Phenylpiperazine derivative

Abstract

The present invention provides a compound having an activation inhibitory effect on a STING pathway. Specifically, the present invention provides a phenylpiperazine derivative represented by formula (I) (in the formula, A, R1 to R8, and Q are as in the specification) or a salt thereof.

Description

Phenylpiperazine derivatives

[0001] The present invention relates to a pharmaceutical agent, particularly to a phenylpiperazine derivative or a salt thereof that has an inhibitory effect on the activation of the STING pathway.

[0002] STING (STimulator of Interferon Genes) plays an important role in the host defense mechanism as a molecule that induces innate immune responses against various RNA and DNA virus infections. STING binds to ligands such as cyclic GMP-AMP (cGAMP), a cyclic dinucleotide produced by cyclic GMP-AMP synthase (cGAS), to activate TANK-binding kinase 1 (TBK1), which then induces type I IFN production via the transcription factor IRF3 (Non-Patent Document 1). Recently, it has been reported that STING is also activated by tumor-derived self-DNA and mitochondrial DNA, inducing a pro-inflammatory response. Therefore, STING has attracted attention as a drug discovery target for cancer and autoimmune diseases (Non-Patent Document 2). Human STING is encoded by a gene called Tmem173. Mutations in this gene have been reported to cause an autoinflammatory disease called STING-Associated Vasculopathy with Onset in Infancy (SAVI). In SAVI patients, STING is constitutively activated due to mutations, leading to excessive inflammation, resulting in abnormal antibody production and tissue damage in the skin and lungs (Non-Patent Document 3). Activating mutations in STING have also been reported in patients with familial lupus nigricans and familial lupus-like syndrome, which are autoinflammatory genetic diseases (Non-Patent Document 4).

[0003] Furthermore, it is known that accumulation of self-DNA in cells due to incomplete DNA degradation leads to constitutive activation of the STING pathway, resulting in autoimmune diseases. Aicardi-Goutières syndrome (AGS) is considered to be one such disease, and it has been reported that the deficiency of STING in this disease model mouse suppresses symptoms (Non-Patent Document 5). In systemic lupus erythematosus (SLE), autoantibodies called antinuclear antibodies, particularly anti-DNA antibodies, are excessively produced, which is thought to cause an excessive immune response. However, it has recently been revealed that activation of the STING pathway induces interferon production, which is important for the pathology of SLE. Specifically, it has been reported that cGAMP contained in the peripheral blood of patients correlates with the pathological score, and that interferon induction by cGAMP in patient serum is suppressed in cells lacking STING (Non-patent Documents 6 and 7).

[0004] Since STING is involved in various immune responses in the body, it has also been reported that STING is involved in many diseases. For example, in studies of sepsis, in which organ damage occurs due to systemic inflammation caused by pathogen infection, it has been reported that deficiency of STING in sepsis model mice alleviates symptoms (Non-Patent Documents 8 and 9). Furthermore, studies using model mice have also revealed the involvement of STING in inflammatory diseases such as non-alcoholic steatohepatitis (NASH) (metabolic disorder-associated steatohepatitis (MASH)), liver fibrosis, acute pancreatitis, and polyarthritis (Non-Patent Documents 10, 11, 12, and 13). Furthermore, it has been revealed that patients with Parkinson's disease, a neurodegenerative disease, have increased inflammatory cytokines due to disruption of mitochondrial homeostasis, and it has been reported that deficiency of STING in model mice improves these abnormalities (Non-Patent Documents 14 and 15).

[0005] It has been reported that STING agonists (activators of the STING pathway) act on immune cells to activate cancer immunity and exhibit antitumor effects. However, recently, it has been revealed that activation of the STING pathway in cancer cells is involved in cancer metastasis, and it has been reported that STING antagonists, which have the opposite effect to agonists, can also be expected to have antitumor effects (Non-Patent Document 16). Therefore, STING pathway activation inhibitors are useful for the treatment of various inflammatory diseases, immune diseases, cancer diseases, etc. in which the STING pathway is involved.

[0006] Patent Document 1 discloses that a compound represented by the following formula inhibits the cGAS / STING signaling pathway, but does not disclose the heteroaryl-substituted phenylpiperazine derivative of the present invention (see Patent Document 1 for the symbols in the formula).

[0007] WO2023 / 174383 publication

[0008] Paludan, S. R. and Bowie, A. G. , Immunity, 2013, 38(5), 870-880 Motwani M. , et al. , Nat. Rev. Genet. , 2019, 20(11), 657-674 Liu, Y. et al. ,N. Engl. J. Med. , 2014, 371(6), 507-518 Jeremiah, N. , et al. , J. Clin. Invest. , 2014, 124(12), 5516-5520 Mackenzie, K. J. , et al. , ENBO J. , 2016, 35(8), 831-844 An, J. , et al. , Arthritis Rheumatol. , 2017, 69(4), 800-807 Kato, Y. , et al. , Ann. Rheum. Dis. , 2018, 77(10), 1507-1515 Zeng, L. , et al. , Sci. Transl. Med. ,2017,9(412)

[0009] Hu, Q. , et al. , EBioMedicine, 2019, 41, 497-508 Yu, Y. , et al. , J. Clin. Invest. , 2019, 129(2), 546-555 Iracheta-Vellve, A. , et al. , J. Biol. Chem. , 2016, 291(52), 26794-26805 Maekawa, H. , et al. , Cell Rep. , 2019, 29(5), 1261-1273. e6Ahn, J. , et al. , Proc. Natl. Acad. Sci. U. S. A. 2012, 109(47), 19386-19391Andrea, A. and Chen, Z. J. , Science, 2019, 363 (6431) Sliter, D. A. , et al. , Nature, 2018, 561 (7722), 258-262 Vashi, N. , Bakhoum, S. F. , Trends Biochem. Sci. , 2021, 46(6), 446-460

[0010] Research and development is underway into pharmaceuticals that inhibit the activation of the STING pathway, but no compounds have yet been officially approved as pharmaceuticals. Therefore, the challenge is to provide STING inhibitors that are useful as pharmaceuticals for inflammatory diseases, immune disorders, cancer, and other diseases.

[0011] The present invention has been achieved by the following (1) to (17): (1) A compound represented by the following formula (I): (In the formula, A represents a heteroaryl group which may have a substituent, and Q represents a structure selected from the following structures (a) to (c): R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a nitro group, or a halogen atom; R ５ , R ６ , R ７ and R ８ each independently represents a hydrogen atom, a cyano group, or a halogen atom; R ９ and R １０each independently represents a hydrogen atom or an alkyl group which may have a substituent; m, n, p, and q each independently represent an integer of 1 or 2; R １ and R ２ , R ２ and R ３ , R ３ and R ４ , or R ９ and R １０ may be bonded to each other to form a ring.) or a salt thereof, (2) the compound of the above (1) or a salt thereof, wherein A is a 6-membered heteroaryl group which may have a substituent, (3) the compound of the above (1) or a salt thereof, wherein A is a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyridazinyl group which may have a substituent, or a pyrazinyl group which may have a substituent, (4) R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom or a halogen atom, (5) the compound of (1) above, wherein Q has the structure (a), or a salt thereof; (6) the compound of (5) above, wherein A is an optionally substituted 6-membered heteroaryl group, or a salt thereof; (7) the compound of (5) above, wherein A is an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, or an optionally substituted pyrazinyl group, or a salt thereof; (8) the compound of (5) above, wherein R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom or a halogen atom, (9) a compound or a salt thereof according to any one of the above (5) to (7), (wherein A represents an optionally substituted heteroaryl group, R １ , R ２ , R ３ and R ４each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a nitro group, or a halogen atom; R １ and R ２ , R ２ and R ３ or R ３ and R ４ may be bonded to each other to form a ring.) or a salt thereof, (10) the compound of (9) above, wherein A is a 6-membered heteroaryl group which may have a substituent, or a salt thereof, (11) the compound of (9) above, wherein A is a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyridazinyl group which may have a substituent, or a pyrazinyl group which may have a substituent, or a salt thereof, (12) R １ , R ２ , R ３ and R ４are each independently a hydrogen atom or a halogen atom; (13) A compound according to any one of (1) to (12) above, or a salt thereof, selected from the group consisting of the following compounds: N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-[4-(pyridin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide;N-(5-chloro-1H-indol-3-yl)-4-[4-(pyrimidin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridazin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridazin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridazin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyrimidin-5-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyridin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyrazin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(4-fluoro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyrimidin-5-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(6-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide;4-{4-[(6-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(3-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(6-methoxypyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methoxypyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methoxypyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(4-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5,6-dimethylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3,6-dimethylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3,5-dimethylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide;N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2,4-dimethylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-ethylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(4-ethylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(4-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(2-cyanopyrimidin-5-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-cyanopyridin-3-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(hydroxymethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(7-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide;N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(fluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(difluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(6-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-cyano-6-methylpyridin-3-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-(4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(4,5-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide;N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,6-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(6,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(4,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide;4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-ethynylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-{4-[(1-methyl-1H-imidazol-2-yl)oxy]phenyl}piperazine-1-carboxamide; 5-(4-{4-[(5,7-difluoro-1H-indol-3-yl)carbamoyl]piperazin-1-yl}phenoxy)pyrimidine-2-carboxylate methyl; 5-(4-{4-[(5,7-difluoro-1H-indol-3-yl)carbamoyl]piperazin-1-yl}phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; methyl 5-(4-{4-[(5,7-difluoro-1H-indol-3-yl)carbamoyl]piperazin-1-yl}phenoxy)pyrimidine-4-carboxylate; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; 4-{3-cyano-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{3-fluoro-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide;N-(5,7-difluoro-1H-indol-3-yl)-4-{2-fluoro-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{2-cyano-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-7-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-7-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; N-(5-chloro-1H-indol-3-yl)-7-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-7-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; (R)-N-(5,7-difluoro-1H-indol-3-yl)-3-methyl-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-8-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-2,8-diazaspiro[4.5]decane-2-carboxamide; (3aR,6aS)-N-(5,7-difluoro-1H-indol-3-yl)-5-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-6-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-2,6-diazaspiro[3.3]heptane-2-carboxamide;N-(5,7-difluoro-1H-indol-3-yl)-2-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-2,8-diazaspiro[4.5]decane-8-carboxamide; N-(3H-benzo[e]indol-1-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-ethyl-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-methyl-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5-nitro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-dimethyl-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; and 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5-vinyl-1H-indol-3-yl)piperazine-1-carboxamide, (14) N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide or a salt thereof, (15) (16) N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide or a salt thereof, (17) a prophylactic or therapeutic agent for systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjogren's syndrome (SS), metabolic steatohepatitis (MASH), nephritis, age-related macular degeneration (AMD), aging-related neurodegenerative diseases, and / or other STING-related diseases, comprising the compound according to any one of (1) to (16) above or a salt thereof;

[0012] The compounds provided by the present invention are useful as pharmaceuticals (pharmaceutical compositions) for preventing or treating diseases known to be associated with STING-mediated cellular responses, such as inflammatory diseases, autoimmune diseases, or cancer. Furthermore, by combining them with other therapeutic agents for inflammatory diseases, autoimmune diseases, or cancer, they are expected to be effective against immune responses, making them useful as therapeutic pharmaceuticals (pharmaceutical compositions). Furthermore, they are useful as STING inhibitors and as reagents for experiments and research.

