Indazole derivatives for treating TRPM3-mediated disorders

Abstract

The present invention relates to a compound useful for the prevention or treatment of a TRPM3-mediated disorder, more specifically a disorder selected from pain and inflammatory hypersensitivity. The present invention also relates to a method for the prevention or treatment of said TRPM3-mediated disorder.

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, inflammatory hypersensitivity, and epilepsy. The present invention also relates to methods for the prevention or treatment of such TRPM3-mediated disorders.

Background Art

[0002] The TRP superfamily consists of proteins having six transmembrane domains (6TM) that are assembled as homo- or hetero-tetramers to form cation-permeable ion channels. The name TRP is derived from the Drosophila trp (transient receptor potential) mutant, which is characterized by transient receptor potential in the fly photoreceptor in response to continuous light. In 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 probably all mammalian organs and cell types, and in recent years, there have been great advances in understanding their physiological roles. The customized selectivity of certain TRP channels enables them to play important roles in the cellular uptake and / or trans-epithelial transport of Ca 2+ , Mg 2+ , and trace metal ions. Furthermore, the sensitivity of TRP channels to a wide range of chemical and physical stimuli enables them to function as dedicated biological sensors involved in processes from vision to taste and touch. In particular, some members of the TRP superfamily show very high sensitivity to temperature. These so-called thermoTRPs are highly expressed in sensory neurons and / or skin keratinocytes and function as major thermosensors for the detection of harmless and harmful (painful) temperatures.

[0004] It is becoming increasingly clear that dysfunctions of TRP channels are directly involved in the etiology 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 brachyolmia, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, mucolipidosis type IV, and familial focal segmental glomerulosclerosis. Furthermore, the function / dysfunction of TRP channels is directly related to 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 dorsal root and trigeminal ganglia and is involved in thermosensation. Pregnenolone sulfate, a neurosteroid, is a known potent activator of TRPM3 (Wagner et al., 2008). Pregnenolone sulfate caused pain in wild-type mice but not in knockout TRPM3 mice. Also, recently, it has been shown that CFA-induced inflammation and inflammatory pain are abolished in TRPM3 knockout mice. Therefore, TRPM3 antagonists can be used as analgesics to counteract pain such as inflammatory pain (Vriens J. et al. Neuron, May 2011). The relationship between TRPM3 and epilepsy has also been established (see, for example, Eur J Hum Genet. 2019 Oct;27(10):1611-1618; Elife 2020 May 19;9:e57190.doi:10.7554 / eLife.57190.DOI:10.7554 / eLife.57190; Channels(Austin).2021;15(1):386-397). Therefore, TRPM3 is also a potential target for the treatment of epilepsy.

[0006] Several TRPM3 antagonists are known, but none of them refer to the compounds of the present invention (Straub I et al. Mol Pharmacol, November 2013). For example, liquiritigenin, a putative TRPM3 blocker, has been described to reduce mechanical and cold allodynia in a rat pain model (Chen L et al. Scientific reports, July 2014). There remains a great medical need for new, alternative, and / or better therapies for the prevention or treatment of TRPM3-mediated disorders, more specifically for pain such as inflammatory pain and epilepsy. There is a strong need for therapies that have good efficacy against a particular type of pain, have low or no side effects (such as no potential for dependence like opioids and no toxicity), and / or have good or better pharmacokinetic or pharmacodynamic properties.

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

Summary of the Invention

[0008] The present invention provides indazole derivatives and pharmaceutical compositions containing such indazole derivatives. The present invention also provides indazole derivatives for use as a medicament, more specifically for use in the prevention and / or treatment of TRPM3-mediated disorders, particularly for use in the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy, and / or for counteracting pain and / or inflammatory hypersensitivity and / or for counteracting epilepsy.

[0009] The present invention also provides the use of an indazole derivative for the prevention and / or treatment of TRPM3-mediated disorders, in particular for the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy, and / or for the manufacture of a pharmaceutical composition or medicament for combating pain and / or inflammatory hypersensitivity and / or epilepsy.

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

[0011] The present invention further provides a method for preparing the indazole derivative of the present invention.

Embodiments for Carrying Out the Invention

[0012] The present invention will be further described, and in some cases with reference to specific embodiments, but the present invention is not limited thereto.

[0013] A first aspect of the present invention is the provision of a compound of formula (I), its stereoisomeric forms, physiologically acceptable salts, solvates, and / or polymorphs,

Chemical formula

[0014] In some embodiments of the indazole derivatives according to the present invention, (a-1) Q is -NR 3 R 4 represents, R 1 is R W represents, R W is -C 1 -C 6 -alkyl, and / or (a-2) Q is -NR 3 R 4 represents, R 5 and R 5 ' of which at least one represents -H, and / or (a-3) Q is -NR 3 R 4 represents, R 6 is -H, and / or (a-4) Q is -NR 3 R 4 represents, R 8 is -H, or or (b-1) (b-1) Q is -NR 3 R 4 represents, R 1 is -CH 2 F, -CHF 2 -CF 3represents -CN, -methyl, -ethyl, -propyl, or -cyclopropyl, and / or (b-2) Q is -NR 3 R 4 represents, and R 5 and R 5 ’ in which at least one does not represent -H, and / or (b-3) Q is -NR 3 R 4 represents, and R 3 represents -H.

[0015] In one embodiment of the indazole derivative according to the present invention, T represents -O-, and U represents -CR 5 R 5 ’-. According to this embodiment, the indazole derivative according to the present invention is a compound of formula (II), its stereoisomeric forms, physiologically acceptable salts, solvates, and / or polymorphs

Chemical formula

[0016] In another embodiment of the indazole derivative according to formula I, T represents -CR 5 R 5 ’-, and U represents -O-.

[0017] In one embodiment of the indazole derivative according to formula I or formula II, R 1 is methyl, ethyl, or another C 1 -C 6 alkyl. In another preferred embodiment, R 1 is methyl.

[0018] In one embodiment of the indazole derivative according to the present invention, Q represents -NR 3 R 4 .

[0019] In one embodiment of the indazole derivative according to the present invention, Q represents -OR 2 .

[0020] In some embodiments of the indazole derivatives according to the present invention, V is a saturated or unsaturated 3- to 14-membered cycloalkyl; 3- to 14-membered heterocycloalkyl, saturated or unsaturated 5- to 14-membered aryl, C 1 -C 6 alkyl, or 5- to 14-membered heteroaryl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, -CF 3 -, -CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 -, =O, =S, -SF 5 -, -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) 2 R Y -, -C(=O)R Y -, -C(=O)OR Y -, or -C(=O)NR Y R Z and is monosubstituted or polysubstituted with substituents selected from

[0021] .

[0022] In some embodiments, the 5- to 14-membered heteroaryl within the definition of V is selected from benzimidazole, benzisoxazole, benzazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, 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, and in each case, unsubstituted or, independently of one another, mono- or polysubstituted with substituents selected from -F, -Cl, -Br, -I, -CF 3 -CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 =O, =S, -SF 5 -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) 2 R Y -C(=O)R Y -C(=O)OR Y or -C(=O)NR Y R Z and is mono- or polysubstituted with substituents selected from these.

[0023] Preferably, the 5- to 14-membered heteroaryl within the definition of V is selected from the group consisting of furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole, pyridine, isoquinoline, benzothiazole, pyridazine, pyrimidine, imidazopyridine, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF 3 、-CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 、=O, =S, -SF 5 、-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) 2 R Y 、-C(=O)R Y 、-C(=O)OR Y 、or -C(=O)NR Y R Z and is mono- or polysubstituted by substituents selected from the group consisting of

[0024] Preferably, the 5- to 14-membered heteroaryl within the definition of V is selected from the group consisting of furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, oxazole-5-yl, isoxazole-4-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, isoquinolin-1-yl, isoquinolin-5-yl, benzo[d]thiazol-2-yl, pyridazin-3-yl, pyrimidin-5-yl, and imidazo[1,2-a]pyridin-6-yl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I,, CF 3 、-CF2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 , =O, =S, -SF 5 , -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) 2 R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z is monosubstituted or polysubstituted with substituents selected from

[0025] In some embodiments, the 5- to 14-membered heteroaryl within the definition of V is selected from the group consisting of pyrazol-3-yl, pyrazol-4-yl, thiazol-4-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I,, CF 3 , -CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 , =O, =S, -SF 5 , -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) 2 R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Zmono- or polysubstituted with a substituent selected from

[0026] In one embodiment, the saturated or unsaturated 3- to 14-membered cycloalkyl within the definition of V is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, including non-condensed or non-bridged, condensed, or bridged cycloalkyl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I,, CF 3 , -CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 , =O, =S, -SF 5 , -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) 2 R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z mono- or polysubstituted with a substituent selected from

[0027] In one embodiment, the 5- to 14-membered aryl within the definition of V is unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF 3 , -CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 , =O, =S, -SF 5 , -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) 2 R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z is phenyl or other 5- to 14-membered aryl that is mono- or polysubstituted with a substituent selected from

[0028] In a further embodiment of the indazole derivative according to the present invention, V is saturated or unsaturated, unsubstituted, and independently of one another, -F, -Cl, -Br, -I, CF 3 、 -CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 、 =O, =S, -SF 5 、 -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) 2 R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z represents 3- to 14-membered heterocycloalkyl that is mono- or polysubstituted with a substituent selected from

[0029] In some embodiments, the 3- to 14-membered heterocycloalkyl within the definition of V is azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxane, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 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, hexahydro-cyclopenta[c]pyrrole, octahydro-cyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, and in each case, unsubstituted or, independently of one another, mono- or polysubstituted by substituents selected from -F, -Cl, -Br, -I, CF 3 、-CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 、=O, =S, -SF 5 、-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) 2 R Y 、-C(=O)R Y 、-C(=O)OR Y 、or -C(=O)NR Y R Z and is mono- or polysubstituted by substituents selected from

[0030] In some embodiments, the 3- to 14-membered heterocycloalkyl within the definition of V is oxane, oxan-4-yl, oxetane, or oxetan-3-yl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF 3 、-CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 、=O, =S, -SF 5 、-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) 2 R Y 、-C(=O)R Y 、-C(=O)OR Y 、or -C(=O)NR Y R Z and is monosubstituted or polysubstituted with substituents selected from

[0031] In another preferred embodiment of the indazole derivative according to the present invention, V is saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF 3 、-CF 2 H, C 1 -C 6 alkyl, -CN, -NO, -NO 2 、=O, =S, -SF 5 、-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) 2 R Y 、-C(=O)R Y 、-C(=O)OR Y 、or -C(=O)NRY R Z mono- or polysubstituted with a substituent selected from, C 1 -C 6 alkyl or C 1 -C 6 represents heteroalkyl.

[0032] In some embodiments of the indazole derivatives according to the present invention, V is unsubstituted, and independently of one another, -F, -Cl, -Br, -I, -CN, -C(=O)OH, -NH 2 , -NO 2 , -OH, =O, -SF 5 ; saturated or unsaturated, unsubstituted, mono- or polysubstituted -C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -C(=O)O-C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -NHC 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -N(C 1-6 -alkyl) 2 ; saturated or unsaturated, unsubstituted, mono- or polysubstituted -O-C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -S(=O) 2 -C 1-6 -alkyl; a 3- to 14-membered cycloalkyl which is saturated or unsaturated, unsubstituted, mono- or polysubstituted, and the 3- to 14-membered cycloalkyl is optionally -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted) is connected via a 3- to 14-membered cycloalkyl; or A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally, -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted) and is monosubstituted or polysubstituted by a substituent selected from 3- to 14-membered heterocycloalkyl.

[0033] In some embodiments, V is unsubstituted, independently of one another, -OH, -F, -Cl, -Br, -I, -SH, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -CN, -NO 2 , -C(=O)OH, -NH 2 , or -N(CH 3 ) 2 ; A saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2 , -C(=O)OH, -NH 2 , C(=O)CHF 2 , and -C(=O)NH 2 and is monosubstituted or polysubstituted by a substituent selected from the group consisting of -C 1-6 -alkyl; A saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 -, -CHF 2 -, -CH 2 F, -OCF 3 -, -OCHF 2 -, -OCH 2 F, SF 5 -, -NO 2 -, -C(=O)OH, -NH 2 , C(=O)CHF 2 , and -C(=O)NH 2 mono- or polysubstituted with a substituent selected from the group consisting of -C 1-6 -heteroalkyl; unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2 , -C(=O)OH, -NH 2 , C(=O)CHF 2 , and -C(=O)NH 2 mono- or polysubstituted with a substituent selected from the group consisting of -OC 1-6 -alkyl; unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2, -C(=O)OH, -NH 2 , C(=O)CHF 2 , and -C(=O)NH 2 -O(C=O)C mono- or polysubstituted with a substituent selected from the group consisting of 1-6 -alkyl; unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2 , -C(=O)OH, -NH 2 , C(=O)CHF 2 , and -C(=O)NH 2 -C(=O)OC mono- or polysubstituted with a substituent selected from the group consisting of 1-6 -alkyl; a 3- to 14-membered cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, in each case unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2 , -C(=O)OH, -NH 2 , C(=O)CHF 2 , and -C(=O)NH 2 a 3- to 14-membered cycloalkyl mono- or polysubstituted with a substituent selected from the group consisting of; Azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxazolidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 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, which is a 3- to 14-membered heterocycloalkyl selected from the group consisting of, in each case, unsubstituted, and, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF 3 、-CHF 2 、-CH 2 F, -OCF 3 、-OCHF 2 、-OCH 2 F, SF 5 、-NO 2 、-C(=O)OH, -NH 2 、C(=O)CHF 2 、and -C(=O)NH 2 selected from the group consisting of substituents, which is mono- or polysubstituted with substituents selected from the group consisting of; is mono- or polysubstituted with substituents selected from the group consisting of.

[0034] In some embodiments, V is, unsubstituted, and, independently of one another, -F, -Cl, -CN, -OH, =O, -C 1-6 -alkyl, methyl, ethyl, -CHF 2, -CF 3 , -C 1-6 -alkylene-NH 2 , -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-NHC(=O)-O-C 1-6 -alkyl, -C(=O)O-C 1-6 , -N(C 1-6 -alkyl) 2 , -OC 1-6 -alkyl, -OCF 3 , -O-C 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 mono- or polysubstituted with a substituent selected from -piperazine substituted with -alkyl.

[0035] In some embodiments of the indazole derivatives according to the present invention, V is (i) unsubstituted, (ii) monosubstituted, (iii) disubstituted, (iv) trisubstituted, or (v) tetrasubstituted.

[0036] In some embodiments of the indazole derivatives according to the present invention, V is (i) unsubstituted, (ii) monosubstituted, or (iii) disubstituted.

[0037] In some embodiments, V is a saturated or unsaturated 3- to 14-membered heterocycloalkyl (preferably 3- to 5-membered heterocycloalkyl), 5- to 14-membered heteroaryl (preferably 5- to 6-membered heteroaryl), saturated or unsaturated 3- to 14-membered cycloalkyl, 5- to 14-membered aryl, or C 1 -C 6 represents alkyl, and in each case is unsubstituted, monosubstituted or polysubstituted, and is preferably a residue selected from the group consisting of the following.

Chemical formula

[0038] In one embodiment, V represents unsubstituted, monosubstituted or polysubstituted -oxetanyl, and preferably

Chemical formula

[0039] In some embodiments, V represents a residue according to general formula (E),

Chemical formula

[0040] In some embodiments, V represents unsubstituted, monosubstituted, or polysubstituted 2-pyridine. In some embodiments, V represents a residue selected from the group consisting of.

Chemical formula

[0041] In some embodiments, V represents unsubstituted, monosubstituted, or polysubstituted 3-pyridine. In preferred embodiments, V represents a residue selected from the group consisting of.

Chemical formula

[0042] In some embodiments, V represents an unsubstituted, mono-substituted, or multi-substituted 4-pyridine. In a preferred embodiment, V represents a residue selected from the group consisting of the following.

Chemical formula

[0043] In some embodiments, optionally, U-CH 2 in the case of, V represents a residue selected from the group consisting of the following.

Chemical formula

[0044] In an alternative embodiment, V represents a residue selected from the group consisting of the following.

Chemical formula

[0045] In some embodiments, V represents an unsubstituted, mono-substituted or multi-substituted bicyclic heteroaryl, preferably selected from the group consisting of the following.

Chemical formula

[0046] In some embodiments, V represents a residue according to general formula (F’),

Chemical formula

Chemical formula

[0047] In some embodiments, V represents a residue according to general formula (G) or (H), [Chemical formula] wherein R G1 and R H1 are selected from the group consisting of -H, -CH 3 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -Cl, azetidinyl, -cyclopropyl, -O-cyclopropyl, and -CHF 2 ; or R G1 and R H1 are selected from the group consisting of -H, -CH 3 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -Cl, and azetidinyl. In other embodiments, V represents a residue according to general formula (G') or (H'), [Chemical formula] wherein R G1 and R H1 are selected from the group consisting of -H, -CH 3 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -Cl, azetidinyl, -cyclopropyl, -O-cyclopropyl, and -CHF 2 ; or R G1 and R H1 are selected from the group consisting of -H, -CH 3 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -Cl, and azetidinyl. 、

[0048] In one embodiment of the indazole derivative according to the present invention, R 1 is -H, -F, -Cl, -Br, -I, -CN; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 - 6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -O-C 1 - 6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C(=O)C 1-6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C(=O)OC 1-6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C(=O)NHC 1-6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C(=O)N(C 1-6 -alkyl) 2 ; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -S(=O)C 1-6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -S(=O) 2 -C 1 - 6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -heteroalkyl, or Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted).

[0049] In some embodiments, R 1 is -H, -F, -Cl, -Br, -I, -C1-6 -Alkyl, -O-C 1-6 -Alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -C 1-6 -Alkylene-NH(C 1-6 -Alkyl), -C 1-6 -Alkylene-N(C 1-6 -Alkyl) 2 , -CF 3 , -CF 2 H, -CFH 2 , -CF 2 Cl, -CFCl 2 , -C 1-6 -Alkylene-CF 3 , -C 1-6 -Alkylene-CF 2 H, -C 1-6 -Alkylene-CFH 2 , -C 1-6 -Alkylene-NH-C 1-6 -Alkylene-CF 3 , -C 1-6 -Alkylene-N(C 1-6 -Alkyl)-C 1-6 -Alkylene-CF 3 , -C(=O)C 1-6 -Alkyl, -C(=O)OC 1-6 -Alkyl, -C(=O)NH 2 , -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, -O-C 1-6 -Alkyl, -unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl.

[0050] In some embodiments, R 1 is, -H, -C 1-6 -Alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -CH 2 F, -CHF 2 , -CF3 represents - non-substituted cyclopentyl or - cyclopropyl. Preferably, R 1 is -H, -C 1-6 - alkyl, -C 1-6 - alkylene - O - C 1-6 - alkyl, -CH 2 F, -CHF 2 represents -CF 3 represents -CF, - cyclopentyl, or non-substituted. In some embodiments, R 1 represents -CH 3 .

