Heterocyclic derivatives for treating TRPM3-mediated disorders

Abstract

The present invention relates to compounds useful for the prevention or treatment of TRPM3-mediated disorders, more particularly disorders selected from pain and inflammatory hypersensitivity. The present invention also relates to methods for the prevention or treatment of said TRPM3-mediated disorders.

Description

[Technical Field]

[0001] The present invention relates to compounds useful for the prevention or treatment of TRPM3-mediated disorders, more specifically, disorders selected from pain and inflammatory hypersensitivity. The present invention also relates to methods for the prevention or treatment of said TRPM3-mediated disorders. [Background technology]

[0002] The TRP superfamily consists of proteins with six transmembrane domains (6TM) that assemble as homotetramers or heterotetramers to form cation-permeable ion channels. The name TRP originates from the Drosophila trp (transient receptor potential) variant, characterized by a transient receptor potential in the fly photoreceptor in response to sustained light. Over the past 15 years, trp-related channels have been identified in yeast, parasites, insects, fish, and mammals, including 27 TRPs in humans. Based on sequence homology, TRP channels can be divided into seven subfamilies: TRPC, TRPV, TRPM, TRPA, TRPP, TRPML, and TRPN.

[0003] Members of the TRP superfamily are expressed in virtually all mammalian organs and cell types, and significant progress has been made in understanding their physiological roles in recent years. The customized selectivity of certain TRP channels is evident in Ca 2+ Mg 2+ This enables them to play a crucial role in the cellular uptake and / or transepithelial transport of trace metal ions. Furthermore, the sensitivity of TRP channels to a wide range of chemical and physical stimuli allows them to function as dedicated biological sensors involved in processes from vision to taste and touch. Specifically, several members of the TRP superfamily exhibit extremely high sensitivity to temperature. These so-called thermo-TRPs are highly expressed in sensory neurons and / or cutaneous keratinocytes and function as primary thermosensors for detecting harmless and harmful (painful) temperatures.

[0004] It is becoming increasingly clear that TRP channel dysfunction is directly involved in the pathogenesis of various hereditary and acquired diseases. In fact, both loss-of-function and gain-of-function mutations in TRP channel genes have been identified as direct causes of hereditary diseases including brachiolemia, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, type IV mucolipidosis, and familial focal segmental glomerulosclerosis. Furthermore, TRP channel dysfunction is directly associated with a wide range of pathological conditions, including chronic pain, hypertension, cancer, and neurodegenerative disorders.

[0005] TRPM3 (transient receptor potential melastatin 3) represents a promising pharmacological target. TRPM3 is expressed in a large subset of small-diameter sensory neurons from the dorsal root and trigeminal ganglion and is involved in heat sensing. The neurosteroid pregnenolone sulfate is a known potent activator of TRPM3 (Wagner et al., 2008). Pregnenolone sulfate induced pain in wild-type mice but not in knockout TRPM3 mice. More recently, it has also been shown that CFA-induced inflammation and inflammatory pain are eliminated in TRPM3 knockout mice. Therefore, TRPM3 antagonists may be used as analgesics to counteract pain, including inflammatory pain (Vriens J. et al. Neuron, May 2011).

[0006] While several TRPM3 antagonists are known, none of them refer to the compound of the present invention (Straub I et al. Mol Pharmacol, November 2013). For example, liquiritigenin, a hypothetical TRPM3 blocker, has been described as reducing mechanical and cold hyperalgesia in a rat pain model (Chen L et al. Scientific reports, July 2014). There remains a great medical need for novel, alternative, and / or better treatments for the prevention or treatment of TRPM3-mediated disorders, more specifically for pain such as inflammatory pain. Good efficacy for certain types of pain, low levels or no side effects (such as no potential for toxicity and no toxicity, as with opioids), and / or good or better pharmacokinetic or pharmacodynamic properties are in great need.

[0007] The present invention provides novel compounds that are TRPM3 antagonists and can be used as modulators of TRPM3-mediated disorders. [Overview of the project]

[0008] The present invention provides benzofuran derivatives and pharmaceutical compositions comprising such benzofuran derivatives. The present invention also provides benzofuran derivatives for use as pharmaceuticals, more specifically for use in the prevention and / or treatment of TRPM3-mediated disorders, in particular for use in the prevention and / or treatment of pain and / or inflammatory hypersensitivity, and / or for use against pain and / or inflammatory hypersensitivity.

[0009] The present invention also provides the use of benzofuran derivatives for the manufacture of pharmaceutical compositions or pharmaceuticals for the prevention and / or treatment of TRPM3-mediated disorders, particularly for the prevention and / or treatment of pain and / or inflammatory hypersensitivity, and / or for counteracting pain and / or inflammatory hypersensitivity.

[0010] The present invention also provides a method for the prevention or treatment of TRPM3-mediated disorders by administering a benzofuran derivative according to the present invention to a subject in need thereof. More specifically, the present invention relates to such methods for the prevention and / or treatment of pain and / or inflammatory hypersensitivity, and / or for counteracting pain and / or inflammatory hypersensitivity.

[0011] The present invention relates to a method for preparing benzofuran derivatives, - The step of reacting benzoquinone with a suitable β-ketoester or enamine derivative to obtain a 5-hydroxybenzofuran-3-carboxylate ester derivative, - The step of obtaining a 5-O-substituted benzofuran-3-carboxylate ester derivative by substituting a previously obtained 5-hydroxybenzofuran-3-carboxylate ester derivative with a suitable derivative or alcohol derivative having a releasing group under Mistunobu conditions, - The step of converting a previously obtained 5-O-substituted benzofuran-3-carboxylic acid ester derivative in a carboxylic acid to obtain a desired benzofuran derivative of the present invention, -A method is further provided which includes the step of combining a previously obtained 5-O-substituted benzofuran-3-carboxylic acid derivative with a suitable amine to obtain a desired amide derivative of the present invention. [Modes for carrying out the invention]

[0012] The present invention may be further described in part with respect to specific embodiments, but is not limited thereto.

[0013] A first aspect of the present invention preferably provides a compound of formula (I), its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs for use in the treatment of pain. [ka] During the ceremony, R 1is -F, -Cl, -Br, -I, -CN, -R W , -OR W , -OC(=O)R W , -NR W R X , -NR W C(=O)R X , -SR W , -S(=O)R W , -S(=O)2R W , -C(=O)R W , -C(=O)OR W , or -C(=O)NR W R X represents, Q is -OR 2 or -NR 3 R 4 represents, R 2 is -R Y represents, R 3 is -OH or -R Y represents, R 4 is -R Y or -S(=O)2R Y represents, or alternatively, R 3 and R 4 together contain 1 to 3 heteroatoms selected from N, O, and S and form a saturated or unsaturated, unsubstituted, or mono- or polysubstituted 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring, T represents -O-, U represents -CR 5 R 5 ’-, or T represents -CR 5 R 5 ’- and U represents -O-, R 5 and R 5 ’ are each independently -R Y represents, R 6 , R 7 , and R 8 are each independently -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W , -OR W , -OC(=O)R W, -NR W R X , -NR W C(=O)R X , -SR W -S(=O)R W -S(=O)2R W -C(=O)R W , -C(=O)OR W , or -C(=O)NR W R X This represents, V is a saturated or unsaturated 3-14 member heterocycloalkyl or 5-14 member heteroaryl, in each case unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z Represents a saturated or unsaturated 3-14 member heterocycloalkyl or 5-14 member heteroaryl that is monosubstituted or polysubstituted with substituents selected from, During the ceremony, R W and R X However, independently of each other, in each case, independently, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group. R Y and R Z However, independently of each other, in each case, independently, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl, Unsubstituted, mono-substituted or multi-substituted 6- to 14-member aryl, wherein the 6- to 14-member aryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case, saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 6- to 14-member aryl, or Unsubstituted, mono-substituted or multi-substituted 5- to 14-member heteroaryl, wherein the 5- to 14-member heteroaryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case, saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 5- to 14-member heteroaryl, represents, or or, R Y and R Z together contain 1 to 3 heteroatoms selected from N, O, and S and form a saturated or unsaturated, unsubstituted, or mono-substituted or multi-substituted 4-, 5-, 6-, 7-, or 8-member heterocyclic ring, "Mono-substituted or multi-substituted" is, in each case, independently of one another, -F, -Cl, -Br, -I, -CN, -C 1-6 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -alkylene-O-CF3, -C 1-6 -alkylene-O-CF2H, -C 1-6 -alkylene-O-CFH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C 1-6 -alkylene-C(=O)-OH, -C(=O)-OC 1-6 -alkyl, -C 1-6-alkylene-C(=O)-OC 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-C(=O)-NH(C 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-C(=O)-N(C 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6 -alkylene-C(=O)-NH(OH), -OH, -C 1-6 -alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -O-C 1-6 -alkyl, -C 1-6 -alkylene-O-C 1-6 -alkyl, -O-C 1-6 -alkylene-O-C 1-6 -alkyl, -O-C 1-6 -alkylene-NH2, -O-C 1-6 -alkylene-NH-C 1-6 -alkyl, -O-C 1-6 -alkylene-N(C 1-6 -alkyl)2, -O-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-O-C(=O)-C 1-6 -alkyl, -O-C(=O)-O-C 1-6 -alkyl, -C 1-6 -alkylene-O-C(=O)-O-C 1-6 -alkyl, -O-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-O-C(=O)-NH(C 1-6 -alkyl), -O-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-O-C(=O)-N(C 1-6 -alkyl)2, -O-S(=O)2-NH2, -C 1-6-Alkylene-OS(=O)2-NH2, -OS(=O)2-NH(C 1-6 -alkyl), -C 1-6 -Alkylene-OS(=O)2-NH(C) 1-6 -alkyl), -OS(=O)2-N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-OS(=O)2-N(C) 1-6 -alkyl)2, -NH2, -NO, -NO2, -C 1-6 -Alkylene-NH2, -NH(C) 1-6 -alkyl), -N (3-14 member cycloalkyl) (C 1-6 -alkyl), -N(C 1-6 -alkyl)-C 1-6 -Alkylene-OH,-N(H)-C 1-6 -alkylene-OH, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -NH-C(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-NH-C(=O)-C 1-6 -alkyl, -NH-C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-C(=O)-OC 1-6 -alkyl, -NH-C(=O)-NH2, -C 1-6 -Alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-C(=O)-N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-C1-6 -alkyl, -N(C 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -N(C 1-6 -alkyl)-C(=O)-NH2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-NH2, -N(C 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -NH-S(=O)2OH, -C 1-6 -Alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -alkyl, -C 1-6 -Alkylene-NH-S(=O)2-C 1-6 -alkyl, -NH-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-OC 1-6 -alkyl, -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C) 1-6 -alkyl), -NH-S(=O)2N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-S(=O)2N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-S(=O)2-OH, -C 1-6 -Alkylene-N(C)1-6 -alkyl)-S(=O)2-OH, -N(C 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -N(C 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -N(C 1-6 -alkyl)-S(=O)2-NH2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH2, -N(C 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 -alkyl, -C 1-6 -Alkilen-SC 1-6 -alkyl, -S(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -C 1-6 -Alkylene-S(=O)2-C 1-6 -alkyl, -S(=O)2-OH, -C 1-6 -Alkylene-S(=O)2-OH, -S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-OC 1-6-alkyl, -S(=O)2-NH2, -C 1-6 -Alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-S(=O)2-NH(C) 1-6 -alkyl), -S(=O)2-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-S(=O)2-N(C) 1-6 -alkyl)2,3-14 member cycloalkyl, -C 1-6 -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl, -C 1-6 -alkylene-(3-14 member heterocycloalkyl), -phenyl, -C 1-6 -alkylene-phenyl, 5-14 member heteroaryl, -C 1-6 This means that the molecule is substituted with one or more substituents selected from -alkylene-(5-14 member heteroaryl), -O-(3-14 member cycloalkyl), -O-(3-14 member heterocycloalkyl), -O-phenyl, -O-(5-14 member heteroaryl), -C(=O)-(3-14 member cycloalkyl), -C(=O)-(3-14 member heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5-14 member heteroaryl), -S(=O)2-(3-14 member cycloalkyl), -S(=O)2-(3-14 member heterocycloalkyl), -S(=O)2-phenyl, -S(=O)2-(5-14 member heteroaryl).

[0014] In preferred embodiments of the benzofuran derivative according to the present invention, (a-1) Q is -OR 2 Represents R 1 However, it represents -CH2F, -CHF2, or -CF3, and / or (a-2) Q is -OR 2 Represents R 5 and R 5 At least one of the ' does not represent -H, and / or (a-3) Q is -OR 2 Represents R 6However, it does not represent -H, and / or (a-4) Q is -OR 2 Represents R 8 However, it does not represent -H, or (b-1) Q is -NR 3 R 4 This represents the following, provided that the following compounds and their salts are not included: [ka] and / or (b-2)Q is -NR 3 R 4 Represents R 1 -CH2F, -CHF2, -CF3, -CN, -propyl, or -cyclopropyl, and / or (b-3)Q is -NR 3 R 4 Represents R 5 and R 5 At least one of the ' does not represent -H, and / or (b-4)Q is -NR 3 R 4 Represents R 3 However, this represents -H.

[0015] In preferred embodiments of the benzofuran derivative according to the present invention, T represents -O- and U represents -CR 5 R 5 '- represents. According to this embodiment, the benzofuran derivative according to the present invention is the compound of formula (II), its stereoisomer, a physiologically acceptable salt, a solvate, and / or polymorph. [ka]

[0016] In another preferred embodiment of the benzofuran derivative according to the present invention, T is -CR 5 R 5 ' represents -, and U represents -O-.

[0017] In preferred embodiments of the benzofuran derivative according to the present invention, Q is -NR 3 R 4 It represents.

[0018] In another preferred embodiment of the benzofuran derivative according to the present invention, Q is -OR 2 It represents.

[0019] In preferred embodiments of the benzofuran derivatives according to the present invention, V is unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z This represents a 5- to 14-membered heteroaryl aryl that is monosubstituted or polysubstituted with substituents selected from ,

[0020] Preferably, the 5-14 member heteroaryl in the definition of V is not an unsubstituted, monosubstituted, or polysubstituted benzofuran.

[0021] Preferably, the 5-14 member heteroaryls in the definition of V are benzimidazole, benzisoxazole, benzoazole, benzodioxol, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinolin, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indidine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxy Selected from sadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, in each case unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z It is monosubstituted or polysubstituted with substituents selected from the following.

[0022] Preferably, the 5-14 member heteroaryls within the definition of V are selected from the group consisting of furan, thiophene, imididazole, pyrazole, oxazole, isoxazole, thiazole, triazole, pyridine, isoquinoline, benzothiazole, pyridazine, pyrimidine, and imidazopyridine, and in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y, -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z It is monosubstituted or polysubstituted with substituents selected from the available options.

[0023] Preferably, the 5-14 member heteroaryls within the definition of V are selected from the group consisting of furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, pyrazole-5-yl, oxazole-5-yl, isoxazole-4-yl, thiazole-2-yl, thiazole-5-yl, 1,2,4-triazole-3-yl, 1,2,3-triazole-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, isoquinoline-1-yl, isoquinoline-5-yl, benzo[d]thiazole-2-yl, pyridazine-3-yl, pyrimidine-5-yl, and imidazo[1,2-a]pyridine-6-yl, and in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z It is monosubstituted or polysubstituted with substituents selected from the available options.

[0024] In another preferred embodiment of the benzofuran derivative according to the present invention, V is saturated or unsaturated, unsubstituted, and independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z This represents a 3- to 14-membered heterocycloalkyl group that is monosubstituted or polysubstituted with substituents selected from the following.

[0025] Preferably, the 3-14 member heterocycloalkyls in the definition of V are azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofurane, tetrahydropyrane, tetrahydrothiopyrane, thiazolidine, thiethane, thiran, thiolane, thiomorpholine, indoline, dihydrobenzofurane, Selected from dihydrobenzothiophene, 1,1-dioxotiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y-OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z It is monosubstituted or polysubstituted with substituents selected from the following.

[0026] Preferably, the 3-14 member heterocycloalkyl group in the definition of V is tetrahydropyran or pyrrolidine, in each case unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z It is monosubstituted or polysubstituted with substituents selected from the available options.

[0027] Preferably, the 3- to 14-membered heterocycloalkyl group in the definition of V is tetrahydropyran-4-yl or pyrrolidine-3-yl, in each case unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)RY -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z It is monosubstituted or polysubstituted with substituents selected from the available options.

[0028] In preferred embodiments of the benzofuran derivatives according to the present invention, V is unsubstituted and independently of each other. -F, -Cl, -Br, -I, -CN, -C(=O)OH, -NH2, -NO2, -OH, =O, -SF5, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -NHC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -N(C) 1-6 -alkyl)2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted, -S(=O)2-C1-6-alkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case is monosubstituted or polysubstituted with substituents selected from saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl groups.

[0029] Preferably, V is non-substitutable and independent of each other. -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2, or -N(CH3)2, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 - A substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which can be monosubstituted or polysubstituted. 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 - A substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which can be monosubstituted or polysubstituted. 1-6 -heteroalkyl, Non-substitutive, mutually independent: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6-OC substituents selected from the group consisting of -alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, either monosubstituted or polysubstituted. 1-6 -Alkyl, Non-substitutive, mutually independent: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -O(C=O)C 1-6 -Alkyl, Non-substitutive, mutually independent: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -C(=O)OC with a substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, either monosubstituted or polysubstituted. 1-6 -Alkyl, A 3- to 14-membered cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, wherein in each case, the elements are unsubstituted and independently of each other are -F, -Cl, -Br, -I, and -C. 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, monosubstituted or polysubstituted, 3- to 14-membered cycloalkyl groups, Azepane, 1,4-Oxazepane, Azetan, Azetidine, Aziridine, Azocane, Diazepane, Dioxane, Dioxolane, Dithiane, Dithiolane, Imidazolidine, Isothiazolidine, Isoxalidine, Morpholine, Oxazolidine, Oxepane, Oxetane, Oxirane, Oxirane, Piperazine, Piperidine, Pyrazolidine, Pyrrolidine, Quinuclidin, Tetrahydrofuran, Tetrahydropyran, Tetrahydrothiopyran, Thiazolidine, Thietan, Thiran, Thiolane, Thiomorpholine, Indoline, Dihydrobenzofuran, Dihydrobe Selected from the group consisting of nziothiophene, 1,1-dioxotiacyclohexane, 2-azabicyclo[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azabicyclo[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case being unsubstituted and independently of each other, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 It is monosubstituted or polysubstituted with a substituent selected from the group consisting of -alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, and is monosubstituted or polysubstituted with a substituent selected from 3 to 14-membered heterocycloalkyl groups.

[0030] Preferably, V is unsubstituted and independently of each other: -F, -Cl, -CN, -OH, =O, -C 1-6 -alkyl, -CHF2, -CF3, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkylene-NHC(=O)-OC 1-6 -alkyl, -C(=O)OC 1-6-alkyl, -N(C 1-6 -alkyl)2, -OC 1-6 -alkyl, -OCF3, -OC 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -S(=O)2-C 1-6 -alkyl, -azetidine, -C 1-6 -alkylene-O-tetrahydropyran, or -C 1-6 -It is monosubstituted or polysubstituted with a substituent selected from alkyl-substituted -piperazines.

[0031] In a preferred embodiment of the benzofuran derivative according to the present invention, V is (i) Is it a non-substitution? (ii) Whether it has been substituted, (iii) Whether it is substituted twice, (iv) It is cubic, or (v) It is quaternarily substituted.

[0032] In a preferred embodiment of the benzofuran derivative according to the present invention, V is (i) Is it a non-substitution? (ii) One substitution, or (iii) Two substitutions have been made.

[0033] In preferred embodiments, V represents a saturated or unsaturated 3-14 member heterocycloalkyl (preferably a 5-member heterocycloalkyl) or a 5-14 member heteroaryl (preferably a 5-member heteroaryl), which in each case is unsubstituted, monosubstituted, or polysubstituted, and is preferably a residue selected from the group consisting of the following: [ka]

[0034] In preferred embodiments, V represents an unsubstituted, monosubstituted, or polysubstituted oxetanyl, preferably, [ka] That is the case.

[0035] In a preferred embodiment, V represents a residue according to general formula (E), [ka] During the ceremony, Y E1 -N=, -NR E2 -, S, O, or -CR E3 = represents Y E2 -N=, -NR E3 -, S, O, or -CR E4 = represents Y E3 -N=, -NR E4 -, S, O, or -CR E5 = represents Y E1 , Y E2 , and Y E3 At least one of them is -CR E3 =, -CR E4 =, and -CR E5 The condition is that it is not equal to. In another preferred embodiment, V represents a residue according to general formula (E), In the formula, YE1 represents -N=, -NRE2-, S, or -CRE3=, YE2 represents -N=, -NRE3-, S, or -CRE4=, and YE3 represents -N=, -NRE4-, S, or -CRE5=, provided that at least one of YE1, YE2, and YE3 is not -CRE3=, -CRE4=, or -CRE5=, respectively. R E1 , R E2 , R E3 , and R E4 These independently represent -H, -CH3, -CH2-cyclopropyl, -CH2CF3, -CH2CHF2, or -CF3, and more specifically, R E1 , R E2 , R E3 , and R E4 These represent -H, -CH3, or -CF3 independently of each other, but preferably R E1 , R E2 , R E3 , and R E4The condition is that only one of them represents a residue that is not -H.

[0036] In a preferred embodiment, V represents an unsubstituted, monosubstituted, or polysubstituted 2-pyridine. In a preferred embodiment, V represents a residue selected from the group consisting of the following: [ka]

[0037] In a preferred embodiment, V represents an unsubstituted, monosubstituted, or polysubstituted 3-pyridine. In a preferred embodiment, V represents a residue selected from the group consisting of the following: [ka]

[0038] In a preferred embodiment, V represents an unsubstituted, monosubstituted, or polysubstituted 4-pyridine. In a preferred embodiment, V represents a residue selected from the group consisting of the following: [ka]

[0039] In a preferred embodiment, V represents a residue selected from the group consisting of the following: [ka]

[0040] In preferred embodiments, V represents an unsubstituted, monosubstituted, or polysubstituted bicyclic heteroaryl, and is preferably selected from the group consisting of the following: [ka]

[0041] In a preferred embodiment, V represents a residue according to general formula (F'), [ka] During the ceremony, Y F1 -N= or -CR F4 = represents Y F2 -N= or -CR F5 = represents Y F3 -N= or -CR F3 = represents Y F1 and Y F2 At least one of them is -CR F4 = and -CR F5 Assuming that it is not equal to, R F1 , R F2 , R F3 , R F4 , and R F5 Each of these independently represents -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, or -azetidinyl, but preferably R F1 , R F2 , R F3 , R F4 , and R F5 The condition is that only one of them represents a residue that is not -H. In another preferred embodiment, V represents a residue according to general formula (F), [ka] During the ceremony, Y F1 -N= or -CR F4 = represents Y F2 -N= or -CR F5 = represents Y F1 and Y F2 At least one of them is -CR F4 = and -CR F5 Assuming that it is not equal to, R F1 , R F2 , R F3 , R F4 , and R F5 Each of these independently represents -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, or -azetidinyl, but preferably R F1 , RF2 , R F3 , R F4 , and R F5 The condition is that only one of them represents a residue that is not -H.

[0042] In a preferred embodiment, V represents a residue according to general formula (G) or (H), [ka] In the formula, R G1 and R H1 is selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, azetidinyl, -cyclopropyl, -O-cyclopropyl, and -CHF2, or R G1 and R H1 The group is selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, and azetidinyl. In other preferred embodiments, V represents a residue according to the general formula (G') or (H'), [ka] In the formula, R G1 and R H1 is selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, azetidinyl, -cyclopropyl, -O-cyclopropyl, and -CHF2, or R G1 and R H1 The group is selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, and azetidinyl.

[0043] In a preferred embodiment of the benzofuran derivative according to the present invention, R 1 teeth, -H, -F, -Cl, -Br, -I, -CN, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-6-alkyl, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -O-C1-6-alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)NHC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)N(C 1-6 -alkyl)2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group, wherein the 3- to 14-membered cycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group.

[0044] Preferably, R 1 -H, -F, -Cl, -Br, -I, -C 1-6 -alkyl, -OC 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 -alkyl, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -Alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6-Alkilen-NH-C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-N(C) 1-6 -Alkilen)-C 1-6 -Alkylene-CF3, -C(=O)C 1-6 -alkyl, -C(=O)OC 1-6 -alkyl, -C(=O)NH2, -C(=O)NHC 1-6 -alkyl, -C(=O)N(C 1-6 -alkyl)2, -S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -OC 1-6 - Represents alkyl, unsubstituted-cyclopropyl, unsubstituted-cyclobutyl, unsubstituted-cyclopentyl, or unsubstituted-cyclohexyl.

[0045] Preferably, R 1 -H, -C 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 - Represents alkyl, -CH2F, -CHF2, -CF3, unsubstituted -cyclopentyl, or -cyclopropyl. Preferably, R 1 -H, -C 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 - Represents alkyl, -CH2F, -CHF2, -CF3, -cyclopentyl, or unsubstituted. Preferably, R 1 This represents -CH3.

[0046] Preferably, R 1 represents -CH2F, -CHF2, -CH3, or -cyclopropyl. Preferably, R 1 represents -CH2F, -CHF2, or -CH3. Preferably, R 1 This represents -C(=O)NH2 or -CHF2.

[0047] Preferably, R 1 -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-3-Alkylene-CF3, -C 1-3 -Alkylene-CF2H, -C 1-3 - Represents alkylene-CFH2 or - cyclopropyl, preferably R 1 -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-3 -Alkylene-CF3, -C 1-3 -Alkylene-CF2H, or -C 1-3 - Represents alkylene-CFH2, more preferably -CH3-

[0048] In a preferred embodiment of the benzofuran derivative according to the present invention, R 2 teeth, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group.

[0049] Preferably, R 2 -H, -C 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 -alkyl, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6-Alkylene-N(C) 1-6 -Alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, or -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C 1-6 - Represents alkylene-CF3

[0050] Preferably, R 2 is -H or -C 1-6 - Represents alkyl groups.

[0051] In a preferred embodiment of the benzofuran derivative according to the present invention, R 3 teeth, -H, -OH, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl, This represents saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 heteroalkyl groups.

[0052] Preferably, R 3 These are -H, -OH, and -C 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -Alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkilen-NH-C1-6 -Alkylene-CF3, or -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C 1-6 - Represents alkylene-CF3

[0053] Preferably, R 3 -H, -OH, or saturated, unsubstituted, or monosubstituted with -OH -C 1-6 - Represents alkyl. Preferably, R 3 This represents -H.

[0054] Preferably, R 3 represents -H, and R 4 represents a residue other than -H.

[0055] In a preferred embodiment of the benzofuran derivative according to the present invention, R 4 teeth, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl, Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, wherein the 6- to 14-membered aryls are optionally linked through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case being saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, An unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl.

