CSF-1R inhibitor and its use

Abstract

This application relates to compounds of formula (I) and formula (I’) which are useful as inhibitors of CSF-IR in the treatment of various diseases. JPEG2025520491000151.jpg9493

Description

Technical Field

[0001] Cross - reference to related applications 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 foregoing applications are incorporated herein by reference.

Background Art

[0002] CSF - 1R, that is, CSF - 1 receptor (colony - stimulating factor 1 receptor), is encoded by the cancer gene c - fms. The human c - fms gene is located at 5q33.3 on chromosome 5 downstream of the β - type platelet - derived growth factor receptor (PDGF_Rβ) gene, and the two genes are connected 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 five disulfide bonds and 11 possible glycosylation sites, and the intracellular region has a Gly - X - Gly - X - X - Gly motif. Lysine at position 616 is the ATP - binding site and is adjacent to a kinase - insert region with 72 amino acids. It is presumed to have the function of recognizing specific substrates (Cold Spring Harb Perspect Biol. 2014, 6(6)).

[0003] 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 conformational change and forms dimers or polymers. After dimerization, the tyrosine kinase activity of the receptor is activated, and tyrosine residues at positions 544, 559, 699, 708, 723, 809, 923, etc. are phosphorylated. Subsequently, it interacts with multiple intracellular signaling pathways such as Ras, MAPK, PI3K, and JAK, resulting in various biological effects in cells (J Cell Biochem. 1988, 38(3): 179-87).

[0004] The tumor microenvironment is a complex ecosystem that provides support for tumor development, growth, and metastasis. Macrophages are particularly abundant among immune cells that migrate to the tumor site and are present at all stages of tumor development. Tumor-associated macrophages (TAMs) have been shown by research to play important roles in tumor development, growth, and metastasis. In primary tumors, macrophages may stimulate angiogenesis, assist in extravasation, survival, and continuous growth of tumor cells, thereby promoting tumor cell metastasis. TAMs also exert an immunosuppressive effect and prevent 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 signaling pathway. Since the CSF-1 / CSF-1R signaling pathway inhibits tumor progression by regulating TAMs and reduces tumor invasiveness and proliferation, as a result, the CSF1 / CSF1R signaling pathway is a potential target for cancer treatment. Overexpression of CSF-1 or CSF-1R is associated with poor tumor aggressiveness and prognosis. Application of CSF-1R inhibitors can affect the exchange of inflammatory factors between TAMs and glioma cells, and research has shown that this can significantly reduce the volume of glioblastoma and reduce tumor invasiveness and proliferation (Nat Med. 2013, 19(10):1264-72). In addition, abnormally high expression of CSF-1 is the main cause of tenosynovial giant cell tumor (one type of rare non-metastatic tumor with giant cell tumor and pigmented villonodular synovitis in the tendon sheath). Patients with tenosynovial giant cell tumor have shown obvious clinical benefits after the use of CSF-1R inhibitors (N Engl J Med. 2015, 373(5):428-37).

[0005] In addition to tumors, the CSF-1R signaling pathway 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.

[0006] Furthermore, increased research has shown that inflammation of the nervous system and abnormal activation of brain microglial cells are important pathogenic factors in related neurodegenerative diseases, especially Alzheimer's disease (Neurobiol Aging. 2000, 21:383-421). In particular, the signaling pathway mediated by CSF-1R plays a dominant role in the activation and proliferation of microglial cells in the brain. Studies have shown that in tissue samples from Alzheimer's disease patients, the expression of CSF-1R is significantly upregulated with abnormal activation and proliferation of microglia (Brain Res., 1994, 639:171-4). Animal model studies have shown that by blocking CSF-1R signaling, microglial proliferation can be effectively inhibited, thereby effectively alleviating disease progression in a mouse model of Alzheimer's disease (Brain. 2016, 139:891-907). In models of other neurodegenerative diseases such as amyotrophic lateral sclerosis, the therapeutic effect of targeting CSF-1R for the disease has been previously demonstrated in proof-of-concept studies (Sci Rep., 2016, 6:25663). Currently, several CSF-1R inhibitor candidates for neurodegenerative diseases are in clinical trials.

[0007] 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

[0008] Described herein are compounds of formula (I) (including the subgenera encompassed by formula (I)) or pharmaceutically acceptable salts thereof that inhibit the activity of CSF-1R. More specifically, the compounds disclosed herein not only effectively inhibit the activity of CSF-1R, but also selectively inhibit CSF-1R over cKit, FLT3, and PDGFR-β (see Tables 2 and 3), have a desired pk profile (see Table 5), and have high exposure in the brain and across the blood-brain barrier (BBB) compared to other known CSF-1R inhibitors (see Table 6).

[0009] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0010] 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.

[0011] The present disclosure further provides a method of inhibiting CSF-1R in a patient, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] The present disclosure also provides a method of treating a disease or condition mediated by CSF-1R or at least partially mediated 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 a 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.

[0013] The present disclosure further provides a method for treating Alzheimer's disease in a subject, comprising administering to the subject a pharmaceutically acceptable composition comprising an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or (2) a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0014] The present disclosure further provides a method for treating progressive supranuclear palsy in a subject, comprising administering to the subject a pharmaceutically acceptable composition comprising an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or (2) a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0015] The present disclosure further provides a method for treating tau-mediated neurodegenerative disorders in a subject, comprising administering to the subject a pharmaceutically acceptable composition comprising an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or (2) a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0016] The present disclosure further provides a method for treating a disease or disorder associated with microglia-mediated inflammation in a subject, comprising administering to the subject a pharmaceutically acceptable composition comprising an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or (2) a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0017] 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 of the methods described herein. In one embodiment, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in any of the methods described herein. In another embodiment, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for any of the methods described herein.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

DETAILED DESCRIPTION OF THE INVENTION

[0019] 1. Compound In a first embodiment, the present disclosure provides a compound represented by formula (I):

CHEM.

[0020] In a second embodiment, the disclosure is a compound according to the first embodiment, or a pharmaceutically acceptable salt thereof, wherein each R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH2) optionally substituted by 1 to 3 deuteriums 0-4 C 1-6 alkoxy, C 1-6 haloalkoxy, 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 * SO2R * , -NR * SO2NR * R * , -P(O)R * R * , -(CH2) 0若しくは1 , -3 - to 12 - membered carbocyclic, -(CH2) 0若しくは1 , -3 - to 12 - membered heterocyclic, -(CH2) 0若しくは1 , -6 - to 10 - membered aryl, or -(CH2) 0若しくは1 , -5 - to 10 - membered heteroaryl, and R 1 , R 2 , R 3 , R 4 , or R 5 , the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy are optionally substituted by one or two groups selected from each R A is independently H, halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, -(CH2) optionally substituted with 1 to 3 deuteriums 0-4 C 1-6 alkoxy, C 1-6 haloalkoxy, 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 * SO₂R * 、 -NR * SO₂NR * R * 、 -P(O)R * R * 、 -(CH₂) 0若しくは1 -3 - 12 - membered carbocyclic, -(CH₂) 0若しくは1 -3 - 12 - membered heterocyclic, -(CH₂) 0若しくは1 -6 - 10 - membered aryl, or -(CH₂) 0若しくは1 -5 - 10 - membered heteroaryl selected, and the carbocyclic, heterocyclic, aryl, or heteroaryl represented by R A is optionally substituted by one or two groups selected from CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, each R B is independently 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 1 - 3 deuteriums 0-4 C 1-6 alkoxy, C 1-6 haloalkoxy, 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 * SO2R * 、 -NR * SO2NR * R * 、 -P(O)R * R * 、 -(CH2) 0若しくは1 -3 to 12-membered carbocyclic, -(CH2) 0若しくは1 -3 to 12-membered heterocyclic, -(CH2) 0若しくは1 -6 to 10-membered aryl, or -(CH2) 0若しくは1 -5 to 10-membered heteroaryl, where the carbocyclic, heterocyclic, aryl, or heteroaryl group represented by R B is optionally substituted by one or two groups selected from CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, or two Rs B together with the ring B atom to which they are attached form a 5,6-membered ring fused to ring B, and the 5,6-membered ring is optionally substituted by one or two groups selected from CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, each R C and R D is independently selected from hydrogen, F, and methyl, a compound, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in the first embodiment.

[0021] In a third embodiment, the present disclosure provides a compound according to the second embodiment, wherein the compound is represented by formula (II-A), a compound,

Chemical formula

[0022] In the fourth embodiment, the present disclosure provides a compound according to the second embodiment, wherein the compound is 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):

Chemical formula

Chemical formula

[0023] In the fifth embodiment, the present disclosure provides a compound according to the second embodiment, wherein the compound is of formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3):

Chemical formula

[0024] In the sixth embodiment, the present disclosure provides a compound according to any one of the second to fifth embodiments, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0025] In a seventh embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 6, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl optionally substituted by one or two R B and each R B is independently 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 deuteriums 0-4 C 1-6 alkoxy, C 1-6 haloalkoxy, 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 * SO2R * , -NR * SO2NR * R * , -P(O)R * R * , -(CH2) 0若しくは1 -3 to 12-membered carbocyclic, -(CH2) 0若しくは1 -3 to 12-membered heterocyclic, -(CH2) 0若しくは1 -6 to 10-membered aryl, or -(CH2) 0若しくは1 membered heteroaryl, and R BThe carbocyclic, heterocyclic, aryl, or heteroaryl group represented by is optionally substituted by one or two halogens or C 1-6 Provide a compound, or a pharmaceutically acceptable salt thereof, optionally substituted by alkyl. The definitions of the remaining variables are provided in any one of Embodiments 2 to 6. Alternatively, the definitions of the variables are provided in Embodiment 1.

[0026] In the eighth embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 6, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5,6-membered monocyclic heteroaryl optionally substituted by one or two R B Each R B is independently 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 by 1 to 3 deuteriums 0-4 C 1-6 alkoxy, C 1-6 haloalkoxy, 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 * SO2R * 、-NR * SO2NR * R * 、-P(O)R * R * 、-(CH2) 0若しくは1 -3 to 12-membered carbocycle, -(CH2) 0若しくは1-3 to 12-membered heterocyclyl, -(CH2) 0若しくは1 -6 to 10-membered aryl, or -(CH2) 0若しくは1 -5 to 10-membered heteroaryl selected, and the carbocyclyl, heterocyclyl, aryl, or heteroaryl of the group represented by R B is optionally substituted by one or two halogens or C 1-6 alkyl, to provide a compound, or a pharmaceutically acceptable salt thereof. Definitions of the remaining variables are provided in any one of Embodiments 2 to 6. Alternatively, the variable definitions are provided in Embodiment 1.

[0027] In Embodiment 9, the present disclosure is a compound according to any one of Embodiments 2 to 6, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl or 5,6-membered monocyclic heteroaryl, each of which is optionally substituted by 1 to 4 R B and two R B together with the Ring B atom to which they are attached form a 5,6-membered ring fused to Ring B, and the 5,6-membered fused ring 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, to provide a compound, or a pharmaceutically acceptable salt thereof. Definitions of the remaining variables are provided in any one of Embodiments 2 to 6. Alternatively, the variable definitions are provided in Embodiment 1.

[0028] In the 10th embodiment, the present disclosure provides a compound according to any one of the 2nd to 6th embodiments, or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazolyl, isoxazolyl, 1,2,4 - oxadiazolyl, thiazolyl, phenyl, pyridyl, pyrimidyl, 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, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of the 2nd to 6th embodiments. Alternatively, the definitions of the variables are provided in the 1st embodiment.

[0029] In the 11th embodiment, the present disclosure provides a compound according to any one of the 2nd to 10th embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently 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 haloalkoxy, 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 * selected from, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of the 2nd to 10th embodiments.

[0030] In the 12th embodiment, the present disclosure is a compound according to any one of the 2nd to 11th embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently 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 haloalkoxy, 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 * selected from, and provides a compound, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of the 2nd to 11th embodiments. Alternatively, the definitions of the variables are provided in the 1st embodiment.

[0031] In the 13th embodiment, the present disclosure is a compound according to any one of the 2nd to 12th embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently H, halogen, -CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -(CH2) optionally substituted with 1 to 3 deuteriums 0-2 C 1-4 alkoxy, C 1-4 haloalkoxy, 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 * and provides a compound selected from, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of Embodiments 2 to 12. Alternatively, the definitions of the variables are provided in Embodiment 1.

[0032] In a fourteenth embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 13, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently 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 haloalkoxy, 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 * and provides a compound selected from, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of Embodiments 2 to 13. Alternatively, the definitions of the variables are provided in Embodiment 1.

[0033] In a fifteenth embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 14, or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently H, halogen, -CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -(CH2) 0-4 C 1-4 alkoxy, C1-4 Haloalkoxy, 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 * It provides a compound selected from, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of the second to fourteenth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment.

[0034] In the sixteenth embodiment, the present disclosure is a compound according to any one of the second to fifteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein each R A is independently H, halogen, -CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C optionally substituted with one to three deuteriums 1-4 alkoxy, C 1-4 haloalkoxy, 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 * It provides a compound selected from, or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in any one of the second to fifteenth embodiments. Alternatively, the definitions of the variables are provided in the first embodiment.

[0035] In the seventeenth embodiment, the present disclosure is a compound according to any one of the second to sixteenth embodiments, wherein each RB is, independently, halogen, -CN, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -(CH2) optionally substituted with 1 to 3 deuteriums 0-2 C 1-4 alkoxy, C 1-4 haloalkoxy, 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 with one or two halogens 0又は1 -3 to 6-membered cycloalkyl, provides a compound. The definitions of the remaining variables are provided in any one of Embodiments 2 to 16. Alternatively, the definitions of the variables are provided in Embodiment 1.

[0036] In the 18th embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 17, wherein each R * is, independently, H or C 1-4 alkyl. The definitions of the remaining variables are provided in any one of Embodiments 2 to 17. In certain embodiments, each R * is, independently, H or C 1-2 alkyl. Alternatively, the definitions of the variables are provided in Embodiment 1.

[0037] In the 19th embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 18, wherein each R 1 is, independently, H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4Selected from haloalkoxy (preferably H), each R 2 is, independently, H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy (preferably, H), and provides a compound. The definitions of the remaining variables are provided in any one of Embodiments 2 to 18. In certain embodiments, R 1 is H, and R 2 is H. Alternatively, the definitions of the variables are provided in Embodiment 1.

[0038] In Embodiment 20, the present disclosure is a compound according to any one of Embodiments 2 to 19, wherein each R 3 is, independently, H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C optionally substituted with 1 to 3 deuteriums 1-4 alkoxy, and C 1-4 haloalkoxy, and provides a compound. The definitions of the remaining variables are provided in any one of Embodiments 2 to 19. Alternatively, the definitions of the variables are provided in Embodiment 1. In certain embodiments, each R 3 is, independently, H, CN, halogen, C 1-4 alkyl, or C optionally substituted with 1 to 3 deuteriums 1-4 alkoxy. In certain embodiments, R 3 is H, CN, F, Cl, -CH3, or -OCH3.