[0013] The present invention will be described in detail below.

[0014] The following terms in this specification have the following meanings unless otherwise specified. The following descriptions are intended to clarify the defined terms, but are not intended to be limiting. Unless a term used in this specification is specifically defined, it is used with a meaning that would be understood by a person skilled in the art. Unless otherwise specified, a "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom. In one embodiment, it is a fluorine atom. In another embodiment, it is a chlorine atom. In yet another embodiment, it is a fluorine atom or a chlorine atom.

[0015] Unless otherwise specified, the term "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (C １－６ Specific examples of the "alkenyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group. Unless otherwise specified, the term "alkenyl group" refers to a linear or branched unsaturated hydrocarbon group having 1 to 6 carbon atoms (C ２－６ Specific examples of the "alkynyl group" include an ethenyl group, a propenyl group, a butenyl group, a butadienyl group, a pentenyl group, a pentadienyl group, a hexenyl group, and a hexadienyl group. Unless otherwise specified, the term "alkynyl group" refers to a linear or branched unsaturated hydrocarbon group having 1 to 6 carbon atoms (C ２－６Specific examples of the "alkynyl group" include an ethynyl group, a propynyl group, a butynyl group, a butadiynyl group, a pentynyl group, a pentadiynyl group, a hexynyl group, and a hexadiynyl group. Unless otherwise specified, the term "alkoxy group" refers to a linear or branched alkyloxy group (C １－６ Specific examples of the alkoxy group include a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, an n-pentyloxy group, and an n-hexyloxy group.

[0016] The term "heteroaryl" refers to, for example, a 5- to 14-membered group derived from a monocyclic or bicyclic aromatic compound containing, in addition to carbon, one or four atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, benzimidazolyl, benzothiophenyl, and benzothiadiazolyl. Monocyclic heteroaryl groups are preferred, and in one embodiment, they are 5- or 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms, with 6-membered heteroaryl being preferred. In other embodiments, examples include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group.

[0017] The term "protecting group" refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group can be removed at an appropriate position. Specific examples include an amino-protecting group, a carboxy-protecting group, and a hydroxy-protecting group. More specific examples include a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz) group, a fluorenylmethoxycarbonyl (Fmoc) group, a trifluoroacetyl group, and a benzyl (Bn) group.

[0018] 1. A A represents a heteroaryl group which may have a substituent. The heteroaryl group portion of the heteroaryl group which may have a substituent is preferably a 5- or 6-membered heteroaryl cyclic group containing 1 to 3 nitrogen atoms, and examples thereof include a pyrazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group. In one embodiment, examples thereof include a 6-membered heteroaryl group such as a pyridyl group, a pyrazinyl group, a pyrimidinyl group, and a pyridazinyl group. The substituent of the heteroaryl group which may have a substituent is not particularly limited, and may have one or more substituents of any type at any chemically possible position at any substitutable position, unless otherwise specified. When there are two or more substituents, the respective substituents may be the same or different. Specific examples of the substituent of the heteroaryl group include a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an alkoxy group which may have a substituent, a cyano group, an amino group which may have a substituent, an alkoxycarbonyl group which may have a substituent, a carbamoyl group which may have a substituent, a heterocyclic group, etc. More specific examples of the substituent of the heteroaryl group include a halogen atom, a C group which may be substituted with a halogen atom or a hydroxy group, １－６ C optionally substituted with an alkyl group, a halogen atom or a hydroxy group ２－６ C optionally substituted with an alkenyl group, a halogen atom or a hydroxy group ２－６ C optionally substituted with an alkynyl group, a halogen atom or a hydroxy group １－６ Alkoxy group, cyano group, C １－６ an amino group optionally substituted with an alkyl group, C １－６ an alkoxycarbonyl group optionally substituted by an alkyl group, C １－６ A carbamoyl group which may be substituted with an alkyl group, and a 5- or 6-membered heterocyclic group containing 1 or 2 oxygen atoms are preferred, and examples thereof include a tetrahydrofuranyl group and a tetrahydropyranyl group.

[0019] The above "C optionally substituted with a halogen atom or a hydroxy group" １－６ Specific examples of the "alkyl group" include the above-mentioned "C １－６ a group in which 1 to 3 hydrogen atoms of the "alkyl group" have been substituted by the above-mentioned "halogen atoms" (for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a 2-fluoroethyl group, a 1,2-difluoropropyl group, a 2,2,2-trifluoroethyl group, etc.), or the above-mentioned "C １－６ Examples of the above-mentioned "C optionally substituted with a halogen atom or a hydroxy group" include groups in which 1 to 3 hydrogen atoms of the "alkyl group" are substituted with hydroxy groups (for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, and a 2-hydroxypropyl group). ２－６ Specific examples of the "alkenyl group" include the above-mentioned "C ２－６ alkenyl group" in which 1 to 3 hydrogen atoms are substituted by the above "halogen atoms" (for example, 3-fluoro-1-propenyl group, 4-fluoro-1-butenyl group, 4,4,4-trifluoro-1-butenyl group, etc.), or the above "C ２－６ Examples of the "alkenyl group" include groups in which 1 to 3 hydrogen atoms are substituted with hydroxy groups (for example, 1-hydroxy-2-propenyl group, 1-hydroxy-3-butenyl group, 2-hydroxy-4-pentenyl group, 1-hydroxy-4-pentenyl group, etc.). ２－６ Specific examples of the "alkynyl group" include the above-mentioned "C ２－６ a group in which 1 to 3 hydrogen atoms of the "alkynyl group" are substituted by the above-mentioned "halogen atoms" (for example, 3,3,3-trifluoro-1-propynyl group, 3-fluoro-1-propynyl group, 4-fluoro-1-butynyl group, etc.), or the above-mentioned "C ２－６ alkynyl groups in which 1 to 3 hydrogen atoms have been substituted by hydroxy groups (for example, 1-hydroxy-2-propynyl group, 2-hydroxy-3-butynyl group, 2-hydroxy-2-methyl-3-butynyl group, 1-hydroxy-3-butynyl group, etc.).

[0020] Examples of the substituents of the "optionally substituted alkyl group," "optionally substituted alkenyl group," "optionally substituted alkynyl group," and "optionally substituted alkoxy group" as substituents of the heteroaryl group include a halogen atom, a hydroxy group, a carboxy group, a formyl group, a formyloxy group, a sulfanyl group, a sulfino group, a sulfo group, a thioformyl group, a thiocarboxy group, a thiocarbamoyl group, a cyano group, a nitro group, an azido group, a hydrazino group, a ureido group, an amidino group, a guanidino group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an alkylsulfanyl group, an alkenylsulfanyl group, an alkynylsulfanyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, Examples of the substituent include an amino group, an imino group, a carbamoyl group, a sulfamoyl group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, and a non-aromatic heterocyclic group. Examples of the substituent of the "optionally substituted amino group" as a substituent of a heteroaryl group include a halogen atom, a hydroxy group, a carboxy group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an alkylsulfanyl group, an alkenylsulfanyl group, an alkynylsulfanyl group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, and an alkynylsulfonyl group.

[0021] The 6-membered heteroaryl group moiety of the optionally substituted 6-membered heteroaryl group is a 6-membered heteroaryl cyclic group containing 1 to 3 nitrogen atoms, and examples thereof include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group. The substituents of the optionally substituted 6-membered heteroaryl group are not particularly limited, and unless otherwise specified, may have one or more substituents of any type at any chemically possible substitutable position, and when there are two or more substituents, the respective substituents may be the same or different. More specific examples of the substituents of the 6-membered heteroaryl group include a chlorine atom, a fluorine atom, a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a hydroxymethyl group, an ethyl group, an ethynyl group, a methoxy group, a cyano group, a dimethylamino group, a methoxycarbonyl group, a dimethylcarbamoyl group, and a tetrahydropyranyl group.

[0022] 2. R １ , R ２ , R ３ and R ４ R １ , R ２ , R ３ and R ４ R each independently represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, a nitro group, or a halogen atom. １ and R ２ , R ２ and R ３ or R ３ and R ４ may be bonded to each other to form a ring. １ , R ２ , R ３ and R ４The substituents of the "optionally substituted alkyl group", "optionally substituted alkenyl group", and "optionally substituted alkynyl group" in R are the same as those of the "optionally substituted alkyl group", "optionally substituted alkenyl group", and "optionally substituted alkynyl group" as the substituents of the heteroaryl group. １ , R ２ , R ３ and R ４ More specifically, examples of the alkyl group include a hydrogen atom, a halogen atom (particularly a chlorine atom or a fluorine atom), and C １－４ Alkyl groups (especially methyl and ethyl groups), C １－４ Alkenyl group (especially ethenyl group), C １－４ Alkynyl group, C １－４ Examples include an alkoxy group (particularly a methoxy group) and a nitro group. １ and R ２ , R ２ and R ３ or R ３ and R ４ Specific examples of groups bonded to each other to form a ring include a phenylene group, a pyrezylene group, a pyrimidylene group, a pyridazylene group, a p-radiylene group, a pyrrolene group, and a pyrazolene group.

[0023] 3. R ５ , R ６ , R ７ and R ８ R ５ , R ６ , R ７ and R ８ R each independently represents a hydrogen atom, a halogen atom, or a cyano group. ５ , R ６ , R ７ and R ８ As the halogen atom, a chlorine atom and a fluorine atom are particularly preferred.

[0024] 4. Q Q represents a structure selected from the following structures (a) to (c). In the compound of structure (a), R ９ and R １０R each independently represents a hydrogen atom or an alkyl group which may have a substituent, and the substitution positions may be on the same carbon atom or on different carbon atoms. ９ and R １０ The alkyl group portion of the "alkyl group which may have a substituent" is a straight-chain or branched C １－６ Alkyl groups are preferred, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and an isobutyl group. ９ and R １０ Specific examples of the substituent of the "optionally substituted alkyl group" include a halogen atom, a hydroxy group, and an amino group. ９ and R １０ Specific examples of when they are bonded to each other to form a ring include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0025] In the compound of structure (b), m, n, p, and q each independently represent an integer of 1 or 2.

[0026] The compound represented by formula (I) in the present invention may have isomers depending on, for example, the type of substituent. In this specification, the chemical structure of only one form of the isomer may be described, but the present invention also includes all isomers (geometric isomers, optical isomers, tautomers, etc.) that can occur structurally, and also includes single isomers or mixtures thereof. In the present invention, "hydrogen atom" includes １ H and ２ H(D) and any one or more of the compounds represented by formula (I) １ H ２ Deuterium-converted compounds converted to H(D) are also included in the compounds represented by formula (I). For example, a methyl group -CH ３ In the case of a compound having the formula: -CD ３ Group, -CD ２ H group, or -CDH ２ Compounds having a group are also included.