[0056] Preferably, R 4 teeth, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C)1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -S(=O)2C 1-6 -Alkyl, -S(=O)2 (3-14 member cycloalkyl), wherein the 3-14 member cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in each case, saturated or unsaturated, unsubstituted, and independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -S(=O)2(3-14 member cycloalkyl), monosubstituted or polysubstituted with substituents selected from the group consisting of -alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6-Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -The substituent is monosubstituted or polysubstituted with a substituent selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl, -C 1-6 -Alkyl, 3-14 member cycloalkyl or -C 1-6 -Alkylene-(3-14 member cycloalkyl), -C 1-6 -Alkylene- is unsubstituted or monosubstituted with -OH, and the 3- to 14-membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in each case is saturated or unsaturated, and in each case is unsubstituted, and independently of each other, -F, -Cl, and -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6-alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -A 3-14 member cycloalkyl or -C cycloalkyl group that is monosubstituted or polysubstituted with a substituent selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl groups, and unsubstituted 5-14 member heteroaryl groups. 1-6 -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl or -C 1-6 -Alkylene-(3-14 member heterocycloalkyl), and -C 1-6 -Alkylene- is either unsubstituted or monosubstituted with -OH, and the 3- to 14-membered heterocycloalkyl is, in each case, azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thiethane, thiran, thiolane Selected from the group consisting of thiomorpholin, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxotiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case being unsubstituted, and independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6-Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -A 3-14 member heterocycloalkyl or -C that is monosubstituted or polysubstituted with a substituent selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl. 1-6 -Alkylene-(3-14 member heterocycloalkyl), Non-substitutive, mutually independent: -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6-alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -phenyl, monosubstituted or polysubstituted with substituents selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl. 5-14 member heteroaryl or -C 1-6 -Alkilen- (5-14 member heteroaryl), -C 1-6-Alkylene- is unsubstituted or monosubstituted with -OH, and the 5-14 member heteroaryl is, in each case, benzimidazole, benzisoxazole, benzoazole, benzodioxol, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinolin, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indidine, isobenzofuran, isoindole, isoquinoline, Selected from the group consisting of isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxiindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, in each case unsubstituted, and independently of each other, -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl, monosubstituted or polysubstituted with substituents selected from the group consisting of 5-14 member heteroaryl or -C 1-6 -Alkilen- (5-14 member heteroaryl) represents this.

[0057] Preferably, R 4 teeth, -H, Saturated, unsubstituted, monosubstituted or polysubstituted with -F, -S(=O)2C 1-6 -Alkyl, Saturated, unsubstituted -S(=O)2 (3-14 member cycloalkyl), Saturated, unsubstituted, and mutually independent: -OH, =O, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2, -OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C(=O)NH2, -C(=O)-NH-C 1-3 -alkyl, -C(=O)-N(C 1-3 -C 1-6 -Alkyl, 3-14 member cycloalkyl or -C 1-6 -Alkylene-(3-14 member cycloalkyl), -C 1-6 -Alkylene- is either unsubstituted or monosubstituted with -OH, and the 3-14 member cycloalkyl group is saturated, unsubstituted, and independently of each other, -C 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6-Alkilen-NH-C 1-6 -Alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -OH, -OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2,-NHC(=O)OC 1-6 -3-14 member cycloalkyl or -C atoms monosubstituted or disubstituted with substituents selected from the group consisting of alkyl groups. 1-6 -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl or -C 1-6 -Alkylene-(3-14 member heterocycloalkyl), and -C 1-6 -Alkylene- is either unsubstituted or monosubstituted with -OH, and the 3-14 member heterocycloalkyl is, in each case, azetane, 1,4-oxazepane, pyrrolidine, piperidine, azepane, diazepane, tetrahydrofuran, tetrahydropyran, oxetane, morpholine, piperazine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, octahydro- Selected from pyrrolo[1,2-a]pyrazine, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, quinuclidine, hexahydro-1H-pyrrolidine, 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, and 1,1-dioxotiacyclohexane, in each case unsubstituted, independently of each other, -F, -OH, =O, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -S(=O)2C 1-6 -alkyl, oxetanyl, pyrimidinyl, -C 1-6 -3-14 member heterocycloalkyl or -C atoms monosubstituted or polysubstituted with substituents selected from the group consisting of alkylene-phenyl. 1-6 -Alkylene-(3-14 member heterocycloalkyl), Unsubstituted phenyl, 5-14 member heteroaryl or -C 1-6 -Alkilen- (5-14 member heteroaryl), -C 1-6 -Alkylene- is either unsubstituted or monosubstituted with -OH, and the 5-14 member heteroaryl is selected in each case from the group consisting of pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, and in each case, unsubstituted, and independently of each other, -C 1-6 -A 5-14 member heteroaryl or -C heteroaryl molecule that is monosubstituted or disubstituted with a substituent selected from the group consisting of -alkyl and -OH. 1-6 -Alkilen- (5-14 member heteroaryl) represents this.

[0058] In a preferred embodiment of the benzofuran derivative according to the present invention, R 3 and R 4 Together, they form a saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted five- or six-membered heterocycle containing one or two heteroatoms selected from N, O, and S.

[0059] Preferably, R 3 and R 4 Together, they form a heterocycle selected from the group consisting of pyrrolidine, piperidine, morpholine, and piperazine, in each case being unsubstituted or independently of each other, -F, -C 1-6 -alkyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH-C1-6 -alkyl, -C(=O)N(C 1-6 -alkyl)2, -C(=O)OC 1-6 -alkyl, -NHC(=O)OC 1-6 -alkyl, unsubstituted -pyridyl, and unsubstituted or -C 1-6 - It is monosubstituted or polysubstituted with substituents selected from the group consisting of 1,2,4-oxadiazole monosubstituted with alkyl. In a preferred embodiment, R 3 and R 4 They do not combine to form unsubstituted, monosubstituted, or polysubstituted morpholines.

[0060] Preferably, R 3 and R 4 Together, Unsubstituted or monosubstituted with -N(CH3)2, pyrrolidine rings Unsubstituted, or -C 1-6 -alkyl, -NH2, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl, -C(=O)OC 1-6 -alkyl, -NHC(=O)OC 1-6 -alkyl, and unsubstituted or -C 1-6 -A piperidine ring, monosubstituted with a substituent selected from the group consisting of 1,2,4-oxadiazole monosubstituted with alkyl, Unsubstituted morpholine rings, or Unsubstituted, or -C 1-6 It forms a piperidine ring, which is N-substituted with substituents selected from the group consisting of alkyl and unsubstituted pyridyl rings.

[0061] In a preferred embodiment, R 3 and R 4 Neither of them represents -H. In a preferred embodiment, R 3 and R 4 These, together with the nitrogen atom to which they are bound, form a residue selected from the following group. [ka]

[0062] In another preferred embodiment, R 3 represents -H, and R 4 This does not represent -H.

[0063] In a preferred embodiment, R 3 represents -H, and R 4 R represents saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl. In preferred embodiments, R 3 represents -H, and R 4 This represents a residue selected from the following group: [ka]

[0064] In a preferred embodiment, R 3 represents -H, and R 4 This is the residue -CR'R''-(CH2) m -OH represents -OH, where m is an integer between 1 and 6, preferably between 1 and 3, and R' and R'' are independent of each other, -H and -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -Alkylene-CF3, -C 1-3 -Alkylene-CF2H, -C 1-3 -Alkylene-CFH2, -C 1-3 -Alkilen-OC 1-3 -alkyl, -C 1-3 -alkylene-OH, -C(=O)-NH2, or C(=O)-NH-C 1-3 -alkyl, preferably -H, -CH3, -C 1-3 -alkylene-OH, -C(=O)-NH2, or C(=O)-NH-C 1-3 - Represents alkyl. In preferred embodiments, at least R' or R'' does not represent -H. In preferred embodiments, neither R' nor R'' represents -H.

[0065] In another preferred embodiment, R 3 represents -H, and R 4represents a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-member cycloalkyl, or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-member heterocycloalkyl.

[0066] In a preferred embodiment, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3-member cycloalkyl, or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3-member heterocycloalkyl. In a preferred embodiment, R 3 represents -H, and R 4 represents a residue selected from the group consisting of.

Chemical formula

[0067] In a preferred embodiment, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-member cycloalkyl (preferably 4-member cycloalkyl), or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-member heterocycloalkyl (preferably 4-member heterocycloalkyl). In a preferred embodiment, R 3 represents -H, and R 4 represents a residue selected from the group consisting of.

Chemical formula

[0068] In a preferred embodiment, R 3 represents -H, and R 4 represents a residue according to general formula (A),

Chemical formula

[0069] In a preferred embodiment, R 3 represents -H, R 4 represents a residue according to general formula (A) defined above, m A is 0 or 1, Y A is selected from -O- and -CR A7 R A8 -, R A1 、R A2 、R A3 、R A4 、R A5 、R A7 、and R A8 are, independently of one another, -H, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C 1-3 -alkyl)2, -C(=O)NH2, or -CHF2, preferably, R A1 、R A2 、R A3 、R A4 、R A5 、R A7 、and R A8 are, independently of one another, -H, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C 1-3 -alkyl)2, or -C(=O)NH2, preferably, R A1 、R A2 、R A3 、R A4 、RA5 , R A7 , and R A8 The condition is that only one of them represents a residue that is not -H.

[0070] In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue according to the general formula (A) defined above, m A However, it is either 0 or 1, Y A However, -O- and -CR A7 R A8 - Selected from, R A1 However, -C 1-3 -alkylene-OH, -C 1-3 -Alkylene-N(C) 1-3 -Alkyl)2, -C(=O)NH2, or -CHF2, preferably R A1 However, -C 1-3 -alkylene-OH, -C 1-3 -Alkylene-N(C) 1-3 -Alkyl)2, or -C(=O)NH2, R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 However, this represents -H.

[0071] In a preferred embodiment, R 3 represents -H, and R 4 R represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl (preferably a 5-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (preferably a 5-membered heterocycloalkyl), or an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl (preferably a 5-membered heteroaryl). In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue selected from the following group: [ka]

[0072] In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue according to general formula (B), [ka] During the ceremony, Y B However, -O-, -NR B8 -, and -CR B9 R B10 - Selected from, R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 , R B9 , and R B10 However, independently of each other, -H, -F, -OH, -C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -Alkilen-OC 1-3 -alkyl, -C 1-3 -Alkylene-CF3, -C 1-3 -Alkylene-CO2H, -C 1-3 -Alkylene-C(=O)OC 1-3 -alkyl, -C(=O)NH2, -C(=O)NH-C 1-3 -alkyl, or -C(=O)N(C 1-3 - Represents alkyl)2, or R B2 and R B3 However, together they represent =O, or R B4 and R B5 However, together they represent = O.

[0073] In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue according to the general formula (B) defined above, Y B However, -O- and -NRB8 - Selected from, R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 However, -H, -F, and -C are independent of each other. 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 - Represents alkylene-CF3 or -C(=O)-NH2, or R B2 and R B3 Together, they represent =O, or R B4 and R B5 Together, they represent =O, but preferably R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 The condition is that only one, two, or three of them represent a residue that is not -H, preferably R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 The condition is that at least one of them represents a residue that is not -H.

[0074] In a preferred embodiment, R 3 represents -H, and R 4 R represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl (preferably a 6-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (preferably a 6-membered heterocycloalkyl), or an unsubstituted, monosubstituted or polysubstituted 6- to 14-membered aryl (preferably a 6-membered aryl), or an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl (preferably a 6-membered heteroaryl). In a preferred embodiment, R 3 represents -H, and R 4This represents a residue selected from the following group: [ka]

[0075] In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue according to general formula (C), [ka] During the ceremony, Y C1 However, -O-, -S(=O)2-, -NR C8 -, and -CR C9 R C10 - Select from, Y C2 However, -CR C11 R C12 - represents or Y C1 However, -CR C9 R C10 - represents Y C2 However, -O-, -S(=O)2-, and -NR C8 - Selected from, R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 However, they are independent of each other. -H, -F, -OH, -C(=O)OC 1-3 -alkyl, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2, -C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene, -C(=O)NH2, -C(=O)NH-C 1-3 -alkyl, or -C(=O)N-(C 1-3 - Represents alkyl)2, or R C2 and RC3 Together, they represent =O, or R C4 and R C5 Together, they represent =O, or R C9 and R C10 Together, they represent =O, or R C11 and R C12 Together, they represent = O.

[0076] In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue according to the general formula (C) defined above, Y C1 However, -O- or -NR C8 - Select from, Y C2 However, -CR C11 R C12 - represents or Y C1 However, -CR C9 R C10 - represents Y C2 However, -O- and -NR C8 - Selected from, R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 However, -H, -F, and -C are independent of each other. 1-3 -alkyl, -C 1-3 -Alkilen - It represents OH or -C(=O)-NH2, but preferably R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12The condition is that only one, two, or three of them represent a residue that is not -H, preferably R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 The condition is that at least one of them represents a residue that is not -H.

[0077] In a preferred embodiment, R 3 represents -H, and R 4 R represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 7-membered cycloalkyl group, or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 7-membered heterocycloalkyl group. In preferred embodiments, R 3 represents -H, and R 4 This represents the following residues. [ka]

[0078] In a preferred embodiment, R 3 represents -H, and R 4This represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group (preferably a 4, 5, or 6-membered cycloalkyl group), which is linked through a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene- group, or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group (preferably a 4, 5, or 6-membered heterocycloalkyl group), which is linked through a saturated or unsaturated, unsubstituted, monosubstituted or The 36-14 member aryl is connected through a polysubstituted -C1-C6-alkylene- or an unsubstituted, monosubstituted or polysubstituted 6- to 14 member aryl (preferably a 6 member aryl), and the 36- to 14 member aryl is connected through a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene- or an unsubstituted, monosubstituted or polysubstituted 5- to 14 member heteroaryl (preferably a 5 member or 6 member heteroaryl), and the 5- to 14 member heteroaryl is connected through a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene-. In a preferred embodiment, R 3 represents -H, and R 4 This represents a residue selected from the following group: [ka]

[0079] In a preferred embodiment, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted five-membered heterocycloalkyl group, which is linked through a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene- or an unsubstituted, monosubstituted or polysubstituted five-membered heteroaryl group, which is linked through a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene-.

[0080] In a preferred embodiment, R 3 represents -H, and R4 This represents a residue selected from the following group: [ka]

[0081] In a preferred embodiment, R 3 represents -H, and R 4 teeth, (i) Residue -CR'R''-(CH2) m -OH, where m is an integer from 1 to 6, preferably an integer from 1 to 3, and R' and R'' are independently -H and -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -Alkylene-CF3, -C 1-3 -Alkylene-CF2H, -C 1-3 -Alkylene-CFH2, -C 1-3 -Alkilen-OC 1-3 -alkyl, or -C 1-3 - Represents alkylene-OH, preferably -H, -CH3, or -C 1-3 -CR'R''-(CH2) represents the alkylene-OH group. m Represents -OH. In a preferred embodiment, at least R' or R'' does not represent -H. In a preferred embodiment, neither R' nor R'' represents -H, or (ii) Residues according to general formula (D), [ka] During the ceremony, m D and n D However, they are 0, 1, 2, or 3, independently of each other, but preferably m D +n D The condition is that ≤ 3, Y D1 is -O-, -S(=O)2-, -S(=O)(=NH)-, -NR D8 -, and -CR D9 R D10 - Select from, Y D2 However, -CR D11 R D12- represents or Y D1 However, -O-, -S(=O)2-, -NR D8 -, and -CR D9 R D10 - Select from, Y D2 However, -CR D11 R D12 - represents or Y D1 However, -CR D9 R D10 - represents Y D2 However, -O-, -S(=O)2-, and -NR D8 - Selected from, R D1 , R D2 , R D3 , R D4 , R D5 , R D6 , R D7 , R D8 , R D9 , R D10 , R D11 , and R D12 However, independently of each other, -H, -F, -OH, -C 1-3 -Alkylene-OH, -C(=O)NH2, -C 1-3 -Alkylene-C(O)NH2, -C(=O)OC 1-3 -alkyl, -NH2, -C 1-3 -Alkylene-NH2, -NH(C) 1-3 -alkyl), -N(C 1-3 -alkyl)2,-NH(C 1-3 -Alkylene-CF3), -C 1-3 -Alkylene-OCH3, -C 1-3 -alkyl, -C 1-3 - Represents alkylene-CF3, or R D2 and R D3 Together, they represent =O, or R D4 and R D5 Together, they represent =O, or R D9 and R D10 Together, they represent =O, or R D11 and R D12 Together, they represent = O, Preferably, m D and n DHowever, they are 0, 1, 2, or 3, independently of each other, but preferably m D +n D The condition is that ≤ 3, Y D1 However, -O-, -NR D8 -, and -CR D9 R D10 - Select from, Y D2 However, -CR D11 R D12 - represents or Y D1 However, -CR D9 R D10 - represents Y D2 However, -O- and -NR D8 - Selected from, R D1 , R D2 , R D3 , R D4 , R D5 , R D6 , R D7 , R D8 , R D9 , R D10 , R D11 , and R D12 However, independently of each other, -H, -F, -OH, -C 1-3 - Represents alkylene-OH, -C(=O)NH2, -CH2NH2, -CH2N(CH3)2, -NHCH2CF3, -CH3, or -CH2CF3, or R D2 and R D3 Together, they represent =O, or R D4 and R D5 Together, they represent =O, or R D9 and R D10 Together, they represent =O, or R D11 and R D12 Together, they represent =O, but preferably R D1 , R D2 , R D3 , R D4 , R D5 , R D6 , R D7 , R D8 , R D9 , R D10 , R D11 , and R D12The condition is that only one, two, or three of them represent a residue that is not -H, preferably R D1 , R D2 , R D3 , R D4 , R D5 , R D6 , R D7 , R D8 , R D9 , R D10 , R D11 , and R D12 The condition is that at least one of them represents a residue that is not -H.

[0082] In a preferred embodiment of the benzofuran derivative according to the present invention, R 5 and R 5 ' are independent of each other, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group, wherein the 3- to 14-membered cycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group.

[0083] Preferably, R 5 and R 5 ' independently represents -H, -C1-C6-alkyl, or -C1-C6-alkylene-N(C1-C6-alkyl)2.

[0084] In a preferred embodiment of the benzofuran derivative according to the present invention, R 5 and R 5 At least one of them is not -H.

[0085] In a preferred embodiment of the benzofuran derivative according to the present invention, R 5 and R 5Both of these are -H.

[0086] In preferred embodiments, T represents -O- and U represents -CR 5 R 5 '- represents the part obtained -O-CR 5 R 5 '- represents a residue selected from the following group. [ka]

[0087] In a preferred embodiment, T is -CR 5 R 5 '- represents U, U represents -O-, and the resulting part -CR 5 R 5 '-O-' represents a residue. [ka]

[0088] In a preferred embodiment, R 5 represents -H, and R 5 ' is -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -Alkylene-CF3, -C 1-3 -Alkylene-CF2H, -C 1-3 -alkylene-CFH2 and -C 1-3 -Alkylene-OH, preferably -H or C 1-3 - Represents a residue selected from the group consisting of alkyl groups.

[0089] In a preferred embodiment of the benzofuran derivative according to the present invention, R 6 , R 7 , and R 8 They are independent of each other, -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6-Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -NHC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -N(C) 1-6 -alkyl)2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 - Represents heteroalkyl.

[0090] Preferably, R 6 , R 7 , and R 8 However, they are independent of each other. -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, -C 1-6 -alkyl, -CF3, -CHF2, -CH2F, -OC 1-6 -alkyl, -OCF3, -OCHF2, -OCH2F, -NHC is either unsubstituted or substituted with one or more substituents selected independently from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2. 1-6 -Alkyl, -N(C) is either unsubstituted or substituted independently with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2. 1-6 -alkyl)2, -C(=O)OC is either unsubstituted or substituted with one or more substituents selected independently from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2. 1-6 -Alkyl, -OC(=O)C 1-6 -Alkyl, Unsubstituted, or substituted with one or more substituents selected independently from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, -C 1-6 - Represents heteroalkyl.

[0091] In a preferred embodiment, R 6 , R 7 , and R 8 These are -H, -F, -Cl, -Br, -I, -CN, and C, independently of each other. 1-3 This represents a residue selected from the group consisting of -alkyl, -CF3, -CF2H, and -CFH2, preferably -H or -F.

[0092] In a preferred embodiment of the benzofuran derivative according to the present invention, R 6represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

[0093] In a preferred embodiment of the benzofuran derivative according to the present invention, R 6 This does not represent -H.

[0094] In a preferred embodiment, R 6 However, this represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or -CH3, preferably -H, -F, -CN, or -CH3.

[0095] In a preferred embodiment of the benzofuran derivative according to the present invention, R 7 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

[0096] In a preferred embodiment of the benzofuran derivative according to the present invention, R 7 This does not represent -H.

[0097] In preferred embodiments, in particular, Q is -NR 3 R 4 When representing R, 7 represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or CH3, preferably -H, -F, -Cl, or -CH3.

[0098] In preferred embodiments, in particular, Q is -OR 2 When representing R, 7 represents -H, or a residue selected from the group consisting of the following: [ka]

[0099] In a preferred embodiment of the benzofuran derivative according to the present invention, R 8 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

[0100] In a preferred embodiment of the benzofuran derivative according to the present invention, R 8This does not represent -H.

[0101] In a preferred embodiment, R 8 represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or CH3, preferably -F.

[0102] In preferred embodiments of the benzofuran derivative according to the present invention, (i)R 6 , R 7 , and R 8 Each of these represents -H, or (ii)R 6 , R 7 , and R 8 Two of them represent -H, and R 6 , R 7 , and R 8 The other of these represents -F, -Cl, -CN, or -CH3, or (iii)R 6 , R 7 , and R 8 One of them represents -H, and R 6 , R 7 , and R 8 The other of these two terms independently represents -F, -Cl, -CN, or -CH3.

[0103] In a particularly preferred embodiment, the compound conforms to general formula (I), -R 1 is represented by -CH3 and / or -R 6 , R 7 , and R 8 Each represents -H, and / or -T represents -O- and / or -U represents -CH2- and / or -V represents thiazolyl, pyridyl, or pyrazolyl, and each of these thiazolyl, pyridyl, and pyrazolyl can be independently monosubstituted or disubstituted with a substituent selected from the group consisting of unsubstituted, -CH3, -F, -CH2CHF2, and -CF3, and / or -Q is NR 3 R4 Represents and / or -R 3 is represented by H and / or -R 4 teeth, [ka] It represents.

[0104] In a preferred embodiment of the present invention, the benzofuran derivative is selected from the group consisting of the following: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38] [Table 1-39] [Table 1-40] [Table 1-41] and their physiologically acceptable salts.

[0105] The benzofuran derivatives according to the present invention are preferably for use in the treatment of pain selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain.

[0106] Another aspect of the present invention relates to a compound of formula (I), [ka] With respect to the stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs defined above, preferably, in the formula, (a-1) Q is -OR 2 Represents R 1 However, it represents -CH2F, -CHF2, or -CF3, and / or (a-2) Q is -OR 2 Represents R 5 and R 5 At least one of the ' does not represent -H, and / or (a-3) Q is -OR 2 Represents R 6 However, it does not represent -H, and / or (a-3) Q is -OR 2 Represents R 8 However, it does not represent -H, or (b-1) Q is -NR 3 R 4 This represents the following, provided that the following compounds and their salts are not included: [ka] and / or (b-2)Q is -NR 3 R 4 Represents R 1 However, it represents -CH2F, -CHF2, -CF3, or -cyclopropyl, and / or (b-3)Q is -NR 3 R 4 Represents R 1 However, it represents -CH2F, -CHF2, or -CF3, and / or (b-4)Q is -NR 3 R 4 Represents R 5 and R 5 At least one of the ' does not represent -H, and / or (b-5)Q is -NR 3 R 4 Represents R 3 However, this represents -H.

[0107] In preferred embodiments (a-1), (a-2), (a-3), (b-1), (b-2), (b-3), and (b-4) of the benzofuran derivative according to the present invention, T represents -O- and U represents -CR5 R 5 '- represents (i.e., the benzofuran derivative is of formula (II)).

[0108] Q, T, U, V, R, including preferred substituents 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 7 , and R 8 All definitions, preferred embodiments, and preferred meanings of the present invention also apply to benzofuran derivatives, including, but not limited to, (a-1), (a-2), (a-3), (b-1), (b-2), (b-3), and (b-4), and are not necessarily limited to their use in the treatment of pain. Accordingly, this aspect of the present invention relates to benzofuran derivatives themselves, compositions comprising benzofuran derivatives, pharmaceuticals comprising benzofuran derivatives, and benzofuran derivatives for use in the prevention and / or treatment of TRPM3-mediated disorders such as pain and / or inflammatory hypersensitivity, and / or benzofuran derivatives for counteracting pain and / or inflammatory hypersensitivity. Preferably, the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain.

[0109] In preferred embodiments of the present invention, the benzofuran derivative is selected from the group consisting of the above-described compounds 001 to 207 and physiologically acceptable salts thereof.

[0110] Another aspect of the present invention relates to a pharmaceutical composition or medicine comprising the compound according to the present invention as described above.

[0111] Any reference in this specification to “one embodiment” or “embodiment” means that a particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment of the present invention. Therefore, the appearance of the phrase “in one embodiment” or “in one embodiment” in various places in this specification does not necessarily all refer to the same embodiment, but it is possible. Furthermore, certain features, structures, or characteristics may be combined in one or more embodiments in any preferred manner, as will be apparent to those skilled in the art from this disclosure. Also, embodiments described in relation to aspects of the present invention may be used in and combined with other aspects of the present invention. Where an indefinite or definite article is used to refer to a singular noun (e.g., “a” or “an” or “the”), unless otherwise specified, this includes the plural form of that noun.

[0112] Similarly, in the description of exemplary embodiments of the present invention, it should be understood that various aspects of the invention may be grouped together in a single embodiment, figure, or description for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various aspects of the invention.

[0113] In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms that are generally optimally present in a substituent or linker. Where otherwise indicated in this application, the number of carbon atoms is understood to represent the optimal maximum number of carbon atoms for that particular substituent or linker.

[0114] As used herein, the terms “leaving group” or “LG” refer to a chemical group that is readily substituted by a nucleophile or readily cleaved or hydrolyzed under basic or acidic conditions. In certain embodiments, the leaving group is selected from halogen atoms (e.g., Cl, Br, I) or sulfonates (e.g., mesylate, tosylate, triflate).

