Indolizine 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 the 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 assemble as homo- or hetero-tetramers to form cation-permeable ion channels. The name TRP is derived from the Drosophila trp (transient receptor potential) mutant that characterizes the 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 likely expressed in 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 makes it possible to play an important role 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 makes it possible 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 thermo-TRPs are highly expressed in sensory neurons and / or skin keratinocytes and function as the main 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). The neurosteroid 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] Although several TRPM3 antagonists are known, none of them refers 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 pain such as inflammatory pain and epilepsy. There is a strong demand for therapies that have good efficacy against certain types 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 indolizine derivatives and pharmaceutical compositions containing such indolizine derivatives. The present invention also provides indolizine 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 epilepsy.

[0009] The present invention also provides the use of indolizine derivatives for the manufacture of a pharmaceutical composition or a medicament for the prevention and / or treatment of TRPM3-mediated disorders, particularly for the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy, and / or for counteracting pain and / or inflammatory hypersensitivity and / or epilepsy.

[0010] The present invention also provides a method for preventing or treating a TRPM3-mediated disorder by administering an indolizine derivative according to the present invention to a subject in need thereof. More specifically, the present invention relates to such a method for preventing and / or treating pain and / or inflammatory hypersensitivity and / or epilepsy, and / or for counteracting pain and / or inflammatory hypersensitivity and / or epilepsy.

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

Embodiments for Carrying Out the Invention

[0012] The present invention will be further described and, in some cases, described with respect 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 stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs,

Chemical formula

[0014] In some embodiments of the indolizine derivatives according to the present invention, (a-1) Q is -NR 3 R 4 represents, R 1 is, R W represents, R W represents -C1-C6-alkyl, and / or (a-2) Q is -NR 3 R 4 represents, R 5 and R 5 ’ of at least one of which represents -H, and / or (a-3) Q is -NR 3 R 4 represents, R 6 represents -H, and / or (a-4) Q is -NR 3 R 4 represents, R 8represents -H, or or (b-1) (b-1)Q represents -NR 3 R 4 and R 1 represents -CH2F, -CHF2, -CF3, -CN, -methyl, -ethyl, -propyl, or -cyclopropyl, and / or (b-2)Q represents -NR 3 R 4 and R 5 and R 5 ’s at least one does not represent -H, and / or (b-3)Q represents -NR 3 R 4 and R 3 represents -H.

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

Chemical formula

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

[0017] In one embodiment of the indolizine derivative according to formula I or formula II, R 1 is methyl, ethyl, or other C1-C6 alkyl. In another preferred embodiment, R 1 is methyl.

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

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

[0020] In some embodiments of the indolizine derivative 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, C1-C6 alkyl, or 5- to 14-membered heteroaryl, in each case unsubstituted, independently of one another, -F, -Cl, -Br, -I, -CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z 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, -CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is mono- or polysubstituted with substituents selected therefrom.

[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, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is monosubstituted or polysubstituted with 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,, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)RY 、 -NR Y R Z 、 -NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)₂R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z is mono - or polysubstituted with a substituent 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,, CF₃, -CF₂H, C₁ - C₆ alkyl, -CN, -NO, -NO₂, =O, =S, -SF₅, -R Y 、 -OR Y 、 -OC(=O)R Y 、 -NR Y R Z 、 -NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)₂R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z is mono - 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-fused or non-bridged, fused, or bridged cycloalkyl, and in each case, unsubstituted or, independently of one another, mono- or polysubstituted with substituents selected from -F, -Cl, -Br, -I, Y , CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is mono- or polysubstituted with substituents selected therefrom.

[0027] In one embodiment, the 5- to 14-membered aryl within the definition of V is phenyl or other 5- to 14-membered aryl, which is unsubstituted or, independently of one another, mono- or polysubstituted with substituents selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is mono- or polysubstituted with substituents selected therefrom.

[0028] In a further embodiment of the indolizine derivative according to the present invention, V is saturated or unsaturated, unsubstituted, and independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and represents a 3- to 14-membered heterocycloalkyl mono- or polysubstituted with substituents selected from

[0029] In some embodiments, 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, isoxazolidine, 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, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is monosubstituted or polysubstituted with substituents selected from the group consisting of.

[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, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is monosubstituted or polysubstituted with substituents selected from

[0031] In another preferred embodiment of the indolizine derivative according to the invention, V is saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z and is monosubstituted or polysubstituted with substituents selected from, and represents C1-C6 alkyl or C1-C6 heteroalkyl.

[0032] In some embodiments of the indolizine derivative according to the invention, V is unsubstituted, independently of one another, -F, -Cl, -Br, -I, -CN, -C(=O)OH, -NH2, -NO2, -OH, =O, -SF5; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C 1-6 -alkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C(=O)O-C 1-6 -alkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -NHC 1-6 -alkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -N(C 1-6 -alkyl)2; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -O-C 1-6 -alkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -S(=O)2-C 1-6 -alkyl; 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 -C1-C6-alkylene- or -C1-C6-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 connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), a 3- to 14-membered heterocycloalkyl, and is mono-substituted or multi-substituted with a substituent selected therefrom.

[0033] In some embodiments, V is unsubstituted, independently of one another, -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2, or -N(CH3)2; Saturated or unsaturated, unsubstituted, 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, and is monosubstituted or polysubstituted with a substituent selected from the group consisting of -C 1-6 -alkyl; Saturated or unsaturated, 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, and is monosubstituted or polysubstituted with a substituent selected from the group consisting of -C 1-6 -heteroalkyl; 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, and is monosubstituted or polysubstituted with a substituent selected from the group consisting of -OC 1-6 -alkyl; 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is mono- or polysubstituted with a substituent selected from the group consisting of -O(C=O)C 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is mono- or polysubstituted with a substituent selected from the group consisting of -C(=O)OC 1-6 -alkyl; 3- to 14-membered cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, where in each case it is unsubstituted, independently of one another, -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 3- to 14-membered cycloalkyl which is mono- or polysubstituted with a substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2; 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, 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is a 3- to 14-membered heterocycloalkyl mono- or polysubstituted with a substituent selected from the group consisting of; mono- or polysubstituted with a substituent selected from the group consisting of.

[0034] In some embodiments, V is, unsubstituted, independently of one another, -F, -Cl, -CN, -OH, =O, -C 1-6 -alkyl, methyl, ethyl, -CHF2, -CF3, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-NHC(=O)-O-C1-6 -Alkyl, -C(=O)O-C 1-6 -Alkyl, -N(C 1-6 -Alkyl)2, -OC 1-6 -Alkyl, -OCF3, -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.