[0051] In some embodiments, R 1 represents -CH 2 F, -CHF 2 represents -CH 3、 or - cyclopropyl. Preferably, R 1 represents -CH 2 F, -CHF 2 or -CH 3 . In some embodiments, R 1 represents -C(=O)NH 2 or -CHF 2 .

[0052] In some embodiments, R 1 represents -H, -C 1-3 - alkyl, -CF 3 represents -CF 2 H, -CFH 2 represents -CF 2 Cl, -CFCl 2 represents -C 1-3 - alkylene - CF 3 represents -C 1-3 - alkylene - CF 2 H, -C 1-3 - alkylene - CFH 2、 or - cyclopropyl. Preferably, R 1 represents -H, -C 1-3 - alkyl, -CF 3 represents -CF 2 H, -CFH 2 represents -CF 2 Cl, -CFCl 2 represents -C 1-3-alkylene-CF 3 、-C 1-3 -alkylene-CF 2 H, or -C 1-3 -alkylene-CFH 2 represents, for example, -CH 3 is.

[0053] In some embodiments of the indazole derivatives according to the present invention, R 2 is -H; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -heteroalkyl; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted) connected via a 3- to 14-membered cycloalkyl; or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted) connected via a 3- to 14-membered heterocycloalkyl.

[0054] In some embodiments, R 2 is -H, -C 1-6 -alkyl, -C 1-6 -alkylene-O-C 1-6 -alkyl, -C 1-6-alkylene-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C 1-6 -alkyl) 2 , -CF 3 , -CF 2 H, -CFH 2 , -CF 2 Cl, -CFCl 2 , -C 1-6 -alkylene-CF 3 , -C 1-6 -alkylene-CF 2 H, -C 1-6 -alkylene-CFH 2 , -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF 3 , or -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF 3 represents.

[0055] In some embodiments, R 2 represents -H or -C 1-6 -alkyl.

[0056] In one embodiment of the indazole derivative according to the present invention, R 3 is -H; -OH; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -alkyl; or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -heteroalkyl.

[0057] In some embodiments, R 3 is -H, -OH, -C 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 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 -CF 3 -CF 2 H, -CFH 2 -CF 2 Cl, -CFCl 2 -C 1-6 -alkylene-CF 3 -C 1-6 -alkylene-CF 2 H, -C 1-6 -alkylene-CFH 2 -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF 3 -or -C 1-6 -alkylene-N(C 1-6 (-alkyl)-C 1-6 -alkylene-CF 3 represents.

[0058] In some embodiments, R 3 represents -H, -OH, or -C 1-6 -alkyl which is saturated, unsubstituted, or mono-substituted with -OH. Preferably, R 3 represents -H.

[0059] In some embodiments, R 3 represents -H, and R 4 represents a residue other than -H.

[0060] In one embodiment of the indazole derivative according to the present invention, R 4 is -H; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -S(=O)C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -S(=O) 2 -C 1 - 6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -heteroalkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), 3- to 14-membered cycloalkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally connected via -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), 3- to 14-membered heterocycloalkyl; Unsubstituted, mono-substituted or multi-substituted 6- to 14-membered aryl, wherein the 6- to 14-membered aryl is optionally connected via -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), 6- to 14-membered aryl, or Unsubstituted, mono-substituted or multi-substituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally connected via -C 1 -C 6 -alkylene- or -C 1 -C 6Represents a 5- to 14-membered heteroaryl connected via -heteroalkylene- (in each case, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted).

[0061] In some embodiments, R 4 is saturated or unsaturated, unsubstituted, and independently of one another, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF 3 、-OH、=O、-OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH 2 、-NHC 1-6 -alkyl, -N(C 1-6 -alkyl) 2 、-NHC(=O)O-C 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NH 2 、-C 1-6 -alkylene-NH-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl) 2 、-C 1-6 -alkylene-NH-C 1-6 -alkylene-CF 3 、-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)O-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF 3 、-C(=O)NH 2 、-C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl) 2 、-S(=O) 2 C 1-6-Alkyl, -phenyl, -C 1-6 -Alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted or polysubstituted with a substituent selected from the group consisting of, -S(=O) 2 C 1-6 -Alkyl; -S(=O) 2 (3- to 14-membered cycloalkyl), wherein the 3- to 14-membered cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in each case, saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -C 1-6 -Alkyl, -C 1-6 -Alkylene-CF 3 , -OH, =O, -OC 1-6 -Alkyl, -C 1-6 -Alkylene-OH, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -NH 2 , -NHC 1-6 -Alkyl, -N(C 1-6 -Alkyl) 2 , -NHC(=O)O-C 1-6 -Alkyl, -N(C 1-6 -Alkyl)C(=O)O-C 1-6 -Alkyl, -C 1-6 -Alkylene-NHC(=O)O-C 1-6 -Alkyl, -C 1-6 -Alkylene-NH 2 , -C 1-6 -Alkylene-NH-C 1-6 -Alkyl, -C 1-6 -Alkylene-N(C 1-6 -Alkyl) 2 , -C 1-6 -Alkylene-NH-C 1-6 -Alkylene-CF 3 , -C(=O)-C 1-6 -Alkyl, -C(=O)OH, -C(=O)O-C 1-6 -Alkyl, -C(=O)O-C 1-6 -Alkylene-CF 3 , -C(=O)NH2 ,-C(=O)NH(C 1-6 -alkyl),-C(=O)N(C 1-6 -alkyl) 2 ,-S(=O) 2 C 1-6 -alkyl,-phenyl,-C 1-6 -alkylene-phenyl,saturated or unsaturated,unsubstituted 3- to 14-membered heterocycloalkyl,and unsubstituted 5- to 14-membered heteroaryl,mono- or polysubstituted with a substituent selected from the group consisting of,-S(=O) 2 (3- to 14-membered cycloalkyl); saturated or unsaturated,unsubstituted,independently of one another,-F,-Cl,-C 1-6 -alkyl,-C 1-6 -alkylene-CF 3 ,-OH,=O,-OC 1-6 -alkyl,-C 1-6 -alkylene-OH,-C 1-6 -alkylene-O-C 1-6 -alkyl,-NH 2 ,-NHC 1-6 -alkyl,-N(C 1-6 -alkyl) 2 ,-NHC(=O)O-C 1-6 -alkyl,-N(C 1-6 -alkyl)C(=O)O-C 1-6 -alkyl,-C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl,-C 1-6 -alkylene-NH 2 ,-C 1-6 -alkylene-NH-C 1-6 -alkyl,-C 1-6 -alkylene-N(C 1-6 -alkyl) 2 ,-C 1-6 -alkylene-NH-C 1-6 -alkylene-CF 3 ,-C(=O)-C 1-6 -alkyl,-C(=O)OH,-C(=O)O-C 1-6 -alkyl,-C(=O)O-C 1-6 -alkylene-CF 3 ,-C(=O)NH2 ,-C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl) 2 ,-S(=O) 2 C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, mono- or polysubstituted with a substituent selected from the group consisting of, -C 1-6 -alkyl; 3- to 14-membered cycloalkyl or -C 1-6 -alkylene-(3- to 14-membered cycloalkyl), wherein -C 1-6 -alkylene- is unsubstituted or mono-substituted with -OH, and the 3- to 14-membered cycloalkyl 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, independently of one another, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF 3 , -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH 2 , -NHC 1-6 -alkyl, -N(C 1-6 -alkyl) 2 , -NHC(=O)O-C 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NH 2 , -C 1-6 -alkylene-NH-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl) 2 , -C1-6 -alkylene-NH-C 1-6 -alkylene-CF 3 , -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)O-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF 3 , -C(=O)NH 2 , -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl) 2 , -S(=O) 2 C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted or polysubstituted with a substituent selected from the group consisting of, 3- to 14-membered cycloalkyl or -C 1-6 -alkylene-(3- to 14-membered cycloalkyl); 3- to 14-membered heterocycloalkyl or -C 1-6 -alkylene-(3- to 14-membered heterocycloalkyl) wherein -C 1-6-alkylene- is unsubstituted or mono-substituted 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, isoxazolidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 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, and is in each case unsubstituted, independently of one another, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF 3 、-OH、=O、-OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH 2 、-NHC 1-6 -alkyl, -N(C 1-6 -alkyl) 2 、-NHC(=O)O-C 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NH 2 、-C 1-6 -alkylene-NH-C 1-6 -alkyl, -C 1-6-alkylene-N(C 1-6 -alkyl) 2 、-C 1-6 -alkylene-NH-C 1-6 -alkylene-CF 3 、-C(=O)-C 1-6 -alkyl、-C(=O)OH、-C(=O)O-C 1-6 -alkyl、-C(=O)O-C 1-6 -alkylene-CF 3 、-C(=O)NH 2 、-C(=O)NH(C 1-6 -alkyl)、-C(=O)N(C 1-6 -alkyl) 2 、-S(=O) 2 C 1-6 -alkyl、-phenyl、-C 1-6 -alkylene-phenyl、saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted or polysubstituted with a substituent selected from the group consisting of, 3- to 14-membered heterocycloalkyl or -C 1-6 -alkylene-(3- to 14-membered heterocycloalkyl); unsubstituted, independently of one another, -F, -Cl, -CN, -C 1-6 -alkyl、-C 1-6 -alkylene-CF 3 、-OH、=O、-OC 1-6 -alkyl、-C 1-6 -alkylene-OH、-C 1-6 -alkylene-O-C 1-6 -alkyl、-NH 2 、-NHC 1-6 -alkyl、-N(C 1-6 -alkyl) 2 、-NHC(=O)O-C 1-6 -alkyl、-N(C 1-6 -alkyl)C(=O)O-C 1-6 -alkyl、-C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl、-C 1-6 -alkylene-NH 2 、-C 1-6 -alkylene-NH-C 1-6-Alkyl, -C 1-6 -Alkylene-N(C 1-6 -Alkyl) 2 、-C 1-6 -Alkylene-NH-C 1-6 -Alkylene-CF 3 、-C(=O)-C 1-6 -Alkyl, -C(=O)OH, -C(=O)O-C 1-6 -Alkyl, -C(=O)O-C 1-6 -Alkylene-CF 3 、-C(=O)NH 2 、-C(=O)NH(C 1-6 -Alkyl), -C(=O)N(C 1-6 -Alkyl) 2 、-S(=O) 2 C 1-6 -Alkyl, -phenyl, -C 1-6 -Alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted or polysubstituted with a substituent selected from the group consisting of; -phenyl; 5- to 14-membered heteroaryl or -C 1-6 -Alkylene-(5- to 14-membered heteroaryl) wherein -C 1-6-alkylene- is unsubstituted or mono-substituted with -OH, and in each case, the 5- to 14-membered heteroaryl is any one selected from the group consisting of benzimidazole, benzisoxazole, benzazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indolizine, 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, and in each case, is unsubstituted and, independently of one another, is -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -alkylene-CF 3 、-OH、=O、-OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH 2 、-NHC 1-6 -alkyl, -N(C 1-6 -alkyl) 2 、-NHC(=O)O-C 1-6 -alkyl, -N(C 1-6 -alkyl)C(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NH 2 、-C 1-6 -alkylene-NH-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl) 2 、-C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3 -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)O-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF 3 -C(=O)NH 2 -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl) 2 -S(=O) 2 C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted or polysubstituted with a substituent selected from the group consisting of, 5- to 14-membered heteroaryl or -C 1-6 -alkylene-(5- to 14-membered heteroaryl), represents.

[0062] In some embodiments, R 4 is -H; saturated, unsubstituted, monosubstituted or polysubstituted with -F -S(=O) 2 C 1-6 -alkyl; saturated, unsubstituted -S(=O) 2 (3- to 14-membered cycloalkyl); saturated, unsubstituted, independently of one another, -OH, =O, -NH 2 , -NHC 1-6 -alkyl, -N(C 1-6 -alkyl) 2 , -OC 1-6 -alkyl, -C 1-6 -alkylene-NH 2 , -C 1-6 -alkylene-NH-C 1-6 -alkyl, -C(=O)NH 2 , -C(=O)-NH-C 1-3 -alkyl, -C(=O)-N(C 1-3 -alkyl) 2 , -unsubstituted phenyl monosubstituted or disubstituted with a substituent selected from the group consisting of, -C 1-6-Alkyl; 3- to 14-membered cycloalkyl or -C 1-6 -Alkylene-(3- to 14-membered cycloalkyl), provided that -C 1-6 -Alkylene- is unsubstituted or mono-substituted with -OH, and the 3- to 14-membered cycloalkyl is saturated, unsubstituted, and independently of one another, -C 1-6 -Alkyl, -C 1-6 -Alkylene-NH 2 、-C 1-6 -Alkylene-NH-C 1-6 -Alkylene-CF 3 、-C 1-6 -Alkylene-OH, -C 1-6 -Alkylene-NHC(=O)O-C 1-6 -Alkyl, -OH, -OC 1-6 -Alkyl, -NH 2 、-N(C 1-6 -Alkyl) 2 、-NHC(=O)O-C 1-6 -Alkyl, and is mono- or di-substituted with a substituent selected from the group consisting of, 3- to 14-membered cycloalkyl or -C 1-6 -Alkylene-(3- to 14-membered cycloalkyl); 3- to 14-membered heterocycloalkyl or -C 1-6 -Alkylene-(3- to 14-membered heterocycloalkyl), provided that -C 1-6 -Alkylene- is unsubstituted or mono-substituted 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, octahydropyrrolo[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, 1,1-dioxothiacyclohexane, and is in each case unsubstituted and independently of one another, -F, -OH, =O, -C1-6 -alkyl, -C 1-6 -alkylene-CF 3 、-C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH 2 、-N(C 1-6 -alkyl) 2 、-C 1-6 -alkylene-NH 2 、-C 1-6 -alkylene-N(C 1-6 -alkyl) 2 、-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)O-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF 3 、-C(=O)NH 2 、-C(=O)NH(C 1-6 -alkyl), -S(=O) 2 C 1-6 -alkyl, oxetanyl, pyrimidinyl, -C 1-6 -alkylene-phenyl, which is monosubstituted or polysubstituted with a substituent selected from the group consisting of 3- to 14-membered heterocycloalkyl or -C 1-6 -alkylene-(3- to 14-membered heterocycloalkyl); -unsubstituted phenyl; 5- to 14-membered heteroaryl or -C 1-6 -alkylene-(5- to 14-membered heteroaryl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, and the 5- to 14-membered heteroaryl is, in each case, selected from the group consisting of pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, and is, in each case, unsubstituted and, independently of one another, monosubstituted or disubstituted with a substituent selected from the group consisting of -C 1-6 -alkyl, -OH, representing 5- to 14-membered heteroaryl or -C 1-6 -alkylene-(5- to 14-membered heteroaryl).

[0063] In one embodiment of the indazole derivative according to the present invention, R 3 and R 4 together form a saturated or unsaturated, unsubstituted, or mono- or polysubstituted 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O, and S.

[0064] In some embodiments, R 3 and R 4 together form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, morpholine, and piperazine, and in each case, unsubstituted, independently of one another, -F, -C 1-6 -alkyl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)NH-C 1-6 -alkyl, -C(=O)N(C 1-6 -alkyl) 2 , -C(=O)O-C 1-6 -alkyl, -NHC(=O)O-C 1-6 -alkyl, -unsubstituted pyridyl, and, unsubstituted or mono- or polysubstituted with a substituent selected from the group consisting of 1,2,4-oxadiazole mono-substituted with -C 1-6 -alkyl. In one embodiment, R 3 and R 4 together do not form an unsubstituted, mono- or polysubstituted morpholine.

[0065] In some embodiments, R 3 and R 4 together an unsubstituted, or pyrrolidine ring mono-substituted with -N(CH 3 ) 2 ; unsubstituted or -C 1-6 -alkyl, -NH 2 , -N(CH 3 ) 2 , -C(=O)NH-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkyl, -NHC(=O)O-C1-6 -alkyl, and unsubstituted or -C 1-6 -alkyl monosubstituted piperidine ring substituted with a substituent selected from the group consisting of 1,2,4-oxadiazole; unsubstituted morpholine ring; or unsubstituted or -C 1-6 -alkyl and -unsubstituted pyridyl group selected from the group consisting of substituents form an N-substituted piperazine ring.

[0066] In some embodiments, R 3 and R 4 both do not represent -H. In some embodiments, R 3 and R 4 together with the nitrogen atom to which they are attached form a residue selected from the group consisting of the following.

Chemical formula

[0067] In other embodiments, R 3 represents -H, and R 4 does not represent -H.

[0068] In some embodiments, R 3 represents -H, and R 4 is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -alkyl. In some embodiments, R 3 represents -H, and R 4 represents a residue selected from the group consisting of the following.

Chemical formula

[0069] In a further embodiment, R 3 represents -H, and R 4 is the residue -CR’R’’-(CH 2 ) mrepresents -OH, where m is an integer from 1 to 6, preferably from 1 to 3. In the formula, R' and R'' are, independently of each other, -H, -C 1-3 -alkyl, -CF 3 , -CF 2 H, -CFH 2 , -C 1-3 -alkylene-CF 3 , -C 1-3 -alkylene-CF 2 H, -C 1-3 -alkylene-CFH 2 , -C 1-3 -alkylene-O-C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C(=O)-NH 2 , or C(=O)-NH-C 1-3 -alkyl, preferably -H, -CH 3 , -C 1-3 -alkylene-OH, -C(=O)-NH 2 , or C(=O)-NH-C 1-3 -alkyl. In one embodiment, at least R' or R'' does not represent -H. In an alternative embodiment, neither R' nor R'' represents -H.

[0070] In a further embodiment, R 3 represents -H, and R 4 represents 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.

[0071] In a further embodiment, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3-membered cycloalkyl, or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3-membered heterocycloalkyl. In some embodiments, R 3 represents -H, and R 4 represents a residue selected from the group consisting of.

Chemical formula

[0072] In some embodiments, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 4-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (preferably, 4-membered heterocycloalkyl). In some embodiments, R 3 represents -H, and R 4 represents a residue selected from the group consisting of the following.

Chemical formula

[0073] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (A),

Chemical formula

[0074] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (A) defined above, wherein 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)NH 2、 or -CHF 2 represents, 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)NH 2 represents, preferably, R A1 , R A2, R A3 , R A4 , R A5 , R A7 , and R A8 Provided that only one of them represents a residue other than -H.

[0075] In some embodiments, R 3 represents -H, and R 4 represents a residue according to the general formula (A) defined above, wherein m A is 0 or 1, Y A is selected from -O- and -CR A7 R A8 -, R A1 is -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C 1-3 -alkyl) 2 , -C(=O)NH 2 , or -CHF 2 represents, preferably, R A1 is -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C 1-3 -alkyl) 2 , or -C(=O)NH 2 represents, R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 represent -H.

[0076] In some embodiments, R 3 represents -H, and R 4is a saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered cycloalkyl (preferably 5-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered heterocycloalkyl (preferably 5-membered heterocycloalkyl), or an unsubstituted, mono- or poly-substituted 5- to 14-membered heteroaryl (preferably 5-membered heteroaryl). In a preferred embodiment, R 3 represents -H, and R 4 represents a residue selected from the group consisting of the following.

