Compound, complement factor d inhibitor, and pharmaceutical composition

Abstract

Provided is a compound represented by formula (1): (in the formula, the definitions for variables are as defined in the description) or a pharmaceutically acceptable salt thereof.

Description

Compounds, Complement Factor D Inhibitors, and Pharmaceutical Compositions

[0001] The present invention relates to compounds, complement factor D inhibitors, and pharmaceutical compositions.

[0002] Complement factor D is a protein contained in the "complement system," one of the body's defense mechanisms, and is involved in immune and inflammatory responses. Various diseases have been reported to be associated with (mediated by) complement factor D.

[0003] Examples of complement factor D-related diseases include age-related macular degeneration (Non-Patent Documents 1 to 3), interstitial pneumonia associated with collagen disease (Non-Patent Document 4), arthritis (Non-Patent Documents 5 to 7), Alzheimer's disease (Non-Patent Document 8), multiple sclerosis (Non-Patent Documents 9 and 10), ulcerative colitis (Non-Patent Documents 11 and 12), diabetic retinopathy (Non-Patent Document 13), glaucoma (Non-Patent Documents 14 and 15), periodontal disease (Non-Patent Documents 16 and 17), and nephropathy (e.g., C3 nephropathy (Non-Patent Document 18)). , IgA nephropathy (Non-Patent Documents 19 and 20), membranoproliferative glomerulonephritis (Non-Patent Document 21), or lupus nephritis (Non-Patent Document 22)), autoimmune diseases (e.g., neuromyelitis optica (Non-Patent Documents 23), scleroderma (Non-Patent Documents 24-26), myasthenia gravis (Non-Patent Document 27), or antineutrophil cytoplasmic antibody-associated vasculitis (Non-Patent Document 28)), paroxysmal nocturnal hemoglobinuria (Non-Patent Document 29), and hemolytic uremic syndrome (Non-Patent Document 30) have been reported.

[0004] Known compounds that inhibit complement factor D include those disclosed in Patent Documents 1 to 4, for example.

[0005] International Publication No. WO 2015 / 130854 International Publication No. WO 2018 / 229543 International Publication No. WO 2020 / 041301 International Publication No. WO 2020 / 051532

[0006] British Journal of Ophthalmology 2006;90:1142-1145Clinical & Experimental Ophthalmology 2023;51:835-852The Lancet 2023;402:1449-1458Open Access Rheumatology:Research and Reviews 2023:15,65-79Nature medicine;17(12):1674-1679Materials Science & Engineering C 127(2021)112234Molecular Therapy:Nucleic Acids Vol.31 March 2023,339-351International Journal of Molecular Sciences 2024,25,817Journal of Neuroinflammation(2016)13:161Brain, Behavior, and Immunity 2020 Jul:87:739-750The Journal of Immunology 2012 June 15;188(12):6309-6318Journal of Clinical Biochemistry and Nutrition 2013 vol.52,No.1,72-75European Journal of Pharmacology 787(2016)94-104Experimental Eye Research 204(2021)108460International Journal of Molecular Sciences 2024,25,2307Journal of Clinical Investigation 2021;131(23): e152973 Journal of International Society of Preventive and Community Dentistry Vol. 12, Issue. 5, September-October 2022, 500-505Nature Reviews Nephrology vol. 15, MARCH 2019, 129-143 Journal of the American Society of Nephrology 26:1503-1512, 2015 Molecular Immunology 114 (2019) 123-132 Nature Genetics 2002 Aug; 31 (4): 424-428 Biomedicine & Pharmacotherapy 153 (2022) 113433 Expert Opin Biol Ther. 2021 August; 21 (8): 1073-1086 Arthritis and Rheumatism 1989 Oct; 32 (10): 1262-1267 Nature Biotechnology vol. 25, 1265-1275 (2007) Journal of Personalized Medicine 2022, 12, 284 ImmunoTargets and Therapy 2020: 9, 317-331 Clinical and Experimental Immunology, 202 (2020): 403-406 Blood (2021) 138 (20): 1928-1938 Annals of Blood 2023; 8:27;

[0007] An object of the present invention is to provide a compound having an inhibitory effect on complement factor D, or a complement factor D inhibitor or pharmaceutical composition containing the compound.

[0008] The present inventors have discovered that compounds having a specific structure have an inhibitory effect on complement factor D.

[0009] The present invention includes the following embodiments: [1] A compound represented by the following formula (1): [In the formula, R １ ~R ４are each independently hydrogen, alkyl, halogen, or haloalkyl; R ５ is O or NR ５Ａ and R ５Ａ is hydrogen, hydroxy, or alkoxy; R ６ is alkyl, NHR ６Ａ or hydroxy, R ６Ａ is hydrogen, hydroxy, or alkoxy; Q １ is N or CH, X １ has the following structure: (Wherein, A1 is an optionally substituted 5- to 7-membered heterocycle containing a nitrogen atom and a carbon atom as ring member atoms, L １ is a single bond or alkylene, and A2 is an optionally substituted aryl or an optionally substituted heteroaryl), or a pharmaceutically acceptable salt thereof. [2] Q １ [3] The compound according to [1], wherein R is N, or a pharmaceutically acceptable salt thereof. ３ and R ４ [4] The compound according to [1] or [2], wherein R is hydrogen, or a pharmaceutically acceptable salt thereof. １ ~R ４ [5] The compound according to any one of [1] to [3], wherein R is hydrogen, or a pharmaceutically acceptable salt thereof. ５ is O and R ６ is alkyl, NH ２ [6] The compound according to any one of [1] to [4], or a pharmaceutically acceptable salt thereof, wherein R ５ is NH, and R ６ However, NHR ６Ａ and R ６Ａ [7] The compound according to any one of [1] to [5], wherein R is hydrogen, hydroxy, or alkoxy, or a pharmaceutically acceptable salt thereof. ５ is NOH, and R ６ [8] The compound according to any one of [1] to [6], wherein R is alkyl, or a pharmaceutically acceptable salt thereof. ６ -C (=R５ )—has the following structure: [8-1] The compound according to any one of [1] to [7], or a pharmaceutically acceptable salt thereof, selected from the group consisting of ６ -C (=R ５ )—has the following structure: [9] The compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the following structure, which may be substituted: [9-1] The compound according to any one of [1] to [8-1], or a pharmaceutically acceptable salt thereof, wherein A1 is selected from the following structure, which may be substituted:

[10] The compound according to any one of [1] to [9], or a pharmaceutically acceptable salt thereof, wherein A1 has at least one substituent selected from the group consisting of alkyl, halogen, and haloalkyl.