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

[0037] In some embodiments, V represents 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 C1-C6 alkyl, in each case unsubstituted, monosubstituted or polysubstituted, and preferably a residue selected from the group consisting of the following.

Chemical formula

[0038] In one embodiment, V represents an unsubstituted, mono-substituted or multi-substituted -oxetanyl, 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, mono-substituted, or multi-substituted 2-pyridine. In some embodiments, V represents a residue selected from the group consisting of:

Chemical formula

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

Chemical formula

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

Chemical formula

[0043] In some embodiments, optionally, when it is U-CH2, V represents a residue selected from the group consisting of:

Chemical formula

[0044] In alternative embodiments, V represents a residue selected from the group consisting of:

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

Chemical formula

[0048] In one embodiment of the indolizine derivative according to the present invention, R 1 is -H, -F, -Cl, -Br, -I, -CN; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-6-alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -O-C1-6-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-C1-6-alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-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 -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), representing 3- to 14-membered cycloalkyl.

[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, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkylene-NH-C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-N(C 1-6 -Alkyl)-C 1-6 -Alkylene-CF3, -C(=O)C 1-6 -Alkyl, -C(=O)OC 1-6 -Alkyl, -C(=O)NH2, -C(=O)NHC 1-6 -Alkyl, -C(=O)N(C 1-6 -Alkyl)2, -S(=O)-C 1-6 -Alkyl, -S(=O)2-C 1-6 -Alkyl, -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, -CH2F, -CHF2, -CF3, -unsubstituted cyclopentyl, or -cyclopropyl. Preferably, R 1 is, -H, -C 1-6 -Alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -CH2F, -CHF2, -CF3, -cyclopentyl, or unsubstituted. In some embodiments, R 1 is, -CH3.

[0051] In some embodiments, R 1 represents -CH2F, -CHF2, -CH 3、 or -cyclopropyl. Preferably, R 1 represents -CH2F, -CHF2, or -CH3. In some embodiments, R 1 represents -C(=O)NH2, or -CHF2.

[0052] In some embodiments, R 1 represents -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -C 1-3 -alkylene-CFH 2、 or -cyclopropyl, and preferably, R 1 represents -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, or -C 1-3 -alkylene-CFH2, for example, -CH3.

[0053] In some embodiments of the indolizine derivatives according to the present invention, R 2 is -H; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-heteroalkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl, where the 3- to 14-membered cycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (either case being saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), 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 connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), representing 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, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, or -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF3.

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

[0056] In one embodiment of the indolizine derivative according to the present invention, R 3 is -H; -OH; a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkyl; or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-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, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, or -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF3.

[0058] In some embodiments, R 3 is -H, -OH, or saturated, unsubstituted, or -OH-monosubstituted -C 1-6 -alkyl. 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 indolizine derivative according to the present invention, R 4 is -H; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, mono- or poly-substituted -C1-C6-heteroalkyl; Saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono- or poly-substituted), 3- to 14-membered cycloalkyl; Saturated or unsaturated, unsubstituted, mono- or poly-substituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono- or poly-substituted), 3- to 14-membered heterocycloalkyl; Unsubstituted, mono- or poly-substituted 6- to 14-membered aryl, wherein the 6- to 14-membered aryl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono- or poly-substituted), 6- to 14-membered aryl; or Unsubstituted, mono- or poly-substituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono- or poly-substituted), 5- to 14-membered heteroaryl.

[0061] In some embodiments, R 4 is Saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -NHC1-6 -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-NH2, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -Alkyl), -C(=O)N(C 1-6 -Alkyl)2, -S(=O)2C 1-6 -Alkyl, -Phenyl, -C 1-6 -Alkylene-Phenyl, saturated or unsaturated, unsubstituted 3- 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)2C 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-CF3, -OH, =O, -OC 1-6 -Alkyl, -C 1-6 -Alkylene-OH, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -NH2, -NHC 1-6 -Alkyl, -N(C1-6 -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-NH2, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-C1-6 -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, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -Alkyl), -C(=O)N(C 1-6 -Alkyl)2, -S(=O)2C 1-6 -Alkyl, -Phenyl, -C 1-6 -Alkylene-Phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted 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 monosubstituted 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-CF3, -OH, =O, -OC 1-6 -Alkyl, -C 1-6 -Alkylene-OH, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -NH2, -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-C1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)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, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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 in each case is unsubstituted, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -C 1-6 -alkylene-NH-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-C1-6 -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -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-C1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, mono- 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 the 5- to 14-membered heteroaryl is in each case 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 is in each case unsubstituted, -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, mono- 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, mono- or polysubstituted with -F -S(=O)2C 1-6 -alkyl; Saturated, unsubstituted -S(=O)2(3- to 14-membered cycloalkyl); Saturated, unsubstituted, independently of one another, -OH, =O, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2, -OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-NH-C 1-6-alkyl, -C(=O)NH2, -C(=O)-NH-C 1-3 -alkyl, -C(=O)-N(C 1-3 -alkyl)2, or monosubstituted or disubstituted with a substituent selected from the group consisting of -unsubstituted phenyl, -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 monosubstituted 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-NH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -OH, -OC 1-6 -alkyl, -NH2, -N(C 1-6 -alkyl)2, -NHC(=O)O-C 1-6 -alkyl, and is monosubstituted or disubstituted 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 in each case, 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 in each case, is unsubstituted, independently of one another, with -F, -OH, =O, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-N(C 1-6 -alkyl)2, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)O-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -S(=O)2C 1-6 -alkyl, oxetanyl, pyrimidinyl, -C 1-6 -alkylene-phenyl, and is mono-substituted 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 mono-substituted with -OH, and the 5- to 14-membered heteroaryl, in each case, is selected from the group consisting of pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, and in each case, is unsubstituted, independently of one another, mono- or di-substituted with a substituent selected from the group consisting of -C 1-6 -alkyl, -OH, a 5- to 14-membered heteroaryl or -C 1-6 -alkylene-(5- to 14-membered heteroaryl).