[0039] In Embodiment 21, the present disclosure is a compound according to any one of Embodiments 2 to 20, wherein each R 4 is, independently, H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4Provided is a compound selected from haloalkoxy. The definitions of the remaining variables are provided in any one of Embodiments 2 to 20. Alternatively, the definitions of the variables are provided in Embodiment 1. In certain embodiments, each R 4 is H, F, or C 1-4 alkoxy. In certain embodiments, R 4 is H, F, or -OCH3.

[0040] In Embodiment 22, the present disclosure provides a compound according to any one of Embodiments 2 to 21, wherein each R 5 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy. The definitions of the remaining variables are provided in any one of Embodiments 2 to 21. Alternatively, the definitions of the variables are provided in Embodiment 1. In certain embodiments, each R 5 is H.

[0041] In Embodiment 23, the present disclosure provides a compound according to any one of Embodiments 2 to 22, wherein each R A is independently selected from H, C 1-2 alkyl, or C 1-2 alkoxy optionally substituted with 1 to 3 deuteriums. The definitions of the remaining variables are provided in any one of Embodiments 2 to 22. Alternatively, the definitions of the variables are provided in Embodiment 1. In certain embodiments, each R A is H or -OCH3.

[0042] In Embodiment 24, the present disclosure provides a compound according to any one of Embodiments 2 to 23, wherein each R B is independently halogen, -OH, C 1-3 alkyl, C 1-3 haloalkyl, -(CH2) optionally substituted with 1 to 3 deuteriums0-2 C 1-2 alkoxy, C 1-2 haloalkoxy, -(CH2) 0-2 NR * R * or a 3- to 6-membered cycloalkyl (preferably) optionally substituted with one or two halogens, and provides a compound selected from the group consisting of. Definitions of the remaining variables are provided in any one of Embodiments 2 to 23. Alternatively, the definitions of the variables are provided in Embodiment 1. In certain embodiments, each R B is independently selected from F, Cl, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2N(CH3)2, -CH2OCH3, -OCH3, -OCHF2, -OCD3, and cyclopropyl optionally substituted with one or two fluorines. In certain embodiments, each R B is independently selected from F, Cl, -OH, -CH3, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -OCH3, -OCHF2, and cyclopropyl.

[0043] In a 25th embodiment, the present disclosure is a compound according to any one of Embodiments 2 to 24, wherein

Chemical formula

Chemical formula

[0044] In a 26th embodiment, the present disclosure is a compound according to any one of Embodiments 2, 13, 14, 16 to 18, 20, 21, 23, and 24, wherein the compound is of formula (IV-A-1):

Chemical formula

[0045] In Embodiment 27, the present disclosure is a compound according to any one of Embodiments 2, 13, 14, 16-18, 20, 21, 23, and 24, wherein the compound is of formula (IV-A-2):

Chemical formula

[0046] In Embodiment 28, the present disclosure is a compound, pharmaceutically acceptable salt, or tautomer thereof according to any one of Embodiments 1-12, 14-19, and 21-27, wherein each R 3 is independently H, halogen, -CN, C 1-6 alkyl optionally substituted with 1 to 3 deuteriums, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C 1-6 alkoxy optionally substituted with 1 to 3 deuteriums, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, -C(O)R * 、-C(O)OR * 、-C(O)NR * R * 、-NR * R * selected from 3-6 membered carbocyclyl, 3-6 membered monocyclic heterocyclyl, 7-10 membered bridged heterocyclyl, phenyl, or 5-6 membered heteroaryl, and R 3The carbocyclic, heterocyclic, phenyl, or heteroaryl 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, and provides a compound, a pharmaceutically acceptable salt, or a tautomer thereof. The definitions of the remaining variables are provided in any of Embodiments 1 to 12, 14 to 19, and 21 to 27.

[0047] In Embodiment 29, the disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of Embodiment 28, wherein each R 3 is independently H, halogen, CN, C optionally substituted with 1 to 3 deuteriums 1-4 alkyl, C optionally substituted with 1 to 3 deuteriums 1-4 alkoxy, NR * R * , -C(O)NR * R * , 3- to 6-membered cycloalkyl, 3- to 6-membered monocyclic heterocyclic, 5- to 6-membered heteroaryl, or 6-oxa-3-azabicyclo[3.1.1]heptanyl, and the cycloalkyl, heterocyclic, or heteroaryl group represented by R 3 is optionally substituted by one or two halogen, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy, and provides a compound, a pharmaceutically acceptable salt, or a tautomer thereof. The definitions of the remaining variables are provided in Embodiment 28.

[0048] In Embodiment 30, the disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of Embodiment 29, wherein each R 3is, independently, selected from H, F, Cl, CN, CH3, OCH3, OCD3, -N(CH3)2, -CON(CH3)2, cyclopropyl, azetidinyl optionally substituted with one or two fluoros or OCH3, imidazole optionally substituted with CH3, morpholinyl, pyridyl, piperazinyl optionally substituted with CH3, pyrrolidinyl optionally substituted with OCH3, pyrazolyl optionally substituted with CH3, thiazole optionally substituted with CH3, or 6-oxa-3-azabicyclo[3.1.1]heptanyl, a compound, a pharmaceutically acceptable salt, or a tautomer thereof. Definitions of the remaining variables are provided in the 29th embodiment.

[0049] In the 31st embodiment, the present disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of the 30th embodiment, wherein each R 3 is, independently, selected from H or OCH3, a compound, a pharmaceutically acceptable salt, or a tautomer thereof. Definitions of the remaining variables are provided in the 30th embodiment.

[0050] In the 32nd embodiment, the present disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of any one of the 1st to 6th, 11th to 25th, and 28th to 31st embodiments, wherein ring B is phenyl, a 5- or 6-membered monocyclic heteroaryl optionally substituted by one or two R B wherein each R B is, independently, halogen, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyalkyl, C 1-4 alkoxy optionally substituted with 1 to 3 deuteriums, C 1-4 haloalkoxy, -C(O)NR * R * ,-(CH2) 0-1 NR * R * ,-NR * C(O)R *, selected from -3 to 6-membered monocyclic carbocyclyl, -3 to 6-membered monocyclic heterocyclyl, and R B wherein said carbocyclyl or heterocyclyl of the group represented by is optionally substituted by one or two halogens or C 1-4 alkyl, to provide a compound, a pharmaceutically acceptable salt, or a tautomer thereof. Definitions of the remaining variables are provided in Embodiments 1-6, 11-25, and 28-31.

[0051] In a 33rd embodiment, the disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of the 32nd embodiment, wherein each R B is independently F, Cl, -OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyalkyl, C optionally substituted with 1 to 3 deuteriums 1-4 alkoxy, C 1-4 haloalkoxy, -C(O)NR * R * , -CH2NR * R * , -NR * C(O)R * , selected from -3 to 5-membered monocyclic cycloalkyl, -3 to 5-membered monocyclic heterocyclyl, and R B wherein said cycloalkyl or heterocyclyl of the group represented by is optionally substituted by one or two F or C 1-2 alkyl, to provide a compound, a pharmaceutically acceptable salt, or a tautomer thereof. Definitions of the remaining variables are provided in the 32nd embodiment.

[0052] In a 34th embodiment, the disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of any one of Embodiments 1-6, 11-25, and 27-31, wherein Ring B is phenyl or 5,6-membered monocyclic heteroaryl, each of which is optionally substituted by 1 to 4 R B and two R Bwhich, together with the ring B atom to which they are attached, form a 5- to 7-membered monocyclic ring or a 6- to 9-membered bicyclic ring fused to ring B, said 5- to 7-membered monocyclic ring or 6- to 9-membered bicyclic ring being optionally substituted with one or two CN, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or 3- to 6-membered cycloalkyl, and provides a compound, a pharmaceutically acceptable salt, or a tautomer thereof. Definitions of the remaining variables are provided in Embodiments 1-6, 11-25, and 27-31.

[0053] In a 35th embodiment, the disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of the 34th embodiment, wherein two R B which, together with the ring B atom to which they are attached,

Chemical formula

[0054] In a 36th embodiment, the disclosure is a compound, a pharmaceutically acceptable salt, or a tautomer thereof of the 35th embodiment, wherein two R B which, together with the ring B atom to which they are attached,

Chemical formula

[0055] In the 37th embodiment, the present disclosure is any one compound, pharmaceutically acceptable salt, or tautomer thereof among the 1st to 36th embodiments, wherein R C is H, and R D is H, and provides a compound, pharmaceutically acceptable salt, or tautomer thereof. The definitions of the remaining variables are provided in the 1st to 36th embodiments.

[0056] In the 38th embodiment, the present disclosure is any compound, pharmaceutically acceptable salt, or tautomer thereof among the 1st, 3rd to 25th, and 28th to 36th embodiments, wherein R C is H, F, or deuterium, and R D is H or deuterium, and provides a compound, pharmaceutically acceptable salt, or tautomer thereof. The definitions of the remaining variables are provided in the 1st, 3rd to 25th, and 28th to 36th embodiments.

[0057] In the 39th embodiment, the present disclosure is a compound represented by formula (I’):

Chemical formula

[0058] In a 40th embodiment, the disclosure is a compound of the 39th embodiment, or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0059] In a 41st embodiment, the disclosure is a compound of the 39th or 40th embodiment, or a pharmaceutically acceptable salt thereof, wherein ring B1 is

Chemical formula

[0060] In one embodiment, the present disclosure provides a compound selected from the compounds disclosed in the examples and Table 1, or a pharmaceutically acceptable salt thereof provided herein.

[0061] 2. Definitions As used herein, the term "halogen" refers to fluoride, chloride, bromide, or iodide.

[0062] The term "alkyl", used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl", means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of the formula -C n H (2n+1) Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms, i.e., C1-6 alkyl. As used herein, a "C 1-6 alkyl" group means a radical having 1 to 6 carbon atoms in a straight-chain or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like.

[0063] The term "haloalkyl" means, in some cases, alkyl substituted with one or more halogen atoms. In one embodiment, the alkyl may be substituted with 1 to 3 halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0064] The term "hydroxyalkyl" means, in some cases, alkyl substituted with one or more (e.g., one or two) hydroxy groups. In one embodiment, the alkyl may be substituted with one hydroxyl group.

[0065] The term "alkenyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by double bonds.

[0066] The term "alkynyl" means an alkyl group in which one or more carbon / carbon single bonds are replaced by triple bonds.

[0067] The term "alkoxy" means an alkyl radical bonded through an oxygen-linked atom, represented by -O-alkyl. For example, "C1-C4 alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0068] The term "alkoxyalkyl" means, in some cases, an alkyl (e.g., C1-6 alkyl) substituted with one or more alkoxy groups (e.g., (C1-C4) alkoxy). In one embodiment, the alkyl may be substituted with one alkoxy group.

[0069] The term "carbocyclic" refers to a 3- to 12-membered non-aromatic hydrocarbon ring system. In one embodiment, the carbocyclic is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated or partially unsaturated. Any replaceable ring atom may be substituted (e.g., by one or more substituents). Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, the carbocyclic is intended to include bridged rings, fused rings, and spiro rings. In a spirocyclic carbocyclic, one atom is common to two different rings. An example of a spirocyclic carbocyclic is spiro[3.3]heptanyl. In a bridged carbocyclic, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclics include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused-ring carbocyclic system, two or more rings may be fused together such that two rings share one common bond.

[0070] The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, the cycloalkyl 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. The cycloalkyl may include multiple 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, etc. The cycloalkyl may also include spiro rings (e.g., a spiro bicyclic ring where two rings are connected through only one atom). Non-limiting examples of spiro 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, etc.

[0071] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur including sulfoxide and sulfone ("3- to 12-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("3- to 7-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and the polycyclic ring system can include a fused ring system, a bridged ring system, or a spiro ring system. The heterocyclyl polycyclic ring system can include a polycyclic ring system having a non-aromatic ring fused to a phenyl or heteroaryl ring, and one or more rings of the polycyclic ring system can contain heteroatoms. When the heterocyclyl group is a polycyclic ring system, the ring system includes at least one non-aromatic ring. Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. The heterocyclyl polycyclic ring system can contain heteroatoms within one or more rings within the polycyclic ring system. Substituents can be present on one or more rings of the polycyclic ring system.

[0072] Spiroheterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl having rings connected via one common carbon atom (referred to as the spiro atom), where the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur including sulfoxide and sulfone, the remaining ring atoms are C, and one or more of the 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.

Chemical formula

[0073] Fused heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group where each ring within the group shares an adjacent pair of ring atoms with another ring of the group, one or more of the rings may contain one or more double bonds, but at least one of the rings is not completely conjugated to the π-electron system, 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 sulfoxide and sulfone, and the remaining ring atoms are C. Representative examples of fused heterocyclyl include, but are not limited to, the following groups.

Chemical formula

[0074] Bridged heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group where any two rings within the group share two separated atoms, the rings may have one or more double bonds, but do not have a completely conjugated π-electron system, the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur including sulfoxide and sulfone as ring atoms, and the remaining ring atoms are C. Representative examples of bridged heterocyclyl include, but are not limited to, the following groups.

Chemical formula

[0075] Generally, a carbocyclic, cycloalkyl, or heterocyclic group may be unsubstituted or substituted with one or more substituents as valence permits, and the substituents may independently be selected from several groups such as oxo, -CN, halogen, alkyl, and alkoxyl, and optionally, the alkyl substitution may be further substituted.

[0076] 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 of the system shares an adjacent pair of carbon atoms with another ring of the system) group having a fully conjugated π electron system. The term "aryl" may be used synonymously with the terms "aryl ring", "carbocyclic aromatic ring", "aryl group", and "carbocyclic aromatic group". Representative examples of aryl are phenyl and naphthyl.

[0077] The term "heteroaryl" refers to a radical of a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl having ring carbon atoms and 1 to 4 ring heteroatoms (typically 1 to 2). The heteroaryl group may be attached via a ring carbon atom or, where valence permits, via a ring nitrogen atom. Generally, heteroaryl may be unsubstituted or substituted with one or more substituents as valence permits, and the substituents are independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH2, NH alkyl, N(alkyl)2), and optionally, the alkyl may be further substituted.

[0078] Examples of monocyclic 5- to 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), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), 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, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. The "substituted heteroaryl group" is substituted with any one or more substitutable ring atoms that are ring carbon or ring nitrogen atoms bonded to hydrogen.