[11] The compound according to any one of [1] to [9-1], or a pharmaceutically acceptable salt thereof, wherein A2 has the following structure, which may be substituted:

[12] The compound according to any one of [1] to

[11] , or a pharmaceutically acceptable salt thereof, wherein A2 has at least one substituent selected from the group consisting of alkyl, halogen, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[13] X １ has the following structure: [13-1] The compound according to any one of [1] to

[12] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of X １ has the following structure:

[14] The compound according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, selected from the following compounds:

[15] A complement factor D inhibitor comprising the compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof.

[16] A pharmaceutical composition comprising the compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof.

[17] The pharmaceutical composition according to

[16] , for use in the treatment and / or prevention of a disease selected from the group consisting of age-related macular degeneration, interstitial pneumonia associated with connective tissue disease, arthritis, Alzheimer's disease, multiple sclerosis, ulcerative colitis, diabetic retinopathy, glaucoma, and periodontal disease.

[18] The pharmaceutical composition according to

[16] , for use in the treatment and / or prevention of a disease selected from the group consisting of nephropathy, autoimmune diseases, paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome.

[0010] [A1] A method for inhibiting complement factor D, comprising administering to a patient in need thereof an effective amount of the compound of any one of [1] to

[14] or a pharmaceutically acceptable salt thereof. [A2] A method for preventing or treating a disease, comprising administering to a patient in need thereof an effective amount of the compound of any one of [1] to

[14] or a pharmaceutically acceptable salt thereof. [A3] The method of [A2], wherein the disease is selected from the group consisting of age-related macular degeneration, interstitial pneumonia associated with connective tissue disease, arthritis, Alzheimer's disease, multiple sclerosis, ulcerative colitis, diabetic retinopathy, glaucoma, and periodontal disease. [A4] The method of [A2], wherein the disease is selected from the group consisting of nephropathy, autoimmune disease, paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome.

[0011] [B1] The compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof for use in inhibiting complement factor D. [B2] The compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease. [B3] The compound according to [B2] or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of age-related macular degeneration, interstitial pneumonia associated with connective tissue disease, arthritis, Alzheimer's disease, multiple sclerosis, ulcerative colitis, diabetic retinopathy, glaucoma, and periodontal disease. [B4] The compound according to [B2] or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of nephropathy, autoimmune disease, paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome.

[0012] [C1] Use of the compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof for inhibiting complement factor D. [C2] Use of the compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof for preventing or treating a disease. [C3] The use according to [C2], wherein the disease is selected from the group consisting of age-related macular degeneration, interstitial pneumonia associated with connective tissue disease, arthritis, Alzheimer's disease, multiple sclerosis, ulcerative colitis, diabetic retinopathy, glaucoma, and periodontal disease. [C4] The use according to [C2], wherein the disease is selected from the group consisting of nephropathy, autoimmune disease, paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome.

[0013] [D1] Use of the compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof in the manufacture of a complement factor D inhibitor. [D2] Use of the compound according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing or treating a disease. [D3] The use according to [D2], wherein the disease is selected from the group consisting of age-related macular degeneration, interstitial pneumonia associated with connective tissue disease, arthritis, Alzheimer's disease, multiple sclerosis, ulcerative colitis, diabetic retinopathy, glaucoma, and periodontal disease. [D4] The use according to [D2], wherein the disease is selected from the group consisting of nephropathy, autoimmune disease, paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome.

[0014] The present invention can provide a compound having an inhibitory effect on complement factor D, or a complement factor D inhibitor or pharmaceutical composition containing the compound.

[0015] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to these and various modifications are possible without departing from the gist of the present invention.

[0016] <Definitions> In this specification, the term "comprise" means that in addition to the elements explicitly stated to be included, other elements may also be included.

[0017] <Pharmaceutical Composition> One embodiment of the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [In the formula, R １ ~R ４ are each independently hydrogen, alkyl, halogen, or haloalkyl; R ５ is O or NR ５Ａ and R ５Ａ is hydrogen, hydroxy, or alkoxy; R ６ is alkyl, NHR ６Ａ or hydroxy, R ６Ａ is hydrogen, hydroxy, or alkoxy; Q １ is N or CH, X １ has the following structure: (Wherein, A1 is an optionally substituted 5- to 7-membered heterocycle containing a nitrogen atom and a carbon atom as ring member atoms, L １ is a single bond or alkylene, and A2 is an optionally substituted aryl or an optionally substituted heteroaryl.

[0018] The compound according to this embodiment or a pharmaceutically acceptable salt thereof has a complement factor D inhibitory activity.

[0019] Herein, alkyl (including alkyl in haloalkyl) may be linear, branched, cyclic, or a combination thereof. Herein, the alkyl moiety contained in alkoxy may be linear, branched, cyclic, or a combination thereof. Herein, alkylene may be linear, branched, cyclic, or a combination thereof.

[0020] In formula (1), R １ and R ２ are each independently hydrogen, alkyl, halogen, or haloalkyl, preferably hydrogen, alkyl, or halogen, and more preferably hydrogen.

[0021] R １ and R ２ When is alkyl, R １ and R ２ may be taken together with the carbon atom to which they are attached to form a cycloalkyl.

[0022] R １ and R ２ The alkyl (including the alkyl in haloalkyl) is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably alkyl having 1 or 2 carbon atoms, and particularly preferably methyl.

[0023] R １ and R ２ The halogen and halo in haloalkyl are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.

[0024] In formula (1), R ３ and R ４ are each independently hydrogen, alkyl, halogen, or haloalkyl, preferably hydrogen, alkyl, or halogen, and more preferably hydrogen.

[0025] R ３ and R ４ When is alkyl, R ３ and R ４may be taken together with the carbon atom to which they are attached to form a cycloalkyl.

[0026] R ３ and R ４ The alkyl (including the alkyl in haloalkyl) is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably alkyl having 1 or 2 carbon atoms, and particularly preferably methyl.

[0027] R ３ and R ４ The halogen and halo in haloalkyl are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.

[0028] In formula (1), R ５ is O or NR ５Ａ and R ５Ａ is hydrogen, hydroxy, or alkoxy. ６ is alkyl, NHR ６Ａ or hydroxy, and R ６Ａ is hydrogen, hydroxy, or alkoxy.