[0063] In one embodiment of the indolizine 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, is unsubstituted, independently of one another, -F, -C 1-6 -alkyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl-, C(=O)N(C 1-6 -alkyl)2, -C(=O)O-C 1-6 -alkyl, -NHC(=O)O-C 1-6 -alkyl, -unsubstituted pyridyl, and, unsubstituted or -C 1-6 -alkyl mono-substituted 1,2,4-oxadiazole, and is mono- or polysubstituted with a substituent selected from the group consisting of. 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 4are combined together, a pyrrolidine ring that is unsubstituted or mono-substituted with -N(CH3)2; unsubstituted or -C 1-6 -alkyl, -NH2, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkyl, -NHC(=O)O-C 1-6 -alkyl, and a piperidine ring mono-substituted with a substituent selected from the group consisting of unsubstituted or mono-substituted -C 1-6 -alkyl 1,2,4-oxadiazole; an unsubstituted morpholine ring; or unsubstituted or -C 1-6 -alkyl and an N-substituted piperazine ring formed with a substituent selected from the group consisting of unsubstituted pyridyl.

[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 represents saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-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 represents a residue -CR’R’’-(CH2) m -OH, where m is an integer from 1 to 6, preferably from 1 to 3, and where R’ and R’’ are, independently of each other, -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -C 1-3 -alkylene-CFH2, -C 1-3 -alkylene-O-C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C(=O)-NH2, or C(=O)-NH-C 1-3 -alkyl, preferably -H, -CH3, -C 1-3 -alkylene-OH, -C(=O)-NH2, or C(=O)-NH-C 1-3 -alkyl. In one embodiment, at least one of 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, mono- or polysubstituted 3- to 14-membered cycloalkyl, or a saturated or unsaturated, unsubstituted, mono- 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, mono- or polysubstituted 3-membered cycloalkyl, or a saturated or unsaturated, unsubstituted, mono- or polysubstituted 3-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]

[0072] In some embodiments, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, mono- or polysubstituted 4-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, mono- 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.

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) as 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 -CHF2, preferably, R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 are, independently of one another, -H, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C 1-3 -alkyl)2, or -C(=O)NH2, preferably, R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 is subject to the condition that only one of them represents a residue other than -H.

[0075] In some embodiments, R 3 represents -H, R 4 represents a residue according to general formula (A) as defined above, in which 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)NH2, or -CHF2, preferably, R A1 is, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C 1-3 -alkyl)2, or -C(=O)NH2, R A2 , R A3 , R A4 , R A5 , R A7 and R A8 represent -H.

[0076] In some embodiments, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl (preferably 5-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered heterocycloalkyl (preferably 5-membered heterocycloalkyl), or an unsubstituted, mono-substituted or multi-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, 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, independently of one another, -H, -F, -C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-CF3, or -C(=O)NH2, or R B2 and R B3 together represent =O, or R B4 and R B5 together represent =O, preferably, R A1 , R A2 , RA3 , R A4 , R A5 , R A7 , and R A8 wherein only one, two, or three of R A1 , R A2 , R A3 , R A4 , R A5 , R A7 , and R A8 represent a residue other than -H, provided that only 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, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl (preferably 6-membered cycloalkyl), or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (preferably 6-membered heterocycloalkyl), or an unsubstituted, monosubstituted or polysubstituted 6- to 14-membered aryl (preferably 6-membered aryl), or an unsubstituted, monosubstituted or polysubstituted 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.

Chemical formula

[0080] In some embodiments, R 3 represents -H, and R 4 represents a residue according to general formula (C),

Chemical formula

[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 is -CR C11 R C12 represents - or YC1 represents -CR C9 R C10 -, and Y C2 represents -O- and -NR C8 - and is selected from, R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 are each independently -H, -F, -C 1-3 -alkyl, -C 1-3 -alkylene-OH, or -C(=O)NH2, preferably, R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 , and R C12 is such that only one, two, or three of them represent non-H residues, preferably, R C1 , R C2 , R C3 , R C4 , R C5 , R C6 , R C7 , R C8 , R C9 , R C10 , R C11 and R C12 is such that one of them represents a non-H residue.

[0082] In some embodiments, R 3 represents -H, and R 4 represents a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 7-membered cycloalkyl, or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 7-membered heterocycloalkyl. In some embodiments, R 3represents -H, and R 4 represents the following residues.

Chemical formula

[0083] In some embodiments, R 3 represents -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), wherein the 3- to 14-membered cycloalkyl is connected via a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkylene-; or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered heterocycloalkyl (preferably 4, 5 or 6-membered heterocycloalkyl), wherein the 3- to 14-membered heterocycloalkyl is connected via a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkylene-; or an unsubstituted, mono-substituted or multi-substituted 6- to 14-membered aryl (preferably 6-membered aryl), wherein the 6- to 14-membered aryl is connected via a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkylene-; or an unsubstituted, mono-substituted or multi-substituted 5- to 14-membered heteroaryl (preferably 5- or 6-membered heteroaryl), wherein the 5- to 14-membered heteroaryl is connected via a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkylene-. 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 connected via a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkylene-; or a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl is connected via a saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkylene-.

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

Chemical formula

[0086] In some embodiments, R 3 represents -H, and R 4 is (i) the residue -CR’R’’-(CH2) 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, -CF3, -CF2H, -CFH2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -C 1-3 -alkylene-CFH2, -C 1-3 -alkylene-O-C 1-3 -alkyl, or -C 1-3 -alkylene-OH, preferably -H, -CH3, 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 indolizine derivatives according to the present invention, R 5 and R 5 ' are, independently of each other, -H; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-heteroalkyl; A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted).

[0089] In some embodiments, R 5 and R 5 ’ each independently represent -H, -C1-C6-alkyl, or -C1-C6-alkylene-N(C1-C6-alkyl)2.

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

[0091] In some embodiments of the indolizine derivatives according to the present invention, both R 5 and R 5 ’ are -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 a residue selected from the group consisting of -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -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 indolizine 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, -SF5, -CN, -NO2, -C(=O)OH, -NH2; 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.

[0096] In some embodiments, R 6, R 7 , and R 8 are each independently -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, -C 1-6 -alkyl, -CF3, -CHF2, -CH2F, -O-C 1-6 -alkyl, -OCF3, -OCHF2, -OCH2F, unsubstituted or independently of one another, substituted with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, -NHC 1-6 -alkyl; unsubstituted or independently of one another, substituted with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, -N(C 1-6 -alkyl)2; unsubstituted or independently of one another, substituted with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, -C(=O)OC 1-6 -alkyl; unsubstituted or independently of one another, substituted with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, -OC(=O)C 1-6 -alkyl; or -C, optionally substituted, or independently of one another, with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2 1-6 -heteroalkyl, is represented.