[0079] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as either "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise stated, it indicates that any portion of the moiety known to those skilled in the art as being available for substitution may be substituted, which includes one or more substituents. If two or more substituents are present, each substituent may be independently selected. Such means for substitution are well known in the art and / or are taught by the present disclosure. An optional substituent can be any substituent suitable for attachment to the moiety.

[0080] When suitable substituents are not specifically listed, exemplary substituents include C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 haloalkyl, C1-5 alkoxy, C1-5 haloalkoxy, halogen, hydroxyl, 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- to 6-membered heteroaryl, including but not limited to these. Each R a1 and each R b1 is independently selected from -H and C1-5 alkyl optionally substituted with hydroxyl or C1-3 alkoxy, and R c1 is -H, C1-5 haloalkyl, or C1-5 alkyl, and the C1-5 alkyl is optionally substituted with hydroxyl or C1-C3 alkoxy.

[0081] As used herein, the symbol

Chemical Structure

[0082] Pharmaceutically acceptable salts The term "pharmaceutically acceptable salts" refers to pharmaceutical salts that are suitable for use in contact with the tissues of humans and lower animals without undue 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, S.M. Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0083] The pharmaceutically acceptable salts of any one of the compounds of the above formula include acid addition salts and base salts.

[0084] Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with 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 salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having acidic groups, such as carboxylic acids, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).

[0085] Pharmaceutically acceptable salts of any one of the compounds of the above formula can be prepared by the following three methods: (i) A method by reacting any one of the compounds of the above formula with a desired acid or base, (ii) By removing an acid- or base-labile protecting group from a suitable precursor of any one of the compounds of the above formula, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base, or (iii) By one or more of the methods of converting one salt of any one of the compounds of the above formula to another salt by reaction with a suitable acid or base, or by a suitable ion exchange column.

[0086] All three reactions are typically carried out in solution. The resulting salt may be recovered by precipitation and filtration, or by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.

[0087] Any one of the compounds of the above formula, and its pharmaceutically acceptable salts, can exist in non-solvated and solvated forms.

[0088] Stereoisomers and Other Variations Any one of the compounds of the above formula may exhibit one or more types of isomers (e.g., optical isomers, geometric isomers, or tautomeric isomers). Such variations are implicit with respect to any one of the compounds of the above formula as defined by reference to their structural features and are thus within the scope of this disclosure.

[0089] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. 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 that have two or more chiral centers that are not identical and are not mirror images of each other.

[0090] When a compound is specified by its chemical name (e.g., when the structure is indicated as “R” or “S”) or its structure (e.g., when the structure is indicated by a “wedge” bond) showing a single enantiomer, the compound is, unless otherwise indicated, at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight of the named or depicted enantiomer in the mixture divided by the total weight in the mixture of both enantiomers.

[0091] The stereochemistry of the disclosed compounds is named or depicted by the structure. When the named or depicted structure encompasses two or more stereoisomers (e.g., like a pair of diastereomers), it should be understood that one of the included stereoisomers or any mixture of the included stereoisomers is included. It should be further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt% or 99.9 wt%. The stereoisomeric purity in this case is determined by dividing the total weight of the stereoisomers included in the mixture by the total weight in the mixture of all stereoisomers.

[0092] When two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by "and", a mixture of the two stereoisomers is intended.

[0093] When two stereoisomers are depicted by their chemical names or structures and their names or structures are connected by "or", one or the other of the two stereoisomers is intended, but both are not intended.

[0094] When a disclosed compound having a chiral center is depicted by the structure without indicating the configuration at that chiral center, the structure is meant to include a compound having an S configuration at that chiral center, a compound having an R configuration at that chiral center, or a compound having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating the configuration at that chiral center as "S" or "R", the name is meant to include a compound having an S configuration at that chiral center, a compound having an R configuration at that chiral center, or a compound having a mixture of R and S configurations at that chiral center.

[0095] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or described without indicating the stereochemistry of the chiral center, its name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or both racemic). When a compound having two or more chiral centers is named or described without indicating the stereochemistry of the chiral centers, its name or structure is understood to encompass all possible diastereomeric forms of one or more diastereomers of the compound (e.g., racemic mixtures), such as diastereomerically pure, diastereomerically enriched, and equimolar mixtures).

[0096] The term "geometric isomers" means isomers in which the orientation of the substituted atoms is different in relation to a carbon-carbon double bond, a carbon ring, or a bridged bicyclic system. The substituted atoms (other than hydrogen) on each side of the carbon-carbon double bond may be in the E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the "E" configuration, the highest-priority substituents are on opposite sides in relation to the carbon-carbon double bond. In the "Z" configuration, the highest-priority substituents are oriented on the same side in relation to the carbon-carbon double bond.

[0097] The substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans", where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbon ring may also be designated as "cis" or "trans". The term "cis" represents substituents on the same side of the plane of the ring, and the term "trans" represents substituents on opposite sides of the plane of the ring. A mixture of compounds in which the substituents are arranged on both the same side and opposite sides of the plane of the ring is referred to as "cis / trans".

[0098] Any one of the compounds of the above formula may exhibit one or more types of tautomerism. Such variations are implicit with respect to any one of the compounds of the above formula as defined to be within the scope of the present disclosure by reference to their structural features.

[0099] Tautomeric isomerism ("tautomerism") can occur when structural isomers are interconvertible via a low energy barrier. This can take the form of, for example, proton tautomerism in any one of the compounds of the above formula containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. Thus, a single compound can exhibit two or more types of isomers.

[0100] In certain examples, tautomeric forms of the disclosed compounds such as the tautomeric structures shown below exist.

Chemical formula

[0101] It should be understood that when a geometric isomer is depicted by name or structure, the named or depicted isomer is present to a greater extent than another isomer, i.e., the geometric isomer purity of the named or depicted geometric isomer is greater than 50% by weight, for example at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight. The purity of the geometric isomer 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.

[0102] It must be emphasized that any one of the compounds of the above formula is depicted herein in a single tautomeric form and that all possible tautomeric forms are included within the scope of the present disclosure.

[0103] 3. Administration and Dosage Typically, the compounds of the present disclosure are administered in an amount effective to treat the conditions described herein. The compounds of the present disclosure can be administered as the compound itself or, alternatively, as a pharmaceutically acceptable salt. For purposes of administration and dosing, the compound itself or its pharmaceutically acceptable salt is simply referred to as the compound of the present disclosure.

[0104] The compounds of the present disclosure are administered by such routes in the form of a pharmaceutical composition adapted to any suitable route and in a dosage effective for the intended treatment. The compounds of the present disclosure can be administered orally, rectally, vaginally, parenterally, or topically.

[0105] The compounds of the present disclosure may be administered orally. Oral administration may involve swallowing such that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used such that the compound enters the bloodstream directly from the mouth.

[0106] In another embodiment, the compounds of the present disclosure may also be administered directly into the bloodstream, intramuscularly, or viscerally. Suitable means for parenteral administration include intravenous administration, intraarterial administration, intraperitoneal administration, intrathecal administration, intracerebroventricular administration, intraurethral administration, intrasternal administration, intracranial administration, intramuscular administration, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

[0107] In another embodiment, the compounds of the present disclosure may be administered topically to the skin or mucosa, i.e., from the skin or transdermally. In another embodiment, the compounds of the present disclosure may be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may be administered directly to the eye or ear.

[0108] The dosing regimen of the compounds of the present disclosure and / or compositions containing such compounds is based on various 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 particular compound used. Thus, the dosing regimen can vary widely. In one embodiment, the total daily dose of the compounds of the present disclosure is typically about 0.001 to about 100 mg / kg (i.e., mg of the compound of the present disclosure per kg of body weight) for the treatment of the indications contemplated herein.

[0109] In the case of oral administration, the composition can be provided in the form of tablets containing 0.1 to 500 milligrams of the active ingredient for symptomatic adjustment of the dosage to the patient. The pharmaceutical typically contains from about 0.01 mg to about 500 mg of the active ingredient. For intravenous administration, the dosage can range from about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0110] Suitable subjects according to the present disclosure include mammalian subjects including non-human mammals such as primates, rodents (such as mice, rats, hamsters, rabbits, etc.). In one embodiment, humans are the suitable subjects. The human subject can be of either sex and at any stage of development.

[0111] 4. Pharmaceutical Composition In another embodiment, the present disclosure includes a pharmaceutical composition. Such a pharmaceutical composition includes the disclosed 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.

[0112] As used herein, "pharmaceutically acceptable carrier or excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. Examples of pharmaceutically acceptable carriers include water, physiological saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc., and one or more of combinations thereof, and may include isotonic agents in the composition, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol or sorbitol. Substances that improve the shelf life or effectiveness of an antibody or antibody portion, such as wetting agents or minor auxiliary substances, such as wetting agents or emulsifying agents, preservatives or buffering agents.

[0113] The compositions of the present disclosure can be in various forms. These include, for example, liquid, semi-solid 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 use.

[0114] Typical compositions are in the form of injectable or infusible solutions, for example, compositions similar to those generally 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.

[0115] Oral administration in solid dosage forms may be presented in discrete units such as, for example, hard or soft capsules, pills, cachets, troches, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral administration may be in the form of a powder or granules. In another embodiment, the oral dosage form is in a sublingual dosage form such as, for example, a troche. In such solid dosage forms, any one of the compounds of the above formula is usually combined with one or more adjuvants. Such capsules or tablets may contain controlled release formulations. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents or may be prepared using enteric coatings.

[0116] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent commonly used in the art (such as water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (such as sweetening agents), and / or fragrances.

[0117] In another embodiment, the present disclosure includes parenteral dosage forms.

[0118] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile aqueous or oily suspensions) may be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0119] In another embodiment, the present disclosure includes topical dosage forms.

[0120] "Local administration" includes, for example, transdermal administration via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for local administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered by a transdermal device, the administration is achieved using a patch of either the reservoir and porous membrane type or the solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated; see, for example, Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0121] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical formulations suitable for eye or ear administration may be in the form of droplets of a micronized suspension or solution in isotonic pH-adjusted sterile saline. Other formulations suitable for eye and ear administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated together with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0122] In the case of nasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is compressed or pumped by the patient using a suitable propellant, or in the form of an aerosol spray from a pressurized container or nebulizer. Formulations suitable for nasal administration are typically in the form of dry powder from a dry powder inhaler (alone, as a mixture, e.g., as a dry blend with lactose, or as mixed component particles mixed with a phospholipid such as phosphatidylcholine, for example), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate a fine mist), or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For nasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

[0123] In another embodiment, the present disclosure includes rectal dosage forms. Such rectal dosage forms may be, for example, in the form of suppositories. Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate.

[0124] 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 of the well-known techniques of pharmacy, such as effective formulations and administration procedures.

[0125] The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulations of drugs are discussed, for example, in Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975, Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980, and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients(3 rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0126] 5. Method of Treatment The compounds of the present disclosure can inhibit CSF-1R and are thus useful for treating diseases in which 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.

[0127] The term "autoimmune disease" refers to a disease or disorder, or a co-separation or symptom thereof, or a condition resulting therefrom, that originates from and / or is directed against an individual's own tissue or organ. Examples of autoimmune diseases include 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, polycythemia vera / essential thrombocythemia post myelofibrosis (PV / ET post myelofibrosis), but are not limited thereto.

[0128] The term "inflammatory disease" or "inflammatory disorder" refers to a pathological condition that causes inflammation, particularly due to 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 diseases (IBD such as Crohn's disease and ulcerative colitis); tissue reperfusion injury caused by surgery, myocardial ischemia such as myocardial infarction, cardiac arrest, reperfusion after heart surgery, and abnormal constriction reactions of coronary arteries after percutaneous coronary angioplasty, ischemic reperfusion injury including surgical tissue reperfusion injury of stroke and abdominal aortic aneurysm, surgical tissue reperfusion injury of stroke and abnormal aortic aneurysm; cerebral edema following stroke; head trauma and hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjögren's syndrome, and vasculitis; diseases associated with leukocyte extravasation; central nervous system (CNS) inflammatory diseases and multiple organ injury syndromes secondary to sepsis or trauma; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases including glomerulonephritis; pyemia; sarcoidosis; immunopathological responses to tissue / organ transplantation; and lung inflammation including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonia, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, etc. Preferably, the symptoms include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other joint conditions, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory diseases, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and fever, and any disease associated with inflammation and related conditions.

[0129] In some embodiments, the autoimmune or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, 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, ischemic reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and chemotherapy drug-induced organ injury.

[0130] The compound of formula (I) described herein or a pharmaceutically acceptable salt thereof can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in a subject having a neurodegenerative disease.

[0131] The term "neurodegenerative disease" refers to a degenerative disease or disorder of the nervous system caused by neurodegeneration 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), corticobasal degeneration, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (CMT), and the like.

[0132] 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).

[0133] The compound of formula (I) described herein or a pharmaceutically acceptable salt thereof can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in a subject having cancer.

[0134] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell growth, decreased cell differentiation, an inappropriate ability to invade surrounding tissue, and / or the ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies. The term "cancer" encompasses diseases of the skin, tissue, organs, bone, cartilage, blood, and blood vessels. The term "cancer" includes primary cancer and, further, metastatic cancer.

[0135] 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 and androgen-independent prostate cancer; testicular cancer; kidney cancer including, for example, metastatic renal cell cancer; urothelial cancer; liver cancer; hepatocellular cancer; lung cancer including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer including, for example, advanced epithelial cancer or primary peritoneal cancer; cervical cancer; endometrial cancer; gastrointestinal stromal tumor (GIST); stomach cancer; esophageal cancer; head and neck cancer including, for example, head and neck squamous cell carcinoma; skin cancer including, for example, melanoma and basal cell carcinoma; neuroendocrine cancer including metastatic neuroendocrine cancer; brain tumors including, for example, glioma, anaplastic glioma, adult glioblastoma, and adult dedifferentiated astrocytoma; bone cancer; sarcomas including, for example, Kaposi's sarcoma; adrenal cancer; mesothelioma; mesothelial cancer; choriocarcinoma; muscle cancer; connective tissue cancer; tenosynovial giant cell tumor; and thyroid cancer.

[0136] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and blast crisis of CML (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); follicular lymphoma; mantle cell lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); multiple myeloma (MM); Waldenström macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-T); and myeloproliferative syndromes.

[0137] 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 cancer, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, and sarcoma.

[0138] In some embodiments, exemplary hematological malignancies include leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); multiple myeloma (MM); and lymphoma, such as Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0139] The term "metabolic disease" refers to a disease or disorder 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 hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency disease, scurvy, vitamin D deficiency disease, etc.

[0140] The term "obesity-related disease" refers to a disease or disorder associated with, resulting from, 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, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, and angina), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, etc.

