bicyclic ring fused to ring B, wherein the 5-7 membered monocyclic ring or the 6-9 membered bicyclic ring is optionally substituted by one or two CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 The definitions of the remaining variables are provided in the first through sixth, eleventh through twenty-fifth, and twenty-seventh through thirty-first embodiments.

[0102] In the thirty-fifth embodiment, the present disclosure provides a compound of the thirty-fourth embodiment, a pharmaceutically acceptable salt or a tautomer thereof, wherein both R B Together with the ring B atoms to which it is attached, it forms a ring selected from:

[0103]

[0104]

[0105] Each of the rings is optionally substituted with one or two groups selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Definitions of the remaining variables are provided in a thirty-fourth embodiment.

[0106] In a thirty-sixth embodiment, the present disclosure provides a compound of the thirty-fifth embodiment, a pharmaceutically acceptable salt or a tautomer thereof, wherein both R B Together with the ring B atoms to which it is attached, it forms a Definitions of the remaining variables are provided in the thirty-fifth embodiment.

[0107] In a thirty-seventh embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt or a tautomer thereof according to any one of the first to thirty-sixth embodiments, wherein R C is H, and R D is H. Definitions of the remaining variables are provided in the first to thirty-sixth embodiments.

[0108] In a thirty-eighth embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt, or a tautomer thereof, of any one of the first, third to twenty-fifth, and twenty-eighth to thirty-sixth embodiments, wherein R C is H, F or deuterium, and R D is H or deuterium. Definitions of the remaining variables are provided in the first, third to twenty-fifth, and twenty-eighth to thirty-sixth embodiments.

[0109] In a thirty-ninth embodiment, the present disclosure provides a compound represented by formula (I'):

[0110]

[0111] or a pharmaceutically acceptable salt thereof, wherein:

[0112] Ring A1 is a 5,6 or 6,6-membered nitrogen-containing bicyclic heteroaryl group;

[0113] Ring B1 is a 3-6 membered monocyclic carbocyclic group or a 3-6 membered monocyclic heterocyclic group;

[0114] Each R A1 are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R *、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R A1 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution;

[0115] Each R B1 are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R* 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B1 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; and / or

[0116] Two R's B1 Together with the ring B1 atoms to which they are attached, they form a 5,6-membered monocyclic ring or a 6-9-membered bicyclic ring fused to ring B1, wherein the 5,6-membered ring or the 6-9-membered bicyclic ring is optionally substituted by one or two CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted with haloalkoxy or 3-6 membered cycloalkyl;

[0117] Each R * Independently selected from the group consisting of: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered carbocyclyl or 4-6 membered heterocyclyl;

[0118] m1 is 0, 1, 2, 3, or 4; and

[0119] n1 is 0, 1, 2 or 3.

[0120] In the fortieth embodiment, the present disclosure provides a compound of the thirty-ninth embodiment, or a pharmaceutically acceptable salt thereof, wherein: yes

[0121]

[0122] in Indicates the point to which -CH2- is attached; represents the points connected by ring B1; and R A1 It is C 1-4 Alkyl or C1-4 Definitions of the remaining variables are provided in the thirty-ninth embodiment.

[0123] In the forty-first embodiment, the present disclosure provides a compound of the thirty-ninth or fortieth embodiment, or a pharmaceutically acceptable salt thereof, wherein:

[0124] Ring B1 is

[0125] R B1 It is C 1-4 Alkyl or C 1-4 alkoxy; and

[0126] n1 is 0 or 1. Definitions of the remaining variables are provided in the thirty-ninth or fortieth embodiment.

[0127] In one embodiment, the present disclosure provides a compound provided herein selected from the compounds disclosed in the Examples and Table 1, or a pharmaceutically acceptable salt thereof.

[0128] 2. Definition

[0129] The term "halogen" as used herein refers to fluoride, chloride, bromide or iodide.

[0130] The term "alkyl" used alone or as part of a larger moiety (such as "alkoxy" or "haloalkyl" and the like) means a radical of the formula -C n H (2n+1) Unless otherwise specified, an alkyl group generally has 1 to 6 carbon atoms, i.e., C 1-6 As used herein, "C 1-6 "Alkyl" means a group having 1 to 6 carbon atoms in a straight or branched chain arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like.

[0131] The term "haloalkyl" means an alkyl group optionally substituted with one or more halogen atoms. In one embodiment, the alkyl group may be substituted with one to three halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0132] The term "hydroxyalkyl" means an alkyl group optionally substituted with one or more (eg, one or two) hydroxy groups. In one embodiment, the alkyl group may be substituted with one hydroxy group.

[0133] The term "alkenyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by a double bond.

[0134] The term "alkynyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by a triple bond.

[0135] The term "alkoxy" means an alkyl group attached via an oxygen linking atom represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy and butoxy.

[0136] The term "alkoxyalkyl" refers to an alkyl group (eg, C1-C4) substituted with one or more alkoxy groups (eg, (C1-C4) alkoxy groups). 1-6 In one embodiment, the alkyl group may be substituted with one alkoxy group.

[0137] The term "carbocyclyl" refers to a 3-12 membered non-aromatic hydrocarbon ring system. In one embodiment, the carbocyclyl is a 3, 4, 5, 6, 7 or 8 membered monocyclic or bicyclic or a 7, 8, 9, 10, 11 or 12 membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated or partially unsaturated. Any substitutable ring atom may be substituted (e.g., by one or more substituents). Examples of such carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl and cyclooctadienyl. In one embodiment, the carbocyclyl is intended to include bridged rings, fused rings and spirocyclic rings. In spirocyclic carbocyclyls, two different rings share one atom. An example of a spirocyclic carbocyclyl is spiro[3.3]heptanyl. In a bridged carbocyclyl, the rings share at least two shared non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantyl. In a fused ring carbocyclyl system, two or more rings may be fused together such that the two rings share a common bond.

[0138] The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, a cycloalkyl group may have 3 to 6 ring carbons. Any substitutable ring atom may be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkyl groups may include a variety of fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and the like. Cycloalkyls also include spirocycles (e.g., spirocycles in which two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0139] The term "heterocyclyl" or "heterocycle" refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("3-12 membered heterocyclyl"), wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones. In some embodiments, the heterocyclyl is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("3- to 7-membered heterocyclyl"), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. The heterocyclyl may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl"); polycyclic ring systems include fused systems, bridged systems, or spiro systems). The heterocyclic polycyclic ring system may include heteroatoms in one or more rings of the polycyclic ring system (including polycyclic ring systems with non-aromatic rings fused to phenyl or heteroaryl rings). When the heterocyclic group is a polycyclic ring system, the ring system includes at least one non-aromatic ring. Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxetanyl, thiepanyl, tetrahydropyridinyl and the like. The heterocyclic polycyclic ring system may include heteroatoms in one or more rings of the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.

[0140] Spiroheterocyclyl refers to a 5- to 12-membered polycyclic heterocyclic group having rings connected by a common carbon atom (called a spiro atom), wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are C, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron system. Representative examples of spiroheterocyclyl include, but are not limited to, the following groups:

[0141]

[0142] Fused heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl, wherein each ring in the group shares a pair of adjacent ring atoms with another ring in the group, wherein one or more rings may contain one or more double bonds, but at least one ring does not have a completely conjugated π electron system, and wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are C. Representative examples of fused heterocyclyls include, but are not limited to, the following groups:

[0143]

[0144] Bridged heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group, wherein any two rings in the group share two non-connected atoms, the rings may have one or more double bonds but do not have a completely conjugated π electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen and sulfur (including sulfoxides and sulfones) as ring atoms, and the remaining ring atoms are C. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

[0145]

[0146] Generally, the carbocyclyl, cycloalkyl or heterocyclyl may be unsubstituted or substituted, where valence permits, with one or more substituents, wherein the substituents may be independently selected from a number of groups such as oxo, -CN, halogen, alkyl and alkoxy, optionally alkyl substitutions may be further substituted.

[0147] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system), and has a completely conjugated π electron system. The term "aryl" can be used interchangeably with the terms "aryl ring", "carbocyclic aromatic ring", "aryl group" and "carbocyclic aromatic group". Representative examples of aryl are phenyl and naphthyl.

[0148] The term "heteroaryl" refers to a group of a 5 to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl is a 5 or 6-membered heteroaryl having ring carbon atoms and 1 to 4 ring heteroatoms (usually 1 to 2). Heteroaryl can be connected by ring carbon atoms, or by ring nitrogen atoms when valence permits. Generally, heteroaryl can be unsubstituted, or substituted by one or more substituents when valence permits, and the substituents are independently selected from halogen, OH, alkyl, alkoxy and amino (e.g., NH2, NH alkyl, N (alkyl)2), optionally, alkyl can be further substituted.

[0149] Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, indolyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl or benzisoxazolyl. "Substituted heteroaryl" is substituted on any one or more substitutable ring atoms that are ring carbon or ring nitrogen atoms bonded to hydrogen.

[0150] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise indicated, it means that any portion of the moiety known to those skilled in the art to be available for substitution may be substituted, including one or more substituents. If more than one substituent is present, each substituent may be independently selected. Such substitution means are well known in the art and / or taught by the present disclosure. The optionally present substituent may be any substituent suitable for attachment to the moiety.

[0151] In the absence of explicit enumeration of suitable substituents, exemplary substituents include, but are not limited to: C 1-5 Alkyl, C 1-5 Hydroxyalkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, halogen, hydroxy, cyano, amino, -CN, -NO2, -OR c1 、-NR a1 R b1 、-S(O) i R a1 、-NR a1 S(O) i R b1 、-S(O) i NR a1 R b1 、-C(=O)OR a1 、-OC(=O)OR a1 、-C(=S)OR a1 、-O(C=S)R a1 、-C(=O)NR a1 R b1 、-NR a1 C(=O)R b1 、-C(=S)NR a1 R b1 、-C(=O)R a1 、-C(=S)R a1 NR a1 C(=S)R b1 、-O(C=O)NR a1 R b1 、-NR a1 (C=S)OR b1 、-O(C=S)NR a1 R b1 、-NR a1 (C=O)NR a1 R b1 、-NR a1 (C=S)NR a1 R b1 , phenyl or 5-6 membered heteroaryl. Each R a1 and each R b1 Independently selected from -H and C 1-5 Alkyl, optionally hydroxy or C 1-3 Alkoxy substituted; R c1 Yes - H, C 1-5 Haloalkyl or C 1-5 Alkyl, where C 1-5 The alkyl group is optionally substituted with a hydroxyl group or a C1-C3 alkoxy group.

[0152] Symbols used in this article Refers to the points where parts are connected.

[0153] Pharmaceutically acceptable salts

[0154] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation and allergic response within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0155] Pharmaceutically acceptable salts of the compounds of any of the above formulae include acid addition salts and basic salts.

[0156] Pharmaceutically acceptable salts of the compounds disclosed herein are included in this teaching. Compounds with basic groups can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid and succinic acid). Compounds with acidic groups (such as carboxylic acids) of this teaching can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0157] Pharmaceutically acceptable salts of compounds of any of the above formulae can be prepared by one or more of three methods:

[0158] (i) by reacting a compound of any of the above formulae with a desired acid or base;

[0159] (ii) by removing an acid or base labile protecting group from a suitable precursor of a compound of any of the above formulae or by ring opening a suitable cyclic precursor (eg a lactone or lactam) using the required acid or base; or

[0160] (iii) converting one salt of a compound of any of the above formulae into another by reaction with an appropriate acid or base or with the aid of a suitable ion exchange column.

[0161] All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to almost non-ionized.

[0162] The compounds of any of the above formulae and pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.

[0163] Stereoisomers and other variants

[0164] Compounds of any of the above formulae may exhibit one or more isomerisms (e.g., optical, geometric, or tautomerism). Such variations are implicit in the compounds of any of the above formulae because they are defined by reference to their structural features and are therefore within the scope of the present disclosure.

[0165] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have the R or S configuration, or can be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

[0166] When a compound is designated by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or by its structure indicating a single enantiomer (e.g., by a "wedge-shaped" bond indicating the configuration), unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). The optical purity is the weight of the named or depicted enantiomer in the mixture divided by the total weight of the two enantiomers in the mixture.

[0167] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereoisomer pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity is determined by dividing the total weight of the stereoisomers encompassed by the name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0168] When two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are linked by "and", a mixture of the two stereoisomers is intended.

[0169] When two stereoisomers are depicted by their chemical names or structures and the names or structures are linked by "or," it means one or the other of the two stereoisomers, but not both.

[0170] When a disclosed compound having a chiral center is depicted by a structure without showing the configuration at the chiral center, the structure is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without using "S" or "R" to indicate the configuration at the chiral center, the name is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0171] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0172] The term "geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a carbocyclic ring, or a bridged bicyclic ring system. According to the Cahn-Ingold-Prelog priority rule, substituent atoms (except hydrogen) on each side of a carbon-carbon double bond can be in the E or Z configuration. In the "E" configuration, the substituents with the highest priority are on opposite sides relative to the carbon-carbon double bond. In the "Z" configuration, the substituents with the highest priority are oriented on the same side relative to the carbon-carbon double bond.

[0173] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to substituents on opposite sides of the double bond. Arrangements of substituents around a carbocyclic ring may also be designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the plane of the ring, and the term "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are disposed on both the same side and opposite sides of the plane of the ring is designated "cis / trans."

[0174] Compounds of any of the above formulae may exhibit one or more tautomerisms. Such variations are implicit to compounds of any of the above formulae because they are defined by reference to their structural features and are therefore within the scope of the present disclosure.

[0175] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") may occur. In compounds of any of the above formulae containing, for example, an imino, keto or oxime group, this may take the form of proton tautomerism, or in compounds containing aromatic moieties, so-called valence tautomerism. It can be seen that a single compound may exhibit more than one type of isomerism.

[0176] In some cases, there are tautomeric forms of the disclosed compounds, such as the tautomeric structures shown below:

[0177]

[0178] When a geometric isomer is depicted by name or structure, it is understood that the named or depicted isomer is present to a greater extent than the other isomer, i.e., the geometric purity of the named or depicted geometric isomer is greater than 50% by weight, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. The geometric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0179] It must be emphasized that compounds of any of the above formulae are drawn herein in a single tautomeric form and that all possible tautomeric forms are included within the scope of the present disclosure.

[0180] 3. Administration and Dosing

[0181] Typically, the compounds of the present disclosure are administered in an amount effective to treat a disorder as described herein. The compounds of the present disclosure may be administered as the compounds themselves, or alternatively, as pharmaceutically acceptable salts. For administration and dosing purposes, the compounds themselves or their pharmaceutically acceptable salts will be referred to as compounds of the present disclosure.

[0182] The compounds of the present disclosure are administered by any appropriate route, in the form of pharmaceutical compositions adapted to such route and in doses effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally or topically.

[0183] The compounds of the present disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, by which the compound enters the bloodstream directly from the oral cavity.

[0184] In another embodiment, the compounds of the present disclosure may also be administered directly into the bloodstream, into a muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle-type (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0185] In another embodiment, the compounds of the present disclosure may also be topically applied to the skin or mucosa, i.e., transdermally or transdermally. In another embodiment, the compounds of the present disclosure may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may also be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be administered directly to the eye or ear.

[0186] The dosage regimen for the compounds of the present disclosure and / or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosage regimen can vary widely. In one embodiment, the total daily dose of the compounds of the present disclosure for treating the indicated conditions discussed herein is generally from about 0.001 to about 100 mg / kg (i.e., mg of the compounds of the present disclosure / kg body weight).

[0187] For oral administration, the composition can be provided in the form of tablets containing 0.1-500 mg of active ingredient for symptomatic adjustment of the dosage for the patient. The medicament generally contains about 0.01 mg to about 500 mg of active ingredient. During constant rate infusion, the intravenous dose can be in the range of about 0.01 to about 10 mg / kg / minute.

[0188] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, such as primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable subjects. Human subjects can be of either sex and at any stage of development.

[0189] 4. Pharmaceutical Composition

[0190] In another embodiment, the present disclosure comprises a pharmaceutical composition. Such a pharmaceutical composition comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0191] As used herein, "pharmaceutically acceptable carriers or excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and physiologically compatible analogs. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and isotonic agents, e.g., sugars, sodium chloride, or polyols, such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents or small amounts of auxiliary substances, such as wetting agents or emulsifiers, preservatives, or buffers, enhance the shelf life or effectiveness of the antibody or antibody portion.

[0192] The compositions of the present disclosure may be in various forms. These forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0193] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0194] Oral administration of solid dosage forms can be presented, for example, in discrete units, such as hard or soft capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, the oral dosage form is a sublingual dosage form, such as, for example, a lozenge. In such solid dosage forms, the compound of any of the above formulas is typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage form may also contain a buffer or may be prepared with an enteric coating.