[0097] In some embodiments, R 6 , R 7 , and R 8 are, independently of one another, -H, -F, -Cl, -Br, -I, -CN, C 1-3 -alkyl, -CF3, -CF2H, and -CFH2, preferably residues selected from the group consisting of -H or -F.

[0098] In some embodiments of the indolizine derivatives according to the invention, R 6 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

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

[0100] In some embodiments, R 6 represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or -CH3, preferably -H, -F, -CN, or -CH3.

[0101] In some embodiments of the indolizine derivatives according to the invention, R 7 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

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

[0103] In some embodiments, particularly when Q represents -NR 3 R 4 when representing, R7 represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or CH3.

[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 indolizine derivatives according to the present invention, R 8 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl.

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

[0107] In some embodiments, R 8 represents a residue selected from the group consisting of -H, -F, -Cl, -CN, or CH3, preferably selected from -F.

[0108] In some embodiments of the indolizine 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 remaining of R 6 , R 7 , and R 8 represent -F, -Cl, -CN, or -CH3, or (iii) one of R 6 , R 7 , and R 8 represents -H, and R 6 , R 7 , and R 8The remainder of them, independently of one another, represents -F, -Cl, -CN, or -CH3.

[0109] In some embodiments, the compound is according to general formula (I), -R 1 represents -CH3, and / or -R 6 , R 7 , and R 8 each represents -H, and / or -T represents -O-, and / or -U represents -CH2-, and / or -V represents thiazolyl, pyridyl, or pyrazolyl, and the thiazolyl, pyridyl, and pyrazolyl can each be mono-substituted or di-substituted, independently of one another, with a substituent selected from the group consisting of unsubstituted, -CH3, -F, -CH2CHF2, and -CF3, and / or -Q represents NR 3 R 4 , and / or -R 3 represents H, and / or -R 4 represents

Chemical formula

Chemical formula

[0110] In exemplary embodiments of the present invention, the indolizine derivative is selected from the group consisting of: Compound 001 - N - [4 - (hydroxymethyl)oxan - 4 - yl] - 2 - methyl - 6 - [(4 - methyl - 1,3 - thiazol - 5 - yl)methoxy]indolizine - 3 - carboxamide, Compound 002 - (2S) - 2 - ({6 - [(2 - fluorophenyl)methoxy] - 2 - methylindolizine - 3 - yl}formamide)propanamide, Compound 003 - (2S)-2-({6-[(2-Fluorophenyl)methoxy]-2-methylindolizin-3-yl}formamido)-3-hydroxypropanamide, Compound 004 - 2(2R)-2-({6-[(2-Fluorophenyl)methoxy]-2-methylindolizin-3-yl}formamido)-3-hydroxypropanamide, Compound 005 - 2-({6-[(2-Fluorophenyl)methoxy]-2-methylindolizin-3-yl}formamido)-3-hydroxy-2-methylpropanamide, Compound 006 - N-(1,3-Dihydroxy-2-methylpropan-2-yl)-6-[(2-fluorophenyl)methoxy]-2-methylindolizine-3-carboxamide, Compound 007 - 6-[(2-Fluorophenyl)methoxy]-N-[3-(hydroxymethyl)-2-oxopyrrolidin-3-yl]-2-methylindolizine-3-carboxamide, Compound 008 - N-(4,4-Difluoropiperidin-3-yl)-6-[(2-fluorophenyl)methoxy]-2-methylindolizine-3-carboxamide, Compound 014 - 3-Hydroxy-2-methyl-2-({2-methyl-6-[(pyridin-2-yl)methoxy]indolizin-3-yl}formamido)propanamide, Compound 015 - N-(1,3-Dihydroxy-2-methylpropan-2-yl)-2-methyl-6-[(pyridin-2-yl)methoxy]indolizine-3-carboxamide, Compound 016 - N-[3-(Hydroxymethyl)-2-oxopyrrolidin-3-yl]-2-methyl-6-[(pyridin-2-yl)methoxy]indolizine-3-carboxamide, Compound 017 - N-(4,4-Difluoropiperidin-3-yl)-2-methyl-6-[(pyridin-2-yl)methoxy]indolizine-3-carboxamide, Compound 018 - 2-({2-Methyl-6-[(pyridin-2-yl)methoxy]indolizin-3-yl}formamido)propanamide, Compound 019 - 2-{[6-(Cyclopropylmethoxy)-2-methylindolizin-3-yl]formamide}-3-hydroxy-2-methylpropanamide, Compound 020 - 6-(Cyclopropylmethoxy)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-methylindolizine-3-carboxamide, Compound 021 - 6-(Cyclopropylmethoxy)-N-[3-(Hydroxymethyl)-2-oxopyrrolidin-3-yl]-2-methylindolizine-3-carboxamide, Compound 023 - 2-{[6-(Cyclopropylmethoxy)-2-methylindolizin-3-yl]formamide}propanamide, Compound 025 - 6-(2,2-Difluoroethoxy)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-methylindolizine-3-carboxamide, Compound 027 - 6-(2,2-Difluoroethoxy)-N-(4,4-difluoropiperidin-3-yl)-2-methylindolizine-3-carboxamide, Compound 028 - 2-{[6-(2,2-Difluoroethoxy)-2-methylindolizin-3-yl]formamide}propanamide, Compound 029 - 3-Hydroxy-2-methyl-2-({2-methyl-6-[(2-methyl-1,3-thiazol-5-yl)methoxy]indolizin-3-yl}formamide)propanamide, Compound 030 - N-(1,3-Dihydroxy-2-methylpropan-2-yl)-2-methyl-6-[(2-methyl-1,3-thiazol-5-yl)methoxy]indolizine-3-carboxamide, Compound 031 - 2-({2-Methyl-6-[(2-methyl-1,3-thiazol-5-yl)methoxy]indolizin-3-yl}formamide)propanamide, Compound 032 - N-(1-Hydroxy-3-methoxy-2-methylpropan-2-yl)-2-methyl-6-[(pyridin-2-yl)methoxy]indolizine-3-carboxamide, Compound 033 - 3 - hydroxy - 2 - ({2 - methyl - 6 - [(pyridin - 2 - yl)methoxy]indolizine - 3 - yl}formamido)propanamide, Compound 034 - 2 - {[6 - (benzyloxy)-2 - methylindolizine - 3 - yl]formamido}-3 - hydroxypropanamide, Compound 035 - 6 - (benzyloxy)-N-(4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl)-2 - methylindolizine - 3 - carboxamide, Compound 036 - N-(4,4 - difluoro - 1 - hydroxy - 2 - methylbutan - 2 - yl)-2 - methyl - 6 - [(pyridin - 2 - yl)methoxy]indolizine - 3 - carboxamide, Compound 037 - N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 6 - [(pyridin - 3 - yl)methoxy]indolizine - 3 - carboxamide, Compound 038 - N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-6 - [(2 - methoxypyridin - 3 - yl)methoxy]-2 - methylindolizine - 3 - carboxamide, Compound 039 - N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methyl - 6 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy}indolizine - 3 - carboxamide, Compound 040 - 6 - [(4 - fluoro - 1 - methyl - 1H - pyrazol - 5 - yl)methoxy]-N - [3 - (hydroxymethyl)-2 - oxopyrrolidin - 3 - yl]-2 - methylindolizine - 3 - carboxamide, Compound 041 - 2 - methyl - 6 - [(pyrazin - 2 - yl)methoxy]-N-(4,4,4 - trifluoro - 1 - hydroxybutan - 2 - yl)indolizine - 3 - carboxamide, Compound 042 - 2 - methyl - 6 - [(pyridin - 3 - yl)methoxy]-N-(4,4,4 - trifluoro - 1 - hydroxybutan - 2 - yl)indolizine - 3 - carboxamide, Compound 043 - 6 - [(2 - methoxypyridin - 3 - yl)methoxy] - 2 - methyl - N - (4,4,4 - trifluoro - 1 - hydroxybutan - 2 - yl)indolizine - 3 - carboxamide, Compound 044 - 2 - methyl - N - (4,4,4 - trifluoro - 1 - hydroxybutan - 2 - yl) - 6 - {[2 - (trifluoromethyl)pyridin - 3 - yl]methoxy}indolizine - 3 - carboxamide, Compound 045 - 6 - [(4 - fluoro - 1 - methyl - 1H - pyrazol - 5 - yl)methoxy] - 2 - methyl - N - (4,4,4 - trifluoro - 1 - hydroxybutan - 2 - yl)indolizine - 3 - carboxamide, Compound 046 - N - [3 - (hydroxymethyl) - 2 - oxopyrrolidin - 3 - yl] - 2 - methyl - 6 - [(pyrazin - 2 - yl)methoxy]indolizine - 3 - carboxamide,