[0029] R ５ is O, then R ６ is preferably alkyl, NH ２ or hydroxy;

[0030] R ５ When is NH, R ６ is preferably NHR ６Ａ and R ６Ａ is preferably hydrogen, hydroxy, or alkoxy, more preferably hydrogen or alkoxy, and even more preferably hydrogen;

[0031] R ５ When is NOH, R ６ is preferably alkyl,

[0032] R ６ -C (=R ５ )- is preferably selected from the following structures:

[0033] R ６ -C (=R ５ )- is more preferably selected from the following structures:

[0034] In formula (1), Q １ is N or CH, preferably N.

[0035] In formula (1), X １ has the following structure: (Wherein, A1 is an optionally substituted 5- to 7-membered heterocycle containing a nitrogen atom and a carbon atom as ring member atoms, L １ is a single bond or alkylene, and A2 is an optionally substituted aryl or an optionally substituted heteroaryl.

[0036] structure １ In the formula (I), A1 is an optionally substituted 5- to 7-membered heterocyclic ring containing a nitrogen atom and a carbon atom as ring member atoms, preferably an optionally substituted 5- to 7-membered heterocyclic ring containing one nitrogen atom and one carbon atom as ring member atoms, and more preferably an optionally substituted 5- or 6-membered heterocyclic ring containing one nitrogen atom and one carbon atom as ring member atoms.

[0037] A1 is preferably selected from the following structures which may be substituted:

[0038] A1 is more preferably selected from the following structures which may be substituted:

[0039] A1 is more preferably selected from the following structures which may be substituted:

[0040] Examples of the substituent for A1 include alkyl (e.g., alkyl having 1 to 6 carbon atoms or 1 to 3 carbon atoms), halogen (e.g., fluorine, chlorine, bromine, or iodine), or haloalkyl (e.g., haloalkyl having 1 to 6 carbon atoms or 1 to 3 carbon atoms).

[0041] structure １In the formula, L1 is a single bond or alkylene, preferably a single bond or alkylene having 1 to 6 carbon atoms, more preferably a single bond or alkylene having 1 to 3 carbon atoms, and even more preferably a single bond.

[0042] structure １ In the formula (I), A2 is an optionally substituted aryl or an optionally substituted heteroaryl, preferably an optionally substituted 6- to 10-membered aryl or an optionally substituted 6- to 10-membered heteroaryl, and more preferably an optionally substituted 6- to 10-membered aryl or an optionally substituted 6- to 10-membered heteroaryl containing a nitrogen atom and a carbon atom as ring member atoms.

[0043] A2 is preferably selected from the following structures which may be substituted:

[0044] A2 is more preferably selected from the following structures which may be substituted.

[0045] Examples of the substituent for A2 include alkyl (e.g., alkyl having 1 to 6 carbon atoms or 1 to 3 carbon atoms), halogen (e.g., fluorine, chlorine, bromine, or iodine), haloalkyl (e.g., haloalkyl having 1 to 6 carbon atoms or 1 to 3 carbon atoms), optionally substituted aryl, and optionally substituted heteroaryl.

[0046] The aryl as a substituent for A2 includes, for example, optionally substituted phenyl and optionally substituted naphthyl. Substituents for phenyl and naphthyl include, for example, halogen (e.g., fluorine, chlorine, bromine, or iodine).

[0047] Examples of the heteroaryl as a substituent for A2 include optionally substituted benzimidazole. Examples of the substituent for benzimidazole include halogen (e.g., fluorine, chlorine, bromine, or iodine).

[0048] In formula (1), X １ is preferably selected from the following structures:

[0049] In formula (1), X １ is more preferably selected from the following structures:

[0050] The compound represented by formula (1) is preferably the following compound:

[0051] The pharmaceutically acceptable salt of the compound represented by formula (1) is not particularly limited as long as it is usable as a pharmaceutical, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and hydrobromide; organic acid salts such as fumarate, maleate, malate, tartrate, succinate, citrate, methanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, lactate, and palmitate; inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, and ammonium salt; and organic base salts such as diethylamine salt, diethanolamine salt, meglumine salt, and N,N'-dibenzylethylenediamine salt.

[0052] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate. In this specification, solvates are included in the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0053] When stereoisomers (e.g., enantiomers and diastereomers) exist in the compound represented by formula (1) or a pharmaceutically acceptable salt thereof, the individual stereoisomers and mixtures thereof (e.g., racemates) are intended to be encompassed in the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0054] <Complement Factor D Inhibitor> One embodiment of the present invention relates to a complement factor D inhibitor comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The complement factor D inhibitor of this embodiment can act locally on the large intestine when orally administered.

[0055] Use of the complement factor D inhibitor of this embodiment makes it possible to treat and / or prevent diseases associated with (mediated by) complement factor D. Such diseases include those described in the section below under "Pharmaceutical Compositions."

[0056] The subjects to which the complement factor D inhibitor of this embodiment and the pharmaceutical composition described below are administered are preferably mammals, more preferably humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, and rabbits, and even more preferably humans.

[0057] <Pharmaceutical Composition> One embodiment of the present invention relates to a pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0058] Examples of diseases that the pharmaceutical composition of this embodiment can prevent or treat include age-related macular degeneration (e.g., dry or wet age-related macular degeneration), interstitial pneumonia associated with connective tissue disease, arthritis, Alzheimer's disease, multiple sclerosis (e.g., progressive multiple sclerosis), ulcerative colitis (e.g., ulcerative colitis or Crohn's disease), diabetic retinopathy, glaucoma, and periodontal disease. These diseases can be particularly targeted when the pharmaceutical composition acts locally. The pharmaceutical composition of this embodiment preferably acts locally on the large intestine when administered orally. The pharmaceutical composition of this embodiment preferably does not exhibit cytotoxicity.

[0059] Examples of diseases that can be prevented or treated by the pharmaceutical composition of this embodiment include nephropathy (e.g., C3 nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, or lupus nephritis), autoimmune diseases (e.g., neuromyelitis optica, scleroderma, myasthenia gravis, or antineutrophil cytoplasmic antibody-associated vasculitis), paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome. These diseases can be particularly targeted when the pharmaceutical composition acts systemically.

[0060] The pharmaceutical composition of this embodiment can be administered orally or parenterally. Examples of dosage forms for oral administration include tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions. Examples of dosage forms for parenteral administration include injections, infusions, drip infusions, eye drops, patches, and suppositories. Although not particularly limited, the pharmaceutical composition of this embodiment is preferably administered orally.

[0061] The pharmaceutical composition of the present embodiment may contain excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, flavoring agents, flavoring agents, stabilizers, thickeners, etc., as needed.