Chemical formula

[0077] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (B),

Chemical formula

[0078] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (B) as defined above, wherein Y B is selected from -O- and -NR B8 -, R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 are each independently -H, -F, -C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-CF 3 , or -C(=O)NH 2 represents, or R B2 and R B3 together represent =O, or R B4 and R B5 together represent =O, preferably, among R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 , only one, two, or three of them represent residues other than -H, preferably, among R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 , at least one of them represents a residue other than -H.

[0079] In some embodiments, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered cycloalkyl (preferably 6-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered heterocycloalkyl (preferably 6-membered heterocycloalkyl), or an unsubstituted, mono- or poly-substituted 6- to 14-membered aryl (preferably 6-membered aryl), or an unsubstituted, mono- or poly-substituted 5- to 14-membered heteroaryl (preferably 6-membered heteroaryl). In a preferred embodiment, R 3 represents -H, and R 4 represents a residue selected from the group consisting of the following. [Chemical formula]

[0080] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (C), [Chemical formula] wherein, Y C1 is selected from -O-, -S(=O) 2 -, -NR C8 -, and -CR C9 R C10 -, and Y C2 represents -CR C11 R C12 -, or Y C1 represents -CR C9 R C10 -, and Y C2 is selected from -O-, -S(=O) 2 -, and -NR C8 -, R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , RC7 , R C8 , R C9 , R C10 , R C11 , and R C12 are, independently of one another, -H, -F, -OH, -C(=O)OC 1-3 -alkyl, -NH 2 , -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)NH 2 , -C(=O)NH-C 1-3 -alkyl, or -C(=O)N(C 1-3 -alkyl) 2 represents: or R C2 and R C3 together represent =O, or R C4 and R C5 together represent =O, or R C9 and R C10 together represent =O, or R C11 and R C12 together represent =O.

[0081] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (C) as defined above, wherein Y C1 is selected from -O- or -NR C8 -, Y C2 represents -CR C11 R C12 -, or Y C1 represents -CR C9 R C10 -, Y C2 represents -O-, and -NR C8 -, and is selected from R C1 , R C2 , R C3 , R C4 , R C5 , RC6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 wherein R, R, R, R, R, R, R, R, R, R, R, and R are each independently -H, -F, -C 1-3 -alkyl, -C 1-3 -alkylene-OH, or -C(=O)NH 2 provided that preferably, only one, two, or three of R, R, R, R, R, R, R, R, R, R, R, and R represent residues other than -H, and preferably, at least one of R, R, R, R, R, R, R, R, R, R, R, and R represents a residue other than -H. C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 represent residues other than -H. C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 and R C12 represent residues other than -H.

[0082] In some embodiments, R represents -H and R represents saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 7-membered cycloalkyl, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 7-membered heterocycloalkyl. In some embodiments, R represents -H and R represents the following residue. 3 , R 4 In some embodiments, R represents -H and R represents the following residue. 3 , R 4 represents the following residue.

Chemical formula

[0083] In some embodiments, R 3represents -H, and R 4 is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl (preferably 3, 4, 5 or 6-membered cycloalkyl), where the 3- to 14-membered cycloalkyl is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkylene-connected 3- to 14-membered cycloalkyl; or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered heterocycloalkyl (preferably 4, 5 or 6-membered heterocycloalkyl), where the 3- to 14-membered heterocycloalkyl is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkylene-connected 3- to 14-membered heterocycloalkyl; or an unsubstituted, mono-substituted or multi-substituted 6- to 14-membered aryl (preferably 6-membered aryl), where the 6- to 14-membered aryl is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkylene-connected 6- to 14-membered aryl; or an unsubstituted, mono-substituted or multi-substituted 5- to 14-membered heteroaryl (preferably 5 or 6-membered heteroaryl), where the 5- to 14-membered heteroaryl is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkylene-connected 5- to 14-membered heteroaryl. In a preferred embodiment, R 3 represents -H, and R 4 represents a residue selected from the group consisting of the following.

Chemical formula

[0084] In some embodiments, R 3 represents -H, and R 4is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkylene-connected 5-membered heterocycloalkyl; or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1 -C 6 -alkylene-connected 5-membered heteroaryl.

[0085] In some embodiments, R 3 represents -H, and R 4 represents a residue selected from the group consisting of.

Chemical formula

[0086] In some embodiments, R 3 represents -H, and R 4 is (i) the residue -CR’R’’-(CH 2 ) m -OH, wherein m is an integer from 1 to 6, preferably an integer from 1 to 3, and R’ and R’’ are independently of each other -H, -C 1-3 -alkyl, -CF 3 , -CF 2 H, -CFH 2 , -C 1-3 -alkylene-CF 3 , -C 1-3 -alkylene-CF 2 H, -C 1-3 -alkylene-CFH 2 , -C 1-3 -alkylene-O-C 1-3 -alkyl, or -C 1-3 -alkylene-OH, preferably -H, -CH 3 , or -C 1-3-alkylene-OH. In one embodiment, at least R’ or R’’ does not represent -H. In one embodiment, neither R’ nor R’’ represents -H, or (ii) a residue according to general formula (D),

Chemical formula

[0087] In some embodiments, R 3 represents -H, and R 4 represents a residue selected from the group consisting of:

Chemical formula

Chemical formula

[0088] In some embodiments of the indazole derivatives according to the present invention, R 5 and R 5 ' are, independently of each other, -H; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -alkyl; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1 -C 6 -heteroalkyl; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C 1 -C 6 -alkylene- or -C 1 -C 6 -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted), representing a 3- to 14-membered cycloalkyl.

[0089] In some embodiments, R 5 and R 5 ' are, independently of each other, -H, -C 1 -C 6 -alkyl, or -C 1 -C 6 -alkylene-N(C 1 -C 6 -alkyl) 2 represents.

[0090] In some embodiments of the indazole derivatives according to the present invention, R 5and R 5 At least one of ’ is not -H.

[0091] In some embodiments of the indazole derivatives according to the present invention, R 5 and R 5 ’ are both -H.

[0092] In some embodiments, T represents -O-, U represents -CR 5 R 5 ’-, and the resulting moiety -O-CR 5 R 5 ’- represents a residue selected from the group consisting of the following.

Chemical formula

[0093] In some embodiments, T represents -CR 5 R 5 ’-, U represents -O-, and the resulting moiety -CR 5 R 5 ’-O- represents the following residue.

Chemical formula

[0094] In some embodiments, R 5 represents -H, and R 5 ’ represents -H, -C 1-3 -alkyl, -CF 3 , -CF 2 H, -CFH 2 , -C 1-3 -alkylene-CF 3 , -C 1-3 -alkylene-CF 2 H, -C 1-3 -alkylene-CFH 2、 and -C 1-3 -alkylene-OH, preferably a residue selected from the group consisting of -H or C 1-3 -alkyl.

[0095] In some embodiments of the indazole derivatives according to the present invention, R 6 , R 7 , and R 8 are, independently of one another, -H; -F, -Cl, -Br, -I, -OH, -SH, -SF 5 , -CN, -NO 2 , -C(=O)OH, -NH 2 ; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -O-C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -NHC 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -N(C 1-6 -alkyl) 2 ; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C(=O)OC 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -OC(=O)C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1-6 -heteroalkyl, representing.

[0096] In some embodiments, R 6 , R 7 , and R 8 are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -SH, -SF 5 , -CN, -NO 2 , -C(=O)OH, -NH 2 , -C 1-6 -alkyl, -CF 3 , -CHF 2 , -CH 2 F, -O-C 1-6 -alkyl, -OCF3 、 -OCHF 2 、 -OCH 2 F、 unsubstituted or, independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF 3 、 -CHF 2 、 -CH 2 F、 -OCF 3 、 -OCHF 2 、 -OCH 2 F、 SF 5 、 -NO 2 、 -C(=O)OH、 -NH 2 、 and -C(=O)NH 2 substituted with one or more substituents selected from -NHC 1-6 -alkyl; unsubstituted or, independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF 3 、 -CHF 2 、 -CH 2 F、 -OCF 3 、 -OCHF 2 、 -OCH 2 F、 SF 5 、 -NO 2 、 -C(=O)OH、 -NH 2 、 and -C(=O)NH 2 substituted with one or more substituents selected from -N(C 1-6 -alkyl) 2 ; unsubstituted or, independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF 3 、 -CHF 2 、 -CH 2 F、 -OCF 3 、 -OCHF 2 、 -OCH 2 F、 SF 5 、 -NO 2 、 -C(=O)OH、 -NH 2 、 and -C(=O)NH 2 substituted with one or more substituents selected from -C(=O)OC 1-6 -alkyl; Unsubstituted or independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2 , -C(=O)OH, -NH 2 , and -C(=O)NH 2 substituted with one or more substituents selected from -OC(=O)C 1-6 -alkyl; or Unsubstituted or independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, SF 5 , -NO 2 , -C(=O)OH, -NH 2 , and -C(=O)NH 2 substituted with one or more substituents selected from -C 1-6 -heteroalkyl, represents.

[0097] In some embodiments, R 6 , R 7 , and R 8 independently of one another represent residues selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, C 1-3 -alkyl, -CF 3 , -CF 2 H, and -CFH 2 , preferably residues selected from the group consisting of -H or -F.

[0098] In some embodiments of the indazole derivatives according to the invention, R 6 is -H, -F, -Cl, -CN, or -C 1 -C 6 -alkyl.

[0099] In some embodiments of the indazole derivatives according to the present invention, R 6 does not represent -H.

[0100] In some embodiments, R 6 is a residue selected from the group consisting of -H, -F, -Cl, -CN, or -CH 3 , preferably -H, -F, -CN, or -CH 3 .

[0101] In some embodiments of the indazole derivatives according to the present invention, R 7 is -H, -F, -Cl, -CN, or -C 1 -C 6 -alkyl.

[0102] In some embodiments of the indazole derivatives according to the present invention, R 7 does not represent -H.

[0103] In some embodiments, particularly when Q represents -NR 3 R 4 , R 7 is a residue selected from the group consisting of -H, -F, -Cl, -CN, or CH 3 .

[0104] In some embodiments, particularly when Q represents -OR 2 , R 7 represents -H, or a residue selected from the group consisting of the following.

Chemical formula

[0105] In some embodiments of the indazole derivatives according to the present invention, R 8 is -H, -F, -Cl, -CN, or -C 1 -C 6 -alkyl.

[0106] In some embodiments of the indazole derivatives according to the present invention, R 8does not represent -H.

[0107] In some embodiments, R 8 represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or CH 3 and preferably selected from -F.

[0108] In some embodiments of the indazole derivatives according to the present invention, (i) R 6 , R 7 , and R 8 each represent -H, or (ii) two of R 6 , R 7 , and R 8 represent -H, and the remainder of R 6 , R 7 , and R 8 represents -F, -Cl, -CN, or -CH 3 , or (iii) one of R 6 , R 7 , and R 8 represents -H, and the remainder of R 6 , R 7 , and R 8 independently of each other represent -F, -Cl, -CN, or -CH 3 .

[0109] In some embodiments, the compound is according to general formula (I), -R 1 represents -CH 3 , and / or -R 6 , R 7 , and R 8 each represent -H, and / or -T represents -O-, and / or -U represents -CH 2 -, and / or -V represents thiazolyl, pyridyl, or pyrazolyl, and the thiazolyl, pyridyl, and pyrazolyl are each, independently of each other, unsubstituted, -CH 3 , -F, -CH 2CHF 2 and -CF 3 may be mono - or di - substituted with a substituent selected from the group consisting of, and / or -Q is NR 3 R 4 and / or -R 3 represents H and / or -R 4 is