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

[0112] In some embodiments, the indolizine derivative is selected from the group consisting of Compounds 001 - 046 shown in Table 1 below, including its stereoisomers and pharmaceutically acceptable salts.

Table 1

[0113] In some embodiments, the indolizine derivative is selected from the group consisting of Compounds 005 - 046 shown in Table 2 below, including its stereoisomers and pharmaceutically acceptable salts.

Table 2 - 1

Table 2 - 2

Table 2-3

[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 indolizine derivatives according to the present invention, including but not limited to (a-1), (a-2), (a-3), (b-1), (b-2), and (b-3), but these are not necessarily limited to use in the treatment of pain. Therefore, this aspect of the present invention relates to the indolizine derivative itself, a composition containing the indolizine derivative, a medicament containing the indolizine derivative, and for use in the prevention and / or treatment of TRPM3-mediated disorders such as pain and / or inflammatory hypersensitivity and / or epilepsy, and / or for counteracting 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 indolizine derivative is selected from the group consisting of the above-mentioned Compound 001 to Compound 004, and physiologically acceptable salts thereof.

[0116] In some embodiments of the present invention, the indolizine derivative is selected from the group consisting of the above-mentioned Compound 005 to Compound 046, and physiologically acceptable salts thereof.

[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 in reference to 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 facilitating 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 a 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 substituted 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 of the compound as a whole. The chemical substructures of protecting groups are diverse. One function of a protecting group is to serve as an intermediate in the synthesis of a parent drug 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 a desired chemical reaction, for example, by creating and breaking chemical bonds in an ordered and planned manner. The protection of a functional group of a compound changes 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 modified properties in vitro and in vivo and, in some cases, optimized properties (such as passage through cell membranes 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 generally it is more desirable if this product is pharmacologically innocuous.

[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 sulfoxides and sulfones, and sulfur, optionally including sulfonates. Optionally, compounds and / or synthetic intermediates 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 sites. 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 site (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp2 double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). The double bond may be in a cis or trans configuration. As used herein, the term "alkynyl" means a normal, secondary, tertiary, linear or branched hydrocarbon having at least one unsaturated site (usually 1 to 3, preferably 1), i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-C≡CH) and 1-propynyl (propargyl, -CH2C≡CH).

[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 removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like. As used herein, the term "alkenylene" means a linear or branched hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene and 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" means a linear or branched hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene and 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, as well as 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 one, two, or three) 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 -CH3 of the alkyl can be replaced by -NH2, and / or one or more -CH2- of the alkyl can be replaced by -NH-, -O-, or -S-. The S atom in the chain can optionally be oxidized with one or two oxygen atoms to give sulfoxide and sulfone, respectively. Further, the heteroalkyl group in the indolizine 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, alcohols, alkyl ethers (e.g., -methoxy, -ethoxy, -butoxy, etc.), primary, secondary, and tertiary alkylamines, amides, ketones, esters, alkyl sulfides, and alkyl sulfones. The term "heteroalkenyl" means a linear or branched alkenyl in which one or more carbon atoms (usually one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain does not contain two adjacent O atoms or two adjacent S atoms. Thus, the term heteroalkenyl includes imines, -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.Accordingly, 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, 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 heteroatoms, i.e., oxygen, nitrogen, or sulfur atoms, 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 oxygen, nitrogen, or sulfur atoms, 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 oxygen, nitrogen, or sulfur atoms, 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 saturated cyclic hydrocarbon radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, fenchyl, decalinyl, adamantyl, etc. 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 a heterocycloalkyl regardless of the ring attached to the core structure. A fused system of a cycloalkyl ring having an aryl ring is considered an aryl regardless of the ring attached to the core structure. A fused system of a cycloalkyl ring having a heteroaryl ring is considered a heteroaryl regardless of the ring attached to the core structure.