[0027] Furthermore, salts of the compound represented by formula (I) in the present invention are preferably those that are not significantly toxic and can be used as pharmaceuticals, i.e., pharmaceutically acceptable salts. Examples of such salts include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid, etc.; organic acid salts with formic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, etc.; alkali metal salts with sodium or potassium, etc.; alkaline earth metal salts with magnesium or calcium, etc.; organic amine salts with lower alkylamines or lower alcoholamines, etc.; basic amino acid salts with lysine, arginine, or ornithine, etc.; and ammonium salts. Among these, salts with p-toluenesulfonic acid or benzenesulfonic acid are preferred. The compound represented by formula (I) and its salts in the present invention include both its internal salts and solvates, such as hydrates. Internal salts, also known as zwitterions, are electrically neutral molecules. Different atoms in each valence bond structure have positive and negative formal charges. Hydrates are classified according to the number of water molecules contained therein, and include, for example, monohydrates, dihydrates, trihydrates, etc. The solvent contained in the solvate may be either water or an organic solvent, and examples of the organic solvent include alcohol (e.g., methanol, ethanol, or n-propanol), acetonitrile, acetone, dimethyl sulfoxide, and dimethylformamide.

[0028] In the present invention, a STING inhibitor refers to a pharmaceutical composition that contains as an active ingredient a compound represented by formula (I) or a salt thereof that exhibits inhibitory activity against the activation of the STING pathway, and that is useful for the treatment and / or prevention of various inflammatory diseases, immune diseases, cancer diseases, and the like in which the STING pathway is involved. More specifically, inflammatory and immune diseases include autoimmune inflammatory diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjogren's syndrome (SS), metabolic disorder-associated steatohepatitis (MASH), nephritis, hepatitis, hepatic fibrosis, polyarthritis, (dry) age-related macular degeneration (AMD), aging-related neurodegenerative diseases, rheumatoid arthritis, Crohn's disease, type I diabetes, ulcerative colitis, lupus nephritis, vasculitis, polymyositis, dermatomyositis, psoriasis, endometriosis, and COPA syndrome, and rare hereditary autoimmune diseases such as Aicardi-Goutières syndrome (AGS), infantile-onset STING-associated vasculopathy (SAVI), familial chilblain lupus (FCL), and familial lupus-like syndrome. Cancer diseases include carcinomas (such as adenocarcinoma, basal cell carcinoma, and squamous cell carcinoma), lymphoma, blastoma, sarcoma, melanoma, leukemia, and lymphoid malignancies. Specific examples of these cancer diseases include gastric cancer, liver cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, lung cancer, pancreatic cancer, renal cancer, cervical cancer, endometrial cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, head and neck cancer, hepatoma, non-Hodgkin's lymphoma, multiple myeloma, myeloproliferative disorders, chronic myeloid leukemia, hematological malignancies, salivary gland cancer, thyroid cancer, esophageal cancer, anal cancer, penile cancer, pharyngeal cancer, nasopharyngeal cancer, tongue cancer, Kaposi's sarcoma, melanoma, malignant mesothelioma, skin cancer, neuroblastoma, and urinary tract cancer. Other diseases in which STING is involved include acute pancreatitis, sepsis, chronic heart failure, myocardial infarction, stroke, alcoholic liver disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0029] The production method of the compound of formula (I) of the present invention will be described using examples, but the present invention is not limited thereto. The compounds in the reaction schemes may each form a salt, and examples of such salts include the same as those of the compound of formula (I). In the production methods shown below, if the defined groups change under the conditions of the method or are unsuitable for carrying out the method, the compound can be easily produced by applying methods commonly used in organic synthetic chemistry, such as functional group protection and deprotection [T. W. Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc. 1999]. Furthermore, the order of reaction steps such as introducing substituents can be changed as necessary.

[0030] The synthesis of the phenylpiperazine derivatives disclosed in the present invention is described in detail below using general reaction schemes. The compounds of the present invention represented by formula (I) disclosed herein can be prepared by the methods described in the following schemes 1 to 11. As shown in the examples, they can also be prepared by modifying general synthetic methods and commercially available starting materials, starting materials that can be synthesized from commercially available compounds by known methods or methods analogous thereto, or methods well known to those skilled in the art. Each variable site shown in the following schemes applies to all functional groups detailed in the compounds provided in the present invention. Tautomers and solvates (e.g., hydrates) of the compounds represented by formula (I) are also included in the present invention.

[0031] The abbreviations and symbols used in the following description have the following meanings: ２O: Di-tert-butyl dicarbonate CDI: 1,1'-carbonyldiimidazole DIPEA: N,N-diisopropylethylamine THF: Tetrahydrofuran TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide Pd(OAc)2: Palladium(II) acetate BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Me4tButylXphos: Di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine Pd ２ (dba) ３ : Tris(dibenzylideneacetone)dipalladium(0) DPPA: Diphenylphosphoryl azide

[0032] [Method for Producing Compound (Ia') of the Present Invention] The compound of the present invention represented by formula (Ia') can be produced, for example, according to Scheme 1. (In the formula, A, R １ , R ２ , R ３ and R ４ are as defined above.) Compound (Ia') of the present invention can be produced by coupling a substituted phenylpiperazine (II) with an aminoindole (III). That is, compound (Ia') can be obtained by reacting aminoindole (III) with 0.5 to 5 molar equivalents, preferably 0.9 to 1.5 molar equivalents, of CDI in a solvent in the presence of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, of a base such as DIPEA, to form the corresponding urea intermediate, which can then be reacted with 0.5 to 5 molar equivalents, preferably 0.7 to 1.5 molar equivalents, of the substituted phenylpiperazine (II). Any solvent inert to the reaction can be used, such as THF, DMF, 1,4-dioxane, or toluene, with THF being preferred. The reaction can be carried out at a temperature ranging from 0°C to 100°C for a period ranging from several minutes to several days, preferably at 0°C to 50°C for 10 minutes to 24 hours. Instead of CDI, other urea-forming agents, such as chloroformate (ArOCOCl), may be used.

[0033] The compound of the present invention represented by formula (Ia') can be produced by the method shown in Scheme 1 as well as, for example, the method shown in Scheme 2 below. (In the formula, A, R １ , R ２ , R ３ and R ４ are as defined above, and Ar represents an aryl group which may have a substituent (an electron-withdrawing substituent such as a nitro group). Compound (Ia') of the present invention can be produced by coupling a substituted phenylpiperazine (II) with a carbamate (IV). That is, compound (Ia') can be obtained by reacting a substituted phenylpiperazine (II) with 0.5 to 3 molar equivalents, preferably 0.7 to 1.5 molar equivalents, of a carbamate (IV) in a solvent. Any solvent inert to the reaction can be used, such as THF, DMF, 1,4-dioxane, or toluene, with DMF being preferred. The reaction can be carried out at a temperature ranging from 0°C to 100°C for a period ranging from several minutes to several days, preferably at room temperature to 80°C for 10 minutes to 24 hours. In this reaction, to improve the reactivity with the substituted phenylpiperazine (II), a carbamate (IV) having a substituent on Ar can be used as appropriate.

[0034] The substituted phenylpiperazine (II) used as a starting material in Scheme 1 and Scheme 2 can be produced, for example, by the method shown in Scheme 3. (In the formula, A is as defined above, X represents a halogen atom, and PG represents a protecting group.) Substituted phenylpiperazine (II) can be produced by a cross-coupling reaction such as a Buchwald / Hartwig reaction using compound (V) and compound (VI), followed by deprotection of the protecting group PG. The coupling reaction can be carried out in a solvent in the presence of a metal catalyst such as palladium, optionally with the use of additives such as a base and a ligand. The solvent may be any solvent inert to the reaction, but is not particularly limited. Preferably, toluene, THF, or 1,4-dioxane is used, and more preferably, toluene. As the metal catalyst, a commercially available palladium catalyst (e.g., Pd(OAc)2) used in cross-coupling reactions can be used. A catalytic amount, i.e., 0.01 to 0.5 molar equivalents, and more preferably, 0.05 to 0.2 molar equivalents, relative to compound (VI) can be added. Examples of bases include tripotassium phosphate and potassium carbonate. The base can be added in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to the halogen source. As a ligand for the metal catalyst, for example, BINAP or Me4tButylXphos is preferably added in a catalytic amount, i.e., 0.02 to 0.5 molar equivalents, more preferably 0.05 to 0.3 molar equivalents. The reaction can be carried out at temperatures ranging from 0°C to 150°C for several minutes to 24 hours, but preferably at 100°C to 120°C for 30 minutes to 16 hours. After the cross-coupling reaction, PG can be deprotected using conditions commonly used in organic synthetic chemistry to obtain the substituted phenylpiperazine (II). In the reaction between compound (V) and compound (VI), if the halogen atom X in compound (V) is highly reactive, an aromatic nucleophilic substitution reaction can also be carried out instead of the cross-coupling reaction. Compound (V) and compound (VI) used as starting materials in Scheme 3 are commercially available or can be produced by known methods or methods analogous thereto.

[0035] The substituted phenylpiperazine (II) used as a starting material in Scheme 1 and Scheme 2 can also be produced by the method shown in Scheme 4, for example. (In the formula, A has the same meaning as defined above, and X represents a halogen atom.) The substituted phenylpiperazine (II) can be produced by a cross-coupling reaction such as a Buchwald / Hartwig type reaction using compound (VII) and piperazine. That is, compound (VII) is coupled in a solvent with 0.5 to 10 molar equivalents, preferably 1.5 to 5 molar equivalents, of piperazine in the presence of a metal catalyst such as palladium, and, if necessary, additives such as a base and a ligand, to give heteroaryloxy-substituted phenylpiperazine (II). The solvent may be any solvent inert to the reaction, and is not particularly limited, but toluene is preferred. The metal catalyst may be a commercially available palladium catalyst (e.g., Pd ２ (dba) ３ A catalytic amount, i.e., 0.01 to 0.5 molar equivalents, and more preferably 0.01 to 0.2 molar equivalents, can be used relative to compound (VII). Examples of bases include cesium carbonate and sodium tert-butoxide. The base can be added in an amount of 1 to 5 molar equivalents, and preferably 1 to 3 molar equivalents, relative to compound (VII). A catalytic amount, i.e., 0.01 to 0.5 molar equivalents, and more preferably 0.01 to 0.3 molar equivalents, of a ligand for the metal catalyst, such as BINAP or Me4tButylXphos, can be added in an amount of 0.01 to 0.5 molar equivalents, and more preferably 0.01 to 0.3 molar equivalents. The reaction can be carried out at a temperature range of 0°C to 150°C for a period of several minutes to 24 hours, but is preferably carried out at 80°C to 120°C for 30 minutes to 16 hours. Alternatively, the reaction can be carried out using a microwave synthesizer, for example, at 80°C to 150°C for 0.5 to 24 hours.