[0141] The terms "subject", "individual", or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0142] The terms "treat", "treating", and "treatment" refer to reversing, alleviating, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be performed after the occurrence of one or more signs or symptoms of a disease (i.e., therapeutic treatment). In other embodiments, treatment may be performed in the absence of signs or symptoms of a disease. For example, treatment can be performed on a susceptible subject before the symptoms appear (e.g., in light of the symptom history and / or exposure to a pathogen) (i.e., prophylactic treatment). After the symptoms have resolved, treatment can also be continued, for example, to delay or prevent their recurrence.

[0143] The terms "condition", "disease", and "disorder" are used interchangeably.

[0144] The terms "administer", "administering", or "administration" refer to methods of introducing the compounds or compositions thereof disclosed herein to a patient. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, etc. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co. Easton, Pa.

[0145] Generally, the effective amount of the compounds taught herein will vary depending on various factors such as the particular drug or compound, pharmaceutical formulation, route of administration, type of disease or disorder, identity of the subject or host being treated, etc., but nevertheless can be routinely determined by one of ordinary skill in the art. The effective amount of the compounds of the present teachings can be readily determined by one of ordinary skill in the art by routine methods known in the art.

[0146] The term "therapeutically effective amount" means an amount that, when administered to a subject, produces a beneficial or desired result, including clinical results, e.g., inhibiting, suppressing, or alleviating the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be an amount effective in the detectable killing or inhibition of cancer cell growth or spread, tumor size or number, or other measures of cancer level, stage, progression, or severity. 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 therapy with other therapies, etc.

[0147] 6. Preparation Any one of the compounds of the above formula can be prepared by the general and specific methods described below using the common general knowledge of those skilled in synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, 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 either commercially available or can be prepared by routine methods known in the art.

[0148] In the preparation of any one of the compounds of the above formula, it should be noted that some of the preparation methods described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in any one of the formulas of the above precursors). The need for such protection varies depending on the nature of the remote functionality and the conditions of the preparation method. The need for such protection can be readily determined by those skilled in the art. The use of such protection / deprotection methods is within the scope of the techniques in the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0149] For example, if a particular compound is left unprotected, it contains a primary amine or carboxylic acid functional group that can interfere with reactions at other sites in the molecule. Thus, such functionality may be protected by an appropriate protecting group that can be removed in a subsequent step. Protecting groups suitable for amine and carboxylic acid protection include those commonly used in peptide synthesis (e.g., N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functionality in any one of the compounds of the above formula.

Example

[0150] The compounds disclosed herein are prepared according to the exemplary procedures provided herein and modifications thereof known to those skilled in the art.

[0151] The schemes described below are intended to provide a general description of the methods used in the preparation of the compounds of the present disclosure.

[0152] Throughout the intermediates and examples, the following abbreviations are used. 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)ferrocene palladium dichloride, PMB-Cl means 1-(chloromethyl)-4-methoxy-benzene, tBu means tert-butyl, THF means tetrahydrofuran, hr means hour, and min means minute.

[0153] Method for synthesizing important intermediates Intermediate 1: 2-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical formula

[0154] 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) were added 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (2.99 g, 11.14 mmol), bis(tri-t-butylphosphine)palladium(0) (474 mg, 928 μmol), and potassium hydroxide solution (1.7 mL, 8 mol / L). The mixture was stirred for 15 h under a nitrogen atmosphere at 15 °C. After evaporation of the solvent, 50 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The residue was further purified by silica gel flash chromatography eluting with a gradient of 15% ethyl acetate in heptane to 35% ethyl acetate in heptane to give 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%).

[0155] Intermediate 2: 2-Methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol [Chemical formula] To a solution of 4-bromo-2-methoxyphenol (20.00 g, 98.51 mmol) in acetone (150 mL) were added potassium carbonate (20.421 g, 147.76 mmol) and bromomethylbenzene (17.69 g, 103.43 mmol). The mixture was heated at 75 °C for 1 h. The mixture was filtered and the filter cake was washed with ethyl acetate (3 × 50 mL). The organic phases were combined, concentrated and purified by silica gel flash chromatography eluting with a gradient of 5% ethyl acetate in heptane to 10% ethyl acetate in heptane to afford 24.02 g of 1-benzyloxy-4-bromo-2-methoxy-benzene as a white solid (yield = 83.11%).

[0156] To a solution of 1-benzyloxy-4-bromo-2-methoxy-benzene (24.00 g, 81.868 mmol) in 1,4-dioxane (500 mL) were added 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (28.52 g, 106.428 mmol), bis(tri-t-butylphosphine)palladium(0) (1.26 g, 2.456 mmol), and potassium hydroxide solution (18.42 mL, 8 mol / L). The mixture was stirred for 15 h under a nitrogen atmosphere at 15 °C. After evaporation of the solvent, 500 mL of water was added to the residue and the mixture was 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 silica gel flash chromatography 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%).

[0157] To a solution of 2-[(4-benzyloxy-3-methoxyphenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.08 g, 34.09 mmol) in 1,4-dioxane (100 mL) were added 4-chloro-7-methoxyquinoline (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 under a nitrogen atmosphere for 15 h. After evaporation of the solvent, the crude residue was purified by silica gel flash chromatography eluting with a gradient of 15% ethyl acetate in heptane to 100% ethyl acetate to afford 10.00 g of 4-[(4-benzyloxy-3-methoxyphenyl)methyl]-7-methoxyquinoline as a white solid (yield = 83.72%).

[0158] To a solution of 4-[(4-benzyloxy-3-methoxyphenyl)methyl]-7-methoxyquinoline (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 under a hydrogen atmosphere for 3 h. The mixture was filtered and the filter cake was washed with methanol (3 × 100 mL). The organic phases were combined, concentrated, and purified by silica gel flash chromatography eluting with a gradient of 35% ethyl acetate in heptane to 100% ethyl acetate to afford 5.50 g of 2-methoxy-4-[(7-methoxy-4-quinolyl)methyl]phenol as a grey solid (yield = 71.78%).

[0159] Intermediate 3: 5-(Bromomethyl)-3-methoxy-2-((5-methoxypyridin-2-yl)methoxy)pyridine [Chemical Structure] 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 for 10 minutes at 0 °C, methyl 6-chloro-5-methoxypyridine-3-carboxylate (30.00 g, 148.80 mmol) was added to the mixture. The mixture was heated to 100 °C for 12 hours and then cooled to room temperature. The mixture was diluted with 1000 mL of water and extracted with ethyl acetate (3 × 1000 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The residue was further purified by silica gel flash chromatography eluting with a gradient of 100% heptane to 50% ethyl acetate in heptane to give 12.00 g of methyl 5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]pyridine-3-carboxylate as an off-white solid (yield = 26.5%).

[0160] To a solution of methyl 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) under a nitrogen atmosphere at 5 °C. After stirring for 1 hour, the reaction was quenched by the successive addition of water (1.8 mL), 15% aqueous sodium hydroxide solution (1.8 mL), and water (5.4 mL). The mixture was filtered, the filtrate was diluted with 500 mL of water, and extracted with ethyl acetate (3 × 500 mL). The combined organic phases were 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 give 5.30 g of (5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methanol as a white solid (yield = 48.64%).

[0161] 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 minutes. The mixture was poured into saturated aqueous sodium bicarbonate 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%).

[0162] Intermediate 4: 8-(Bromomethyl)-3-methoxy-1,5-naphthyridine

Chemical formula

[0163] To a solution of 3-methoxy-8-methyl-1,5-naphthyridine (300 mg, 1.73 mmol) in carbon tetrachloride (10 mL) were 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 for 2 hours under a 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 100% heptane to 30% ethyl acetate in heptane to afford 150 mg of 8-(bromomethyl)-3-methoxy-1,5-naphthyridine as a yellow solid (yield = 25.8%).

[0164] Intermediate 5: 3-Methoxy-2-[(5-methoxypyridin-2-yl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Chemical formula

[0165] 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) were 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 for 12 h under a nitrogen atmosphere. After evaporation of the solvent, the residue was diluted with brine (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The residue was further purified by silica gel flash chromatography eluting with a gradient of 100% heptane to 50% ethyl acetate in heptane to give 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 as a pale yellow solid (yield = 79.5%).

[0166] Intermediate 6: 5-Methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-ol

Chemical Structure

[0167] General method for synthesizing representative examples Method A: [Chemical formula] Example 1: 7-Methoxy-4-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]quinolone [Chemical formula] 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 with 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 under a nitrogen atmosphere for 1 hour. After evaporation of the solvent, the crude residue was purified by silica gel flash chromatography 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]quinolone as a pale yellow solid (yield = 91.68%). 1 H NMR (400 MHz, DMSO) δ 8.73 (d, J = 4.5 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.24 (dd, J = 9.2, 2.7 Hz, 1H), 7.16 (d, J = 4.5 Hz, 1H), 6.98 - 6.89 (m, 4H), 6.68 (dd, J = 8.2, 1.9 Hz, 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) + .

[0168] Example 2: 4-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1,7-naphthyridine

Chem.

[0169] Example 3: 4-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)quinolone

Chemical Structure

[0170] Method B:

Chem.

Chem.

[0171] Example 8: 7-Methoxy-4-(3-methoxy-4-(pyridin-3-ylmethoxy)benzyl)quinolone

Chemical Structure

[0172] Example 18: 4-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-3-methoxybenzyl)-7-methoxyquinoline

Chemical Structure

[0173] Method C:

Chemical Structure

Chemical Structure

[0174] 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 under a nitrogen atmosphere for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The combined organic phases were 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 50% ethyl acetate in heptane to give 5 mg of 7-methoxy-4-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)quinoline as a pale yellow solid (yield = 6.83%).1 1H NMR (400 MHz, DMSO) δ 8.73 (d, J = 4.4 Hz, 1H), 8.25 (t, J = 2.0 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 2.0 Hz, 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) + .

[0175] Example 15: 4 - ((5 - Methoxy - 6 - ((5 - methoxypyridin - 2 - yl)methoxy)pyridin - 3 - yl)methyl)-1,5 - naphthyridine

Chemical formula

[0176] 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 with 5-(bromomethyl)-3-methoxy-2-[(5-methoxypyridin-2-yl)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 under a nitrogen atmosphere for 16 h. 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-methoxypyridin-2-yl)methoxy]-3-pyridyl]methyl]-1,5-naphthyridine as an off-white solid (yield = 23.58%). 1 1H NMR (400 MHz, DMSO) δ 9.09 (dd, J = 4.1, 1.7 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.44 (dd, J = 8.5, 1.7 Hz, 1H), 8.26 (t, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.5, 4.1 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.39 (d, J = 1.7 Hz, 3H), 5.31 (s, 2H), 4.57 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H). MS (m / z): 389.1 (M+H) + .

[0177] Method D:

Chemical formula

Chemical formula

[0178] Example 32: 3-Methoxy-8-((5-methoxy-6-((6-methoxypyridazin-3-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

Chemical Structure

[0179] To a solution of 3-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-6-methoxypyridazine (1.00 g, 3.07 mmol) in 1,4-dioxane (10 mL) were 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 for 16 hours under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography eluting with a gradient of 20% ethyl acetate to 50% ethyl acetate in heptane to give 1.00 g of 3-methoxy-6-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]pyridazine as a white solid (yield = 87.39%).

[0180] To a solution of 4-(bromomethyl)-7-methoxyquinoline (50 mg, 198 μmol) in 1,4-dioxane (10 mL) were 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)ferrocene palladium dichloride (13 mg, 20 μmol), and water (2 mL). The mixture was heated to 90 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography eluting with a gradient of 50% ethyl acetate in heptane to 5% methanol in dichloromethane to give 6 mg of 3-methoxy-8-[[5-methoxy-6-[(6-methoxypyridazin-3-yl)methoxy]-3-pyridyl]methyl]-1,5-naphthyridine as a white solid (yield = 7.24%). 1 H NMR(400 MHz,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),7.41(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) + .

[0181] Example 46: 5-(((3-Methoxy-5-((7-methoxy-1,5-naphthyridin-4-yl)methyl)pyridin-2-yl)oxy)methyl)-3-methylisoxazole

Chemical formula

[0182] 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) were 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 for 5 hours under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography eluting with a gradient of 5% ethyl acetate in heptane to 35% ethyl acetate in heptane to give 850 mg of 5-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]-3-methyl-isoxazole as an off-white solid (yield = 91.81%).

[0183] To a solution of 4-(bromomethyl)-7-methoxyquinoline (35 mg, 138 μmol) in 1,4-dioxane (25 mL) were added 5-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]-3-methylisoxazole (126 mg, 364 μmol), tripotassium orthophosphate (105 mg, 495 μmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (98 mg, 150 μmol), and water (5 mL). The mixture was heated to 90 °C for 12 h under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography 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-pyridyl]oxymethyl]-3-methylisoxazole (yield = 55.28%). 1 H NMR (400 MHz, DMSO) δ 8.82 (dd, J = 6.5, 3.7 Hz, 2H), 7.79 (d, J = 2.9 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.8, 3.1 Hz, 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) + .

[0184] 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

Chemical Structure

[0185] 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 h. 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 in heptane to give 1.83 g of 3-oxo-6,7-dihydro-3H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazin-8(4H)-ium-3a-ide as a pale yellow solid (yield = 76.94%).

[0186] To a suspension of 3-oxo-6,7-dihydro-3H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazin-8(4H)-ium-3a-ide (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 h. 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 pale yellow solid (yield = 91.83%).

[0187] A suspension of lithium aluminum hydride (540 mg, 14.23 mmol) in anhydrous THF (30 mL) was added with 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 h. After quenching the reaction by using H2O and 15% aqueous NaOH solution, the mixture was filtered and concentrated to give 1.42 g of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethanol as a pale yellow oil (yield = 78.57%).

[0188] 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 h 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 give 1.12 g of 2-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine as a pale yellow oil (yield = 72.51%).

[0189] A solution of 2-[(5-bromo-3-methoxy-2-pyridyl)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 with 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 for 12 h under a nitrogen atmosphere. The mixture was purified by silica gel flash chromatography eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate to obtain 1.10 g of 2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine as a light brown solid (yield = 86.32%).

[0190] A solution of 4-(bromomethyl)-7-methoxy-quinoline (30 mg, 119 μmol) in 1,4-dioxane (10 mL) was added with 2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]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)ferrocene palladium dichloride (8 mg, 12.4 μmol)), and water (2 mL). The mixture was heated to 90 °C for 3 h under a nitrogen atmosphere. The mixture was purified by silica gel flash chromatography eluting with a gradient of 100% ethyl acetate to 60% tetrahydrofuran in ethyl acetate to obtain 12 mg of 2-[[3-methoxy-5-[(7-methoxy-1,5-naphthyridin-4-yl)methyl]-2-pyridyl]oxymethyl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (yield = 23.36%). 11H NMR (400 MHz, DMSO) δ 8.82 (dd, J = 7.3, 3.7 Hz, 2H), 7.79 (d, J = 2.9 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.41 (d, J = 4.5 Hz, 1H), 7.32 (d, J = 1.8 Hz, 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) + .