[0130] As used herein, the term "saturated or unsaturated heterocycloalkyl" encompasses saturated heterocycloalkyl, as well as unsaturated non-aromatic heterocycloalkyl, containing at least one heteroatom, i.e., N, O, or S as a ring member. As used herein, the term "heterocycloalkyl", unless otherwise specified, 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. As used herein, the term "heterocycloalkenyl", unless otherwise specified, 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. As used herein, the term "heterocycloalkynyl", unless otherwise specified, 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.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), especially Chapters 1, 3, 4, 6, 7, and 9, “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 - present), especially 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 heterocycloalkyl regardless of the ring bonded to the core structure. A fused system of a heterocycloalkyl ring having an aryl ring is regarded as heterocycloalkyl regardless of the ring bonded to the core structure. A fused system of a heterocycloalkyl ring having a heteroaryl ring is regarded as 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-ring fused together. A fused system of an aryl ring having a cycloalkyl ring is regarded as aryl regardless of the ring bonded to the core structure. A fused system of an aryl ring having a heterocycloalkyl ring is regarded as heterocycloalkyl regardless of the ring bonded to the core structure. Thus, indoline, dihydrobenzofuran, dihydrobenzothiophene, etc. are regarded as heterocycloalkyl according to the present invention. A fused system of an aryl ring having a heteroaryl ring is regarded as 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 carbon-bonded heterocycle 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", etc. mean chemical structures defined herein, and each part is substituted with one or more substituents, meaning that one or more hydrogen atoms of that part are each independently replaced with a substituent. For example, -C 1-6 -alkyl can include -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, etc. Similarly, -C 1-6 -alkyl that can be polysubstituted with substituents independently selected from -F and -Cl can include -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CCl3, CCl2CCl3, -CHClF, -CClF2, -CCl2CF3, -CF2CCl3, -CClFCCl2F, etc. The designation of any substituent found at multiple sites in the compounds of the present invention shall 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 the amount of an active compound or pharmaceutical that induces 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 symptoms of a disease or disorder being treated.

[0139] As used herein, the term "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 terms "antagonist" or "inhibitor" refer to a compound capable of producing a functional antagonism of the TRPM3 ion channel, including, depending on the context, a competitive antagonist, a non-competitive antagonist, a desensitizing agonist, and a partial agonist. 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 affected by the regulation of the TRPM3 ion channel, including a state mediated by the TRPM3 ion channel.

[0142] As used herein, the term "TRPM3-mediated disorder" refers to a disorder or disease 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 described 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 state characterized by one or more features of inflammation, including edema, erythema, hyperthermia, and pain, and / or an excessive physiological or pathophysiological response to one or more types of stimuli, including thermal, mechanical, and / or chemical stimuli.

[0143] The indolizine derivatives of the present invention have been shown or are understood to be antagonists or modulators of TRPM3. Accordingly, the present invention provides the compound itself, the compound for use as a medicament, 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 indolizine derivative of the present invention.

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

[0145] The pharmaceutical composition or combined preparation according to the present invention may contain the indolizine derivative of the present invention over a wide range of contents depending on the intended use and the expected effect of the preparation. Generally, the content of the indolizine derivative of the present 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, in view of the fact that they do not necessarily directly exert their combined therapeutic effect simultaneously in the mammal being treated, the corresponding composition can 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 can be formulated in a manner suitable for an administration route different from that of the other ingredients. For example, one of them can be in the form of an oral or parenteral formulation, while the other can be in the form of an ampoule for intravenous injection or an aerosol.

[0147] One of ordinary skill in the art will also recognize that the indolizine derivatives of the present invention can exist in many different protonation states, depending, inter alia, on the pH of their environment. The structural formulas provided herein depict compounds in only one of several possible protonation states, but these structures are exemplary, and the present invention is not limited to any particular protonation state. It will be understood that any and all protonated forms of the compounds are intended to fall within the scope of the present 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 can optionally be salts of the compounds herein, particularly, for example, Na + , Li + , K + , Ca 2+ , and Mg 2+It includes a pharmaceutically acceptable non-toxic salt containing. Such salts can be derived by the combination of a suitable cation, for example, alkali metal and alkaline earth metal ions, or ammonium and quaternary amino ions, with an acidic anion moiety, typically a carboxylic acid. The indolizine derivatives of the present invention can have multiple positive or negative charges. The net charge of the indolizine derivatives of the present invention can be either positive or negative. Any associated counterion is typically determined by the synthetic method and / or isolation method by which the compound is obtained. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetic acid, trifluoroacetic acid, 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 associated with any type of counterion. Further, since the compound can exist in various different forms, the present invention is intended to include not only the form of the compound associated with the counterion (e.g., dry salt), but also the form not associated with the counterion (e.g., aqueous solution or organic solution). Metal salts are typically prepared by reacting a metal hydroxide with the compound of the present invention. Examples of metal salts prepared in such a manner are Li + 、Na + 、and K +It is a salt containing. Less soluble metal salts can be precipitated from a solution of more soluble salts 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 contain the indolizine 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, particularly natural amino acids found as protein components, are also included within the scope of the present invention. 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 indolizine derivatives of the present invention also include their physiologically acceptable salts. Examples of physiologically acceptable salts of the indolizine 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 other suitable bases. Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of the compound combined with a suitable cation such as Na + and NX4 + (wherein X is typically independently selected from -H or -C 1-4 -alkyl groups). However, salts of acids and bases that are not physiologically acceptable may also be recognized for use, for example, in the preparation or purification of physiologically acceptable compounds. All salts are within the scope of the present invention, whether in a form derived from a physiologically acceptable acid or base or not.

[0151] As used herein, the term "enantiomer" means, unless otherwise specified, each optically active form of the indolizine derivative of the present invention having an optical purity or enantiomeric excess (determined by standard methods in the art) 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%.

[0152] As used herein, the term "isomer" means all possible isomeric forms, including tautomeric and stereochemical forms, that a compound of the formulas herein may have, but does not include positional isomers. Typically, the structures shown herein illustrate only one tautomer or resonance form of a compound, but the corresponding alternative configurations are equally contemplated. Unless otherwise specified, the chemical name of a compound denotes 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 formulas herein may have at least one chiral center), as well as stereochemically pure or enriched compounds. More specifically, the stereocenters may have either an R or S configuration, and multiple bonds may have either a cis or 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" relate to compounds having a stereoisomer excess of at least about 80% (i.e., at least 90% of one isomer and a maximum of 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, respectively diastereomeric excess, 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 indolizine 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. The 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.Methods for determining optical purity include creating chiral esters such as menthyl or Mosher's esters, a-methoxy-a-(trifluoromethyl)phenylacetate (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 methods 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, etc. (“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 a 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 the three-dimensional lattice sites. Different polymorphs of the compound of formula (I) can differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing mode, fluidity, and / or solid-state stability.