Chemical formula

Chemical formula

[0110] In exemplary embodiments of the present invention, the indazole derivatives are selected from the group consisting of: Compound 001 - N - [4 - (hydroxymethyl)oxan - 4 - yl] - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 002 - 5 - (benzyloxy) - N - (4,4 - difluoropyrrolidin - 3 - yl) - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 003 - N - (3,3 - difluoropiperidin - 4 - yl) - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 004 - 5 - (benzyloxy) - N - [1 - (hydroxymethyl)cyclopropyl] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 005 - N - (1 - hydroxy - 2 - methylpropan - 2 - yl) - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 006 - 2 - methyl - N - (1 - methyl - 1H - pyrazol - 3 - yl) - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 007 - 2 - methyl - N - (2 - oxopyrrolidin - 3 - yl) - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 008 - 5 - (benzyloxy) - 2 - methyl - N - (2 - oxopyrrolidin - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 009 - N - (1,3 - dihydroxy - 2 - methylpropan - 2 - yl) - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 010 - N - [4 - hydroxyoxolan - 3 - yl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 011 - 5 - (benzyloxy) - N - [4 - hydroxyoxolan - 3 - yl] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 012 - N - (3 - hydroxy - 2,2 - dimethylpropyl) - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 013 - 2 - methyl - N - (1 - methyl - 1H - pyrazol - 3 - yl) - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 014 - 5 - (benzyloxy) - 2 - methyl - N - (1 - methyl - 1H - pyrazol - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 015 - N - (1 - hydroxy - 2 - methylpropan - 2 - yl) - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 016 - N - (1,3 - dihydroxy - 2 - methylpropan - 2 - yl) - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 017 - 5-(benzyloxy)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-methyl-2H-indazole-3-carboxamide, Compound 018 - 2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-N-(1-methyl-1H-pyrazol-3-yl)-2H-indazole-3-carboxamide, Compound 019 - N-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-5-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}-2H-indazole-3-carboxamide, Compound 020 - 5-(benzyloxy)-N-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-2H-indazole-3-carboxamide, Compound 021 - N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 022 - N-[1-(hydroxymethyl)cyclopropyl]-2-methyl-5-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}-2H-indazole-3-carboxamide, Compound 023 - 5-(benzyloxy)-N-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-2H-indazole-3-carboxamide, Compound 024 - N-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 025 - 5-(benzyloxy)-N-[(6-hydroxypyridin-2-yl)methyl]-2-methyl-2H-indazole-3-carboxamide, Compound 026 - 3-hydroxy-2-[(2-methyl-5-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}-2H-indazol-3-yl)formamido]propanamide, Compound 027 - 3 - hydroxy - 2 - ({2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)propanamide, Compound 028 - N - [1 - (hydroxymethyl)cyclobutyl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 029 - N - [4 - (hydroxymethyl)oxan - 4 - yl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 030 - N - (3 - carbamoyloxetane - 3 - yl) - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 031 - N - (3 - carbamoyloxetane - 3 - yl) - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 032 - N - (4,4 - difluoro - 1 - methylpyrrolidin - 3 - yl) - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 033 - 5 - (benzyloxy) - N - (1 - carbamoylcyclobutyl) - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 034 - 5 - (benzyloxy) - N - (4,4 - difluoro - 1 - methylpyrrolidin - 3 - yl) - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 035 - N - [(6 - hydroxypyridin - 2 - yl)methyl] - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 036 - N - [(6 - hydroxypyridin - 2 - yl)methyl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 037 - N - [1 - (2 - hydroxyethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 038 - 5 - (benzyloxy)-N - [1 - (2 - hydroxyethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 039 - N - [1 - (2 - hydroxyethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 040 - 2 - methyl - N - (1 - methylpyrrolidin - 3 - yl)-5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy}-2H - indazole - 3 - carboxamide, Compound 041 - 5 - (benzyloxy)-N - (3 - carbamoyloxetane - 3 - yl)-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 042 - N - {[1 - (dimethylamino)cyclobutyl]methyl}-2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy}-2H - indazole - 3 - carboxamide, Compound 043 - N - [1 - (hydroxymethyl)cyclobutyl]-2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 044 - N - [1 - (hydroxymethyl)cyclobutyl]-2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 045 - 5 - (benzyloxy)-2 - methyl - N - [2 - (2 - oxo - 1,3 - oxazolidin - 3 - yl)ethyl]-2H - indazole - 3 - carboxamide, Compound 046 - N - {[1 - (dimethylamino)cyclobutyl]methyl}-2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 047 - N - [1 - (hydroxymethyl)cyclopropyl] - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 048 - N - [1 - (2 - hydroxyethyl)cyclobutyl] - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 049 - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - N - [2 - methyl - 2 - (morpholin - 4 - yl)propyl] - 2H - indazole - 3 - carboxamide, Compound 050 - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - N - [1 - (2,2,2 - trifluoroethyl)pyrrolidin - 3 - yl] - 2H - indazole - 3 - carboxamide, Compound 051 - 5 - (benzyloxy) - N - [1 - (2 - hydroxyethyl)cyclobutyl] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 052 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - N - [2 - methyl - 2 - (morpholin - 4 - yl)propyl] - 2H - indazole - 3 - carboxamide, Compound 053 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - N - [2 - (2 - oxo - 1,3 - oxazolidin - 3 - yl)ethyl] - 2H - indazole - 3 - carboxamide, Compound 054 - 2 - methyl - N - [(5 - oxopyrrolidin - 2 - yl)methyl] - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 055 - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - N - [2 - (2 - oxo - 1,3 - oxazolidin - 3 - yl)ethyl] - 2H - indazole - 3 - carboxamide, Compound 056 - N - [4 - hydroxyoxolan - 3 - yl] - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 057 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - N - [1 - (2,2,2 - trifluoroethyl)pyrrolidin - 3 - yl] - 2H - indazole - 3 - carboxamide, Compound 058 - N - [4 - (hydroxymethyl)oxan - 4 - yl] - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 059 - 5 - (benzyloxy) - 2 - methyl - N - [2 - methyl - 2 - (morpholin - 4 - yl)propyl] - 2H - indazole - 3 - carboxamide, Compound 060 - 5 - (benzyloxy) - 2 - methyl - N - [1 - (2,2,2 - trifluoroethyl)pyrrolidin - 3 - yl] - 2H - indazole - 3 - carboxamide, Compound 061 - N - (1 - carbamoylcyclobutyl) - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 062 - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - N - (2 - oxopyrrolidin - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 063 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - N - [(5 - oxopyrrolidin - 2 - yl)methyl] - 2H - indazole - 3 - carboxamide, Compound 064 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - N - (2 - oxopyrrolidin - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 065 - N - [1 - (2 - hydroxyethyl)cyclobutyl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 066 - 5-(benzyloxy)-2-methyl-N-[(5-oxopyrrolidin-2-yl)methyl]-2H-indazole-3-carboxamide, Compound 067 - N-[1-(hydroxymethyl)cyclopropyl]-2-methyl-5-[(1-methyl-1H-pyrazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 068 - 2-methyl-N-[2-methyl-2-(morpholin-4-yl)propyl]-5-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}-2H-indazole-3-carboxamide, Compound 069 - 2-methyl-5-[(1-methyl-1H-pyrazol-5-yl)methoxy]-N-[(5-oxopyrrolidin-2-yl)methyl]-2H-indazole-3-carboxamide, Compound 070 - N-(1-carbamoylcyclobutyl)-2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 071 - 2-methyl-5-[(1-methyl-1H-pyrazol-5-yl)methoxy]-N-(1-methylpyrrolidin-3-yl)-2H-indazole-3-carboxamide, Compound 072 - N-{[1-(dimethylamino)cyclobutyl]methyl}-2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 073 - 2-methyl-N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}-2H-indazole-3-carboxamide, Compound 074 - 5-(benzyloxy)-N-[4-(hydroxymethyl)oxan-4-yl]-2-methyl-2H-indazole-3-carboxamide, Compound 075 - 2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-N-(1-methylpyrrolidin-3-yl)-2H-indazole-3-carboxamide, Compound 076 - N-(1 - hydroxy - 2 - methylpropan - 2 - yl)-2 - methyl - 5 - {[2-(trifluoromethyl)pyridin - 3 - yl]methoxy}-2H - indazole - 3 - carboxamide, Compound 077 - 2 - methyl - N - [1-(2,2,2 - trifluoroethyl)pyrrolidin - 3 - yl]-5 - {[2-(trifluoromethyl)pyridin - 3 - yl]methoxy}-2H - indazole - 3 - carboxamide, Compound 078 - 5 - (benzyloxy)-N - {[(1 - dimethylaminocyclobutyl)methyl]}-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 079 - N - [1-(2 - hydroxyethyl)cyclobutyl]-2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 080 - N - [(3S,4S)-4 - hydroxyoxolan - 3 - yl]-2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 081 - N - (4,4 - difluoro - 1 - methylpyrrolidin - 3 - yl)-2 - methyl - 5 - {[2-(trifluoromethyl)pyridin - 3 - yl]methoxy}-2H - indazole - 3 - carboxamide, Compound 082 - (2S)-2 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazol - 3 - yl}formamido)propanamide, Compound 083 - (2R)-2 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazol - 3 - yl}formamido)propanamide, Compound 084 - 2 - methyl - N - (1 - methylpiperidin - 4 - yl)-5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 085 - N - (4 - carbamoyloxan - 4 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 086 - N - [1 - (Hydroxymethyl)cyclobutyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 087 - N - (3 - carbamoyloxyoxetan - 3 - yl) - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 088 - N - (4,4 - difluoro - 1 - methylpyrrolidin - 3 - yl) - 2 - methyl - 5 - [(1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 089 - N - [(6 - hydroxypyridin - 2 - yl)methyl] - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 090 - N - [1 - (2 - hydroxyethyl) - 2 - oxopyrrolidin - 3 - yl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 091 - 5 - (Benzyloxy) - 2 - methyl - N - (1,1,1 - trifluoro - 3 - hydroxypropan - 2 - yl) - 2H - indazole - 3 - carboxamide, Compound 092 - 5 - (Benzyloxy) - 2 - methyl - N - (1 - methylpyrrolidin - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 093 - 5 - [(2 - fluorophenyl)methoxy] - 2 - methyl - N - (1 - methylpiperidin - 4 - yl) - 2H - indazole - 3 - carboxamide, Compound 094 - 5 - [(2 - fluorophenyl)methoxy] - N - [1 - (hydroxymethyl)cyclobutyl] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 095 - 5 - [(2 - fluorophenyl)methoxy] - N - [1 - (hydroxymethyl)cyclopropyl] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 096 - 5 - [(2 - fluorophenyl)methoxy] - N - [4 - (hydroxymethyl)oxan - 4 - yl] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 097 - N - (4 - carbamoyloxyoxan - 4 - yl) - 5 - [(2 - fluorophenyl)methoxy] - 2 - methyl - 2H - indazole - 3 - carboxamide, Compound 098 - (2R) - 2 - ({5 - [(2 - fluorophenyl)methoxy] - 2 - methyl - 2H - indazol - 3 - yl}formamido)propanamide, Compound 099 - (2S) - 2 - ({5 - [(2 - fluorophenyl)methoxy] - 2 - methyl - 2H - indazol - 3 - yl}formamido)propanamide, Compound 100 - N - [3 - (hydroxymethyl)oxetan - 3 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 101 - (2S) - 2 - ({2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazol - 3 - yl}formamido)propanamide, Compound 102 - 2 - methyl - N - (oxan - 4 - yl) - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 103 - 2 - methyl - 2 - ({2 - methyl - 5 - [(2 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazol - 3 - yl}formamido)propanamide, Compound 104 - N - [1 - (hydroxymethyl)cyclopropyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 105 - N - [3 - (hydroxymethyl)oxetan - 3 - yl] - 2 - methyl - 5 - [(2 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 106 - N - [4 - (hydroxymethyl)oxan - 4 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 107 - N-(4-carbamoyloxyoxan-4-yl)-2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 108 - N-[1-(hydroxymethyl)cyclobutyl]-2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 109 - N-[3-(hydroxymethyl)oxetan-3-yl]-2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 110 - 2-methyl-2-({2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 111 - 2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-N-(1-methylpiperidin-4-yl)-2H-indazole-3-carboxamide, Compound 112 - 2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-N-(1-methylpiperidin-4-yl)-2H-indazole-3-carboxamide, Compound 113 - (2R)-3-hydroxy-2-({2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 114 - N-[1-(hydroxymethyl)cyclopropyl]-2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 115 - 2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-N-(oxan-4-yl)-2H-indazole-3-carboxamide, Compound 116 - (2S)-3-hydroxy-2-({2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 117 - (2R)-2-({2-Methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 118 - (2R)-2-({2-Methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 119 - (2S)-2-({2-Methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 120 - 2-Methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-N-(oxan-4-yl)-2H-indazole-3-carboxamide, Compound 121 - (2R)-2-{[5-(Cyclopropylmethoxy)-2-methyl-2H-indazol-3-yl]formamido}propanamide, Compound 122 - 2-Methyl-5-{[2-(trifluoromethyl)pyridin-3-yl]methoxy}-2H-indazole-3-carboxylic acid, Compound 123 - 2-Methyl-5-[(1-methyl-1H-pyrazol-5-yl)methoxy]-2H-indazole-3-carboxylic acid, Compound 124 - N-[4-(Hydroxymethyl)oxan-4-yl]-2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 125 - (2R)-3-Hydroxy-2-({2-methyl-5-[(pyridin-2-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 126 - (2S)-3-Hydroxy-2-({2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 127 - N-(1,3 - Dihydroxy - 2 - methylpropan - 2 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 128 - N-(3,3 - Difluoropiperidin - 4 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 129 - 5 - (Cyclobutylmethoxy)-N-(1,3 - dihydroxy - 2 - methylpropan - 2 - yl)-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 130 - (2S)-2 - {[5 - (Cyclobutylmethoxy)-2 - methyl - 2H - indazol - 3 - yl]formamido}-3 - hydroxypropanamide, Compound 131 - N-(1,3 - Dihydroxy - 2 - methylpropan - 2 - yl)-2 - methyl - 5 - [(2 - methyl - 1,3 - oxazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 132 - N-(3,3 - Difluoropiperidin - 4 - yl)-2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 133 - 5 - (Cyclopropylmethoxy)-N-(cyclopropylmethyl)-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 134 - 2 - {[5 - (Cyclopropylmethoxy)-2 - methyl - 2H - indazol - 3 - yl]formamido}-2 - methylpropanamide, Compound 135 - 5 - (Cyclopropylmethoxy)-N-(1,3 - dihydroxy - 2 - methylpropan - 2 - yl)-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 136 - (2R)-2 - {[5 - (Cyclopropylmethoxy)-2 - methyl - 2H - indazol - 3 - yl]formamido}-3 - hydroxypropanamide, Compound 137 - (2S)-2 - {[5 - (Cyclopropylmethoxy)-2 - methyl - 2H - indazol - 3 - yl]formamido}-3 - hydroxypropanamide, Compound 138 - (2S,3R)-2-{[5-(Cyclopropylmethoxy)-2-methyl-2H-indazol-3-yl]formamide}-3-hydroxybutanamide, Compound 139 - (2S)-2-{[5-(Cyclopropylmethoxy)-2-methyl-2H-indazol-3-yl]formamide}propanamide, Compound 140 - 5-(Cyclopropylmethoxy)-N-(2-methanesulfonamidoethyl)-2-methyl-2H-indazole-3-carboxamide, Compound 141 - (2S)-3-hydroxy-2-({2-methyl-5-[(2-methyl-1,3-oxazol-5-yl)methoxy]-2H-indazol-3-yl}formamide)propanamide, Compound 142 - (2S,3R)-3-hydroxy-2-({2-methyl-5-[(2-methyl-1,3-oxazol-5-yl)methoxy]-2H-indazol-3-yl}formamide)butanamide, Compound 143 - (2S)-2-{[5-(Cyclopentylmethoxy)-2-methyl-2H-indazol-3-yl]formamide}-3-hydroxypropanamide, Compound 144 - 5-(Cyclopentylmethoxy)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-methyl-2H-indazole-3-carboxamide, Compound 145 - 2-{[5-(Cyclopentylmethoxy)-2-methyl-2H-indazol-3-yl]formamide}-2-methylpropanamide, Compound 146 - 5-[(1-Cyanocyclopropyl)methoxy]-N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-methyl-2H-indazole-3-carboxamide, Compound 147 - N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]-2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 148 - (2S)-2-({5-[(1-cyanocyclopropyl)methoxy]-2-methyl-2H-indazol-3-yl}formamido)-3-hydroxypropanamide, Compound 149 - (2S,3R)-3-hydroxy-2-({2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)butanamide, Compound 150 - N-(2,2-difluoroethyl)-2-methyl-5-[(2-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazole-3-carboxamide, Compound 151 - 3-hydroxy-2-methyl-2-({2-methyl-5-[(4-methyl-1,3-thiazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 152 - N-[(3R)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-2-methyl-5-[(pyridin-2-yl)methoxy]-2H-indazole-3-carboxamide, Compound 153 - N-[(3S)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-2-methyl-5-[(pyridin-2-yl)methoxy]-2H-indazole-3-carboxamide, Compound 154 - 3-hydroxy-2-methyl-2-({2-methyl-5-[(1-methyl-1H-pyrazol-5-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 155 - 3-hydroxy-2-methyl-2-({2-methyl-5-[(1-methyl-1H-pyrazol-3-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 156 - 3-hydroxy-2-methyl-2-({2-methyl-5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2H-indazol-3-yl}formamido)propanamide, Compound 157 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(2 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazol - 3 - yl}formamide)propanamide, Compound 158 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(oxan - 4 - yl)methoxy]-2H - indazol - 3 - yl}formamide)propanamide, Compound 159 - 5 - (cyclobutylmethoxy)-N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 160 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(2 - methyl - 1,3 - thiazol - 4 - yl)methoxy]-2H - indazol - 3 - yl}formamide)propanamide, Compound 161 - 5 - (cyclopropylmethoxy)-N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 162 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazol - 3 - yl}formamide)propanamide, Compound 163 - N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 164 - N - (3 - carbamoyloxolane - 3 - yl)-2 - methyl - 5 - [(6 - methylpyridin - 3 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 165 - N - (3 - carbamoyloxolane - 3 - yl)-5 - (cyclopropylmethoxy)-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 166 - N - (3 - carbamoyloxolane - 3 - yl)-5 - [(2 - fluorophenyl)methoxy]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 167 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(oxetan - 3 - yl)methoxy]-2H - indazol - 3 - yl}formamide)propanamide, Compound 168 - N - (3 - carbamoyloxolane - 3 - yl)-2 - methyl - 5 - [(pyridin - 3 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 169 - N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 5 - [(6 - methylpyridin - 3 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 170 - N - (3 - carbamoyloxolane - 3 - yl)-2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 171 - 5 - [(2 - fluorophenyl)methoxy]-N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 172 - 3 - hydroxy - 2 - [(5 - methoxy - 2 - methyl - 2H - indazol - 3 - yl)formamide]-2 - methylpropanamide, Compound 173 - 2 - {[5 - (cyclobutylmethoxy)-2 - methyl - 2H - indazol - 3 - yl]formamide}-3 - hydroxy - 2 - methylpropanamide, Compound 174 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(6 - methylpyridin - 3 - yl)methoxy]-2H - indazol - 3 - yl}formamide)propanamide, Compound 175 - N - (3 - carbamoyloxolane - 3 - yl)-5 - {[2 - (difluoromethyl)phenyl]methoxy}-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 176 - 5 - {[2 - (difluoromethyl)phenyl]methoxy}-N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 177 - N - [3 - (Hydroxymethyl) - 2 - oxopyrrolidin - 3 - yl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 178 - N - (3 - carbamoyloxolane - 3 - yl) - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 179 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(2 - methyl - 1,3 - oxazol - 5 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)propanamide, Compound 180 - N - [3 - (Hydroxymethyl) - 2 - oxopyrrolidin - 3 - yl] - 2 - methyl - 5 - [(pyridin - 3 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 181 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(5 - methylpyridin - 2 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)propanamide, Compound 182 - N - (4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl) - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 183 - 2 - methyl - N - [3 - (methylcarbamoyl)oxolane - 3 - yl] - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 184 - 3 - hydroxy - N,N,2 - trimethyl - 2 - ({2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)propanamide, Compound 185 - 3 - hydroxy - N,2 - dimethyl - 2 - ({2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)propanamide, Compound 186 - N - [3 - (dimethylcarbamoyl)oxolan - 3 - yl] - 2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazole - 3 - carboxamide, Compound 187 - 2 - {[5 - (2,2 - difluoroethoxy) - 2 - methyl - 2H - indazol - 3 - yl]formamide} - 3 - hydroxy - 2 - methylpropanamide, Compound 188 - 2 - ({2 - ethyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazol - 3 - yl}formamide) - 3 - hydroxy - 2 - methylpropanamide, Compound 189 - 2 - (hydroxymethyl) - 2 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)butanamide, Compound 190 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(pyridin - 3 - yl)methoxy] - 2H - indazol - 3 - yl}formamide)propanamide, Compound 191 - 2 - [(5 - {[2 - (difluoromethyl)phenyl]methoxy} - 2 - methyl - 2H - indazol - 3 - yl)formamide] - 3 - hydroxy - 2 - methylpropanamide, Compound 192 - 3 - hydroxy - 2 - methyl - 2 - [(2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazol - 3 - yl)formamide]propanamide, Compound 193 - 3 - hydroxy - N,N,2 - trimethyl - 2 - [(2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy} - 2H - indazol - 3 - yl)formamide]propanamide, Compound 194 - 2 - ({5 - [(2 - fluorophenyl)methoxy] - 2 - methyl - 2H - indazol - 3 - yl}formamide) - 3 - hydroxy - 2 - methylpropanamide, Compound 195 - 3 - hydroxy - 2 - methyl - 2 - ({5 - [(2 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2 - (propan - 2 - yl) - 2H - indazol - 3 - yl}formamide)propanamide, Compound 196 - 3 - hydroxy - 2 - methyl - 2 - ({2 - methyl - 5 - [(3 - methylcyclobutyl)methoxy]-2H - indazol - 3 - yl}formamide)propenamide, Compound 197 - 5 - (benzyloxy)-2 - methyl - 2H - indazole - 3 - carboxylic acid, Compound 198 - 5 - [(2 - fluorophenyl)methoxy]-2 - methyl - 2H - indazole - 3 - carboxylic acid, Compound 199 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]-2H - indazole - 3 - carboxylic acid, Compound 200 - N - (4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl)-5 - {[2 - (difluoromethyl)phenyl]methoxy}-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 201 - N - (4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 202 - N - (4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl)-2 - methyl - 5 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy}-2H - indazole - 3 - carboxamide, Compound 203 - N - (4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl)-5 - [(2 - fluorophenyl)methoxy]-2 - methyl - 2H - indazole - 3 - carboxamide, Compound 204 - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-N - (2,2,2 - trifluoroethyl)-2H - indazole - 3 - carboxamide, Compound 205 - N - (2 - hydroxyethyl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 206 - N - [(1H - imidazol - 2 - yl)methyl]-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 207 - N - [3 - (dimethylamino) - 2,2 - dimethylpropyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 208 - N - (2,2 - difluoro - 2 - phenylethyl) - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 209 - N - {[2 - fluoro - 6 - (trifluoromethyl)phenyl]methyl} - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 210 - N - {[3 - (difluoromethoxy)phenyl]methyl} - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 211 - N - (4,4 - difluoropiperidin - 3 - yl) - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 212 - N - (4,4 - difluoropiperidin - 3 - yl) - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 213 - N - (5,5 - difluoropiperidin - 3 - yl) - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 214 - N - (5,5 - difluoropiperidin - 3 - yl) - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 215 - 2 - methyl - 5 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy] - N - (pyrrolidin - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 216 - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - (pyrrolidin - 3 - yl) - 2H - indazole - 3 - carboxamide, Compound 217 - N - [3,3 - difluoro - 1 - (hydroxymethyl)cyclobutyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 218 - 3 - [(1 - {2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazol - 3 - yl}ethenyl)amino] - 5 - (trifluoromethyl)pyridin - 2 - ol, Compound 219 - N - [5 - (hydroxymethyl) - 2,2 - dimethyl - 1,3 - dioxan - 5 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 220 - N - [1 - (4 - fluorophenyl) - 2 - hydroxyethyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 221 - N - [2 - hydroxy - 1 - (pyridin - 2 - yl)ethyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 222 - N - [3 - (trifluoromethyl)pyrrolidin - 3 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 223 - N - [1 - (4 - fluorophenyl) - 3 - hydroxypropyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 224 - 2 - (9 - [(2 - fluorophenyl)methoxy] - 1H,3H,4H,5H - [1,4]diazepino[1,2 - b]indazol - 1 - one - 2 - yl) - 3 - hydroxypropanamide, Compound 225 - 2 - (9 - [(2 - fluorophenyl)methoxy] - 1H,2H,3H,4H - pyrazino[1,2 - b]indazol - 1 - one - 2 - yl) - 3 - hydroxypropanamide, Compound 226 - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - (4,4,4 - trifluoro - 1 - hydroxybutan - 2 - yl) - 2H - indazole - 3 - carboxamide, Compound 227 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy]-N-[4,4,4 - trifluoro - 1 - hydroxy - 3 - (trifluoromethyl)butan - 2 - yl]-2H - indazole - 3 - carboxamide, Compound 228 - N-(4,4 - difluoro - 1 - hydroxybutan - 2 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 229 - N-[1 - (dimethylamino)-4,4 - difluoro - 2 - methylbutan - 2 - yl]-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 230 - N-(4,4 - difluoro - 1 - methoxy - 2 - methylbutan - 2 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 231 - N-(4 - fluoro - 1 - hydroxy - 4 - methylpentan - 2 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 232 - N-(1 - hydroxy - 2 - methyl - 3 - oxobutan - 2 - yl)-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 233 - 4,4 - difluoro - 2 - (hydroxymethyl)-2 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazol - 3 - yl}formamido)butanamide, Compound 234 - 4 - fluoro - 2 - (hydroxymethyl)-2 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazol - 3 - yl}formamido)butanamide, Compound 235 - N-[2,2 - difluoro - 1 - (hydroxymethyl)cyclopropyl]-2 - methyl - 5 - [(pyridin - 2 - yl)methoxy]-2H - indazole - 3 - carboxamide, Compound 236 - N - [trans - 2 - (difluoromethyl) - 1 - (hydroxymethyl)cyclopropyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 237 - N - [cis - 2 - (difluoromethyl) - 1 - (hydroxymethyl)cyclopropyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 238 - N - [1 - (1 - cyclopropyl - 1H - imidazol - 2 - yl) - 2 - hydroxyethyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 239 - N - [1 - hydroxy - 2 - (1 - methyl - 1H - pyrazol - 3 - yl)propan - 2 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 240 - 4 - hydroxy - 3 - ({2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazol - 3 - yl}formamido)butanamide, Compound 241 - N - [2 - hydroxy - 1 - (oxan - 4 - yl)ethyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 242 - N - {1 - hydroxy - 3 - [2 - (trifluoromethyl) - 1H - imidazol - 1 - yl]propan - 2 - yl} - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 243 - N - [1 - hydroxy - 3 - (pyrimidin - 2 - yl)propan - 2 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 244 - N - [3,3 - difluoro - 1 - hydroxy - 3 - ((pyridin - 2 - yl))propan - 2 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 245 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - (4,4,4 - trifluoro - 2 - hydroxybutyl) - 2H - indazole - 3 - carboxamide, Compound 246 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - [trans - 4 - (trifluoromethyl)pyrrolidin - 3 - yl] - 2H - indazole - 3 - carboxamide, Compound 247 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - [cis - 4 - (trifluoromethyl)pyrrolidin - 3 - yl] - 2H - indazole - 3 - carboxamide, Compound 248 - N - [3 - (2,2 - difluoroethyl)piperidin - 3 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 249 - N - (2 - difluoromethyl - 1 - hydroxypropan - 3 - yl) - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 250 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - (3,3 - difluoro - 1 - hydroxy - 2 - methylpropan - 2 - yl) - 2H - indazole - 3 - carboxamide, Compound 251 - N - [2 - hydroxy - 1 - (1 - methyl - 1H - pyrazol - 3 - yl)ethyl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 252 - N - [1 - hydroxy - 3 - (pyridin - 2 - yl)propan - 2 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 253 - N - [3 - (hydroxymethyl) - 2 - oxopyrrolidin - 3 - yl] - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 254 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - (1,1,1 - trifluoro - 3 - hydroxypropan - 2 - yl) - 2H - indazole - 3 - carboxamide, Compound 255 - 2 - Methyl - 5 - [(pyridin - 2 - yl)methoxy] - N - (4,4,4 - trifluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl) - 2H - indazole - 3 - carboxamide, Compound 256 - 9 - [(2 - fluorophenyl)methoxy] - 1H,2H,3H,4H - pyrazino[1,2 - b]indazol - 1 - one, Compound 257 - 9 - (Benzyloxy) - 1H,2H,3H,4H - pyrazino[1,2 - b]indazol - 1 - one, Compound 258 - N - (1 - Hydroxy - 3 - methoxy - 2 - methylpropan - 2 - yl) - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 259 - N - (1,3 - Dihydroxypropan - 2 - yl) - 2 - methyl - 5 - [(pyridin - 2 - yl)methoxy] - 2H - indazole - 3 - carboxamide, Compound 260 - 2 - (1,3 - Dihydroxypropan - 2 - yl) - 9 - [(2 - fluorophenyl)methoxy] - 1H,2H,3H,4H - pyrazino[1,2 - b]indazol - 1 - one, Compound 261 - 9 - [(2 - fluorophenyl)methoxy] - 2 - (2 - hydroxyethyl) - 1H,2H,3H,4H - pyrazino[1,2 - b]indazol - 1 - one, Compound 262 - N - (1,3 - Dihydroxypropan - 2 - yl) - 5 - [(2 - fluorophenyl)methoxy] - 2 - methyl - 2H - indazole - 3 - carboxamide,