[0191] 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 [Chemical formula] A solution of sodium nitrite (4.255 g, 61.67 mmol) in H2O (10 mL) was added to a solution of (2S,4R)-4-methoxypyrrolidine-2-carboxylic acid (7.000 g, 38.54 mmol) in concentrated hydrochloric acid (10 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was extracted with dichloromethane (50 mL × 20). The organic layer was dried over sodium sulfate and concentrated to give 6.00 g of (2S,4R)-4-methoxy-1-nitroso-pyrrolidine-2-carboxylic acid as a pale yellow solid.

[0192] 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 h. After evaporation of the solvent, the residue was purified by silica gel flash chromatography eluting with a gradient of 65% ethyl acetate to 100% ethyl acetate in heptane to afford 3.00 g of (R)-5-methoxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7(4H)-ium-3a-ide as a brown solid (yield = 60.84%).

[0193] To a suspension of (R)-5-methoxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7(4H)-ium-3a-ide (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 h. After evaporation of the solvent, the residue was purified by silica gel flash chromatography eluting with a gradient of 5% ethyl acetate to 100% ethyl acetate in heptane to afford 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%).

[0194] To a suspension of lithium aluminium hydride (1.00 g, 26.35 mmol) in anhydrous THF (20 mL) was added a suspension of ethyl (5R)-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (1.80 g, 8.56 mmol) in THF (20 mL) at -20 °C. The mixture was stirred at 25 °C for 1 h. After quenching the reaction by using H2O and 15% aqueous NaOH solution, the mixture was filtered and concentrated to afford 1.30 g of [(5R)-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]methanol as a brown oil.

[0195] 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 minutes, 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 hour 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 50% ethyl acetate in heptane to 100% ethyl acetate to give 400 mg of (5R)-2-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole as a pale yellow oil (yield = 25.12%).

[0196] To a solution of (5R)-2-[(5-bromo-3-methoxy-2-pyridyl)oxymethyl]-5-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (400 mg, 1.13 mmol) in 1,4-dioxane (20 mL) were 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 for 1 hour under a nitrogen atmosphere. The mixture purified by silica gel flash chromatography eluting with a gradient of 5% ethyl acetate in heptane to 100% ethyl acetate gave 400 mg of (5R)-5-methoxy-2-[[3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole as a brown oil (yield = 88.27%).

[0197] To a solution of 4-(bromomethyl)-7-methoxyquinoline (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-pyridyl]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)ferrocene palladium dichloride (19 mg, 29.4 μmol), and water (1 mL). The mixture was heated to 95 °C for 2 h under a nitrogen atmosphere. The mixture was purified by silica gel flash chromatography eluting with a gradient of 100% ethyl acetate to 20% ethanol in ethyl acetate to give 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 (400 MHz, DMSO) δ 8.82 (dd, J = 6.8, 3.7 Hz, 2H), 7.79 (d, J = 2.9 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.40 (d, J = 4.5 Hz, 1H), 7.31 (d, J = 1.7 Hz, 1H), 6.02 (s, 1H), 5.16 (s, 2H), 4.58 (ddd, J = 8.5, 6.0, 2.4 Hz, 1H), 4.52 (s, 2H), 4.25 (dd, J = 11.8, 5.7 Hz, 1H), 4.02 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H), 3.69 (s, 3H), 3.30 (s, 3H), 3.11 (dd, J = 16.7, 6.4 Hz, 1H), 2.79 (dd, J = 16.6, 2.2 Hz, 1H). MS (m / z): 448.1 (M+H) + .

[0198] Method E:

Chemical Structure

[0199] To a solution of 3-methoxy-2-[(5-methoxy-2-pyridyl)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) were 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 under a nitrogen atmosphere for 3 hours. After evaporating 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 obtain 2.5 mg of 4-[[5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]methyl]-1,7-naphthyridine as a white solid (yield = 2.87%). 111H NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.98 (d, J = 4.4 Hz, 1H), 8.65 (d, J = 5.8 Hz, 1H), 8.26 (s, 1H), 8.17 (d, J = 5.8 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 1.6 Hz, 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) + .

[0200] Example 22: 8 - ((5 - Methoxy - 6 - ((5 - methoxypyridin - 2 - yl)methoxy)pyridin - 3 - yl)methyl)pyrido[3,2 - d]pyrimidine [Chemical formula] To a solution of 8 - methylpyrido[3,2 - d]pyrimidine (50 mg, 344 μmol) dissolved in acetonitrile (10 mL) were 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 for 15 h under a 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 afford 20 mg of 8 - (bromomethyl)pyrido[3,2 - d]pyrimidine as a white solid (yield = 25.92%).

[0201] A solution of 3-methoxy-2-[(5-methoxy-2-pyridyl)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 with 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 under a nitrogen atmosphere for 3 hours. 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 3.0 mg of 8-[[5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]methyl]pyrido[3,2-d]pyrimidine as a white solid (yield = 8.63%). 1 H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 9.51 (s, 1H), 9.05 (d, J = 4.4 Hz, 1H), 8.26 (t, J = 1.8 Hz, 1H), 7.81 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.38 (t, J = 2.5 Hz, 3H), 5.31 (s, 2H), 4.53 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H). MS (m / z): 390.1 (M + H) + .

[0202] Example 62: 3-Chloro-8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine

Chemical Structure

[0203] To a solution of 5-chloropyridin-3-amine (150 g, 1.17 mol) dissolved in isopropanol (1500 mL), 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (278 g, 1.39 mol) was added. The mixture was heated at 80 °C for 2 hours and then cooled. A large number of solids precipitated and the mixture was filtered. The filter cake was washed three times with 150 ml of isopropyl alcohol and dried to obtain 325 g of 5-[[(5-chloro-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione as a yellow solid. (Crude product).

[0204] To phenyl ether (3000 mL), 5-[[(5-chloro-3-pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (325 g, 1.15 mol) was added little by little at 200 °C. The mixture was heated at 200 °C for 0.5 hour and then cooled to 60 °C. A large number of solids precipitated and the mixture was filtered. The filter cake was washed three times with 1000 ml of heptane and dried to obtain 138 g of 7-chloro-1H-1,5-naphthyridin-4-one as a brown solid. (Crude product).

[0205] A solution of 7-chloro-1H-1,5-naphthyridin-4-one (133.9 g, 550 mmol) dissolved in N,N-dimethylformamide (2070 mL) was slowly added dropwise with phosphorus tribromide (256.5 g, 948 mmol) at 0 °C. The mixture was stirred at 20 °C for 3.5 hours. The mixture was poured into ice water (10 L), and saturated aqueous Na2CO3 solution was added to adjust the pH value of the mixture to 7 - 8. A large number of solids precipitated, and the mixture was filtered. The filter cake was washed 5 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)

[0206] 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-trioxatriphosphorinane (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 under a nitrogen atmosphere for 36 hours. The mixture was filtered, and the filter cake was washed 2 times with 200 mL of ethyl acetate. After fractionation, 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 obtain 75 g of 3-chloro-8-methyl-1,5-naphthyridine as a pale yellow solid (yield = 92.19%).

[0207] To a solution of 3-chloro-8-methyl-1,5-naphthyridine (75.0 g, 420 mmol) dissolved in acetonitrile (1875 mL) was added methanesulfonic acid (80.71 g, 840 mmol). After stirring at 20 °C for 1 hour, 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 hours. After evaporating the solvent, water (1.5 L) and saturated aqueous NaOH were added to the mixture to adjust the pH value of the mixture to 7.5. A large number of solids precipitated and the mixture was filtered. The filter cake was washed 5 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).

[0208] To a solution of 3-chloro-8-(dibromomethyl)-1,5-naphthyridine (141.3 g, 420 mmol) dissolved in methanol (420 mL) were added diethyl phosphite (87.01 g, 630 mmol) and N,N-diisopropylethylamine (81.43 g, 630 mmol). The mixture was heated at 20 °C for 5 hours. After evaporating the solvent, water (3.0 L) and saturated aqueous NaOH were added to the mixture to adjust the pH value of the mixture to 8.5. A large number of solids precipitated and the mixture was filtered. The filter cake was washed 5 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%).

[0209] To a solution of 8-(bromomethyl)-3-chloro-1,5-naphthyridine (25.00 g, 97.08 mmol) dissolved in 1,4-dioxane (1250 mL) were 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 under a nitrogen atmosphere for 16 h. After evaporation of the solvent, the residue was purified by silica gel flash chromatography eluting with a gradient of 50% ethyl acetate in heptane to 100% ethyl acetate to afford 11.00 g of 3-chloro-8-[[5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]methyl]-1,5-naphthyridine as an off-white solid (yield = 26.80%). 1 H NMR (400 MHz, DMSO) δ 9.11 (d, J = 2.4 Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.28 - 8.22 (m, 1H), 7.64 (dd, J = 17.7, 3.1 Hz, 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) + .

[0210] Example 65: 8-((5-Methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridine-3-carbonitrile

Chemical Structure

[0211] To a solution of 3-methoxy-2-[(5-methoxy-2-pyridyl)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), 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) were added. The mixture was heated at 90 °C for 2 h under a nitrogen atmosphere. After evaporation of the solvent, the residue was purified by silica gel flash chromatography 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-pyridyl)methoxy]-3-pyridyl]methyl]-1,5-naphthyridine-3-carbonitrile as a white solid (yield = 27.43%). 11H NMR (400 MHz, DMSO) δ 9.37 (d, J = 2.0 Hz, 1H), 9.12 (d, J = 2.0 Hz, 1H), 9.05 (d, J = 4.4 Hz, 1H), 8.28 - 8.23 (m, 1H), 7.75 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 1.8 Hz, 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) + .

[0212] Method F:

Chem.

Chem.

[0213] Method G: General route for the synthesis of compound of formula (I) when Q = N and X1 is C=O

Chem.

Chem.

Chem.

[0214] A solution of (5-methoxy-2-pyridyl)methanol (269 mg, 1.933 mmol) dissolved in 1,4-dioxane (5 mL) was added to potassium t-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 h. 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-pyridyl)methoxy]pyridine as a pale yellow solid (yield = 77.29%).

[0215] To a solution of 5-bromo-3-(difluoromethoxy)-2-[(5-methoxy-2-pyridyl)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 a nitrogen atmosphere for 2 h. 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 20% ethyl acetate in heptane to give 500 mg of 3-(difluoromethoxy)-2-[(5-methoxy-2-pyridyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a pale yellow solid (yield = 88.47%).

[0216] To a solution of 4-(bromomethyl)-7-methoxyquinoline (50 mg, 198 μmol) in 1,4-dioxane (1 mL) was added 3-(difluoromethoxy)-2-[(5-methoxypyridin-2-yl)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)ferrocene palladium dichloride (13 mg, 20 μmol), and water (0.2 mL). The mixture was heated to 90 °C for 1.5 h under a nitrogen atmosphere. After evaporation of the solvent, the residue was purified by silica gel flash chromatography eluting with a gradient of 50% ethyl acetate in heptane to 100% ethyl acetate to afford 30 mg of 8-[[5-(difluoromethoxy)-6-[(5-methoxypyridin-2-yl)methoxy]-3-pyridyl]methyl]-3-methoxy-1,5-naphthyridine as a white solid (yield = 33.42%). 1 H NMR (400 MHz, DMSO) δ 8.82 (dd, J = 5.6, 3.7 Hz, 2H), 8.25 (t, J = 1.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 4.5 Hz, 1H), 7.40 (d, J = 1.8 Hz, 2H), 7.16 (t, J = 73.8 Hz, 1H), 5.37 (s, 2H), 4.54 (s, 2H), 3.99 (s, 3H), 3.82 (s, 3H). MS (m / z): 455.1 (M+H) + .

[0217] Method I:

Chemical formula

Chemical formula

[0218] A solution of [5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]-(7-methoxy-1,5-naphthyridin-4-yl)methanone (100 mg, 231 μmol) dissolved in MeOH (20 mL) was added with NaBH₄ (18 mg, 476 μmol). The mixture was stirred at 25 °C for 1 h. 20 ml of water was added to the mixture, which was then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Mg₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a gradient of 20% ethyl acetate to 100% acetic acid in heptane to afford 60 mg of [5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]-(7-methoxy-1,5-naphthyridin-4-yl)methanol as a yellow oil (yield = 59.72%).

[0219] A solution of [5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]-(7-methoxy-1,5-naphthyridin-4-yl)methanol (60 mg, 138 μmol) dissolved in DCM (10 mL) was added with diethylaminosulfur trifluoride (DAST) (67 mg, 416 μmol). The mixture was stirred at 25 °C for 1 hour. 20 ml of NaHCO3 was added to the mixture, and it was 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 silica gel flash chromatography eluting with a gradient of 20% ethyl acetate to 100% acetic acid in heptane to obtain 20 mg of 8-[fluoro[5-methoxy-6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]methyl]-3-methoxy-1,5-naphthyridine as a white solid (yield = 33.18%). 1 1H NMR (400 MHz, DMSO) δ 9.04 (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) + .

[0220] Method J:

Chemical Structure

Chemical Structure

[0221] Example 119: 4-(8-((5-methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridin-3-yl)morpholine

Chemical Structure

[0222] Method K:

Chemical formula

Chemical formula

[0223] Example 138: 5-(8-((5-Methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-1,5-naphthyridin-3-yl)-2-methylthiazole [Chemical formula] 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 with 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 a nitrogen atmosphere for 1 hour. After evaporating 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 obtain 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 (400 MHz, DMSO) δ 9.41 (d, 1H), 8.92 (d, 1H), 8.54 (d, 1H), 8.46 (d, 1H), 8.25 (d, 1H), 7.67 (d, 1H), 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) + .

[0224] Example 140: 8-((5-Methoxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-3-(pyridin-3-yl)-1,5-naphthyridine

Chemical formula

[0225] Method L:

Chemical Structure

Chemical Structure

[0226] To a solution of 6-bromo-2-(4-methoxy-1-piperidyl)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 for 2 h under a 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 in heptane to give 300 mg of 2-(4-methoxy-1-piperidyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline as a yellow oil (yield = 58.17%).

[0227] To a solution of 4-(bromomethyl)-7-methoxy-quinoline (70 mg, 277 μmol) in 1,4-dioxane (10 mL) were 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)ferrocene palladium dichloride (20 mg, 28 μmol), and water (2 mL). The mixture was heated to 90 °C for 2 hours under a 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 30 mg of 3-methoxy-8-[[2-(4-methoxy-1-piperidyl)quinoxalin-6-yl]methyl]-1,5-naphthyridine as a yellow solid (yield = 26.11%). 1 H NMR (400 MHz, DMSO) δ 8.78 - 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) + .