[0115] The term "protecting group" refers to a part of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The basic chemical structures of protecting groups vary considerably. One function of protecting groups is to serve as intermediates in the synthesis of parent drug substances. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See "Protective Groups in Organic Chemistry," Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often used to mask the reactivity of a particular functional group in order to improve the efficiency of a desired chemical reaction, for example, to form and break chemical bonds in a regularly planned manner. Protecting a functional group of a compound alters other physical properties of the protected functional group besides its reactivity, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0116] Protected compounds may also exhibit altered properties, and in some cases, properties optimized in vitro and in vivo (such as cell membrane passage and resistance to enzymatic degradation or capture). In this role, protected compounds with intended therapeutic effects may be called prodrugs. Another function of protecting groups is to convert a parent drug into a prodrug, thereby releasing the parent drug upon conversion to the prodrug in vivo. Since active prodrugs can be absorbed more effectively than the parent drug, prodrugs may have greater in vivo potential than their parent drugs. Protecting groups are removed either in vitro in the case of chemical intermediates or in vivo in the case of prodrugs. With respect to chemical intermediates, it is not particularly important that the resulting product after deprotection (e.g., an alcohol) is physiologically acceptable, but generally, it is more desirable that the product is pharmacologically harmless.

[0117] As used herein, the term “heteroatom” means an atom selected from nitrogen, oxygen, and sulfur, including sulfoxides and sulfones, that can be quaternized.

[0118] As used herein, the term “saturated or unsaturated alkyl” includes saturated alkyls, as well as unsaturated alkyls such as alkenyls and alkynyls. As used herein, the term “alkyl” means a normal, secondary or tertiary, linear or branched hydrocarbon that does not have an unsaturated moiety. Examples include methyl, ethyl, 1-propyl(n-propyl), 2-propyl(iPr), 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl(s-Bu), 2-dimethyl-2-propyl(t-Bu), 1-pentyl(n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. As used herein, the term “alkenyl” means a normal, secondary or tertiary, linear or branched hydrocarbon having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., a carbon-carbon, sp2 double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). The double bond may be in a cis or trans configuration. As used herein, the term “alkynyl” means a normal, secondary, tertiary, linear or branched hydrocarbon having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., a carbon-carbon, sp3 triple bond. Examples include, but are not limited to, ethynyl (-C≡CH) and 1-propynyl (propargyl, -CH2C≡CH).

[0119] As used herein, the term “saturated or unsaturated alkylene” includes saturated alkylenes, as well as unsaturated alkylenes such as alkenylene, alkynylene, and alkenynylene. As used herein, the term “alkylene” means a saturated, linear, or branched hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-). As used herein, the term “alkenylene” means a linear or branched hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkene having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., carbon-carbon, sp2 double bond. As used herein, the term "alkynylene" means a linear or branched hydrocarbon radical having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene, which have a carbon-carbon, sp triple bond.

[0120] As used herein, the term “saturated or unsaturated heteroalkyl” includes saturated heteroalkyls, as well as unsaturated heteroalkyls such as heteroalkenyls, heteroalkynyls, and heteroalkenyls. As used herein, the term “heteroalkyl” means a linear or branched alkyl group in which one or more carbon atoms (usually one, two, or three) are replaced by heteroatoms, i.e., oxygen, nitrogen, or sulfur atoms, and the chain does not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 atoms in the alkyl group may be replaced by -NH2, and / or one or more -CH2- atoms in the alkyl group may be replaced by -NH-, -O-, or -S-. The S atoms in the chain can optionally be oxidized with one or two oxygen atoms to obtain sulfoxides and sulfones, respectively. Furthermore, the heteroalkyl groups in the benzofuran derivatives of the present invention may contain an oxo or thio group on any carbon or heteroatom that results in a stable compound. Exemplary heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers (e.g., -methoxy, -ethoxy, -butoxy), primary, secondary, and tertiary alkylamines, amides, ketones, esters, alkyl sulfides, and alkyl sulfones. The term "heteroalkenyl" means a linear or branched alkenyl in which one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, and the chain does not contain two adjacent oxygen atoms or two adjacent sulfur atoms. Thus, the term heteroalkenyl includes imines, -O-alkenyls, -NH-alkenyls, -N(alkenyl)2, -N(alkyl)(alkenyl), and -S-alkenyls. As used herein, the term "heteroalkynyl" means a linear or branched alkynyl in which one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain does not contain two adjacent oxygen atoms or two adjacent sulfur atoms.Therefore, the term heteroalkynyl includes -cyano, -O-alkynyl, -NH-alkynyl, -N(alkynyl)2, -N(alkyl)(alkynyl), -N(alkenyl)(alkynyl), and -S-alkynyl.

[0121] As used herein, the term “saturated or unsaturated heteroalkylene” includes saturated heteroalkylenes, as well as unsaturated heteroalkylenes such as heteroalkenylenes, heteroalkylynylenes, and heteroalkenylenes. As used herein, the term “heteroalkylene” means a linear or branched alkylene in which one or more carbon atoms (usually one, two, or three) are replaced by heteroatoms, i.e., oxygen, nitrogen, or sulfur atoms, and the chain shall not contain two adjacent oxygen atoms or two adjacent sulfur atoms. As used herein, the term “heteroalkenylene” means a linear or branched alkenylene in which one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, and the chain shall not contain two adjacent oxygen atoms or two adjacent sulfur atoms. As used herein, the term "heteroalkylylene" means a linear or branched alkylylene in which one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain does not contain two adjacent oxygen atoms or two adjacent sulfur atoms.

[0122] As used herein, the term “saturated or unsaturated cycloalkyl” includes saturated cycloalkyls as well as unsaturated cycloalkyls such as cycloalkenyls and cycloalkynyls. As used herein, unless otherwise specified, the term “cycloalkyl” means saturated cyclic hydrocarbon radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, phentyl, dekalinyl, and adamantyl. As used herein, the term “cycloalkenyl” means a non-aromatic cyclic hydrocarbon radical having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., a carbon-carbon, sp2 double bond. Examples include, but are not limited to, cyclopentenyl and cyclohexenyl. The double bond may be in a cis or trans configuration. As used herein, the term “cycloalkynyl” means a non-aromatic cyclic hydrocarbon radical having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., a carbon-carbon, sp triple bond. An example is cyclohept-1-ene. A condensation system of cycloalkyl rings containing a heterocycloalkyl ring is considered heterocycloalkyl regardless of the ring bonded to the core structure. A condensation system of cycloalkyl rings containing an aryl ring is considered aryl regardless of the ring bonded to the core structure. A condensation system of cycloalkyl rings containing a heteroaryl ring is considered heteroaryl regardless of the ring bonded to the core structure.

[0123] As used herein, the term “saturated or unsaturated heterocycloalkyl” includes saturated heterocycloalkyls, as well as unsaturated non-aromatic heterocycloalkyls containing at least one heteroatom, i.e., N, O, or S as a ring member. As used herein, the term “heterocycloalkyl” means “cycloalkyl” unless otherwise specified, provided that one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, and the chain does not contain two adjacent O atoms or two adjacent S atoms. As used herein, the term “heterocycloalkenyl” means “cycloalkenyl” unless otherwise specified, provided that one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, and the chain does not contain two adjacent O atoms or two adjacent S atoms. As used herein, the term “heterocycloalkynyl” means “cycloalkynyl” unless otherwise specified, provided that one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, and the chain does not contain two adjacent O atoms or two adjacent S atoms.Examples of saturated and unsaturated heterocycloalkyls include azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyrane, tetrahydrothiopyrane, thiazolidine, thiethane, thiran, thiolane, and thiomol. Examples include, but are not limited to, forline, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxotiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine. Further heterocycloalkyls in the sense of the present invention are described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (WABenjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), particularly volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C. Wand Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566. When a heterocycloalkyl does not contain nitrogen as a ring member, it is typically bonded through carbon. When a heterocycloalkyl contains nitrogen as a ring member, it may be bonded through nitrogen or carbon.A condensation system of heterocycloalkyl rings containing a cycloalkyl ring is considered a heterocycloalkyl group regardless of the ring bonded to the core structure. A condensation system of heterocycloalkyl rings containing an aryl ring is considered a heterocycloalkyl group regardless of the ring bonded to the core structure. A condensation system of heterocycloalkyl rings containing a heteroaryl ring is considered a heteroaryl group regardless of the ring bonded to the core structure.

[0124] As used herein, the term "aryl" means aromatic hydrocarbon. Typical aryl groups include, but are not limited to, one-membered, two-membered, or three-membered radicals derived from benzene, naphthalene, anthracene, biphenyl, etc., which are condensed together. A condensation system of aryl rings having a cycloalkyl ring is considered aryl regardless of the ring bonded to the core structure. A condensation system of aryl rings having a heterocycloalkyl ring is considered heterocycloalkyl regardless of the ring bonded to the core structure. Therefore, indoline, dihydrobenzofuran, dihydrobenzothiophene, etc., are considered heterocycloalkyl according to the present invention. A condensation system of aryl rings having a heteroaryl ring is considered heteroaryl regardless of the ring bonded to the core structure.

[0125] As used herein, the term “heteroaryl” means an aromatic ring system containing at least one heteroatom, i.e., an aromatic ring system member of the aromatic ring system, which is N, O, or S. Examples of heteroaryls include, but are not limited to, benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinolin, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indidine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxyindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine.

[0126] As a further example, carbon-bonded heterocycles are bonded at positions 2, 3, 4, 5, or 6 of pyridine, positions 3, 4, 5, or 6 of pyridazine, positions 2, 4, 5, or 6 of pyrimidine, positions 2, 3, 5, or 6 of pyrazine, positions 2, 3, 5, or 5 of furan, tetrahydrofuran, thiophene, pyrrole, or tetrahydropyrrole, positions 2, 3, 4, or 5 of oxazole, imidazole, or thiazole, positions 3, 4, or 5 of isoxazole, prazole, or isothiazole, positions 2 or 3 of aziridine, positions 2, 3, or 4 of azetidine, positions 2, 3, 4, 5, 6, 7, or 8 of quinoline, or positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline.

[0127] Preferred carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. For example, nitrogen-bonded heterocycles are bonded at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine, and position 9 of carbazole or β-carbolin. Preferred nitrogen-bonded heterocycles include 1-aziridyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. Further heteroaryls in the sense of the present invention are described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (WABenjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), particularly volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C. Wand Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0128] When used herein with respect to substituents, unless otherwise specified, terms such as "monosubstituted," "disubstituted," "trisubstituted," and "polysubstituted" mean the chemical structures as defined herein, where each part is substituted with one or more substituents, and where one or more hydrogen atoms in that part are independently replaced by substituents. For example, -C which can be polysubstituted with -F. 1-6 -Alkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, etc. Similarly, -C can be polysubstituted with substituents selected independently from -F and -Cl. 1-6 -alkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CCl3, CCl2CCl3, -CHClF, -CClF2, -CCl2CF3, -CF2CCl3, -CClFCCl2F, and the like. Any substituents found at more than one site in the compounds of the present invention shall be independently selected.

[0129] As used herein, and unless otherwise specified, the term “solvate” includes, but is not limited to, alcohols, ketones, esters, ethers, and nitriles, and any combination that can be formed by the derivatives of the present invention having a suitable inorganic solvent (e.g., hydrate) or organic solvent.

[0130] As used herein, the term “subject” refers to an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation, or experimentation, including humans.

[0131] As used herein, the term “therapeutic dose” refers to the amount of an active compound or pharmaceutical product that elicits a biological or pharmacokinetic response in a tissue system, animal, or human, as sought by researchers, veterinarians, physicians, or other clinicians, including relief or partial relief of the symptoms of the disease or disorder being treated.

[0132] As used herein, “composition” is intended to include products containing a therapeutically effective amount of a specified component, as well as any products obtained directly or indirectly from a combination of specified components in specified amounts.

[0133] As used herein, the terms “antagonist” or “inhibitor” refer to compounds capable of producing functional antagonists of TRPM3 ion channels, including, depending on the context, competitive antagonists, non-competitive antagonists, desensitizing agonists, and partial agonists.

[0134] For the purposes of this invention, the term "TRPM3-modulated" is used to refer to states affected by modulation of a TRPM3 ion channel, including states mediated by a TRPM3 ion channel.

[0135] As used herein, the term “TRPM3-mediated disorder” refers to a disorder or condition comprising pain and inflammatory hypersensitivity states, in which the use of a TRPM3 antagonist prevents, treats, (partially) alleviates or improves the symptoms. According to the International Association for the Study of Pain, for the purposes of this invention, pain is an unpleasant sensory and emotional experience associated with, or described in terms of, actual or potential tissue damage. Preferably, the TRPM3-mediated disorder is pain selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain. For the purposes of this invention, the term “inflammatory hypersensitivity” is used to refer to a condition characterized by one or more features of inflammation, including edema, erythema, abnormally high fever, and pain, and / or an excessive physiological or pathophysiological response to one or more types of stimuli, including thermal, mechanical, and / or chemical stimuli.

[0136] The benzofuran derivatives of the present invention have been shown to be TRPM3 antagonists, and therefore, the present invention provides compounds for use as pharmaceuticals, more specifically for use as pharmaceuticals in the prevention or treatment of TRPM3-mediated disorders in subjects having a therapeutically effective amount of the benzofuran derivative of the present invention.

[0137] In a preferred embodiment of the present invention, the benzofuran derivative of the present invention is the sole pharmacologically active compound administered for therapeutic purposes. In another preferred embodiment of the present invention, the benzofuran derivative of the present invention may be used in combination with other therapeutic agents for the treatment or prevention of TRPM3-mediated disorders. Therefore, the present invention also, -One or more compounds from the formulas and embodiments of this specification, and -The present invention relates to the use of a composition comprising one or more further therapeutic or prophylactic agents used as biologically active agents in the form of a complex preparation for simultaneous, separate, or sequential use, for the prevention or treatment of TRPM3-mediated disorders.

[0138] The pharmaceutical compositions or compound preparations according to the present invention may contain the benzofuran derivative of the present invention over a wide range of content, depending on the intended use and the expected effect of the preparation. Generally, the content of the benzofuran derivative of the present invention in the compound preparation is in the range of 0.1 to 99.9% by weight, preferably 1 to 99% by weight, and more preferably 5 to 95% by weight.

[0139] Given that when several active ingredients are used in combination, they do not necessarily exert their joint-healing effects directly at the same time in the mammal being treated, the corresponding composition may also be in the form of a medical kit or package containing two components separately but in adjacent storage compartments or sections. Therefore, in the latter context, each active ingredient may be formulated in a manner suitable for a different route of administration than that of the other components; for example, one of them may be in the form of an oral or parenteral formulation, while the other may be in the form of an ampoule or aerosol for intravenous injection.

[0140] Those skilled in the art will also recognize that the benzofuran derivatives of the present invention can exist in many different protonation states, particularly depending on the pH of their environment. Although the structural formulas provided herein show only one of several possible protonation states of the compound, these structures are illustrative, and it will be understood that the present invention is not limited to any particular protonation state, and any and all protonation forms of the compound are intended to fall within the scope of the invention.

[0141] As used herein, the term “pharmaceutically acceptable salt” means a non-toxic salt form of the therapeutic activity that the compounds of the formulas herein may form. Therefore, the compounds of the present invention may optionally be salts of the compounds herein, in particular, for example, Na + Li + , K + Ca 2+ , and Mg 2+The present invention includes pharmaceutically acceptable non-toxic salts containing [a specific compound]. Such salts may include those derived from a combination of a suitable cation, e.g., alkali and alkaline earth metal ions, or ammonium and quaternary amino ions, and an acidic anionic moiety, typically a carboxylic acid. The benzofuran derivatives of the present invention may have multiple positive or negative charges. The net charge of the benzofuran derivatives of the present invention may be either positive or negative. Any associated counterion is typically determined by the synthesis and / or isolation method used to obtain the compound. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetates, trifluoroacetates, and mixtures thereof. The identity of any associated counterion is not a key feature of the present invention, and it will be understood that the present invention includes compounds that associate with any type of counterion. Furthermore, since compounds can exist in a variety of different forms, the present invention is intended to include not only forms of compounds that associate with counterions (e.g., dry salts) but also forms that do not associate with counterions (e.g., aqueous solutions or organic solutions). Metal salts are typically prepared by reacting a metal hydroxide with the compounds of the present invention. An example of a metal salt prepared in this way is Li + na + , and K +These are salts containing [a specific compound]. Less soluble metal salts can be precipitated from solutions of more soluble salts by the addition of a suitable metal compound. In addition, salts can be formed from the acid addition of certain organic and inorganic acids to a basic center, typically an amine, or an acidic group. Examples of such suitable acids include, for example, hydrohalogen acids, such as hydrochloric acid or hydrobromic acid, inorganic acids such as sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), and p-aminosalicylic acid. Furthermore, this term also includes solvates that the compounds of the formulas herein and their salts can form, such as hydrates, alkoxides, and solvates. Finally, it should be understood that the compositions herein include their non-ionized benzofuran derivatives of the present invention, as well as their zwitterionic forms and, in the case of hydrates, combinations with stoichiometric amounts of water.

[0142] Salts of parent compounds having one or more amino acids, particularly natural amino acids found as protein components, are also included within the scope of the present invention. Amino acids typically have a side chain with a basic or acidic group, such as lysine, arginine, or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0143] The benzofuran derivatives of the present invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the benzofuran derivatives of the present invention include alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + (In the formula, X is -C) 1-6Examples of salts derived from appropriate bases (such as alkyl groups) include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of compounds containing a hydroxyl group include Na + and NX4 + The compound comprises anions of the compound combined with suitable cations such as (wherein X is typically independently -H or -C) 1-4 (Selected from alkyl groups). However, salts of physiologically unacceptable acids and bases may also be permitted for use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether or not they form physiologically acceptable acids or bases, are within the scope of the present invention.

[0144] As used herein, and unless otherwise specified, the term “enantiomer” means each individual optically active form of the benzofuran derivative of the present invention having an optical purity or enantiomer excess of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, more preferably at least 98% (as determined by standard methods of the art).

[0145] As used herein, the term “isomer” means all possible isomeric forms, including tautomers and stereochemical forms, that a compound of the formula herein may have, but not positional isomers. Typically, the structures shown herein illustrate only one tautomer or resonance form of a compound, but corresponding alternative configurations are also intended. Unless otherwise specified, the chemical name of a compound refers to a mixture of all possible stereochemical isomers, which include all diastereomers and enantiomers of the basic molecular structure (since a compound of the formula herein may have at least one chiral center), as well as stereochemically pure or concentrated compounds. More specifically, the stereocenter may have either an R or S conformation, and the multiple bonds may have either a cis or trans conformation.

[0146] The pure isomeric form of a compound is defined as an isomer that substantially does not contain other enantiomeric or diastereomeric forms of the same basic molecular structure. Specifically, the terms “stereoisomerically pure” or “chiral pure” refer to compounds having a stereoisomer excess of at least about 80% (i.e., at least 90% of one isomer and up to 10% of the other possible isomers), preferably at least 90%, more preferably at least 94%, and most preferably at least 97%. The terms “enantiomerically pure” and “diastereoselectively pure” should be understood in a similar manner, taking into account the enantiomer excess and diastereomer excess, respectively, of the mixture in question.

[0147] The separation of stereoisomers can be achieved by standard methods known to those skilled in the art. One enantiomer of the benzofuran derivative of the present invention can be separated so as to be substantially free of its opposite enantiomer by methods such as the formation of a diastereomer using an optically active decomposition agent ("Stereochemistry of Carbon Compounds," (1962) by ELEliel, McGraw Hill, Lochmuller, CH, (1975) J. Chromatogr., 113:(3) 283-302). The separation of isomers in a mixture can be achieved by any preferred method, including (1) the formation of an ionic diastereomer salt with a chiral compound and separation by fractional crystallization or other methods, (2) the formation of a diastereomer compound with a chiral derivatization reagent, separation of the diastereomer, and conversion to a pure enantiomer, or (3) the enantiomer can be directly separated under chiral conditions. In method (1), diastereomer salts can be formed by the reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine) with asymmetric compounds having acidic functionality, such as carboxylic acids and sulfonic acids. Diastereomer salts can be induced to be separated by fractional crystallography or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic acids or sulfonic acids such as camphor sulfonic acid, tartaric acid, mandelic acid, or lactic acid may result in the formation of diastereomer salts. Alternatively, by method (2), a diastereomer pair can be formed by reacting the substrate to be degraded with one enantiomer of the chiral compound (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomer compounds can be obtained by reacting an asymmetric compound with an enantiomerically pure chiral derivatization reagent such as a menthyl derivative, followed by separation and hydrolysis of the diastereomer to form a free, enantiomerically concentrated compound.The method for determining the optical purity involves preparing a chiral ester of the racemic mixture, e.g., menthyl ester or Mosher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), and analyzing the NMR spectrum for the presence of the two atropisomerous diastereomers. The stable diastereomers can be separated and isolated by forward-phase and reverse-phase chromatography according to the method for separating atropisomerous naphthyl-isoquinolines (Hoye, T., WO96 / 15111). Under method (3), the racemic mixture of the two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, particularly cellulose or amylose derivatives. Commercially available polysaccharide-based chiral stationary phases include ChiralCel® CA, OA, OB5, OC5, OD, OF, OG, OJ, and OK, and Chiralpak® AD, AS, OP(+), and OT(+). Suitable eluents or mobile phases for use in combination with these polysaccharide chiral stationary phases are hexane and other alcohols, modified with alcohols such as ethanol and isopropanol. ("Chiral Liquid Chromatography" (1989) W.J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513:375-378).

[0148] The terms cis and trans are used herein in accordance with chemical information retrieval nomenclature and include references to the positions of substituents on the cyclic portion. The absolute stereochemical configurations of compounds of the formulas described herein can be readily determined by those skilled in the art, for example, using well-known methods such as X-ray diffraction.

[0149] When a compound is crystallized from a solution or slurry, it can crystallize in different spatial lattice arrangements (this property is called "polymorphism"), forming crystals with different crystalline forms, each of which is known as a "polymorph." Thus, as used herein, the term "polymorph" refers to the crystalline form of the compound of formula (I), where the molecule is localized in a three-dimensional lattice region. Different polymorphs of the compound of formula (I) may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, accumulation mode, fluidity, and / or solid-state stability.

[0150] The benzofuran derivatives of the present invention and their physiologically acceptable salts (hereinafter collectively referred to as "active ingredients") can be administered by any suitable route, including oral, rectal, nasal, topical (including ocular, oral, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intranasal, intravenous, intra-arterial, intradermal, intrathecal, and epidural) administration, depending on the condition being treated. The preferred route of administration may vary, for example, depending on the recipient's condition.

[0151] In particular, for the treatment of TRPM3-mediated disorders in humans and other mammals or animals, the therapeutically effective amount of compound preparation is preferably the amount of TRPM3 ion channel inhibition of the compound as defined herein, corresponding to an amount that ensures a plasma level of 1 μg / ml to 100 mg / ml, optionally 10 mg / ml.

[0152] Preferred doses of the compounds or compositions of the present invention should be used to treat or prevent TRPM3-mediated disorders in subjects. Depending on the pathological condition being treated and the patient's condition, the effective dose may be divided into several subunits per day or administered at intervals of more than one day.

[0153] The present invention further provides (pharmaceutical) compositions comprising one or more benzofuran derivatives of the present invention, more specifically, all of formula (I) and other formulas and embodiments described herein, and more specific aspects or embodiments thereof. Furthermore, the present invention provides compounds or (pharmaceutical) compositions of the present invention, more specifically, all of formula (I) and other formulas and embodiments described herein, and more specific aspects or embodiments thereof, for use as drugs, more specifically for use in the treatment of pain. TRPM3-mediated disorders are selected from pain and inflammatory hypersensitivity conditions.

[0154] The benzofuran derivatives of the present invention may be formulated with conventional carriers and excipients, which are selected according to common practice. The tablets contain excipients, flowing agents, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery by means other than oral administration. The formulations may optionally contain excipients as described in the “Handbook of Pharmaceutical Excipients” (1986).

[0155] Thereafter, the term “pharmaceutically acceptable carrier” as used herein means any material or substance on which the active ingredient is formulated, for example, by dissolving, dispersing, or diffusing the composition to facilitate its application or dissemination to a gene locus to be treated, and / or to facilitate its storage, transport, or handling without impairing its efficacy. A pharmaceutically acceptable carrier may be a solid or a liquid, or a gas compressed to form a liquid, i.e., the compositions of the present invention can be suitably used as concentrates, emulsions, solutions, granules, dust, sprays, aerosols, suspensions, ointments, creams, tablets, pellets, or powders.

[0156] Suitable pharmaceutical carriers for use in the pharmaceutical compositions and formulations thereof are well known to those skilled in the art, and there are no particular limitations on their selection within the present invention. These may also include additives such as wetting agents, dispersants, stickers, adhesives, emulsifiers, surfactants, solvents, coatings, antimicrobial and antifungal agents, and isotonic agents, provided that similar additives are consistent with the pharmaceutical practice, i.e., carriers and additives that do not cause permanent harm to mammals. The pharmaceutical compositions of the present invention can be prepared by any known method, for example, in a one-step or multi-step procedure, by uniformly mixing, coating, and / or grinding the active ingredient with the selected carrier material and, if necessary, other additives such as surfactants. They may also be prepared by micronization to obtain them in the form of microspheres, usually having a diameter of about 1 to 10 gm, for example, for the production of microcapsules for the controlled or sustained release of the active ingredient.

[0157] Benzofuran derivatives can be administered alone, but it is preferable that they exist as part of a pharmaceutical formulation. Both veterinary and human formulations of the present invention, as described above, comprise at least one active ingredient, and therefore one or more pharmaceutically acceptable carriers, and optionally other therapeutic ingredients. The carrier is “acceptable” in the sense that it is optimally compatible with the other components of the formulation and is not harmful to its recipient. The formulations include those suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. The formulations may be conveniently presented in unit dosage forms and may be prepared by any method well known in the art of pharmaceuticals. Such methods include the step of associating the active ingredient with carriers constituting one or more accessory components. Generally, formulations are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, or a finely divided solid carrier, or both, and shaping the product as needed.

[0158] Formulations of the present invention suitable for oral administration may be presented as separate units (e.g., capsules, cachets, or tablets containing a predetermined amount of the active ingredient), as powders or granules, as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions. The active ingredient may also be presented as a bolus, lick, or paste.

[0159] Tablets can be prepared by compression or molding with one or more adjuncts as optional. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and formulated to provide sustained or controlled release of the active ingredient. In the case of infections of the eye or other external tissues, e.g., mouth and skin, the formulation can optionally be applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20 w / w% (containing the active ingredient in the range of 0.1% to 20% in increments of 0.1 w / w%, such as 0.6 w / w%, 0.7 w / w%, etc.), preferably 0.2 to 15 w / w%, most preferably 0.5 to 10 w / w%. When formulated into an ointment, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream having an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least 30 w / w% polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400), and mixtures thereof. Topical formulations may preferably contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0160] The oily phase of the emulsion of the present invention may be composed of known components in known ways. The phase may simply contain an emulsifier (also known as a diuretic), but preferably a mixture of at least one emulsifier with a fat or oil, or a mixture of both fat and oil. Optionally, a hydrophilic emulsifier may be included together with a lipophilic emulsifier acting as a stabilizer. It is also preferable to include both oil and fat. Together, with or without a stabilizer, the emulsifiers constitute a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of the cream formulation.