[0062] The dosage of the pharmaceutical composition of this embodiment varies depending on the condition and weight of the patient, the type of compound, the type of disease, the route of administration, etc., and an appropriate amount can be determined by a physician.

[0063] <Method for Producing Compound> The compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be synthesized by appropriately utilizing known methods. Examples of synthesis routes include the following schemes A to D.

[0064] R in Schemes A to D １ ~R ４ , A1, L １ , and A2 are as described above.

[0065] For the reaction conditions of each step in Schemes A to D, see, for example, the examples described below, as well as WO 2015 / 130854, WO 2018 / 229543, WO 2020 / 041301, and WO 2020 / 051532.

[0066] The method for synthesizing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is not limited to the above schemes A to D, and a person skilled in the art can appropriately design an appropriate synthetic route depending on the structure of the final compound.

[0067] The present invention will be described in more detail below using examples and comparative examples, but the technical scope of the present invention is not limited to these.

[0068] <Abbreviation> Boc: tert-butoxycarbonyl Cy ３ P.HBF ４ : Tricyclohexylphosphine tetrafluoroborate DIPEA : N,N-diisopropylethylamine DMF : N,N-dimethylformamide DMSO : Dimethyl sulfoxide HATU : 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Pd(dppf)Cl ２ : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh ３ ) ４ : Tetrakis(triphenylphosphine)palladium(0) SEM : 2-(trimethylsilyl)ethoxymethyl T3P : Propylphosphonic anhydride

[0069] <Synthesis of Compounds> [Synthesis Example 1-1] 6-iodo-1,3-dihydroisobenzofuran-5-amine N-Bromosuccinimide (13.8 g) was added to a mixture of 1,3-dihydro-2-benzofuran-5-amine (10.0 g) and acetonitrile (80 ml) at -10°C, and the mixture was stirred for 2 hours under ice-cooling. The resulting solid was collected by filtration, washed with hexane / ethyl acetate, and dried to give the title compound (7.5 g). 1H NMR (400 MHz, DMSO-d6) δ 4.85 (s, 4H), 5.28 (d, J = 21.2 Hz, 2H), 6.69 (s, 1H), 7.27 (s, 1H).

[0070] Synthesis Example 1-2: 6-methyl-1,3-dihydroisobenzofuran-5-amine To a mixture of 6-bromo-1,3-dihydroisobenzofuran-5-amine (7.0 g) in 1,4-dioxane (90 ml) and water (30 ml), methylboronic acid (11.7 g), tripotassium phosphate (24.3 g), tricyclohexylphosphine tetrafluoroborate (1.4 g), and palladium(II) acetate (0.73 g) were added at room temperature, and the mixture was heated at 120°C for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.2 g). 1H NMR (400 MHz, DMSO-d6) δ2.04 (s, 3H), 4.76 (s, 2H), 4.83 (s, 4H), 6.50 (s, 1H), 6.83 (s, 1H).

[0071] Synthesis Example 1-3 5,7-dihydro-1H-furo[3,4-f]indazole To a mixture of 6-methyl-1,3-dihydroisobenzofuran-5-amine (3.0 g) and water (27 mL), 12N hydrochloric acid (7.2 mL) was added dropwise under ice cooling. To this mixture, an aqueous solution of NaNO (1.38 g) dissolved in water (2.4 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. Next, an aqueous solution of sodium tetrafluoroborate (2.4 g) dissolved in water (3.6 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. The solid was collected by filtration and dissolved in chloroform (90 mL). 18-crown-6 (106 mg) and potassium acetate (3.9 g) were added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Dichloromethane and water were added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.0 g), which was used in the next reaction without purification. MS (ESI) m / z: 161.1 [M+H]+ 1H NMR (DMSO-d6) δ 12.98 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 5.05 (s, 2H), 5.02 (s, 2H).

[0072] Synthesis Example 1-4 3-iodo-5,7-dihydro-1H-furo[3,4-f]indazole To a stirred mixture of 5,7-dihydro-1H-furo[3,4-f]indazole (2.9 g) and DMF (54 mL), potassium hydroxide (1.47 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Next, a solution of iodine (11 g) in DMF (120 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration and washed with hexane to obtain the title compound (3.7 g), which was used in the next reaction without purification. MS (ESI) m / z: 287.0 [M+H]+ H NMR (DMSO-d6) δ 13.43 (s, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 5.05 (s, 2H), 5.04 (s, 2H).

[0073] Synthesis Example 1-5: tert-Butyl 2-(3-iodo-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate To a mixture of 3-iodo-5,7-dihydro-1H-furo[3,4-f]indazole (10.0 g), anhydrous potassium carbonate (14.47 g), and DMF (170 mL), tert-butyl bromoacetate (7.7 mL) was added at room temperature and stirred for 16 hours. Ice-cold water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (11.3 g). LC / MS (ESI) m / z: 401.1 [M+H]+ 1H NMR (DMSO-d6) δ 7.55 (s, 1H), 7.33 (s, 1H), 5.27 (s, 2H), 5.06 (d, J = 4.7 Hz, 4H), 1.41 (s, 9H).

[0074] Synthesis Example 1-6: tert-Butyl 2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate tert-Butyl 2-(3-iodo-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (500 mg), acetonitrile (15 ml), triethylamine (3 ml), zinc cyanide (220 mg), zinc dust (40 mg), and Pd(dppf)Cl ２ A mixture of (45 mg) was heated at 80°C under an argon atmosphere for 16 hours. The reaction mixture was cooled to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (280 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H), 5.09 (d, J = 7.0 Hz, 4H), 5.46 (s, 2H), 7.79 (s, 2H).

[0075] Synthesis Example 1-7: tert-Butyl 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate To a stirred solution of tert-butyl 2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (291 mg) in DMSO (3 ml) were added potassium carbonate (20 mg) and then 30% aqueous hydrogen peroxide (0.5 ml) under ice-cooling. The mixture was stirred at room temperature for 2 hours, then ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (200 mg). LC / MS (ESI) m / z: 318.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H), 5.07 (s, 4H), 5.30 (s, 2H), 7.39 (s, 1H), 7.59 (s, 1H), 7.69 (s, 1H), 8.05 (s, 1H).