[0228] Method M:

Chem.

Chem.

[0229] To a solution of 6-bromo-2-(4-methoxycyclohex-1-en-1-yl)quinoxaline (350 mg, 1.097 mmol) dissolved in 1,4-dioxane (20 mL) were 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 for 2 h under a 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 40% ethyl acetate in heptane to give 350 mg of 2-(4-methoxycyclohex-1-en-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline as a white solid (yield = 87.15%).

[0230] To a solution of 4-(bromomethyl)-7-methoxyquinoline (100 mg, 395 μmol) in 1,4-dioxane (10 mL) was added 2-(4-methoxycyclohex-1-en-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 for 2 h under a nitrogen atmosphere. After evaporation of the solvent, the residue was purified by silica gel flash chromatography eluting with a gradient of 15% ethyl acetate to 100% ethyl acetate in heptane to afford 100 mg of 2-(4-methoxycyclohex-1-en-1-yl)-6-[(7-methoxy-1,5-naphthyridin-4-yl)methyl]quinoxaline as a white solid (yield = 61.36%).

[0231] To a solution of 2-(4-methoxycyclohex-1-en-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 h 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 to 100% acetonitrile in H2O to afford 10 mg of 6-((7-methoxy-1,5-naphthyridin-4-yl)methyl)-2-(4-methoxycyclohexyl)quinoxaline as a white solid (yield = 9.95%). 1 H NMR (400 MHz, DMSO) δ 8.83 - 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) + .

[0232] Method N:

Chem.

Chem.

[0233] 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) were 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 for 12 h under a nitrogen atmosphere. 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 200 mg of 2-[(5-methoxy-2-pyridyl)methoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a white solid (yield = 43.12%).

[0234] To a solution of 4-(bromomethyl)-7-methoxyquinoline (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)ferrocene palladium dichloride (19 mg, 29 μmol), and water (1 mL). The mixture was heated to 90 °C for 12 h under a nitrogen atmosphere. 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 100% ethyl acetate to give 35 mg of 3-methoxy-8-[[6-[(5-methoxy-2-pyridyl)methoxy]-3-pyridyl]methyl]-1,5-naphthyridine as a white solid (yield = 30.84%). 1 H NMR (400 MHz, CDCl3) δ 8.78 (t, J = 3.7 Hz, 2H), 8.33 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.55 (dd, J = 8.5, 2.4 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 8.5, 2.9 Hz, 2H), 6.79 (d, J = 8.5 Hz, 1H), 5.44 (s, 2H), 4.57 (s, 2H), 4.02 (s, 3H), 3.88 (s, 3H) MS (m / z): 489.1 (M+H) + .

[0235] Method O:

Chemical formula

[0236] Additional compounds were prepared by modification of the methods exemplified herein. All of the compounds and their corresponding characterization data are presented in Table 1 below.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

[0237] Biochemical assay To perform the enzymatic step, the working solution was prepared in an enzyme buffer (12.5 nM SEB, 1 mM DTT, 5 mM MgCl2, 1 mM MnCl2). The reaction was carried out in a 384-well plate at room temperature for 1 hour using 2.5 μL of inhibitor or enzyme buffer, 2.5 μL of recombinant human proteins (CSF-1R, c-Kit, PDGFRβ, and FLT3), and 5 μL of substrate / ATP mixture. After adding the detection mixture (5 μl of Sa-XL665 and 5 μl of TK-antibody-cryptate), the plate was sealed and incubated at room temperature for 1 hour. Detection was performed using a Spark reader (Tecan) with standard HTRF protocol settings. IC 50 determination was performed using GraphPad Prism software (GraphPad, Inc.). The selectivity ratio was determined by the IC 50 of other kinases (cKit, FLT3, PDGFR-1β) and the IC 50 of multiple CSF-1R.

[0238] Cell proliferation assay Ba / F3_CSF-1R (stable expression of human CSF-1R kinase) was cultured in RPMI1640 medium supplemented with 10% FBS and 100 ng / ml of recombinant human CSF-1. EOC2 was cultured in DMEM medium supplemented with 10% FBS and 100 ng / ml of recombinant mouse CSF-1. Cells were seeded in a 384-well plate for 24 hours (1×10 3 cells / well for Ba / F3_CSF1R cells, 5×10 2 cells / well for EOC2 cells), and then treated with the compound for 72 hours. The cell growth rate was determined using a CellCounting-Lite luciferase-based ATP detection assay (Vazyme) according to the manufacturer's protocol. IC 50 determination was performed using GraphPad Prism software (GraphPad, Inc.).

[0239] Biological activity data The enzymatic activity and cell inhibitory activity of representative compounds disclosed in this specification are presented in Table 2 below.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

[0240] Selectivity data of the selected compounds against CSF1R with respect to cKit, FLT3, and PDGFR-β are shown in Table 3 below.

Table 3-1

Table 3-2

[0241] The structures of the reference compounds GW2580, PLX5622, BLZ945, and Comparative Subject A are provided below. GW2580:

Chem.

Chem.

Chem.

Chem.

[0242] In Vivo PK Study The PK profile was 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 - 30 g, 6 - 8 weeks old, male) were randomly divided into five groups of 21 mice each. The formulated test compounds were subjected to PK testing. The test compounds were administered at 45 mg / kg via p.o. and 2 mg / kg via i.v. After administration, blood samples and brain samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours. On the other hand, brain samples were collected at 1, 4, 8, and 24 hours. Blood samples were placed on ice, and serum was collected after centrifugation. Serum samples were frozen and stored at -70°C. Brain samples were dried on filter paper, snap-frozen on dry ice, and further stored at -70°C. Then, blood samples and brain samples were further analyzed by LC-MS / MS (Triple Quad6500+).

[0243] The formulations of the selected compounds and the reported inhibitors are presented in Table 4 below.

Table 4

[0244] The in vivo ADMET data of the selected compounds and the reported inhibitors are presented in Tables 5 and 6 below.

Table 5

Table 6

[0245] Based on the in vivo ADME data, Example 16 is T 1 / 2showed a moderate clearance (CL = 0.448 L / hr / kg) of 2.52 hours, a moderate distribution, and an excellent absorption of F215%. Example 45, when administered to mice as the free base, had a T of 14.2 hours (2 mpk, IV). 1 / 2 showed a low clearance (CL = 0.134 L / hr / kg) at T. Example 45 also showed a moderate absorption of F55% after oral treatment (45 mpk) in mice. Example 73 had a T of 2.52 hours 1 / 2 showed a moderate clearance, a moderate distribution of Vss of 0.461 L / kg, and an excellent high Cmax of 100367 ng / mL. Example 116 had a V of 9.54 L / kg SS showed a very high distribution, which could result in a low Cmax. Example 134 showed a moderate clearance, exposure, and a high absorption of F of 227%. Example 136 showed ADME properties equivalent to those of Example 073.

[0246] Plasma Protein Binding Studies On the day of the experiment, plasma was thawed while flowing cold tap water, and centrifuged at 3220×g for 5 minutes to remove thrombus. The pH value was checked and recorded. Only plasma within 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 immersed in ultrapure water at room temperature for approximately 1 hour. Subsequently, each membrane strip containing two membranes was separated, immersed in ethanol:water (20:80 v:v) for approximately 20 minutes, and then either used immediately or stored in the solution at 2 - 8°C for up to 1 month. Before the experiment, the membrane was rinsed for use and immersed in ultrapure water for 20 minutes. Working solutions (400 μM) of the test compound and the control compound were prepared. To achieve the final concentration, an aliquot (3 μL) of the working solution was added to the blank matrix (597 μL) and mixed thoroughly. Fifty - μL aliquots filled with the matrix containing the test compound or the control compound, three each, were transferred to a sample collection plate. Immediately, the samples were matched with the blank buffer on the opposite side to obtain a final volume of 100 μL with a volume ratio of matrix: dialysis buffer (1:1, v:v) in each well. The stop solution was added to these T0 samples of the test compound and the control compound. The plate was sealed and shaken at 800 rpm for 10 minutes. Then, these T0 samples were stored at 2 - 8°C while waiting for further processing together with the other post - dialysis samples. The dialysis apparatus was assembled according to the manufacturer's instructions. One - hundred - μL aliquots filled with the matrix containing the test compound or the control compound, three each, were transferred to the donor side of each dialysis well, and 100 μL of dialysis buffer was filled into the recipient side of the well. Then, the plate was rotated at approximately 100 rpm for 4 hours in a humidified incubator containing 5% CO2 at 37 ± 1°C. At the end of dialysis, 50 - μL aliquots of the samples from the buffer side and the matrix side of the dialysis device were collected into a new 96 - well plate (sample collection plate). An equal volume of the blank matrix (buffer or matrix) on the opposite side was added to each sample to reach a final volume of 100 μL with a volume ratio of matrix: dialysis buffer of 1:1 (v:v) in each well. All samples were further processed by protein precipitation for LC / MS / MS analysis.

[0247] Brain Protein Binding Research On the day of the experiment, the brain homogenate was thawed in a water bath at room temperature and then incubated at 37 °C for 10 minutes before use. The dialysis membrane was pretreated according to the manufacturer's instructions: the dialysis membrane strip was immersed in ultrapure water at room temperature for approximately 1 hour. Subsequently, each membrane strip containing two membranes was separated and immersed in ethanol: water (20:80 v:v) for approximately 20 minutes and then used immediately or stored in solution at 2 - 8 °C for up to 1 month. Before the experiment, the membrane was rinsed for use and immersed in ultrapure water for 20 minutes. Next, working solutions (400 μM) of the test compound and the control compound were prepared. To achieve the final concentration, an aliquot (3 μL) of the working solution was added to the blank matrix (597 μL) and mixed thoroughly. Aliquots of 50 μL each, filled with the matrix containing the test compound or the control compound, were transferred to the sample collection plate in triplicate. Immediately, the samples were matched with the blank buffer on the opposite side to obtain a final volume of 100 μL with a volume ratio of matrix: dialysis buffer (1:1, v:v) in each well. The stop solution was added to these T0 samples of the test compound and the control compound. The plate was sealed and shaken at 800 rpm for 10 minutes. Then, these T0 samples were stored at 2 - 8 °C while waiting for further processing with the other post - dialysis samples. The dialysis apparatus was assembled according to the manufacturer's instructions. Aliquots of 100 μL each, filled with the matrix containing the test compound or the control compound, were transferred in triplicate to the donor side of each dialysis well, and 100 μL of dialysis buffer was filled into the recipient side of the well. Then, the plate was rotated at approximately 100 rpm for 4 hours in a humidified incubator containing 5% CO2 at 37 ± 1 °C. At the end of dialysis, aliquots of 50 μL of the samples from the buffer side and the matrix side of the dialysis device were collected into a new 96 - well plate (sample collection plate). An equal volume of the opposite blank matrix (buffer or matrix) was added to each sample to reach a final volume of 100 μL with a 1:1 (v:v) volume ratio of matrix: dialysis buffer in each well. All samples were further processed by protein precipitation for LC / MS / MS analysis.

[0248] The BBB penetration data of the selected compounds and the reported inhibitors are presented in Tables 7 and 8 below.

Table 7

Table 8

[0249] 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.

[0250] p-CSF1R ELISA assay

Table 9

[0251] p - CSF1R and p - ERK1 / 2 Western blot assay Reagents and cell lines were purchased through the supplier Fisher Scientific. Mouse 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. The same media formulation was used throughout unless otherwise specified. One day before the experiment, BV2 cells were trypsinized and counted. A total of 1×10 6The cells were placed in a 12-well PDL-coated plate and returned to a 37°C CO2 incubator for overnight culture. At the start of the experiment, the cells were serum-starved for 4 hours with pre-warmed DMEM / F12 only. The inhibitor was dissolved in DMSO, and the cells were pre-treated with the inhibitor at the indicated concentrations at a DMSO volume not exceeding 0.1% of the volume of the medium for 30 minutes, followed by stimulation with 100 ng / mL of recombinant mouse CSF1 (R&D Systems) for 5 minutes. The cells were lysed with RIPA buffer supplemented with protease and phosphatase inhibitor cocktail (Halt-Pierce) and benzonase (EMD Millipore). The lysate was incubated at room temperature for 15 minutes and centrifuged at 16,200 g for 10 minutes at 4°C to pellet the insoluble fraction. The supernatant was collected, and the protein concentration was determined using the Rapid BCA kit (Pierce), and the absorbance was measured with a Spectramax M5 (Molecular Devices). Twenty micrograms of total protein were loaded for each condition, electrophoresed through a 4-12% Bis-Tris SDS-PAGE gel (Invitrogen), and transferred onto a PVDF membrane using the iBlot2 system (Invitrogen). Immunoblotting was performed against phospho-CSF1R (Cell Signaling, 3155S, diluted 1:1000) and phospho-ERK1 / 2 (Cell Signaling, 9101S, diluted 1:1000), followed by stripping with NewBlot IR stripping buffer (Li-Cor) for 15 minutes, and re-detection of CSF1R (Cell Signaling, 3152S, diluted 1:2000), ERK1 / 2 (Cell Signaling, 9107S, diluted 1:1000), and beta-tubulin (Abcam, ab179513, diluted 1:5000).

[0252] Effect of CSF1Ri on BV2 cell proliferation Reagents and cell lines were purchased through Fisher Scientific, the supplier. 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. The same media formulation was used throughout unless otherwise specified. 1000 BV2 cells per well were seeded into 96-well tissue culture-treated plates (Corning). Inhibitor and / or CSF1 (100 ng / mL) were added and cultured for 72 hours. To perform the Cell Titer Glo assay, the media were aspirated from the wells. 100 uL of fresh growth media + 100 uL of Cell Titer Glo reagent (Promega) were added and the plates were incubated at room temperature for 15 minutes. 100 uL from each sample was transferred to a white solid-bottom plate (Corning) for luminescence readings (560 nm) on a Spectramax M5 (Molecular Devices).

[0253] Results Effect of CSF1Ri on the CSF1R signaling pathway To better understand the pharmacodynamic effects of the lead compound on the CSF1R signaling pathway, the levels of phosphorylated versions of the downstream MAP kinases CSF1R (p-CSF1R) and ERK1 / 2 (p-ERK1 / 2) were analyzed in mouse microglia-like BV2 cells stimulated with recombinant mouse CSF1. BV2 cells were pre-treated with Example 16 or reference compound (1000 nM to 0.3 nM) for 30 minutes, stimulated with CSF1 (100 ng / mL) for 5 minutes, and then the cells were lysed and the lysates were run on an SDS-PAGE gel. CSF1 treatment consistently increased CSF1R and ERK1 / 2 phosphorylation in BV2 cells (compare lanes 1 and 2 in Figures 1A, 1B, 1C). Pre-incubation of cells with GW2580 (Figure 1A) and comparator A (Figure 1B) abrogated CSF1R signaling in a concentration-dependent manner. Example 16 also abrogated CSF1 signaling in a concentration-dependent manner (Figure 1C). Quantification of the p-CSF1R and p-ERK1 / 2 immune signals from the Western blot is shown in Figure 2 (GW2580 - Figure 2A, comparator A - Figure 2B, Example 16 - Figure 2C). Example 16 inhibited CSF1R signaling with mean EC50 values of 47.2 nM for p-CSF1R and 21.4 nM for p-ERK1 / 2 inhibition (Table A). Thus, Example 16 is at least as effective as the reference compound in blocking the CSF1R signaling pathway in BV2 cells.