[0157] The indolizine 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 eye, oral, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intranasal, intravenous, intraarterial, intradermal, 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 preparation 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 a TRPM3-mediated disorder 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 (pharmaceutical) compositions comprising one or more indolizine derivatives of the present invention, more specifically, all formula (I) and other formulas and embodiments described herein, and their more specific aspects or embodiments. Further, the present invention provides the compounds or (pharmaceutical) compositions of the present invention, more specifically, all formula (I) and other formulas and embodiments described herein, and their more specific aspects or embodiments, for use as a drug, more specifically, for use in the treatment of pain. The TRPM3-mediated disorders are selected from pain and inflammatory hypersensitive conditions and epilepsy.

[0161] The indolizine 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 by means other than oral administration. The formulations optionally contain excipients as described in the "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 the application or dispersion of the composition to the site to be treated, e.g., by dissolving, dispersing, or diffusing the composition, and / or to facilitate its storage, transport, or handling without impairing its effectiveness. A pharmaceutically acceptable carrier can be a solid or a liquid, or a gas compressed to form a liquid, i.e., the compositions of the present invention can be suitably used as concentrates, emulsions, solutions, granules, 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] Indolizine 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 ingredients. 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 formulations 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 may optionally be coated or scored and formulated so as to provide for a sustained 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 formulation 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% (including active ingredients in the range of 0.1% to 20% in increments of 0.1 w / w% such as 0.6 w / w%, 0.7 w / w%, etc.), preferably 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 paraffin-based 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 may 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 formulation 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 analogs.

[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 a fat and an oil. Optionally, the hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Regardless of the presence or absence of a stabilizer, the emulsifiers together constitute a so-called emulsifying wax, and the wax, together with the oil and the fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0168] Since the solubility of the active compound in most oils that are likely to be used in pharmaceutical emulsion formulations is very low, 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, particularly 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 by rapid inhalation through the nasal cavity from a container of powder held close to the nose, i.e., in the sniffing tobacco manner, 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 increments 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 as is known in the art to be suitable.

[0172] Compositions suitable for parenteral administration may include aqueous and non-aqueous sterile injection solutions that may contain an antioxidant, a buffer, a bacteriostatic agent, and a solute that renders the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain a suspending agent and a thickening agent. 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 that 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 aforementioned types.

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

[0174] It should be understood that, in addition to the components particularly mentioned above, the formulations of the present invention may include other conventional agents in 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 indolizine derivatives of the present invention, controlled-release pharmaceutical formulations (the "controlled-release formulations") containing one or more indolizine derivatives of the present invention as active ingredients can be provided, and the release of the active ingredient can be controlled and regulated to allow for less frequent administration 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 indolizine 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 indolizine derivatives of the present invention. The indolizine 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 into the active pharmaceutical ingredient in vivo.