[0036] The substituted phenylpiperazine (II) used as a starting material in Scheme 1 and Scheme 2 can also be produced by the method shown in Scheme 5, for example. (In the formula, A has the same meaning as defined above.) Substituted phenylpiperazine (II) can be produced by reacting compound (VIII) with bis(2-chloroethyl)amine hydrochloride. That is, substituted phenylpiperazine (II) can be obtained by reacting compound (VIII) in a solvent with 0.5 to 3 molar equivalents, preferably 0.8 to 1.5 molar equivalents, of bis(2-chloroethyl)amine in the presence of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, of a base such as potassium carbonate. Any solvent inert to the reaction can be used, such as 1-butanol, 1,4-dioxane, or toluene, with 1-butanol being preferred. The reaction can be carried out at a temperature ranging from 0°C to 180°C for a period ranging from several minutes to several days, but is preferably carried out at 100°C to 150°C for 10 minutes to 24 hours.

[0037] The aminoindole (III) used as the starting material in Scheme 1 can be produced, for example, by the method shown in Scheme 6. (In the formula, R １ , R ２ , R ３ and R ４are as defined above, and PG represents a protecting group.) Aminoindole (III) can be produced by deprotecting compound (XI), which is obtained by Fischer indole synthesis using compound (IX) and compound (X). Specifically, compound (XI) can be obtained by reacting compound (IX) with 0.5 to 1.5 molar equivalents of compound (X) in a solvent under Fischer indole synthesis conditions. Any solvent inert to the reaction can be used, including chloroform, 1,2-dichloroethane, THF, or toluene, with a 1,2-dichloroethane / toluene mixed solvent being preferred. The reaction can be carried out at a temperature ranging from 0°C to 100°C for a period ranging from several minutes to several days, preferably at room temperature to 100°C for 30 minutes to 24 hours. Aminoindole (III) can be obtained by treating the protecting group of the resulting compound (XI) under deprotection conditions commonly used in organic synthetic chemistry. Compound (IX) and compound (X) used as starting materials in Scheme 6 are commercially available or can be produced by known methods or methods analogous thereto.

[0038] The aminoindole (III) used as the starting material in Scheme 1 can also be produced by the method shown in Scheme 7, for example. (In the formula, R １ , R ２ , R ３ and R ４are as defined above.) Aminoindole (III) can be produced by reducing the nitro group of compound (XIII), which is obtained by nitrating compound (XII). That is, compound (XIII) can be obtained by reacting compound (XII) with fuming nitric acid and acetic anhydride under nitration reaction conditions commonly used in organic chemistry. The nitrating agent is not particularly limited, but for example, 1 to 3 molar equivalents of fuming nitric acid in the presence of acetic anhydride can be used. The reaction can be carried out at a temperature ranging from -20°C to 50°C for several minutes to several days, but is preferably carried out at 0°C to room temperature for 10 minutes to 8 hours. Aminoindole (III) can be obtained by reducing the nitro group of the obtained compound (XIII) in a solvent using a reduction method commonly used in organic synthetic chemistry, such as catalytic reduction using palladium carbon or metal reduction using tin, zinc, or iron. In order to improve the yield of the reduction reaction, the aminoindole (III) may be converted to a compound in which the amino group is protected with a Boc group. ２ By reacting with O, a compound in which the amino group of aminoindole (III) is protected with a Boc group can be obtained. The Boc group can be deprotected under conditions commonly used in organic chemistry, such as with hydrochloric acid. Compound (XII), which is used as a starting material in Scheme 7, can be obtained as a commercially available product or can be produced by a known method or a method similar thereto.

[0039] The carbamate (IV) used as the starting material in Scheme 2 can be produced, for example, by the method shown in Scheme 8. (In the formula, R １ , R ２ , R ３ and R ４are as defined above, and Ar represents an aryl group which may have a substituent (an electron-withdrawing substituent such as a nitro group, or an electron-donating substituent such as an alkyl group). Carbamate (IV) can be produced by reacting ArOH with the isocyanate group of compound (XV), which is obtained by a Curtius rearrangement reaction using compound (XIV) and DPPA. That is, compound (XV) can be produced by reacting compound (XIV) in a solvent with 0.5 to 3 molar equivalents, preferably 0.8 to 1.5 molar equivalents, of DPPA and 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, of a base such as triethylamine. Any solvent inert to the reaction may be used, such as THF or 1,4-dioxane, with THF being preferred. The reaction can be carried out at a temperature ranging from 0°C to 150°C for a period of several minutes to several days, but is preferably carried out at 50°C to 120°C for 10 minutes to 24 hours. Carbamate (IV) can be obtained by reacting the obtained compound (XV) with 0.5 to 10 molar equivalents, preferably 2 to 5 molar equivalents, of ArOH in a solvent. Any solvent inert to the reaction can be used, such as THF, DMF, 1,4-dioxane, or toluene, with a mixed solvent of toluene and DMF being preferred. The reaction can be carried out at a temperature ranging from 0°C to 150°C for a period ranging from several minutes to several days, preferably at 80°C to 120°C for 10 minutes to 24 hours. Compound (XIV), used as a starting material in Scheme 8, is commercially available or can be produced by known methods or methods analogous thereto.

[0040] The carbamate (IV) used as the starting material in Scheme 2 can also be produced by the method shown in Scheme 9, for example. (In the formula, R １ , R ２ , R ３ and R ４are as defined above, and Ar represents an aryl group which may have a substituent (an electron-withdrawing substituent such as a nitro group). Carbamate (IV) can be produced by reacting aminoindole (III) with ArOCOCl. That is, carbamate (IV) can be obtained by reacting aminoindole (III) with 0.5 to 3 molar equivalents, preferably 0.8 to 1.5 molar equivalents, of ArOCOCl in a solvent in the presence of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, of a base such as DIPEA. Any solvent inert to the reaction may be used, such as THF or 1,4-dioxane, with THF being preferred. The reaction can be carried out at a temperature ranging from 0°C to 100°C for a period of several minutes to several days, preferably at 0°C to room temperature for 10 minutes to 24 hours.

[0041] Compound (VII) used as a starting material in Scheme 4 can be produced, for example, by the method shown in Scheme 10. (In the formula, A is as defined above, and X represents a halogen atom.) Compound (VII) can be produced by a cross-coupling reaction such as the Ullman reaction using compound (XVI) and compound (XVII). That is, compound (VII) can be obtained by coupling compound (XVI) in a solvent with 0.5 to 3 molar equivalents, preferably 0.5 to 1.5 molar equivalents, of compound (XVII) in the presence of a metal such as copper, and, if necessary, additives such as a base and a ligand. The solvent may be any solvent inert to the reaction, and is not particularly limited, but pyridine is preferred. As the metal, commercially available copper (e.g., copper(II) oxide) that is used in cross-coupling can be used. Preferably, 0.5 to 5.0 molar equivalents, more preferably 1.0 to 3.0 molar equivalents, are added relative to compound (XVI). The reaction can be carried out at a temperature range of 0°C to 150°C for several minutes to 24 hours, but is preferably carried out at 80°C to 130°C for 30 minutes to 16 hours. Alternatively, the reaction can be carried out using a microwave synthesis apparatus, for example, at 80°C to 150°C for 0.5 to 24 hours. Compound (XVI) and compound (XVII), which are used as starting materials in Scheme 10, are commercially available or can be produced by known methods or methods analogous thereto.

[0042] [Method for Producing Compound (I) of the Present Invention] The compound of the present invention represented by formula (I) can be produced, for example, by Scheme 11. (In the formula, A, Q, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８are the same as defined above, and Q-H indicates that the terminal amino group has a secondary amine structure.) Compound (I) of the present invention can be produced using compound (XVIII) and aminoindole (III) in accordance with the method described in Scheme 1. Compound (XVIII) used as a starting material in Scheme 11 can be produced from the corresponding starting material (a commercially available product, a known method, or a method similar thereto, or a compound produced by a method similar to the method described in Scheme 10) in accordance with the methods described in Scheme 3, Scheme 4, and Scheme 5. Compound (III) can also be produced according to Scheme 6 above. Note that the compound of formula (I) of the present invention having a desired functional group at a desired position can be obtained by appropriately combining the above methods and carrying out a method commonly used in organic synthetic chemistry (e.g., a substitution reaction with a fluoro group using a deoxyfluorinating agent, a nucleophilic substitution reaction of an amino group, an alkylation reaction of an amino group, a cross-coupling reaction such as the Mitsunobu reaction, the Sonogashira reaction, or the Suzuki-Miyaura reaction, or a reduction of a carbon-carbon double bond by a hydrogenation reaction).

[0043] [Use of Compound (I) of the Present Invention] The compound of formula (I) of the present invention or a salt thereof can be administered after preparation into various forms. For example, it can be prepared in the form of a conventional pharmaceutical preparation (pharmaceutical composition) suitable for oral, parenteral, or topical administration. Formulations for oral administration include solid preparations such as tablets, granules, powders, or capsules, and liquid preparations such as syrups. These preparations can be prepared by conventional methods. Solid preparations can be prepared using conventional pharmaceutical carriers such as starches such as lactose and cornstarch, crystalline cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethylcellulose, talc, magnesium stearate, and the like. Capsules can be prepared by encapsulating the thus prepared granules or powder in a conventional manner. Syrups can be prepared by dissolving or suspending the compound of formula (I) of the present invention or a salt thereof in an aqueous solution containing sucrose, carboxymethylcellulose, or the like using conventional methods. Formulations for parenteral administration include injections such as intravenous drip infusions. Injection formulations can also be prepared by conventional methods and may contain, as appropriate, isotonic agents (e.g., mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, or mannose), stabilizers (e.g., sodium sulfite, albumin), and preservatives (e.g., benzyl alcohol or methyl p-hydroxybenzoate). The dose of the compound of formula (I) or its salt of the present invention can vary depending on the severity of the disease, the age and weight of the patient, the dosage form, etc., but is typically in the range of 1 mg to 1,000 mg per day for adults. It can be administered orally or parenterally in a single dose, or in two or three divided doses. The compound of formula (I) or its salt of the present invention can also be used as a STING inhibitor or as a reagent for experiments and research. Radiolabeled compounds of the compound of formula (I) of the present invention can also be used as molecular probes for PET.

[0044] In another embodiment, the present invention relates to the use of compound (I) of the present invention or a salt thereof in the manufacture of a medicament for preventing or treating a STING-associated disease. In another embodiment, the present invention relates to the use of compound (I) of the present invention or a salt thereof for preventing or treating a STING-associated disease. In another embodiment, the present invention relates to compound (I) of the present invention or a salt thereof for preventing or treating a STING-associated disease. In another embodiment, the present invention relates to a method for preventing or treating a STING-associated disease, comprising administering to a patient an effective amount of compound (I) of the present invention or a salt thereof.