[0076] Synthesis Example 1-8 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid To a mixture of tert-butyl 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (395 mg) and dichloromethane (8 ml), trifluoroacetic acid (2 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the precipitate was dried to obtain the title compound (350 mg), which was used in the next reaction without purification. LC / MS (ESI) m / z: 262.2 [M+H]+

[0077] [Synthesis Example 1-9] 5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole 6-bromo-7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole Sodium hydride (2.5 g, 60% oil) was added to a mixture of 5-bromo-4-chloro-1H-1,3-benzodiazole (10.0 g) and THF (50 ml) under ice-cooling. After stirring for 10 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (15 ml) was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Ice-cooled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound mixture (12.0 g). LC / MS (ESI) m / z: 363.02 [M+H]+

[0078] [Synthesis Example 1-10] 3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-fluoroaniline 3-(7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-2-fluoroaniline A mixture of 5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole and 6-bromo-7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (6.0 g), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.8 g), potassium carbonate (6.9 g), 1,4-dioxane (125 ml) and water (20 ml) was treated with Pd(PPh ３ ) ４ (1.9 g) was added, and the mixture was heated at 100° C. for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a mixture of the title compounds (5.8 g). LC / MS (ESI) m / z: 392.51 [M+H]+

[0079] Synthesis Example 1-11 tert-butyl (2S,4R)-2-((3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate tert-butyl (2S,4R)-2-((3-(7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (10.41 g) in DMF (125 ml), DIPEA (18 ml) and then HATU (22.6 g) were added and stirred at room temperature for 10 minutes. To the mixture, a mixture of 3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-fluoroaniline and 3-(7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-2-fluoroaniline (11.7 g) was added at room temperature, and the mixture was stirred at the same temperature for 17 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound mixture (16.5 g). LC / MS (ESI) m / z: 607.2 [M+H]+

[0080] Synthesis Example 1-12 (2S,4R)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide dihydrochloride (17) To a solution of a mixture (7 g) of tert-butyl (2S,4R)-2-((3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate and tert-butyl (2S,4R)-2-((3-(7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate in dichloromethane (100 ml) was added 4N hydrogen chloride / 1,4-dioxane solution (200 ml) under ice-cooling, and the reaction mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, diethyl ether was added to the residue, and the solid matter was collected by filtration and washed with diethyl ether to give the title compound (5.0 g). LC / MS (ESI) m / z: 377.1 [M+H]+

[0081] Example 1 1-(2-((2S,4R)-2-((3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxamide To a mixture of 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (560 mg) and pyridine (20 ml), EDC·HCl (1.8 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To the mixture, (2S,4R)—N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide dihydrochloride (700 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 16 hours. After concentration under reduced pressure, ice-cold water was added, and the resulting solid was collected by filtration and purified by silica gel column chromatography (methanol / dichloromethane) to obtain the title compound (104 mg). LC / MS (ESI) m / z: 620.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 2.08 - 2.28 (m, 1H), 2.55 - 2.62 (m, 1H), 3.87-4.02 (m, 1H), 4.15-4.28 (m, 1H), 4.75 (t, J = 8.5 Hz, 1H), 4.91 - 5.08 (m, 4H), 5.39 - 5.75 (m, 3H), 7.05-7.23 (m, 3H), 7.36 (s, 1H), 7.51 (s, 1H), 7.56 - 7.72 (m, 2H), 7.94 - 7.98 (m, 1H), 8.03 (s, 1H), 8.36 (s, 1H), 9.98 (s, 1H), 12.74 - 12.94 (m, 1H).

[0082] Synthesis Example 2-1 tert-butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate To a mixture of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (1.0 g) and dichloroethane (20 ml), DIPEA (3.9 ml) and then N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (3.15 g) were added at room temperature, and the mixture was stirred at the same temperature for 10 minutes. 6-Bromo-3-methylpyridin-2-amine (656 mg) was added to the mixture, and the mixture was heated at 80°C for 16 hours. After cooling the reaction mixture to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (800 mg). LC / MS (ESI) m / z: 410.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 0.61 (dd, J = 5.4, 2.4 Hz, 1H), 0.68 (t, J = 5.6 Hz, 1H), 1.01 - 1.16 (m, 1H), 1.20 (s, 3H), 1.39 (s, 9H), 1.91 - 1.95 (m, 1H), 2.11 (s, 3H), 3.10 - 3.14 (m, 1H), 4.06 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 10.20 (s, 1H).

[0083] Synthesis Example 2-2 (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide To a solution of tert-butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg) in dichloromethane (10 ml), 4N hydrogen chloride / 1,4-dioxane solution (10 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added to the residue, followed by extraction with 5% methanol / dichloromethane solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (200 mg), which was used in the next reaction without purification. LC / MS (ESI) m / z: 310.1 [M+H]+

[0084] Example 2 1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxamide To a mixture of 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (182 mg), DMF (4 ml), DIPEA (0.5 ml), and T3P (50% ethyl acetate solution) (0.8 ml), (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (150 mg) was added at room temperature, and the mixture was stirred at the same temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (YMC-Actus C18 (20 × 250 mm, 5 μm) 10 mM aqueous ammonium acetate solution / acetonitrile) to obtain the title compound (80 mg). LC / MS (ESI) m / z: 553.3 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 0.88 - 1.01 (m, 2H), 1.33 (s, 3H), 1.99 - 2.17 (m, 4H), 2.45 - 2.55 (m, 1H), 3.47 - 3.52 (m, 1H), 4.46 - 4.50 (m, 1H), 5.03-5.10 (m, 4H), 5.40 (d, J = 17.2 Hz, 1H), 5.61 (d, J = 17.2 Hz, 1H), 7.36 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.62 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 10.25 (s, 1H).

[0085] Synthesis Example 3-1 tert-butyl (2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate To a mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (500 mg), dichloromethane (10 ml), and DIPEA (1.18 ml), 1-chloro-N,N,2-trimethyl-1-propenylamine (0.3 ml) and then 6-bromo-3-methylpyridin-2-amine (19) (561 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (600 mg). LC / MS (ESI) m / z: 404.0 [M+H]+

[0086] Synthesis Example 3-2 (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide To a solution of tert-butyl (2S,4R)-2-(6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (600 mg) in dichloromethane (10 ml), 4N hydrogen chloride / 1,4-dioxane solution (10 ml) was added under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. Saturated sodium bicarbonate solution was added, and the mixture was extracted with 5% methanol / dichloromethane solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (350 mg), which was used in the next reaction without purification. LC / MS (ESI) m / z: 304.1 [M+H]+

[0087] Example 3 1-(2-((2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxamide To a mixture of 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (131 mg), DMF (4 ml), and DIPEA (0.3 ml), T3P (50% ethyl acetate solution) (0.6 ml) and (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (100 mg) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 16 hours, after which a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by NH-modified silica gel column chromatography (methanol / dichloromethane) to obtain the title compound (48 mg). LC / MS (ESI) m / z: 545.13 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 1.98 (s, 3H), 2.05 - 2.25 (m, 1H), 2.59 - 2.63 (m, 1H), 2.78 - 3.02 (m, 1H), 4.12-4.27 (m, 1H), 4.58 (t, J = 8.6 Hz, 1H), 4.95 - 5.06 (m, 4H), 5.36-5.47 (m, 2H), 5.63 (d, J = 17.2 Hz, 1H), 7.35 - 7.49 (m, 3H), 7.58-7.66 (m, 2H), 8.03 (s, 1H), 10.47 (s, 1H).