[0254] Since BV2 cells are of mouse origin, it was decided to set up a pharmacodynamic assay in the human THP-1 cell line using a well-established p-CSF1R ELISA assay. THP1 cells were pre-treated with the compound in a 10-point concentration-response curve (CRC) with 3-fold dilution steps for 1 hour and then stimulated with hCSF1. The cells were lysed and the pCSF1R levels were quantified as described in the Materials and Methods section. Individual CRCs are presented in Figure 3 and the calculated EC50 values are presented in Table B. Thus, Example 16 showed concentration-dependent blockade of CSF1R phosphorylation in human THP1 cells and the calculated EC50 was 10.8 nM.

Table 10

Table 11

[0255] Effect of CSF1Ri on microglia proliferation and survival The functional outputs of CSF1R signaling in microglia are cell proliferation and survival. An assay was set up to measure the effect of this compound on microglia proliferation. BV2 cells were stimulated with CSF1 (100 ng / mL) for 72 hours, which resulted in an enhancement of cell proliferation by about 2-fold compared to vehicle-treated cells, as evaluated by the Cell Titer Glow assay (Figure 4A). CSF1-induced proliferation was abrogated by the CSF1R inhibitors GW2580 and BLZ945 in a concentration-dependent manner (Figure 4B, Figure 4C). Example 16 also showed a concentration-dependent inhibition of BV2 cell proliferation (Figure 4D). The calculated EC50 values in this assay are shown in Table C.

Table 12

[0256] To evaluate the potency of the CSF1R inhibitors disclosed herein, primary brain glia were isolated from rat cerebral cortex and grown in vitro. This glial culture was approximately 20% microglia and was supported mainly by astrocytes that constituted the remainder of the population. Brain glia were exposed to the CSF1R inhibitor for 3 days, followed by paraformaldehyde fixation and immunofluorescent staining with the microglia marker Iba1. The glia were imaged using a high-content imager, and changes in microglia content were quantified. GraphPad Prism was used to apply four-parameter logistic regression to determine the potency of the CSF1R inhibitor. Example 16, a CSF1R inhibitor, demonstrated a dose-dependent inhibition of primary rat microglia survival after 3 days of exposure (Figure 5A). Examples 73, 134, and 136, which are CSF1R inhibitors, demonstrated a dose-dependent inhibition of primary rat microglia survival 3 days after exposure (Figure 5B).

[0257] Effect of CSF1Ri on the inhibition of CSF1R phosphorylation The THP-1 human monocyte-like cell line has intact CSF1R signaling that enables detection of the activation state of this pathway when stimulated by recombinant CSF. THP-1 cells were grown in vitro and pretreated with a CSF1R inhibitor for 1 hour, then stimulated with recombinant human M-CSF for 5 minutes. Cells were lysed and lysates were assayed for activated CSF1R (pCSF1R) using ELISA. Four-parameter logistic regression was applied using GraphPad Prism to determine the potency of the CSF1R inhibitor. The calculated IC 50 values are shown in Table D. Example 16, a CSF1R inhibitor, demonstrates dose-dependent inhibition of CSF1R phosphorylation in CSF1R-stimulated THP-1 monocytes (Figure 6). [Table 13]

[0258] Effect of CSF1Ri on hiPSC-MG survival To demonstrate the efficacy of compounds in a highly translatable human model, human induced pluripotent stem cell-derived microglia (hiPSC-MG) cultures were established and the effect of the compound on hiPSC-MG survival was examined. Briefly, hiPSC-MG were stabilized for 3 days after thawing and treated with a CSF1R inhibitor for 48 hours. Microglia survival was finally evaluated using the Presto-Blue viability assay (Figures 7A and 7B). The percent viability values representing cell viability were calculated from each Presto-Blue fluorescence value normalized to the DMSO-treated control (i.e., DMSO set as 100%). CSF1R-dependent cell survival was inhibited in a concentration-dependent manner by all CSF1R inhibitors used herein (Figures 7A and 7B). In particular, the IC 50 values of Example 16 (Figure 7A), Example 73 (Figure 7B), and Example 134 (Figure 7B) are lower than those of BLZ945 (Figure 7B), demonstrating the excellent potency of the compound in human microglia.

[0259] In vivo microglia depletion effect of Example 134 To measure the in vivo pharmacodynamic effect, microglia depletion after repeated dosing of this compound in naive animals was quantified. Female C57BL / 6 mice were administered Example 134 (0, 50, 100, or 200 mg / kg / day, respectively) by oral gavage BID for 7 days. After the final dose, the mice were perfused with PBS followed by 4% paraformaldehyde (PFA). The brains were fixed overnight in 4% PFA and then transferred to 30% sucrose solution. Sagittal sections were sliced, stained with the microglia marker Iba1, and counterstained with DAPI. The brain sections were then imaged under 20x wide-field imaging, and the microglia density in the cerebral cortex and hippocampus was quantified.

[0260] The microglia depletion effect of Example 134 in the brain is shown in FIGS. 8A, 8B, and Table E. For Example 134, a dose-dependent decrease in microglia density was observed. In the cerebral cortex, the microglia density decreased significantly (by more than 22%, more than 91%, and more than 98%) at doses of 50, 100, and 200 mg / kg, respectively, compared to the vehicle control (FIG. 8A). In the hippocampus, the microglia density decreased significantly (by more than 83% and more than 93%) in both the 100 mg / kg group and the 200 mg / kg group compared to the vehicle control (see FIG. 8B). In summary, Example 134 exhibits a potent depletion effect in the brain at low dosages of 50 mg / kg / day in the cerebral cortex and 100 mg / kg / day in the hippocampus. [Table 14]

[0261] Summary Example 16 was tested in the pharmacodynamic assays (p-CSF1R ELISA assay, p-CSF1R and p-ERK1 / 2 Western blot assays) and cell-based efficacy assays (BV2 cell proliferation assay, rat microglia survival assay, CSF1R phosphorylation inhibition assay, hiPSC-MG survival assay) referred to above. In the in vivo pharmacodynamic study, Example 134 was tested. The pharmacodynamic assays showed that Example 16 is a potent inhibitor of CSF1R and is equivalent, if not more potent, than the reference compounds GW2580, BLZ945, and Comparative Subject A. The efficacy assays showed that Example 16 is a potent inhibitor of CSF1-directed proliferation of the microglia-like BV2 cell line and has a calculated EC50 value consistent with Example 16 exerting an on-target effect. In addition, the efficacy assays have shown that Example 16 accounts for strong inhibition of CSF1R phosphorylation. The microglia survival assay has shown that Examples 16, 73, 134, and 136 demonstrate strong inhibition of primary rat microglia survival. The hiPSC-MG survival assay demonstrated the excellent potency of this compound in the function of human microglia, and the calculated IC 50 values of Examples 16, 73, and 134 are lower compared to BLZ945. The in vivo study has shown that Example 134 demonstrates a strong depletion effect in the brain at low dosages of 50 mg / kg / day in the cerebral cortex and 100 mg / kg / day in the hippocampus.

Claims

1. A compound represented by formula (I): 【Chemical 1】 a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein Q is C or N, When Q is N, Q-X １ is a single bond, and X １ is C=O, When Q is C, Q-X １ is a double bond, and X １ is N or CR １ and Z is CH or NH, When Z is NH, Z-X ３ is a single bond, and X ３ is C=O, When Z is CH, Z-X ３ is a double bond, and X ３ is N or CR ３ and X ２ is N or CR ２ and X ４ is N or CR ４ and X ５ is N or CR ５ and Each R １ 、R ２ 、R ３ 、R ４ 、and R ５ is, independently, H, halogen, -CN, -OH, C optionally substituted with 1 to 3 deuteriums １－６ alkyl, C １－６ haloalkyl, C １－６ hydroxyalkyl, C ２－６ alkenyl, C ２－６ alkynyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-SO ２ R ＊ 、-(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、 -NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、-P(O)R ＊ R ＊ 、-(CH ２ ) ０若しくは１ -3 to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ -3 to 12-membered heterocyclyl, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ - selected from 5- to 10-membered heteroaryl, wherein the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R １ , R ２ , R ３ , R ４ , or R ５ is optionally substituted by one or two groups selected from CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and C １－６ haloalkoxy, Each A １ , A ２ , A ３ , and A ４ is independently N or CR Ａ , A １ , A ２ , A ３ , and A ４ Among them, two or less are N, Each R Ａ independently represents halogen, -CN, -OH, C １－６ alkyl, C １－６ Haloalkyl, C １－６ Hydroxylalkyl, C １－６ Alkoxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH optionally substituted with 1 to 3 deuteriums ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ 、-C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-SO ２ R ＊ 、 -(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、 -P(O)R ＊ R ＊ 、-(CH ２ ) ０若しくは１ - a 3- to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ - a 3- to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ - a 6- to 10-membered aryl, or -(CH ２ ) ０若しくは１ - selected from a 5- to 10-membered heteroaryl, and the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ａ is optionally substituted by one or two groups selected from 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 is independently 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, -(CH optionally substituted with 1 to 3 deuteriums ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ 、-C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-SO ２ R ＊ 、 -(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、 -P(O)R ＊ R ＊ 、 -(CH ２ ) ０若しくは１ - a 3- to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ - a 3- to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ - a 6- to 10-membered aryl, or -(CH ２ ) ０若しくは１ - a 5- to 10-membered heteroaryl, wherein the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ｂ is optionally substituted by one or two groups selected from CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and C １－６ haloalkoxy, and / or Two Rs Ｂ together with the ring B atoms to which they are attached form a 5- to 7-membered monocyclic ring or a 6- to 9-membered bicyclic ring fused to ring B, and the 5- to 7-membered monocyclic ring or 6- to 9-membered bicyclic ring is CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ optionally substituted with one or two groups selected from haloalkoxy and C3-C6 cycloalkyl, Each R Ｃ and R Ｄ is independently selected from hydrogen, deuterium, F, and methyl, Each R ＊ is 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- to 6-membered carbocyclic, or 4- to 6-membered heterocyclic m is 0, 1, 2, 3, or 4, the compound, its pharmaceutically acceptable salt, or its tautomer.

2. Each R １ 、R ２ 、R ３ 、R ４ 、and R ５ is, independently, H, halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, C １－６ hydroxyalkyl, C ２－６ alkenyl, C ２－６ alkynyl, -(CH optionally substituted with 1 to 3 deuteriums ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ 、-C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-SO ２ R ＊ 、 -(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、 -P(O)R ＊ R ＊ 、-(CH ２ ) ０若しくは１ -3 to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ -3 to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ -5 to 10-membered heteroaryl, wherein the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R １ 、R ２ 、R ３ 、R ４ 、or R ５ is optionally substituted by one or two groups selected from CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and C １－６ haloalkoxy, Each R Ａ is independently H, halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, C １－６ hydroxyalkyl, C ２－６ alkenyl, C ２－６ alkynyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ 、-C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-SO ２ R ＊ 、-(CH ２ ) ０－４ NR ＊ R ＊ 、 -NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、-P(O)R ＊ R ＊ 、 -(CH ２ ) ０若しくは１ -3 to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ -3 to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ -5 to 10-membered heteroaryl, and the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ａ is CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and C １－６ optionally substituted by one or two groups selected from haloalkoxy, Each R Ｂ independently represents halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, C １－６ hydroxyalkyl, C ２－６ alkenyl, C ２－６ alkynyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -SO ２ R ＊ , -(CH ２ ) ０－４ NR ＊ R ＊ , -NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、-P(O)R ＊ R ＊ 、 -(CH ２ ) ０若しくは１ - a 3- to 12-membered carbocyclic ring, -(CH ２ ) ０若しくは１ - a 3- to 12-membered heterocyclic ring, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ -selected from 5 to 10-membered heteroaryl, and the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ｂ is CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and C １－６ optionally substituted by one or two groups selected from haloalkoxy, or Two Rs Ｂ together with the ring B atoms to which they are attached forming a 5- or 6-membered ring fused to ring B, wherein the 5- or 6-membered ring is CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, and C １－６ optionally substituted with one or two groups selected from haloalkoxy, Each R Ｃ and R Ｄ is independently selected from hydrogen, F, and methyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

4. The compound according to claim 2, wherein the compound is represented by 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): 【Chemical Formula 3-1】 [Chemical Formula 3-2] or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2, wherein the compound is represented by formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), or formula (III-C-3): 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof.

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

7. Ring B is phenyl optionally substituted by one or two Rs Ｂ where each R Ｂ is independently halogen, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl C １－６ hydroxyalkyl, C ２－６ alkenyl, C ２－６ alkynyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-OR ＊ 、-SO ２ R ＊ 、-(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、 -NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、-P(O)R ＊ R ＊ 、-(CH ２ ) ０若しくは１ -3 to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ -3 to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ -5 to 10-membered heteroaryl, wherein the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ｂ is optionally substituted by one or two halogens or C １－６ alkyl, the compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof.

8. Ring B is a 5- or 6-membered monocyclic heteroaryl optionally substituted by one or two Rs Ｂ where each R Ｂ is independently halogen, -CN, -OH, C １－６ alkyl C １－６ haloalkyl, C １－６ hydroxyalkyl, C ２－６ alkenyl, C ２－６ alkynyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -OR ＊ , -SO ２ R ＊ , -(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、 -P(O)R ＊ R ＊ 、-(CH ２ ) ０若しくは１ -3 to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ -3 to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ -5 to 10-membered heteroaryl, wherein the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ｂ is optionally substituted by one or two halogens or C １－６ alkyl, the compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof.

9. Ring B is phenyl or a 5- or 6-membered monocyclic heteroaryl, each of which is optionally substituted by 1 to 4 Rs Ｂ and two Rs Ｂ together with the ring B atom to which they are attached form a 5- or 6-membered ring fused to ring B, and said 5- or 6-membered fused ring is one or two CN, halogen, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, or C １－４ a compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with haloalkoxy.

10. Ring B is pyrazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, phenyl, pyridyl, pyrimidyl, 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 compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof.