[0195] In another embodiment, oral administration may be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also include adjuvants such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners) and / or aromatics.

[0196] In another embodiment, the present disclosure encompasses parenteral dosage forms.

[0197] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion. Injectable preparations (ie, sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants, wetting agents and / or suspending agents.

[0198] In another embodiment, the present disclosure comprises a topical dosage form.

[0199] "Topical application" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhaled administration. Compositions for topical application also include, for example, topical gels, sprays, ointments and creams. Topical preparations may include compounds that enhance the absorption or penetration of active ingredients through the skin or other affected areas. When the compounds of the present disclosure are applied by a transdermal device, a reservoir and a porous membrane type or a solid matrix type patch will be used to complete the application. Typical preparations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, sheets, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see, for example, Finnin and Morgan, J. Pharm. Sci., 88: 955-958, 1999.

[0200] Preparations suitable for topical application to eyes include, for example, eye drops, in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical preparations suitable for eye or ear administration may be in the form of drops of micronized suspensions or solutions in isotonic, pH-adjusted sterile saline. Other preparations suitable for eye and ear administration include ointments, biodegradable implants (i.e., absorbable gel sponges, collagen) and non-biodegradable implants (i.e., silicones), thin slices, lenses, and microparticles or vesicular systems (such as nonionic bodies (niosomes) or liposomes). Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum (gelan gum)) may be incorporated with preservatives (such as benzalkonium chloride (benzalkoniumchloride)). Such preparations may also be delivered by iontophoresis.

[0201] For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently in the form of solutions or suspensions from pump spray containers squeezed or pumped by the patient, or as aerosol spray presentations from pressurized containers or nebulizers, delivered using suitable propellants. Formulations suitable for intranasal administration are generally administered in the following forms: dry powder from a dry powder inhaler (alone; as a mixture, for example, as a dry blend with lactose; or as mixed component particles, for example, mixed with phospholipids (such as phosphatidylcholine)); or as an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably a nebulizer using electrohydrodynamics to generate a fine mist) or a nebulizer (with or without a suitable propellant, for example 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). For intranasal applications, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

[0202] In another embodiment, the present disclosure includes rectal dosage forms. Such rectal dosage forms can be in the form of, for example, suppositories. Cocoa butter is a traditional suppository base, but a variety of alternatives can be used if appropriate.

[0203] Other carrier materials and modes of administration known in the pharmaceutical art may also be used.The pharmaceutical compositions of the present disclosure may be prepared by any well-known pharmaceutical techniques, such as effective formulation and administration procedures.

[0204] The above considerations for effective formulation and administration procedures are well known in the art and are described in standard textbooks. The formulation of drugs is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 1999.

[0205] 5. Treatment Methods

[0206] The compounds of the present disclosure can inhibit CSF-1R and are therefore useful for treating diseases where the underlying pathology is mediated in whole or in part by CSF-1R. Such diseases include autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cancer, metabolic diseases, obesity or obesity-related diseases.

[0207] The term "autoimmune disease" refers to a disease or condition that originates from and / or is directed against an individual's own tissues or organs, or a co-segregate or manifestation thereof, or a condition resulting therefrom. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), collagen-induced arthritis, psoriasis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, asthma, autoimmune nephritis, idiopathic thrombocytopenic purpura (ITP), and myeloproliferative diseases such as myelofibrosis, post-polycythemia vera / essential thrombocythemia myelofibrosis (post-PV / ET myelofibrosis).

[0208] The term "inflammatory disease" or "inflammatory disorder" refers to a pathological state in which inflammation results, inter alia, from neutrophil chemotaxis. Non-limiting examples of inflammatory diseases include systemic and local inflammation, inflammation associated with immunosuppression, organ transplant rejection, allergic diseases, inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (IBD, such as Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including tissue reperfusion injury caused by surgery, myocardial ischemia (such as myocardial infarction), cardiac arrest, abnormal contractile response of coronary vessels after reperfusion and percutaneous transluminal coronary angioplasty, surgical tissue reperfusion injury of stroke and abdominal aortic aneurysm; cerebral edema secondary to stroke; cranial trauma and hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease ( disease); dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome, and vasculitis; diseases involving leukocytic infiltration; central nervous system (CNS) inflammatory diseases and multiple organ injury syndrome secondary to sepsis or trauma; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases including glomerulonephritis; sepsis; sarcoidosis; immunopathological reactions to tissue / organ transplantation; pulmonary inflammation including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, etc. Preferably, indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritis disorders, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and pyresis, as well as any disease associated with inflammation and related disorders.

[0209] In some embodiments, the autoimmune disease or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behcet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, ischemia-reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and chemotherapy drug-induced organ damage.

[0210] The compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in a subject suffering from a neurodegenerative disease.

[0211] The term "neurodegenerative disease" refers to a degenerative disease or disorder of the nervous system caused by neuronal degeneration and apoptosis. Examples of neurodegenerative diseases include, but are not limited to, Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), cortical basal degeneration, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (CMT), etc.

[0212] In some embodiments, the neurodegenerative disease is selected from Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA).

[0213] The compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in a subject suffering from cancer.

[0214] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growth at allosteric sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies. The term "cancer" encompasses diseases of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" encompasses primary cancers, and further metastatic cancers.

[0215] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; colon cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent prostate cancer and androgen-independent prostate cancer; testicular cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial or primary peritoneal cancer; cervical cancer; endometrial cancer; gastrointestinal stromal tumor (GIST); gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, melanoma and basal carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas, adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone cancer; sarcomas, including, for example, Kaposi's sarcoma (Kaposi's sarcoma); adrenal cancer; mesothelioma; mesothelial carcinoma; choriocarcinoma; muscle cancer; connective tissue cancer; tenosynovial giant cell tumor; and thyroid cancer.

[0216] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL); follicular lymphoma; mantle cell lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); multiple myeloma (MM); Waldenstrom macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ring sideroblasts ( sideroblast (RARS), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-T); and myeloproliferative syndromes.

[0217] In some embodiments, solid tumors include ovarian cancer, lung cancer (including non-small cell lung cancer), glioblastoma (GBM), tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial carcinoma, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, and sarcoma.

[0218] In some embodiments, typical hematological malignancies include leukemias, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); multiple myeloma (MM); and lymphomas, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0219] The term "metabolic disease" refers to a disease or condition caused by a metabolic problem, including metabolic disorders and hypermetabolism. Examples of metabolic diseases include, but are not limited to, osteoporosis, diabetes, diabetic ketoacidosis, hyperglycemia and hyperosmotic syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, etc.

[0220] The term "obesity-related disease" refers to a disease or condition that is associated with, caused by, or caused by obesity. Examples of obesity-related diseases include, but are not limited to, diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, heart rhythm abnormalities, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, and angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.

[0221] The terms "subject," "individual," or "patient," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0222] The terms "treatment", "treat" and "treating" refer to reversing, alleviating or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in view of a history of symptoms and / or in view of pathogen exposure). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent their recurrence.

[0223] The terms "disease," "disease," and "condition" are used interchangeably.

[0224] The terms "administer," "administering," or "administration" refer to methods of introducing a compound disclosed herein, or a composition thereof, into or onto a patient. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Company, Easton, Pa.

[0225] Generally, although the effective amount of the compounds taught herein varies according to various factors such as the following: the given drug or compound, the pharmaceutical preparation, the route of administration, the type of disease or condition, the identity of the subject or host being treated, and the like, it can still be routinely determined by those skilled in the art. The effective amount of the compounds taught herein can be easily determined by those skilled in the art by conventional methods known in the art.

[0226] The term "therapeutically effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results (e.g., inhibiting, suppressing, or reducing the symptoms of the subject's treated disorder as compared to a control). For example, a therapeutically effective amount can be an amount effective for detectably killing cancer cells or inhibiting the growth or spread of cancer cells; the size or number of tumors; or other measures of the level, stage, progression, or severity of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject; the severity of the disease, the particular anticancer agent, its mode of administration, combination treatment with other therapies, and the like.

[0227] 6. Preparation

[0228] Compounds of any of the above formulae can be prepared by the following general and specific methods using the common knowledge of those familiar with synthetic organic chemistry. Such common knowledge can be found in standard reference books such as: Comprehensive Organic Chemistry, Barton and Ollis, ed., Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience). The starting materials used herein are commercially available or can be prepared by conventional methods known in the art.

[0229] In the preparation of compounds of any of the above formulas, it should be noted that some of the preparation methods described herein may require protection of distal functional groups (e.g., primary amines, secondary amines, carboxyl groups in the precursors of any of the above formulas). The need for such protection will vary depending on the nature of the distal functional group and the conditions of the preparation method. Those skilled in the art can easily determine the need for such protection. The use of such protection / deprotection methods is also within the scope of this technology. For a general description of protecting groups and their uses, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0230] For example, some compounds contain primary amine or carboxylic acid functional groups, which, if not protected, may interfere with reactions at other sites of the molecule. Therefore, such functional groups may be protected by appropriate protecting groups, which may be removed in subsequent steps. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (such as N-tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are generally chemically non-reactive under the reaction conditions and can generally be removed without chemically altering other functional groups in the compounds of any of the above formulae.

[0231] Example

[0232] The compounds disclosed herein are prepared according to the exemplary procedures provided herein and modifications thereof known to those skilled in the art.

[0233] The schemes set forth below are intended to provide a general description of the methods used in preparing the compounds of the present disclosure.

[0234] The following abbreviations are used throughout the intermediates and examples: Ac means acetyl, ACN means acetonitrile, AcOH means acetic acid, AIBN means 2,2'-azobis(2-methylpropionitrile), Bn means benzyl, Bpin means 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, (Bpin)2 means bis(pinacolato)diboron, DCM means dichloromethane, DMF means N,N-dimethylformamide, Et means ethyl, LG means leaving group, LAH means lithium aluminum hydride, Me means methyl, NBS means N-bromosuccinimide, Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(dtbpf)Cl2 means 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride, PMB-Cl means 1-(chloromethyl)-4-methoxy-benzene, tBu means tert-butyl, THF means tetrahydrofuran, hr means hour, and min means minute.

[0235] Methods for the synthesis of key intermediates

[0236] Intermediate 1: 2-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0237]

[0238] To a solution of 4-bromo-2-methoxy-phenol (3.00 g, 14.78 mmol) in acetone (50 mL) was added sodium iodide (1.11 g, 7.388 mmol), potassium carbonate (4.08 g, 29.55 mmol), 1-(chloromethyl)-4-methoxy-benzene (4.63 g, 29.55 mmol). The mixture was heated at 80 °C for 1 hr. The mixture was filtered and the filter cake was washed with ethyl acetate (3 x 50 mL). The organic phases were combined and concentrated to give 3.00 g of 4-bromo-2-methoxy-1-[(4-methoxyphenyl)methoxy]benzene as a white solid (yield = 62.82%).

[0239] To a solution of 4-bromo-2-methoxy-1-[(4-methoxyphenyl)methoxy]benzene (3.000 g, 9.283 mmol) in 1,4-dioxane (50 mL) was added 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolan (2.99 g, 11.14 mmol), bis(tri-tert-butylphosphine)palladium(0) (474 ​​mg, 928 μmol) and potassium hydroxide solution (1.7 mL, 8 mol / L). The mixture was stirred at 15 °C for 15 hr under nitrogen atmosphere. After evaporation of the solvent, 50 mL of water was added to the residue and extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 35% ethyl acetate in heptane) to afford 2.00 g of 2-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as an off-white solid (yield = 56.07%).

[0240] Intermediate 2: 2-methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol

[0241]

[0242] To a solution of 4-bromo-2-methoxy-phenol (20.00 g, 98.51 mmol) in acetone (150 mL) was added potassium carbonate (20.421 g, 147.76 mmol), bromotoluene (17.69 g, 103.43 mmol). The mixture was heated at 75 °C for 1 hr. The mixture was filtered and the filter cake was washed with ethyl acetate (3 x 50 mL). The organic phases were combined, concentrated and purified by flash chromatography on silica gel (eluting with a gradient of 5% ethyl acetate in heptane to 10% ethyl acetate in heptane) to give 24.02 g of 1-benzyloxy-4-bromo-2-methoxy-benzene as a white solid (yield = 83.11%).

[0243] To a solution of 1-benzyloxy-4-bromo-2-methoxy-benzene (24.00 g, 81.868 mmol) in 1,4-dioxane (500 mL) was added 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolan (28.52 g, 106.428 mmol), bis(tri-tert-butylphosphine)palladium(0) (1.26 g, 2.456 mmol) and potassium hydroxide solution (18.42 mL, 8 mol / L). The mixture was stirred at 15 °C for 15 hr under nitrogen atmosphere. After evaporation of the solvent, 500 mL of water was added to the residue and extracted with ethyl acetate (3×250 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 5% ethyl acetate in heptane to 12% ethyl acetate in heptane) to afford 17.10 g of 2-[(4-benzyloxy-3-methoxy-phenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid (yield = 58.62%).

[0244] To a solution of 2-[(4-benzyloxy-3-methoxy-phenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.08 g, 34.09 mmol) in 1,4-dioxane (100 mL) was added 4-chloro-7-methoxy-quinoline (6.00 g, 30.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.27 g, 3.10 mmol), potassium carbonate (8.57 g, 61.97 mmol) and water (20 mL). The mixture was heated at 100° C. for 15 hr under nitrogen atmosphere. After evaporation of the solvent, the crude residue was purified by silica gel flash chromatography (gradient elution with 15% ethyl acetate in heptane to 100% ethyl acetate) to give 10.00 g of 4-[(4-benzyloxy-3-methoxy-phenyl)methyl]-7-methoxy-quinoline as a white solid (yield = 83.72%).

[0245] To a solution of 4-[(4-benzyloxy-3-methoxy-phenyl)methyl]-7-methoxy-quinoline (10.00 g, 25.94 mmol) in methanol (100 mL) was added palladium hydroxide on carbon (1.50 g). The mixture was heated at 80 °C for 3 hr under a hydrogen atmosphere. The mixture was filtered and the filter cake was washed with methanol (3 x 100 mL). The organic phases were combined, concentrated and purified by flash chromatography on silica gel (eluting with a gradient of 35% ethyl acetate in heptane to 100% ethyl acetate) to give 5.50 g of 2-methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol as a grey solid (yield = 71.78%).

[0246] Intermediate 3: 5-(Bromomethyl)-3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)pyridine

[0247]

[0248] To a solution of (5-methoxypyridin-2-yl)methanol (24.90 g, 178.94 mmol) in 1,4-dioxane (200 mL) was added potassium tert-butoxide (21.80 g, 194.28 mmol) at 0°C. After stirring at 0°C for 10 min, 6-chloro-5-methoxy-pyridine-3-carboxylic acid methyl ester (30.00 g, 148.80 mmol) was added to the mixture. The mixture was heated to 100°C and maintained for 12 hr, then cooled to room temperature. The mixture was diluted with water 1000 mL and extracted with ethyl acetate (3×1000 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 100% heptane to 50% ethyl acetate in heptane) to afford 12.00 g of methyl 5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]picolinate as an off-white solid (yield = 26.5%).

[0249] To a solution of 5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]pyridine-3-carboxylate (12.00 g, 39.44 mmol) in THF (200 mL) was added lithium aluminum hydride (1.80 g, 47.43 mmol) at 5°C under a nitrogen atmosphere. After stirring for 1 hr, water (1.8 mL), 15% aqueous sodium hydroxide solution (1.8 mL) and water (5.4 mL) were added to the mixture successively to quench the reaction. The mixture was filtered, and the filtrate was diluted with water (500 mL) and extracted with ethyl acetate (3×500 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in heptane to 100% ethyl acetate) to afford 5.30 g of (5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methanol as a white solid (yield = 48.64%).

[0250] To a solution of (5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methanol (5.00 g, 18.10 mmol) in dichloromethane (200 mL) was added phosphorus tribromide (1.97 g, 7.28 mmol) dropwise at 5 °C. The mixture was stirred at 10 °C for 10 min. The mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (300 mL). The organic layer was concentrated at 40 °C to give 6.00 g of 5-(bromomethyl)-3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)pyridine as a colorless gum (yield = 97.74%).

[0251] Intermediate 4: 8-(Bromomethyl)-3-methoxy-1,5-naphthyridine

[0252]

[0253] To a solution of trimethylboroxane (1.17 g, 14.14 mmol) dissolved in THF (4 mL) was added 8-chloro-3-methoxy-1,5-naphthyridine (500 mg, 2.57 mmol), potassium carbonate (532 mg, 3.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (93 mg, 127 μmol) and water (0.8 mL). The mixture was heated in a microwave reactor at 100 °C under a nitrogen atmosphere for 1 hr. After evaporation of the solvent, the residue was diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 100% heptane to 50% ethyl acetate in heptane) to give 300 mg of 3-methoxy-8-methyl-1,5-naphthyridine as a white solid (yield = 67%).