[0161] The selection of oils or fats suitable for formulation is based on achieving the desired cosmetic properties, as the solubility of active compounds in most oils likely to be used in pharmaceutical emulsion formulations is very low. Therefore, the cream should be a non-fatty, non-contaminating, and washable product with suitable consistency to avoid leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters may be used, such as a blend of branched esters known as coconut fatty acid diisoadipate, isocetyl stearate, propylene glycol diester, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or crodamol CAP, with the latter three being preferred esters. These may be used alone or in combination, depending on the required properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0162] Formulations suitable for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent of the active ingredient. The active ingredient may optionally be present in such formulations at a concentration of 0.5 to 20%, preferably 0.5 to 10%, particularly about 1.5 w / w%. Formulations suitable for topical administration to the mouth include lozenges containing the active ingredient in a flavoring base, usually sucrose and acacia or tragacanth, celatin and glycerin, or inert bases such as sucrose and acacia, and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0163] Formulations for rectal administration may be presented as suppositories using a suitable base containing, for example, cocoa butter or salicylate. Formulations suitable for nasal administration, where the carrier is solid, contain a coarse powder having a particle size in the range of 20 to 500 microns (with particle sizes in the range of 20 to 500 microns in 5-micron increments, such as 30 microns or 35 microns), and are administered by inhalation, i.e., by rapid inhalation via the nasal route from a container of powder held close to the nose. Formulations suitable for nasal administration contain an aqueous or oily solution of the active ingredient, for example, to be administered as a nasal spray or nasal dropper. Formulations suitable for aerosol administration may be prepared according to conventional methods and delivered together with other therapeutic agents.

[0164] Formulations suitable for vaginal administration may exist as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, containing, in addition to the active ingredient, a carrier known to be suitable in the art.

[0165] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injections or infusions that may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. The formulations may be presented in unit-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier (e.g., water) immediately before use. Immediate injection solutions and suspensions may be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0166] A preferred unit-dose formulation is one that contains a daily dose or a daily unit subdose of the active ingredient, or an appropriate fraction thereof, as described herein.

[0167] In particular, please understand that, in addition to the components mentioned above, the formulations of the present invention may include other conventional agents in the art, depending on the type of formulation in question (for example, those suitable for oral administration may include flavoring agents).

[0168] Using the benzofuran derivatives of the present invention, controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more benzofuran derivatives of the present invention as active ingredients can be provided, and the release of the active ingredient can be controlled and regulated to enable less frequent administration or to improve the pharmacokinetic or toxicity profile of a given compound of the present invention. Orally administered controlled-release formulations in which separate units contain one or more benzofuran derivatives of the present invention can be prepared according to conventional methods.

[0169] Another embodiment of the present invention relates to various precursor or “prodrug” forms of the benzofuran derivatives of the present invention. It may be desirable to formulate the benzofuran derivatives of the present invention in the form of chemical species that are not significantly biologically active themselves but, upon delivery to animals, mammals, or humans, undergo chemical reactions catalyzed by the normal functions of the body, particularly chemical reactions catalyzed by enzymes present in the stomach or serum, which have the effect of releasing the compounds as defined herein. Accordingly, the term “prodrug” relates to these species that are converted into active pharmacokinetic components in vivo.

[0170] The benzofuran derivative prodrugs of the present invention may have any form suitable for formulation, for example, esters are a non-limiting general prodrug form. However, in this case, the prodrug may necessarily exist in a form in which the covalent bond is cleaved by the action of an enzyme present at the target gene locus. For example, the CC covalent bond may be selectively cleaved by one or more enzymes at the target gene locus, and therefore, readily hydrolyzable precursors, in particular, prodrugs in forms other than esters and amides, may be used. The pharmaceutically active pharmacokinetic components in the prodrug may have different structures known in the art, such as amino acid or peptide structures, alkyl chains, and sugar moieties.

[0171] For the purposes of the present invention, the term “therapeutably suitable prodrug” is defined herein as “a compound that, by one or more biological transformations, is converted in vivo to a therapeutically active form without excessive toxicity, irritation, or allergic reaction upon contact with the tissue of an animal, mammal, or human to which the prodrug has been administered, thereby achieving the intended therapeutic outcome.”

[0172] More specifically, as used herein, the term “prodrug” refers to an inactive or significantly less active derivative of a compound, such as those represented by the structural formulas described herein, which undergo spontaneous or enzymatic conversion in the body to release the pharmacologically active form of the compound. For a comprehensive discussion, see Rautio J. et al. (“Prodrugs: design and clinical applications,” Nature Reviews Drug Discovery, 2008, doi:10.1038 / nrd2468).

[0173] Representative benzofuran derivatives of the present invention can be synthesized according to the general synthetic methods described below, which are illustrated in the following scheme. Since the scheme is illustrative, the present invention should not be construed as being limited by the specific chemical reactions and conditions described in the scheme and examples. The various starting materials used in the scheme are commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein and within the scope of the skill of those skilled in the art.

[0174] Preferred embodiments of the present invention are summarized in the following clauses 1 to 51.

[0175] 1. Compounds of formula (I), their stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, [ka] Preferably, a compound of formula (I), its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs for use in the treatment of pain, During the ceremony, R 1 However, -F, -Cl, -Br, -I, -CN, -R W , -OR W -OC(=O)R W , -NR W R X , -NR W C(=O)R X , -SRW -S(=O)R W -S(=O)2R W -C(=O)R W , -C(=O)OR W , or -C(=O)NR W R X This represents, Q, -OR 2 or -NR 3 R 4 This represents, R 2 However, -R Y This represents, R 3 However, -OH or -R Y This represents, R 4 However, -R Y Or -S(=O)2R Y Does it represent, Alternatively, R 3 and R 4 These combine to form a saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted 4, 5, 6, 7, or 8-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. T represents -O-, and U represents -CR 5 R 5 '- represents - or T is -CR 5 R 5 '- represents U, and U represents -O-, R 5 and R 5 'But, independently of each other, -R Y This represents, R 6 , R 7 , and R 8 However, independently of each other, -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W , -OR W -OC(=O)R W , -NR W R X , -NR W C(=O)R X , -SR W -S(=O)R W -S(=O)2R W -C(=O)R W, -C(=O)OR W , or -C(=O)NR W R X This represents, V is a saturated or unsaturated 3-14 member heterocycloalkyl or 5-14 member heteroaryl, in each case unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z Represents a saturated or unsaturated 3-14 member heterocycloalkyl or 5-14 member heteroaryl that is monosubstituted or polysubstituted with substituents selected from, During the ceremony, R W and R X However, independently of each other, in each case, independently, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group. R Y and R Z However, independently of each other, in each case, independently, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group. Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, wherein the 6- to 14-membered aryls are optionally linked through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case being saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, An unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl, Alternatively, R Y and R Z These combine to form a saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted 4, 5, 6, 7, or 8-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. "Single substitution or multiple substitution" in each case independently and mutually independent of -F, -Cl, -Br, -I, -CN, -C 1-6 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkylene-O-CF3, -C 1-6 -Alkylene-O-CF2H, -C 1-6 -Alkylene-O-CFH2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C 1-6 -alkylene-C(=O)-OH, -C(=O)-OC 1-6 -alkyl, -C 1-6 -Alkylene-C(=O)-OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-C(=O)-NH(C 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-C(=O)-N(C 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6-alkylene-C(=O)-NH(OH), -OH, -C 1-6 -Alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -OC 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 -alkyl, -OC 1-6 -Alkilen-OC 1-6 -alkyl, -OC 1-6 -Alkylene-NH2, -OC 1-6 -Alkilen-NH-C 1-6 -alkyl, -OC 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -OC(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-OC(=O)-C 1-6 -alkyl, -OC(=O)-OC 1-6 -alkyl, -C 1-6 -Alkylene-OC(=O)-OC 1-6 -alkyl, -OC(=O)-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-OC(=O)-NH(C) 1-6 -alkyl), -OC(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-OC(=O)-N(C) 1-6 -alkyl)2, -OS(=O)2-NH2, -C 1-6 -Alkylene-OS(=O)2-NH2, -OS(=O)2-NH(C 1-6 -alkyl), -C 1-6 -Alkylene-OS(=O)2-NH(C) 1-6 -alkyl), -OS(=O)2-N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-OS(=O)2-N(C) 1-6 -alkyl)2, -NH2, -NO, -NO2, -C 1-6 -Alkylene-NH2, -NH(C) 1-6 -alkyl), -N (3-14 member cycloalkyl) (C 1-6 -alkyl), -N(C1-6 -alkyl)-C 1-6 -Alkylene-OH,-N(H)-C 1-6 -alkylene-OH, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -NH-C(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-NH-C(=O)-C 1-6 -alkyl, -NH-C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-C(=O)-OC 1-6 -alkyl, -NH-C(=O)-NH2, -C 1-6 -Alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-C(=O)-N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -N(C 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -N(C 1-6 -alkyl)-C(=O)-NH2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-NH2, -N(C 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -Alkylene-N(C)1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -NH-S(=O)2OH, -C 1-6 -Alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -alkyl, -C 1-6 -Alkylene-NH-S(=O)2-C 1-6 -alkyl, -NH-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-OC 1-6 -alkyl, -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C) 1-6 -alkyl), -NH-S(=O)2N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-S(=O)2N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-S(=O)2-OH, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-OH, -N(C 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -N(C 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -N(C 1-6 -alkyl)-S(=O)2-NH2, -C1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH2, -N(C 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 -alkyl, -C 1-6 -Alkilen-SC 1-6 -alkyl, -S(=O)-C 1-6 -alkyl, -C 1-6 -Alkylene-S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -C 1-6 -Alkylene-S(=O)2-C 1-6 -alkyl, -S(=O)2-OH, -C 1-6 -Alkylene-S(=O)2-OH, -S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-OC 1-6 -alkyl, -S(=O)2-NH2, -C 1-6 -Alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-S(=O)2-NH(C) 1-6 -alkyl), -S(=O)2-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-S(=O)2-N(C) 1-6 -alkyl)2,3-14 member cycloalkyl, -C 1-6 -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl, -C 1-6-alkylene-(3-14 member heterocycloalkyl), -phenyl, -C 1-6 -alkylene-phenyl, 5-14 member heteroaryl, -C 1-6 Compounds, their stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, meaning those substituted with one or more substituents selected from -alkylene-(5-14 member heteroaryl), -O-(3-14 member cycloalkyl), -O-(3-14 member heterocycloalkyl), -O-phenyl, -O-(5-14 member heteroaryl), -C(=O)-(3-14 member cycloalkyl), -C(=O)-(3-14 member heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5-14 member heteroaryl), -S(=O)2-(3-14 member cycloalkyl), -S(=O)2-(3-14 member heterocycloalkyl), -S(=O)2-phenyl, and -S(=O)2-(5-14 member heteroaryl).

[0176] 2. T represents -O-, and U represents -CR 5 R 5 '- represents the compound itself or the compound for use as described in Clause 1.

[0177] 3.T is -CR 5 R 5 '- represents -O-, and U represents -O-, the compound itself or the compound for use as described in Clause 1.

[0178] 4.Q is -NR 3 R 4 The compound itself or for use as described in any one of clauses 1 to 3.

[0179] 5. Q is -OR 2 The compound itself or for use as described in any one of clauses 1 to 3.

[0180] 6. V is non-substituted and independent of each other: -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y, -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z A compound representing a 5-14 member heteroaryl, monosubstituted or polysubstituted with a substituent selected from, either as described in any one of clauses 1 to 5, or as a compound for use.

[0181] 7. The 5- to 14-membered heteroaryl compound itself, or a compound for use, as described in Clause 6, which is not a benzofuran.

[0182] 8. The 5-14 member heteroaryl is benzimidazole, benzisoxazole, benzoazole, benzodioxol, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinolin, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indidine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazo Selected from ol, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, in each case unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y-S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself or for use as described in Clause 6 or 7, which is monosubstituted or polysubstituted with a substituent selected from the above.

[0183] 9. The 5-14 member heteroaryl is selected from the group consisting of furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole, pyridine, isoquinoline, benzothiazole, pyridazine, pyrimidine, and imidazopyridine, and in each case, unsubstituted, and independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself or for use as described in any one of clauses 6 to 8, which is monosubstituted or polysubstituted with a substituent selected from the above.

[0184] 10. The 5-14 member heteroaryl is selected from the group consisting of furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, pyrazole-5-yl, oxazole-5-yl, isoxazole-4-yl, thiazole-2-yl, thiazole-5-yl, 1,2,4-triazole-3-yl, 1,2,3-triazole-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, isoquinoline-1-yl, isoquinoline-5-yl, benzo[d]thiazole-2-yl, pyridazine-3-yl, pyrimidine-5-yl, and imidazo[1,2-a]pyridine-6-yl, and in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself or for use as described in any one of clauses 6 to 9, which is monosubstituted or polysubstituted with a substituent selected from the above.

[0185] 11. V is saturated or unsaturated, unsubstituted, and independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y, or -C(=O)NR Y R Z A compound representing a 3- to 14-membered heterocycloaryl, monosubstituted or polysubstituted with a substituent selected from, either as described in any one of clauses 1 to 5, or as a compound for use.

[0186] 12. The 3-14 member heterocycloalkyl is azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofurane, tetrahydropyrane, tetrahydrothiopyrane, thiazolidine, thiethane, thiran, thiolane, thiomorpholine, indoline, dihydrobenzofurane, dihydro Selected from benzothiophene, 1,1-dioxotiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound described in Clause 11, or the compound for use, is monosubstituted or polysubstituted with a substituent selected from the above.

[0187] 13. The 3- to 14-membered heterocycloalkyl group is tetrahydropyran or pyrrolidine, and in each case, it is unsubstituted and independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself or for use as described in Clause 11 or 12, which is monosubstituted or polysubstituted with a substituent selected from the above.

[0188] 14. The 3- to 14-membered heterocycloalkyl group is tetrahydropyran-4-yl or pyrrolidine-3-yl, and in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y -S(=O)R Y -S(=O)2R Y -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself or for use as described in any one of the clauses 11 to 13, which is monosubstituted or polysubstituted with a substituent selected from ,

[0189] 15. V is non-substitutive and independent of each other. -F, -Cl, -Br, -I, -CN, -C(=O)OH, -NH2, -NO2, -OH, =O, -SF5, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -NHC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -N(C) 1-6 -alkyl)2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted, -S(=O)2-C1-6-alkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case monosubstituted or polysubstituted with substituents selected from saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl groups, either as described in any one of the preceding clauses or as a compound for use.

[0190] 16. V is non-substitutive and independent of each other. -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2, -N(CH3)2, -cyclopropyl, or -O-cyclopropyl, preferably selected from -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2, or -N(CH3)2, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Selected from the group consisting of -alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, -C(=O)NH2, and -cyclopropyl, preferably -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 - A substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which can be monosubstituted or polysubstituted. 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 - A substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which can be monosubstituted or polysubstituted. 1-6 -heteroalkyl, Non-substitutive, mutually independent: -F, -Cl, -Br, -I, -C1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -OC substituents selected from the group consisting of -alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, either monosubstituted or polysubstituted. 1-6 -Alkyl, Non-substitutive, mutually independent: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -O(C=O)C 1-6 -Alkyl, Non-substitutive, mutually independent: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -C(=O)OC with a substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, either monosubstituted or polysubstituted. 1-6 -Alkyl, A 3- to 14-membered cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, wherein in each case, the elements are unsubstituted and independently of each other are -F, -Cl, -Br, -I, and -C. 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6-Alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, monosubstituted or polysubstituted, 3- to 14-membered cycloalkyl groups, Azepane, 1,4-Oxazepane, Azetan, Azetidine, Aziridine, Azocane, Diazepane, Dioxane, Dioxolane, Dithiane, Dithiolane, Imidazolidine, Isothiazolidine, Isoxalidine, Morpholine, Oxazolidine, Oxepane, Oxetane, Oxirane, Oxirane, Piperazine, Piperidine, Pyrazolidine, Pyrrolidine, Quinuclidin, Tetrahydrofuran, Tetrahydropyran, Tetrahydrothiopyran, Thiazolidine, Thietan, Thiran, Thiolane, Thiomorpholine, Indoline, Dihydrobenzofuran, Dihydrobe Selected from the group consisting of nziothiophene, 1,1-dioxotiacyclohexane, 2-azabicyclo[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azabicyclo[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydro-cyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case being unsubstituted and independently of each other, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 The compound itself or for use as described in any one of the preceding clauses, which is monosubstituted or polysubstituted with a substituent selected from the group consisting of -alkynyl, -OH,=O, -SH,=S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, or which is monosubstituted or polysubstituted with a substituent selected from a 3- to 14-membered heterocycloalkyl group.

[0191] 17. V is non-substituted and independent of each other: -F, -Cl, -CN, -OH, =O, -C1-6 -alkyl, -CHF2, -CF3, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkylene-NHC(=O)-OC 1-6 -alkyl, -C(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)2, -OC 1-6 -alkyl, -OCF3, -OC 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -S(=O)2-C 1-6 -alkyl, -azetidine, -C 1-6 -alkylene-O-tetrahydropyran, or -C 1-6 The compound itself or for use as described in any one of the preceding clauses, which is monosubstituted or polysubstituted with substituents selected from alkyl-substituted piperazines, or which represents an unsubstituted, monosubstituted or polysubstituted oxetanyl.

[0192] 18. V is, (i) Is it a non-substitution? (ii) Whether it has been substituted, (iii) Whether it is substituted twice, (iv) It is cubic, or (v) The compound itself or for use of any one of the preceding clauses that is tetrasubstituted.

[0193] 19.R 1 but, -H, -F, -Cl, -Br, -I, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-6-alkyl, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -O-C1-6-alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)NHC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)N(C 1-6 -alkyl)2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group, wherein the 3- to 14-membered cycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group, either as a compound itself or for use as described in any one of the preceding clauses.

[0194] 20.R 1 is -H, -F, -Cl, -Br, -I, -C 1-6 -alkyl, -OC 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 -alkyl, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -Alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C1-6 -Alkylene-N(C) 1-6 -Alkilen)-C 1-6 -Alkylene-CF3, -C(=O)C 1-6 -alkyl, -C(=O)OC 1-6 -alkyl, -C(=O)NHC 1-6 -alkyl, -C(=O)N(C 1-6 -alkyl)2, -S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -OC 1-6 A compound, either by itself or for use, representing an alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl as described in any one of the preceding clauses.

[0195] 21.R 1 However, -H, -C 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 - Represents alkyl, -CH2F, -CHF2, -CF3, unsubstituted cyclopentyl, or unsubstituted cyclopropyl, preferably R 1 However, -H, -C 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 -A compound, either by itself or for use, representing an alkyl, -CH2F, -CHF2, -CF3, or unsubstituted cyclopentyl compound as described in any one of the preceding clauses.

[0196] 22.R 1 However, it represents -CH2F, -CHF2, -CH3, or unsubstituted cyclopropyl, preferably R 1 However, the compound itself or for use of any one of the preceding clauses, representing -CH2F, -CHF2, or -CH3.

[0197] 23.R 2 but, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case monosubstituted or polysubstituted with substituents selected from saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl groups, either as described in any one of the preceding clauses or as a compound for use.

[0198] 24.R 2 However, -H, -C 1-6 -alkyl, -C 1-6 -Alkilen-OC 1-6 -alkyl, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -Alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 --Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, or -C 1-6 -Alkylene-N(C) 1-6 -Alkilen)-C 1-6 -A compound representing alkylene-CF3, either as described in any one of the preceding clauses, or a compound for use.

[0199] 25.R 2 However, -H or -C1-6 - A compound representing an alkyl group, either by itself or for use as described in any one of the preceding clauses.

[0200] 26.R 3 but, -H, -OH, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl, A compound, either by itself or for use, representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl group as described in any one of the preceding clauses.

[0201] 27.R 3 However, -H, -OH, -C 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -Alkylene-N(C) 1-6 -Alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, or -C 1-6 -Alkylene-N(C) 1-6 -alkyl)-C 1-6 -A compound representing alkylene-CF3, either as described in any one of the preceding clauses, or a compound for use.

[0202] 28.R 3 However, -H, -OH, or saturated, unsubstituted, or monosubstituted with -OH -C 1-6 - A compound representing an alkyl group, either by itself or for use as described in any one of the preceding clauses.

[0203] 29.R 4 but, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group. Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, wherein the 6- to 14-membered aryls are optionally linked through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case being saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, An unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally linked through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl, either as described in any one of the preceding clauses, or as a compound for use.

[0204] 30.R 4 but, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -S(=O)2C 1-6 -Alkyl, -S(=O)2 (3-14 member cycloalkyl), wherein the 3-14 member cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in each case, saturated or unsaturated, unsubstituted, and independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -S(=O)2(3-14 member cycloalkyl), monosubstituted or polysubstituted with substituents selected from the group consisting of -alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl, Saturated or unsaturated, unsubstituted, independently of each other, -F, -Cl, -C1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -The substituent is monosubstituted or polysubstituted with a substituent selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl, -C 1-6 -Alkyl, 3-14 member cycloalkyl or -C 1-6 -Alkylene-(3-14 member cycloalkyl), -C 1-6-Alkylene- is unsubstituted or monosubstituted with -OH, and the 3- to 14-membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in each case is saturated or unsaturated, and in each case is unsubstituted, and independently of each other, -F, -Cl, and -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -A 3-14 member cycloalkyl or -C cycloalkyl group that is monosubstituted or polysubstituted with a substituent selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl groups, and unsubstituted 5-14 member heteroaryl groups. 1-6 -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl or -C 1-6 -Alkylene-(3-14 member heterocycloalkyl), and -C 1-6 -Alkylene- is either unsubstituted or monosubstituted with -OH, and the 3- to 14-membered heterocycloalkyl is, in each case, azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thiethane, thiran, thiolane Selected from the group consisting of thiomorpholin, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxotiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolidine, hexahydrocyclopenta[c]pyrrole, octahydro-cyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case being unsubstituted, and independently of each other, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6-Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -A 3-14 member heterocycloalkyl or -C that is monosubstituted or polysubstituted with a substituent selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl. 1-6 -Alkylene-(3-14 member heterocycloalkyl), Non-substitutive, mutually independent: -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -phenyl, monosubstituted or polysubstituted with substituents selected from the group consisting of alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl. 5-14 member heteroaryl or -C 1-6 -Alkilen- (5-14 member heteroaryl), -C 1-6 -Alkylene- is unsubstituted or monosubstituted with -OH, and the 5-14 member heteroaryl is, in each case, benzimidazole, benzisoxazole, benzoazole, benzodioxol, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinolin, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indidine, isobenzofuran, isoindole, isoquinoline, Selected from the group consisting of isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxiindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, in each case unsubstituted, and independently of each other, -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -NHC1-6 -alkyl, -N(C 1-6 -alkyl)2,-NHC(=O)OC 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -alkyl, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3-14 member heterocycloalkyl, and unsubstituted 5-14 member heteroaryl, monosubstituted or polysubstituted with substituents selected from the group consisting of 5-14 member heteroaryl or -C 1-6 A compound representing -alkylene-(5-14 member heteroaryl), either by itself or for use as described in any one of the preceding clauses.

[0205] 31.R 4 but, -H, Saturated, unsubstituted, monosubstituted or polysubstituted with -F, -S(=O)2C 1-6 -Alkyl, Saturated, unsubstituted -S(=O)2 (3-14 member cycloalkyl), Saturated, unsubstituted, and independently of each other, -OH, -OC 1-6 -alkyl, -N(C 1-6 -alkyl)2, -C1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -C 1-6 -Alkyl, 3-14 member cycloalkyl or -C 1-6 -Alkylene-(3-14 member cycloalkyl), -C 1-6 -Alkylene- is either unsubstituted or monosubstituted with -OH, and the 3-14 member cycloalkyl group is saturated, unsubstituted, and independently of each other, -C 1-6 -alkyl, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkilen-NH-C 1-6 -Alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -Alkylene-NHC(=O)OC 1-6 -alkyl, -OH, -OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2,-NHC(=O)OC 1-6 -3-14 member cycloalkyl or -C atoms monosubstituted or disubstituted with substituents selected from the group consisting of alkyl groups. 1-6 -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl or -C 1-6 -Alkylene-(3-14 member heterocycloalkyl), and -C 1-6-Alkylene- is either unsubstituted or monosubstituted with -OH, and the 3- to 14-membered heterocycloalkyl is, in each case, azetane, 1,4-oxazepane, pyrrolidine, piperidine, azepane, diazepane, tetrahydrofuran, tetrahydropyran, oxetane, morpholine, piperazine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, octahydro Selected from lollo[1,2-a]pyrazine, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, quinuclidine, hexahydro-1H-pyrrolidine, 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, and 1,1-dioxotiacyclohexane, in each case unsubstituted, independently of each other, -F, -OH, =O, -C 1-6 -alkyl, -C 1-6 -Alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -Alkilen-OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2, -C 1-6 -Alkylene-NH2, -C 1-6 -Alkylene-N(C) 1-6 -alkyl)2, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -Alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -S(=O)2C 1-6 -alkyl, oxetanyl, pyrimidinyl, -C 1-6 -3-14 member heterocycloalkyl or -C atoms monosubstituted or polysubstituted with substituents selected from the group consisting of alkylene-phenyl. 1-6 -Alkylene-(3-14 member heterocycloalkyl), Unsubstituted phenyl, 5-14 member heteroaryl or -C 1-6 -Alkilen- (5-14 member heteroaryl), -C 1-6-Alkylene- is either unsubstituted or monosubstituted with -OH, and the 5-14 member heteroaryl is selected in each case from the group consisting of pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, and in each case, unsubstituted, and independently of each other, -C 1-6 -A 5-14 member heteroaryl or -C heteroaryl molecule that is monosubstituted or disubstituted with a substituent selected from the group consisting of -alkyl and -OH. 1-6 A compound representing -alkylene-(5-14 member heteroaryl), either by itself or for use as described in any one of the preceding clauses.

[0206] 32.R 3 and R 4 The compound itself or for use as described in any one of the preceding clauses, which together contain one or two heteroatoms selected from N, O, and S, and form a saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted five- or six-membered heterocycle.

[0207] 33.R 3 and R 4 However, together they form a heterocycle selected from the group consisting of pyrrolidine, piperidine, morpholine, and piperazine, and in each case, they are unsubstituted or, independently of each other, -C 1-6 -alkyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl, -C(=O)N(C 1-6 -alkyl)2, -C(=O)OC 1-6 -alkyl, -NHC(=O)OC 1-6 -alkyl, unsubstituted-pyridyl, and unsubstituted or -C 1-6 - The compound itself or for use as described in any one of the preceding clauses, which is monosubstituted or polysubstituted with a substituent selected from the group consisting of 1,2,4-oxadiazole monosubstituted with alkyl.