11. Each R １ is independently H, halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, -(CH ２ ) ０－４ C １－４ alkoxy, C １－４ haloalkoxy, C １－４ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -(CH ２ ) ０－４ NR ＊ R ＊ , -NR ＊ C(O)R ＊ , and -NR ＊ C(O)OR ＊ The compound according to any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, selected from

12. Each R ２ is independently H, halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, -(CH ２ ) ０－４ C １－４ alkoxy, C １－４ haloalkoxy, C １－４ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -(CH ２ ) ０－４ NR ＊ R ＊ , -NR ＊ C(O)R ＊ , and -NR ＊ C(O)OR ＊ The compound according to any one of claims 2 to 11, or a pharmaceutically acceptable salt thereof, selected from

13. Each R ３ is independently H, halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－２ C １－４ alkoxy, C １－４ haloalkoxy, C １－４ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -(CH ２ ) ０－４ N.R. ＊ R ＊ , -NR ＊ C(O)R ＊ , and -NR ＊ C(O)OR ＊ 13. The compound according to any one of claims 2 to 12, or a pharma- ceutically acceptable salt thereof, selected from:

14. Each R ４ is independently H, halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, -(CH ２ ) ０－４ C １－４ alkoxy, C １－４ haloalkoxy, C １－４ Hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -(CH ２ ) ０－４ N.R. ＊ R ＊ , -NR ＊ C(O)R ＊ , and -NR ＊ C(O)OR ＊ 14. The compound according to any one of claims 2 to 13, or a pharma- ceutically acceptable salt thereof, selected from:

15. Each R ５ is independently H, halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, -(CH ２ ) ０－４ C １－４ alkoxy, C １－４ haloalkoxy, 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 ＊ The compound according to any one of claims 2 to 14, or a pharmaceutically acceptable salt thereof, selected from

16. Each R Ａ is independently H, halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, C optionally substituted with 1 to 3 deuteriums １－４ alkoxy, C １－４ haloalkoxy, C １－４ hydroxyalkoxy, -C(O)R ＊ -C(O)OR ＊ , -C(O)NR ＊ R ＊ , -(CH ２ ) ０－４ N.R. ＊ R ＊ , -NR ＊ C(O)R ＊ , and -NR ＊ C(O)OR ＊ 16. The compound according to any one of claims 2 to 15, or a pharma- ceutically acceptable salt thereof, selected from:

17. Each R Ｂ is independently halogen, -CN, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ hydroxyalkyl, optionally substituted with 1 to 3 deuteriums - (CH ２ ) ０－２ C １－４ alkoxy, C １－４ haloalkoxy, C １－４ hydroxyalkoxy, -C(O)R ＊ , -C(O)OR ＊ , -C(O)NR ＊ R ＊ 、-(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、and -(CH ２ ) ０又は１ - optionally substituted with one or two halogens and selected from 3- to 6-membered cycloalkyl, a compound according to any one of claims 2 to 16, or a pharmaceutically acceptable salt thereof.

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

19. Each R １ is independently 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 is independently H, halogen, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, and C １－４ The compound according to any one of claims 2 to 18, or a pharmaceutically acceptable salt thereof, selected from haloalkoxy (preferably H).

20. Each R ３ is independently H, halogen, C １－４ alkyl, C １－４ Haloalkyl, C optionally substituted with 1 to 3 deuteriums １－４ Alkoxy, and C １－４ haloalkoxy (preferably H, CN, halogen, C １－４ alkyl, or C optionally substituted with 1 to 3 deuteriums １－４ alkoxy), a compound according to any one of claims 2 to 19, or a pharmaceutically acceptable salt thereof.

21. Each R ４ is independently 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), the compound according to any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof.

22. Each R ５ is independently H, halogen, C １－４ alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ Haloalkoxy (preferably H), the compound according to any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof.

23. Each R Ａ is independently H, C １－２ alkyl, or C optionally substituted with 1 to 3 deuteriums １－２ alkoxy (preferably H, -OCH ３ , or -OCD ３ ), the compound according to any one of claims 2 to 22, or a pharmaceutically acceptable salt thereof.

24. Each R Ｂ independently represents halogen, -OH, C １－３ alkyl, C １－３ haloalkyl, optionally substituted with 1 to 3 deuteriums, -(CH ２ ) ０－２ C １－２ alkoxy, C １－２ haloalkoxy, -(CH ２ ) ０－２ NR ＊ R ＊ , or 3- to 6-membered cycloalkyl optionally substituted with one or two halogens (preferably F, Cl, -OH, -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CHF ２ , -CF ３ , -CH ２ N(CH ３ ) ２ , -CH ２ OCH ３ , -OCH ３ , -OCHF ２ , -OCD ３ , cyclopropyl optionally substituted with one or two fluoros), a compound according to any one of claims 2 to 23, or a pharmaceutically acceptable salt thereof.

25. 【Fig. 6】 is 【Chemical Formula 7】 the compound according to any one of claims 2 to 24, its pharmaceutically acceptable salt.

26. The compound according to claim 26, wherein the compound is represented by formula (IV-A-1): 【Chemical Formula 8】 The compound according to any one of claims 2, 13, 14, 16 to 18, 20, 21, 23, and 24, represented by, or a pharmaceutically acceptable salt thereof.

27. The compound, wherein the compound is of formula (IV-A-2): 【Chemical Formula 9】 The compound according to any one of claims 2, 13, 14, 16 to 18, 20, 21, 23, and 24, represented by, or a pharmaceutically acceptable salt thereof.

28. Each R ３ is independently H, halogen, -CN, C optionally substituted with 1 to 3 deuteriums １－６ alkyl C １－６ haloalkyl, C １－６ hydroxyalkyl, -C optionally substituted with 1 to 3 deuteriums １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ 、-C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、 -NR ＊ R ＊ , selected from 3- to 6-membered carbocyclyl, 3- to 6-membered monocyclic heterocyclyl, 7- to 10-membered bridged heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, phenyl, or heteroaryl of the group represented by R ３ 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, a compound, pharmaceutically acceptable salt, or tautomer thereof according to any one of claims 1 to 12, 14 to 19, and 21 to 27.

29. Each R ３ is independently H, halogen, CN, C optionally substituted with 1 to 3 deuteriums １－４ alkyl, C optionally substituted with 1 to 3 deuteriums １－４ alkoxy, NR ＊ R ＊ , -C(O)NR ＊ R ＊ , 3- to 6-membered cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, 5- to 6-membered heteroaryl, or Selected from 6-oxa-3-azabicyclo[3.1.1]heptanyl, R ３ wherein said cycloalkyl, heterocyclyl, or heteroaryl of said group represented by R is optionally substituted by one or two halogens, C １－２ alkyl, C １－２ haloalkyl, C １－２ alkoxy, or C １－２ The compound, pharmaceutically acceptable salt, or tautomer thereof according to claim 28, which is optionally substituted by haloalkoxy.

30. Each R ３ is independently H, F, Cl, CN, CH ３ , OCH ３ , OCD ３ , -N(CH ３ ) ２ 、-CON(CH ３ ) ２ 、cyclopropyl, azetidinyl optionally substituted with one or two fluoro or OCH ３ , imidazole optionally substituted with CH ３ , morpholinyl, pyridyl, piperazinyl optionally substituted with CH ３ , pyrrolidinyl optionally substituted with OCH ３ , pyrazolyl optionally substituted with CH ３ , thiazole optionally substituted with CH ３ , or 6-oxa-3-azabicyclo[3.1.1]heptanyl, the compound, pharmaceutically acceptable salt, or tautomer thereof according to claim 29.

31. Each R ３ is independently selected from H or OCH ３ and the compound, pharmaceutically acceptable salt, or tautomer thereof according to claim 30

32. Ring B is a 5- or 6-membered monocyclic heteroaryl optionally substituted by phenyl, one or two Rs Ｂ wherein each R Ｂ is independently halogen, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxyalkyl C optionally substituted with 1 to 3 deuteriums １－４ alkoxy, C １－４ haloalkoxy, -C(O)NR ＊ R ＊ 、-(CH ２ ) ０－１ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、- a 3- to 6-membered monocyclic carbocyclic, - a 3- to 6-membered monocyclic heterocyclic, and the carbocyclic or heterocyclic of the group represented by R Ｂ is one or two halogens or C １－４ The compound, pharmaceutically acceptable salt, or tautomer thereof according to any one of claims 1 to 6, 11 to 25, and 28 to 31, optionally substituted by alkyl.

33. Each R Ｂ independently is F, Cl, -OH, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxyalkyl, C optionally substituted with 1 to 3 deuteriums １－４ alkoxy, C １－４ haloalkoxy, -C(O)NR ＊ R ＊ , -CH ２ NR ＊ R ＊ , -NR ＊ C(O)R ＊ , -3- to 5-membered monocyclic cycloalkyl, -3- to 5-membered monocyclic heterocyclyl, wherein the cycloalkyl or heterocyclyl of the group represented by R Ｂ is optionally substituted by one or two F or C １－２ alkyl, the compound, pharmaceutically acceptable salt, or tautomer thereof according to claim 32.

34. Ring B is phenyl or a 5- or 6-membered monocyclic heteroaryl, each of which is optionally substituted by 1 to 4 R Ｂ and two R Ｂ together with the ring B atom to which they are attached form a 5- to 7-membered monocyclic ring or a 6- to 9-membered bicyclic ring fused to ring B, and the 5- to 7-membered monocyclic ring or 6- to 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 haloalkoxy, or 3- to 6-membered cycloalkyl, a compound, pharmaceutically acceptable salt, or tautomer thereof according to any one of claims 1 to 6, 11 to 25, and 28 to 31.

35. Two Rs Ｂ together with the ring B atoms to which they are attached 【Chemical 10】 form a ring selected from, each of which is halogen, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, and C １－４ The compound, pharmaceutically acceptable salt, or tautomer thereof according to claim 34, optionally substituted with one or two groups selected from haloalkoxy.

36. Two Rs Ｂ together with the ring B atoms to which they are attached 【Chemical Formula 11】 The compound, pharmaceutically acceptable salt, or tautomer thereof according to claim 35, which forms a ring selected from:

37. R Ｃ is H, and R Ｄ is H, the compound, pharmaceutically acceptable salt, or tautomer thereof according to any one of claims 1 to 36.

38. R Ｃ is H, F, or deuterium, and R Ｄ is H or deuterium, the compound, pharmaceutically acceptable salt, or tautomer thereof according to any one of claims 1, 3 to 25, and 28 to 36.

39. A compound represented by formula (I'): 【Chemical 12】 Or a pharmaceutically acceptable salt thereof, wherein Ring A1 is a 5,6- or 6,6-membered nitrogen-containing bicyclic heteroaryl, Ring B1 is a 3- to 6-membered monocyclic carbocyclic or 3- to 6-membered monocyclic heterocyclic ring, Each R Ａ１ is independently halogen, -CN, -OH, C １－６ alkyl, C １－６ Haloalkyl, C １－６ Hydroxylalkyl, C １－６ Alkoxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -(CH optionally substituted with 1 to 3 deuteriums ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ -C(O)OR ＊ -C(O)NR ＊ R ＊ -SO ２ R ＊ and -(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、 -P(O)R ＊ R ＊ ,-(CH ２ ) ０若しくは１ -a 3- to 12-membered carbocyclic,-(CH ２ ) ０若しくは１ -a 3- to 12-membered heterocyclic,-(CH ２ ) ０若しくは１ -a 6- to 10-membered aryl, or-(CH ２ ) ０若しくは１ -a 5- to 10-membered heteroaryl, wherein the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ａ１ is substituted with one or two CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ optionally substituted by haloalkoxy, Each R Ｂ１ independently represents 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, -(CH optionally substituted with 1 to 3 deuteriums ２ ) ０－４ C １－６ alkoxy, C １－６ haloalkoxy, C １－６ hydroxyalkoxy, -C(O)R ＊ 、-C(O)OR ＊ 、-C(O)NR ＊ R ＊ 、-SO ２ R ＊ 、 -(CH ２ ) ０－４ NR ＊ R ＊ 、-NR ＊ C(O)R ＊ 、-NR ＊ C(O)OR ＊ 、-NR ＊ SO ２ R ＊ 、-NR ＊ SO ２ NR ＊ R ＊ 、 -P(O)R ＊ R ＊ ,-(CH ２ ) ０若しくは１ -3 to 12-membered carbocyclic, -(CH ２ ) ０若しくは１ -3 to 12-membered heterocyclic, -(CH ２ ) ０若しくは１ -6 to 10-membered aryl, or -(CH ２ ) ０若しくは１ -5 to 10-membered heteroaryl, and the carbocyclic, heterocyclic, aryl, or heteroaryl of the group represented by R Ｂ１ is one or two CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ optionally substituted by haloalkoxy, and / or Two Rs Ｂ１ together with the ring B1 atoms to which they are attached forms a 5- or 6-membered monocyclic ring or a 6- to 9-membered bicyclic ring fused to ring B1, wherein the 5- or 6-membered ring or 6- to 9-membered bicyclic ring is optionally substituted with one or two CN, halogen, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, or 3- to 6-membered cycloalkyl, Each R ＊ is 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- to 6-membered carbocyclic, or 4- to 6-membered heterocyclic m1 is 0, 1, 2, 3, or 4, n1 is 0, 1, 2, or 3, the compound, or a pharmaceutically acceptable salt thereof.

40. 【Figure 13】 is 【Chemical 14】 where wherein 【Chemical Formula 15】 represents the point where -CH ２ - is attached, 【Chemical 16】 represents the point to which ring B1 is attached, and R Ａ１ is C １－４ alkyl or C １－４ alkoxy, the compound according to claim 39, or a pharmaceutically acceptable salt thereof.

41. Ring B1 is 【Chemical 17】 where R Ｂ１ is C １－４ alkyl or C １－４ alkoxy, and n1 is 0 or 1, the compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof.

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

43. A pharmaceutical composition comprising the 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 by CSF-1R or at least partially mediated by CSF-1R in a subject, the method comprising administering to the subject in need thereof an effective amount of the compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

45. The method according to 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 autoimmune disease or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, 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, ischemic reperfusion injury of parenchymal organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and chemotherapy drug-induced organ injury, 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 ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary motor and sensory neuropathy (CMT), The cancer is a solid tumor or 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, renal cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, leukemia, lymphoma, or myeloma, the method according to claim 45.

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

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

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

50. A method for treating a disease or disorder accompanied by microglia-mediated inflammation in a subject, comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

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

52. Use according to 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 autoimmune disease or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, 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, ischemic reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and chemotherapy drug-induced organ injury. 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 ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and Charcot-Marie-Tooth disease (CMT). The cancer is a solid tumor or 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 cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, leukemia, lymphoma, or myeloma. Use according to claim 52.

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

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

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

57. Use of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder associated with microglia-mediated inflammation in a subject.

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