[0045] The compound of formula (I) or a salt thereof of the present invention can be used in combination with one or more therapeutic agents for other inflammatory diseases, autoimmune diseases, and cancer. Examples of therapeutic agents for other inflammatory diseases, autoimmune diseases, and cancer include (a) alkylating agents such as cisplatin, ifosfamide, melphalan, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, alboplatin, cyclophosphamide, and oxaliplatin, (b) cytotoxic compounds such as dichloroacetic acid, 2-deoxyglucose, actinomycin, anthracyclines, anthracenediones, and clofamidine, and (c) PD-1, PD-L1, IL-2, IL-10, TGFβ, CTLA-4, CD27, CD40L, HVEM, CD80, CD244, CD28, and CD39. (d) immune checkpoint inhibitors that target immune checkpoint receptors selected from the group consisting of ribozyme, TIM3, VEGF, and CD30 (specifically, nivolumab, pemvirolizumab, cemiplimab, asozolizumab, avelumab, durvalumab, ipilimumab, and tremelimumab); (e) antimetabolites such as methotrexate, fluorouracil (5-FU), gemcitabine, capezitabine, cytarabine, and vemetrexed; and (f) stilbenoids such as resveratrol, piceatannol, pinosylvin, pterostilbene, α-viniferin, ampelopsin A, and diptoindonesin C. Furthermore, when compound (I) of the present invention or a salt thereof is used particularly for inflammatory or immune diseases, it can be used in combination with one or more therapeutic agents used to treat STING-related diseases other than cancer, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjogren's syndrome (SS), metabolic disorder-associated steatohepatitis (MASH), nephritis, hepatitis, age-related macular degeneration (AMD), aging-related neurodegenerative diseases, rheumatoid arthritis, Crohn's disease, type I diabetes, ulcerative colitis, lupus nephritis, vasculitis, polymyositis, dermatomyositis, psoriasis, Aicardi-Goutieres syndrome (AGS), infantile-onset STING-associated vasculopathy (SAVI), or COPA syndrome.Specifically, (a) steroids such as prednisolone, dexamethasone, betamethasone, hydrocortisone, triamcinolone, and methylprednisolone; (b) immunomodulators such as cyclophosphamide, tacrolimus, methotrexate, azathioprine, mycophenolate mofetil, rituximab, interferon beta-1a, interferon beta-1b, and fingolimod; (c) antimalarials such as hydroxychloroquine; (d) aspirin, loxoprofen, diclofenac, indomethacin, naproxen, ibuprofen, and fluticasone; (e) nonsteroidal anti-inflammatory drugs such as buprofen and celecoxib; (f) antifolates such as methotrexate, pemetrexed, pralatrexate, raltidorexed, and trimetrexate; (g) TNF inhibitors such as infliximab, etanercept, adalimumab, and golimumab; (h) IL-6 receptor inhibitors such as tocilizumab and sarilumab; and (i) JAK inhibitors such as tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib.

[0046] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples. 1 H-NMR) and mass spectrometry (MS). 1 Unless otherwise specified, H-NMR was measured at 400 MHz, and exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. Note that "br." means a broad signal. HPLC preparative chromatography was performed in gradient mode using a commercially available ODS column with water / acetonitrile (containing formic acid), water / methanol (containing formic acid), or water / acetonitrile (containing ammonium bicarbonate) as the eluent.

[0047] Reference Example 1 Preparation of 5,7-difluoro-1H-indol-3-amine hydrochloride (Step 1) Preparation of N-(5,7-difluoro-1H-indol-3-yl)-2,2,2-trifluoroacetamide Trifluoroacetic anhydride (7.98 g, 38 mmol) was added dropwise to a THF solution (40 mL) of 2,2-diethoxyethan-1-amine (4.6 g, 34.5 mmol) and DIPEA (5.36 g, 41.4 mmol). After stirring at room temperature for 40 minutes, the reaction mixture was washed twice with a mixed solution of saturated brine (15 mL) and concentrated hydrochloric acid (1.15 mL), and the organic layer was evaporated under reduced pressure. The resulting residue (5.36 g) was dissolved in a 1,2-dichloroethane / toluene mixed solvent (1:1, 40 mL). To this solution was added (2,4-difluorophenyl)hydrazine hydrochloride (5.2 g, 28.8 mmol), and the mixture was stirred at 50°C for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by amine-modified silica gel chromatography (hexane:ethyl acetate = 1:0-7:3) to obtain the title compound (3.5 g). LCMS (m / z) 263.0 [MH] - .

[0048] (Step 2) Preparation of 5,7-difluoro-1H-indol-3-amine hydrochloride A mixture of N-(5,7-difluoro-1H-indol-3-yl)-2,2,2-trifluoroacetamide (3.5 g, 13.25 mmol) and 2N hydrochloric acid / ethanol solution (30 mL) was stirred at 80°C overnight. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the resulting residue. The solid was collected by filtration and dried to obtain the title compound (2.3 g). LCMS (m / z) 169.1 [M+H] + .

[0049] Reference Example 2 Preparation of 2-methyl-5-[4-(piperazin-1-yl)phenoxy]pyrimidine hydrochloride (Step 1) Preparation of tert-butyl 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxylate A toluene solution (20 mL) of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (1000 mg, 3.59 mmol), 5-bromo-2-methylpyrimidine (684 mg, 3.95 mmol), tripotassium phosphate (1525 mg, 7.19 mmol), Me4tButylXphos (86 mg, 0.18 mmol), and Pd(OAc)2 (40 mg, 0.18 mmol) was stirred in a sealed tube at 120°C for 14 hours. The same reaction was carried out again. The reaction mixtures obtained from the two reactions were mixed, and the insoluble matter was filtered through Celite. Silica gel was added to the filtrate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 1:0-2:3) to yield the title compound (1516 mg). 1 LCMS (m / z) 371.2 [M+H] + .

[0050] (Step 2) Preparation of 2-methyl-5-[4-(piperazin-1-yl)phenoxy]pyrimidine hydrochloride To a solution of tert-butyl 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxylate (1516 mg, 4.09 mmol) in ethyl acetate (10 mL) was added a 4N hydrochloric acid / ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 3 hours, followed by further stirring at 50°C for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The solid was washed with ethyl acetate and dried to obtain the title compound (1250 mg). 1 LCMS (m / z) 271.1 [M+H] + .

[0051] Reference Example 3 Preparation of 2-methyl-5-[4-(piperazin-1-yl)phenoxy]pyrazine (Step 1) Preparation of tert-butyl 4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxylate A DMF suspension (20 mL) of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (2000 mg, 7.19 mmol), 2-chloro-5-methylpyrazine (1016 mg, 7.9 mmol), and potassium carbonate (1490 mg, 10.78 mmol) was stirred at 100°C for 2.5 hours and then further stirred at 120°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate / water, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The resulting organic layers were combined, washed with water, and then washed twice with saturated brine. Silica gel was added to the organic layer, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0-1:1) to yield the title compound (2149 mg). 1 H NMR (DMSO-d6) δ 8.32 (d, J = 1.4 Hz, 1H), 8.04 (dd, J = 1.4, 0.7 Hz, 1H), 7.08 - 6.93 (m, 4H), 3.50 - 3.43 (m, 4H), 3.10 - 3.04 (m, 4H), 2.42 (d, J = 0.7 Hz, 3H), 1.42 (s, 9H); LCMS (m / z) 371.2 [M+H] + .

[0052] (Step 2) Preparation of 2-methyl-5-[4-(piperazin-1-yl)phenoxy]pyrazine A mixture of tert-butyl 4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxylate (2149 mg, 5.8 mmol) and 2N hydrochloric acid / ethanol solution (15 mL) was stirred at 50°C for 80 minutes. Methanol was added to the reaction mixture, and to the resulting solution, amine-modified silica gel was added, and the solvent was evaporated under reduced pressure. The resulting residue was purified by amine-modified silica gel chromatography (chloroform:methanol = 1:0-9:1) to obtain the title compound (797 mg). 1H NMR (DMSO-d6) δ 8.31 (d, J = 1.4 Hz, 1H), 8.04 (dd, J = 1.5, 0.8 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.97 - 6.91 (m, 2H), 3.04 - 2.97 (m, 4H), 2.86 - 2.79 (m, 4H), 2.44 - 2.40 (m, 3H); LCMS (m / z) 271.1 [M+H] + .

[0053] Reference Example 4 Preparation of 2-methyl-3-[4-(piperazin-1-yl)phenoxy]pyrazine trifluoroacetate (Step 1) Preparation of tert-butyl 4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxylate To a DMF solution (5 mL) of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (300 mg, 1.08 mmol), 2-chloro-3-methylpyrazine (277 mg, 2.15 mmol) and potassium carbonate (447 mg, 3.23 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water and then extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (30% ethyl acetate / petroleum ether) to give the title compound (130 mg). 1 H NMR (500MHz, CDCl3) δ 8.09 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 0.5, 2.5 Hz, 1H), 7.07 - 7.04 (m, 2H), 6.98 - 6.96 (m, 2H), 3.59 - 3.56 (m, 4H), 3.13 - 3.11 (m, 4H), 2.64 (s, 3H), 1.49 (s, 9H); LCMS (m / z) 371.2 [M+H] + .

[0054] (Step 2) Preparation of 2-methyl-3-[4-(piperazin-1-yl)phenoxy]pyrazine trifluoroacetate To a dichloromethane solution (5 mL) of tert-butyl 4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxylate (130 mg, 0.35 mmol), TFA (1.5 mL) was added at 0° C., and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give the title compound (110 mg). LCMS (m / z) 271.2 [M+H] + .

[0055] Reference Example 5 Preparation of 4,5-difluoro-1H-indol-3-amine hydrochloride (Step 1) Preparation of 4,5-difluoro-3-nitro-1H-indole To a solution (15 mL) of 4,5-difluoro-1H-indole (2.45 g, 16 mmol) and acetic anhydride (3.528 g, 34.6 mmol), a solution (9 mL) of fuming nitric acid (1.059 g, 16.8 mmol) in acetic acid was added dropwise at 0°C, and the mixture was stirred at room temperature for 1.5 hours. Water (30 mL) was added to the reaction mixture, and after cooling to 0°C, the precipitated solid was collected by filtration. The solid was purified by amine-modified silica gel chromatography (hexane:ethyl acetate = 1:0-0:1, then ethyl acetate:methanol = 9:1) to obtain the title compound (2.04 g). 1 H NMR (DMSO-d6) δ 12.94 (s, 1H), 8.73 (s, 1H), 7.44 - 7.35 (m, 2H); LCMS (m / z) 197.1 [MH] - .

[0056] (Step 2) Production of tert-butyl(4,5-difluoro-1H-indol-3-yl)carbamic acid 4,5-Difluoro-3-nitro-1H-indole (2.04 g, 10.3 mmol) was added to a mixed solvent of methanol / THF / saturated aqueous ammonium chloride (1:1:1, 75 mL), and zinc powder (3.366 g, 51.5 mmol) was added to this suspension at 0°C. After stirring for 5 minutes, Boc ２O (2.472 g, 11.33 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was filtered through Celite to remove insoluble matter. The filtrate was concentrated under reduced pressure, and the residue was purified by amine-modified silica gel chromatography (hexane:ethyl acetate=1:0-1:1) to obtain the title compound (2.22 g). 1 LCMS (m / z) 267.1 [MH] - .

[0057] (Step 3) Preparation of 4,5-difluoro-1H-indol-3-amine hydrochloride A mixture of tert-butyl(4,5-difluoro-1H-indol-3-yl)carbamate (2.22 g, 8.28 mmol) and 4N hydrochloric acid / ethyl acetate solution (10 mL) was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and dried to obtain the title compound (1.35 g). 1 LCMS (m / z) 169.1 [M+H] + .