[0208] 34.R 3 and R 4But together, Unsubstituted or monosubstituted with -N(CH3)2, pyrrolidine rings Unsubstituted, or -C 1-6 -alkyl, -NH2, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl, -C(=O)OC 1-6 -alkyl, -NHC(=O)OC 1-6 -alkyl, and unsubstituted or -C 1-6 -A piperidine ring, monosubstituted with a substituent selected from the group consisting of 1,2,4-oxadiazole monosubstituted with alkyl, Unsubstituted morpholine rings, or Unsubstituted, or -C 1-6 A compound, either by itself or for use, that forms a piperidine ring, which is N-substituted with substituents selected from the group consisting of alkyl and unsubstituted pyridyl compounds.

[0209] 35.R 5 and R 5 'But, independently of each other, -H, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6 alkyl groups, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl, A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group, wherein the 3- to 14-membered cycloalkyl group is optionally linked via -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group, either as a compound itself or for use as described in any one of the preceding clauses.

[0210] 36.R 5 and R 5The compounds described in any one of the preceding clauses, either themselves or for use, where each independently represents -H, -C1-C6-alkyl, or -C1-C6-alkylene-N(C1-C6-alkyl)2.

[0211] 37.R 5 and R 5 At least one of the compounds described in any one of the preceding clauses does not represent -H, either the compound itself or the compound for use.

[0212] 38.R 6 , R 7 , and R 8 However, they are independent of each other. -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -NHC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -N(C) 1-6 -alkyl)2, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC(=O)C 1-6 -Alkyl, Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 - A compound, either by itself or for use, that represents a heteroalkyl compound as described in any one of the preceding clauses.

[0213] 39.R 6 , R 7 , and R 8 However, they are independent of each other. -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, -C 1-6 -alkyl, -CF3, -CHF2, -CH2F, -OC 1-6 -alkyl, -OCF3, -OCHF2, -OCH2F, -NHC is either unsubstituted or substituted with one or more substituents selected independently from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2. 1-6 -Alkyl, -N(C) is either unsubstituted or substituted independently with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2. 1-6 -alkyl)2, -C(=O)OC is either unsubstituted or substituted with one or more substituents selected independently from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2. 1-6 -Alkyl, -OC(=O)C 1-6 -Alkyl, or Unsubstituted, or substituted with one or more substituents selected independently from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, -C 1-6 - A compound, either by itself or for use, that represents a heteroalkyl compound as described in any one of the preceding clauses.

[0214] 40.R 6 The compound itself or for use of any one of the preceding clauses, which represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

[0215] 41.R 6 However, the compound itself or for use as described in any one of the preceding clauses, which does not represent -H.

[0216] 42.R 7 The compound itself or for use of any one of the preceding clauses, which represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

[0217] 43.R 7 However, the compound itself or for use as described in any one of the preceding clauses, which does not represent -H.

[0218] 44.R 8 The compound itself or for use of any one of the preceding clauses, which represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

[0219] 45.R 8 However, the compound itself or for use as described in any one of the preceding clauses, which does not represent -H.

[0220] 46. (i)R 6 , R 7 , and R 8 Each of these represents -H, or (ii)R 6 , R 7 , and R 8 Two of them represent -H, and R 6 , R 7 , and R 8 The other of these represents -F, -Cl, -CN, or -CH3, or (iii)R 6 , R 7 , and R 8 One of them represents -H, and R 6 , R 7 , and R 8 The other of the two compounds independently represents -F, -Cl, -CN, or -CH3, either the compound itself or a compound for use as described in any one of the preceding clauses.

[0221] 47. A compound itself or a compound for use, selected from the group consisting of compounds 001 to 207 described above, and a physiologically acceptable salt thereof.

[0222] 48. The pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain, either by the compound itself or for use as described in any one of the preceding clauses.

[0223] 49. The compound itself or for use described in any one of the preceding clauses, wherein the pain is postoperative pain.

[0224] 50. (a) Q is -OR 2 This represents, (a-1)R 1 However, it represents -CH2F, -CHF2, or -CF3, and / or (a-2)R 5 and R 5 At least one of the ' does not represent -H, and / or (a-3)R 6 However, it does not represent -H, and / or (a-4)R 8 However, it does not represent -H, or (b) Q is -NR 3 R 4 This represents, (b-1) Provided that the following compounds and their salts are not included, [ka] and / or (b-2)R 1 However, it represents -CH2F, -CHF2, or -CF3, -CN, -propyl, or -cyclopropyl, and / or (b-3)R 5 and R 5 At least one of the ' does not represent -H, and / or (b-4)R 3 However, the compound of formula (I), its stereoisomer, physiologically acceptable salt, solvate, and / or polymorph, as described in any one of the preceding clauses, representing -H.

[0225] 51. A pharmaceutical composition or medicine comprising a compound described in any one of the preceding clauses. [Examples]

[0226] The following embodiments are provided to further illustrate the present invention and are not intended in any way to limit the scope of the invention.

[0227] Representative compounds of the present invention can be synthesized according to the general synthesis methods described below, which are illustrated in the following scheme. Since the scheme is illustrative, the present invention should not be construed as being limited by the specific chemical reactions and conditions described in the scheme and examples. The various starting materials used in the scheme are commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein and within the scope of the skill of those skilled in the art.

[0228] In this specification, the abbreviations used in particular in schemes and examples are as follows: ACN-Acetonitrile, AcOH-Acetic acid, ADDP-1,1'-(Azodicarbonyl)dipiperizide, aq.-Aqueous solution, AIBN-Azobisisobutyronitrile, CAN-Cerium ammonium nitrate, COMU-(1-Cyano-2-Ethoxy-2-Oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, DABCO-1,4-Diazabicyclo[2.2.2]octane, DAST-Diethylaminosulfate trifluoride, DBU-1,8-Diazabicyclo[5.4.0]undeca-7-ene, DCC-N,N'-Dicyclohexylcarbodiimide, DCM-Dichloromethane, DEAD-Diethylazodicarboxylate, DIA-Diastereomer, DIAD-Diisopropyl azodicarboxylate, DEA-Diethylamine, DIPEA-Diisopropyl-Ethyl Luamine, DME-1,2-dimethoxyethane, DMF-N,N-dimethylformamide, DMSO-dimethyl sulfoxide, DTBAD-tert-butylazodicarboxylate, EDCI or EDC-1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, En-enantiomer, Et2O-diethyl ether, EtOH-ethanol, siRNA-ethyl acetate, Eq.-equivalent, FA-formic acid, FCC-flash column chromatography, h-hour, HATU-O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HPLC-high performance liquid chromatography, IPA-isopropyl alcohol, LAH-lithium aluminum hydride, LG-releasing group, MeOH-methanol, MgSO4-magnesium sulfate, min.-min, Na2SO4-sodium sulfate, NBS-N-bromosuccinimide, NMP-1-methyl-2-pyrrolidinone, Pd(PPh3)4-tetrakis-(triphenylphosphine)-palladium(0), Pd2(dba)3-tris(dibenzylideneacetone)dipalladium, Pet ether-petroleum ether, PPh3-triphenylphosphine, PS-DIEA-polystyrene-supported diisopropyl-ethylamine, PS-PPh3-polystyrene-supported triphenylphosphine, PyBop-benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, PTSA-p-toluenesulfonic acid, R F: Frontier ratio, RM: Reaction mixture, RP: Reverse phase, RT: Room temperature, sat.: Saturated, SEM: [2-(trimethylsilyl)ethoxy]methyl acetal, SFC: Supercritical fluid chromatography, SPE: Solid phase extraction, TBDMS: Tert: Butyldimethylsilyl ether, TBAF: Tetrabutylammonium hydroxide, TBAI: Tetrabutylammonium iodide, TEA: Triethylamine, THF: Tetrahydrofuran, TFA: Trifluoroacetic acid, TLC: Thin film chromatography, TPP: Triphenylphosphine, IPA: Isopropyl alcohol, TMS: Trimethylsilyl, T3P: Propylphosphonic anhydride.

[0229] The compounds of interest having structures according to general formula (A), and all other formulas and embodiments thereof described herein, can be prepared as outlined in general chemical scheme 1. [ka] Scheme 1: All R1, R2, R3, R4, and R5 are as described for the compounds of the present invention.

[0230] The para-benzoquinone of formula 1 can be condensed with the ketoester of formula 2 (either commercially available or synthesized by procedures known to those skilled in the art) (wherein R2 is an ester protecting group (e.g., methyl, ethyl, t-Bu, etc.) in the presence of a Lewis acid (e.g., titanium(IV) chloride, zinc(II) chloride, etc.) in a polar solvent (e.g., DCM, MeOH, EtOH, etc.) in the temperature range of 0 to 100°C) to obtain the intermediate of formula 4. More detailed information can be found in the following references (Bioorg. Med. Chem. 2012, 20, 4237-4244 and FR1319594). Alternatively, the para-benzoquinone of formula 1 can be reacted with the enamine of formula 3 (either commercially available or synthesized by procedures known to those skilled in the art) at a temperature range of 0 to 100°C in the presence of a protic acid (e.g., trifluoroacetic acid, para-toluenesulfonic acid, etc.) in a polar solvent (e.g., DCM, MeOH, EtOH, etc.). More detailed information can be found in the following reference (J. Heterocyclic Chem. 2006, 43, 873). Next, the intermediate of formula 4 is converted to the desired compound of formula 7 via nucleophilic substitution using the intermediate of formula 5 (which is either commercially available or synthesized), where LG is a releasing group in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs2CO3, etc.) in a polar solvent (e.g., acetonitrile, DMF, NMP, etc.) with or without a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.) in the temperature range of 0–100°C. Alternatively, the intermediate of formula 4 can also be reacted with the intermediate of formula 6 (which is either commercially available or synthesized) in the presence of an azodicarboxylate reagent (e.g., DEAD, DIAD, ADDP, etc.) and a phosphine (e.g., tributylphosphine, triphenylphosphine, etc.) in a solvent (e.g., THF, toluene, etc.) in the temperature range of 0–100°C to obtain the desired compound of formula 7. Subsequently, the ester derivative 7 can be converted to the desired compound of formula 8 by a standard saponification reaction.The desired compound of formula 10 can be obtained from the acid derivative of formula 8 by reaction with the amine derivative of formula 9 (commercially available or synthesized by procedures known in the art or as described in the following examples) under standard peptide bonding conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.). Alternatively, the carboxylic acid derivative of formula 8 can be converted to an acid chloride derivative by procedures known to those skilled in the art or as described in the following examples, and then reacted with the amine of formula 9 to obtain the desired compound of formula 10 by procedures known to those skilled in the art or as described in the following examples.

[0231] In more specific embodiments, the compounds of the present invention can be synthesized as shown in Scheme 2. [ka] Scheme 2: All R1, R2, R3, R4, and R5 are as described for the compounds of the present invention.

[0232] A 5-hydroxy-benzofuran-3-carboxylic acid derivative 11 (either commercially available or synthesized by procedures known in the art or as described in the following examples) can be reacted with an amine derivative of formula 9 (either commercially available or synthesized by procedures known in the art or as described in the following examples) under standard peptide bonding conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.) to obtain an intermediate of formula 12. Alternatively, a compound of formula 13 (synthesized as described in Scheme 1) can be converted to an intermediate of formula 12 by hydrogenation with a reducing agent (e.g., hydrogen gas, ammonium formate, cyclohexadiene, etc.) using a catalyst (more preferably Pd or Pt) in a solvent (e.g., THF, EtOH, etc.). Next, the intermediate of formula 12 can be converted to the desired compound of formula 10 (wherein LG is a releasing group in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs2CO3, etc.) in a polar solvent (e.g., acetonitrile, DMF, NMP, etc.) with or without a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.) in the temperature range of 0 to 100°C. Alternatively, the intermediate of formula 12 can also be reacted with the intermediate of formula 6 (commercially available or synthesized) in the presence of an azodicarboxylate reagent (e.g., DEAD, ADDP, DIAD, tert-butylazodicarboxylate, etc.) and a phosphine (e.g., tributylphosphine, triphenylphosphine, etc.) in a solvent (e.g., THF, toluene, etc.) at a temperature range of 0 to 100°C to obtain the desired compound of formula 10.

[0233] In more specific embodiments, the compounds of the present invention can be synthesized as shown in Scheme 3. [ka] Scheme 3: All R1, R2, R3, R4, R5, R7, and R8 are as described for the compounds of the present invention.

[0234] The substituted para-benzoquinone derivatives of formula 14 can be condensed with the ketoesters of formula 2 (either commercially available or synthesized by procedures known to those skilled in the art) (wherein R2 is an ester protecting group (e.g., methyl, ethyl, t-Bu, etc.) in the presence of a Lewis acid (e.g., titanium(IV) chloride, zinc(II) chloride, etc.) in a polar solvent (e.g., DCM, MeOH, EtOH, etc.) over a temperature range of 0 to 100°C) to obtain mixtures of the substituted intermediates of formulas 15 and 16. Further information can be found in the following references (Bioorg. Med. Chem. 2012, 20, 4237-4244 and FR1319594). The intermediates of formula 15 and / or 16 can then be converted to the desired compounds of formula 17 and / or 18 via nucleophilic substitution using the intermediate of formula 5 (which is either commercially available or synthesized) (wherein LG is a releasing group, in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs2CO3, etc.) in a polar solvent (e.g., acetonitrile, DMF, NMP, etc.) with or without a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.) in a temperature range of 0 to 100°C). Alternatively, the intermediates of formulas 15 and / or 16 can also be reacted with the intermediate of formula 6 (commercially available or synthesized) in the presence of an azodicarboxylate reagent (e.g., DEAD, DIAD, ADDP, etc.) and a phosphine (e.g., tributylphosine, triphenylphosphine, etc.) in a solvent (e.g., THF, toluene, etc.) over a temperature range of 0 to 100°C to obtain the desired compounds of formulas 17 and / or 18. The ester derivatives 17 and / or 18 can then be converted to the desired carboxylic acids of formulas 19 and / or 20 by standard saponification reactions. The desired compounds of formulas 21 and / or 22 can be obtained from the acid derivatives of formulas 19 and / or 20 by reaction with the amine derivative of formula 9 (commercially available or synthesized by procedures known in the art or as described in the following examples) under standard peptide bonding conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.)The mixture of compounds 21 and 22 can be separated (e.g., by silica gel, HPLC, SFC, or preparative CFC) to obtain the desired compound of formula 21 or 22.

[0235] In more specific embodiments, the compounds of the present invention can be synthesized as shown in Scheme 4. [ka] Scheme 4: All R1, R2, R3, R4, R5, R7, and R8 are as described for the compounds of the present invention.

[0236] The intermediate of formula 4 can be halogenated with a suitable halogenating agent (e.g., bromine, N-bromosuccinimide, etc.) in a solvent (e.g., chloroform, water, etc.) to obtain the desired intermediate 23. The desired compound of formula 26 can be obtained by an Ullmann-type reaction with CuCN followed by a Mitsunobu-type reaction (commercially available or synthesized) with the intermediate of formula 6. Alternatively, the desired compound of formula 26 can be obtained by a Mitsunobu-type reaction (commercially available or synthesized) with the intermediate of formula 6 followed by a Suzuki reaction. The ester derivative 26 can then be converted to the desired compound of formula 27 by a standard saponification reaction. The desired compound of formula 28 can be obtained from the acid derivative of formula 27 by a reaction with the amine derivative of formula 9 (commercially available or synthesized by procedures known in the art or as described in the following examples) under standard peptide bonding conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.) with a procedure known in the art or synthesized as described in the following examples).

[0237] In more specific embodiments, the compounds of the present invention can be synthesized as shown in Scheme 5. [ka] Scheme 5: All R1, R2, R3, and R4 are as described for the compounds of the present invention.

[0238] The intermediate of formula 4 can be halogenated with a suitable halogenating agent (e.g., select fluor) in a solvent (e.g., chloroform, acetonitrile, etc.) to obtain the desired intermediates 29 and 30. The intermediates of formula 29 and / or 30 can be reacted with the intermediate of formula 6 (commercially available or synthesized) in the presence of an azodicarboxylate reagent (e.g., DEAD, DIAD, ADDP, etc.) and a phosphine (e.g., tributylphosphine, triphenylphosphine, etc.) in a solvent (e.g., THF, toluene, etc.) at a temperature range of 0 to 100°C to obtain the desired compounds of formula 31 and / or 32. The ester derivatives 31 and / or 32 can then be converted to the corresponding carboxylic acids of formula 33 and / or 34 by standard saponification reactions. The desired compounds of formula 35 and / or 36 can be obtained from the acid derivatives of formula 33 and / or 34 by reaction with the amine derivative of formula 9 (commercially available or synthesized by procedures known in the art or as described in the following examples) under standard peptide bonding conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.). The mixture of compounds 35 and 36 can be separated (e.g., by silica gel, HPLC, SFC, or preparative CFC) to obtain the desired compound of formula 35 or 36.

[0239] [Examples] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] Table 2-6 Table 2-7 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21]

[0240] The following examples are provided to illustrate the present invention and are not intended in any way to limit the scope of the invention.

[0241] Part A describes the preparation of the compound, and Part B describes the pharmacological examples.

[0242] Part A All starting materials not explicitly mentioned are commercially available (for example, details of suppliers such as Acros, Avocado, Aldrich, Fluka, FluoroChem, MatrixScientific, Maybridge, Merck, and Sigma can be found, for example, in the SciFinder® database), or their synthesis is already accurately described in the specialized literature (for example, experimental guidelines can be found in the Reaxys® database or the SciFinder® database, respectively), or they can be prepared using conventional methods known to those skilled in the art.

[0243] The reactions were carried out under an inert atmosphere (mainly argon and N2) as needed. The number of equivalents of reagents, the amount of solvent used, and the reaction temperature and time may vary slightly between different reactions performed by similar methods. The processing and purification methods were adapted according to the characteristic properties of each compound and may vary slightly for similar methods. The yields of the prepared compounds were not optimized.

[0244] The notation "equivalent" ("eq.", "eq," or "equiv.") means molar equivalent, "RT" or "rt" means room temperature T (23±7℃), "M" indicates concentration in mol / l, "sol." means solution, and "conc." means concentration. The mixing ratio of solvents is usually expressed as a volume / volume ratio.

[0245] The main analytical characterization is as follows for all exemplary compounds and selected intermediate products: 1 H-NMR spectroscopy and / or mass spectrometry (MS, [M+H] + and / or [MH] - This was carried out by m / z at . In certain cases, for example, positional isomers and / or diastereomers may be formed during the reaction / if they are formed, for example, 13 Additional analyses, such as 13C NMR and NOE (nuclear Overhauser effect) NMR experiments, were performed in some cases.

[0246] The analytical instruments used included, for example, a BRUKER 400MHz or BRUKER 500MHz machine (Software Topspin) for NMR analysis, and alternatively, BRUKER AVANCE 300MHz and 400MHz. For LC / MS analysis, for example, an Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI) or an Agilent 1200 SERIES, Mass: 6130 SQD (ESI / APCI) (Software Chemistation) was used. For analytical HPLC, for example, Waters (Software Empower), Agilent-1200-ELSD (Software Chemistation), or Agilent-1260 (Software OpenLAB) were used. Analytical SFC was performed using, for example, PIC solution (Software: SFC PICLAB ONLINE), WATERS-X5 (Software MASSLYNX), or WATERS-UPC2 (Empower).

[0247] Preparative HPLC was performed using, for example, Waters 2998 (Software Empower) or YMC (Software K-Prep). Preparative SFC was performed using, for example, Waters SFC-200 (Software Chromscope or Super chrome), Waters SFC-80 (Super chrome), or PIC PIC-175 (Software S10-100).

[0248] The structure of an exemplary compound containing a stereocenter is, if known, depicted and named using absolute stereochemistry. In the case of unknown absolute stereochemistry, the compound may be a racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia1 and Dia2 indicate that the diastereosomers were separated but their stereochemistry is unknown. En1 and En2 indicate that both enantiomers were separated but their absolute configuration is unknown. Unless the chemical name of the compound specifies the exact stereochemistry, the suffixes following the compound code indicate, respectively, that the compound containing the stereocenter was obtained as a racemic mixture or a mixture of diastereomers.

[0249] The LC / MS analyses described in the experimental section were also performed using a Dionex Ultimate 3000 HPLC system (equipped with a PDA detector) connected to a Brucker Esquire 6000 mass spectrometer (equipped with a multimode source, ESI / APCI) (Method L in the table below). Alternatively, the LC / MS analyses described in the experimental section were performed using a Waters system combining an Acquity UPLC H class with an Acquity UPLC PDA detector and an Acquity TQ detector (ESI) (Method U in the table below).

[0250] Conditions used for HPLC analysis in the experimental section. The LC / MS analysis described in the experimental section was performed using a Dionex Ultimate 3000 HPLC system (equipped with a PDA detector) connected to a Brucker Esquire 6000 mass spectrometer (equipped with a multimode source and ESI / APCI). Separation was performed using a SunFire C18, 3.5 μm, 3.0 x 100 mm column, a SunFire C18 equipped column, a 3.5 μm, 3.0 x 20 mm guard column, or an X-Bridge C18 equipped column, an X-Bridge C18 100 x 3.0 mm column, and a 3.5 μm, 3.0 x 20 mm guard column kept at 30°C. The DAD acquisition wavelength was set within the range of 190 to 420 nm (Method L in the table below). Elution was performed using the methods described in the table below. Solvent A: 0.1% LC-MS grade formic acid in milliQ water. Solvent B: 10 mM NH4OAc (LC-MS grade) in milliQ water, adjusted to pH 10 using an aqueous solution of NH3, LC-MS grade. Solvent C: LC-MS grade acetonitrile. [Table 4]

[0251] Conditions used for ULC analysis in the experimental section. The LC / MS analysis described in the experimental section was performed using a Waters system combining an Acquity UPLC H class with an Acquity UPLC PDA detector and an Acquity TQ detector (ESI). Separation was performed using an Acquity UPLC HSS C18, 2.1 × 50 mm, 1.8 μM column equipped with a prefilter and kept at 40°C, or an Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μM column equipped with a prefilter and kept at 40°C, with the PAD acquisition wavelength set to the range of 210-420 nm (Method U in the table below). Elution was performed by the method described in the table below. Solvent A: 0.1% formic acid LC-MS grade in milliQ water. Solvent B: 10 mM NH4OAc (LC-MS grade) in milliQ water, adjusted to pH 10 using an aqueous solution of NH3, LC-MS grade. Solvent C: Acetonitrile, LC-MS grade. [Table 5]

[0252] The preparative HPLC purification described in the experimental section was performed using a Waters 2489 UV / Vis detector, a Waters 2545 Binary gradient module, a Waters Fraction Collector III, and a Waters Dual Flex syringe. Separation was performed using an X-Bridge Prep C18 column, 100 × 19 mm; an X-Bridge C18 column, 19 × 10 mm, or a 5 μm column equipped with a 5 μm guard column; or a SunFire Prep C18 ODB column (5 μm; 19 × 10 mm) equipped with a SunFire C18 guard column (5 μm; 19 × 100 mm). Elution was performed using the methods described in the table below, with detection wavelengths fixed at 210 and 254 nm. Solvent A: 0.1% LC-MS grade formic acid in milliQ water. Solvent B: 10 mM NH4OAc (LC-MS grade) in milliQ water, adjusted to pH 10 using an aqueous solution of NH3, LC-MS grade. Solvent C: LC-MS grade acetonitrile. [Table 6]

[0253] Synthesis of 2-methyl-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxylic acid (compound 018). [ka] Step 1: To a solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (0.100 g, 0.45 mmol) in THF (10 mL) and NMP (1 mL), cesium carbonate (0.444 g, 1.36 mmol) was added, and the RM was stirred at room temperature for 25 minutes. Then, 2-(bromomethyl)-5-(tolufluoromethyl)furan (0.104 mg, 0.45 mmol) was added, and the stirred solution was heated at 95°C until the 5-hydroxy-2-methylbenzofuran-3-carboxylate was consumed. The mixture was cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FC on silica gel using an siRNA gradient (0% to 80%) in heptane to obtain 0.167 g (100%) of ethyl 2-methyl-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxylate.

[0254] Step 2: To a solution of ethyl 2-methyl-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxylate (0.167 g, 0.45 mmol) in a mixture of water-EtOH-MeOH-THF (6:3:3:1, 12 mL), sodium hydroxide (0.102 g, 1.8 mmol) was added, and the RM was heated under reflux until the ethyl 5-(benzyloxy)-2-methylbenzofuran-3-carboxylate was consumed. After cooling, volatiles were removed under reduced pressure, the residue was dissolved in water, and washed with DCM. The mixture was acidified with aqueous hydrochloric acid (6N) to a pH of approximately 2 and extracted with RINKAN. The resulting organic layer was washed with water and brine, dried over magnesium sulfate, and filtered to obtain 147.6 mg (89%) of 2-methyl-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxylic acid (compound 018).

[0255] Compounds 016 and 017 were prepared in the same manner as compound 018 (using appropriate reagents and purification methods known to those skilled in the art).

[0256] Synthesis of 2-methyl-5-((2-(trifluoromethyl)benzyl)oxy)benzofuran-3-carboxylic acid (compound 101). [ka] Step 1: Tributylphosphine (1.7 mL, 6.5 mmol) was added dropwise to a stirred mixture of methyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (1 g, 4.6 mmol), 2-(trifluoromethyl)pyridine-3-yl)methanol (1.28 g, 6.9 mmol), and ADDP (1.66 g, 6.5 mmol) in dry THF (5 mL) under argon. The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was purified by FCC on silica gel using an IgG gradient (0-20%) in heptane to obtain 1.4 g (83%) of methyl 2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate. M / Z(+): 366 (M+H), M / Z(-): 364 (MH).

[0257] Step 2: To a solution of methyl 2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (1.40 g, 3.8 mmol) in a mixture of MeOH-THF (1:1, 40 mL), a solution of sodium hydroxide (2 N, 5 mL, 40 mmol) was added, and the mixture was heated overnight at 75 °C. After cooling, volatiles were removed under reduced pressure, and the remaining residue was dissolved in water. The mixture was acidified with HCl solution (6 N) until the pH was approximately 5. The white precipitate was washed with water and dried under reduced pressure to obtain 1.30 g (96%) of 2-methyl-5-((2-(trifluoromethyl)benzyl)oxy)benzofuran-3-carboxylic acid (compound 101).

[0258] Compounds 099, 100, and 102 were prepared in the same manner as compound 101 (using appropriate reagents and purification methods known to those skilled in the art).