[0111] The indazole 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. The indazole derivatives according to the present invention are also for use in the treatment of epilepsy.

[0112] In some embodiments, the indazole derivative is selected from the group consisting of Compounds 1 - 262 shown in Table 1 below, including its stereoisomers and pharmaceutically acceptable salts.

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

[0113] In some embodiments, the indazole derivative is selected from the group consisting of compounds 200-262 shown in Table 2 below, including its stereoisomers and pharmaceutically acceptable salts.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

[0114] Q, T, U, V, R containing the disclosed substituents 1 , R 2 , R 3 , R 4 , R 5 , R 5 ’, R 6 , R 7 , and R 8 All definitions, embodiments, and meanings of R also apply equally to the indazole derivatives according to the present invention, including but not limited to (a-1), (a-2), (a-3), (b-1), (b-2), and (b-3), which are not necessarily limited to use in the treatment of pain. Thus, this aspect of the present invention relates to the indazole derivative itself, a composition containing the indazole derivative, a medicament containing the indazole derivative, and the use of the indazole derivative for the prevention and / or treatment of TRPM3-mediated disorders such as pain and / or inflammatory hypersensitivity and / or epilepsy, and / or for combating pain and / or inflammatory hypersensitivity and / or epilepsy. Preferably, the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain.

[0115] In some embodiments of the present invention, the indazole derivative is selected from the group consisting of the above-mentioned compounds 001 to 199 and their physiologically acceptable salts.

[0116] In some embodiments of the present invention, the indazole derivative is selected from the group consisting of the above-mentioned compounds 200 to 262 and their physiologically acceptable salts.

[0117] Another aspect of the present invention relates to a pharmaceutical composition or medicament containing the compound according to the present invention as described above.

[0118] Throughout this specification, references to "one embodiment" or "an embodiment" mean that the particular features, structures, or characteristics described in connection with that embodiment are included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, although they may. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as will be apparent to those skilled in the art from this disclosure. Also, the embodiments described for aspects of the invention may be used in, and combined with, other aspects of the invention. When an indefinite or definite article is used with a singular noun (e.g., "a" or "an", "the"), this includes the plural form of that noun unless otherwise specified.

[0119] Similarly, in the description of exemplary embodiments of the invention, it should be understood that various aspects of the invention may be grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various aspects of the invention.

[0120] In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms that are generally optimally present in the substituent or linker. It is understood that, unless otherwise indicated in this application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.

[0121] As used herein, the term "leaving group" or "LG" means a chemical group that is readily replaced by a nucleophile or readily cleaved or hydrolyzed under basic or acidic conditions. In certain embodiments, the leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

[0122] The term "protecting group" refers to a moiety of a compound that masks or modifies the properties of a functional group or the properties of the compound as a whole. The chemical substructures of protecting groups are diverse. One function of a protecting group is to function as an intermediate in the synthesis of a prodrug substance. 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 hide the reactivity of a particular functional group and to assist in the efficiency of desired chemical reactions, such as creating and breaking chemical bonds in an orderly and planned manner. The protection of a functional group of a compound can change other physical properties of the compound other than the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. A chemically protected intermediate can itself be biologically active or inactive.

[0123] A protected compound can also exhibit altered properties in vitro and in vivo and, in some cases, optimized properties (such as cell membrane permeability and resistance to enzymatic degradation or capture). In this role, a protected compound having the intended therapeutic effect can be referred to as a prodrug. Another function of a protecting group is to convert a parent drug into a prodrug, whereby the parent drug is released upon conversion of the prodrug in vivo. Since an active prodrug can be absorbed more effectively than the parent drug, the prodrug can have greater efficacy in vivo than the parent drug. The protecting group is removed either in vitro in the case of a chemical intermediate or in vivo in the case of a prodrug. With respect to a chemical intermediate, it is not particularly important that the resulting product (e.g., an alcohol) after deprotection be physiologically acceptable, although it is generally more desirable if this product is pharmacologically harmless.

[0124] As used herein, the term "heteroatom" means an atom selected from nitrogen, oxygen which can be quaternized or can exist as an oxide, sulfur oxides including sulfoxide and sulfone, and sulfur optionally including sulfonate. Optionally, a compound and / or a synthetic intermediate may contain heteroatoms such as boron, phosphorus, and silicon.

[0125] As used herein, the term "saturated or unsaturated alkyl" includes saturated alkyl and unsaturated alkyl such as alkenyl and alkynyl. As used herein, the term "alkyl" means a normal, secondary or tertiary, linear or branched hydrocarbon having no 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 unsaturated moiety (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp2 double bond. Examples include ethylene or vinyl (-CH=CH 2 )), allyl (-CH 2 CH=CH 2 ), and 5-hexenyl (-CH 2 CH 2 CH 2 CH 2 CH=CH 2) include, but are not limited to. 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 site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond. Examples include ethynyl (-C≡CH), and 1-propynyl (propargyl, -CH 2 C≡CH), but are not limited thereto.

[0126] As used herein, the term "saturated or unsaturated alkylene" includes saturated alkylene and unsaturated alkylene such as alkenylene, alkynylene, alkenynylene. As used herein, the term "alkylene" means a saturated, linear or branched hydrocarbon radical having two monovalent radical centers obtained by removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene radicals include methylene (-CH 2 -), 1,2-ethyl (-CH 2 CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2-) and the like, but not limited thereto. As used herein, the term "alkenylene" refers to 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 site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp2 double bond. As used herein, the term "alkynylene" refers to 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 site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond.

[0127] As used herein, the term "saturated or unsaturated heteroalkyl" includes saturated heteroalkyl and unsaturated heteroalkyl such as heteroalkenyl, heteroalkynyl, heteroalkenynyl. As used herein, the term "heteroalkyl" means a linear or branched alkyl in which one or more carbon atoms (usually 1, 2, or 3) are replaced by heteroatoms, i.e., oxygen, nitrogen, or sulfur atoms, provided that the chain does not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH 3 can be replaced by -NH 2 and / or one or more -CH of the alkyl 2- means that it can be replaced by -NH-, -O-, or -S-. The S atom in the chain can optionally be oxidized by one or two oxygen atoms to obtain sulfoxide and sulfone, respectively. Further, the heteroalkyl group in the indazole derivative of the present invention can contain an oxo or thio group on any carbon or heteroatom that would result in a stable compound. Exemplary heteroalkyl groups include, but are not limited to, alcohol, alkyl ether (e.g., -methoxy, -ethoxy, -butoxy, etc.), primary, secondary, and tertiary alkylamine, amide, ketone, ester, alkyl sulfide, and alkyl sulfone. 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, provided that the chain does not contain two adjacent O atoms or two adjacent S atoms. Thus, the term heteroalkenyl includes imine, -O-alkenyl, -NH-alkenyl, -N(alkenyl) 2 , -N(alkyl)(alkenyl), and -S-alkenyl. 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 O atoms or two adjacent S atoms. Thus, the term heteroalkynyl includes -cyano, -O-alkynyl, -NH-alkynyl, -N(alkynyl) 2 , -N(alkyl)(alkynyl), -N(alkenyl)(alkynyl), and -S-alkynyl.

[0128] As used herein, the term "saturated or unsaturated heteroalkylene" includes saturated heteroalkylene and unsaturated heteroalkylene such as heteroalkenylene, heteroalkynylene, and heteroalkenynylene. 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 a heteroatom, i.e., an oxygen, nitrogen, or sulfur atom, provided that the chain does not contain two adjacent O atoms or two adjacent S 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 an oxygen, nitrogen, or sulfur atom, provided that the chain does not contain two adjacent O atoms or two adjacent S atoms. As used herein, the term "heteroalkynylene" means a linear or branched alkynylene in which one or more carbon atoms (usually one, two, or three) are replaced by an oxygen, nitrogen, or sulfur atom, provided that the chain does not contain two adjacent O atoms or two adjacent S atoms.

[0129] As used herein, the term "saturated or unsaturated cycloalkyl" includes saturated cycloalkyl and unsaturated cycloalkyl such as cycloalkenyl and cycloalkynyl. As used herein, the term "cycloalkyl", unless otherwise specified, means a saturated cyclic hydrocarbon radical such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, fenchyl, decalinyl, adamantyl and the like. As used herein, the term "cycloalkenyl" means a non-aromatic cyclic hydrocarbon radical having at least one site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp2 double bond. Examples include, but are not limited to, cyclopentenyl and cyclohexenyl. The double bond may be in the cis or trans configuration. As used herein, the term "cycloalkynyl" means a non-aromatic cyclic hydrocarbon radical having at least one site of unsaturation (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond. An example is cyclohepta-1-yne. A fused system of a cycloalkyl ring having a heterocycloalkyl ring is considered to be a heterocycloalkyl regardless of the ring attached to the core structure. A fused system of a cycloalkyl ring having an aryl ring is considered to be an aryl regardless of the ring attached to the core structure. A fused system of a cycloalkyl ring having a heteroaryl ring is considered to be a heteroaryl regardless of the ring attached to the core structure.

[0130] As used herein, the term "saturated or unsaturated heterocycloalkyl" includes saturated heterocycloalkyl, which contains at least one heteroatom, i.e., N, O, or S as a ring member, and unsaturated non-aromatic heterocycloalkyl. As used herein, the term "heterocycloalkyl" means "cycloalkyl" 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 O atoms or two adjacent S atoms, unless otherwise specified. As used herein, the term "heterocycloalkenyl" means "heterocycloalkenyl" 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 O atoms or two adjacent S atoms, unless otherwise specified. As used herein, the term "heterocycloalkynyl" means "heterocycloalkynyl" 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 O atoms or two adjacent S atoms, unless otherwise specified.Examples of saturated and unsaturated heterocycloalkyls include, but are not limited to, azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxazolidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 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 meaning of the present invention are described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, 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 - present), particularly Volumes 13, 14, 16, 19, and 28, Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996), and J. Am. Chem. Soc. (1960) 82:5566. When the heterocycloalkyl does not contain nitrogen as a ring member, it is typically bonded via carbon. When the heterocycloalkyl contains nitrogen as a ring member, it can be bonded via nitrogen or carbon.A fused system of a heterocycloalkyl ring having a cycloalkyl ring is regarded as a heterocycloalkyl regardless of the ring bonded to the core structure. A fused system of a heterocycloalkyl ring having an aryl ring is regarded as a heterocycloalkyl regardless of the ring bonded to the core structure. A fused system of a heterocycloalkyl ring having a heteroaryl ring is regarded as a heteroaryl regardless of the ring bonded to the core structure.

[0131] As used herein, the term "aryl" means an aromatic hydrocarbon. Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, etc., which are monocyclic or two or three rings fused together. A fused system of an aryl ring having a cycloalkyl ring is regarded as an aryl regardless of the ring bonded to the core structure. A fused system of an aryl ring having a heterocycloalkyl ring is regarded as a heterocycloalkyl regardless of the ring bonded to the core structure. Thus, indoline, dihydrobenzofuran, dihydrobenzothiophene, etc. are regarded as heterocycloalkyls according to the present invention. A fused system of an aryl ring having a heteroaryl ring is regarded as a heteroaryl regardless of the ring bonded to the core structure.

[0132] As used herein, the term "heteroaryl" means an aromatic ring system containing at least one heteroatom, i.e., N, O, or S, as a ring member of the aromatic ring system. Examples of heteroaryl include, but are not limited to, benzimidazole, benzisoxazole, benzazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indolizine, 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.

[0133] As a further example, the carbocyclic ring is bonded at the 2-, 3-, 4-, 5- or 6-position of pyridine, the 3-, 4-, 5- or 6-position of pyridazine, the 2-, 4-, 5- or 6-position of pyrimidine, the 2-, 3-, 5- or 6-position of pyrazine, the 2-, 3-, 4- or 5-position of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, the 2-, 4- or 5-position of oxazole, imidazole or thiazole, the 3-, 4- or 5-position of isoxazole, pyrazole or isothiazole, the 2- or 3-position of aziridine, the 2-, 3- or 4-position of azetidine, the 2-, 3-, 4-, 5-, 6-, 7- or 8-position of quinoline, or the 1-, 3-, 4-, 5-, 6-, 7- or 8-position of isoquinoline.

[0134] Examples of the carbon-bonded heterocyclic ring 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. As an example, the nitrogen-bonded heterocyclic ring is bonded to the 1-position 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, the 2-position of isoindole or isoindoline, the 4-position of morpholine, and the 9-position of carbazole or β-carboline. Examples of the nitrogen-bonded heterocyclic ring include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. Further heteroaryl in the meaning of the present invention is described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, 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 - present), particularly Volumes 13, 14, 16, 19, and 28, Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996), and J. Am. Chem. Soc. (1960) 82:5566.

[0135] As used herein with respect to substituents, unless otherwise specified, terms such as "monosubstituted", "disubstituted", "trisubstituted", "polysubstituted" mean chemical structures defined herein, and each moiety is substituted with one or more substituents, meaning that one or more hydrogen atoms of the moiety are each independently replaced with a substituent. For example, -C which may be polysubstituted with -F 1-6 -alkyl is -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , CF 2 CF 3 and the like. Similarly, -C which may be polysubstituted with substituents independently selected from -F and -Cl 1-6 -alkyl is -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , CF 2 CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 CCl 3 , CCl 2 CCl 3 , -CHClF, -CClF 2 , -CCl 2 CF 3 , -CF 2 CCl 3 , -CClFCCl 2 F and the like. The designation of any substituent found at multiple sites in the compounds of the present invention is to be independently selected.

[0136] As used herein, unless otherwise specified, the term "solvate" includes any combination that can be formed by a derivative of the present invention with a suitable inorganic solvent (e.g., hydrate) or an organic solvent such as, but not limited to, alcohol, ketone, ester, ether, nitrile, etc.

[0137] As used herein, the term "subject" refers to an animal, preferably a mammal, most preferably a human, who is the subject of treatment, observation, or experiment.

[0138] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical that elicits a biological or pharmaceutical response in a tissue system, animal, or human, as determined by a researcher, veterinarian, physician, or other clinician, including the alleviation or partial alleviation of the symptoms of a disease or disorder being treated.

[0139] As used herein, "composition" is intended to encompass a product containing a therapeutically effective amount of a designated ingredient, as well as any product directly or indirectly obtained from a combination of a designated amount of a designated ingredient.

[0140] As used herein, the term "antagonist" or "inhibitor" refers to a compound that can produce a functional antagonism of the TRPM3 ion channel, including competitive antagonists, non-competitive antagonists, desensitizing agonists, and partial agonists, depending on the context. Generally, "antagonist" and "inhibitor" can be understood to modulate TRPM3.

[0141] For the purposes of the present invention, the term "TRPM3-regulated" is used to refer to a state that is affected by the regulation of the TRPM3 ion channel, including states mediated by the TRPM3 ion channel.

[0142] As used herein, the term "TRPM3-mediated disorder" refers to disorders or diseases consisting of pain and inflammatory hypersensitivity symptoms, and epilepsy, in which the use of an antagonist or modulator of TRPM3 prevents, treats, (partially) alleviates, or improves the symptoms. According to the International Association for the Study of Pain, for the purposes of the present invention, pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or explained from the perspective of such damage. Preferably, the TRPM3-mediated disorder is preferably pain selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain. For the purposes of the present invention, the term "inflammatory hypersensitivity" is used to refer to a condition characterized by one or more features of inflammation, including edema, erythema, hyperthermia, and pain, and / or by an excessive physiological or pathophysiological response to one or more types of stimuli, including thermal, mechanical, and / or chemical stimuli.

[0143] The indazole derivatives of the present invention have been shown or are understood to be antagonists or modulators of TRPM3, and thus the present invention provides the compound itself, the compound for use as a medicament, and more specifically, the compound for use as a medicament in the prevention or treatment of TRPM3-mediated disorders in a subject using a therapeutically effective amount of the indazole derivative of the present invention.