[0254] To a solution of 3-methoxy-8-methyl-1,5-naphthyridine (300 mg, 1.73 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (306 mg, 1.73 mmol) and 2,2'-azobis(2-methylpropionitrile) (28 mg, 173 μmol). The mixture was heated to 80 °C under a nitrogen atmosphere for 2 hr. The mixture was filtered and the filter cake was washed with ethyl acetate (3 x 50 mL). The filtrates were combined, concentrated and further purified by silica gel flash chromatography (eluting with a gradient of 100% heptane to 30% ethyl acetate in heptane) to give 150 mg of 8-(bromomethyl)-3-methoxy-1,5-naphthyridine as a yellow solid (yield = 25.8%).

[0255] Intermediate 5: 3-methoxy-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0256]

[0257] To a solution of (5-methoxypyridin-2-yl)methanol (2.47 g, 17.72 mmol) in 1,4-dioxane (30 mL) was added potassium tert-butoxide (2.49 g, 22.15 mmol) at 0°C. After stirring at 0°C for 10 min, 5-bromo-2-chloro-3-methoxypyridine (3.942 g, 17.72 mmol) was added to the mixture. The mixture was heated to 80°C for 2 hr and then cooled to room temperature. Saturated aqueous ammonia chloride (10 mL) was added to quench the reaction. After evaporation of the solvent, the residue was diluted with brine (50 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 100% heptane to 50% ethyl acetate in heptane) to afford 3.64 g of 5-bromo-3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)pyridine (yield = 79.5%) as a light yellow solid.

[0258] To a solution of 5-bromo-3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)pyridine (4.000 g, 12.30 mmol) in 1,4-dioxane (50 mL) was added bis(pinacolato)diboron (4.69 g, 18.45 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.000 g, 1.367 mmol) and potassium acetate (2.415 g, 12.302 mmol). The mixture was heated to 80 °C under nitrogen atmosphere for 12 hr. After evaporation of the solvent, the residue was diluted with brine (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 100% heptane to 50% ethyl acetate in heptane) to afford 3.64 g of 3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (yield = 79.5%) as a light yellow solid.

[0259] Intermediate 6: 5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-ol

[0260]

[0261] To a solution of 3-methoxy-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (400 mg, 1.08 mmol) in methanol (20 mL) was added 30% aqueous hydrogen peroxide solution (146 mg, 1.29 mmol). The mixture was stirred at 25 °C for 15 hr. 10 ml of saturated aqueous sodium thiosulfate solution was added to the mixture and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 140 mg of 5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]pyridine-3-ol as a white solid (yield = 49.68%).

[0262] General Methods for Synthesis of Representative Examples

[0263] Method A:

[0264]

[0265] Example 1: 7-methoxy-4-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]quinolinone

[0266]

[0267] To a solution of 2-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (242 mg, 630 μmol) in 1,4-dioxane (15 mL) was added 4-bromo-7-methoxy-quinoline (100 mg, 420 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 41 μmol), potassium carbonate (174 mg, 1.26 mmol) and water (3 mL). The mixture was heated at 100° C. for 1 hr under nitrogen atmosphere. After evaporation of the solvent, the crude residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 160 mg of 7-methoxy-4-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]quinolinone as a light yellow solid (yield = 91.68%). 1H NMR (400MHz, DMSO) δ8.73(d,J=4.5Hz,1H),8.11(d,J=9.2Hz,1H),7.40(d,J=2.6Hz,1H),7.36-7.31(m,2H),7.24(dd,J=9.2,2.7Hz,1H), 7.16(d,J=4.5Hz,1H),6.98-6.89(m,4H),6.68(dd,J=8.2,1.9Hz,1H),4.92(s,2H),4.35(s,2H),3.91(s,3H),3.75(s,3H),3.70(s,3H). MS(m / z):416.1(M+H) + .

[0268] Example 2: 4-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1,7-naphthyridine

[0269]

[0270] To a solution of 2-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg, 911 μmol) in 1,4-dioxane (15 mL) was added 4-chloro-1,7-naphthyridine (100 mg, 608 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 60 μmol), potassium carbonate (252 mg, 1.82 mmol) and water (3 mL). The mixture was heated at 100° C. for 1 hr under nitrogen atmosphere. After evaporation of the solvent, the crude residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 120 mg of 7-methoxy-4-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]quinolinone as a white solid (yield = 51.11%). 1 H NMR (400MHz, DMSO) δ9.39(s,1H),8.97(d,J=4.3Hz,1H),8.62(d,J=5.8Hz,1H),8.11(d,J=5.8Hz,1H),7.55(d,J=4.3Hz,1 H),7.34(d,J=8.5Hz,2H),7.03-6.89(m,4H),6.73(d,J=8.1Hz,1H),4.93(s,2H),4.41(s,2H),3.75(s,3H),3.72(s,3H). MS(m / z):387.1(M+H) + .

[0271] Example 3: 4-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)quinolinone

[0272]

[0273] To a solution of 2-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (277 mg, 721 μmol) in 1,4-dioxane (15 mL) was added 4-bromoquinoline (100 mg, 481 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 48 μmol), potassium carbonate (199 mg, 1.44 mmol) and water (3 mL). The mixture was heated at 100° C. for 2 hr under nitrogen atmosphere. After evaporation of the solvent, the crude residue was purified by silica gel flash chromatography (gradient eluting with 15% ethyl acetate in heptane to 50% ethyl acetate in heptane) to give 120 mg of 4-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)quinoline as a white solid (yield = 64.77%). 1 HNMR (400MHz, DMSO) δ8.82(d,J=4.4Hz,1H),8.22(d,J=8.2Hz,1H),8.03(d,J=8.2Hz,1H),7.78-7.70(m,1H),7.61(dd,J=11.2,4.0Hz, 1H),7.33(dd,J=9.8,6.5Hz,3H),7.00-6.89(m,4H),6.70(dd,J=8.2,1.6Hz,1H),4.93(s,2H),4.40(s,2H),3.75(s,3H),3.71(s,3H). MS(m / z):386.1(M+H) + .

[0274] Method B:

[0275]

[0276] Example 6: 4-(4-(imidazo[1,2-a]pyridin-7-ylmethoxy)-3-methoxybenzyl)-7-methoxyquinoline

[0277]

[0278] 7-(Chloromethyl)imidazo[1,2-a]pyridine (85 mg, 510 μmol), potassium carbonate (71 mg, 514 μmol) were added to a solution of 2-methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol (100 mg, 339 μmol) in DMF (10 mL). The mixture was heated at 80 ° C for 12 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was concentrated and purified by silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in heptane to 10% methanol in dichloromethane) to give 50 mg of 4-(4-(imidazo[1,2-a]pyridin-7-ylmethoxy)-3-methoxybenzyl)-7-methoxyquinoline as a light yellow solid (yield = 34.71%). 1 H NMR (400MHz, DMSO) δ8.72 (d, J=4.4Hz, 1H), 8.53 (dd, J=7.2, 1.2Hz, 1H), 8.11 (d,J=9.2Hz,1H),7.94-7.93(m,1H),7.64-7.49(m,2H),7.39(d,J=2.8Hz,1H ),7.24(dd,J=9.2,2.8Hz,1H),7.16(d,J=4.4Hz,1H),7.02-6.88(m,3H),6.6 9(dd,J=8.0,2.0Hz,1H),5.09(s,2H),4.36(s,2H),3.91(s,3H),3.75(s,3H). MS(m / z):426.1(M+H) + .

[0279] Example 8: 7-methoxy-4-(3-methoxy-4-(pyridin-3-ylmethoxy)benzyl)quinolinone

[0280]

[0281] 3-(Bromomethyl)pyridine hydrobromide (150 mg, 593 μmol) and potassium carbonate (190 mg, 1.38 mmol) were added to a solution of 2-methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol (160 mg, 542 μmol) in DMF (5 mL). The mixture was stirred at 20 ° C for 16 hr. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (25 mL). The organic layer was concentrated and purified by high performance liquid chromatography (gradient elution with 10% acetonitrile in water to 65% acetonitrile in water) to obtain 46 mg of 7-methoxy-4-(3-methoxy-4-(pyridin-3-ylmethoxy)benzyl)quinoline (yield = 22.08%) as an off-white solid. 1H NMR (400MHz, DMSO) δ8.73(d,J=4.5Hz,1H),8.63(d,J=1.6Hz,1H),8.54(dd,J=4.8 ,1.5Hz,1H),8.11(d,J=9.2Hz,1H),7.83(dt,J=7.8,1.9Hz,1H),7.47-7.34(m,2H) ,7.24(dt,J=13.0,6.5Hz,1H),7.17(d,J=4.5Hz,1H),6.98(dd,J=7.1,5.1Hz,2H) ,6.70(dd,J=8.2,1.9Hz,1H),5.07(s,2H),4.36(s,2H),3.91(s,3H),3.72(s,3H). MS (m / z): 387.1 (M+H) + .

[0282] Example 18: 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-3-methoxybenzyl)-7-methoxyquinoline

[0283]

[0284] To a solution of 2-methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol (100 mg, 339 μmol) in DMF (10 mL) was added 2-(bromomethyl)imidazo[1,2-a]pyridine (72 mg, 341 μmol), potassium carbonate (57 mg, 412 μmol). The mixture was heated at 80 °C for 12 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was concentrated and purified by silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in heptane to 6% methanol in dichloromethane) to give 25 mg of 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-3-methoxybenzyl)-7-methoxyquinoline as a light yellow solid (yield = 17.35%). 1H NMR (400MHz, DMSO) δ8.73(d,J=4.4Hz,1H),8.54-8.51(m,1H),8.12(d,J=9.2Hz,1H ),7.95(s,1H),7.52(d,J=8.8Hz,1H),7.40(d,J=2.8Hz,1H),7.30-7.20(m,2H),7. 17(d,J=4.4Hz,1H),7.04(d,J=8.4Hz,1H),6.97(d,J=2.0Hz,1H),6.93-6.84(m,1H ), 6.69 (dd, J = 8.0, 2.0Hz, 1H), 5.12 (s, 2H), 4.35 (s, 2H), 3.91 (s, 3H), 3.71 (s, 3H). MS(m / z):426.1(M+H) + .

[0285] Method C:

[0286]

[0287] Example 13: 7-methoxy-4-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)quinolinone

[0288]

[0289] To a solution of 4-chloro-7-methoxy-quinoline (5.00 g, 25.823 mmol) dissolved in 1,4-dioxane (100 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (7.22 g, 28.432 mmol), potassium acetate (3.80 g, 38.72 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.89 g, 2.583 mmol). The mixture was heated at 100°C for 3 hrs under nitrogen atmosphere. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (400 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 20% ethyl acetate in heptane to 100% ethyl acetate) to afford 3.00 g of 7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline as a brown solid (yield = 40.74%).

[0290] To a solution of 7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (50 mg, 175 μmol) dissolved in 1,4-dioxane (10 mL) was added 5-(bromomethyl)-3-methoxy-2-[(5-methoxy-2-pyridyl)methoxy]pyridine (60 mg, 177 μmol), potassium carbonate (37 mg, 268 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 18 μmol) and water (2 mL). The mixture was heated at 100° C. for 2 hr under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 20% ethyl acetate in heptane to 50% ethyl acetate in heptane) to afford 5 mg of 7-methoxy-4-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)quinoline (yield = 6.83%) as a light yellow solid. 1 HNMR (400MHz, DMSO) δ8.73(d,J=4.4Hz,1H),8.25(t,J=2.0Hz,1H),8.17(d,J=9.2Hz,1H),7.60(d,J=2.0Hz,1H),7.41 -7.38(m,3H),7.31-7.26(m,2H),7.29-7.15(m,1H),5.30(s,2H),4.38(s,2H),3.92(s,3H),3.82(s,3H),3.74(s,3H). MS(m / z):418.1(M+H) + .

[0291] Example 15: 4-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

[0292]

[0293] To a solution of 4-chloro-1,5-naphthyridine (2.000 g, 12.151 mmol) dissolved in 1,4-dioxane (100 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.39 g, 13.35 mmol), potassium acetate (1.79 g, 18.22 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (889 mg, 1.22 mmol). The mixture was heated at 100° C. for 18 hr under a nitrogen atmosphere. The mixture was filtered and the filtrate was washed with ethyl acetate (100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give 3.00 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridine as a brown solid (yield = 40.74%).

[0294] To a solution of crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridine (113 mg, 441 μmol) dissolved in 1,4-dioxane (10 mL) was added 5-(bromomethyl)-3-methoxy-2-[(5-methoxy-2-pyridyl)methoxy]pyridine (100 mg, 295 μmol), potassium carbonate (122 mg, 883 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 30 μmol) and water (2 mL). The mixture was heated at 100° C. for 16 hr under nitrogen atmosphere. The mixture was filtered and the filter cake was washed with ethyl acetate (3×50 mL). The filtrates were combined, concentrated and further purified by silica gel flash chromatography (eluting with a gradient of 50% ethyl acetate in heptane to 100% ethyl acetate) to afford 27 mg of 4-[[5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-1,5-naphthyridine as an off-white solid (yield = 23.58%). 1 H NMR (400MHz, DMSO) δ9.09(dd,J=4.1,1.7Hz,1H),8.91(d,J=4.4Hz,1H),8.44(dd,J=8.5,1.7Hz,1H),8.26(t,J=1.8Hz,1H),7.83(dd,J=8 .5,4.1Hz,1H),7.68(d,J=1.8Hz,1H),7.58(d,J=4.4Hz,1H),7.39(d,J=1.7Hz,3H),5.31(s,2H),4.57(s,2H),3.82(s,3H),3.75(s,3H). MS(m / z):389.1(M+H) +.

[0295] Method D:

[0296]

[0297] Example 16: 3-methoxy-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

[0298]

[0299] To a solution of 8-(bromomethyl)-3-methoxy-1,5-naphthyridine (50 mg, 198 μmol) in 1,4-dioxane (25 mL) was added 3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (147 mg, 395 μmol), tripotassium orthophosphate (126 mg, 593 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (10 mg, 19.8 μmol) and water (5 mL). The mixture was heated to 90 °C under nitrogen atmosphere for 12 hr. After evaporation of the solvent, the residue was diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (eluting with a gradient of 50% ethyl acetate in heptane to 5% ethanol in ethyl acetate) to afford 19 mg of 3-methoxy-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine as an off-white solid (yield = 31%). 1 H NMR (400MHz, DMSO) δ8.82(dd,J=6.4,3.7Hz,2H),8.28-8.22(m,1H),7.79(d,J=2.8Hz,1H),7.65(d,J=1. 6Hz, 1H), 7.38 (td, J = 12.0, 3.1Hz, 4H), 5.31 (s, 2H), 4.52 (s, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H). MS(m / z):419.1(M+H) + .

[0300] Example 32: 3-methoxy-8-((5-methoxy-6-((6-methoxypyridazin-3-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

[0301]

[0302] To a solution of (6-methoxypyridazine-3-yl)methanol (0.63 g, 4.50 mmol) in 1,4-dioxane (13 mL) was added potassium tert-butoxide (0.66 g, 5.85 mmol) at 0 ° C. After stirring at 0 ° C for 10 min, 5-bromo-2-chloro-3-methoxypyridine (1.00 g, 4.50 mmol) was added to the mixture. The mixture was heated to 100 ° C and maintained for 2 hr, then cooled to room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was concentrated to give 1.00 g of 3-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-6-methoxy-pyridazine as a white solid (yield = 68.21%).

[0303] To a solution of 3-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-6-methoxy-pyridazine (1.00 g, 3.07 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (934 mg, 3.68 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (224 mg, 306 μmol) and potassium acetate (602 mg, 6.13 mmol). The mixture was heated to 100° C. under a nitrogen atmosphere for 16 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over magnesium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (eluting with a gradient of 20% ethyl acetate in heptane to 50% ethyl acetate) to afford 1.00 g of 3-methoxy-6-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxymethyl]pyridazine as a white solid (yield = 87.39%).

[0304] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (50 mg, 198 μmol) in 1,4-dioxane (10 mL) was added 3-methoxy-6-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]pyridazine (88 mg, 236 μmol), tripotassium orthophosphate (126 mg, 594 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (13 mg, 20 μmol)) and water (2 mL). The mixture was heated to 90° C. under a nitrogen atmosphere for 2 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over magnesium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (eluting with a gradient of 50% ethyl acetate in heptane to 5% methanol in dichloromethane) to afford 6 mg of 3-methoxy-8-[[5-methoxy-6-[(6-methoxypyridazin-3-yl)methoxy]-3-pyridinyl]methyl]-1,5-naphthyridine as a white solid (yield = 7.24%). 1 H NMR (400MHz, DMSO) δ8.83(d,J=2.88Hz,1H),8.81(d,J=4.48Hz,1H),7.79(d,J=2.88Hz,1H),7.66(d,J=2.48Hz,1H),7.64(s,1H),7.4 1(d,J=4.44Hz,1H),7.38(d,J=1.8Hz,1H),7.23(d,J=9.08Hz,1H),5.47(s,2H),4.52(s,2H),4.02(s,3H),4.00(s,3H),3.73(s,3H). MS(m / z):420.1(M+H) + .