[0259] The following compounds were prepared in the same manner as compound 101 (using appropriate reagents and purification methods known to those skilled in the art). [Table 7]

[0260] Synthesis of 2-methyl-5-((1-methyl-1H-pyrazole-3-yl)methoxy)benzofuran-3-carboxylic acid (compound 008). [ka] Step 1: Ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (100 mg, 0.45 mmol), (1-methyl-1H-pyrazole-5-yl)methanol (0.075 g, 0.68 mmol), and PPh3 (119 mg, 0.45 mmol) were dissolved in THF (5 mL) and cooled to 0°C. Then, DIAD (0.134 mL, 0.68 mmol) was added dropwise, and the RM was stirred at room temperature for 36 hours. Volatile substances were removed under reduced pressure, the residue was diluted with DCM, and washed sequentially with aqueous NaOH (1N), water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The compound was purified by FCC on silica gel using an siRNA gradient (20-100%) of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate in heptane to obtain 0.071 g (50%) of the desired compound.

[0261] Step 2: An aqueous solution of NaOH (2N, 6 mL, 12 mmol) was added to a solution of ethyl 2-methyl-5-((1-methyl-1H-pyrazole-5-yl)methoxy)benzofuran-3-carboxylate (0.071 g, 0.25 mmol) in MeOH (4 mL) and ethanol (2 mL), and the mixture was stirred at 80°C for 4 hours. After cooling, the mixture was diluted with water and washed with DCM. The aqueous layer was acidified to pH=4 with an aqueous solution of HCl (6N). The resulting solid was filtered and dried to obtain 33 mg (51%) of 2-methyl-5-((1-methyl-1H-pyrazole-3-yl)methoxy)benzofuran-3-carboxylic acid (compound 008).

[0262] The following compounds were prepared in the same manner as compound 008 (using appropriate reagents and purification methods known to those skilled in the art): compounds 001, 002, 004, 005, 006, 007, 009, 010, 011, 012, 013, and 014.

[0263] The following compounds were prepared in the same manner as compound 008 (using appropriate reagents and purification methods known to those skilled in the art). [Table 8]

[0264] Synthesis of 2-methyl-5-((5-methylisoxazole-3-yl)methoxy)benzofuran-3-carboxylic acid (compound 215). [ka] Step 1: To a stirred solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (0.4 g, 1.8 mmol) and (5-methylisoxazole-3-yl)methylmethanesulfonate (0.52 g, 2.7 mmol) in acetonitrile (25 mL), Cs2CO3 (1.18 g, 3.6 mmol) was added at room temperature. The reaction mixture was heated to 70 °C and maintained at this temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography using 100-200 mesh with 5% ethyl acetate in pet ether as the eluent to obtain ethyl 2-methyl-5-((5-methylisoxazole-3-yl)methoxy)benzofuran-3-carboxylate (0.4 g, 70%) as a pale yellow solid. TLC system: 30% ethyl acetate in pet ether, RF: 0.2.

[0265] Step 2: 5 mL of 2N NaOH aqueous solution was added at room temperature to a stirred solution of ethyl 2-methyl-5-((5-methylisoxazole-3-yl)methoxy)benzofuran-3-carboxylate (0.4 g, 1.26 mmol) in methanol (5 mL) and THF (5 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL), acidified with 1N HCl aqueous solution (10 mL) until the pH was approximately 2, filtered, and dried under vacuum to obtain 2-methyl-5-((5-methylisoxazole-3-yl)methoxy)benzofuran-3-carboxylic acid (250 mg, 70%) as a white solid. TLC system: 50% ethyl acetate in pet ether, RF: 0.2 [M+H] + (m / z): 288.1

[0266] The following compounds were prepared in the same manner as compound 215 (using appropriate reagents (including mesylates, chlorides, and bromides) and purification methods known to those skilled in the art). [Table 9]

[0267] Synthesis of 5-((2-aminopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 225). [ka] Step 1: To a pre-stirred solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (0.900 g, 4.09 mmol) in THF (30 ml), NaH (60%) (0.313 g, 8.18 mmol) was added lot-wise at 0°C under an argon atmosphere, followed by the addition of 3-(chloromethyl)pyridine-2-amine (2239-1) (0.871 g, 6.13 mmol) at 0°C under an argon atmosphere. The reaction mixture was heated to 60°C for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 0-30% ethyl acetate in pet-ether as the eluent to obtain ethyl 5-((2-aminopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (0.30 g, 23%) as a white solid. TLC system: 50% ethyl acetate in pet-ether, Rf: 0.3.

[0268] Step 2: To a pre-stirred solution of ethyl 5-((2-aminopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (0.30 g, 0.92 mmol) in THF:MeOH:H2O (1:1:1, 30 ml), NaOH (0.11 g, 2.76 mmol) was added at room temperature. The reaction mixture was then heated to 50°C, and the reaction mixture was stirred at 50°C for 6 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated to obtain the crude substance, which was diluted with ice water and the pH was adjusted with 1N HCl aqueous solution to approximately 2 to obtain a solid. The obtained solid was filtered and dried to obtain 5-((2-aminopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (0.22 g, 80%) as an off-white solid. TLC system: 10% MeOH in CH2Cl2, Rf: 0.2.[M+H] + (m / z): 299.1

[0269] Synthesis of 2-methyl-5-((2-methylpyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (compound 247). [ka] Step 1: To a solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (800 g, 3.636 mmol) and (2-methylpyridine-3-yl)methylmethanesulfonate (1.4 g, 7.272 mmol) in DMF (5 mL), K2CO3 (1.5 g, 10.909 mmol) was added at 0°C. The reaction mixture was allowed to return to room temperature and stirred at the same temperature for 12 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice water (100 mL) and stirred for 30 minutes. The solid was collected by filtration and dried to obtain 1.2 g (92%) of ethyl 2-methyl-5-((2-methylpyridine-3-yl)methoxy)benzofuran-3-carboxylate as an off-white solid. TLC system: 20% ethyl acetate in PET ether, RF: 0.20

[0270] Step 2: A solution of ethyl 2-methyl-5-((2-methylpyridine-3-yl)methoxy)benzofuran-3-carboxylate (1.2 g, 3.692 mmol) and NaOH (295 mg, 7.384 mmol) in EtOH:THF:H2O (2:2:1, 5.0 mL) was stirred at 70°C for 16 hours. The progress of the reaction was monitored by TLC. The solvent was distilled, and then water (20 mL) was added to the crude residue. The aqueous phase was washed with diethyl ether (2 × 10 mL). The aqueous layer was acidified with 2N HCl, and the resulting precipitated solid was collected by filtration, washed with water (10 mL), and dried under reduced pressure to obtain 2-methyl-5-((2-methyl-4-(trifluoromethyl)thiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 91%) as an off-white solid. TLC system: 10% MeOH in dichloromethane; RF: 0.10.[M+H] + (m / z): 298.1

[0271] Synthesis of 5-((5-(2-hydroxyethoxy)pyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 241). [ka] Step 1: To a stirred solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (5 g, 22.7 mmol) and (5-methoxypyridine-2-yl)methanol (3.79 g, 27.2 mmol) in THF (150 mL), ADDP (11.4 g, 46 mmol) was added, followed by the addition of Bu3P (9.2 g, 46 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. After separation, the aqueous layer was extracted with ethyl acetate (150 mL x 2). The combined organic extracts were concentrated under reduced pressure to obtain the residue. The residue was purified by flash chromatography (silica gel, 100-200 mesh size) using a gradient of ethyl acetate in hexane (5-40%) to obtain 5-((5-methoxypyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylate (3g, 8.7 mmol, 38%) as a pale yellow solid. TLC system: 30% ethyl acetate in PET ether, RF: 0.35.

[0272] Step 2: To a stirred solution of ethyl 5-((5-methoxypyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylate (500 mg, 1.4 mmol) in CH2Cl2 (20 mL), AlCl3 (390 mg, 2.9 mmol) was gradually added at 0°C, and the reaction mixture was stirred at 50°C for 2 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction product was concentrated under reduced pressure to obtain the residue. The residue was treated with saturated NaHCO3 solution (pH approximately 7) and partitioned between water and dichloromethane. After separation, the aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic extract was concentrated under reduced pressure to obtain ethyl 5-((5-hydroxypyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylate (180 mg, 5 mmol) as a pale yellow solid. TLC system: 50% ethyl ether in pet ether, RF: 0.3

[0273] Step 3: To a stirred solution of ethyl 5-((5-hydroxypyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylate (600 mg, 1.8 mmol) in DMF (20 mL), (2-bromoethoxy)(tert-butyl)dimethylsilane (657 mg, 2.7 mmol) was added at 0°C, and the reaction mixture was stirred at 60°C for 6 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction product was partitioned between water and ethyl acetate. After separation, the aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic extract was concentrated under reduced pressure to obtain ethyl 5-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylate (600 mg, 1.2 mmol) as a pale yellow solid. TLC system: 30% acetate in PET ether, RF: 0.7.

[0274] Step 4: To a stirred solution of ethyl 5-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylate (600 mg, 1.2 mmol) in THF (20 mL), NaOH (148 mg, 3 mmol) in water (3 mL) was added, followed by the addition of MeOH (3 mL) at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the reaction product was concentrated under reduced pressure. The residue was stirred in 1N HCl (pH approximately 2) for 30 minutes, and then partitioned between water and dichloromethane. After separation, the aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic extracts were concentrated under reduced pressure to obtain 5-((5-(2-hydroxyethoxy)pyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (300 mg, 8 mmol) as an off-white solid. TLC system: 5% MeOH in dichloromethane, RF: 0.4 [M+H] + (m / z): 344.0

[0275] Synthesis of 5-((2-(dimethylamino)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 222). [ka] Step 1: To a pre-stirred solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (2.5 g, 0.011 mmol) in acetonitrile (50 mL), Cs2CO3 (7.3 g, 0.022 mmol) and 2-chloro-3-(chloromethyl)pyridine (2.1 g, 0.0132 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was heated to 80°C for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was filtered, the filter cake was washed with acetonitrile (50 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by grace chromatography using 0-20% ethyl acetate in pet-ether as the eluent to obtain ethyl 5-((2-chloropyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (2.0 g, 63%) as an off-white solid. TLC system: 30% acetate in PET ether, RF: 0.6.

[0276] Step 2: A solution of ethyl 5-((2-chloropyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (500 mg, 1.44 mmol) and an N,N-dimethylamine solution in ethanol (10 mL, 5 M) was heated in a microwave at 150 °C for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Grace flash chromatography using 0-5% ethyl acetate in pet ether as the eluent to obtain ethyl 5-((2-(dimethylamino)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (180 mg, 39%) as an off-white solid. TLC system: 30% ethyl acetate in pet ether, RF: 0.5.

[0277] Step 3: To a stirred solution of ethyl 5-((2-(dimethylamino)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (300 mg, 0.847 mmol) in THF:MeOH:H2O (1:1:0.5, 25 ml), NaOH (170 mg, 4.27 mmol) was added at room temperature, and the mixture was heated to 50°C. The reaction mixture was stirred at 50°C for 4 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum, diluted with ice water, and the pH was adjusted with 1N HCl aqueous solution to approximately 2 to obtain a solid. This solid was filtered and dried to obtain 5-((2-(dimethylamino)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (170 mg, 61%) as a white solid. TLC system: 30% siRNA in PET ether, RF:0.1.[M+H] + (m / z): 327.2.

[0278] Synthesis of 5-((2-cyclopropylpyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 701). [ka] Step 1: ADDP (806.08 mg, 3.196 mmol) and n-Bu3P (646.5 mg, 3.196 mmol) were added to a pre-stirred solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (500 mg, 2.283 mmol) and (2-bromopyridine-3-yl)methanol (643.4 mg, 3.42 mmol) in THF (10 mL) at room temperature. The RM was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The RM was diluted with water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by flash column chromatography using 0.1% formic acid in water and acetonitrile in water as eluents to obtain ethyl 5-((2-bromopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (520 mg, crude) as a yellow solid. The next step was performed without further purification.

[0279] Step 2: Pd(PPh2)2Cl2 (45.04 mg, 0.06 mmol) was added at room temperature to a stirred solution of ethyl 5-((2-bromopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (250 mg, 0.6426 mmol), cyclopropylboronic acid (83.38 mg, 0.9640 mmol), and K3PO4 (409.15 mg, 1.9278 mmol) in 1,4-dioxane (10 mL) and water (4 mL). The reaction mixture was degassed with Ar gas at room temperature for 15 minutes. The reaction mixture was heated to 100 °C and stirred at 100 °C for 16 hours. The progress of the reaction was monitored by TLC. The reaction product was filtered on a Celite bed, the filtrate was diluted with water (20 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude product was purified by Grace flash column chromatography using 0.1% formic acid in water and acetonitrile as eluents to obtain ethyl 5-((2-cyclopropylpyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (150 mg, crude) as a brown solid. The next step was performed without purification. TLC system: 100% ethyl acetate, RF: 0.4.

[0280] Step 3: A solution of NaOH (91.4 mg, 2.285 mmol) in water (8 mL) was added at room temperature to a stirred solution of ethyl 5-((2-cyclopropylpyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (80 mg, 0.228 mmol) in methanol (2 mL) and THF (2 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, diluted with water (15 mL), and the pH was adjusted with 1N HCl solution to approximately 5. The precipitated solid was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain 5-((2-cyclopropylpyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (6) (100 mg, crude) as a viscous brown liquid. The next step was performed without purification. TLC system: 10% MeOH in dichloromethane; RF: 0.2.

[0281] Synthesis of 5-((2-aminopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 230). [ka] Step 1: To a stirred solution of ethyl 2-formyl-5-((2-methoxypyridine-3-yl)methoxy)benzofuran-3-carboxylate (1.5 g, 13.8 mmol) in CH2Cl2 (100 ml), DAST (4.47 g, 28 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours, and the progress of the reaction was monitored by TLC. Ice-cold water was added to the reaction mixture, and an aqueous solution of NaHCO3 was added to adjust the pH to approximately 7, followed by extraction with ethyl acetate (3 × 100 mL). The combined extract was washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude material (1.4 g). The crude product was purified by column chromatography using silica gel (100-200 mesh) and 20% ethyl acetate in pet ether as the eluent to obtain ethyl 2-(difluoromethyl)-5-((2-methoxypyridine-3-yl)methoxy)benzofuran-3-carboxylate (1 g) as a white solid. TLC system: 20% ethyl acetate in pet ether, Rf: 0.6.

[0282] Step 2: To a stirred solution of ethyl 2-(difluoromethyl)-5-((2-methoxypyridine-3-yl)methoxy)benzofuran-3-carboxylate (1 g, 1.4 mmol), LiOH.H2O (110 mg, 2.8 mmol) in THF:H2O:MeOH (3:1:1) (25 mL) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. The solvent was removed, and the reaction mixture was treated with citrate to adjust the pH to approximately 1. The resulting precipitate was filtered. The solid was dried under vacuum to obtain 2-(difluoromethyl)-5-((2-methoxypyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (1 g, 68%) as an off-white solid. TLC system: 5% MeOH in CH2Cl2, Rf: 0.2 [M+H] + (m / z): 350.0.

[0283] Synthesis of 5-((2-(azetidine-1-yl)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 236). [ka] Step 1: To a stirred solution of ethyl 5-((2-chloropyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (4.0 g, 11.59 mmol, 1.0 equivalent) in DMSO (40 ml) at 0°C, K2CO3 (15.99 g, 115.90 mmol, 10 equivalents) was added at 0°C, and the mixture was stirred for 5 minutes. Azetidine (5.39 g, 57.97 mmol, 5 equivalents) was added to the reactant, and the mixture was stirred at 120°C for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice water (50 ml), and the product was extracted with ELISA (300 ml). The ethyl acetate layer was washed with ice water (50 ml) and brine (25 ml), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by Grace flash column chromatography using 20% ​​siRNA-pet ether as the eluent to obtain ethyl 5-((2-(azetidine-1-yl)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (0.380 g, 9%, off-white solid). TLC system: 30% ethyl acetate in pet ether, Rf: 0.3.

[0284] Step 2: To a stirred solution of ethyl 5-((2-(azetidine-1-yl)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (0.700 g, 1.91 mmol, 1.0 equivalent) in THF:MeOH:H2O (1:1:1) (60 ml), NaOH (0.29 g, 5.73 mmol, 3.0 equivalent) was added at room temperature, and the mixture was then heated to 50°C. The reaction mixture was stirred at 50°C for 18 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was concentrated to obtain the crude product, diluted with ice water, and precipitated by adjusting the pH to 2 with a 1N HCl solution. The contents were stirred for a further 30 minutes, and then the solid was filtered and dried to obtain 5-((2-(azetidine-1-yl)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (0.400 g, 61% white solid). TLC system: 100% ethyl acetate, Rf: 0.2 [M+H]+ (m / z): 339.0.

[0285] Synthesis of 5-((2-cyanopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 238). [ka] Step 1: To a stirred solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (0.8 g, 3.63 mmol, 1.0 equivalent) in 10 ml of ACN at 0°C, Cs2CO3 (3.55 g, 10.89 mmol, 3 equivalents) was added, and the mixture was stirred for 5 minutes. Subsequently, 3-(bromomethyl)picolinonitrile (0.85 g, 4.36 mmol, 1.2 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 18 hours and monitored by TLC. The reaction mixture was diluted with ice water (100 ml) and extracted with RINKAN (300 ml). The organic layer was washed with ice water (100 ml) and brine (50 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by Grace flash column chromatography using 20% ​​siRNA as the eluent in pet ether to obtain ethyl 5-((2-cyanopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (1.0 g, 81%, off-white solid). TLC system: 20% siRNA-pet ether, 2:8, Rf: 0.3.

[0286] Step 2: NaOH (0.35 g, 8.92 mmol, 3.0 equivalents) was added at room temperature to ethyl 5-((2-cyanopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate (1.0 g, 2.97 mmol, 1.0 equivalent) in THF:MeOH:H2O (1:1:1) (120 ml). The reaction mixture was then heated at 50°C for 18 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was concentrated, diluted with ice water, and the pH was adjusted to approximately 2 with 1N HCl solution. A precipitate was obtained by stirring for 30 minutes. The precipitate was filtered and dried under vacuum to obtain a mixture of 5-((2-cyanopyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 238) and 5-((2-carbamoylpyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (0.75 g, crude). [M+H] + (m / z): 309.0, TLC system: 50% ammonium PET ether, Rf: 0.1.

[0287] The following compounds were prepared in the same manner as compound 238 (using appropriate reagents and purification methods known to those skilled in the art). [Table 10]

[0288] Synthesis of 2-methyl-5-(((2-(trifluoromethyl)pyridine-3-yl)oxy)methyl)benzofuran-3-carboxylic acid (compound 252). [ka] Step 1: DABCO (2.78 g, 24.75 mmol) was added at room temperature to a stirred mixture of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 24.75 mmol) and ethylbuta-2-inoate (3.32 g, 29.70 mmol) in acetonitrile (100 mL). The resulting reaction mixture was then heated under reflux for 4 hours. The solvent was distilled under reduced pressure, the residue was diluted with ethyl acetate (300 mL), and the resulting solution was sequentially washed with 1N HCl (100 mL), 1N NaOH aqueous solution (2 × 75 mL), water (100 mL), and brine (150 mL). The solution was then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 10% ethyl acetate in pet-ether as the eluent to obtain ethyl 3-(2-bromo-4-formylphenoxy)buta-2-enoate (1.5 g, 29%) as an off-white solid. TLC system: 20% ethyl acetate in pet-ether, Rf: 0.7.

[0289] Step 2: A solution mixture of ethyl 3-(2-bromo-4-formylphenoxy)buta-2-enoate (1.2 g, 3.821 mmol) and TEA (0.21 mL, 1.528 mmol) in acetonitrile (25.0 mL) was degassed with argon for 5 minutes, and then bis(tri-tert-butylphosphine)palladium(0) (195 mg, 0.382 mmol) was added. The resulting reaction mixture was heated under reflux for 2 hours. The progress of the reaction was monitored by TLC. (Note: Another batch on a 250 mg scale was work-treated in combination with this reaction mixture using the same procedure). The reaction mixture was concentrated directly under reduced pressure. The crude product was partitioned between water (100 mL) and ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain ethyl 5-formyl-2-methylbenzofuran-3-carboxylate (1.0 g, 90%) as an off-white crystalline solid. TLC system: 10% ethyl acetate in pet ether, Rf: 0.7.

[0290] Step 3: NaBH4 (398 mg, 10.775 mmol) was gradually added at 0°C to a solution mixture of ethyl 5-formyl-2-methylbenzofuran-3-carboxylate (1.0 g, 4.310 mmol) in EtOH:THF (1:1) (40.0 mL), and the resulting reaction mixture was stirred for 30 minutes. The reaction mixture was then quenched with water (5.0 mL) and concentrated under reduced pressure. The crude compound was diluted with ethyl acetate (50 mL), washed with water (2 × 50 mL) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain ethyl 5-(hydroxymethyl)-2-methylbenzofuran-3-carboxylate (900 mg, crude) as a colorless oil. TLC system: 20% ethyl acetate in pet ether, Rf: 0.4.

[0291] Step 4: A mixture of ethyl 5-(hydroxymethyl)-2-methylbenzofuran-3-carboxylate (700 mg, 2.991 mmol), TPP (1.17 g, 4.487 mmol), and CBr4 (1.48 g, 4.487 mmol) in THF (40.0 mL) was stirred at 0°C and then heated to ambient temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (100 mL), washed with NaHCO3 solution (50 mL), water (50 mL), and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain ethyl 5-(bromomethyl)-2-methylbenzofuran-3-carboxylate (1.25 g, crude) as a pale yellow, thick, viscous product. TLC system: 10% ethyl acetate in pet ether, Rf: 0.6.

[0292] Step 5: To a suspension of 2-(trifluoromethyl)pyridine-3-ol (600 mg, 3.680 mmol) and K2CO3 (1.26 g, 9.20 mmol) in acetonitrile (30 mL), ethyl 5-(bromomethyl)-2-methylbenzofuran-3-carboxylate (1.32 g, 4.41 mmol) was added, and the resulting reaction mixture was maintained at 90°C for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with water (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 20% ​​ethyl acetate in pet-ether as the eluent to obtain ethyl 2-methyl-5-(((2-(trifluoromethyl)pyridine-3-yl)oxy)methyl)benzofuran-3-carboxylate (800 mg, 58%) as a red solid. TLC system: 20% ethyl acetate in pet-ether, Rf: 0.5.

[0293] Step 6: To a stirred solution of ethyl 2-methyl-5-(((2-(trifluoromethyl)pyridine-3-yl)oxymethyl)benzofuran-3-carboxylate) (800 mg, 2,110 mmol) in ethanol:THF (1:1) (40 mL), a solution of NaOH (253 mg, 6,332 mmol) dissolved in water (10 mL) was added, and the resulting reaction mixture was maintained at 60 °C for 1 hour with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, poured into ice-cold water (100 mL), acidified with 1 N HCl to a pH of approximately 5.0, and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (100 mL), followed by washing with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 2-methyl-5-(((2-(trifluoromethyl)pyridine-3-yl)oxy)methyl)benzofuran-3-carboxylic acid (800 mg, crude) as a red solid. TLC system: 10% MeOH in dichloromethane, Rf: 0.4 [M+H] + (m / z): 352.0.

[0294] Synthesis of 2,4-dimethyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (compound 251). [ka] Step 1: 2-(trifluoromethyl)pyridine-3-yl)methanol (0.887 mg, 5.01 mmol), ADDP (0.946 mg, 4.67 mmol), and tri-n-butylphosphine (1.18 g, 4.67 mmol) were sequentially added to a pre-stirred solution of ethyl 4-bromo-5-hydroxy-2-methylbenzofuran-3-carboxylate (1.0 g, 3.34 mmol) in THF (50 mL) under an argon atmosphere at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was poured into water (80 mL) and subsequently extracted with ethyl acetate (2 × 60 mL). The combined organic layers were sequentially washed with water (30 mL) and brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 0-20% ethyl acetate in pet-ether as the eluent to obtain ethyl 4-bromo-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (0.600 g, crude) as a pale yellow liquid. TLC system: 20% ethyl acetate in pet-ether, Rf: 0.6.

[0295] Step 2: A suspension of ethyl 4-bromo-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (0.6 g, 1.31 mmol), methylboronic acid (0.157 g, 2.62 mmol), and K2CO3 (0.542 g, 3.93 mmol) in 1,4-dioxane:water (9:1) (10 mL) in a sealed tube was degassed with argon for 10 minutes, and then Pd(PPh3)4 (0.151 g, 0.13 mmol) was added. The resulting reaction mixture was degassed again for 10 minutes and then heated at 120°C for 16 hours. The progress of the reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ethyl acetate (2 × 30 mL). The combined filtrate was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by flash column chromatography on silica gel (100-200 mesh) using 0-20% ethyl acetate in pet-ether as the eluent to obtain ethyl 2,4-dimethyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (0.5 g, 71%) as a colorless liquid. TLC system: 20% ethyl acetate in pet-ether, Rf: 0.7.

[0296] Step 3: A solution of NaOH (0.203 g, 5.08 mmol) in water (4 mL) was added to a pre-stirred solution of ethyl 2,4-dimethyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (0.5 g, 1.27 mmol) in a methanol:THF (1:1) (14 mL) mixture. The resulting reaction mixture was heated at 60 °C for 4 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled and poured into ice-cold water (30 mL), and acidified with 1 N HCl until the pH was approximately 2. The crude product was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain 2,4-dimethyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (0.350 g, 65%) as an off-white solid. This crude product was used in the next step without further purification. TLC system: 50% ethyl acetate in pet ether, Rf: 0.3 [M+H] + (m / z): 366.1

[0297] Synthesis of 2-cyclopropyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (compound 265). [ka] Step 1: To a stirred solution of benzoquinone (1.5 g, 13.8 mmol) in IPA (50 ml), ZnCl2 (9.4 g, 69.44 mmol) was added, followed by the addition of methyl 3-cyclopropyl-3-oxopropanoate (7.8 g, 55.55 mmol) at room temperature. The reaction mixture was stirred under reflux for 6 hours, and the progress of the reaction was monitored by TLC. Ice-cold water was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (2 × 300 mL). The combined extract was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude substance (3 g). The crude substance was purified by column chromatography using silica gel (100-200 mesh) and 20% ethyl acetate in pet ether as the eluent to obtain methyl 2-cyclopropyl-5-hydroxybenzofuran-3-carboxylate (800 mg, 74%) as a brown solid. TLC system: 50% ethyl acetate in PET ether, RF: 0.63.

[0298] Step 2: To a stirred solution of methyl 2-cyclopropyl-5-hydroxybenzofuran-3-carboxylate (300 mg, 1.29 mmol) in CH3CN (25 mL), Cs2CO3 (1.2 g, 3.87 mmol) was added under an argon atmosphere at 0°C, followed by the addition of (4-methylthiazole-5-yl)methylmethanesulfonate (370 mg, 1.93 mmol). The reaction mixture was stirred at 50°C for 16 hours. The progress of the reaction was monitored by TLC. The solvent was removed, ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 100 mL). The combined extract was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product (400 mg). The crude product was purified by column chromatography using silica gel (100-200 mesh) and 25% ethyl acetate in pet ether as the eluent to obtain methyl 2-cyclopropyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylate (200 mg, 45%) as a brown solid. TLC system: 50% ethyl acetate in pet ether, RF: 0.42.