[0144] In a preferred embodiment of the present invention, the indazole derivative of the present invention is the only pharmacologically active compound administered for treatment. In another embodiment of the present invention, the indazole derivative of the present invention can be used in combination with other therapeutic agents for the treatment or prevention of TRPM3-mediated disorders. Thus, the present invention also - one or more compounds of the formulas and embodiments herein, -For the prevention or treatment of TRPM3-mediated disorders, the use of a composition comprising one or more further therapeutic or prophylactic agents used as biologically active agents in the form of a combined preparation for simultaneous, separate or sequential use.

[0145] The pharmaceutical composition or combined preparation according to the invention may contain the indazole derivative of the invention over a wide range of contents, depending on the intended use and the expected effect of the preparation. Generally, the content of the indazole derivative of the invention in the combined preparation is in the range of 0.1 to 99.9% by weight, preferably 1 to 99% by weight, more preferably 5 to 95% by weight.

[0146] When several active ingredients are used in combination, taking into account the fact that they do not necessarily directly exert their combined therapeutic effect simultaneously in the mammal being treated, the corresponding composition may also be in the form of a medical kit or package containing two components in separate but adjacent reservoirs or compartments. Thus, in the latter situation, each active ingredient may be formulated in a manner suitable for an administration route different from that of the other ingredients, for example, one of them may be in the form of an oral or parenteral preparation, while the other may be in the form of an ampoule for intravenous injection or an aerosol.

[0147] Those skilled in the art will also recognize that the indazole derivatives of the invention can exist in many different protonation states, especially depending on the pH of their environment. The structural formulas provided herein show compounds of only one of several possible protonation states, but these structures are illustrative and the invention is not limited to any particular protonation state, and it will be understood that any and all protonated forms of the compounds are intended to fall within the scope of the invention.

[0148] As used herein, the term "pharmaceutically acceptable salt" or "physiologically acceptable salt" means a therapeutically active, non-toxic salt form that can be formed by the compounds of the formulas herein. Thus, the compounds of the present invention optionally include salts of the compounds herein, particularly, for example, salts with cations such as Na + , Li + , K + , Ca 2+ , and Mg 2+ that are pharmaceutically acceptable and non-toxic. Such salts can include those derived by combination of a suitable cation, such as an alkali metal and alkaline earth metal ion, or ammonium and quaternary amino ion, with an acidic anion moiety, typically a carboxylic acid. The indazole derivatives of the present invention can have multiple positive or negative charges. The net charge of the indazole derivatives of the present invention can be either positive or negative. Any associated counterion is typically determined by the synthetic and / or isolation methods by which the compound is obtained. Exemplary counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. The identity of any associated counterion is not an important feature of the present invention, and it will be understood that the present invention includes compounds that associate with any type of counterion. Further, since the compounds can exist in various different forms, the present invention is intended to include not only forms of the compounds that associate with counterions (e.g., dry salts), but also forms that do not associate with counterions (e.g., aqueous or organic solutions). Metal salts are typically prepared by reacting a metal hydroxide with the compounds of the present invention. Examples of metal salts prepared in such a manner are Li + , Na + , and K +It is a salt containing. A less soluble metal salt can be precipitated from a solution of a more soluble salt by the addition of a suitable metal compound. In addition, the salt can be formed from the acid addition of certain organic and inorganic acids to basic centers, typically amines, or acidic groups. 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, phosphoric acid, or organic acids such as 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), p-aminosalicylic acid, etc. Further, the term also includes solvates, such as hydrates, alcoholates, etc., that the compounds of the formulas herein and their salts can form. Finally, it should be understood that the compositions herein include the indazole derivatives of the present invention in their non-ionized form, as well as zwitterionic forms, and in combination with a stoichiometric amount of water as hydrates.

[0149] Salts of the parent compounds with one or more amino acids, especially natural amino acids found as protein components, are also included within the scope of the present invention. The amino acids typically have side chains with basic or acidic groups such as, for example, lysine, arginine, or glutamic acid, or neutral groups such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0150] The indazole derivatives of the present invention also include their physiologically acceptable salts. Examples of physiologically acceptable salts of the indazole derivatives of the present invention include alkali metals (e.g., sodium), alkaline earths (e.g., magnesium), ammonium, and NX4 + (wherein X is -C 1-6-alkyl), and salts derived from suitable bases such as. Physiologically acceptable salts of a hydrogen atom or an amino group include 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 salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of the compound combined with a suitable cation such as Na + and NX4 + etc. (wherein X is typically independently selected from -H or -C 1-4 -alkyl group). However, salts of acids and bases that are not physiologically acceptable may also be recognized, for example, for use in the preparation or purification of physiologically acceptable compounds. All salts are within the scope of the present invention regardless of whether they are in a form derived from a physiologically acceptable acid or base.

[0151] As used herein, the term "enantiomer" means, unless otherwise specified, each optically active form of the indazole derivative of the present invention having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, more preferably at least 98% (determined by standard methods in the art).

[0152] As used herein, the term "isomer" means all possible isomeric forms, including tautomeric and stereochemical forms, that a compound of the formula herein may have, but does not include positional isomers. Typically, the structures shown herein illustrate only one tautomeric or resonance form of a compound, but the corresponding alternative configurations are equally contemplated. Unless otherwise specified, the chemical name of a compound refers to a mixture of all possible stereochemical isomeric forms, which mixture contains all diastereomers and enantiomers of the basic molecular structure (since the compounds of the formula herein may have at least one chiral center), as well as stereochemically pure or enriched compounds. More specifically, a stereocenter may have either an R configuration or an S configuration, and a multiple bond may have either a cis configuration or a trans configuration.

[0153] A pure isomeric form of the compound is defined as an isomer that is substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. Specifically, the terms "stereoisomerically pure" or "chiral pure" refer to compounds having a stereoisomeric excess of at least about 80% (i.e., at least 90% of one isomer and at most 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 "diastereomerically pure" should be understood in a similar manner, taking into account the enantiomeric excess and diastereomeric excess, respectively, of the mixture in question.

[0154] The separation of stereoisomers is achieved by standard methods known to those skilled in the art. One enantiomer of the indazole derivatives of the present invention can be separated to substantially exclude its opposite enantiomer by methods such as the formation of diastereomers using an optically active resolving agent (“Stereochemistry of Carbon Compounds,” (1962) E.L. Eliel, McGraw Hill, Lochmuller, C.H., (1975) J. Chromatogr., 113: (3) 283 - 302). The separation of isomers in a mixture can be achieved by any suitable method including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to pure enantiomers, or (3) the ability of enantiomers to be directly separated under chiral conditions. In method (1), diastereomeric salts can be formed by the reaction of an enantiomerically pure chiral base such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine) with an asymmetric compound having an acidic functionality such as carboxylic acids and sulfonic acids. Diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. The addition of a chiral carboxylic acid or sulfonic acid such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in the formation of diastereomeric salts for the separation of optical isomers of amino compounds. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent such as a methyl derivative, followed by separation and hydrolysis of the diastereomers to obtain a free enantiomerically enriched compound.The method for determining optical purity involves preparing chiral esters such as menthyl ester or Mosher's ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165) from a racemic mixture, purifying by, and analyzing the NMR spectrum for the presence of two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal and reverse phase chromatography according to the method for the separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96 / 15111). In method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, especially cellulose or amylose derivatives. Commercially available polysaccharide-based chiral stationary phases are 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 the polysaccharide chiral stationary phase are hexane etc. modified with alcohols such as ethanol, 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).

[0155] The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of substituents on the cyclic moiety. The absolute stereochemical configuration of the compounds of the formulas described herein can be readily determined by one of ordinary skill in the art using well-known methods such as, for example, X-ray diffraction.

[0156] When a compound crystallizes from solution or slurry, it can crystallize in different spatial lattice arrangements (this property is called "polymorphism") and form crystals with different crystal morphologies, each of which is known as a "polymorph". Thus, the term "polymorph" as used herein refers to the crystal form of the compound of formula (I), where the molecules are localized at three-dimensional lattice sites. Different polymorphs of the compound of formula (I) can differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, mode of accumulation, fluidity, and / or solid-state stability.

[0157] The indazole derivatives of the present invention and their physiologically acceptable salts (hereinafter collectively referred to as the active ingredients) can be administered by any suitable route appropriate for the condition being treated, including oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intranasal, intravenous, intraarterial, intracutaneous, intrathecal, and epidural). The preferred route of administration can vary, for example, depending on the condition of the recipient.

[0158] In particular, for the treatment of TRPM3-mediated disorders in humans and other mammals, or animals, a therapeutically effective amount of the compound for the preparation of the compound is preferably the amount that inhibits the TRPM3 ion channel of the compound as defined herein and corresponds to the amount that ensures a plasma level of 1 μg / ml to 100 mg / ml.

[0159] A suitable dosage of the compound or composition of the present invention should be used to treat or prevent TRPM3-mediated disorders in a subject. Depending on the pathological condition being treated and the condition of the patient, the effective amount can be divided into several subunits per day or administered at intervals over more than one day.

[0160] The present invention further provides a (pharmaceutical) composition comprising one or more indazole derivatives of the present invention, more specifically, all formulas (I) and other formulas and embodiments described herein, and more specific aspects or embodiments thereof. Further, the present invention provides the compounds or (pharmaceutical) compositions of the present invention, more specifically, all formulas (I) and other formulas and embodiments described herein, and more specific aspects or embodiments thereof, for use as a drug, more specifically, for use in the treatment of pain. The TRPM3-mediated disorder is selected from pain and inflammatory hypersensitive conditions and epilepsy.

[0161] The indazole derivatives of the present invention can be formulated with conventional carriers and excipients, which are selected according to normal practice. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and are generally isotonic when intended for delivery other than oral administration. The formulations optionally contain excipients as described in "Handbook of Pharmaceutical Excipients" (1986).

[0162] Thereafter, the term "pharmaceutically acceptable carrier" as used herein means any material or substance in which the active ingredient is formulated to facilitate, for example, the application or dispersion of the composition to the site to be treated by dissolving, dispersing, or diffusing it, and / or to facilitate its storage, transport, or handling without impairing its effectiveness. A pharmaceutically acceptable carrier can be a solid, 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, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets, or powders.

[0163] Suitable pharmaceutical carriers for use in the pharmaceutical composition and its formulations are well-known to those skilled in the art and are not particularly limited in their selection within the present invention. They may also include additives such as wetting agents, dispersants, stickers, adhesives, emulsifiers, surfactants, solvents, coating agents, antibacterial and antifungal agents, and isotonic agents, provided that they are compatible with pharmaceutical practice, i.e., carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present invention can be prepared by any known method, for example, by uniformly mixing, coating, and / or grinding the selected carrier material and, optionally, other additives such as surfactants with the active ingredient in a one-step or multi-step procedure. They can also be prepared by micronization to obtain them in the form of microspheres having a diameter of usually about 1 to 10 gm, for example, for the production of microcapsules for the controlled or sustained release of the active ingredient.

[0164] Indazole derivatives can be administered alone, but it is preferred that they be presented as pharmaceutical formulations. The formulations of the present invention for both veterinary and human use include, as described above, at least one active ingredient together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic components. The carrier is "acceptable" in the sense that it is most preferably compatible with the other ingredients of the formulation and not harmful to its recipient. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well-known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, or a finely divided solid carrier, or both, and, if necessary, shaping the product.

[0165] The pharmaceutical preparations of the present invention suitable for oral administration may be presented as individual units, such as capsules, cachets, or tablets, each 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 liquid emulsions. The active ingredient may also be presented as a bolus, a lozenge, or a paste.

[0166] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in free-flowing form, such as a powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, a preservative, a surfactant, or a dispersing agent. Molded tablets can be produced by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can optionally be coated or scored and formulated to provide for slow or controlled release of the active ingredient therein. In the case of infections of the eye or other external tissues, such as the mouth and skin, the preparation may be applied optionally as a topical ointment or cream containing the active ingredient in an amount, for example, of from 0.075 to 20 w / w% (ranging from 0.1% to 20% in increments of 0.1 w / w% such as 0.6 w / w%, 0.7 w / w%, etc.), preferably from 0.2 to 15 w / w%, most preferably from 0.5 to 10 w / w%. When formulated in an ointment, the active ingredient can be used with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream having an oil-in-water cream base. Optionally, the aqueous phase of the cream base can contain, for example, at least 30 w / w% of a polyhydric alcohol, i.e., an alcohol 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. The topical preparation may desirably contain a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0167] The oily phase of the emulsion of the present invention can be composed of known components by known methods. The phase can simply contain an emulsifier (also known as an emulgent), but preferably contains a mixture of at least one emulsifier and a fat or an oil, or a mixture with both fats and oils. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to contain both oils and fats. With or without a stabilizer, the emulsifiers together constitute a so-called emulsifying wax, and the wax, together with the oils and fats, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0168] Due to the very low solubility of the active compound in most oils that are likely to be used in pharmaceutical emulsion formulations, the selection of a suitable oil or fat for the formulation is based on achieving the desired cosmetic properties. Thus, the cream should be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight-chain or branched-chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched-chain esters known as Crodamol CAP can be used, with the last three being preferred esters. These can 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 can be used.

[0169] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally 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 oral cavity usually include lozenges containing the active ingredient in a flavoring base such as sucrose and acacia or tragacanth; troches containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0170] Formulations for rectal administration can be presented, for example, as suppositories using a suitable base containing cocoa butter or salicylate. Formulations suitable for nasal administration where the carrier is solid are administered in a manner of sniffing tobacco, i.e., by rapid inhalation through the nasal cavity from a container of powder maintained close to the nose, and include, for example, a coarse powder having a particle size in the range of 20 to 500 microns (including particle sizes in the range of 20 to 500 microns in 5-micron units such as 30 microns, 35 microns, etc.). Formulations suitable for administration as a nasal spray or as nasal drops where the carrier is liquid include an aqueous or oily solution of the active ingredient. Formulations suitable for aerosol administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents.

[0171] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, a carrier known in the art to be suitable.

[0172] Compositions suitable for parenteral administration may include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents. 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 (i.e., lyophilized) state which requires only the addition of a sterile liquid carrier (e.g., water) immediately prior to use. Immediate injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the above-described types.

[0173] Preferred unit dose formulations contain the daily dose or unitary sub-dose of the active ingredient, or an appropriate fraction thereof, as hereinabove described.

[0174] It should be understood that, in addition to the particularly mentioned ingredients, the formulations of the present invention may include other conventional agents of the art, taking into account the type of formulation in question (e.g., those suitable for oral administration may include flavoring agents).

[0175] Using the indazole derivatives of the present invention, controlled release pharmaceutical formulations (the "controlled release formulations") containing one or more indazole derivatives of the present invention as the active ingredient can be provided, and the release of the active ingredient can be controlled and adjusted to allow for less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given compound of the present invention. Controlled release formulations adapted for oral administration in separate units containing one or more indazole derivatives of the present invention can be prepared according to conventional methods.

[0176] Another embodiment of the present invention relates to various precursors or "prodrug" forms of the indazole derivatives of the present invention. The indazole derivatives of the present invention are not significantly biologically active per se, but when delivered to an animal, mammal, or human, they undergo chemical reactions catalyzed by enzymes present in the normal functions of the body, particularly in the stomach or serum, and it may be desirable to formulate such chemical reactions in the form of chemical species that have the effect of releasing the compounds defined herein. Thus, the term "prodrug" relates to these species that are converted to the active pharmaceutical ingredient in vivo.

[0177] The prodrugs of the indazole derivatives of the present invention can have any form suitable for a formulation. For example, esters are a non-limiting general prodrug form. However, in this case, the prodrug can necessarily exist in a form in which the covalent bond is cleaved by the action of an enzyme present at the target site. For example, a C-C covalent bond can be selectively cleaved by one or more enzymes at the target site, and thus prodrugs in forms other than easily hydrolyzable precursors, especially esters, amides, etc., can be used. The counterpart of the active pharmaceutical ingredient in the prodrug can have different structures such as amino acid or peptide structures, alkyl chains, sugar moieties, etc., as known in the art.

[0178] For the purposes of the present invention, the term "therapeutically suitable prodrug" is defined herein as "a compound that is converted in vivo to a therapeutically active form by one or more biological conversions when in contact with the tissues of an animal, mammal, or human to which the prodrug has been administered, and is modified to achieve the intended therapeutic outcome without undue toxicity, irritation, or allergic reaction."

[0179] More specifically, as used herein, the term "prodrug" relates to an inactive or significantly less active derivative of a compound represented by the structural formulas described herein that undergoes spontaneous or enzymatic conversion reactions in the body to release the pharmacologically active form of the compound. For a comprehensive overview, see Rautio J. et al. ("Prodrugs: design and clinical applications" Nature Reviews Drug Discovery, 2008, doi:10.1038 / nrd2468).

[0180] Representative indazole derivatives of the present invention are described below and can be synthesized according to the general synthetic methods exemplified in the following schemes. Since the schemes are illustrative, the present invention should not be construed as being limited by the specific chemical reactions and specific conditions described in the schemes and examples. The various starting materials used in the schemes can be commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein and are within the scope of the skill of those skilled in the art.

[0181] Exemplary embodiments of the present invention are summarized as the following clauses 1 to 51. 1. A compound of formula (I), its stereoisomeric forms, physiologically acceptable salts, solvates, and / or polymorphs,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Examples

[0182] The following examples are provided to further illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0183] Representative compounds of the present invention can be synthesized according to the general synthetic methods described below and are exemplified in the following schemes. Since the schemes are illustrative, the present invention should not be construed as being limited by the specific chemical reactions and specific conditions described in the schemes and examples. The various starting materials used in the schemes are either commercially available or can be prepared by methods well known to those skilled in the art. The variables are as defined herein and are within the skill level of those skilled in the art.

[0184] In this specification, the abbreviations used, particularly in the schemes and examples, are as follows. ABC - aqueous solution of ammonium bicarbonate, ACN - acetonitrile, AcOH - acetic acid, ADDP - 1,1'-(azodicarbonyl)dipiperide, aq. - aqueous, AIBN - azobisisobutyronitrile, CAN - cerium(IV) ammonium nitrate, COMU - (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium, hexafluorophosphate, DABCO - 1,4-diazabicyclo[2.2.2]octane, DAST - diethylaminosulfur trifluoride, DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene, DCC - N,N'-dicyclohexylcarbodiimide, DCM - dichloromethane, DEAD - diethyl azodicarboxylate, DIA - diastereomer, DIAD - diisopropyl azodicarboxylate, DEA - diethylamine, DIPEA - diisopropyl-ethylamine, DME - 1,2-dimethoxyethane, DMF - N,N-dimethylformamide, DMSO - dimethyl sulfoxide, DPPA - diphenylphosphoryl azide, DTBAD - tert-butyl azodicarboxylate, EDCI or EDC - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, En - enantiomer, Et2O - diethyl ether, EtOH - ethanol, EtOAc - 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 - leaving group, MeOH - methanol, MgSO4 - magnesium sulfate, min. - minute, Ms - methanesulfonyl, Na 2 SO 4- Sodium sulfate, NBS - N - bromosuccinimide, nBuLi - n - butyllithium, 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 - diisopropylethylamine supported on polystyrene, PS - PPh3 - triphenylphosphine supported on polystyrene, PyBop - benzotriazol - 1 - yloxytrypyrrolidinophosphonium hexafluorophosphate, PTSA - p - toluenesulfonic acid, RF: ratio of frontiers, 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 fluoride hydrate, TBAI - tetrabutylammonium iodide, TEA - triethylamine, THF - tetrahydrofuran, TFA - trifluoroacetic acid, TLC - thin layer chromatography, TPP - triphenylphosphine, IPA - isopropyl alcohol, TMS - trimethylsilyl, T3P - propylphosphonic anhydride.