[0088] Synthesis Example 4-1 tert-butyl (2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (500 mg) in DMF (10 ml), DIPEA (2.15 ml) and then T3P (50% ethyl acetate solution) (1.35 ml) were added at room temperature. (3-Chloro-2-fluorophenyl)methanamine (0.27 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (450 mg). LC / MS (ESI) m / z: 375.3 [M+H]+

[0089] Synthesis Example 4-2 (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide To a solution of tert-butyl (2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (350 mg) in dichloromethane (5 ml), 4N hydrogen chloride / 1,4-dioxane solution (7 ml) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added to the residue, followed by extraction with a 5% methanol / dichloromethane mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (240 mg), which was used in the next reaction without purification. LC / MS (ESI) m / z: 275.0 [M+H]+

[0090] Example 4 1-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxamide To a mixture of 2-(3-carbamoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (237 mg), DMF (10 ml), and DIPEA (0.5 ml), T3P (50% ethyl acetate solution) (0.8 ml) and (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (26) (172 mg) were added sequentially at room temperature. After stirring at the same temperature for 16 hours, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (YMC-Actus C18 (20 × 250 mm, 5 μm) 10 mM aqueous ammonium acetate solution / acetonitrile) to obtain the title compound (165 mg). LC / MS (ESI) m / z: 518.4 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ1.95-2.18 (m, 1H), 2.40-2.50 (m, 1H), 3.81 - 3.95 (m, 1H), 4.10 -4.50 (m, 4H), 4.85 - 5.10 (m, 4H), 5.33 - 5.66 (m, 3H), 6.87 - 7.98 (m, 1H), 7.14 - 7.45 (m, 3H), 7.50 (s, 1H), 7.64 (s, 1H), 8.05 (s, 1H), 8.62 (s, 1H).

[0091] Synthesis Example 5-1 tert-Butyl 2-(3-iodo-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate To a mixture of tert-butyl 2-(3-iodo-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (7) (4.5 g) and toluene (68 mL), Pd(PPh ３ ) ４(1.3 g), followed by tributyl(1-ethoxyvinyl)tin (5.7 mL) was added. The mixture was heated at 110°C for 16 hours under a nitrogen atmosphere, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added to the residue, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (90 mL), and 2N hydrochloric acid (13.5 mL) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (hexane / ethyl acetate) to give the title compound (3.3 g). 1H NMR (DMSO-d6) δ 8.06 (s, 1H), 7.65 (s, 1H), 5.41 (s, 2H), 5.08 (s, 4H), 2.62 (s, 3H), 1.43 (s, 9H).

[0092] Synthesis Example 5-2 2-(3-acetyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid To a solution of tert-butyl 2-(3-iodo-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (2.6 g) in dichloromethane (78 mL) was added dropwise trifluoroacetic acid (13 mL) under ice cooling. The mixture was stirred at room temperature for 8 hours and then concentrated under reduced pressure. The residue was dissolved in chloroform and concentrated under reduced pressure. The solid was collected by filtration to give the target compound (1.5 g), which was used in the next reaction without further purification. LC / MS (ESI) m / z: 261.25 [M+H]+ 1H NMR (DMSO-d6) δ 13.26 (s, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 5.42 (s, 2H), 5.08 (s, 4H), 2.61 (s, 3H).

[0093] Example 5 (2S,4R)-1-(2-(3-acetyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide To a mixture of 2-(3-acetyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (4.6 g) and pyridine (30 ml), EDC·HCl (10.17 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. To the mixture, (2S,4R)—N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (8.7 g) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of ice-cold water. The solid was collected by filtration and purified by silica gel column chromatography (methanol / dichloromethane) to obtain the title compound (1.8 g). LC / MS (ESI) m / z: 619.30 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 2.08 - 2.28 (m, 1H), 2.50-2.60 (m, 4H), 3.93 - 4.09 (m, 1H), 4.14 - 4.28 (m, 1H), 4.75 (t, J = 8.5 Hz, 1H), 4.91 - 5.07 (m, 4H), 5.48 - 5.62 (m, 2H), 5.76 (d, J = 17.8 Hz, 1H), 7.09 - 7.24 (m, 3H), 7.50 - 7.68 (m, 2H), 7.88 - 7.95 (m, 1H), 8.03 (s, 1H), 8.28 (s, 1H), 9.49 - 9.75 (m, 1H), 12.45 - 12.70 (m, 1H).

[0094] Example 6 (2S,4R)—N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoro-1-(2-(3-(1-(hydroxyimino)ethyl)-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)pyrrolidine-2-carboxamide To a mixture of (2S,4R)-1-(2-(3-acetyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide (160 mg) and pyridine (12 ml), hydroxylamine hydrochloride (89 mg) was added at room temperature, and the mixture was heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue was added 5% citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (YMC-Actus C18 (20 x 250 mm, 5 µm) 10 mM aqueous ammonium acetate solution / acetonitrile) to give the title compound (31 mg). LC / MS (ESI) m / z: 634.5 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 2.08 - 2.22 (m, 1H), 2.27 (s, 3H), 2.55 - 2.62 (m, 1H), 3.89 - 4.05 (m, 1H), 4.14 - 4.28 (m, 1H), 4.74 (t, J = 8.0 Hz, 2H), 4.91 - 5.08 (m, 4H), 5.35 - 5.63 (m, 3H), 7.08 - 7.27 (m, 3H), 7.43 (s, 1H), 7.52 - 7.68 (m, 1H), 7.92-8.01 (m, 2H), 8.36 (s, 1H), 9.95 (s, 1H), 11.24 (s, 1H), 12.50 (s, 1H).