[0299] Step 3: To a stirred solution of methyl 2-cyclopropyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylate (200 mg, 0.583 mmol) in MeOH and THF (1:1, 10 ml), 2N NaOH (4 ml) was added at 0°C, and the reaction mixture was stirred at 50°C for 4 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and acidified with 1N aqueous HCl until the pH was approximately 2, and extracted with ethyl acetate (3 × 50 mL). The combined extract was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-cyclopropyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (120 mg, crude) as an off-white solid. [M+H] + (m / z): 330.1

[0300] The following compounds were prepared in the same manner as compound 265 (using appropriate reagents and purification methods known to those skilled in the art). [Table 11]

[0301] Synthesis of tert-butyl 3-(((3-(ethoxycarbonyl)-2-methylbenzofuran-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (compound 079), 5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 019), and 2-methyl-5-(pyrrolidine-3-ylmethoxy)benzofuran-3-carboxylic acid (compound 003). [ka] Step 1: To a cold solution of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate (0.110 g, 0.5 mmol), tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.148 g, 0.75 mmol), and PS-PPh3 (load approximately 1.83 mmol / g, 0.546 g, 1 mmol) in THF (ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate 4 mL / mmol), a solution of DIAD (0.148 mL, 0.75 mmol) in THF (0.4 mL) was slowly added. The RM was stirred at room temperature for 18 hours, and volatile matter was removed under reduced pressure. The crude substance was purified by FCC on silica gel using a DCM gradient (0% to 100%) in heptane to obtain 0.057 g (28%) of tert-butyl 3-(((3-(ethoxycarbonyl)-2-methylbenzofuran-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (compound 079).

[0302] Step 2: To a solution of tert-butyl 3-(((3-(ethoxycarbonyl)-2-methylbenzofuran-5-yl)oxy)methyl)pyrrolidine-1-carboxylate (compound 079) (0.057 g, 0.141 mmol) in a mixture of MeOH-EtOH (2:1, 4.2 mL), an aqueous solution of NaOH (1 N, 4.2 mL, 4.2 mmol) was added, and the RM was heated under reflux for 18 hours. After cooling, volatiles were removed under reduced pressure, and the remaining residue was solubilized in water. The mixture was acidified with an aqueous solution of HCl (6 N) until the pH was approximately 2. The white precipitate was washed with water and dried under high vacuum to obtain 0.052 g (98%) of 5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 019).

[0303] Step 3: To a solution of 5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methoxy)-2-methylbenzofuran-3-carboxylic acid (compound 019) (0.050 g, 0.133 mmol) in THF (1 mL), a solution of HCl (4N in dioxane, 1 mL) was added, and the RM was stirred for 18 hours. The volatiles were removed under reduced pressure, and the remaining residue was dried under high vacuum to obtain 0.029 g (70%) of 3-(((3-carboxy-2-methylbenzofuran-5-yl)oxy)methyl)pyrrolidine-1-ium chloride (compound 003).

[0304] Compound 015 was prepared in the same manner as compound 019 (using appropriate reagents and purification methods known to those skilled in the art).

[0305] Synthesis of 2-methyl-N-(1-methylpiperidine-4-yl)-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxamide (compound 069). [ka] Step 1: HATU (235 mg, 0.62 mmol) was added to a solution of 2-methyl-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxylic acid (compound 018) (140 mg, 0.41 mmol) and DIPEA (0.21 mL, 1.2 mmol) in DCM (5 mL). After 4 hours at room temperature, 1-methylpiperidine-4-amine (I-7) (59 mg, 0.51 mmol) was added, and the RM was stirred overnight. The RM was then diluted with DCM and successively washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and filtered. The volatile components were removed under reduced pressure, and the crude material was purified by FCC on silica gel using a MeOH gradient (0%~20%) in DCM to obtain 128 mg (71%) of 2-methyl-N-(1-methylpiperidine-4-yl)-5-((5-(trifluoromethyl)furan-2-yl)methoxy)benzofuran-3-carboxamide (compound 069).

[0306] The following compounds were prepared in the same manner as compound 069 (using appropriate reagents and purification methods known to those skilled in the art, including chiral HPLC or chiral SFC): Compounds 037, 039, 047, 049, 052, 054, 058, 059, 060, 061, 072, 078, 097, 098, 104, 107, 109, 117, 119, 128, 129, 132-En1, 132-En2, 133, 135-En1, 135-En1, 1 39, 142, 143, 146, 148-En1, 148-En2, 150, 152, 154, 156, 158, 159-En1, 159 -En2、161、167、ラセミ170、171、178、181、192、200、ラセミ203、204、206、270-En1、 270-En2, 274, 275, 308, 309, 312, 314, 315-En1, 315-En2, 316-En1, 316-En 2. 317-En1, 317-En2, 322, 323, 331, 334, 337, 339, 341, 343, 344, 345, 346, 3 51, 352, 357, 358, 359, 370, 371, 372, 373, 374, 384, 385, 390, 391, 392, 393 ,394,399,400,401-En1,401-En2,414,415,416,417,418,419,420,421,42 2. 423, 424, 425, 426, 427, 428, 429, 430, 431, 481, 482, 483, 484, 485, 486, 489-En1, 489-En2, 490-En1, 490-En2, 491-En1, 491-En2, 492, 493, 494, 495 ,496,497,498,499,500,501,504,505,506,507,523,524,525,526,527,5 28, 529, 531-En1, 531-En2, 532-En1, 532-En2, 533-En1, 533-En2, 534-En1, 534-En2, 535-En1, 535-En2, 536-En1, 536-En2, 537, 574, 576, 602, 603, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, compound 623-En1, compound 623-En2, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 641-En1, 641-En2, 642-En1, 642-En2, 643-En1, 643-En2, 646-En1,646-En2, 647-En1, 647-En2, 648-En1, 648-En2, 649, 651, 652, 659, 660, 661-En1, 661-En2, 664, 665, 666 , 668, 670, 672, 674, 676, 678, 680, 682, 683, 684, 685, 686, 688, 690, 692, 694, 695, 696, 697, 698, 700, 70 2, 704, 705, 706, 708, 710, 711, 712, 714, 715, 716, 718, 721, 722-En1, 722-En2, 723-En2, 724-En1, 724-E n2, 726-En1, 726-En2, 727-En1, 727-En2, 727-En3, 727-En4, 738-En1, 738-En2, 739-En1, 739-En2, 741,

[0307] Synthesis of 2-methyl-N-(2-oxopyrrolidine-3-yl)-5-(thiophene-3-ylmethoxy)benzofuran-3-carboxamide (compound 035) [ka] Step 1: Oxalyl chloride (0.300 mL, 2.96 mmol) and DMF (2 drops) were added to a mixture of 2-methyl-5-(thiophene-3-ylmethoxy)benzofuran-3-carboxylic acid (compound 011) (100 mg, 0.35 mmol) in DCM (5 mL). The resulting mixture was stirred for 4 hours. The RM was concentrated under reduced pressure to obtain 2-methyl-5-(thiophene-3-ylmethoxy)benzofuran-3-carbonyl chloride.

[0308] Step 2: A solution of 2-methyl-5-(thiophen-3-ylmethoxy)benzofuran-3-carbonyl chloride dissolved in DCM (3 mL) was added to a mixture of 3-aminopyrrolidine-2-one (0.052 g, 0.520 mmol) and DIPEA (0.121 mL, 0.520 mmol). The RM was stirred at room temperature for 18 hours. The resulting solid was filtered and purified by FCC on silica gel using a MeOH gradient (0%~20%) in DCM to obtain 0.023 g (18%) of 2-methyl-N-(2-oxopyrrolidine-3-yl)-5-(thiophen-3-ylmethoxy)benzofuran-3-carboxamide (compound 035).

[0309] The following compounds were prepared in the same manner as compound 035 (using appropriate reagents and purification methods known to those skilled in the art): Compounds 036, 080, 081, 082, 083, 084, and 085.

[0310] Synthesis of tert-butyl(S)-3-(2-methyl-5-((5-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide)-pyrrolidine-1-carboxylate (compound 073). [ka] Step 1: Tert-butyl(S)-3-aminopyrroloridine-1-carboxylate (1.1 g, 5.7 mmol) was added to a solution of 5-hydroxy-2-methylbenzofuran-3-carboxylic acid (1 g, 5.2 mmol), HATU (1.98 g, 5.2 mmol), and DIPEA (2.7 mL, 15.6 mmol) in DMF (10 mL). After 60 hours, the reaction product was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. After separation, the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a MeOH gradient (0-6%) in DCM to obtain 0.94 g (50%) tert-butyl-(S)-3-(5-hydroxy-2-methylbenzofuran-3-carboxamide)pyrroloridine-1-carboxylate. M / Z(+):361(M+H).M / Z(-):359(MH). 1 H NMR (DMSO-d6,300MHz)δppm:9.26(s,1H),8.17(d,J=6.4Hz,1H),7.32(d,J=9.0Hz,1H),6.99(d,J=1.88Hz,1H),6.70(dd,J=8.9,2.1Hz,1H),4. 35-4.50(m,1H),3.51-3.3.65(m,1H),3.35-3.49(m,1H),3.15-3.31(m ,1H),2.53(s.,3H),2.02-2.19(m,1H),1.84-1.99(m,1H),1.41(s,9H).

[0311] Step 2: Tributylphosphine (0.155 mL, 0.583 mmol) was added dropwise to a stirred mixture of tert-butyl-(S)-3-(5-hydroxy-2-methylbenzofuran-3-carboxamide)pyrrolidine-1-carboxylate (0.150 g, 0.416 mmol), (5-methylpyridine-3-yl)methanol (0.081 g, 0.624 mmol), and ADDP (0.150 g, 0.583 mmol) in dry THF (5 mL) under argon. The mixture was stirred at room temperature for 2 hours, and then the reaction was concentrated under reduced pressure. The residue was purified twice by FCC on silica gel using a gradient of MeOH in DCM (0-6%) in the first step and a gradient of MeOH in  (0-4%) in the second step to obtain 0.113 g (58%) of tert-butyl(S)-3-(2-methyl-5-((5-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (compound 073).

[0312] The following compounds were prepared in the same manner as compound 073 (using appropriate reagents and purification methods known to those skilled in the art): Compounds 026, 027, 030, 031, 032, 033, 034, 038, 040, 042, 043, 044, 046, 051, 057, 064, 065, 066, 077, 078, 086, 087, 088, 089, 090, 091, 092, 093, 094, 095, and 096.

[0313] (S)-2-methyl-5-((5-methylpyridine-3-yl)methoxy)-N-(pyrrolidine-3-yl)benzofuran-3-carboxamide (compound 028). [ka] A solution of hydrogen chloride in 1,4-dioxane (4M, 4mL, 16 mmol) was added to a solution of tert-butyl(S)-3-(2-methyl-5-((5-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (compound 073) (0.105 g, 0.22 mmol) in DCM (3 mL). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was then purified by a supported SiliaBond-propylsulfonic acid column using a gradient of a solution of 3N ammonia in MeOH (0-100%) in DCM to obtain 78 mg (95%) of (S)-2-methyl-5-((5-methylpyridine-3-yl)methoxy)-N-(pyrrolidine-3-yl)benzofuran-3-carboxamide (compound 028).

[0314] The following compounds were prepared in the same manner as compound 028 (using appropriate reagents and purification methods known to those skilled in the art): Compounds 020, 021, 022, 023, 034, 025, 029, 048, 050, 053, 055, 056, 062, 063, 067, 068, 070, 071, 074, 075, and 076.

[0315] Synthesis of 2-methyl-N-(1-methylpiperidine-4-yl)-5-(thiophen-2-ylmethoxy)benzofuran-3-carboxamide (compound 041). [ka] Step 1: 5-(benzyloxy)-2-methylbenzofuran-3-carboxylic acid (2.6 g, 9.2 mmol), HATU (5.2 g, 13.8 mmol, 1.5), and DIPEA (4.8 mL, 27.6 mmol) were dissolved in DCM (50 mL). After stirring at room temperature for 4 hours, 1-methylpiperidine-4-amine (1.2 mL, 9.7 mmol) was added, and RM was stirred overnight at room temperature. RM was diluted in 80 mL of DCM and washed with saturated sodium bicarbonate solution and brine. The solvent was removed under reduced pressure. The residue was purified by FCC on silica gel using a MeOH gradient (0-20%) in DCM to obtain 1.4 g (48%) of 5-(benzyloxy)-2-methyl-N-(1-methylpiperidine-4-yl)benzofuran-3-carboxamide. 1 H NMR(DMSO d6,300MHz)δppm7.89(d,1H);7.50-7.29(m,6H);7.22(d,1H);6.96(dd,1H);5.13(s,2H);3.85-3.65(m,1H);2.75(br d,2H);2.56(s,3H);2.16(s,3H);1.98(ddd,2H);1.85-1.74(m,2H);1.67-1.51(m,2H).

[0316] Step 2: A suspension of 5-(benzyloxy)-2-methyl-N-(1-methylpiperidine-4-yl)benzofuran-3-carboxamide (500 mg, 1.32 mmol) and Pd / C (70 mg, 0.065 mmol) in THF (13 mL) was stirred at room temperature under atmospheric pressure with hydrogen until the starting materials disappeared. The RM was then filtered through a Celite pad, and the filtrate was evaporated under reduced pressure to obtain 350 mg (92%) of 5-hydroxy-2-methyl-N-(1-methylpiperidine-4-yl)benzofuran-3-carboxamide, which was used without further purification. 1H NMR(DMSO d6,300MHz)δ(ppm):9.25(s,1H);7.84(d,1H);7.31(d,1H);6.99(d,1H);6.69(dd,1H);3.80-3.65(m,1 H);2.80-2.70(m,2H);2.52(s,3H);2.16(s,3H);2.04-1.89(m,2H);1.84-1.74(m,2H);1.58(ddd,2H).

[0317] Step 3: To a cold solution of 5-hydroxy-2-methyl-N-(1-methylpiperidine-4-yl)benzofuran-3-carboxamide (75 mg, 0.26 mmol), thiophene-2-yl methanol (45 mg, 0.39 mmol), and PS-PPh3 (1.8 mmol / g, 289 mg, 0.52 mmol) in THF (3 mL), a solution of DIAD (75 μL, 0.39 mmol) in THF (0.8 mL) was slowly added. The RM was stirred at room temperature for 18 hours, and volatile matter was removed under reduced pressure. The crude product was purified by preparative HPLC (Method H1) to obtain 8 mg (8%) of 2-methyl-N-(1-methylpiperidine-4-yl)-5-(thiophene-2-ylmethoxy)benzofuran-3-carboxamide (Compound 041).

[0318] Compound 045 was prepared in the same manner as compound 041 (using appropriate reagents and purification methods known to those skilled in the art).

[0319] Synthesis of N-(4,4-difluoropyrrolinidine-3-yl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 105) [ka] Step 1: To a stirred solution of compound 101 (250 mg, 0.71 mmol) in 50 mL of DCM, DIPEA (0.3 mL, 1.78 mmol), HATU (297 mg, 0.78 mmol), and tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (237 mg, 1.07 mmol) in 1 mL of DCM were added at room temperature. The RM was stirred for 18 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the RM was diluted in 300 mL of DCM, washed with saturated NaHCO3 (50 mL), water (2 × 50 mL), and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Grace FCC using 50% butyl-pet ether as the eluent to obtain tert-butyl 3,3-difluoro-4-(2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (350 mg, 88%).

[0320] Step 2: To a stirred solution of tert-butyl 3,3-difluoro-4-(2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (350 mg, 0.63 mmol) in DCM (20 ml), TFA (1 mL) was added at 0°C. The RM was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. The RM was concentrated, diluted in DCM (300 mL), washed with saturated NaHCO3 (2 × 50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with Et2O (10 mL) to obtain compound 105 (250 mg, 77% from the two steps). Preparative chiral SFC was performed to obtain compound 105-En1 and compound 105-En2.

[0321] The following compounds were prepared in the same manner as compound 105 (using appropriate reagents and purification methods known to those skilled in the art): Compounds 103-En1, 103-En2, 106-En1, 106-En2, 111-En1, 111-En2, 115-En1, 115-En2, 125-En1, 125-En2, 205-En1, 205-En2, 207-En 1, 207-En2, 173, 189, 190, 310-En1, 310-En2, 313-En1, 313-En2, 336-En1, 336-En2, 338-En1, 338-En2, 342-En1, 342-En2, 538- En1, 539-En1, 539-En2, 540-En1, 540-En2, 541-En1, 541-En2, 542-En1, 542-En2, 543-En1, 543-En2, 544-En2, 545-En1, 545-En 2, 546-En1, 547-En1, 547-En2, 548-En1, 548-En2, 549-En1, 549-En2, 550-En1, 550-En2, 551-En1, 551-En2, 552-En1, 552-En2, 553-En1, 553-En2, 554-En1, 554-En2, 555-En1, 555-En2, 556-En1, 556-En2, 557-En1, 557-En2, 558-En1, 558-En2, 559-En1, 55 9-En2, 560-En1, 560-En2, 561-En1, 561-En2, 562-En1, 562-En2, 563-En1, 563-En2, 564-En1, 564-En2, 565-En1, 565-En2, 566- En1, 566-En2, 567-En1, 567-En2, 568-En1, 568-En2, 569-En1, 569-En2, 570-En1, 570-En2, 571-En1, 571-En2, 572-En1, 572-En 2, 573-En1, 573-En2, 635-En1, 635-En2, 636-En1, 636-En2, 637-En1, 637-En2, 638-En1, 638-En2, 639-En1, 639-En2, 663, 717.

[0322] Synthesis of N-(1-((dimethylamino)methyl)cyclobutyl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (compound 108). [ka] Step 1: 37% formaldehyde in water (0.21 mL, 2.5 mmol) was added at 0°C under an argon atmosphere to a pre-stirred solution of compound 137 (100 mg, 0.26 mmol) in MeOH (10 mL). Then, glacial acetic acid (2 drops) and NaCNBH3 (32.6 mg, 0.51 mmol) were added to the reactants. The reaction mixture (RM) was allowed to reach room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. The RM was poured into water (25 mL) and extracted with SiO2 (3 × 25 mL). The combined organic layer was dried with saturated NaHCO3 (25 mL), water (25 mL), and brine (25 mL) over Na2SO4, and excess solvent was removed under reduced pressure. The crude product was purified by flash chromatography using 0-50% acetonitrile in 0.1% FA as the eluent, followed by purification by reverse-phase preparative HPLC to obtain compound 108 (55 mg, 51%).

[0323] Compound 140 was prepared in the same manner as compound 108 (using appropriate reagents and purification methods known to those skilled in the art).

[0324] Synthesis of N-(3,3-difluoropiperidine-4-yl)-4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)-benzofuran-3-carboxamide (compound 112) [ka] Step 1: 2-(trifluoromethyl)pyridine-3-yl)methanol (2.23 g, 12.6 mmol), ADDP (2.96 g, 11.7 mmol), and tri-n-butylphosphine (2.37 g, 11.7 mmol) were added at 0°C under an argon atmosphere to a mixture of ethyl 4-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate and ethyl 6-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate (2.0 g, 8.4 mmol) in THF (50 mL). The RM was allowed to reach room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC. The RM was poured into water (100 mL) and extracted with ethyl phosphate (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 10-20% butyl in pet ether as the eluent, followed by purification by reverse-phase preparative HPLC to obtain a mixture of ethyl 4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (300 mg, 8%) and ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (400 mg, 11%).

[0325] Step 2: 10 mL of 2N NaOH was added at room temperature to a solution of ethyl 4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (250 mg, 0.62 mmol) in a mixture of MeOH (15 mL) and THF (5 mL). The resulting RM was heated at 80°C for 3 hours. The progress of the reaction was monitored by TLC. The RM was cooled to room temperature, poured into ice-cold water (50 mL), and acidified with 1N HCl until the pH was approximately 2. The crude product was extracted with Â(3 × 50 mL), washed with water (100 mL), then washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain 4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (220 mg, 95%). The crude product was used in the next step without purification.

[0326] Step 3: To a solution of 4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (200 mg, 0.54 mmol) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (191 mg, 0.81 mmol) in DMF (15 mL), DIPEA (0.2 mL, 1.08 mmol) was added at 0°C under an argon atmosphere, followed by HATU (412 mg, 1.08 mmol). The RM was allowed to reach room temperature and stirred for 1 hour. The progress of the reaction was monitored by TLC. The RM was diluted with ice-cold water (50 mL) and filtered. The solid obtained in this manner was washed with water (50 mL) and dried under reduced pressure to obtain tert-butyl 3,3-difluoro-4-(4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)piperidine-1-carboxylate (250 mg, 78%).

[0327] Step 4: 4M HCl in dioxane (5 mL) was added dropwise at 0°C under an argon atmosphere to a solution of tert-butyl 3,3-difluoro-4-(4-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)piperidine-1-carboxylate (0.25 g, 0.42 mmol) in DCM (20 mL). The RM was warmed to room temperature and stirred for 5 hours. The progress of the reaction was monitored by TLC. Excess solvent was evaporated under vacuum, the residue was cooled to 0°C, extracted with saturated NaHCO3 until the pH was approximately 9, and then extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 112 (200 mg, 96%). Preparative chiral SFC was performed on a racemic mixture of compound 112 to obtain compound 112-En1 and compound 112-En2.

[0328] Synthesis of N-(3,3-difluoropiperidine-4-yl)-6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 113) and N-(3,3-difluoropiperidine-4-yl)-7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 176) [ka] Step 1: To a pre-stirred solution of CAN (27.41 g, 50.00 mmol) in water (60 mL), 2-chlorobenzene-1,4-diol (3.0 g, 23.80 mmol) was added at 0°C. The resulting RM was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The organic compounds were extracted with Et2O (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The clear filtrate was passed through a silica gel column and eluted with diethyl ether. The collected fraction was evaporated under vacuum to obtain 2-fluorocyclohexa-2,5-diene-1,4-dione (2.5 g, 84%).

[0329] Step 2: To a pre-stirred solution of 2-fluorocyclohexa-2,5-diene-1,4-dione (2.5 g, 20.16 mmol) in toluene (30 mL), ethyl 3-oxobutanoate (7.86 g, 60.48 mmol) was added under an argon atmosphere at room temperature, followed by the addition of anhydrous ZnCl2 (3.29 g, 24.19 mmol). The resulting RM was heated under reflux and maintained at this temperature for 16 hours using a Dean-Stark apparatus. The progress of the reaction was monitored by TLC. The RM was cooled to room temperature, filtered through a Celite pad, and the Celite pad was washed with ELISA (70 mL). The combined clear filtrate was concentrated under reduced pressure. The crude product was purified by FCC on silica gel using 0-10% siRNA in pet-ether as the eluent to obtain a mixture of ethyl 7-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate and ethyl 6-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate (0.8 g, 21%).

[0330] Step 3: (2-(trifluoromethyl)pyridine-3-yl)methanol (1.11 g, 6.30 mmol), ADDP (1.48 g, 5.88 mmol), and tri-n-butylphosphine (1.38 mL, 5.88 mmol) were sequentially added under an argon atmosphere at room temperature to a pre-stirred solution of a mixture of ethyl 6-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate and ethyl 7-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate (1.0 g, 4.20 mmol) in THF (30 mL). The RM was stirred at the same temperature for 2 hours. The progress of the reaction was monitored by TLC. The RM was poured into water (100 mL) and extracted with RINKAN (2 × 100 mL). The combined organic layers were sequentially washed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 0-20% butyl in pet-ether as the eluent to obtain a mixture of ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (1.1 g, 66%). The crude product was used in further steps without purification.

[0331] Step 4: A solution of NaOH (0.44 g, 11.08 mmol) in water (8 mL) was added dropwise at room temperature to a pre-stirred solution of ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylate (1.1 g, 2.77 mmol) in a mixture of MeOH (15 mL) and THF (7 mL). The resulting RM was heated to 60 °C and maintained for 4 hours. The progress of the reaction was monitored by TLC. The RM was cooled to room temperature, poured into ice water (50 mL), and acidified with 1 N HCl until the pH was approximately 2. The crude product was extracted with ELISA (2 × 50 mL). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain a mixture of 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 99%). This crude product was used in the next step without purification.

[0332] Step 5: To a solution of 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 2.71 mmol) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (0.74 g, 3.25 mmol) in DMF (20 mL), DIPEA (1.45 mL, 8.13 mmol) was added at 0°C under an argon atmosphere, followed by the addition of HATU (2.05 g, 5.42 mmol). The RM was allowed to reach room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. The RM was diluted with water (100 mL), and the organic compounds were extracted with ELISA (2 × 70 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica using 0-55% butyl and pet-ether as eluents to obtain a mixture of tert-butyl 3,3-difluoro-4-(6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxyamide)piperidine-1-carboxylate and tert-butyl 3,3-difluoro-4-(7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxyamide)piperidine-1-carboxylate (1.0 g, 62%).

[0333] Step 6: 4.0 M HCl (13.62 mL, 13.62 mmol) in dioxane was added dropwise at 0°C to a pre-stirred solution of a mixture (1.0 g, 1.70 mmol) of tert-butyl 4-(6-chloro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)-3,3-difluoropiperidine-1-carboxylate and tert-butyl 4-(7-chloro-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)-3,3-difluoropiperidine-1-carboxylate in DCM (15 mL). The RM was allowed to reach room temperature and stirred for 6 hours. The progress of the reaction was monitored by TLC. The RM was concentrated under reduced pressure, the residue was based with saturated NaHCO3 (100 mL), and the organic compounds were extracted with 10% MeOH (3 × 50 mL) in DCM. The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0-60% acetonitrile and 0.1% FA in water as the eluent to obtain a mixture of compound 113 and compound 176 (0.72 g, 87%). Preparative chiral SFC was performed on the mixture of racemic compound 113 and racemic compound 176 to obtain compound 113-En1, compound 113-En2, compound 176-En1, and compound 176-En2.

[0334] The following compounds were prepared in the same manner as described for the synthesis of compounds 113 and 176 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art): compounds 572-En1, 572-En2, 573-En1, and 573-En2.

[0335] Synthesis of N-(1-(2-hydroxyethyl)cyclobutyl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (compound 114) [ka] Step 1: To a pre-stirred solution of compound 102 (0.3 g, 0.989 mmol) and 2-(1-aminocyclobutyl)ethane-1-ol (0.148 g, 1.285 mmol) in DMF (10 mL), DIPEA (0.675 mL, 3.959 mmol) was added under an argon atmosphere at 0°C, followed by the addition of HATU (0.752 g, 1.978 mmol). The RM was stirred at the same temperature for 1 hour. The progress of the reaction was monitored by LC-MS. The RM was diluted with saturated NaHCO3 (80 mL), and the crude product was extracted with SiO2 (2 × 50 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to obtain compound 114 (0.18 g, 45%).