[0185] The subject compounds having the structures according to the general formula (A) and all other general formulas described herein and their embodiments can be prepared as outlined in General Chemical Scheme 1.

Chemical formula

[0186] Scheme 1: All V, R 1 , R 3 , R 4 , and R 5 are as described for the compounds of the present invention. In each occurrence of R 5 , up to two independent substituents are contemplated (i.e., R5 and R 5’ )。

[0187] The 5-iodo-1H-indazole-3-carboxylic acid of Formula 1 can be converted to the intermediate of Formula 3 via a nucleophilic substitution reaction at a temperature in the range of 0 to 100 °C in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs 2 CO 3 etc.) in a polar solvent (e.g., acetonitrile, DMF, NMP, etc.) using an intermediate of Formula 2 (commercially available or synthetic) (where LG is a leaving group (e.g., halide, sulfonic acid ester, etc.)), with or without a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.). The compound of Formula 3 can be reacted with a boron reagent (e.g., bis(pinacolato)diboron, etc.) under cross-coupling reaction conditions at a temperature from room temperature to reflux in the presence of a metal catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc.) and a base (e.g., K 2 CO 3 , potassium acetate, etc.) in a solvent (e.g., DMF, dioxane, etc.) to obtain the intermediate of Formula 4. Subsequently, the alcohol derivative 5 can be obtained from Intermediate 4 via oxidative cleavage of the boron ester in the presence of an oxidizing agent (e.g., Oxone, etc.) and water in a solvent (e.g., acetone, etc.). Then, the intermediate of Formula 5 can be obtained using an intermediate of Formula 6a (commercially available or synthetic) (wherein LG is a leaving group (e.g., halide, sulfonic acid ester, etc.)) in a polar solvent (e.g., acetonitrile, DMF, NMP, and the like) in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs 2 CO 3In the presence of, for example, a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.), it can be converted to the desired compound of formula 7 via a nucleophilic substitution reaction at a temperature ranging from 0 to reflux, with or without the chelating agent. Alternatively, the intermediate of formula 5 can be reacted with an intermediate of formula 6b (commercially available or synthesized) in a solvent (e.g., THF, toluene, etc.) in the presence of an azodicarboxylate reagent (e.g., DEAD, DIAD, ADDP, etc.) and a phosphine (e.g., tributylphosphine, triphenylphosphine, etc.) at a temperature in the range of 0 to 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 via a standard saponification reaction. The desired compound of formula 10 can be obtained from the acid derivative of formula 8 by reaction with an 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 coupling 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 procedures of the following examples, and then reacted with the amine of formula 9 by procedures known to those skilled in the art or as described in the procedures of the following examples to obtain the desired compound of formula 10. [Chemical Formula]

[0188] Scheme 2: All V, n, R 1 , R 3 , R 4 , and R 5 are as described for the compounds of the present invention. For each occurrence of R 5 , a maximum of two independent substituents are contemplated (i.e., R 5 and R 5’ ). The integer n can range from 1 to 10 in some embodiments.

[0189] In an alternative embodiment, the 5-iodo-1H-indazole-3-carboxylic acid of formula 11 is converted to the intermediate of formula 13 via a nucleophilic substitution reaction at a temperature in the range of 0 to 100 °C, with or without a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.), in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs 2 CO 3 etc.) using an intermediate of formula 12 (commercially available or synthetic, where LG is a leaving group (e.g., halide, sulfonate ester, etc.)) in a polar solvent (e.g., acetonitrile, DMF, NMP, etc.). The compound of formula 13 can be reacted with a boron reagent (e.g., bis(pinacolato)diboron, etc.) under cross-coupling reaction conditions at a temperature from room temperature to reflux in the presence of a metal catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc.) and a base (e.g., K 2 CO 3 , potassium acetate, etc.) in a solvent (e.g., DMF, dioxane, etc.) to obtain the intermediate of formula 14. Subsequently, the alcohol derivative 15 can be obtained from the intermediate 14 via oxidative cleavage of the boron ester in the presence of an oxidizing agent (e.g., Oxone, etc.) and water in a solvent (e.g., acetone, etc.). Then, the intermediate of formula 15 is prepared using an intermediate of formula 16a (commercially available or synthetic, where LG is a leaving group (e.g., halide, sulfonate ester, etc.)) in a polar solvent (e.g., acetonitrile, DMF, NMP, and the like) in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs 2 CO 3In the presence of a chelating agent (e.g., 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.), with or without a chelating agent, it can be converted to the desired compound of formula 17 via a nucleophilic substitution reaction at a temperature ranging from 0 to reflux. Alternatively, the intermediate of formula 15 can be reacted with an intermediate of formula 16b (commercially available or synthesized) in a solvent (e.g., THF, toluene, etc.) in the presence of an azodicarboxylate reagent (e.g., DEAD, DIAD, ADDP, etc.) and a phosphine (e.g., tributylphosphine, triphenylphosphine, etc.) at a temperature in the range of 0 to 100 °C to obtain the desired compound of formula 17. Subsequently, the ester derivative 17 can be converted to the desired compound of formula 18 via a standard saponification reaction. The desired compound of formula 20 can be obtained from the acid derivative of formula 18 by reaction with an amine derivative of formula 19 (commercially available or synthesized by procedures known in the art or as described in the following examples) under standard peptide coupling 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 18 can be converted to an acid chloride derivative by procedures known to those skilled in the art or as described in the procedures of the following examples, and then reacted with an amine of formula 19 by procedures known to those skilled in the art or as described in the procedures of the following examples to obtain the desired compound of formula 20.

Table 3-1

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Table 3-3

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Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

[0190] The following examples are provided to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0191] Part A represents the preparation of the compound, and Part B represents the pharmacological examples.

[0192] Part A All starting materials not explicitly described are either commercially available (e.g., details of suppliers such as ABCR, Apollo Scientific Combi-Blocks, Enamine, FluoroChem, Matrix Scientific, Maybridge, Merck, TCI can be found, for example, in the SciFinder® database), or their synthesis is already accurately described in the specialized literature (e.g., 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.

[0193] The reactions were carried out under an inert atmosphere (mainly argon and N 2 ) if necessary. The number of equivalents of the reagents and the amount of solvent used, as well as the reaction temperature and time, may vary slightly between different reactions carried out by similar methods. The processing and purification methods are adapted according to the characteristic properties of each compound and may vary slightly in similar methods. The yields of the prepared compounds have not been optimized.

[0194] The designation "equivalent" ("eq.", "eq", or "equiv.") means molar equivalent, "RT" or "rt" means room temperature T (23 ± 7 °C), "M" is the indication of concentration in mol / l, "sol." means solution, and "conc." means concentrated. The mixing ratio of solvents is usually expressed as volume / volume ratio.

[0195] The main analytical characterizations were carried out for all exemplary compounds and selected intermediates 1 by 1H-NMR spectroscopy and / or mass spectrometry (MS, m / z for [M+H] + and / or [M−H] - . In certain cases, for example, when positional isomers and / or diastereomers could have been / have been formed during the reaction, for example, 13Additional analyses such as 13C NMR and NOE (Nuclear Overhauser Effect) NMR experiments were sometimes carried out.

[0196] The analytical instruments used were, for example, for NMR analysis, BRUKER 400MHz or BRUKER 500MHz machines (software Topspin), alternatively, BRUKER AVANCE 300MHz and 400Mhz were used. For LC / MS analysis, for example, Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI), or Agilent 1200 SERIES, Mass: 6130 SQD (ESI / APCI) (software Chemistation) were used. Analytical HPLC was measured with, for example, Waters (software Empower), Agilent-1200-ELSD (software Chemistation), or Agilent-1260 (software OpenLAB). Analytical SFC was carried out with, for example, PIC solution (software: SFC PICLAB ONLINE), WATERS-X5 (software MASSLYNX), or WATERS-UPC2 (Empower).

[0197] Preparative HPLC was carried out with, for example, Waters 2998 (software Empower) or YMC (software K-Prep). Preparative SFC was carried out with, for example, Waters, SFC-200 (software Chromscope or Super chrome), Waters, SFC-80 (Super chrome), or PIC, PIC-175 (software S10-100).

[0198] The structures of exemplary compounds containing a stereocenter, when known, are depicted and named with the absolute stereochemistry. In the case of unknown absolute stereochemistry, the compound can be either a racemate, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia1 and Dia2 mean that the diastereoisomers were separated, but the stereochemistry is unknown. En1 and En2 mean that both enantiomers were separated, but the absolute configuration is unknown. When no suffix is attached after the compound code, it means that the compounds containing a stereocenter were obtained as a racemic mixture or a mixture of diastereomers respectively, unless the chemical name of the compound specifies the exact stereochemistry.

[0199] Synthesis of methyl 5-hydroxy-2-methyl-2H-indazole-3-carboxylate (Int-01). [Chemical formula]

[0200] Step 1: To a stirred solution of (5-iodo-1H-indazole-3-carboxylic acid (36 g, 0.12 mol) in DMF (500 ml), K 2 CO 3 (86.38 g, 0.625 mol) was added, followed by methyl iodide (23.5 ml, 0.375 mol) at room temperature. The RM was stirred at 80 °C for 4 h. The RM was filtered through a celite bed and washed with EtOAc (3 × 100). The filtrate was poured into ice water and the resulting aqueous solution was extracted with EtOAc (3 × 700 ml). The combined organic layers were washed with water (2 × 350 ml), followed by brine (350 ml), dried over anhydrous Na 2 SO 4 and concentrated to give a crude product. The crude product was purified by FCC (silica gel 100 - 200 mesh, using 15% EtOAc in hexane as the eluent) to give methyl 5-iodo-2-methyl-2H-indazole-3-carboxylate. 1H-NMR (400 MHz, CDCl3) δ [ppm]: 8.41 (s, 1H), 7.58 - 7.56 (dd, 1H), 7.52 - 7.50 (d, 1H), 4.48 (s, 3H), 4.03 (s, 3H).

[0201] Step 2: To a stirred solution of methyl 5-iodo-2-methyl-2H-indazole-3-carboxylate (7.5 g, 0.023 mol) in 1,4-dioxane (150 ml) was added bis-pin (8.76 g, 0.0345 mol), followed by potassium acetate (6.77 g, 0.069 mol) at room temperature. The RM was degassed with nitrogen for 10 minutes, then Pd(dppf)Cl2.DCM adduct (0.56 g, 0.00069 mol) was added and heated at 110 °C for 16 hours. The RM was filtered through a Celite bed and washed with EtOAc. The combined filtrate was concentrated to give methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (7.5 g) as a brown solid. 1 H-NMR(400MHz,CDCl 3 )δ [ppm]: 8.50 (s, 1H), 7.72 (s, 2H), 4.51 (s, 3H), 4.05 (s, 3H), 1.25 (s, 12H).

[0202] Step 3: To a stirred solution of methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (7.5 g, 0.023 mol) in acetone (150 ml) was added dropwise a solution of oxone (14.13 g, 0.023 mol) in water (150 ml) at 0 °C. The RM was stirred at 0 °C for 2 hours. The RM was diluted with EtOAc (200 ml). The two layers were separated and the aqueous layer was extracted with EtOAc (200 ml). The combined organic layers were washed with water (150 ml), followed by brine (150 ml), Na 2 SO 4It was dried and concentrated to obtain a crude product. The crude product was purified by FCC (silica gel 100 - 200 mesh, using 30% EA in hexane as the eluent) to obtain methyl 5-hydroxy-2-methyl-2H-indazole-3-carboxylate (Int-01) (2.6 g, 53%) as an off-white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.66 (s, 1H), 7.62 - 7.60 (d, 1H), 7.16 - 7.15 (d, 1H), 6.96 - 6.93 (dd, 1H), 4.35 (s, 3H), 3.93 (s, 3H).

[0203] Synthesis of 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-02).

Chemical Structure

[0204] Step 1: To a stirred solution of 1-(tert-butyl-dimethyl-silanyloxy)-propan-2-one (25 g, 132.7 mmol) in EtOH (250 ml) was added 4-methoxybenzylamine (19.08 ml, 146 mmol) at room temperature. Trimethylsilyl cyanide (19.93 ml, 159.286 mmol) and subsequently ammonium chloride (2.13 g, 39.8 mmol) were added to the RM at room temperature. The RM was stirred at 80 °C for 16 h. The RM was concentrated. The crude product was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated. The crude product was purified by FCC (using 100 - 200 silica gel, eluting with 10% EtOAc - hexane) to obtain 3-(tert-butyl-dimethyl-silanyloxy)-2-(4-methoxy-benzylamino)-2-methyl-propionitrile (25 g, 57%) as a yellow liquid. 1H-NMR (400 MHz, DMSO) δ [ppm]: 7.25 - 7.23 (d, 2H), 6.68 - 6.86 (d, 2H), 3.72 - 3.68 (m, 6H), 3.51 - 3.48 (m, 1H), 1.36 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H).

[0205] Step 2: To a stirred solution of 3-(tert-butyl-dimethyl-silanyloxy)-2-(4-methoxy-benzylamino)-2-methyl-propionitrile (10 g, 29.9 mmol) in DMSO (100 ml) was added potassium carbonate (28.92 g, 209.243 mmol) at room temperature. Hydrogen peroxide (14.03 ml, 298.92 mmol) was added dropwise to the reaction mixture at 0 °C. The RM was stirred at room temperature for 16 h. The RM was quenched with ice-cold water and extracted with MTBE. The organic portion was dried over Na 2 SO 4 and concentrated. The resulting crude material was purified by FCC (using 100 - 200 silica gel, eluting with 50% EtOAc - hexane) to give 3-(tert-butyl-dimethyl-silanyloxy)-2-(4-methoxy-benzylamino)-2-methyl-propionamide (3.4 g, 33%) as an oily liquid. 1 H-NMR (400 MHz, DMSO) δ [ppm]: 7.26 - 7.24 (d, 3H), 7.06 (s, 1H), 6.87 - 6.85 (d, 2H), 3.72 (s, 3H), 3.70 - 3.68 (m, 1H), 3.58 - 3.56 (m, 1H), 3.51 - 3.50 (d, 2H), 2.04 (m, 1H), 1.15 (s, 3H), 0.85 (s, 9H), 0.03 (s, 6H).

[0206] Step 3: To a stirred solution of -(tert-butyl-dimethyl-silanyloxy)-2-(4-methoxy-benzylamino)-2-methyl-propionamide (3 g, 8.509 mmol) in MeOH (60 ml) was added palladium hydroxide (1.5 g) at room temperature. The RM was stirred at room temperature under H 2It was stirred under gas balloon pressure for 4 hours. The RM was filtered through a celite bed and washed with 10% MeOH-DCM. The filtrates were combined and concentrated to give 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-02) (1.5 g, 76%) as an off-white solid. 1 1H-NMR (400 MHz, DMSO) δ [ppm]: 7.25 (s, 1H), 6.95 (s, 1H), 3.77 - 3.74 (d, 1H), 3.70 - 3.68 (m, 1H), 3.27 - 3.24 (d, 1H), 1.82 (s, 2H), 1.04 (s, 3H), 0.85 (s, 9H), 0.02 (s, 6H).

[0207] Synthesis of 5-hydroxy-2-methyl-2H-indazole-3-carboxylic acid (Int-03).

Chemical Structure

[0208] Step 1: To a stirred solution of methyl 5-methoxy-2-methyl-2H-indazole-3-carboxylate (2.5 g, 11.36 mmol, 1.0 equiv) in toluene (100 ml), AlCl3 (4.53 g, 34.09 mmol, 4 equiv) was added at room temperature, and then the reaction mixture was heated to 110 °C for 2 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was distilled under vacuum to give a crude product, which was diluted with ice water (10 ml), then stirred for 10 minutes, filtered, and the precipitated solid was washed with diethyl ether to give 5-hydroxy-2-methyl-2H-indazole-3-carboxylic acid (Int-03) (1.0 g, 47%, off-white solid). TLC system: 60% EtOAc / Pet ether, RF: 0.1.

[0209] Synthesis of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (Int-04).

Chemical Structure

[0210] Step 1: To a stirred solution of methyl 5-methoxy-2-methyl-2H-indazole-3-carboxylate (500 mg, 2.27 mmol) in MeOH:THF (1:1; 20 mL), NaOH (900 mg, 22.72 mmol) in water (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h and the progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), acidified to pH ~1 with 1N aqueous HCl and stirred for 30 min. The solid precipitate was filtered, washed with water (10 mL) and dried under vacuum to give 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (Int-04) (350 mg, crude) as an off-white solid. TLC system: 40% ethyl acetate in pet-ether, Rf: 0.21.

[0211] Synthesis of 2-amino-2-(hydroxymethyl)butanamide (Int-05).

Chemical formula

[0212] Step 1: A mixture of sodium cyanide (4.45 g, 90.90 mmol), ammonium chloride (4.9 g, 90.90 mmol), and ammonia solution (7M in methanol, 120 mL) in methanol (65 ml) was stirred at room temperature for 10 min and then 1-hydroxybutan-2-one (4.0 g, 45.45 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, filtered through a celite bed and the celite bed was washed with methanol (50 mL). The combined filtrates were concentrated under vacuum. Ethyl acetate (80 mL) was added to the residue and the mixture was filtered. The filtrate was concentrated under vacuum. The residue was co-distilled with dichloromethane (2 x 50 mL) to give 2-amino-2-(hydroxymethyl)butanenitrile (4.2 g) as a pale yellow residue. TLC system: 100% ethyl acetate, RF: 0.3.

[0213] Step 2: To a stirred solution of 2-amino-2-(hydroxymethyl)butanenitrile (2.0 g, 17.54 mmol) in ethanol (20 mL) cooled to 0 °C was added KOH (1.47 g, 26.31 mmol), followed by dropwise addition of 30% H 2 O 2 (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC, and the reaction mixture was concentrated under vacuum. The crude product was diluted with 10% methanol in dichloromethane (2 × 50 mL), stirred for 20 min, and filtered. The filtrate was concentrated under reduced pressure to give 2-amino-2-(hydroxymethyl)butanamide (Int-05) (1.8 g) as a thick residue. TLC system: 10% methanol in dichloromethane, RF: 0.1.

[0214] Synthesis of 4,4-difluoro-1-methoxy-2-methylbutan-2-amine hydrochloride (Int-06).