[0305] Example 46: 5-(((3-methoxy-5-((7-methoxy-1,5-naphthyridin-4-yl)methyl)pyridin-2-yl)oxy)methyl)-3-methylisoxazole

[0306]

[0307] To a solution of (3-methylisoxazol-5-yl)methanol (1.00 g, 8.84 mmol) in 1,4-dioxane (30 mL) was added potassium tert-butoxide (1.09 g, 9.73 mmol) at 0 ° C. After stirring at 0 ° C for 10 min, 5-bromo-2-chloro-3-methoxypyridine (1.97 g, 8.84 mmol) was added to the mixture. The mixture was heated to 80 ° C and maintained for 3 hr, then cooled to room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was concentrated and purified by flash chromatography on silica gel (eluted with a gradient of 100% heptane to 25% ethyl acetate in heptane) to give 1.69 g of 5-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-3-methyl-isoxazole as a white solid (yield = 63.83%).

[0308] To a solution of 5-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-3-methyl-isoxazole (800 mg, 2.68 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (700 mg, 2.74 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200 mg, 273 μmol) and potassium acetate (550 mg, 5.60 mmol). The mixture was heated to 90° C. under nitrogen atmosphere for 5 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over magnesium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (gradient elution with 5% ethyl acetate in heptane to 35% ethyl acetate in heptane) to afford 850 mg of 5-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxymethyl]-3-methyl-isoxazole as an off-white solid (yield = 91.81%).

[0309] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (35 mg, 138 μmol) in 1,4-dioxane (25 mL) was added 5-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]-3-methyl-isoxazole (126 mg, 364 μmol), tripotassium orthophosphate (105 mg, 495 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (98 mg, 150 μmol)) and water (5 mL). The mixture was heated to 90° C. under nitrogen atmosphere for 12 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over magnesium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate) to give 30 mg of 5-[[3-methoxy-5-[(7-methoxy-1,5-naphthyridin-4-yl)methyl]-2-pyridinyl]oxymethyl]-3-methyl-isoxazole (yield = 55.28%). 1 H NMR (400MHz, DMSO) δ8.82(dd,J=6.5,3.7Hz,2H),7.79(d,J=2.9Hz,1H),7.67(d,J=1.8Hz,1H),7.39( dd,J=8.8,3.1Hz,2H),6.39(s,1H),5.39(s,2H),4.53(s,2H),3.99(s,3H),3.73(s,3H),2.21(s,3H). MS(m / z):393.1(M+H) + .

[0310] Example 73: 2-(((3-methoxy-5-((7-methoxy-1,5-naphthyridin-4-yl)methyl)pyridin-2-yl)oxy)methyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

[0311]

[0312] To a solution of morpholine-3-carboxylic acid (3.929 g, 23.44 mmol) in concentrated hydrochloric acid (3.5 mL) and H2O (3 mL) was added a solution of sodium nitrite (2.588 g, 37.51 mmol) in H2O (3 mL) at 0°C. The mixture was stirred at 0°C for 2 hr. The mixture was extracted with dichloromethane (50 mL×20). The organic layer was dried over magnesium sulfate and concentrated to obtain 2.68 g of 4-nitrosomorpholine-3-carboxylic acid (yield = 71.39%) as a light yellow oil.

[0313] To a solution of 4-nitrosomorpholine-3-carboxylic acid (2.68 g, 16.73 mmol) in dichloromethane (30 mL) was added trifluoroacetic anhydride (3.515 g, 16.73 mmol) at 5 °C. The mixture was stirred at 5 °C for 2 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 65% ethyl acetate in heptane to 100% ethyl acetate) to give 1.83 g of 3-oxo-6,7-dihydro-3H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8(4H)-ium-3a-inium salt as a light yellow solid (yield = 76.94%).

[0314] To a suspension of 3-oxo-6,7-dihydro-3H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8(4H)-ium-3a-inium salt (1.83 g, 12.88 mmol) in xylene (30 mL) was added ethyl prop-2-ynoate (2.32 g, 11.83 mmol) at 20°C. The mixture was heated at 135°C for 12 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 5% ethyl acetate in heptane to 50% ethyl acetate in heptane) to give 2.32 g of ethyl 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate as a light yellow solid (yield = 91.83%).

[0315] To a suspension of lithium aluminum hydride (540 mg, 14.23 mmol) in anhydrous THF (30 mL) was added a suspension of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate (2.30 g, 11.72 mmol) in THF (20 mL) at -20 ° C. The mixture was stirred at 20 ° C for 3 hr. After the reaction was quenched by using H2O and 15% NaOH aqueous solution, the mixture was filtered and concentrated to give 1.42 g of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-ylmethanol as a light yellow oil (yield = 78.57%).

[0316] To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethanol (700 mg, 4.54 mmol) in 1,4-dioxane (30 mL) was added potassium tert-butoxide (580 mg, 5.17 mmol) at 0°C. After stirring at 0°C for 10 min, 5-bromo-2-chloro-3-methoxypyridine (1.01 g, 4.54 mmol) was added to the mixture. The mixture was heated to 80°C for 3 hr and then cooled to room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was concentrated and purified by silica gel flash chromatography (eluting with a gradient of 100% heptane to 100% ethyl acetate) to afford 1.12 g of 2-[(5-bromo-3-methoxy-2-pyridinyl)oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine as a light yellow oil (yield = 72.51%).

[0317] To a solution of 2-[(5-bromo-3-methoxy-2-pyridinyl)oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (1.12 g, 3.29 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (1.732 g, 6.82 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 342 μmol) and potassium acetate (670 mg, 6.83 mmol). The mixture was heated to 80° C. under nitrogen atmosphere for 12 hr. The mixture was purified by silica gel flash chromatography (eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate) to afford 1.10 g of 2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine as a light brown solid (yield = 86.32%).

[0318] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (30 mg, 119 μmol) in 1,4-dioxane (10 mL) was added 2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (47 mg, 121 μmol), tripotassium orthophosphate (75 mg, 353 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8 mg, 12.4 μmol) and water (2 mL). The mixture was heated to 90° C. under nitrogen atmosphere for 3 hr. The mixture was purified by silica gel flash chromatography (eluting with a gradient of 100% ethyl acetate to 60% tetrahydrofuran in ethyl acetate) to afford 12 mg of 2-[[3-methoxy-5-[(7-methoxy-1,5-naphthyridin-4-yl)methyl]-2-pyridinyl]oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (yield = 23.36%). 1 H NMR (400MHz, DMSO) δ8.82(dd,J=7.3,3.7Hz,2H),7.79(d,J=2.9Hz,1H),7.67(d,J=1.9Hz,1H),7.41(d,J=4.5Hz,1H),7 .32(d,J=1.8Hz,1H),6.07(s,1H),5.18(s,2H),4.75(s,2H),4.52(s,2H),4.09-4.01(m,4H),3.99(s,3H),3.69(s,3H). MS(m / z):434.1(M+H) + .

[0319] Example 136: (R)-3-methoxy-8-((5-methoxy-6-((5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

[0320]

[0321] To a solution of (2S, 4R)-4-methoxypyrrolidine-2-carboxylic acid (7.000 g, 38.54 mmol) in concentrated hydrochloric acid (10 mL) was added a solution of sodium nitrite (4.255 g, 61.67 mmol) in H2O (10 mL) at 0 ° C. The mixture was stirred at 25 ° C for 2 hr. The mixture was extracted with dichloromethane (50 mL×20). The organic layer was dried over sodium sulfate and concentrated to obtain 6.00 g of (2S, 4R)-4-methoxy-1-nitroso-pyrrolidine-2-carboxylic acid as a light yellow solid.

[0322] To a solution of (2S,4R)-4-methoxy-1-nitroso-pyrrolidine-2-carboxylic acid (5.50 g, 31.58 mmol) in dichloromethane (40 mL) was added trifluoroacetic anhydride (10.613 g, 50.53 mmol) at 0°C. The mixture was stirred at 25°C for 1 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 65% ethyl acetate in heptane to 100% ethyl acetate) to give 3.00 g of (R)-5-methoxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxadiazole-7(4H)-ium-3a-inium salt as a brown solid (yield = 60.84%).

[0323] To a suspension of (R)-5-methoxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxadiazole-7(4H)-ium-3a-inium salt (3.00 g, 19.21 mmol) in xylene (40 mL) was added ethyl prop-2-ynoate (7.539 g, 76.86 mmol) at 20°C. The mixture was heated at 135°C for 16 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate) to give 1.80 g of ethyl (5R)-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate as a yellow oil (yield = 44.56%).

[0324] To a suspension of lithium aluminum hydride (1.00 g, 26.35 mmol) in anhydrous THF (20 mL) was added a suspension of (5R)-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid ethyl ester (1.80 g, 8.56 mmol) in THF (20 mL) at -20 ° C. The mixture was stirred at 25 ° C for 1 hr. After the reaction was quenched by using H2O and 15% NaOH aqueous solution, the mixture was filtered and concentrated to give 1.30 g of [(5R)-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanol as a brown oil.

[0325] To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethanol (756 mg, 4.50 mmol) in 1,4-dioxane (20 mL) was added potassium tert-butoxide (900 mg, 8.02 mmol) at 0°C. After stirring at 0°C for 10 min, 5-bromo-2-chloro-3-methoxypyridine (1.00 g, 4.50 mmol) was added to the mixture. The mixture was heated to 95°C for 1 hr and then cooled to room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was concentrated and purified by silica gel flash chromatography (gradient eluting with 50% ethyl acetate in heptane to 100% ethyl acetate) to afford 400 mg of (5R)-2-[(5-bromo-3-methoxy-2-pyridinyl)oxymethyl]-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole as a light yellow oil (yield = 25.12%).

[0326] To a solution of (5R)-2-[(5-bromo-3-methoxy-2-pyridinyl)oxymethyl]-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (400 mg, 1.13 mmol) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (430 mg, 1.69 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (124 mg, 169 μmol) and potassium acetate (332 mg, 3.38 mmol). The mixture was heated to 95° C. under nitrogen atmosphere for 1 hr. The mixture was purified by silica gel flash chromatography (eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate) to give 400 mg of (5R)-5-methoxy-2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxymethyl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole as a brown oil (yield = 88.27%).

[0327] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (50 mg, 198 μmol) in 1,4-dioxane (5 mL) was added (5R)-5-methoxy-2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxymethyl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (110 mg, 274 μmol), tripotassium orthophosphate (126 mg, 594 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (19 mg, 29.4 μmol) and water (1 mL). The mixture was heated to 95° C. under nitrogen atmosphere for 2 hr. The mixture was purified by silica gel flash chromatography (eluting with a gradient of 100% ethyl acetate to 20% ethanol in ethyl acetate) to afford 10 mg of (R)-3-methoxy-8-((5-methoxy-6-((5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (yield = 11.31%). 1 H NMR (400MHz, DMSO) δ8.82(dd,J=6.8,3.7Hz,2H),7.79(d,J=2.9Hz,1H),7.67(d,J=1.7Hz,1 H),7.40(d,J=4.5Hz,1H),7.31(d,J=1.7Hz,1H),6.02(s,1H),5.16(s,2H),4.58(ddd,J=8.5 ,6.0,2.4Hz,1H),4.52(s,2H),4.25(dd,J=11.8,5.7Hz,1H),4.02(d,J=2.4Hz,1H),4.00(s ,3H),3.69(s,3H),3.30(s,3H),3.11(dd,J=16.7,6.4Hz,1H),2.79(dd,J=16.6,2.2Hz,1H). MS(m / z):448.1(M+H) + .

[0328] Method E:

[0329]

[0330] Example 19: 4-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,7-naphthyridine

[0331]

[0332] Phosphorus tribromide (405 mg, 1.50 mmol) was added dropwise to a solution of 1,7-naphthyridin-4-ylmethanol (80 mg, 499 μmmol) dissolved in dichloromethane (10 mL) at 0 ° C. The mixture was stirred at 15 ° C for 15 hr. Saturated aqueous NaHCO3 (15 mL) was added to the mixture and extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Mg2SO4, filtered and concentrated to give 50 mg of 4-(bromomethyl)-1,7-naphthyridine as a white solid (yield = 50%).

[0333] To a solution of 3-methoxy-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (125 mg, 334 μmol) dissolved in 1,4-dioxane (10 mL) was added 4-(bromomethyl)-1,7-naphthyridine (50 mg, 225.15 μmol), potassium carbonate (93 mg, 673 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) and water (2 mL). The mixture was heated at 95° C. for 3 hrs under nitrogen atmosphere. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 2.5 mg of 4-[[5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-1,7-naphthyridine as a white solid (yield = 2.87%). 1 H NMR (400MHz, DMSO) δ9.41 (s, 1H), 8.98 (d, J = 4.4Hz, 1H), 8.65 (d, J = 5.8Hz, 1H), 8.26 (s, 1H), 8.17 (d, J = 5.8Hz, 1H), 7.66 (s,1H),7.57(d,J=4.4Hz,1H),7.40(d,J=1.6Hz,2H),7.32(s,1H),5.31(s,2H),4.44(s,2H),3.82(s,3H),3.75(s,3H). MS(m / z):389.1(M+H) + .

[0334] Example 22: 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)pyrido[3,2-d]pyrimidine

[0335]

[0336] To a solution of 8-methylpyrido[3,2-d]pyrimidine (50 mg, 344 μmol) dissolved in acetonitrile (10 mL) was added N-bromosuccinimide (183 mg, 1.028 mmol), 2,2'-azobis(2-methylpropionitrile) (113 mg, 688 μmol) and acetic acid (0.02 mL). The mixture was heated to 80 °C under nitrogen atmosphere for 15 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 20 mg of 8-(bromomethyl)pyrido[3,2-d]pyrimidine as a white solid (yield = 25.92%).

[0337] To a solution of 3-methoxy-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (66 mg, 177 μmol) dissolved in 1,4-dioxane (10 mL) was added 8-(bromomethyl)pyrido[3,2-d]pyrimidine (20 mg, 89 μmol), potassium carbonate (37 mg, 268 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8 μmol) and water (2 mL). The mixture was heated at 90° C. for 3 hr under a nitrogen atmosphere. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 3.0 mg of 8-[[5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]pyrido[3,2-d]pyrimidine as a white solid (yield = 8.63%). 1 H NMR (400MHz, DMSO) δ9.68 (s, 1H), 9.51 (s, 1H), 9.05 (d, J = 4.4Hz, 1H), 8.26 (t, J = 1.8Hz, 1H), 7.81 (d, J = 4.4 Hz,1H),7.68(d,J=1.8Hz,1H),7.38(t,J=2.5Hz,3H),5.31(s,2H),4.53(s,2H),3.82(s,3H),3.75(s,3H). MS(m / z):390.1(M+H) + .

[0338] Example 62: 3-Chloro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

[0339]

[0340] 2,2-dimethyl-1,3-dioxane-4,6-dione (200 g, 1.39 mmol) was added to diethoxymethoxyethane (905 g, 6.11 mol). The mixture was heated to 90 °C for 1 hr. The mixture was concentrated to give 281.6 g of 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a red oil. (Crude product).

[0341] 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (278g, 1.39mol) was added to a solution of 5-chloropyridine-3-amine (150g, 1.17mol) dissolved in isopropanol (1500mL). The mixture was heated at 80 ° C for 2hr, then cooled. A large amount of solid was precipitated and the mixture was filtered. The filter cake was washed three times with 150ml isopropanol and dried to obtain 325g of 5-[[(5-chloro-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione as a yellow solid. (crude product).

[0342] 5-[[(5-chloro-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (325 g, 1.15 mol) was added portionwise to phenyl ether (3000 mL) at 200 ° C. The mixture was heated at 200 ° C for 0.5 hr and then cooled to 60 ° C. A large amount of solid was precipitated and the mixture was filtered. The filter cake was washed three times with 1000 ml of heptane and dried to give 138 g of 7-chloro-1H-1,5-naphthyridine-4-one as a brown solid. (Crude product).

[0343] Phosphorus tribromide (256.5 g, 948 mmol) was slowly added dropwise to a solution of 7-chloro-1H-1,5-naphthyridine-4-one (133.9 g, 550 mmol) dissolved in N,N-dimethylformamide (2070 mL) at 0 ° C. The mixture was stirred for 3.5 hr at 20 ° C. The mixture was poured into ice water (10 L) and a saturated Na2CO3 aqueous solution was added to adjust the pH value of the mixture to 7-8. A large amount of solid was precipitated and the mixture was filtered. The filter cake was washed five times with 200 ml of water and dried to obtain 133.9 g of 8-bromo-3-chloro-1,5-naphthyridine as a yellow solid. (crude product).