[0058] Reference Example 6 Preparation of 2-chloro-5-[4-(piperazin-1-yl)phenoxy]pyrazine trifluoroacetate (Step 1) Preparation of tert-butyl 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}piperazine-1-carboxylate To a DMF solution (5 mL) of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (300 mg, 1.08 mmol), 2,5-dichloropyrazine (322 mg, 2.16 mmol) and potassium carbonate (447 mg, 3.23 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with ice water and then extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and diethyl ether was added to the resulting residue. The solid was collected by filtration and dried to obtain the title compound (150 mg). 1 H NMR (500MHz, CDCl3) δ 8.17 - 8.15 (m, 1H), 8.10 (d, J = 0.9 Hz, 1H), 7.06 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 3.63 - 3.56 (m, 4H), 3.15 - 3.12 (m, 4H), 1.49 (s, 9H); LCMS (m / z) 391.4 [M+H] + .

[0059] (Step 2) Preparation of 2-chloro-5-[4-(piperazin-1-yl)phenoxy]pyrazine trifluoroacetate To a dichloromethane solution (5 mL) of tert-butyl 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}piperazine-1-carboxylate (150 mg, 0.38 mmol), TFA (1.5 mL) was added at 0° C., and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to obtain the title compound (120 mg). 1 LCMS (m / z) 291.2 [M+H] + .

[0060] Reference Example 7 Preparation of 2-methoxy-5-[4-(piperazin-1-yl)phenoxy]pyrimidine trifluoroacetate (Step 1) Preparation of tert-butyl 4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxylate A toluene solution (5 mL) of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (250 mg, 0.90 mmol) and 5-bromo-2-methoxypyrimidine (176 mg, 0.93 mmol) was stirred and degassed with argon gas. Next, tripotassium phosphate (385 mg, 1.81 mmol), MetButylXphos (43 mg, 0.09 mmol), and Pd(OAc) (10 mg, 0.04 mmol) were added, and the mixture was degassed with argon gas and stirred at 120°C for 16 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (25% ethyl acetate / petroleum ether) to yield the title compound (120 mg). LCMS (m / z) 387.4 [M+H] + .

[0061] (Step 2) Preparation of 2-methoxy-5-[4-(piperazin-1-yl)phenoxy]pyrimidine trifluoroacetate To a dichloromethane solution (5 mL) of tert-butyl 4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxylate (120 mg, 0.31 mmol), TFA (1.5 mL) was added at 0° C., and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give the title compound (80 mg). LCMS (m / z) 287.3 [M+H] + .

[0062] Example 1 Preparation of N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide CDI (697 mg, 4.3 mmol) was added to a THF solution (25 mL) of 5,7-difluoro-1H-indol-3-amine hydrochloride (Reference Example 1, 800 mg, 3.91 mmol) and DIPEA (607 mg, 4.7 mmol), and the mixture was stirred at 0° C. for 35 minutes. 2-Methyl-5-[4-(piperazin-1-yl)phenoxy]pyrimidine hydrochloride (Reference Example 2, 1000 mg, 3.26 mmol) and DIPEA (1214 mg, 9.4 mmol) were added to this reaction solution, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate / water, and the separated organic layer was washed with water. Amine-modified silica gel was added to the organic layer, and the solvent was then evaporated under reduced pressure. The resulting residue was roughly purified by amine-modified silica gel chromatography (chloroform:methanol=1:0-49:2) and further purified by silica gel chromatography (chloroform:methanol=1:0-97:3) to obtain the title compound (540 mg). 1 H NMR (DMSO-d6) δ 11.36 - 11.31 (m, 1H), 8.42 (s, 2H), 8.35 (s, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 9.7, 2.2 Hz, 1H), 7.09 - LCMS (m / z) 465.1 [M+H] + .

[0063] Example 2 Preparation of N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide CDI (95 mg, 0.59 mmol) was added to a THF solution (5 mL) of 5,7-difluoro-1H-indol-3-amine hydrochloride (Reference Example 1, 100 mg, 0.49 mmol) and DIPEA (96 mg, 0.74 mmol), and the mixture was stirred at 0°C for 20 minutes. 2-Methyl-5-[4-(piperazin-1-yl)phenoxy]pyrazine (Reference Example 3, 90 mg, 0.33 mmol) was added to this reaction solution, and the mixture was stirred at room temperature for 80 minutes. The reaction mixture was diluted with ethyl acetate / water, and the separated organic layer was washed with water. Silica gel was added to the organic layer, and the solvent was evaporated under reduced pressure to give a residue, which was crudely purified by silica gel chromatography (chloroform:methanol = 1:0-97:3) and further purified by amine-modified silica gel chromatography (hexane:ethyl acetate = 1:0-3:7) to give the title compound (67 mg). 1 H NMR (DMSO-d6) δ 11.36 - 11.31 (m, 1H), 8.37 - 8.31 (m, 2H), 8.08 - 8.03 (m, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 9.7, 2.3 Hz, LCMS (m / z) 465.2 [M+H] + .

[0064] Example 3 Preparation of N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide To a THF suspension (5 mL) of 5,7-difluoro-1H-indol-3-amine hydrochloride (Reference Example 1, 100 mg, 0.49 mmol), CDI (87 mg, 0.54 mmol) and DIPEA (74 mg, 0.57 mmol) were added, and the mixture was stirred at 0°C for 20 minutes. 2-Methyl-3-[4-(piperazin-1-yl)phenoxy]pyrazine trifluoroacetate (Reference Example 4, 110 mg, 0.29 mmol) and DIPEA (148 mg, 1.14 mmol) were added to this reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified using HPLC preparative chromatography to obtain the title compound (55 mg). 1 H NMR (DMSO-d6) δ 11.37 - 11.31 (m, 1H), 8.35 (s, 1H), 8.18 - 8.15 (m, 1H), 7.97 - 7.93 (m, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 9.7, 2.3 Hz, 1H), 7.10 - 7.00 (m, 4H), 6.94 (ddd, J = 11.7, 9.6, 2.3 Hz, 1H), 3.68 - 3.60 (m, 4H), 3.21 - 3.14 (m, 4H), 2.58 - 2.53 (m, 3H); LCMS (m / z) 465.1 [M+H] + .

[0065] Example 4 Preparation of N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide To a THF solution (2 mL) of 4,5-difluoro-1H-indol-3-amine hydrochloride (Reference Example 5, 36.7 mg, 0.179 mmol) and DIPEA (31.6 mg, 0.244 mmol), 4-nitrophenyl chloroformate (37.8 mg, 0.187 mmol) was added, and the mixture was stirred at 0°C for 85 minutes. To this reaction solution, a DMF solution (3 mL) of 2-methyl-5-[4-(piperazin-1-yl)phenoxy]pyrimidine hydrochloride (Reference Example 2, 50 mg, 0.163 mmol) and DIPEA (63.2 mg, 0.488 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate / water, and the separated organic layer was washed twice with water. Amine-modified silica gel was added to the organic layer, and the solvent was then evaporated under reduced pressure. The resulting residue was roughly purified by amine-modified silica gel chromatography (chloroform:methanol=1:0-49:1) and further purified by silica gel chromatography (chloroform:methanol=1:0-97:3) to obtain the title compound (22 mg). 1 H NMR (DMSO-d6) δ 11.17 - 11.12 (m, 1H), 8.41 (s, 2H), 8.18 (s, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.17 - 6.99 (m, 6H), 3.63 - 3.56 (m, 4H), 3.17 - 3.11 (m, 4H), 2.59 (s, 3H); LCMS (m / z) 465.2 [M+H] + .

[0066] Example 5 Preparation of 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide To a THF suspension (5 mL) of 5,7-difluoro-1H-indol-3-amine hydrochloride (Reference Example 1, 100 mg, 0.49 mmol), CDI (87 mg, 0.54 mmol) and DIPEA (74 mg, 0.57 mmol) were added, and the mixture was stirred at 0°C for 30 minutes. 2-Chloro-5-[4-(piperazin-1-yl)phenoxy]pyrazine trifluoroacetate (Reference Example 6, 120 mg, 0.30 mmol) and DIPEA (148 mg, 1.14 mmol) were added to this reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified using HPLC preparative chromatography to obtain the title compound (66 mg). 1 H NMR (DMSO-d6) δ 11.36 - 11.31 (m, 1H), 8.38 - 8.31 (m, 3H), 7.52 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 9.7, 2.3 Hz, 1H), 7.15 - 7.07 (m, LCMS (m / z) 485.0 [M+H] + .

[0067] Example 6 Preparation of N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide To a THF suspension (5 mL) of 5,7-difluoro-1H-indol-3-amine hydrochloride (Reference Example 1, 80 mg, 0.39 mmol), CDI (70 mg, 0.43 mmol) and DIPEA (58 mg, 0.45 mmol) were added, and the mixture was stirred at 0°C for 30 minutes. 2-Methoxy-5-[4-(piperazin-1-yl)phenoxy]pyrimidine trifluoroacetate (Reference Example 7, 80 mg, 0.20 mmol) and DIPEA (116 mg, 0.90 mmol) were added to this reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified using HPLC preparative chromatography to obtain the title compound (25 mg). 1 H NMR (DMSO-d6) δ 11.36 - 11.30 (m, 1H), 8.42 (s, 2H), 8.34 (s, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 9.7, 2.3 Hz, 1H), 7.07 - 6.89 (m, 5H), 3.90 (s, 3H), 3.66 - 3.59 (m, 4H), 3.17 - 3.10 (m, 4H); LCMS (m / z) 481.2 [M+H] + .

[0068] Example 7 Preparation of N-(1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide formate (Step 1) Preparation of 3-isocyanato-1H-indole DPPA (8.20 g, 29.8 mmol) and triethylamine (3.77 g, 37.2 mmol) were added to a THF solution (40 mL) of 1H-indole-3-carboxylic acid (4.00 g, 24.8 mmol), and the mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate. The mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution, then with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was suspended and washed with ethyl acetate to obtain the title compound (2.53 g). 1H NMR (CDCl3) δ 8.65 (br.s, 1H), 8.32 - 8.23 ​​(m, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7.48 - 7.39 (m, 1H), 7.39 - 7.29 (m, 2H).

[0069] (Step 2) Preparation of phenyl (1H-indol-3-yl)carbamate 3-Isocyanato-1H-indole (250 mg, 1.58 mmol) was dissolved in a mixed solvent of toluene / DMF (5:1, 12 mL), phenol (744 mg, 7.90 mmol) was added, and the mixture was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature and then diluted with chloroform. The mixture was washed with water, and the aqueous layer was extracted with chloroform, and the resulting organic layers were combined. The organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was roughly purified by silica gel chromatography (hexane:ethyl acetate = 1:0-0:1). The resulting crude product was suspended and washed with ethyl acetate to give the title compound (56 mg). 1 H NMR (DMSO-d6) δ 10.83 (br.s, 1H), 9.99 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.48 - 7.40 (m, 3H), 7.37 - 7.30 (m, 1H), 7.29 - 7.21 (m, 3H), 7.12 - 7.07 (m, 1H), 7.02 - 6.97 (m, 1H); LCMS(m / z) 253.2 [M+H] + .