Chemical formula

Claims

1. A compound of formula (I), a stereoisomeric form thereof, a physiologically acceptable salt, solvate, and / or polymorph, wherein 【Chemical 1】 wherein R １ is -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) ２ R 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 and represents R ２ represents -R Ｙ and R ３ represents -OH or -R Ｙ and R ４ is -R Ｙ or -S(=O) ２ R Ｙ represents, or Alternatively, R ３ and R ４ together form a saturated or unsaturated, unsubstituted, or mono- or polysubstituted 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S T represents -O-, and U represents -CR ５ R ５ ’-, or T represents -CR ５ R ５ ’-, and U represents -O- R ５ and R ５ ’ are, independently of each other, -R Ｙ to represent, R ６ 、 R ７ 、 and R ８ are, independently of one another, -F, -Cl, -Br, -I, -CN, -NO ２ 、 -SF ５ 、 -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) ２ R Ｗ 、 -C(=O)R Ｗ 、 -C(=O)OR Ｗ 、 or -C(=O)NR Ｗ R Ｘ represent, V is a saturated or unsaturated 3- to 14-membered heterocycloalkyl, saturated or unsaturated 3- to 14-membered cycloalkyl, 5- to 14-membered aryl, C １ -C ６ alkyl or 5- to 14-membered heteroaryl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, -CF ３ , -CF ２ H, C １ -C ６ alkyl, -CN, -NO, -NO ２ , =O, =S, -SF ５ , -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) ２ R Ｙ , -C(=O)R Ｙ , -C(=O)OR Ｙ , or -C(=O)NR Ｙ R Ｚ and is monosubstituted or polysubstituted with substituents selected from R Ｗ and R Ｘ are each independently, in each case independently, -H; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C １ -C ６ -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C １ -C ６ -heteroalkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), a 3- to 14-membered cycloalkyl; or A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted) and is represented by a 3- to 14-membered heterocycloalkyl connected via R Ｙ and R Ｚ are, independently of each other and in each case independently, -H; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C １ -C ６ -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C １ -C ６ -heteroalkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally, -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted) connected via a 3- to 14-membered cycloalkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally connected via -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted) to a 3- to 14-membered heterocycloalkyl; Unsubstituted, monosubstituted or polysubstituted 6- to 14-membered aryl, wherein the 6- to 14-membered aryl is optionally -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted) connected via a 6- to 14-membered aryl, or A non-replaced, mono-replaced or multi-replaced 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, non-replaced, mono-replaced or multi-replaced) and represents a 5- to 14-membered heteroaryl connected via it, or Alternatively, R Ｙ and R Ｚ together form a saturated or unsaturated, unsubstituted, or mono- or polysubstituted 4-, 5-, 6-, 7- or 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S, Here, "monosubstituted or polysubstituted" in each case independently represents -F, -Cl, -Br, -I, -CN, -C １－６ -alkyl, -CF ３ 、-CF ２ H, -CFH ２ 、-CF ２ Cl, -CFCl ２ 、-C １－６ -alkylene-CF ３ 、-C １－６ -alkylene-CF ２ H, -C １－６ -alkylene-CFH ２ 、-C １－６ -alkylene-O-CF ３ 、-C １－６ -alkylene-O-CF ２ H, -C １－６ -alkylene-O-CFH ２ 、-C １－６ -alkylene-NH-C １－６ -alkylene-CF ３ 、-C １－６ -alkylene-N(C １－６ -alkyl)-C １－６ -alkylene-CF ３ 、-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-CF ３ 、-C(=O)-NH ２ 、-C １－６ -alkylene-C(=O)-NH ２ 、-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, -OCF ３ , -OCF ２ H, -OCFH ２ , -OCF ２ Cl, -OCFCl ２ , -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-NH ２ , -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 , -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 -NH ２ , -C １－６ -alkylene-O-S(=O) ２ -NH ２ , -O-S(=O) ２ -NH(C １－６ -alkyl), -C １－６ -alkylene-O-S(=O) ２ -NH(C １－６ -alkyl), -O-S(=O) ２ -N(C １－６ -alkyl) ２ , -C １－６ -alkylene-O-S(=O) ２ -N(C １－６ -alkyl) ２ , -NH ２ , -NO, -NO ２ , -C １－６ -alkylene-NH ２ , -NH(C １－６ -alkyl), -N(3- to 14-membered 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)-O-C １－６ -alkyl, -C １－６ -alkylene-NH-C(=O)-O-C １－６ -alkyl, -NH-C(=O)-NH ２ , -C １－６ -alkylene-NH-C(=O)-NH ２ , -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 , -N(C １－６ -alkyl)-C(=O)-O-C １－６ -alkyl, -C １－６ -alkylene-N(C １－６ -alkyl)-C(=O)-O-C １－６ , -N(C １－６ -alkyl)-C(=O)-NH ２ , -C １－６ -alkylene-N(C １－６ -alkyl)-C(=O)-NH ２ , -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 , -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) ２ OH, -C １－６ -alkylene-NH-S(=O) ２ OH, -NH-S(=O) ２ , -C １－６ -alkyl, -C １－６ -alkylene-NH-S(=O) ２ , -C １－６ , -NH-S(=O) ２ , -O-C １－６ , -C １－６ -alkylene-NH-S(=O) ２ , -O-C １－６ , -alkyl, -NH-S(=O) ２ , -NH ２ , -C １－６ -alkylene-NH-S(=O) ２ -NH ２ 、-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) ２ N(C １－６ -alkyl) ２ 、-C １－６ -alkylene-NH-S(=O) ２ N(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 -O-C １－６ -alkyl、-C １－６ -alkylene-N(C １－６ -alkyl)-S(=O) ２ -O-C １－６ -alkyl、-N(C １－６ -alkyl)-S(=O) ２ -NH ２ 、-C １－６ -alkylene-N(C １－６ -alkyl)-S(=O) ２ -NH ２ 、-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, -SF ５ , -SCF ３ , -SCF ２ H, -SCFH ２ , -S-C １－６ -alkyl, -C １－６ -alkylene-S-C 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 , -S(=O)-OH, -C １－６ -alkylene-S(=O) ２ , -S(=O)-OH ２ , -S(=O)-O-C １－６ -alkyl, -C １－６ -alkylene-S(=O) ２ , -S(=O)-O-C １－６ -alkyl, -S(=O) ２ , -S(=O)-NH ２ , -C １－６ -alkylene-S(=O) ２ , -S(=O)-NH ２ , -S(=O) ２ , -S(=O)-NH(C １－６ -alkyl), -C １－６ -alkylene-S(=O) ２ , -S(=O)-NH(C １－６ -alkyl), -S(=O) ２ , -S(=O)-N(C １－６ -alkyl) ２ , -C １－６ -alkylene-S(=O) ２ , -S(=O)-N(C １－６ -alkyl) ２ , 3- to 14-membered cycloalkyl, -C １－６ -alkylene-(3- to 14-membered cycloalkyl), 3- to 14-membered heterocycloalkyl, -C １－６ -alkylene-(3- to 14-membered heterocycloalkyl), -phenyl, -C １－６ -alkylene-phenyl, 5- to 14-membered heteroaryl, -C １－６ -alkylene-(5- to 14-membered heteroaryl), -O-(3- to 14-membered cycloalkyl), -O-(3- to 14-membered heterocycloalkyl), -O-phenyl, -O-(5- to 14-membered heteroaryl), -C(=O)-(3- to 14-membered cycloalkyl), -C(=O)-(3- to 14-membered heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5- to 14-membered heteroaryl), -S(=O) ２ -(3- to 14-membered cycloalkyl), -S(=O) ２ -(3- to 14-membered heterocycloalkyl), -S(=O) ２ -phenyl, -S(=O) ２ - (5- to 14-membered heteroaryl), which means being substituted with one or more substituents independently selected from each other, a compound, its stereoisomeric forms, physiologically acceptable salts, solvates, and / or polymorphs.

2. R ３ The compound according to claim 1, wherein R represents -H.

3. R ４ The compound according to claim 2, wherein R represents a residue other than -H.

4. R １ The compound according to any one of claims 1 to 3, wherein R represents -methyl or ethyl.

5. T represents -O-, and U represents -CR ５ R ５ '- and the compound according to any one of claims 1 to 3.

6. R ５ and R ５’ each of the said Rs representing Ｙ is H, a compound according to any one of claims 1 to 5.

7. V is a 5- to 14-membered heteroaryl selected from (i) benzimidazole, benzisoxazole, benzazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, 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, and in each case, unsubstituted, independently of one another, -F, -Cl, -CN, -OH, =O, -C １－６ -alkyl, -CHF ２ , -CF ３ , -C １－６ -alkylene-NH ２ , -C １－６ -alkylene-NHC(=O)O-C １－６ -alkyl, -C １－６ -alkylene-OH, -C １－６ -alkylene-CHF ２ , -C １－６ -alkylene-CF ３ , -C １－６ -alkylene-cyclopropyl, -cyclopropyl, -O-cyclopropyl, -C １－６ -alkylene-NHC(=O)-O-C １－６ -alkyl, -C(=O)O-C １－６ -alkyl, -N(C １－６ -alkyl) ２ , -OC １－６ -alkyl, -OCF ３ , -O-C 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 monosubstituted or polysubstituted with a substituent selected from -piperazine substituted with -alkyl, especially in any case unsubstituted, independently of each other, -F, -Cl, -CN, -OH, =O, -C １－６ -alkyl, -CHF ２ -CF ３ -C １－６ -alkylene-NH ２ -C １－６ -alkylene-NHC(=O)O-C １－６ -alkyl, -C １－６ -alkylene-OH, -C １－６ -alkylene-NHC(=O)-O-C １－６ -alkyl, -C(=O)O-C １－６ -alkyl, -N(C １－６ -alkyl) ２ -OC １－６ -alkyl, -OCF ３ -O-C 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 represents a 5- to 14-membered heteroaryl monosubstituted or polysubstituted with a substituent selected from -piperazine substituted with -alkyl, or (ii) represents unsubstituted, monosubstituted or polysubstituted -oxetanyl, the compound according to any one of claims 1 to 6.

8. The saturated or unsaturated 3- to 14-membered cycloalkyl within the definition of V is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, including non-condensed or non-bridged, condensed, or bridged cycloalkyl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I,, CF ３ , -CF ２ H, C １ -C ６ alkyl, -CN, -NO, -NO ２ , =O, =S, -SF ５ , -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) ２ R Ｙ , -C(=O)R Ｙ , -C(=O)OR Ｙ , or -C(=O)NR Ｙ R Ｚ The compound according to any one of claims 1 to 6, which is mono-substituted or multi-substituted with substituents selected from

9. The 5- to 14-membered aryl within the definition of V is unsubstituted or, independently of one another, is mono- or polysubstituted with substituents selected from -F, -Cl, -Br, -I, CF ３ , -CF ２ H, C １ -C ６ alkyl, -CN, -NO, -NO ２ , =O, =S, -SF ５ , -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) ２ R Ｙ , -C(=O)R Ｙ , -C(=O)OR Ｙ , or -C(=O)NR Ｙ R Ｚ and is phenyl or another 5- to 14-membered aryl, and is a compound according to any one of claims 1 to 6 which is mono- or polysubstituted with substituents selected from the above.

10. The 3- to 14-membered heterocycloalkyl within the definition of V is selected from azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxane, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 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, hexahydro-cyclopenta[c]pyrrole, octahydro-cyclopenta[c]pyrrole, and octahydro-pyrrolo[1,2-a]pyrazine, and in each case, unsubstituted or, independently of one another, mono- or polysubstituted with substituents selected from -F, -Cl, -Br, -I, CF ３ 、 -CF ２ H, C １ -C ６ alkyl, -CN, -NO, -NO ２ 、 =O, =S, -SF ５ 、 -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) ２ R Ｙ 、 -C(=O)R Ｙ 、 -C(=O)OR Ｙ 、 or -C(=O)NR Ｙ R Ｚ and is mono- or polysubstituted with substituents selected from, a compound according to any one of claims 1 to 6.

11. V is saturated or unsaturated, unsubstituted, and independently of one another, -F, -Cl, -Br, -I, CF ３ , -CF ２ H, C １ , -C ６ alkyl, -CN, -NO, -NO ２ , =O, =S, -SF ５ , -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) ２ R Ｙ , -C(=O)R Ｙ , -C(=O)OR Ｙ , or -C(=O)NR Ｙ R Ｚ and is monosubstituted or polysubstituted with substituents selected from -C １ -C ６ alkyl or C １ -C ６ heteroalkyl, a compound according to any one of claims 1 to 6.

12. The compound according to any one of claims 1 to 6, wherein V is a residue selected from the group consisting of 【Chemical 2】

13. R １ is -H, -F, -Cl, -Br, -I, -C １－６ -alkyl, -O-C １－６ -alkyl, -C １－６ -alkylene-O-C １－６ -alkyl, -C １－６ -alkylene-NH(C １－６ -alkyl), -C １－６ -alkylene-N(C １－６ -alkyl) ２ , -CF ３ , -CF ２ H, -CFH ２ , -CF ２ Cl, -CFCl ２ , -C １－６ -alkylene-CF ３ , -C １－６ -alkylene-CF ２ H, -C １－６ -alkylene-CFH ２ , -C １－６ -alkylene-NH-C １－６ -alkylene-CF ３ , -C １－６ -alkylene-N(C １－６ -alkyl)-C １－６ -alkylene-CF ３ , -C(=O)C １－６ -alkyl, -C(=O)OC １－６ -alkyl, -C(=O)NH ２ , -C(=O)NH-C １－６ -alkyl, -C(=O)N(C １－６ -alkyl) ２ , -S(=O)-C １－６ -alkyl, -S(=O) ２ -C １－６ -alkyl, -O-C １－６ -alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl, the compound according to claim 1.

14. R ３ is -H, -OH, -C １－６ -alkyl, -C １－６ -alkylene-OH, -C １－６ -alkylene-O-C １－６ -alkyl, -C １－６ -alkylene-NH ２ , -C １－６ -alkylene-NH(C １－６ -alkyl), -C １－６ -alkylene-N(C １－６ -alkyl) ２ , -CF ３ , -CF ２ H, -CFH ２ , -CF ２ Cl, -CCl ２ , -C １－６ -alkylene-CF ３ , -C １－６ -alkylene-CF ２ H, -C １－６ -alkylene-CFH ２ , -C １－６ -alkylene-NH-C １－６ -alkylene-CF ３ , or -C １－６ -alkylene-N(C １－６ -alkyl)-C １－６ -alkylene-CF ３ The compound according to claim 1, wherein it represents

15. R ４ is -H; Saturated, unsubstituted, monosubstituted or polysubstituted with -F -S(=O) ２ C １－６ -alkyl; Saturated, unsubstituted —S(=O) ２ (3- to 14-membered cycloalkyl); Saturated, unsubstituted, monosubstituted or polysubstituted -C １－６ -alkyl; Each of unsubstituted, mono-substituted, or multi-substituted 3- to 14-membered cycloalkyl or -C １－６ -alkylene-(3- to 14-membered cycloalkyl); Unsubstituted, monosubstituted, or polysubstituted 3- to 14-membered heterocycloalkyl or -C １－６ -alkylene-(3- to 14-membered heterocycloalkyl); Each of unsubstituted, mono-substituted, or multi-substituted, -phenyl, or -C １－６ -alkylene-phenyl; or Each unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl or -C １－６ -alkylene-(5- to 14-membered heteroaryl), the compound according to any one of claims 1 to 14.

16. R ４ is a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl (preferably 3, 4, 5 or 6-membered cycloalkyl), wherein the 3- to 14-membered cycloalkyl is a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ -alkylene- connected 3- to 14-membered cycloalkyl; or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (preferably 4, 5 or 6-membered heterocycloalkyl), wherein the 3- to 14-membered heterocycloalkyl is a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ -alkylene- connected 3- to 14-membered heterocycloalkyl; or an unsubstituted, monosubstituted or polysubstituted 6- to 14-membered aryl (preferably 6-membered aryl), wherein the 6- to 14-membered aryl is a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ -alkylene- connected 6- to 14-membered aryl; or an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl (preferably 5- or 6-membered heteroaryl), wherein the 5- to 14-membered heteroaryl is a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ -alkylene- connected 5- to 14-membered heteroaryl, a compound according to any one of claims 1 to 14.

17. R ３ is H, and R ４ is a residue selected from the group consisting of the following, the compound according to any one of claims 1 to 16. 【Chemical Formula 3-1】 【Chemical Figure 3-2】

18. R ３ and R ４ together form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, morpholine, and piperazine, and in each case, unsubstituted, independently of one another, -F, -C １－６ -alkyl, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)NH-C １－６ -alkyl, -C(=O)N(C １－６ -alkyl) ２ , -C(=O)O-C １－６ -alkyl, -NH-C(=O)O-C １－６ -alkyl, -unsubstituted pyridyl, and 1,2,4-oxadiazole mono- or polysubstituted with a substituent selected from the group consisting of unsubstituted or -C １－６ -alkyl mono-substituted 1,2,4-oxadiazole, the compound according to claim 1.

19. R ５ and R ５ ’ are each independently -H; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C １ -C ６ -alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C １ -C ６ -heteroalkyl; A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally -C １ -C ６ -alkylene- or -C １ -C ６ -heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted) and is connected via a 3- to 14-membered cycloalkyl as claimed in claim 1.

20. R ６ , R ７ , and R ８ are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -SH, -SF ５ , -CN, -NO ２ , -C(=O)OH, -NH ２ , -C １－６ -alkyl, -CF ３ -, -CHF ２ -, -CH ２ F, -O-C １－６ -alkyl, -OCF ３ -, OCHF ２ -, OCH ２ F, Non-replaced, or independently of each other, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ substituted with one or more substituents selected from -NHC １－６ -alkyl; Non-replaced, or independently of each other, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ substituted with one or more substituents selected from -N(C １－６ -alkyl) ２ ; Non-replaced, or independently of each other, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ substituted with one or more substituents selected from -C(=O)OC １－６ -alkyl; Non-replaced or independently of each other, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ substituted with one or more substituents selected from -OC(=O)C １－６ -alkyl; or Unsubstituted or, independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ substituted with one or more substituents selected from -C １－６ -heteroalkyl, the compound according to any one of claims 1 to 19.

21. The compound according to claim 1, selected from the group consisting of compounds 001 to 199 shown in the following table 【Chemical Formula 4-1】 【Chemical Formula 4-2】 【Chemical Formula 4-3】 [Chemical Formula 4-4] [Chemical Formula 4-5] 【Chemical Formula 4-6】 【Chemical Formula 4-7】 【Chemical Formula 4-8】

22. The compound according to claim 1, selected from the group consisting of compounds 200 to 262 shown in the following table 【Chemical Formula 5-1】 【Chemical Formula 5-2】 【Chemical Formula 5-3】 【Chemical Formula 5-4】 【Chemical Formula 5-5】

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22

24. The compound according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23, for use in the treatment of pain

25. The compound or pharmaceutical composition for use in the treatment of pain according to claim 24, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain, preferably postoperative pain

26. A method of treating pain, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to any one of claims 23 to 25

27. The method according to claim 26, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain, preferably postoperative pain

28. The compound according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23, for use in the treatment of epilepsy

29. A method of treating epilepsy, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23

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