[0344] To a solution of 8-bromo-3-chloro-1,5-naphthyridine (110.9 g, 455 mmol) dissolved in THF (440 mL) was added a solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (57.17 g, 455 mmol) dissolved in THF (440 mL), potassium carbonate (94.38 g, 683 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.67 g, 22.78 mmol) and water (176 mL). The mixture was heated at 60° C. for 36 hr under a nitrogen atmosphere. The mixture was filtered and the filter cake was washed twice with 200 mL of ethyl acetate. After partitioning, the organic phases were combined, dried over magnesium sulfate, filtered, concentrated and purified by silica gel flash chromatography (eluting with a gradient of 15% ethyl acetate in heptane to 50% ethyl acetate in heptane) to give 75 g of 3-chloro-8-methyl-1,5-naphthyridine as a light yellow solid (yield = 92.19%).

[0345] Methanesulfonic acid (80.71 g, 840 mmol) was added to a solution of 3-chloro-8-methyl-1,5-naphthyridine (75.0 g, 420 mmol) dissolved in acetonitrile (1875 mL). After stirring at 20 ° C for 1 h, azo-bis-isobutyronitrile (10.34 g, 62.97 mmol) and bromine (268.4 g, 1.68 mol) were added to the mixture. The mixture was heated at 78 ° C for 20 hr. After evaporating the solvent, water (1.5 L) and saturated NaOH aqueous solution were added to the mixture to adjust the pH value of the mixture to 7.5. A large amount of solid was precipitated and the mixture was filtered. The filter cake was washed five times with 100 ml of water and dried to obtain 141.3 g of 3-chloro-8-(dibromomethyl)-1,5-naphthyridine as a yellow solid. (crude product).

[0346] To a solution of 3-chloro-8-(dibromomethyl)-1,5-naphthyridine (141.3 g, 420 mmol) dissolved in methanol (420 mL) was added diethyl phosphite (87.01 g, 630 mmol), N,N-diisopropylethylamine (81.43 g, 630 mmol). The mixture was heated at 20 ° C for 5 hr. After evaporation of the solvent, water (3.0 L) and saturated aqueous NaOH solution were added to the mixture to adjust the pH value of the mixture to 8.5. A large amount of solid was precipitated and the mixture was filtered. The filter cake was washed five times with 100 ml of methyl tert-butyl ether and dried to obtain 90.00 g of 8-(bromomethyl)-3-chloro-1,5-naphthyridine as an off-white solid. (yield = 83.21%).

[0347] To a solution of 8-(bromomethyl)-3-chloro-1,5-naphthyridine (25.00 g, 97.08 mmol) dissolved in 1,4-dioxane (1250 mL) was added 3-methoxy-2-[(5-methoxy-2-pyridyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (36.25 mg, 97.39 mmol), tripotassium phosphate (61.75 g, 291 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (355 mg, 4.85 mmol) and water (250 mL). The mixture was heated at 78° C. for 16 hr under a nitrogen atmosphere. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 50% ethyl acetate in heptane to 100% ethyl acetate) to give 11.00 g of 3-chloro-8-[[5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-1,5-naphthyridine as an off-white solid (yield = 26.80%). 1 H NMR (400MHz, DMSO) δ9.11(d,J=2.4Hz,1H),8.94(d,J=4.4Hz,1H),8.61(d,J=2.4Hz,1H),8.28-8.22(m,1 H),7.64(dd,J=17.7,3.1Hz,2H),7.41-7.33(m,3H),5.31(s,2H),4.55(s,2H),3.82(s,3H),3.75(s,3H). MS(m / z):423.0(M+H) + .

[0348] Example 65: 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine-3-carbonitrile

[0349]

[0350] To a solution of 8-methyl-1,5-naphthyridine-3-carbonitrile (70 mg, 414 μmol) dissolved in tetrachloromethane (7 mL) was added N-bromosuccinimide (74 mg, 416 μmol) and 2,2'-azobis(2-methylpropionitrile) (14 mg, 85 μmol). The mixture was heated to 80 °C under nitrogen atmosphere for 16 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 100% heptane to 35% ethyl acetate in heptane) to give 35 mg of 8-(bromomethyl)-1,5-naphthyridine-3-carbonitrile as an off-white solid (yield = 34.10%).

[0351] To a solution of 3-methoxy-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16 mg, 43 μmol) dissolved in 1,4-dioxane (10 mL) was added 8-(bromomethyl)-1,5-naphthyridine-3-carbonitrile (35 mg, 35 μmol), potassium carbonate (147 mg, 105 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3 mg, 4 μmol) and water (2 mL). The mixture was heated at 90° C. for 2 hr under nitrogen atmosphere. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 50% ethyl acetate in heptane to 100% ethyl acetate) to give 4.0 mg of 8-[[5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-1,5-naphthyridine-3-carbonitrile as a white solid (yield = 27.43%). 1 H NMR (400MHz, DMSO) δ9.37(d,J=2.0Hz,1H),9.12(d,J=2.0Hz,1H),9.05(d,J=4.4Hz,1H),8.28-8.23(m,1H),7.75 (d,J=4.4Hz,1H),7.65(d,J=1.8Hz,1H),7.41-7.34(m,3H),5.30(s,2H),4.56(s,2H),3.83(s,3H),3.75(s,3H). MS(m / z):414.1(M+H) + .

[0352] Method F:

[0353]

[0354] Example 54: 3-methoxy-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)oxy)-1,5-naphthyridine

[0355]

[0356] To a solution of 5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]pyridin-3-ol (50 mg, 191 μmol) dissolved in N,N-dimethylformamide (3 mL) was added cesium carbonate (100 mg, 307 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (30 mg, 154 μmol). The mixture was heated at 120 °C for 1 hr under nitrogen atmosphere. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 40 mg of 3-methoxy-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)oxy)-1,5-naphthyridine as a white solid (yield = 61.72%). 1 H NMR (400MHz, DMSO) δ8.75(d,J=2.8Hz,1H),8.70(d,J=5.2Hz,1H),8.30(d,J=2.2Hz,1H),7.80(d,J=2.8Hz,1H),7. 72(d,J=2.4Hz,1H),7.51-7.40(m,3H),6.79(d,J=5.2Hz,1H),5.39(s,2H),4.01(s,3H),3.85(s,3H),3.81(s,3H). MS(m / z):421.0(M+H) + .

[0357] Method G:

[0358] General route for the synthesis of compounds of formula (I) (when Q=N, X1 is C=O)

[0359]

[0360] Method H:

[0361]

[0362] Example 68: 8-((5-(difluoromethoxy)-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-methoxy-1,5-naphthyridine

[0363]

[0364] To a solution of 5-bromo-2-chloro-pyridin-3-ol (5.00 g, 23.988 mmol) dissolved in N,N-dimethylformamide (120 mL) was added sodium chlorodifluoroacetate (7.363 g, 47.975 mmol) and K2CO3 (4.973 g, 35.982 mmol). The mixture was heated at 100 °C for 1 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 100% heptane to 5% ethyl acetate in heptane) to give 5.10 g of 5-bromo-2-chloro-3-(difluoromethoxy)pyridine as a colorless oil (yield = 82.26%).

[0365] To a solution of (5-methoxy-2-pyridinyl)methanol (269 mg, 1.933 mmol) dissolved in 1,4-dioxane (5 mL) was added potassium tert-butoxide (282 mg, 2.513 mmol) and 5-bromo-2-chloro-3-(difluoromethoxy)pyridine (500 mg, 1.935 mmol). The mixture was heated at 100 ° C for 1 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 100% heptane to 10% ethyl acetate in heptane) to give 540 mg of 5-bromo-3-(difluoromethoxy)-2-[(5-methoxy-2-pyridinyl)methoxy]pyridine as a light yellow solid (yield = 77.29%).

[0366] To a solution of 5-bromo-3-(difluoromethoxy)-2-[(5-methoxy-2-pyridinyl)methoxy]pyridine (500 mg, 1.385 mmol) dissolved in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (527 mg, 2.075 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (152 mg, 208 μmol) and potassium acetate (408 mg, 4.157 mmol). The mixture was heated to 100° C. under nitrogen atmosphere for 2 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (gradient elution with 5% ethyl acetate in heptane to 20% ethyl acetate in heptane) to give 500 mg of 3-(difluoromethoxy)-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a light yellow solid (yield = 88.47%).

[0367] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (50 mg, 198 μmol) in 1,4-dioxane (1 mL) was added 3-(difluoromethoxy)-2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 296 μmol), tripotassium orthophosphate (126 mg, 594 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (13 mg, 20 μmol)) and water (0.2 mL). The mixture was heated to 90°C under nitrogen atmosphere for 1.5 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 50% ethyl acetate in heptane to 100% ethyl acetate) to give 30 mg of 8-[[5-(difluoromethoxy)-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-3-methoxy-1,5-naphthyridine as a white solid (yield = 33.42%). 1 HNMR (400MHz, DMSO) δ8.82(dd,J=5.6,3.7Hz,2H),8.25(t,J=1.8Hz,1H),8.05(d,J=2.0Hz,1H),7.79(d,J=2.9Hz,1H),7.65(d,J=1. 9Hz, 1H), 7.46 (d, J = 4.5Hz, 1H), 7.40 (d, J = 1.8Hz, 2H), 7.16 (t, J = 73.8Hz, 1H), 5.37 (s, 2H), 4.54 (s, 2H), 3.99 (s, 3H), 3.82 (s, 3H). MS(m / z):455.1(M+H) + .

[0368] Method I:

[0369]

[0370] Example 84: 8-(Fluoro(5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-methoxy-1,5-naphthyridine

[0371]

[0372] To a solution of 3-methoxy-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (220 mg, 526 μmol) dissolved in 1,4-dioxane (20 mL) was added SeO2 (1.167 g, 10.515 mmol). The mixture was heated at 60 ° C for 15 hr. The mixture was filtered and the solvent was evaporated. The residue was purified by silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in heptane to 100% ethyl acetate) to give 160 mg of [5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]-(7-methoxy-1,5-naphthyridine-4-yl)methanone as a yellow solid (yield = 70.38%).

[0373] To a solution of [5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]-(7-methoxy-1,5-naphthyridin-4-yl)methanone (100 mg, 231 μmol) dissolved in MeOH (20 mL) was added NaBH4 (18 mg, 476 μmol). The mixture was stirred at 25 °C for 1 hr. 20 ml of water was added to the mixture, followed by extraction with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Mg2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a gradient of 20% ethyl acetate in heptane to 100% ethyl acetate) to give 60 mg of [5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]-(7-methoxy-1,5-naphthyridin-4-yl)methanol as a yellow oil (yield = 59.72%).

[0374] To a solution of [5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]-(7-methoxy-1,5-naphthyridin-4-yl)methanol (60 mg, 138 μmol) dissolved in DCM (10 mL) was added diethylaminosulfur trifluoride (DAST) (67 mg, 416 μmol). The mixture was stirred at 25 °C for 1 hr. 20 ml of NaHCO3 was added to the mixture and extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous Mg2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a gradient of 20% ethyl acetate in heptane to 100% ethyl acetate) to give 20 mg of 8-[fluoro-[5-methoxy-6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-3-methoxy-1,5-naphthyridine as a white solid (yield = 33.18%). 1H NMR(400MHz,DMSO)δ9.04(s,1H),8.74(s,1H),8.24(s,1H),7.83-7.87(m,2H),7.73(s,1H), 7.61(d,1H),7.42(s,1H),7.37(s,2H),5.31(s,2H),3.98(s,3H),3.81(s,3H),3.77(s,3H). MS(m / z):437.1(M+H) + .

[0375] Method J:

[0376]

[0377] Example 100: 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-N,N-dimethyl-1,5-naphthyridin-3-amine

[0378]

[0379] To a solution of 3-fluoro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (200 mg, 492 μmol) dissolved in N,N-dimethylformamide (3 mL) was added methylamine hydrochloride (80 mg, 981 μmol) and DIPEA (320 mg, 2.476 mmol). The mixture was heated in a microwave reactor at 180 °C under nitrogen atmosphere for 1 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 90 mg of 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-N,N-dimethyl-1,5-naphthyridine-3-amine (yield = 42.39%) as a light yellow solid. 1 H NMR(400MHz,DMSO)δ8.87(d,1H),8.67(d,1H),8.25(s,1H),7.64(s,1H),7.33-7.37(m,3H), 7.27(s,1H),7.20(s,1H),5.30(s,2H),4.46(s,2H),3.82(s,3H),3.74(s,3H),3.12(s,6H). MS(m / z):432.1(M+H) + .

[0380] Example 119: 4-(8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridin-3-yl)morpholine

[0381]

[0382] To a solution of 3-fluoro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (220 mg, 541 μmol) dissolved in N-methylpyrrolidone (2 mL) was added morpholine (176 mg, 2.02 mmol) and K2CO3 (320 mg, 2.069 mmol). The mixture was heated in a microwave reactor at 200 °C under nitrogen atmosphere for 1 hr. After evaporation of the solvent, the residue was purified by reverse phase column chromatography (eluting with a gradient of 10% acetonitrile in water to 100% acetonitrile) to give 40 mg of 4-(8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine-3-yl)morpholine (yield = 15.61%) as a white solid. 1 H NMR(400MHz,DMSO)δ9.04(s,1H),8.03(d,1H),8.25(s,1H),7.63(s,1H),7.53(s,1H) ,7.29-7.37(m,4H),5.30(s,2H),4.48(s,2H),3.82(s,7H),3.7(s,3H),3.40(m,4H). MS(m / z):475.1(M+H) + .

[0383] Method K:

[0384]

[0385] Example 134: 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-3-yl)-1,5-naphthyridine

[0386]

[0387] To a solution of 3-chloro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (850 mg, 2.01 mmol) dissolved in 1,4-dioxane (15.0 mL) and H2O (3.0 mL) were added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (627 mg, 3.013 mmol), K2CO3 (834 mg, 6.034 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg, 201 μmol). The mixture was heated at 80°C for 16 hr under nitrogen atmosphere. After evaporation of the solvent, the residue was purified by reverse phase column chromatography (eluting with a gradient of 100% ethyl acetate to 70% tetrahydrofuran in ethyl acetate) to give 700 mg of 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-(1-methyl-1H-pyrazol-3-yl)-1,5-naphthyridine as a white solid (yield = 74.33%). 1H NMR (400MHz, DMSO) δ9.55(d,J=2.1Hz,1H),8.89(d,J=4.4Hz,1H),8.68(d,J=2.1Hz,1H),8.25(t,J=1.7Hz,1H),7.88(d,J=2.2Hz,1H),7.69(d,J=1.7 Hz,1H),7.51(d,J=4.4Hz,1H),7.39(dd,J=4.9,1.8Hz,3H),7.10(d,J=2.3 Hz,1H),5.30(s,2H),4.56(s,2H),3.98(s,3H),3.81(s,3H),3.74(s,3H). MS(m / z):469.1(M+H)+.

[0388] Example 138: 5-(8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridin-3-yl)-2-methylthiazole

[0389]

[0390] To a solution of 3-chloro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (70 mg, 166 μmol) dissolved in 1,4-dioxane (2.5 mL) and H2O (0.5 mL) was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (56 mg, 249 μmol), K2CO3 (69 mg, 499 μmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 17.8 μmol). The mixture was heated in a microwave reactor at 100°C under nitrogen atmosphere for 1 hr. After evaporation of the solvent, the residue was purified by reverse phase column chromatography (eluting with a gradient of 10% ethyl acetate in heptane to 100% ethyl acetate) to give 8 mg of 5-(8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridin-3-yl)-2-methylthiazole as an off-white solid (yield = 16.48%). 1 H NMR(400MHz,DMSO)δ9.41(d,1H),8.92(d,1H),8.54(d,1H),8.46(d,1H),8.25(d,1H),7.67(d,1 H),7.58(d,1H),7.38(d,3H),5.30(s,2H),4.56(s,2H),3.82(s,3H),3.75(s,3H),2.76(s,3H). MS(m / z):486.1(M+H) + .

[0391] Example 140: 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-(pyridin-3-yl)-1,5-naphthyridine

[0392]

[0393] To a solution of 3-chloro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine (60 mg, 142 μmol) dissolved in 1,4-dioxane (3.0 mL) and H2O (0.6 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58 mg, 283 μmol), K2CO3 (60 mg, 434 μmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 14.2 μmol). The mixture was heated in a microwave reactor at 90 °C under nitrogen atmosphere for 1 hr. After evaporation of the solvent, the residue was purified by reverse phase column chromatography (eluting with a gradient of 10% ethyl acetate in heptane to 100% ethyl acetate) to give 20 mg of 8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-(pyridin-3-yl)-1,5-naphthyridine as a white solid (yield = 30.28%). 1 HNMR(400MHz,DMSO)δ9.49(s,1H),9.20(s,1H),8.96(s,1H),8.78(s,1H),8.71(d,1H),8.39-8.42(m,1H),8.25 (s,1H),7.68(s,1H),7.59-7.62(m,2H),7.38-7.41(m,3H),5.31(s,2H),4.60(s,2H),3.82(s,3H),3.76(s,3H). MS(m / z):466.1(M+H) + .