[0070] (Step 3) Preparation of 1-benzyl-4-[4-(pyridin-4-yloxy)phenyl]piperazine Potassium carbonate (57.9 mg, 0.419 mmol) was added to a DMF solution (2 mL) of 4-(4-benzylpiperazin-1-yl)phenol (75 mg, 0.279 mmol) and 4-fluoropyridine hydrochloride (41.1 mg, 0.307 mmol), and the mixture was stirred at 100°C for 2.5 hours. To complete the reaction, the mixture was further stirred at 120°C overnight. The reaction mixture was cooled to room temperature, and chloroform was added to the reaction mixture. The mixture was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous ammonium chloride. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 1:0-0:1, then ethyl acetate:methanol = 19:1) to give the title compound (13 mg). LCMS (m / z) 346.2 [M+H] + .

[0071] (Step 4) Preparation of 1-[4-(pyridin-4-yloxy)phenyl]piperazine Palladium hydroxide (5 mg) was added to a methanol solution (1 mL) of 1-benzyl-4-[4-(pyridin-4-yloxy)phenyl]piperazine (13 mg, 0.038 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours, followed by further stirring at 40°C for 2 hours. The reaction mixture was cooled to room temperature, and insoluble materials were removed by filtration through Celite. The filtrate was evaporated under reduced pressure to give the title compound (9.6 mg). LCMS (m / z) 256.2 [M+H] + .

[0072] (Step 5) Preparation of N-(1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide formate. A DMF solution (0.5 mL) of 3-isocyanato-1H-indole (9.49 mg, 0.038 mmol) and 1-[4-(pyridin-4-yloxy)phenyl]piperazine (9.6 mg, 0.038 mmol) was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, and chloroform was added to the reaction mixture. After washing with water, the solvent was evaporated under reduced pressure. The resulting residue was crudely purified by silica gel chromatography (hexane:ethyl acetate = 1:0-0:1, then ethyl acetate:methanol = 19:1) and further purified using HPLC preparative chromatography to obtain the title compound (4 mg). 1 H NMR (DMSO-d6) δ 10.75 - 10.70 (m, 1H), 8.53 (s, 1H), 8.46 - 8.39 (m, 2H), 8.33 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.31 (dt, J = 8.1, 0.9 Hz, 1H), 7.14 - 7.02 (m, 5H), 7.00 - 6.92 (m, 1H), 6.89 - 6.83 (m, 2H), 3.68 - 3.61 (m, 4H), 3.23 - 3.17 (m, 4H); LCMS (m / z) 414.3 [M+H] + .

[0073] Example 8 Preparation of N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide (Step 1) Preparation of ethyl 2-(4-bromophenoxy)acetate Potassium carbonate (17.9 g, 129.5 mmol) and triethylamine (14.77 g, 86.7 mmol) were added to a solution of 4-bromophenol (15.0 g, 86.7 mmol) in acetonitrile (300 mL), and the mixture was stirred at 90°C for 6 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (20 g). 1 H NMR (CDCl3) δ 7.42 - 7.36 (m, 2H), 6.83 - 6.76 (m, 2H), 4.59 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[0074] (Step 2) Preparation of 5-(4-bromophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one To a THF solution (400 mL) of ethyl 2-(4-bromophenoxy)acetate (20.0 g, 77.2 mmol), 60% sodium hydride (4.34 g, 108.5 mmol) and ethyl formate (22.7 g, 306.1 mmol) were added at 0°C, and the mixture was stirred at 45°C for 16 hours. The solvent from the reaction mixture was evaporated under reduced pressure, and to the resulting residue, thiourea (8.81 g, 115.8 mmol) and ethanol (400 mL) were added, followed by stirring at 90°C for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was diluted with water, and saturated aqueous sodium bicarbonate was added, followed by extraction twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10 g). LCMS (m / z) 299.1 [M+H] + .

[0075] (Step 3) Preparation of 5-(4-bromophenoxy)pyrimidin-4-ol To a THF solution (250 mL) of 5-(4-bromophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (10.0 g, 33.4 mmol), 30% aqueous hydrogen peroxide solution (80 mL) was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution, and reduced with aqueous sodium thiosulfate solution. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was suspended and washed with diethyl ether to give the title compound (4.5 g). 1 LCMS (m / z) 267.1 [M+H] + .

[0076] (Step 4) Preparation of 5-(4-bromophenoxy)-4-chloropyrimidine To a DMF suspension (2 mL) of 5-(4-bromophenoxy)pyrimidin-4-ol (4.5 g, 15.8 mol), thionyl chloride (45 mL) was added and stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was neutralized with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3 g). LCMS (m / z) 285.0 [M+H] + .

[0077] (Step 5) Preparation of 5-(4-bromophenoxy)-N,N-dimethylpyrimidin-4-amine To a THF suspension (5 mL) of 5-(4-bromophenoxy)-4-chloropyrimidine (2.0 g, 6.8 mmol), 2 M dimethylamine / THF solution (7 mL) was added, and the mixture was stirred at 80°C in a sealed tube for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (50% ethyl acetate / petroleum ether) to give the title compound (1.2 g). 1 LCMS (m / z) 294.2 [M+H] + .

[0078] (Step 6) Preparation of tert-butyl 4-(4-{[4-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxylate To a toluene solution (8 mL) of tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol), 5-(4-bromophenoxy)-N,N-dimethylpyrimidin-4-amine (1170 mg, 3.98 mmol), sodium tert-butoxide (643 mg, 6.69 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (manufactured by Aldrich, 250 mg, 0.54 mmol), and Pd(OAc) (60 mg, 0.27 mmol) were added, and the mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate) to yield the title compound (220 mg). LCMS (m / z) 400.4 [M+H] + .

[0079] (Step 7) Preparation of N,N-dimethyl-5-(4-(piperazin-1-yl)phenoxy)pyrimidin-4-amine trifluoroacetate To a dichloromethane solution (5 mL) of tert-butyl 4-(4-{[4-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxylate (200 mg, 0.50 mmol), TFA (1.5 mL) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give the title compound (150 mg). LCMS (m / z) 300.2 [M+H] + .

[0080] (Step 8) Preparation of N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide CDI (87 mg, 0.54 mmol) and DIPEA (74 mg, 0.57 mmol) were added to a THF suspension (5 mL) of 5,7-difluoro-1H-indol-3-amine hydrochloride (Reference Example 1, 100 mg, 0.49 mmol), and the mixture was stirred at 0°C for 30 minutes. To this reaction solution, N,N-dimethyl-5-(4-(piperazin-1-yl)phenoxy)pyrimidin-4-amine trifluoroacetate (150 mg, 0.36 mmol) and DIPEA (148 mg, 1.14 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by HPLC preparative chromatography to yield the title compound (38 mg). 1 H NMR (DMSO-d6) δ 11.36 - 11.31 (m, 1H), 8.38 - 8.32 (m, 2H), 7.88 (s, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.27 (dd, J = 9.7, 2.3 Hz, 1H), LCMS (m / z) 494.3 [M+H] + .

[0081] The following example compounds [Table 1] were produced using the corresponding starting materials (commercially available products or compounds derived from commercially available compounds by known methods or methods similar thereto) according to the methods described in the above examples, and, where necessary, by appropriately combining methods commonly used in organic synthetic chemistry. The physicochemical data of each compound are shown in [Table 2].

[0082]

[0083]

[0084] Example 59 Preparation of N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide tosylate To a THF solution (600 mL) of N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide (Example 4, 17.92 g, 38.6 mmol), p-toluenesulfonic acid monohydrate (7.34 g, 38.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with THF, and then dried to obtain the title compound (23.08 g). 1H NMR (DMSO-d6) δ 11.16 (s, 1H), 8.45 (s, 2H), 8.22 (s, 1H), 7.51 - 7.44 (m, 2H), 7.31 (d, J = 2.6 Hz, 1H), 7.18 - 7.01 (m, 8H), 3.68 - 3.57 (m, 4H), 3.25 - 3.16 (m, 4H), 2.60 (s, 3H), 2.29 (s, 3H); LCMS (m / z) 465.3 [M+H] + .

[0085] Example 60 Preparation of N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide besylate To a suspension (11.5 mL) of N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide (Example 4, 573 mg, 1.23 mmol) in ethanol, an ethanol solution (2 mL) of benzenesulfonic acid monohydrate (376 mg, 2.13 mmol) was added and stirred at room temperature overnight. The solid was collected by filtration, washed with ethanol (1.2 mL), and dried overnight to give the title compound (639 mg). 1 H NMR (Methanol-d4) 8.45 (s, 2H), 7.87 - 7.79 (m, 2H), 7.47 - 7.38 (m, 3H), 7.38 - 7.32 (m, 2H), 7.26 (s, 1H), 7.21 - 7.14 (m, 2H), 7.09 LCMS (m / z) 465.3 [M+H] + .

[0086] The following example compounds [Table 3] were produced using the corresponding starting materials (commercially available products or compounds derived from commercially available compounds by known methods or methods similar thereto) according to the methods described in the above examples, and, where necessary, by appropriately combining methods commonly used in organic synthetic chemistry. The physicochemical data of each compound are shown in [Table 4].

[0087]

[0088]

[0089] Test Example 1: Inhibition test of intracellular human STING (hSTING) pathway using reporter cells. STING activates the transcription factor IRF3 upon ligand stimulation, so STING activity can be evaluated by a reporter assay using a secreted alkaline phosphatase (SEAP reporter) inserted downstream of an IRF-inducible promoter. That is, HEK-Blue cells inserted with a SEAP reporter were used. ＴＭ The hSTING inhibitory activity of test compounds was evaluated using ISG cells (Invivogen, #hkb-isg-1). hSTING activation was performed by stimulation with the small molecule ligand Compound 3 as described in the literature (Ramanjulu, J.M., et al., Nature. 2018, 564 (7736), 439-443). HEK-Blue cells were placed in a 96-well plate. ＴＭ ISG cells were seeded and incubated at 37°C, 5% CO ２ The cells were cultured overnight in an incubator. A test compound solution adjusted to a final concentration of 0.001 to 10 μM was added to each well of the cell culture plate, and the cells were incubated with CO ２ After culturing in an incubator for 1 hour, Compound 3 (final concentration 10 nM) was added and CO ２After culturing for 21 hours in an incubator, the culture supernatant was collected from each well and the reporter activity was measured by the alkaline phosphatase color reaction.

[0090] (Method of evaluating inhibitory activity) The reporter activity in the group without test compound and with Compound 3 added was set to 100%, and the reporter activity in the group without test compound and with Compound 3 added was set to 0%, and the IC was calculated by regression analysis of the inhibition rate calculated from the reporter activity at each compound concentration and the test compound concentration (logarithm). ５０ As a control compound, the compound of Example I-12 described in Patent Document 1 was evaluated under the conditions of Test Example 1.