[0095] Synthesis Example 7-1: Methyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxylate To a mixture of tert-butyl 2-(3-iodo-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (1 g), methanol (40 ml), and TEA (0.7 ml), 1,3-bis(diphenylphosphino)propane (346 mg) and then palladium(II) acetate (84 mg) were added, and the mixture was heated at 100°C for 16 hours under a positive pressure of carbon monoxide (autoclave, 80 psi). The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (584 mg). LC / MS (ESI) m / z: 333.3 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.92 (s, 3H), 5.09 (s, 4H), 5.40 (s, 2H), 7.67 (s, 1H), 7.95 (s, 1H).

[0096] Synthesis Example 7-2 2-(3-(methoxycarbonyl)-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid To a solution of methyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxylate (584 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml) under ice-cooling. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was collected by filtration and washed with diethyl ether to give the title compound (400 mg). LC / MS (ESI) m / z: 277.1 [M+H]+

[0097] Synthesis Example 7-3: Methyl 1-(2-((2S,4R)-2-((3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxylate To a mixture of 2-(3-(methoxycarbonyl)-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (483 mg), DMF (10 ml), and DIPEA (1.76 ml), T3P (50% ethyl acetate solution) (1.1 ml) and then (2S,4R)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide dihydrochloride (785 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (330 mg). LC / MS (ESI) m / z: 635.3 [M+H]+

[0098] Example 7 1-(2-((2S,4R)-2-((3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxylic acid To a mixture of methyl 1-(2-((2S,4R)-2-((3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-5,7-dihydro-1H-furo[3,4-f]indazole-3-carboxylate (312 mg) and THF (15 mL), lithium hydroxide monohydrate (164 mg) was added at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous potassium hydrogen sulfate solution was added to the residue, followed by extraction with a 5% methanol / dichloromethane mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (YMC-Actus C18 (20 × 250 mm, 5 μm) 10 mM aqueous ammonium acetate solution / acetonitrile) to obtain the title compound (70 mg). LC / MS (ESI) m / z: 621.5 [M+H]+ 1H NMR (401 MHz, DMSO-d6) δ2.08-2.19 (m, 1H), 2.55-2.63 (m, 1H), 3.87-4.04 (m, 1H), 4.14-4.27 (m, 1H), 4.75 (t, J = 8.8 Hz, 1H), 4.91 - 5.08 (m, 5H), 5.51-5.71 (m, 3H), 7.07 - 7.25 (m, 3H), 7.49 (s, 1H), 7.55-7.62 (m,1H), 7.93 - 8.03 (m, 2H), 8.35 (s, 1H), 9.97 (s, 1H).

[0099] Synthesis Example 8-1 2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid To a stirred solution of tert-butyl 2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetate (2.0 g) and dichloromethane (30 ml), 4N hydrogen chloride / 1,4-dioxane solution (50 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was collected by filtration and washed with diethyl ether to give the title compound (1.85 g). 1H NMR (400 MHz, DMSO-d6) δ 5.08 (s, 2H), 5.09 (s, 2H), 5.46 (s, 2H), 7.79 (s, 1H), 7.80 (s, 1H), 13.21 - 13.58 (m, 1H).

[0100] Synthesis Example 8-2 (2S,4R)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-1-(2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide To a mixture of 2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetic acid (800 mg), DMF (20 ml), and DIPEA (2.4 ml), T3P (50% ethyl acetate solution) (2.6 ml) and (2S,4R)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide dihydrochloride (1 g) were added sequentially at room temperature. The mixture was stirred at the same temperature for 16 hours, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (500 mg). LC / MS (ESI) m / z: 602.5 [M+H]+

[0101] Example 8 (2S,4R)-1-(2-(3-carbamimidoyl-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide trifluoroacetate (2S,4R)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-1-(2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide (300 mg) was added with a solution of hydrogen chloride gas saturated in methanol (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (5 ml). To this was added a 7N ammonia / methanol solution (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Kinetex evo C18 (21.2 × 250 mm, 5 μm) 0.1% aqueous trifluoroacetic acid / acetonitrile)) to obtain the title compound (25 mg). LC / MS (ESI) m / z: 619.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 2.10 - 2.28 (m, 1H), 2.55 - 2.62 (m, 1H), 3.93 - 4.09 (m, 1H), 4.14 - 4.28 (m, 1H), 4.75 (t, J = 8.5 Hz, 1H), 4.97 - 5.11 (m, 4H), 5.45 - 5.65 (m, 2H), 5.80 (d, J = 17.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.30 - 7.36 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.87 (s, 1H), 7.94 (t, J = 7.8 Hz, 1H), 8.44 (s, 1H), 9.07 (s, 1H), 9.33 (s, 2H), 10.01 (s, 1H).

[0102] Example 9 (2S,4R)—N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-4-fluoro-1-(2-(3-(N-hydroxycarbamimidoyl)-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)pyrrolidine-2-carboxamide To a mixture of (2S,4R)-N-(3-(4-chloro-1H-benzo[d]imidazol-5-yl)-2-fluorophenyl)-1-(2-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide (200 mg), methanol (10 ml), and potassium carbonate (68 mg), hydroxylamine hydrochloride (58 mg) was added at room temperature, and the mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (YMC-Actus C18 (20 × 250 mm, 5 μm) 10 mM aqueous ammonium acetate solution / acetonitrile) to obtain the title compound (75 mg). LC / MS (ESI) m / z 635.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ2.08 - 2.27 (m, 1H), 2.55 - 2.60 (m, 1H), 3.84 - 4.00 (m, 1H), 4.13 - 4.25 (m, 1H), 4.74 (t, J = 8.4 Hz, 1H), 4.93 - 5.03 (m, 4H), 5.33 - 5.48 (m, 2H), 5.55-5.63 (m, 3H), 7.05-7.11 (m, 1H), 7.15 - 7.23 (m, 2H), 7.44 (s, 1H), 7.55-7.70 (m, 1H), 7.92 (s, 1H), 7.96 (t, J = 7.2 Hz, 1H), 8.36 (s, 1H), 9.78 (s, 1H), 9.97 (s, 1H), 12.86 (s, 1H).

[0103] Comparative Example 1 In Comparative Example 1, the following Danicopan was used.

[0104] Comparative Example 2 In Comparative Example 2, the following Vemircopan was used.