[0394] Method L:

[0395]

[0396] Example 153: 3-methoxy-8-[[2-(4-methoxy-1-piperidinyl)quinoxalin-6-yl]methyl]-1,5-naphthyridine

[0397]

[0398] To a solution of 6-bromo-2-chloro-quinoxaline (0.50 g, 2.053 mmol) dissolved in acetonitrile (10 mL) was added 4-methoxypiperidine (0.473 g, 4.107 mmol) and K2CO3 (0.567 g, 4.103 mmol). The mixture was stirred at 90 ° C for 15 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluted with a gradient of 15% ethyl acetate in heptane to 50% ethyl acetate in heptane) to give 0.45 g of 6-bromo-2-(4-methoxy-1-piperidinyl)quinoxaline as a yellow solid (yield = 68.01%).

[0399] To a solution of 6-bromo-2-(4-methoxy-1-piperidinyl)quinoxaline (450 mg, 1.397 mmol) dissolved in 1,4-dioxane (15 mL) was added bis(pinacolato)diboron (532 mg, 2.095 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 140 μmol) and potassium acetate (411 mg, 4.188 mmol). The mixture was heated to 100 °C under nitrogen atmosphere for 2 hr. After evaporation of the solvent, the residue was purified by silica gel flash chromatography (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 300 mg of 2-(4-methoxy-1-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline as a yellow oil (yield = 58.17%).

[0400] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (70 mg, 277 μmol) in 1,4-dioxane (10 mL) was added 2-[(5-methoxy-2-pyridyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 mg, 271 μmol), tripotassium orthophosphate (176 mg, 829 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (20 mg, 28 μmol) and water (2 mL). The mixture was heated to 90° C. under nitrogen atmosphere for 2 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 30 mg of 3-methoxy-8-[[2-(4-methoxy-1-piperidinyl)quinoxalin-6-yl]methyl]-1,5-naphthyridine as a yellow solid (yield = 26.11%). 1H NMR (400MHz, DMSO) δ8.78-8.83(m,3H),7.70(s,1H),7.78(s,1H),7.45-7.57(m,3H),4.72(s,2H),4. 09-4.15(m,2H),4.00(s,3H),3.37-3.49(m,3H),3.29(s,3H),1.91-1.95(m,2H),1.44-1.52(m,2H). MS(m / z):417.1(M+H) + .

[0401] Method M:

[0402]

[0403] Example 154: 6-((7-methoxy-1,5-naphthyridin-4-yl)methyl)-2-(4-methoxycyclohexyl)quinoxaline

[0404]

[0405] To a solution of 6-bromo-2-chloro-quinoxaline (0.50 g, 2.053 mmol) dissolved in 1,4-dioxane (10 mL) was added 2-(4-methoxycyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.489 g, 2.054 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (150 mg, 205 μmol), K2CO3 (0.568 g, 4.11 mmol) and H2O (2 mL). The mixture was stirred at 75°C for 2 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 40% ethyl acetate in heptane) to give 0.35 g of 6-bromo-2-(4-methoxycyclohexen-1-yl)quinoxaline as a white solid (yield = 68.01%).

[0406] To a solution of 6-bromo-2-(4-methoxycyclohexen-1-yl)quinoxaline (350 mg, 1.097 mmol) dissolved in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (417 mg, 1.642 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 110 μmol) and potassium acetate (322 mg, 3.281 mmol). The mixture was heated to 100° C. under nitrogen atmosphere for 2 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (gradient elution with 15% ethyl acetate in heptane to 40% ethyl acetate in heptane) to give 350 mg of 2-(4-methoxycyclohexen-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline as a white solid (yield = 87.15%).

[0407] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (100 mg, 395 μmol) in 1,4-dioxane (10 mL) was added 2-(4-methoxycyclohexen-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (144 mg, 393 μmol), tripotassium orthophosphate (251 mg, 1.182 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 40 μmol) and water (2 mL). The mixture was heated to 90° C. under nitrogen atmosphere for 2 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 100 mg of 2-(4-methoxycyclohexen-1-yl)-6-[(7-methoxy-1,5-naphthyridin-4-yl)methyl]quinoxaline as a white solid (yield = 61.36%).

[0408] To a solution of 2-(4-methoxycyclohexen-1-yl)-6-[(7-methoxy-1,5-naphthyridin-4-yl)methyl]quinoxaline (100 mg, 242 μmol) in ethyl acetate (10 mL) and methanol (5 mL) was added 50 mg of Pd / C. The mixture was stirred at 20 °C for 1 hr under a hydrogen atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (eluting with a gradient of 5% acetonitrile in H2O to 100% acetonitrile) to give 10 mg of 6-((7-methoxy-1,5-naphthyridin-4-yl)methyl)-2-[(7-methoxy-1,5-naphthyridin-4-yl)methyl)-2-[(7-methoxy-1,5-naphthyridin-4-yl)methyl)-2-[(7-methoxy-1,5-naphthyridin-4-yl)methyl)-4-methoxycyclohexyl)quinoxaline as a white solid (yield = 9.95%). 1H NMR (400MHz, DMSO) δ8.83-8.84(m,3H),7.93-7.95(m,2H),7.77-7.80(m,2H),7.49(d,1H),4.83(s,2H),4.00( s,3H),3.50(s,1H),3.25(s,3H),2.99-3.05(m,1H),1.86-1.99(m,4H),1.66-1.70(m,2H),1.53-1.60(m,2H). MS(m / z):415.2(M+H) + .

[0409] Method N:

[0410]

[0411] Example 151: 3-methoxy-8-((6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

[0412]

[0413] Potassium tert-butoxide (1.00 g, 8.912 mmol) and 5-bromo-2-fluoro-pyridine (1.00 g, 5.682 mmol) were added to a solution of (5-methoxy-2-pyridyl)methanol (1.00 g, 7.186 mmol) dissolved in 1,4-dioxane (15 mL). The mixture was stirred at 20 ° C for 1 hr. Saturated NH4Cl solution was added to the mixture to quench the reaction. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluted with a gradient of 100% heptane to 20% ethyl acetate in heptane) to give 1.67 g of 2-[(5-bromo-2-pyridyl)oxymethyl]-5-methoxy-pyridine as a white solid (yield = 99.58%).

[0414] To a solution of 2-[(5-bromo-2-pyridyl)oxymethyl]-5-methoxy-pyridine (400 mg, 1.355 mmol) dissolved in 1,4-dioxane (15 mL) was added bis(pinacolato)diboron (516 mg, 2.032 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (99 mg, 136 μmol) and potassium acetate (266 mg, 2.71 mmol). The mixture was heated to 100° C. under nitrogen atmosphere for 12 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (gradient elution from 5% ethyl acetate in heptane to 50% ethyl acetate in heptane) to give 200 mg of 2-[(5-methoxy-2-pyridinyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a white solid (yield = 43.12%).

[0415] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (81 mg, 320 μmol) in 1,4-dioxane (5 mL) was added 2-[(5-methoxy-2-pyridyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 mg, 292 μmol), tripotassium orthophosphate (155 mg, 730 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (19 mg, 29 μmol) and water (1 mL). The mixture was heated to 90°C under nitrogen atmosphere for 12 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate) to give 35 mg of 3-methoxy-8-[[6-[(5-methoxy-2-pyridinyl)methoxy]-3-pyridinyl]methyl]-1,5-naphthyridine as a white solid (yield = 30.84%). 1 H NMR (400MHz, CDCl3) δ8.78(t,J=3.7Hz,2H),8.33(d,J=2.7Hz,1H),8.16(d,J=2.0Hz,1H),7.67(d,J=2.8Hz,1H),7.55(dd,J=8.5,2.4H z,1H),7.40(d,J=8.6Hz,1H),7.21(dd,J=8.5,2.9Hz,2H),6.79(d,J=8.5Hz,1H),5.44(s,2H),4.57(s,2H),4.02(s,3H),3.88(s,3H). MS(m / z):489.1(M+H) + .

[0416] Method O:

[0417]

[0418] Example 158: 3-methoxy-8-((2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-1,5-naphthyridine

[0419] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (150 mg, 593 μmol) in 1,4-dioxane (10 mL) was added 2-tetrahydropyran-4-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (200 mg, 609 μmol), tripotassium orthophosphate (388 mg, 1.828 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 61 μmol) and water (2 mL). The mixture was heated to 90° C. under nitrogen atmosphere for 2 hr. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel (eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate) to give 100 mg of 3-methoxy-8-[(2-tetrahydropyran-4-ylpyrazolo[1,5-a]pyridin-5-yl)methyl]-1,5-naphthyridine as a white solid (yield = 43.83%). 1H NMR (400MHz, DMSO) δ8.80-8.83(m,2H),8.46(d,1H),7.79(d,1H),7.41-7.47(m,2H),6.73(d,1H),6.32(s,1H),4.59 (s,2H),3.99(s,3H),3.89-3.92(m,2H),3.42-3.48(m,2H),2.95-3.00(m,1H),1.84-1.87(m,2H),1.65-1.75(m,2H). MS(m / z):375.2(M+H) + .

[0420] Additional compounds were prepared by modification of the methods exemplified herein. All compounds and their corresponding characterization data are presented in Table 1 below.

[0421] Table 1

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] Biochemical analysis

[0464] For the enzymatic step, a working solution was prepared in enzymatic buffer (12.5 nM SEB, 1 mM DTT, 5 mM MgCl2, 1 mM MnCl2). The reaction was performed at room temperature for 1 hour in a 384-well plate with 2.5 μL inhibitor or enzymatic buffer, 2.5 μL recombinant human protein (CSF-1R, c-kit, PDGFRβ and FLT3) and 5 μL substrate / ATP mixture. After adding the detection mixture (5 μl Sa-XL 665 and 5 μl TK-antibody-cryptate), the plate was sealed and incubated at room temperature for 1 hour. Detection was performed with a Spark reader (Tecan) using standard HTRF protocol settings. IC was performed using GraphPad Prism software (GraphPad Corporation). 50 Determined by IC of other kinases (cKit, FLT3, PDGFR-1β) 50 and CSF-1R IC 50 The selectivity factor is determined by the multiple of .

[0465] Cell proliferation analysis

[0466] Ba / F3_CSF-1R (stable expression of human CSF-1R kinase) was cultured in RPMI1640 medium supplemented with 10% FBS and 100 ng / ml recombinant human CSF-1. EOC2 was cultured in DMEM medium supplemented with 10% FBS and 100 ng / ml recombinant mouse CSF-1. Cells were plated in 384-well plates (1×10 for Ba / F3_CSF1R cells). 3 cells / well, and for EOC2 cells 5×10 2 Cells were added to the cells for 24 hours and then treated with the compounds for 72 hours. Cell growth rate was determined using the CellCounting-Lite luciferase-based ATP detection assay (Vazyme) according to the manufacturer's protocol. IC was performed using GraphPad Prism software (GraphPad Corporation). 50 Sure.

[0467] Biological activity data

[0468] The enzymatic and cytostatic activities of representative compounds disclosed herein are presented in Table 2 below.

[0469] Table 2

[0470]

[0471]

[0472]

[0473]

[0474] NA is not available.

[0475] The selectivity data of selected compounds against CSF1R relative to cKit, FLT3, PDGFR-β are presented in Table 3 below.

[0476] Table 3

[0477]

[0478]

[0479]

[0480] The structures of reference compounds GW2580, PLX5622, BLZ945 and Comparator A are provided below.

[0481] GW2580:

[0482]

[0483] PLX5622:

[0484]

[0485] BLZ945:

[0486]

[0487] Comparative A

[0488]

[0489] In vivo PK studies

[0490] PK characteristics were determined in CD1 mice, and all procedures and protocols were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. CD1 mice were purchased from JH Laboratory Animal Co., Ltd. CD1 mice (23-30g, 6-8 weeks, male) were randomly divided into five groups consisting of 21 mice per group. PK studies were performed on the formulated test compounds. The test compounds were administered orally at 45mg / kg and intravenously at 2mg / kg. After administration, blood samples and brain samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24h. Brain samples were collected at 1, 4, 8 and 24h. Blood samples were placed on wet ice, and serum was collected after centrifugation. Serum samples were frozen and stored at -70°C. Brain samples were dried on filter paper, quickly frozen on dry ice and further stored at -70°C. Then, blood samples and brain samples were further analyzed by LC-MS / MS (Triple Quad 6500+).

[0491] Selected compounds and formulations of reported inhibitors are presented in Table 4 below.

[0492] Table 4

[0493]

[0494]

[0495] In vivo ADMET data for selected compounds and reported inhibitors are presented in Tables 5 and 6 below.

[0496] Table 5

[0497]

[0498] Table 6

[0499]

[0500]

[0501] Based on in vivo ADME data, Example 16 showed moderate clearance (CL = 0.448 L / hr / kg) with a T of 2.52 hr. 1 / 2 , moderate distribution and excellent absorption with F 215%. When administered to mice as the free base, Example 45 exhibited low clearance (CL = 0.134 L / hr / kg) with a T of 14.2 hr. 1 / 2 (2 mpk, IV). Example 45 also showed moderate absorption of F 55% after oral treatment in mice (45 mpk). Example 73 showed moderate clearance with a T of 2.52 hr. 1 / 2 、V SS The distribution was moderate at 0.461 L / kg and the Cmax was excellent at 100367 ng / mL. Example 116 shows that V SS Very high distribution of 9.54 L / kg, which may result in low Cmax. Example 134 showed moderate clearance, exposure and high absorption with F of 227%. Example 136 exhibited comparable ADME properties to Example 073.

[0502] Plasma protein binding studies

[0503] On the day of the experiment, the plasma was thawed under running cold tap water and centrifuged at 3220 × g for 5 min to remove any clots. Check the pH value and record it. Only plasma in the range of pH 7.0 to pH 8.0 was used. The dialysis membrane was pretreated according to the manufacturer's instructions: the dialysis membrane strip was soaked in ultrapure water at room temperature for about 1 hr. Afterwards, each membrane strip containing 2 membranes was separated and soaked in ethanol: water (20: 80v: v) for about 20 min, after which it was ready for use or stored in solution at 2-8°C for up to 1 month. Prior to the experiment, the membrane was rinsed and soaked in ultrapure water for 20 min for use. Working solutions (400 μM) of test compounds and control compounds were prepared. An aliquot (3 μL) of the working solution was incorporated into a blank matrix (597 μL) to achieve the final concentration and mixed thoroughly. Aliquots of 50 μL of the loaded matrix containing the test compound or control compound were transferred to the sample collection plate in triplicate. Immediately match the sample with the relative blank buffer to obtain a final volume of 100 μL in each well with a volume ratio of matrix: dialysis buffer (1: 1, v: v). Stop solution is added to these T0 samples of test compound and control compound. The plate is sealed and shaken at 800 rpm for 10 min. These T0 samples are then stored at 2-8 ° C, waiting for further processing with other post-dialysis samples. Assemble the dialysis instrument according to the manufacturer's instructions. 100 μL of aliquots of the loaded matrix containing test compound or control compound are transferred to the donor side of each dialysis well in triplicate, and 100 μL of dialysis buffer is loaded to the receiving side of the well. The plate is then rotated at about 100 rpm for 4 hours at 37 ± 1 ° C in a humidified incubator with 5% CO2. At the end of dialysis, aliquots of 50 μL samples from the buffer side and matrix side of the dialysis device are placed in a new 96-well plate (sample collection plate). An equal volume of the relative blank matrix (buffer or matrix) was added to each sample to achieve a final volume of 100 μL with a 1:1 (v:v) matrix:dialysis buffer volume ratio in each well. All samples were further processed by protein precipitation for LC / MS / MS analysis.