[0336] Synthesis of 2-methyl-5-((4-methylthiazole-5-yl)methoxy)-N-(1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)benzofuran-3-carboxamide (compound 116) [ka] Step 1: To a solution of compound 102 (600 mg, 1.98 mmol) in DCM (10 ml), DIPEA (1.77 ml, 9.90 mmol, 5 equivalents) was added dropwise at 0°C, and the RM was stirred for 10 minutes. Tert-butyl 3-aminopyrrolidine-1-carboxylate (552 mg, 2.97 mmol) and HATU (1.12 g, 2.97 mmol) were added to the RM. After the addition was complete, the ice bath was removed, and the RM was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The RM was extracted with DCM (2 × 100 ml), the combined organic layer was washed with water (100 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude 2-methyl-5-((4 - Methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (1.03 g) was obtained.

[0337] Step 2: To a solution of 2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 2.12 mmol) in 15 ml of DCM at 0°C, 3 ml of 4 M aqueous HCl (5.3 mmol) was added dropwise at 0°C over 5 minutes, and then the ice bath was removed. The RM was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reactants were concentrated directly to obtain the crude product, which was washed with Et2O (15 ml) to obtain pure 2-methyl-5-((4-methylthiazole-5-yl)methoxy)-N-(pyrrolidine-3-yl)benzofuran-3-carboxamide hydrochloride (700 mg, 94%).

[0338] Step 3: To a stirred solution of 2-methyl-5-((4-methylthiazole-5-yl)methoxy)-N-(pyrrolidine-3-yl)benzofuran-3-carboxamide hydrochloride (700 mg, 1.71 mmol) in acetonitrile (20 ml), Cs2CO3 (328 mg, 5.13 mmol) and CF2CH2OTf (598 mg, 2.57 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was cooled to 0°C, quenched with ice water (100 ml), and extracted with Âr (2 × 100 ml). The combined organic layer was washed with water (120 ml) and brine solution (120 ml), dried over anhydrous Na2SO4, and concentrated to obtain the residue. This residue was purified by FCC using 80% SiO2 in pet ether as the eluent to obtain compound 116 (280 mg, 74%). Compound 116 was further purified by normal-phase SFC-Prep to obtain 190 mg (24%) of compound 116. Preparative chiral SFC was performed on a racemic mixture of compound 116 to obtain compound 116En1 and compound 116En2.

[0339] Synthesis of N-(1-(2-hydroxyethyl)-2-oxopyrrolidine-3-yl)-2-methyl-5-((2(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 120) [ka] Step 1: Under an argon atmosphere, at 0°C, compound O64 (850 mg, 1.963 mmol) and methyl 2-bromoacetate (450.4 mg, 2.944 mmol) from DMF (5 mL) were added at 0°C to a suspension of 60% NaH (314 g, 7.852 mmol) in DMF (10 mL). The RM was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was diluted with ice water (150 mL), extracted with ethyl acetate (3 × 300 mL), the combined organic layer was washed with brine (100 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated. The residue was purified by FCC to obtain the crude product (650 mg).

[0340] Step 2: To a solution of methyl 2-(3-(2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-yl)acetate (600 mg, 1.18 mmol) in MeOH (15 mL), NaBH4 (136.5 mg, 4.15 mmol) was gradually added at 0°C under an argon atmosphere, and the solution was then heated to 80°C for 3 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, RM was quenched with acetone (25 mL) and ice water (150 mL), extracted with Âx (3 × 300 mL), and the combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by FCC to obtain compound 120 (280 mg, 30% in two steps). Preparative chiral SFC was performed on racemic compound 120 to obtain compound 120-En1 and compound 120-En2.

[0341] The following compounds were prepared in the same manner as compounds 120-En1 and 120-En2 (using appropriate reagents and purification methods known to those skilled in the art): Compounds 134-En1, 134-En2, 151-En1, and 151-En2.

[0342] Synthesis of N-(3-(2-hydroxyethyl)tetrahydrofuran-3-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (compound 121) [ka] Step 1: To a stirred solution of dihydrofuran-3(2H)-one (5.0 g, 58.11 mmol) in toluene (60 ml), Ph3P=CHC(O)OCH2CH3 (23.22 ml, 69.74 mmol) was added, and the RM was then heated to 110°C and stirred for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was cooled to room temperature and concentrated to obtain the crude product, which was purified by Grace FCC using 20% ​​siRNA in PET ether as the eluent to obtain ethyl(Z)-2-(dihydrofuran-3(2H)-ylidene) acetate (7.2 g, 80%).

[0343] Step 2: To a stirred solution of ethyl(Z)-2-(dihydrofuran-3(2H)-ylidene) (5.0 g, 32.05 mmol) in toluene (60 ml), methanol NH3 (7 M, 25 ml, 128.2 mmol) was added, and the RM was then heated to 80°C and stirred in a steel container for 16 hours. The progress of the reaction was monitored by TLC. The RM was cooled to room temperature and concentrated to obtain crude methyl 2-(3-aminotetrahydrofuran-3-yl) acetate (4.7 g, 92%).

[0344] Step 3: To a stirred solution of compound 102 (800 mg, 2.64 mmol) in DCM (30 ml), DIPEA (1.89 ml, 10.56 mmol) and HATU (1.5 g, 3.96 mmol) were added, followed by the addition of methyl 2-(3-aminotetrahydrofuran-3-yl) acetate (629 mg, 3.96 mmol) at 0°C. The RM was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the RM was diluted with water (100 ml) and extracted with DCM (100 ml). The combined organic layers were washed with water (30 ml) and brine solution (25 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by Grace FCC using 3% MeOH in DCM as the eluent to obtain methyl 2-(3-(2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide)tetrahydrofuran-3-yl)acetate (650 mg, 55%).

[0345] Step 4: To a stirred solution of methyl 2-(3-(2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide)tetrahydrofuran-3-yl)acetate (650 mg, 1.463 mmol) in THF (20 ml), LAH powder (61.19 mg, 1.61 mmol) was added in small amounts at -30°C. The RM was slowly warmed to room temperature and stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the RM was quenched with saturated Na2SO4 solution (100 mL) and extracted with siRNA (100 ml). The combined organic layers were washed with water (30 ml) and brine solution (25 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by Grace FCC using 6% MeOH in CH2Cl2 as the eluent to obtain compound 121 (210 mg, 35%). Preparative chiral SFC was performed on racemic compound 121 to obtain compound 121-En1 and compound 121-En2.

[0346] Compounds 126-En1 and 126-En2 were prepared in the same manner as compounds 121-En1 and 121-En2 (using appropriate reagents and purification methods known to those skilled in the art).

[0347] Synthesis of 7-fluoro-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-2-methyl-5-((4-methylthiazole-5-yl)-methoxy)benzofuran-3-carboxamide (compound 122) and 6-fluoro-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (compound 182) [ka] Step 1: (4-methylthiazole-5-yl)methanol (0.65 g, 5.04 mmol), ADDP (1.18 g, 4.70 mmol), and tri-n-butylphosphine (1.15 mL, 4.70 mmol) were sequentially added at 0°C under an argon atmosphere to a pre-stirred solution of ethyl 7-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate and ethyl 6-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate (0.8 g, 3.36 mmol) in THF (30 mL). The RM was allowed to reach room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC. The RM was poured into water (50 mL) and extracted with ethyl (2 × 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by FCC on silica gel using 0-20% siRNA in pet-ether as the eluent to obtain a mixture (0.7 g, 59%) of ethyl 6-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylate.

[0348] Step 2: A solution of NaOH (0.27 g, 6.87 mmol) in water (5 mL) was added at room temperature to a pre-stirred solution of ethyl 6-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxyl)benzofuran-3-carboxylate compound and ethyl 7-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylate (0.6 g, 1.71 mmol) in a mixture of MeOH (6 mL) and THF (3 mL). The resulting RM was heated to 60 °C and maintained at this temperature for 4 hours. The progress of the reaction was monitored by TLC. The RM was cooled to room temperature, poured into ice-cold water (50 mL), and acidified with 1 N HCl (pH approximately 2). The crude product was extracted with ELISA (2 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), followed by washing with brine (50 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain a mixture (0.6 g, 92%) of 6-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (compound 243) and 7-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (compound 245).

[0349] Step 3: A mixture of 6-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (600 mg, 1.86 mmol) and 7-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxylic acid (0.356 g, 2.24 mmol) and methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (0.356 g, 2.24 mmol) was pre-mixed in DMF (10 mL) at 0°C under an argon atmosphere. DIPEA (0.96 mL, 5.60 mmol) was added, followed by HATU (1.41 g, 3.72 mmol). The RM was allowed to reach room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. RM was diluted with water (50 mL), and the organic compounds were extracted with ethyl acetate (2 × 50 mL), followed by washing with water (50 mL) and brine (50 mL). The organic layer was dried on anhydrous sodium 2 SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 0-55% ethyl acetate and pet ether as eluents to obtain a mixture (0.5 g, 57%) of methyl 4-(6-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide)tetrahydro-2H-pyran-4-carboxylate and methyl 4-(7-fluoro-2-methyl-5-((4-methiazole-5-yl)methoxy)benzofuran-3-carboxamide)-tetrahydro-2H-pyran-4-carboxylate.

[0350] Step 4: NaBH4 (1.02 g, 27.05 mmol) was gradually added at 0°C to a pre-stirred solution of a mixture of methyl 4-(6-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide)tetrahydro-2H-pyran-4-carboxylate and methyl 4-(7-fluoro-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide)tetrahydro-2H-pyran-4-carboxylate (0.5 g, 1.08 mmol) in a mixture of MeOH (10 mL) and THF (5 mL). The RM was allowed to reach room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. The RM was diluted with water (50 mL), and the organic compounds were extracted with ELISA (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0-60% acetonitrile and 0.1% FA in water as the eluent to obtain a mixture of compound 122 and compound 182 (0.28 g, 59%). Preparative chiral SFC was performed on the mixture of compounds 111 and 182 to obtain compound 122 and compound 182.

[0351] The following compounds were prepared in the same manner as described for the synthesis of compounds 112 and 182 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art): compounds 360-En1, 360-En2, 361, 362, 364, 365-En1, 365-En2, 366, 367, 369, 587, and 588.

[0352] The following compounds were prepared in the same manner as described in step 3 for the synthesis of compounds 243 and 245 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art): compounds 244 and 246.

[0353] Synthesis of N-(4,4-difluoro-1-methylpyrrolidine-3-yl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)-benzofuran-3-carboxamide (compound 124) [ka] Step 1: To a stirred solution of compound 105 (400 mg, 0.88 mmol) in MeOH (20 ml), 37% HCHO (0.5 mL) and acetic acid (0.1 mL) were added at 0°C. The RM was stirred at 0°C for 30 minutes, and then NaCNBH3 (109 mg, 1.76 mmol) was added at 0°C. The RM was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was quenched with water (50 mL). The product was extracted with Depositphotos (3 × 100 mL), and the combined organic layer was washed with saturated NaHCO3 (50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with Et2O (10 mL) to obtain compound 124 (370 mg, 90%). Preparative chiral SFC was performed on a racemic mixture of compound 124 to obtain compound 124-En1 and compound 124-En2.

[0354] The following compounds were prepared in the same manner as compound 105 (using appropriate reagents and purification methods known to those skilled in the art): Compounds 110-En1, 110-En2, 118-En1, 118-En2, 123-En1, 123-En2, 130-En1, 130-En2, 131-En1, 131-En2, 141-En1, 141-En2, 163-En1, and 163-En2.

[0355] Synthesis of N-(1-(2-hydroxyethyl)cyclobutyl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 127) [ka] Step 1: To a pre-stirred solution of compound 101 (0.52 g, 1.480 mmol) and 2-(1-aminocyclobutyl)ethane-1-ol (0.222 g, 1.924 mmol) in DMF (20 mL), DIPEA (1.01 mL, 5.920 mmol) was added under an argon atmosphere at 0°C, followed by the addition of HATU (1.13 g, 2.96 mmol). The RM was stirred at the same temperature for 2 hours. The progress of the reaction was monitored by LC-MS. The RM was diluted with saturated NaHCO3 (100 mL), and the crude product was extracted with SiO2 (2 × 60 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to obtain compound 127 (0.110 g, 16%).

[0356] Synthesis of N-(1-(aminomethyl)cyclobutyl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 136). [ka] A solution of N-(1-cyanocyclobutyl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (450 mg, 1.048 mmol) in MeOH (10 mL) was added dropwise to a slurry of Raney-Ni (200 mg) in MeOH (10 mL) at room temperature. The RM was stirred under H2 balloon pressure for 16 hours. The RM was filtered through a Celite pad, and the Celite pad was washed with MeOH (80 mL). The combined clear filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to obtain compound 136 (0.3 g, 66%).

[0357] Synthesis of N-(1-(aminomethyl)cyclobutyl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxyamide (compound 137). [ka] Step 1: To a solution of compound 102 (2.0 g, 6.6 mmol) and 1-aminocyclobutan-1-carbonitrile (950 mg, 9.9 mmol) in DMF (20 mL), DIPEA (2.43 mL, 13.2 mmol) was added at 0°C under an argon atmosphere, followed by HATU (5.0 g, 13.2 mmol). The RM was allowed to reach room temperature and stirred for 1 hour. The progress of the reaction was monitored by TLC. The RM was quenched with cold water (120 mL), the precipitated solid was filtered, and dried under reduced pressure to obtain N-(1-cyanocyclobutyl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (1.7 g, 68%).

[0358] Step 2: To a pre-stirred solution of N-(1-cyanocyclobutyl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (500 mg, 1.3 mmol) in a mixture of MeOH (10 mL) and THF (5 mL), CoCl2.6H2O (468 mg, 1.96 mmol) was added, followed by the addition of NaBH4 (150 mg, 3.9 mmol) at 0°C. The RM was stirred at the same temperature for 30 minutes. The progress of the reaction was monitored by LC-MS. The RM was poured into water (30 mL) and extracted with  (3 × 50 mL). The combined organic layer was washed with water (2 × 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 0-20% acetonitrile in 0.1% FA as the eluent, followed by purification by reverse-phase preparative HPLC to obtain compound 137 (80 mg, 16%).

[0359] Synthesis of 2-methyl-N-(1H-pyrazole-3-yl)-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxyamide (compound 138) [ka] Step 1: To a stirred solution of 1H-pyrazole-3-amine (5 g, 60.24 mmol) in DMF (50 mL), NaH (60% in oil) (4.819 g, 120.48 mmol) was added at 0°C. The RM was stirred at 0°C for 30 minutes, and SEMCl (11.7 mL, 66.26 mmol) was added at 0°C. The RM was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was diluted with siRNA (700 mL). The organic layer was washed with water (5 × 100 mL) and brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by Grace FCC using 100% toluene as the eluent to obtain 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine (2.3 g, 18%).

[0360] Step 2: To a stirred solution of compound 101 (200 mg, 0.56 mmol) in DCM (10 mL), DIPEA (0.3 mL, 1.71 mmol), HATU (325 mg, 0.85 mmol), and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine (182 mg, 0.85 mmol) were added at room temperature. The RM was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was diluted with DCM (200 mL), the organic layer was washed with water (2 × 50 mL), saturated NaHCO3 (50 mL), and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The residue was purified by Grace FCC using 45% butyl in pet ether as the eluent to obtain 2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)benzofuran-3-carboxamide (100 mg, 32%).

[0361] Step 3: To a stirred solution of 2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)benzofuran-3-carboxamide (100 mg, 0.18 mmol) in DCM (10 mL), TFA (0.5 mL) was added at 0°C. The RM was stirred at room temperature for 24 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was poured into ice water (20 mL), based with saturated NaHCO3 solution (20 mL) until the pH was approximately 9, and extracted with DCM (3 × 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The residue was purified by Grace FCC using 100% Â as the eluent to obtain compound 138. The product was further purified by HPLC.

[0362] Synthesis of 2-methyl-5-((4-methylthiazole-5-yl)methoxy)-N-(1-((2,2,2-trifluoroethyl)amino)methyl)cyclobutyl)-benzofuran-3-carboxamide (compound 145) [ka] Step 1: 2,2,2-trifluoroacetaldehyde monohydrate (77% in water, 0.85 mL, 5.1 mmol) was added to a solution of compound 137 (200 mg, 0.51 mmol) in MeOH (15 mL) at 0°C under an argon atmosphere. Glacial acetic acid (3 drops) and NaCNBH3 (65 mg, 1.0 mmol) were then added to the reaction mixture. The resulting RM was heated at 80°C for 16 hours. The RM was cooled to room temperature, poured into water (50 mL), and extracted with Depositphotos (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3 (25 mL), water (50 mL), and brine (50 mL), dried over Na2SO4, and excess solvent was removed under reduced pressure. The crude product was purified by flash chromatography using 0-50% acetonitrile in 0.1% FA as the eluent, followed by purification by reverse-phase preparative HPLC to obtain compound 145 (30 mg, 12%).

[0363] Compound 153 was prepared in the same manner as compound 145 (using appropriate reagents and purification methods known to those skilled in the art).

[0364] Synthesis of N-(4-hydroxytetrahydrofuran-3-yl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)-benzofuran-3-carboxamide (compound 147) [ka] Step 1: To a stirred solution of 3,6-dioxabicyclo[3.1.0]hexane (0.2 g, 2.27 mmol) in EtOH (10 ml), 5 ml of aqueous NH4OH was added in a 100 ml steel container, and the steel container was tightly sealed. RM was heated in the steel container to 80°C for 18 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, RM was concentrated to obtain the crude product, which was co-distilled three times with toluene to obtain 4-aminotetrahydrofuran-3-ol (0.16 g, 65%).

[0365] [ka] Step 2: To a solution of compound 101 (0.35 g, 0.99 mmol) in DCM (20 ml), DIPEA (0.91 ml, 4.98 mmol) and HATU (0.568 g, 1.49 mmol) were added at 0°C, followed by the dropwise addition of a solution of 4-aminotetrahydrofuran-3-ol (0.151 g, 1.49 mmol) in DCM at 0°C. The RM was then stirred at room temperature for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, the RM was diluted with water (20 ml), extracted with DCM (3 × 30 ml), the combined organic layer was washed with water (50 ml) and brine solution (25 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by FCC using 60% siRNA-PET ether as the eluent to obtain compound 147 (0.30 g, 69%). Preparative chiral SFC was performed on racemic compound 147 to obtain compounds 147Dia1-En1 and 147Dia1-En2.

[0366] Compounds 162-Dia1-En1, 162-Dia1-En2, 386-En1, 386-En2, 387-En1, 387-En2, 388-En1, 388-En2, 389-En1, 389-En2, 653-En1, 653-En2, 654-En1, 654-En2, 655-En1, 655-En2, 656-En1, and 656-En2 were prepared in the same manner as compounds 147-Dia1-En1 and 147-Dia1-En2 (using appropriate reagents and purification methods known to those skilled in the art).

[0367] Synthesis of 2-methyl-N-(1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)-benzofuran-3-carboxamide (compound 149) [ka] Step 1: To a stirred solution of compound 101 (400 mg, 1.14 mmol) in DCM (15 mL), DIPEA (0.5 mL, 2.85 mmol) and HATU (476 mg, 1.25 mmol) were added at room temperature. The RM was stirred at room temperature for 5 minutes, and tert-butyl 3-aminopyrrolidine-1-carboxylate (233 mg, 1.25 mmol) was added at room temperature. The RM was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was diluted with DCM (200 mL). The organic layer was washed with saturated NaHCO3 solution (100 mL), water (100 mL), and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by Grace FCC using 45% ethyl phosphate in pet ether as the eluent to obtain tert-butyl 3-(2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (450 mg, 76%).

[0368] Step 2: To a stirred solution of tert-butyl 3-(2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (450 mg, 0.86 mmol) in DCM (10 ml), 4N HCl in dioxane (5 mL) was added at 0°C. The RM was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the RM was concentrated and dried to obtain 2-methyl-N-(pyrrolidine-3-yl)-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (520 mg, crude product).

[0369] Step 3: To a stirred solution of 2-methyl-N-(pyrrolidine-3-yl)-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (500 mg, 1.02 mmol) in CH3CN (50 ml), Cs2CO3 (1.33 g, 4.07 mmol) and CF3CH2OTf (472 mg, 2.03 mmol) were added at room temperature. The RM was heated to 50°C and stirred at 50°C for 1 hour. The progress of the reaction was monitored by LC-MS. After the completion of the reaction, the RM was cooled to room temperature, diluted with Â(250 mL), washed with water (2 × 50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by RP-preparative HPLC to obtain compound 149 (280 mg, 64% in two steps). Preparative chiral SFC was performed on racemic compound 149 to obtain compounds 149-En1 and 149-En2.

[0370] Synthesis of N-(4,4-difluoro-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (compound 155) and 2,2,2-trifluoroethyl3,3-difluoro-4-(2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide)pyrrolidine-1-carboxylate (compound 172) [ka] Step 1: To a solution of compound 106 (400 mg, 0.982 mmol) in DMF (20 ml), Cs2CO3 (958 mg, 2.948 mmol) was added at room temperature. The RM was stirred at room temperature for 5 minutes, and then CF3CH2OTf (342 mg, 1.474 mmol) was added at room temperature. The RM was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was diluted with water (100 ml) and extracted with siRNA (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by RP-preparative HPLC to obtain a mixture of compound 155 and compound 172 (320 mg, 45%). Preparative chiral SFC was performed on a mixture of racemic compound 155 and racemic compound 152 to obtain compound 155-En1, compound 155-En2, compound 172-En1, and compound 172-En2.

[0371] Racemic compound 175 was prepared in the same manner as compound 155-En1, compound 155-En2, compound 172-En1, and compound 172-En2 (using appropriate reagents and purification methods known to those skilled in the art).

[0372] Synthesis of N-(4,4-difluoro-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide (compound 157) [ka] Step 1: To a stirred solution of compound 105 (600 mg, 1.318 mmol) in DMF (20 ml), NaH (56.9 mg, 3.954 mmol) was added at 0°C. The RM was stirred at 0°C for 5 minutes, and then CF3CH2OTf (609 mg, 2.637 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was diluted with ice water (50 mL) and extracted with ₹ (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by RP-preparative HPLC to obtain compound 157 (170 mg, 24%). Preparative chiral SFC was performed on racemic compound 157 to obtain compound 157-En1 and compound 157-En2.

[0373] Synthesis of N-(1-(2-hydroxyethyl)-2-oxopyrrolidine-3-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide (compound 160) [ka] Step 1: Compound 042 (800 mg, 2.07 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (980 mg, 4.14 mmol) from DMF (10 ml) were added at 0°C to a suspension of 60% NaH (240 mg, 6.21 mmol) in DMF (5.0 ml). The reaction mass (RM) was raised to room temperature and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. RM was extracted with DCM (2 × 100 ml), the combined organic layer was washed with ...

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony, R １ is CH3 which may be substituted with F; Q is -NR ３ R ４ And; R ３ H is; R ４ teeth, 【Chemistry 2】 And; T is -O-, and U is -CH2-; R ６ , R ７ , and R ８ H is each and V is a five-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, or a six-membered heteroaryl selected from the group consisting of pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl, where the five-membered heteroaryl and the six-membered heteroaryl may be substituted with a C1-C3 alkyl or a C1-C3 alkoxy which may be substituted with -F, -Cl, or -F. Compounds represented by, or their stereoisomers, pharmaceutically acceptable salts, and / or solvates.

2. The compound according to Claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt, and / or solvate thereof, wherein R1 is -CH3.

3. R 4 is 【Transformation 3】 The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, and / or solvate.

4. R 4 is 【Chemistry 4】 The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, and / or solvate.

5. R 4 is 【Transformation 5】 The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, and / or solvate.

6. The compound according to Claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt, and / or solvate thereof, wherein V is a five-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, wherein the five-membered heteroaryl may be substituted with a C1-C3 alkyl group which may be substituted with -F, -Cl, or -F, or a C1-C3 alkoxy group which may be substituted with -F.

7. The compound according to Claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt, and / or solvate thereof, wherein V is a six-membered heteroaryl selected from the group consisting of pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl, wherein the six-membered heteroaryl may be substituted with a C1-C3 alkyl which may be substituted with -F, -Cl, or -F, or a C1-C3 alkoxy which may be substituted with -F.

8. (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)thiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methyl-4-(trifluoromethyl)thiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methyloxazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazole-4-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((3-(trifluoromethyl)-1H-pyrazole-4-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((5-methylisoxazole-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((5-methylthiazole-4-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((6-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyridazine-3-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyrimidine-4-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((1-(2,2-difluoroethyl)-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-(difluoromethoxy)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,4-dimethylthiazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,5-dimethylthiazole-4-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((3-(difluoromethyl)pyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((4-fluoro-1-methyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-imidazole-2-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyridine-2-ylmethoxy)benzofuran-3-carboxamide; N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((1-(2,2-difluoroethyl)-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-(difluoromethyl)pyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide; N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,4-dimethylthiazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-hydroxypyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide; N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((4-fluoro-1-methyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((6-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-5-((1-(2,2-difluoroethyl)-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-5-((4-fluoro-1-methyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyridine-3-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((1,4-dimethyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((4-chloro-1-methyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((4-chloro-1-isopropyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((3-methylisoxazole-5-yl)methyl)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((1-isopropyl-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2,4-dimethyloxazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-methyloxazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-isopropylthiazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((5-methylthiazole-2-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazole-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((1-(cyclopropylmethyl)-1H-pyrazole-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((4-(trifluoromethyl)thiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(thiazole-2-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(thiazole-5-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((1-methyl-1H-pyrazole-4-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((5-methylpyridine-2-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylpyrimidine-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyrimidine-2-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyrazine-2-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((2-methoxypyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-(pyridine-4-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-5-((2-methoxypyridine-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-((2-methyloxazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-2-methyl-5-(pyridine-2-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropan-2-yl)-5-((5-fluoropyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-5-((5-fluoropyridine-2-yl)methoxy)-2-methylbenzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(difluoromethyl)-5-((4-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(difluoromethyl)-5-((6-methylpyridine-3-yl)methoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(difluoromethyl)-5-(pyridine-2-ylmethoxy)benzofuran-3-carboxamide; (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(difluoromethyl)-5-((2-methylthiazole-5-yl)methoxy)benzofuran-3-carboxamide; and (S)-N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(difluoromethyl)-5-((2-methyloxazole-5-yl)methoxy)benzofuran-3-carboxamide, Compounds selected from, or their stereoisomers, pharmaceutically acceptable salts, and / or solvates.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer thereof, a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition according to claim 9 for use in the treatment of pain.

11. The pharmaceutical composition according to claim 10, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain.

12. The pharmaceutical composition according to claim 10, wherein the pain is postoperative pain.

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