[0091] (Evaluation Results) Table 5 shows the inhibitory activity of representative compounds of the present invention against hSTING.

[0092] This result indicates that the compound of formula (I) of the present invention has strong inhibitory activity against the STING pathway, unlike the compound of Example I-12 described in Patent Document 1.

[0093] Test Example 2: Test for inhibition of human IFN-β production stimulated by cGAMP The inhibitory activity of a test compound against STING activation was evaluated by measuring the amount of IFN-β produced when stimulated with the endogenous ligand cGAMP using the human monocytic cell line THP-1 cells. THP-1 cells (ATCC) were seeded on a 96-well plate, and PMA (Santa Cruz Biotechnology) adjusted to a post-addition concentration of 100 nM was added. The cells were incubated at 37°C, 5% CO ２ The plate was cultured overnight in an incubator (RPMI 1640 medium containing 10% FBS, 50 U / mL penicillin, and 50 μg / mL streptomycin). A test compound solution adjusted to a final concentration of 0.01 to 10 μM was added to each well of the plate, and the plate was then incubated with CO ２The cells were cultured for 1 hour in an incubator (final DMSO concentration: 0.1%). 2',3'-cGAMP (ChemieTek, #CT-CGAMP) was introduced into the cells at 0.12 μg / well by transfection using Lipofectamine 2000 (Invitrogen). ２ The cells were further cultured in the incubator for 18 hours. The culture supernatant was collected from each well, and the amount of human IFN-β produced in the culture supernatant was measured by ELISA using R&D human IFN-β Duoset (R&D Systems).

[0094] (Method of evaluating inhibitory activity) The amount of human IFN-β produced in the group without test compound and with cGAMP added was set to 100%, and the amount of human IFN-β produced in the group without test compound and with cGAMP added was set to 0%, and the IC was calculated by regression analysis of the inhibition rate calculated from the amount of human IFN-β produced at each compound concentration and the test compound concentration (logarithm). ５０ The value was calculated.

[0095] (Evaluation Results) The IFN-β production inhibitory activity of the representative compounds of the present invention is shown in Table 6. The IFN-β production inhibitory activity was measured using IC ５０ Values ​​of less than 0.1 μM are indicated by ***, values ​​of 0.1 μM or more and less than 1 μM are indicated by **, values ​​of 1 μM or more and less than 10 μM are indicated by *, and values ​​of 10 μM or more are indicated by -. NT means unevaluated.

[0096] This result indicates that the compound of formula (I) of the present invention has a strong inhibitory effect on the production of IFN-β induced by the activation of STING in cells.

[0097] Test Example 3: In vivo STING inhibition test using a CMA-stimulated STING activation mouse model. Mice were administered the mouse STING agonist CMA (10-carboxymethyl-9-acridanone), and the inhibitory effect of compound (I) of the present invention on the production of cytokines (IFN-β and IL-6) released into the blood after stimulation of the STING pathway was evaluated. (Preparation of test compound solution) DMSO, polyethylene glycol #400, and 30% (w / v) hydroxypropyl-β-cyclodextrin were added to the test compound in this order and mixed well (solvent composition: 5:20:75) to prepare a test compound solution. A solution with the same solvent composition but without the test compound was used for the solvent-treated group. C57BL / 6N mice (female, 7-8 weeks old) were orally administered with vehicle or a test compound solution adjusted to a test dose (10 mg / kg) (4 mice per group). One hour after administration, CMA (Tokyo Chemical Industry Co., Ltd.) suspended in 0.5% methylcellulose solution was administered intraperitoneally to the mice at a dose of 224 mg / kg. Two hours after CMA administration, blood was collected from each mouse, and plasma IFN-β and IL-6 concentrations were measured using a Duoset ELISA Kit (R&D Systems). The plasma cytokine (IFN-β or IL-6) concentration in the vehicle group was set to 100% and the corresponding plasma cytokine concentration in untreated mice to 0%, and the inhibition rate was calculated from the corresponding plasma cytokine concentration in each test compound administration group.

[0098] (Evaluation Results) Table 7 shows the inhibitory activity of representative compounds of the present invention against hSTING.

[0099] As shown in Table 7, the representative compounds of the present invention suppressed cytokine production induced by STING pathway stimulation compared to the solvent group. This result indicates that the compound of formula (I) of the present invention has an inhibitory effect on the production of IFN-β and IL-6 induced by STING activation in vivo in mice.

[0100] The compounds provided by the present invention are useful as pharmaceuticals (pharmaceutical compositions) for preventing or treating diseases known to be associated with STING-mediated cellular responses, such as inflammatory diseases, autoimmune diseases, or cancer. Furthermore, by combining them with therapeutic agents for other inflammatory diseases, autoimmune diseases, or cancer, they are expected to be effective against immune responses, making them useful as therapeutic pharmaceuticals (pharmaceutical compositions). Furthermore, they are useful as STING inhibitors and as reagents for experiments and research.

Claims

1. The following formula (I): (In the formula, A represents a heteroaryl group which may have a substituent, and Q represents a structure selected from the following structures (a) to (c): R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a nitro group, or a halogen atom; R ５ , R ６ , R ７ and R ８ each independently represents a hydrogen atom, a cyano group, or a halogen atom; R ９ and R １０ each independently represents a hydrogen atom or an alkyl group which may have a substituent; m, n, p, and q each independently represent an integer of 1 or 2; R １ and R ２ , R ２ and R ３ , R ３ and R ４ , or R ９ and R １０ may be bonded to each other to form a ring, or a salt thereof.

2. The compound of claim 1 or a salt thereof, wherein A is an optionally substituted 6-membered heteroaryl group.

3. The compound of claim 1 or a salt thereof, wherein A is an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, or an optionally substituted pyrazinyl group.

4. R １ , R ２ , R ３ and R ４ The compound or salt thereof according to claim 1, wherein each of the groups independently represents a hydrogen atom or a halogen atom.

5. The compound of claim 1 or a salt thereof, wherein Q has the structure (a).

6. The compound of claim 5, wherein A is an optionally substituted 6-membered heteroaryl group, or a salt thereof.

7. The compound of claim 5 or a salt thereof, wherein A is an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, or an optionally substituted pyrazinyl group.

8. R １ , R ２ , R ３ and R ４ The compound or salt thereof according to claim 7, wherein each of is independently a hydrogen atom or a halogen atom.

9. Below formula (Ia') (wherein A represents an optionally substituted heteroaryl group, R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a nitro group, or a halogen atom; R １ and R ２ , R ２ and R ３ or R ３ and R ４ or a salt thereof.

10. The compound of claim 9, or a salt thereof, wherein A is an optionally substituted 6-membered heteroaryl group.

11. The compound of claim 9 or a salt thereof, wherein A is an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyridazinyl group, or an optionally substituted pyrazinyl group.

12. R １ , R ２ , R ３ and R ４ The compound or salt thereof according to claim 9, wherein each of is independently a hydrogen atom or a halogen atom.

13. The compound according to claim 1 or a salt thereof, selected from the group consisting of the following compounds: N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-[4-(pyridin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyrimidin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridazin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyrazin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridazin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridazin-5-yloxy)phenyl]piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-[4-(pyridin-3-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyridin-3-yloxy)phenyl]piperazine-1-carboxamide;N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyrazin-2-yloxy)phenyl]piperazine-1-carboxamide; N-(4-fluoro-1H-indol-3-yl)-4-[4-(pyridin-4-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-[4-(pyridin-5-yloxy)phenyl]piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(dimethylamino)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(6-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(6-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(3-chloropyrazin-2-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(6-methoxypyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methoxypyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methoxypyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(4-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(5,6-dimethylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3,6-dimethylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3,5-dimethylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2,4-dimethylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide;N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(2-ethylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(4-ethylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(4-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(2-cyanopyrimidin-5-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-cyanopyridin-3-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(hydroxymethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(7-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(fluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide;N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[2-(difluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; N-(6-fluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-cyano-6-methylpyridin-3-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(1H-indol-3-yl)-4-(4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(4,5-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,6-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,6-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(6,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(6,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(4,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,7-difluoro-1H-indol-3-yl)-4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(5-chloropyrazin-2-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; 4-{4-[(2-methoxypyrimidin-5-yl)oxy]phenyl}-N-(5,6,7-trifluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-ethynylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-4-{4-[(1-methyl-1H-imidazol-2-yl)oxy]phenyl}piperazine-1-carboxamide; 5-(4-{4-[(5,7-difluoro-1H-indol-3-yl)carbamoyl]piperazin-1-yl}phenoxy)pyrimidine-2-carboxylate methyl; 5-(4-{4-[(5,7-difluoro-1H-indol-3-yl)carbamoyl]piperazin-1-yl}phenoxy)-N,N-dimethylpyrimidine-2-carboxamide; methyl 5-(4-{4-[(5,7-difluoro-1H-indol-3-yl)carbamoyl]piperazin-1-yl}phenoxy)pyrimidine-4-carboxylate; N-(5,7-difluoro-1H-indol-3-yl)-4-(4-{[4-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-yl]oxy}phenyl)piperazine-1-carboxamide; 4-{3-cyano-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{3-fluoro-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-4-{2-fluoro-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{2-cyano-4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5,7-difluoro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5-chloro-1H-indol-3-yl)-7-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-7-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; N-(5-chloro-1H-indol-3-yl)-7-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-7-{4-[(5-methylpyrazin-2-yl)oxy]phenyl}-4,7-diazaspiro[2.5]octane-4-carboxamide; (R)-N-(5,7-difluoro-1H-indol-3-yl)-3-methyl-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-8-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-2,8-diazaspiro[4.5]decane-2-carboxamide; (3aR,6aS)-N-(5,7-difluoro-1H-indol-3-yl)-5-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-6-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-2,6-diazaspiro[3.3]heptane-2-carboxamide; N-(5,7-difluoro-1H-indol-3-yl)-2-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-2,8-diazaspiro[4.5]decane-8-carboxamide;N-(3H-benzo[e]indol-1-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-ethyl-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; N-(5-methyl-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5-nitro-1H-indol-3-yl)piperazine-1-carboxamide; N-(5,7-dimethyl-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide; and 4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}-N-(5-vinyl-1H-indol-3-yl)piperazine-1-carboxamide.

14. N-(5,7-difluoro-1H-indol-3-yl)-4-{4-[(3-methylpyrazin-2-yl)oxy]phenyl}piperazine-1-carboxamide or a salt thereof.

15. N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-methylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide or a salt thereof.

16. N-(4,5-difluoro-1H-indol-3-yl)-4-{4-[(2-ethynylpyrimidin-5-yl)oxy]phenyl}piperazine-1-carboxamide or a salt thereof.

17. A preventive or therapeutic agent for systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjogren's syndrome (SS), metabolic steatohepatitis (MASH), nephritis, age-related macular degeneration (AMD), aging-related neurodegenerative diseases, and / or other STING-related diseases, comprising the compound or salt thereof according to any one of claims 1 to 16.

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