[0504] Brain protein binding studies

[0505] On the day of the experiment, brain homogenates were thawed in a water bath at room temperature, followed by incubation at 37°C for 10 min before use. The dialysis membrane was pretreated according to the manufacturer's instructions: the dialysis membrane strips were soaked in ultrapure water at room temperature for about 1 hr. Afterwards, each membrane strip containing 2 membranes was separated and soaked in ethanol: water (20:80 v: v) for about 20 min, after which it was ready for use or stored in solution at 2-8°C for up to 1 month. Prior to the experiment, the membrane was rinsed and soaked in ultrapure water for 20 min for use. Then a working solution (400 μM) of the test compound and control compound was prepared. An aliquot (3 μL) of the working solution was added to the blank matrix (597 μL) to achieve the final concentration and mixed thoroughly. Aliquots of 50 μL of the loaded matrix containing the test compound or the control compound were transferred to the sample collection plate in triplicate. The sample was immediately matched with the relative blank buffer to obtain a final volume of 100 μL in each well with a volume ratio of matrix: dialysis buffer (1: 1, v: v). Stop solution is added to these T0 samples of test compound and control compound. Plate is sealed and vibrated at 800rpm for 10min. Then these T0 samples are stored at 2-8 ℃, waiting for further processing with other post-dialysis samples. Dialysis instrument is assembled according to manufacturer's instructions. Aliquots of 100 μL loading matrix containing test compound or control compound are transferred to the donor side of each dialysis well in triplicate, and 100 μL dialysis buffer is loaded to the receiving side of the well. Then the plate is rotated at about 100rpm for 4 hours at 37 ± 1 ℃ in a humidified incubator with 5% CO2. At the end of dialysis, aliquots of 50 μL samples from the buffer side and matrix side of the dialysis device are placed in a new 96-well plate (sample collection plate). In each sample, an equal volume of relative blank matrix (buffer or matrix) is added, so as to reach the final volume of 100 μL and the matrix of 1:1 (v:v) in each well: the volume ratio of dialysis buffer. All samples were further processed by protein precipitation for LC / MS / MS analysis.

[0506] BBB penetration data for selected compounds and reported inhibitors are presented in Tables 7 and 8 below.

[0507] Table 7

[0508]

[0509] Table 8

[0510]

[0511]

[0512] When orally administered to mice, both Example 16 and Example 45 showed high exposure in the brain and high BBB penetration, with Kp,uu values ​​of 1.10 and 0.96, respectively.

[0513] p-CSF1R ELISA analysis

[0514] 1.1 Materials

[0515]

[0516] 1.2 Cell culture

[0517] 1. Prepare medium for THP-1 cell culture according to ATCC instructions. The basal medium used for this cell line is RPMI-1640 medium. To prepare complete growth medium, add the following components to the basal medium: 2-mercaptoethanol to a final concentration of 0.05 mM; fetal bovine serum to a final concentration of 10%; P / S to a final concentration of 1%.

[0518] 2. The culture can be maintained by adding fresh medium or replacing the medium. 5 When the cell concentration reaches 8×10 5 Cell concentration should not exceed 1.5×10 6 Cells / mL. Medium renewal: every 3 to 4 days.

[0519] 1.3 Reagent preparation

[0520] 1. Dissolve the recombinant human M-CSF lyophilized powder to a concentration of 5 μg / ml according to the instructions, distribute and store in a -80°C refrigerator.

[0521] 2. Prepare lysis buffer just before use. (Complete lysis buffer: 1 ml 10X incomplete lysis buffer from ELISA kit, 8.9 ml DPBS and 100 μl Halt(tm) protease and phosphatase inhibitor cocktail (100X))

[0522] 1.4 Procedure

[0523] 1. Before inoculating cells, centrifuge the cells at 1000 rpm for 5 min. After centrifugation, resuspend the cell pellet with pre-warmed culture medium and separate the cells by pipetting up and down 6 times with a 10 ml serological pipette. Dilute the cell suspension to 2.5 × 10 6 The final concentration was 10 cells / ml. 80 μl of cell suspension (2×10 5 cells) were added to the wells of a 96-well plate.

[0524] 2. Dissolve the compound stock solution at 10 mM in DMSO. Start with 5 mM (5 μl + 5 μl DMSO) and dilute at 4-fold dilutions, 8 dose points. For the control of 100% inhibition, the reference compound PLX3397 concentration is 2.5 mM. Then dilute the compound with culture medium in the middle plate (2 μl compound + 198 μl culture medium). Transfer 20 μl of the diluted compound from the middle plate to the cell plate. Incubate the cell plate at 37°C / 5% CO2 for 1 h.

[0525] 3. After 1 h of compound treatment, add 25 μl of 5x M-CSF (250 ng / ml) to the 96-well plate; the final concentration of human M-CSF is 50 ng / ml;

[0526] 4. After 2-5 min M-CSF treatment, centrifuge the cell plate at 4000 rpm (cooled) for 10 min, remove the medium and gently wash the cells once with 200 μl / well ice-cold 1X PBS. Then centrifuge the cell plate at 4000 rpm (cooled) for 10 min, remove the PBS and add 100 μl / well ice-cold 1X cell lysis buffer to the 96-well plate. Gently shake the plate at 4°C for 2 h.

[0527] 5. After the microwell strips have reached room temperature, add 90 μl of cell lysate to the appropriate wells. Seal with tape and press firmly on top of the microwells. Incubate the plate at 37°C for 2 h.

[0528] 6. Gently remove the tape and wash the wells 5 times with 1X Wash Buffer, 200 μl per well each time.

[0529] 7. Add 100 μl of reconstituted detection antibody to each well. Seal with tape and incubate the plate at 37°C for 1 h.

[0530] 8. Gently remove the tape and wash the wells 5 times with 1X Wash Buffer, 200 μl per well each time.

[0531] 9. Add 100 μl of reconstituted HRP-linked secondary antibody to each well. Seal with tape and incubate the plate at 37°C for 30 min.

[0532] 10. Gently remove the tape and wash the wells 5 times with 1X Wash Buffer, 200 μl per well each time.

[0533] 11. Add 100 μl of TMB substrate to each well. Seal with tape and incubate the plate at 37°C for 15 min.

[0534] 12. Add 100 μl of stop solution to each well. Shake gently for a few seconds. Read the absorbance at 450 nm within 30 minutes after adding the stop solution.

[0535] 1.5 Data Analysis

[0536] Calculations and Formulas: The following calculations and formulas are used for data analysis using the XL Fit software:

[0537] 1. The mean value of "cells stimulated with M-CSF in the presence of DMSO" was set to 0%.

[0538] 2. The mean value of "cells stimulated with M-CSF in the presence of 5 μM PLX3397" was set to 100%.

[0539] 3. All other values ​​are expressed as percentages relative to the positive control.

[0540] 4. Calculate the mean of 0% inhibition and 100% inhibition of phospho-CSF1R and similarly for the standard deviation (Stdev).

[0541] 5. Calculate the Cv for 0% inhibition and 100% inhibition (Cv = standard deviation / mean value*100)

[0542] 6. Calculate the Z factor, Z factor = 1-3 (standard deviation MAX + standard deviation MIN) / (average MAX - average MIN)

[0543] 7. Inhibition % = (average 0% inhibition - sample value) / (average 0% inhibition - average 100% inhibition)

[0544] 8. Calculate S / B, S / B = average 0% inhibition / average 100% inhibition.

[0545] 9. Perform curve fitting using the fitting model (205), the details of which are: 4-parameter logistic model or sigmoidal dose-response model.

[0546] Fit = (A + ((BA) / (1 + ((C / x)^D))))

[0547] inv=(C / ((((BA) / (yA))-1)^(1 / D)))

[0548] res = (y-fit)

[0549] 10. Data Acceptance Criteria: Use the following criteria for data QC:

[0550] 10.1 Z factor: >0.50, based on 0% and 100% inhibition controls.

[0551] 10.2 Reference compound IC50 values ​​were consistent between runs.

[0552] p-CSF1R and p-ERK1 / 2 Western blot analysis

[0553] Reagents and cell lines were purchased from the supplier Fisher Scientific. A murine microglial cell line, BV2 cells (Accegen), were cultured in T75 flasks in DMEM / F12 (Gibco) supplemented with 10% FBS, 1% penicillin-streptomycin, and 0.1% amphotericin B and split twice a week. Unless otherwise stated, the same medium formulation was always used. One day before the experiment, BV2 cells were trypsinized and counted. A total of 1×10 6 Cells were plated in 12-well PDL-coated plates and cultured overnight at 37°C in a CO2 incubator. At the beginning of the experiment, cells were serum starved for 4 hours with preheated DMEM / F12 only. The inhibitors were dissolved in DMSO, and the cells were pretreated with the indicated concentration of inhibitors in DMSO with a volume not exceeding 0.1% of the volume of the culture medium for 30 minutes, followed by stimulation with 100ng / mL of recombinant mouse CSF1 (R&D Systems) for 5 minutes. The cells were lysed with RIPA buffer supplemented with a mixture of protease and phosphatase inhibitors (Halt-Pierce) and benzonase (EMD Millipore). The lysate was incubated at room temperature for 15 minutes and centrifuged at 16200g for 10 minutes at 4°C to precipitate the insoluble fraction. The supernatant was collected, and the protein concentration was determined using a Rapid BCA kit (Pierce), and the absorbance was measured on a SpectramaxM5 (Molecular Devices). 20 μg of total protein from each condition was loaded and electrophoresed on 4-12% Bis-Tris SDS-PAGE gels (Invitrogen) and transferred to PVDF membranes using the iBlot2 system (Invitrogen). Immunoblotting for phospho-CSF1R (Cell Signaling, 3155S, 1:1000 dilution) and phospho-ERK1 / 2 (Cell Signaling, 9101S, 1:1000 dilution) was performed, followed by stripping with NewBlotIR stripping buffer (Li-Cor) for 15 minutes and reprobing for CSF1R (Cell Signaling, 3152S, 1:2000 dilution), ERK1 / 2 (Cell Signaling, 9107S, 1:1000 dilution) and β-tubulin (Abcam, ab179513, 1:5000 dilution).

[0554] Effect of CSF1Ri on the proliferation of BV2 cells

[0555] Reagents and cell lines are purchased via supplier Fisher Scientific.BV2 cells (Accegen) are cultivated in T75 flasks in DMEM / F12 (Gibco) supplemented with 10% FBS, 1% penicillin-streptomycin and 0.1% amphotericin B, and split twice a week.Unless otherwise stated, the same culture medium formulation is always used.1000 BV2 cells per well are inoculated in a 96-well tissue culture treated plate (Corning).Inhibitors and / or CSF1 (100ng / mL) are added and cultured for 72 hours.To implement Cell Titer Glo analysis, culture medium is aspirated from the hole.100 μL fresh growth medium+100 μL Cell Titer Glo reagent (Promega) is added, and the plate is incubated at room temperature for 15 minutes.100 μL from each sample is transferred to a white solid bottom plate (Corning) for luminescent reading (560nm) on SpectramaxM5 (Molecular Devices).

[0556] result

[0557] Effects of CSF1Ri on CSF1R signaling pathway

[0558] To better understand the pharmacodynamic effects of our lead compounds on the CSF1R signaling pathway, we analyzed the levels of phosphorylated forms of CSF1R (p-CSF1R) and ERK1 / 2 (p-ERK1 / 2) (downstream MAP kinases) in murine microglial-like BV2 cells stimulated with recombinant mouse CSF1. BV2 cells were pretreated with Example 16 or reference compounds (1000 nM-0.3 nM) for 30 minutes and stimulated with CSF1 (100 ng / mL) for 5 minutes, followed by cell lysis and running the lysates on SDS-PAGE gels. CSF1 treatment consistently increased CSF1R and ERK1 / 2 phosphorylation in BV2 cells ( Figure 1 A. Figure 1 B. Figure 1 C- Compare lane 1 with lane 2). Figure 1 A) and Comparative A( Figure 1 B) Pre-incubation of cells abolished CSF1R signaling in a concentration-dependent manner. Example 16 also abolished CSF1 signaling in a concentration-dependent manner ( Figure 1 C). Quantification of p-CSF1R and p-ERK1 / 2 immunosignals from Western blots is shown in Figure 2 (GW2580- Figure 2 A; Comparative A- Figure 2 B, Example 16- Figure 2 C). Example 16 inhibited CSF1R signaling with an average EC50 value of 47.2 nM for p-CSF1R inhibition and an average EC50 value of 21.4 nM for p-ERK1 / 2 inhibition (Table A). Thus, Example 16 was at least as effective as the reference compound in blocking the CSF1R signaling pathway in BV2 cells.

[0559] Since BV2 cells are of murine origin, we decided to set up a pharmacodynamic analysis in the human THP-1 cell line using the well-established p-CSF1R ELISA assay. THP1 cells were pretreated with compounds in 3-fold dilution steps in a 10-point concentration-response curve (CRC) for 1 hour and then stimulated with hCSF1. Cells were lysed and pCSF1R levels were quantified as described in the Materials and Methods section. Individual CRCs are presented in Figure 3 The calculated EC50 values ​​are presented in Table B. Thus, Example 16 shows a concentration-dependent blockade of CSF1R phosphorylation in human THP1 cells with a calculated EC50 of 10.8 nM.

[0560] Table A

[0561]

[0562] Table B

[0563]

[0564] Effects of CSF1Ri on the proliferation and survival of microglia

[0565] The functional output of CSF1R signaling in microglia is cell proliferation and survival. We established an assay to measure the effects of our compounds on microglial proliferation. We stimulated BV2 cells with CSF1 (100 ng / mL) for 72 hours, which resulted in an approximately 2-fold enhancement in cell proliferation compared to vehicle-treated cells, as assessed by Cell TiterGlow assay ( Figure 4 A). CSF1-induced proliferation was abolished by CSF1R inhibitors (GW2580 and BLZ945) in a concentration-dependent manner ( Figure 4 B. Figure 4 C). Example 16 also showed a concentration-dependent inhibition of BV2 cell proliferation ( Figure 4 D) The EC50 values ​​calculated in this analysis are shown in Table C.

[0566] Table C

[0567]

[0568] To evaluate the efficacy of the CSF1R inhibitors disclosed herein, we isolated and expanded primary brain glial cells from rat cortex in vitro. The glial cell culture is about 20% microglia, which is mainly supported by astrocytes that make up the remaining population. Brain glial cells were exposed to CSF1R inhibitors for 3 days, followed by paraformaldehyde fixation and immunofluorescence staining for the microglial marker Iba1. Glial cells were imaged using a high-content imager and changes in microglial content were quantified. Using GraphPad Prism, a four-parameter logistic regression was applied to determine the efficacy of CSF1R inhibitors. CSF1R inhibitors (Example 16) showed a dose-dependent inhibition of primary rat microglial survival after 3 days of exposure ( Figure 5 A). CSF1R inhibitors (Examples 73, 134 and 136) showed dose-dependent inhibition of primary rat microglial survival after 3 days of exposure ( Figure 5 B).

[0569] Effect of CSF1Ri on the inhibition of CSF1R phosphorylation

[0570] The THP-1 human monocyte-like cell line has intact CSF1R signaling, which allows probing the activation state of this pathway upon stimulation with recombinant CSF. THP-1 cells were expanded in vitro and pretreated with CSF1R inhibitors for 1 hour, followed by stimulation with recombinant human M-CSF for 5 minutes. Cells were lysed and lysates were probed for activated CSF1R (pCSF1R) using ELISA. Four-parameter logistic regression was applied to determine the potency of CSF1R inhibitors using GraphPad Prism. Calculated IC 50 The values ​​are shown in Table D. CSF1R Inhibitor Example 16 demonstrates dose-dependent inhibition of CSF1R phosphorylation in CSF1R-stimulated THP-1 monocytes ( Figure 6 ).

[0571] Table D

[0572] Compound ID <![CDATA[Average IC 50 (nM)*]]> PLX3397 45.4 Embodiment 134 5.4 Embodiment 136 32.5

[0573] Effect of CSF1Ri on the survival of hiPSC-MG

[0574] To demonstrate compound efficacy in a highly translatable human model, we established human induced pluripotent stem cell-derived microglial (hiPSC-MG) cultures and examined the effects of our compounds on hiPSC-MG survival. Briefly, hiPSC-MGs were stabilized for three days after thawing and treated with CSF1R inhibitors for 48 h. Microglial survival was finally assessed using the Presto-Blue viability assay ( Figure 7 A and Figure 7 B). Percent survival values ​​representing cell viability were calculated from each Presto-Blue fluorescence value normalized to the DMSO-treated control (ie, DMSO was set to 100%). All CSF1R inhibitors used herein inhibited CSF1R-dependent cell survival in a concentration-dependent manner ( Figure 7 A and Figure 7 B). Specifically, Example 16 ( Figure 7 A), Example 73 ( Figure 7 B) and Example 134 ( Figure 7 B) IC 50 The value is lower than BLZ945( Figure 7 B), confirming the excellent potency of our compounds in human microglia.

[0575] In vivo microglial depletion of Example 134

[0576] To measure the pharmacodynamic effects in vivo, we quantified the microglial depletion after repeated administration of our compounds in naive animals. Female C57BL / 6 mice were given Example 134 (0, 50, 100 or 200 mg / kg / day, respectively) BID by oral gastric tube gavage for 7 days. After the final dose, mice were perfused with PBS and then perfused with 4% paraformaldehyde (PFA). The brain was post-fixed overnight in 4% PFA and then transferred to a 30% sucrose solution. Sagittal sections were sliced ​​and stained for microglial marker Iba1, and counterstained for DAPI. The brain slices were then imaged under 20X wide field imaging, and microglial density was quantified in the cortex and hippocampus.