[0105] Test Example 1: Complement Factor D (FD) Inhibitory Activity Measurement Method Veronal Buffer (10 mM MgCl ２ Complement factor B (final concentration: 400 nM), C3b (final concentration: 280 nM), and test compound solutions (final concentrations: 3000 nM, 1000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0 nM) were mixed on ice in a 1000 mL PBS containing 1% ethanol, and then FD (final concentration: 1 nM) was added and the mixture was incubated at 37°C for 40 minutes to prepare a sample (total volume: 10 μL). To each sample, 3.3 μL of 4x Laemmli Sample Buffer (containing 10% 2-mercaptoethanol) was added, and the mixture was heat-denatured at 95°C for 5 minutes. SDS-PAGE was then performed using a polyacrylamide gel (SuperSep Ace 15%) and Tris / Glycine / SDS Buffer. After electrophoresis, the gel was stained with Oriole Fluorescent Gel Stain, and the stained image was captured using a ChemiDoc Imaging System (BIO-RAD). The intensity of the bands representing Ba in the Oriole-stained image was quantified using ImageJ. The FD inhibition rate was set to 100% when no FD was added, and 0% when no test compound was added. The FD inhibition rate for each compound was calculated. In addition, curve fitting was performed using a four-parameter logistic function as a regression model, and the inflection point was taken as IC50. IC50 values ​​<200 nM were rated as "A," and IC50 values ​​between 200 and 1000 nM were rated as "B." The results are shown in Table 1.

[0106]

[0107] Test Example 2: Measurement of Blood Concentration After Oral Administration The test compound was crushed in a mortar and suspended by adding 0.5% methylcellulose solution in small amounts at a concentration of 15 mg / mL. Eight-week-old male C57BL / 6 mice were orally administered with 150 mg / kg of the compound. Blood was collected 0.5, 1, 2, 4, 8, and 10 hours later to obtain plasma. For comparative examples, the compound was administered at 50 mg / kg. Plasma concentrations were measured by LC-MS to determine the maximum plasma concentration (Cmax). Plasma Cmax of >500 ng / mL was evaluated as "A," 50-500 ng / mL as "B," and <50 ng / mL as "C." The results are shown in Table 2.

[0108]

[0109] Test Example 3: AUC Measurement After Intravenous Administration The test compound was dissolved to 0.1 mg / mL using a mixed solvent (DMSO: a 1:1 mixture of Solutol HS15 and Ethanol: physiological saline at 10:10:80) to prepare a dosing solution. The test compound was intravenously administered to 6-8 week old male C57BL / 6 mice at 1 mg / kg, and blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours later to obtain plasma. The plasma concentration was measured by LC-MS, and the AUC ０→ｔ The AUC after intravenous administration was calculated. ０－ｔ However, when the concentration was >1000 ng*h / mL, the evaluation was "A", when it was 100 to 1000 ng*h / mL, the evaluation was "B", and when it was <100 ng*h / mL, the evaluation was "C". The results are shown in Table 3.

[0110]

[0111] Test Example 4: Measurement of Concentration in Colon Tissue The test compound was crushed in a mortar and suspended by adding 0.5% methylcellulose solution in small amounts at a concentration of 15 mg / mL. Eight-week-old male C57BL / 6 mice were orally administered with 150 mg / kg of test compound. Ten hours later, the mice were sacrificed by exsanguination, and colon tissue samples were collected. For comparative examples, the test compound was administered at 50 mg / kg. Colon tissue was pretreated, and the tissue concentration of the compound was measured by LC-MS. The colon tissue concentration 10 hours after administration was divided by the plasma Cmax determined by the method of Test Example 2. A value of <1 was assigned an "A," a value of 1 to 5 was assigned a "B," and a value of >5 was assigned a "C." The results are shown in Table 4.

[0112]

[0113] Test Example 5: Measurement of Cytotoxicity Cytotoxicity and mitochondrial toxicity were measured using the following method as a cytotoxicity test. HepG2 cells (5 x 10(3) cells / well) acclimated to glucose medium (25 mM glucose DMEM, Thermo Fisher) or galactose medium (10 mM galactose DMEM, Thermo Fisher) were seeded into a 384-well plate containing a compound at a final concentration of 100 μM (final DMSO concentration of 1%) and cultured at 37°C in a 5% CO2 incubator for 24 hours. After 24 hours, the amount of intracellular ATP was measured using Cell Titer-Glo (registered trademark) (Promega), and the ATP content relative to the solvent control group was calculated.

[0114] Evaluation results: When the ATP content in the glucose medium containing the test substance was 90% or less, it was judged to have cytotoxicity. Also, when the ATP content in the galactose medium containing the test substance was 20% or more lower than the ATP content in the glucose medium, it was judged to have mitochondrial toxicity. As a result, neither cytotoxicity nor mitochondrial toxicity was observed in Examples 1 and 5.

Claims

The following formula (1): [In the formula, R １ ~R ４ are each independently hydrogen, alkyl, halogen, or haloalkyl; R ５ is O or NR ５Ａ and R ５Ａ is hydrogen, hydroxy, or alkoxy; R ６ is alkyl, NHR ６Ａ or hydroxy, R ６Ａ is hydrogen, hydroxy, or alkoxy; Q １ is N, X １ has the following structure: (In the formula, A1 is an optionally substituted 5- to 7-membered heterocycle containing a nitrogen atom and a carbon atom as ring member atoms, L １ is a single bond or alkylene, A2 is an optionally substituted aryl or an optionally substituted heteroaryl. have] or a pharmaceutically acceptable salt thereof. R ３ and R ４ is hydrogen, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. R １ ~R ４ is hydrogen, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. R ５ is O, R ６ is alkyl, NH ２ or hydroxy; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. R ５ is NH, R ６ However, NHR ６Ａ and R ６Ａ is hydrogen, hydroxy, or alkoxy; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. R ５ is NOH, R ６ is alkyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. R ６ -C (=R ５ )—has the following structure: Selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 　 A1 is an optionally substituted structure: Selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 　 A1 has at least one substituent selected from the group consisting of alkyl, halogen, and haloalkyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 　 A2 is an optionally substituted structure: Selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 　 A2 has at least one substituent selected from the group consisting of alkyl, halogen, haloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. X １ has the following structure: Selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. The compound represented by formula (1) is the following compound: Selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 　 A complement factor D inhibitor comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 　 A pharmaceutical composition comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 　 The pharmaceutical composition according to claim 15, for use in the treatment and / or prevention of a disease selected from the group consisting of age-related macular degeneration, interstitial pneumonia associated with collagen disease, arthritis, Alzheimer's disease, multiple sclerosis, ulcerative colitis, diabetic retinopathy, glaucoma, and periodontal disease.

16. The pharmaceutical composition of claim 15 for use in the treatment and / or prevention of a disease selected from the group consisting of nephropathy, autoimmune diseases, paroxysmal nocturnal hemoglobinuria, and hemolytic uremic syndrome.

Images