[0577] Example 134 The effect of microglial depletion in the brain is shown in Figure 8 A. Figure 8 B and Table E. We observed a dose-dependent decrease in microglial cell density of Example 134. In the cortex, microglial cell density was significantly reduced at doses of 50, 100, and 200 mg / kg (>22%, >91%, and >98%), respectively, compared to vehicle control ( Figure 8A). In the hippocampus, microglial cell density was significantly lower in both the 100 mg / kg (>83%) and 200 mg / kg groups (>93%) relative to vehicle control (see Figure 8 B). In summary, Example 134 showed strong depletion effects in the brain at doses as low as 50 mg / kg / day in the cortex and at 100 mg / kg / day in the hippocampus.

[0578] Table E

[0579]

[0580]

[0581] Overview

[0582] Example 16 was tested in the above-mentioned pharmacodynamic analysis (p-CSF1R ELISA analysis, p-CSF1R and p-ERK1 / 2 Western blot analysis) and cell-based efficacy analysis (BV2 cell proliferation analysis, rat microglial survival analysis, CSF1R phosphorylation inhibition analysis, hiPSC-MG survival analysis). Example 134 was tested in an in vivo pharmacodynamic study. The pharmacodynamic analysis showed that Example 16 is a potent inhibitor of CSF1R and is comparable to, if not more potent than, the reference compounds GW2580, BLZ945, and Comparator A. The efficacy analysis has shown that Example 16 is a potent inhibitor of CSF1-directed microglial-like BV2 cell line proliferation, and its calculated EC50 value is consistent with Example 16 exerting an on-target effect. In addition, the efficacy analysis has shown that Example 16 exhibits strong inhibition of CSF1R phosphorylation. Microglial cell survival assays have shown that Examples 16, 73, 134 and 136 exhibited strong inhibition of primary rat microglial cell survival. hiPSC-MG survival assays confirm the superior potency of our compounds in human microglial function, with the calculated IC 50 The values ​​were lower compared to BLZ945. In vivo studies showed that Example 134 exhibited strong depletion effects in the brain at doses as low as 50 mg / kg / day in the cortex and at 100 mg / kg / day in the hippocampus.

Claims

1. A compound represented by formula (I): Its pharmaceutically acceptable salt or tautomer, wherein: Q is C or N; When Q is N, QX 1 is a single bond and X 1 It is C=O; When Q is C, QX 1 is a double bond and X 1 Is N or CR 1 ; Z is CH or NH; When Z is NH, ZX 3 is a single bond and X 3 It is C=O; When Z is CH, ZX 3 is a double bond and X 3 Is N or CR 3 ; X 2 Is N or CR 2 ; X 4 Is N or CR 4 ; X 5 Is N or CR 5 ; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, -CN, -OH, C optionally substituted with one to three deuteriums 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0- 4C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R 1 , R 2 , R 3 , R 4 or R 5 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; A 1 , A 2 , A 3 and A 4 Each independently is N or CR A ; and A 1 , A 2 , A 3 and A 4 No more than two of them are N; Each R A are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R A The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Ring B is phenyl, or a 5- or 6-membered monocyclic heteroaryl; Each R B independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; and / or Two R's B Together with the ring B atoms to which they are attached, they form a 5-7 membered monocyclic ring or a 6-9 membered bicyclic ring fused to ring B, wherein the 5-7 membered monocyclic ring or the 6-9 membered bicyclic ring is optionally substituted by one or two groups selected from the group consisting of CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and 3-6 membered cycloalkyl; R C and R D are each independently selected from hydrogen, deuterium, F and methyl; Each R * Independently selected from the group consisting of: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3-6 membered carbocyclyl or 4-6 membered heterocyclyl; and m is 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R 1 , R 2 , R 3 , R 4 or R 5 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Each R A are independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R A The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Each R B independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two groups selected from the following: CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; or Two R's B Together with the ring B atoms to which they are attached, they form a 5,6-membered ring fused to ring B, wherein the 5,6-membered ring is optionally substituted with one or two groups selected from the group consisting of CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; and R C and R D are each independently selected from hydrogen, F and methyl.

3. The compound according to claim 2, wherein the compound is represented by formula (II-A): or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2, wherein the compound is represented by any one of Formula (III-A-1), Formula (III-A-2), Formula (III-A-3), Formula (III-A-4), Formula (III-A-5), Formula (III-A-6) or Formula (III-A-7): or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2, wherein the compound is represented by any one of Formula (III-B-1), Formula (III-B-2), Formula (III-C-1), Formula (III-C-2), or Formula (III-C-3): or a pharmaceutically acceptable salt thereof.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 2 to 5, wherein is phenyl or pyridyl, each of which is optionally substituted by one or two R A replace.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 2 to 6, wherein ring B is optionally substituted by one or two R B Substituted phenyl, each R B are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-OR * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two halogen or C 1-6 Alkyl substitution.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 2 to 6, wherein ring B is optionally substituted by one or two R B Substituted 5,6-membered monocyclic heteroaryl, each R B are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-OR * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two halogen or C 1-6 Alkyl substitution.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 2 to 6, wherein ring B is phenyl or a 5,6-membered monocyclic heteroaryl group, each of which is optionally substituted by one to four R B Replace, and the two R B Together with the ring B atoms to which they are attached, they form a 5,6-membered ring fused to ring B, wherein the 5,6-membered fused ring is optionally fused via one or two CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution.

10. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, indazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl or benzo[d][1,3]dioxolyl.

11. A compound according to any one of claims 2 to 10 or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * .

12. A compound according to any one of claims 2 to 11 or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * .

13. A compound according to any one of claims 2 to 12, or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, -(CH2) optionally substituted with one to three deuterium 0-2 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * .

14. A compound according to any one of claims 2 to 13 or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * .

15. A compound according to any one of claims 2 to 14 or a pharmaceutically acceptable salt thereof, wherein each R 5 are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, -(CH2) 0-4 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-NR * R * 、-NR * C(O)R * and-NR * C(O)OR * .

16. A compound according to any one of claims 2 to 15 or a pharmaceutically acceptable salt thereof, wherein each R A are independently selected from H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * and-NR * C(O)OR * .

17. A compound according to any one of claims 2 to 16 or a pharmaceutically acceptable salt thereof, wherein each R B are independently selected from halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, -(CH2) optionally substituted with one to three deuterium 0-2 C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * and -(CH2) optionally substituted by one or two halogens 0或1 -3-6 membered cycloalkyl.

18. A compound according to any one of claims 2 to 17 or a pharmaceutically acceptable salt thereof, wherein each R * independently H or C 1-4 Alkyl (preferably H or C 1-2 alkyl).

19. A compound according to any one of claims 2 to 18, or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy (preferably H); and each R 2 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy (preferably H).

20. A compound according to any one of claims 2 to 19 or a pharmaceutically acceptable salt thereof, wherein each R 3 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 haloalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy and C 1-4 Haloalkoxy (preferably H, CN, halogen, C 1-4 alkyl or C optionally substituted with one to three deuterium 1-4 alkoxy).

21. A compound as claimed in any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy (preferably H, F or C 1-4 alkoxy).

22. A compound as claimed in any one of claims 2 to 21 or a pharmaceutically acceptable salt thereof, wherein each R 5 are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy (preferably H).

23. A compound as described in any one of claims 2 to 22, or a pharmaceutically acceptable salt thereof, wherein each R A Independently selected from H, C 1-2 alkyl or C optionally substituted with one to three deuterium 1-2 Alkoxy (preferably H, -OCH3 or -OCD3).

24. A compound as described in any one of claims 2 to 23, or a pharmaceutically acceptable salt thereof, wherein each R B independently selected from halogen, -OH, C 1-3 Alkyl, C 1-3 haloalkyl, -(CH2) optionally substituted with one to three deuterium 0-2 C 1-2 Alkoxy, C 1-2 Haloalkoxy, -(CH2) 0-2 NR * R * Or a 3-6 membered cycloalkyl optionally substituted with one or two halogens (preferably F, Cl, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2N(CH3)2, -CH2OCH3, -OCH3, -OCHF2, -OCD3, cyclopropyl optionally substituted with one or two fluorines).

25. A compound as described in any one of claims 2 to 24 or a pharmaceutically acceptable salt thereof, wherein yes 26. The compound of any one of claims 2, 13, 14, 16 to 18, 20, 21, 23 and 24, wherein the compound is represented by formula (IV-A-1): or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 2, 13, 14, 16 to 18, 20, 21, 23 and 24, wherein the compound is represented by formula (IV-A-2): or a pharmaceutically acceptable salt thereof.

28. A compound as described in any one of claims 1 to 12, 14 to 19 and 21 to 27, a pharmaceutically acceptable salt or a tautomer thereof, wherein each R 3 are independently selected from H, halogen, -CN, C optionally substituted with one to three deuteriums 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 hydroxyalkyl, optionally substituted with one to three deuteriums -C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-NR * R * , 3-6 membered carbocyclic group, 3-6 membered monocyclic heterocyclic group, 7-10 membered bridged heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein R 3 The carbocyclic group, heterocyclic group, phenyl group or heteroaryl group in the group represented by is optionally substituted by one or two CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution.

29. The compound of claim 28, its pharmaceutically acceptable salt or tautomer, wherein each R 3 are independently selected from H, halogen, CN, C optionally substituted with one to three deuteriums 1-4 alkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, NR * R * 、-C(O)NR * R * , 3-6 membered cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-6 membered heteroaryl or 6-oxa-3-azabicyclo[3.1.1]heptyl, wherein R 3 The cycloalkyl, heterocyclic or heteroaryl groups in the groups represented by are optionally substituted by one or two halogens, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Haloalkoxy substitution.

30. The compound of claim 29, its pharmaceutically acceptable salt or tautomer, wherein each R 3 Independently selected from H, F, Cl, CN, CH3, OCH3, OCD3, -N(CH3)2, -CON(CH3)2, cyclopropane, azetidinyl optionally substituted with one or two fluorine or OCH3, imidazole optionally substituted with CH3, morpholinyl, pyridinyl, piperazinyl optionally substituted with CH3, pyrrolidinyl optionally substituted with OCH3, pyrazolyl optionally substituted with CH3, thiazole or 6-oxa-3-azabicyclo[3.1.1]heptanyl optionally substituted with CH3.

31. The compound of claim 30, its pharmaceutically acceptable salt or tautomer, wherein each R 3 Independently selected from H or OCH3.

32. A compound as described in any one of claims 1 to 6, 11 to 25 and 28 to 31, a pharmaceutically acceptable salt or a tautomer thereof, wherein ring B is phenyl, a 5- or 6-membered monocyclic heteroaryl, optionally substituted by one or two R B Replace, each R B independently selected from halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)NR * R * 、-(CH2) 0-1 NR * R * 、-NR * C(O)R * , -3-6 membered monocyclic carbocyclic group, -3-6 membered monocyclic heterocyclic group; wherein R B The carbocyclic or heterocyclic group in the group represented by is optionally substituted by one or two halogen or C 1-4 Alkyl substitution.

33. The compound of claim 32, its pharmaceutically acceptable salt or tautomer, wherein each R B Independently selected from F, Cl, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyalkyl, optionally substituted with one to three deuterium 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)NR * R * 、-CH2NR * R * 、-NR * C(O)R * , -3-5 membered monocyclic cycloalkyl, -3-5 membered monocyclic heterocyclic group; wherein R B The cycloalkyl or heterocyclic group in the group represented by 1-2 Alkyl substitution.

34. A compound, a pharmaceutically acceptable salt or a tautomer thereof as described in any one of claims 1 to 6, 11 to 25 and 28 to 31, wherein ring B is phenyl or a 5,6-membered monocyclic heteroaryl, each of which is optionally substituted by one to four R B Replace, and the two R B Together with the ring B atoms to which they are attached, they form a 5-7 membered monocyclic ring or a 6-9 membered bicyclic ring fused to ring B, wherein the 5-7 membered monocyclic ring or the 6-9 membered bicyclic ring is optionally substituted by one or two CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Substituted with haloalkoxy or 3-6 membered cycloalkyl.

35. The compound of claim 34, its pharmaceutically acceptable salt or tautomer, wherein two R B Together with the ring B atoms to which it is attached, it forms a ring selected from: Each of the rings is optionally substituted with one or two groups selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

36. The compound of claim 35, its pharmaceutically acceptable salt or tautomer, wherein two R B Together with the ring B atoms to which it is attached, it forms a Ring.

37. A compound, a pharmaceutically acceptable salt or a tautomer thereof as described in any one of claims 1 to 36, wherein R C is H, and R D It's H.

38. A compound, a pharmaceutically acceptable salt or a tautomer thereof as described in any one of claims 1, 3 to 25 and 28 to 36, wherein R C is H, F or deuterium, and R D It is H or deuterium.

39. A compound represented by formula (I'): or a pharmaceutically acceptable salt thereof, wherein: Ring A1 is a 5,6 or 6,6-membered nitrogen-containing bicyclic heteroaryl group; Ring B1 is a 3-6 membered monocyclic carbocyclic group or a 3-6 membered monocyclic heterocyclic group; Each R A1 are independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R A1 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; Each R B1 independently selected from halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted with one to three deuterium 0-4 C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-SO2R * 、-(CH2) 0-4 NR * R * 、-NR * C(O)R * 、-NR * C(O)OR * 、-NR * S02R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0或1 -3-12 membered carbocyclic group, -(CH2) 0或1 -3-12 membered heterocyclic group, -(CH2) 0或1 -6-10 membered aryl or -(CH2) 0或1 -5-10 membered heteroaryl; wherein R B1 The carbocyclic group, heterocyclic group, aryl group or heteroaryl group in the group represented by is optionally substituted by one or two CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; and / or Two R's B1 Together with the ring B1 atoms to which they are attached, they form a 5,6-membered monocyclic ring or a 6-9-membered bicyclic ring fused to ring B1, wherein the 5,6-membered ring or the 6-9-membered bicyclic ring is optionally substituted by one or two CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted with haloalkoxy or 3-6 membered cycloalkyl; Each R * Independently selected from the group consisting of: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered carbocyclyl or 4-6 membered heterocyclyl; m1 is 0, 1, 2, 3, or 4; and n1 is 0, 1, 2 or 3.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein yes wherein -* indicates the point to which -CH2- is attached; -** indicates the point to which ring B1 is attached; and R A1 It is C 1-4 Alkyl or C 1-4 Alkoxy.

41. The compound of claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein: Ring B1 is R B1 It is C 1-4 Alkyl or C 1-4 alkoxy; and n1 is 0 or 1.

42. A compound of Table 1 or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

44. A method of treating a disease mediated at least in part by CSF-1R in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein the disease is an autoimmune disease, an inflammatory disease, a neurodegenerative disease, cancer, a metabolic disease, obesity, or an obesity-related disease.

46. ​​The method of claim 45, wherein The autoimmune or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behcet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, ischemia-reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome and chemotherapy drug-induced organ damage; The neurodegenerative disease is selected from Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar disorders, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and hereditary motor and sensory neuropathy (CMT); and The cancer is a solid tumor or a hematological malignancy, such as ovarian cancer, lung cancer (including non-small cell lung cancer), brain tumor (including glioblastoma (GBM)), tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial carcinoma, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, leukemia, lymphoma or myeloma.

47. A method of treating Alzheimer's disease in a subject, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

48. A method of treating progressive supranuclear palsy in a subject, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

49. A method of treating a tau-mediated neurodegenerative disorder in a subject, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

50. A method of treating a disease or condition involving microglia-mediated inflammation in a subject, the method comprising administering to the subject an effective amount of a compound as described in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

51. Use of a compound as claimed in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease mediated at least in part by CSF-1R in a subject.

52. The use of claim 51, wherein the disease is an autoimmune disease, an inflammatory disease, a neurodegenerative disease, cancer, a metabolic disease, obesity or an obesity-related disease.

53. The use of claim 52, wherein The autoimmune or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behcet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, ischemia-reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome and chemotherapy drug-induced organ damage; The neurodegenerative disease is selected from Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar disorders, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and hereditary motor and sensory neuropathy (CMT); and The cancer is a solid tumor or a hematological malignancy, such as ovarian cancer, lung cancer (including non-small cell lung cancer), brain tumor (including glioblastoma (GBM)), tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial carcinoma, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, leukemia, lymphoma or myeloma.

54. Use of a compound as claimed in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating Alzheimer's disease in a subject.

55. Use of a compound as claimed in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating progressive supranuclear palsy in a subject.

56. Use of a compound as claimed in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a tau protein-mediated neurodegenerative disorder in a subject.

57. Use of a compound as described in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition involving microglia-mediated inflammation in a subject.

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