[0177] The prodrugs of the indolizine 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 readily hydrolysable precursors, particularly esters, amides, etc. can be used. The counterparts 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 into a therapeutically active form by one or more biological conversions when contacted 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" refers 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 indolizine derivatives 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 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 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 stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, [Chemical formula] Preferably, optionally, a compound of formula (I), its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs for use in the treatment of pain or epilepsy or in a method for treating pain or epilepsy, 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)₂R W 、 -C(=O)R W 、 -C(=O)OR W 、 or -C(=O)NR W R X represents Q is -OR 2 or -NR 3 R 4 represents R 2 is -R Y represents R 3 is -OH or -R Y represents R 4 is -R Y or -S(=O)₂R Y represents, or alternatively, R 3 and R 4 together form a saturated or unsaturated, unsubstituted, or mono - or poly - substituted 4, 5, 6, 7, or 8 - membered heterocyclic ring containing 1 - 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 represents R 6 、R 7 、 and R 8 are independently of each other -F, -Cl, -Br, -I, -CN, -NO₂, -SF₅, -R W 、 -OR W 、 -OC(=O)R W 、 -NR W R X 、 -NR W C(=O)R X 、 -SR W 、 -S(=O)R W 、 -S(=O)₂R W 、 -C(=O)RW 、 -C(=O)OR W 、 or -C(=O)NR W R X represents, V represents a saturated or unsaturated 3- to 14-membered heterocycloalkyl, a saturated or unsaturated 3- to 14-membered cycloalkyl, a 5- to 14-membered aryl, a C1-C6 alkyl, or a 5- to 14-membered heteroaryl, and in each case, unsubstituted, independently of each other, -F, -Cl, -Br, -I, -CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2 、=O、=S、-SF 5 、- RY 、-O RY 、-OC(=O) RY 、-N RY R Z 、- NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)2R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z is monosubstituted or polysubstituted with substituents selected from R W and R X are, independently of each other, in each case independently, -H; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl, wherein the 3- to 14-membered cycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted), 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 connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), representing a 3- to 14-membered heterocycloalkyl, R Y and R Z are, independently of each other, in each case independently -H; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkyl; A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-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 -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), representing 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 -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), representing a 3- to 14-membered heterocycloalkyl; An unsubstituted, mono-substituted or multi-substituted 6- to 14-membered aryl, wherein the 6- to 14-membered aryl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), representing a 6- to 14-membered aryl; or Unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted), or represents a 5- to 14-membered heteroaryl, or R Y and R Z together form a saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted 4-, 5-, 6-, 7- or 8-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, wherein "monosubstituted or polysubstituted" in each case independently represents -F, -Cl, -Br, -I, -CN, -C 1-6 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -alkylene-O-CF3, -C 1-6 -alkylene-O-CF2H, -C 1-6 -alkylene-O-CFH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF3, -C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C 1-6 -alkylene-C(=O)-OH, -C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-C(=O)-OC 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6-alkylene-C(=O)-NH(C 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-C(=O)-N(C 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6 -alkylene-C(=O)-NH(OH), -OH, -C 1-6 -alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -O-C 1-6 -alkyl, -C 1-6 -alkylene-O-C 1-6 -alkyl, -O-C 1-6 -alkylene-O-C 1-6 -alkyl, -O-C 1-6 -alkylene-NH2, -O-C 1-6 -alkylene-NH-C 1-6 -alkyl, -O-C 1-6 -alkylene-N(C 1-6 -alkyl)2, -O-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-O-C(=O)-C 1-6 -alkyl, -O-C(=O)-O-C 1-6 -alkyl, -C 1-6 -alkylene-O-C(=O)-O-C 1-6 -alkyl, -O-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-O-C(=O)-NH(C 1-6 -alkyl), -O-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-O-C(=O)-N(C 1-6 -alkyl)2, -O-S(=O)2-NH2, -C 1-6 -alkylene-O-S(=O)2-NH2, -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, -NH2, -NO, -NO2, -C 1-6 -alkylene-NH2, -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)-NH2, -C 1-6 -alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-C(=O)-N(C 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -N(C 1-6 -alkyl)-C(=O)-O-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl)-C(=O)-O-C 1-6 -alkyl, -N(C 1-6-(alkyl)-C(=O)-NH2, -C 1-6 -alkylene-N(C 1-6 -(alkyl)-C(=O)-NH2, -N(C 1-6 -(alkyl)-C(=O)-NH(C 1-6 -(alkyl), -C 1-6 -alkylene-N(C 1-6 -(alkyl)-C(=O)-NH(C 1-6 -(alkyl), -N(C 1-6 -(alkyl)-C(=O)-N(C 1-6 -(alkyl)2, -C 1-6 -alkylene-N(C 1-6 -(alkyl)-C(=O)-N(C 1-6 -(alkyl)2, -NH-S(=O)2OH, -C 1-6 -alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -(alkyl), -C 1-6 -alkylene-NH-S(=O)2-C 1-6 -(alkyl), -NH-S(=O)2-O-C 1-6 -(alkyl), -C 1-6 -alkylene-NH-S(=O)2-O-C 1-6 -(alkyl), -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 -(alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C 1-6 -(alkyl), -NH-S(=O)2N(C 1-6 -(alkyl)2, -C 1-6 -alkylene-NH-S(=O)2N(C 1-6 -(alkyl)2, -N(C 1-6 -(alkyl)-S(=O)2-OH, -C 1-6 -alkylene-N(C 1-6 -(alkyl)-S(=O)2-OH, -N(C 1-6 -(alkyl)-S(=O)2-C 1-6 -(alkyl), -C 1-6 -alkylene-N(C 1-6 -(alkyl)-S(=O)2-C 1-6 -(alkyl), -N(C1-6 -(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-NH2, -C 1-6 -alkylene-N(C 1-6 -(alkyl)-S(=O)2-NH2, -N(C 1-6 -(alkyl)-S(=O)2-NH(C 1-6 -(alkyl), -C 1-6 -alkylene-N(C 1-6 -(alkyl)-S(=O)2-NH(C 1-6 -(alkyl), -N(C 1-6 -(alkyl)-S(=O)2-N(C 1-6 -(alkyl)2, -C 1-6 -alkylene-N(C 1-6 -(alkyl)-S(=O)2-N(C 1-6 -(alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -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-OH, -C 1-6 -alkylene-S(=O)2-OH, -S(=O)2-O-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-O-C 1-6 -alkyl, -S(=O)2-NH2, -C 1-6 -alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -(alkyl), -C 1-6 -alkylene-S(=O)2-NH(C 1-6 -(alkyl), -S(=O)2-N(C 1-6-alkyl)2, -C 1-6 -alkylene-S(=O)2-N(C 1-6 -alkyl)2, 3- 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 selected from, a compound, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs. 2. T represents -O-, and U represents -CR 5 R 5 ’-, the compound itself according to clause 1, or a compound for use. 3. T represents -CR 5 R 5 ’-, and U represents -O-, the compound itself according to clause 1, or a compound for use. 4. Q represents -NR 3 R 4 -, the compound itself according to any one of clauses 1 to 3, or a compound for use. 5. Q represents -OR 2 -, the compound itself according to any one of clauses 1 to 3, or a compound for use. 6. V represents a saturated or unsaturated 3- to 14-membered heterocycloalkyl, saturated or unsaturated 3- to 14-membered cycloalkyl, 5- to 14-membered aryl, C1-C6 alkyl, or 5- to 14-membered heteroaryl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, -CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself according to any one of clauses 1 to 5, or the compound for use, which is mono- or polysubstituted with substituents selected from 7. The compound itself according to clause 6, or the compound for use, wherein the 5- to 14-membered heteroaryl is mono- or polysubstituted. An 8.5- to 14-membered heteroaryl 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 by a substituent selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself according to clause 6 or 7, or a compound for use, which is mono- or polysubstituted by a substituent selected from the above, A 9.5- to 14-membered heteroaryl 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 or, independently of one another, mono- or polysubstituted by a substituent selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -ORY 、 -OC(=O)R Y 、 -NR Y R Z 、 -NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)2R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z The compound itself according to any one of clauses 6 - 8, or the compound for use, which is mono - substituted or polysubstituted with a substituent selected from 10.5 - to 14 - membered heteroaryl is selected from the group consisting of furan - 2 - yl, furan - 3 - yl, thiophene - 2 - yl, thiophene - 3 - yl, pyrazol - 3 - yl, pyrazol - 4 - yl, pyrazol - 5 - yl, oxazol - 5 - yl, isoxazol - 4 - yl, thiazol - 2 - yl, thiazol - 4 - yl, thiazol - 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, CF3, -CF2H, C1 - C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y 、 -OR Y 、 -OC(=O)R Y 、 -NR Y R Z 、 -NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)2R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R ZThe compound itself according to any one of clauses 6 to 9, or the compound for use, which is mono- or polysubstituted with a substituent selected from 11. V is saturated or unsaturated, unsubstituted, and independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself according to any one of clauses 1 to 5, or the compound for use, which represents 3- to 14-membered heteroaryl and is mono- or polysubstituted with a substituent selected from 12.3 to 14-membered heterocycloalkyl is selected from 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 in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself according to clause 11, or the compound for use, which is mono- or polysubstituted with substituents selected from 13.3 to 14-membered heterocycloalkyl is oxane, or oxetanel, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -RY 、 -OR Y 、 -OC(=O)R Y 、 -NR Y R Z 、 -NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)2R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z The compound itself according to clause 11 or 12, or the compound for use, which is mono-substituted or poly-substituted with a substituent selected from 14. The 14- to 14-membered heterocycloalkyl is oxan-4-yl or oxetan-3-yl, and in each case, unsubstituted, independently of one another, -F, -Cl, -Br, -I, -CN, -NO, -NO2, =O, =S, -SF5, -R Y 、 -OR Y 、 -OC(=O)R Y 、 -NR Y R Z 、 -NR Y C(=O)R Z 、 -SR Y 、 -S(=O)R Y 、 -S(=O)2R Y 、 C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z The compound itself according to any one of clauses 11 to 13, or the compound for use, which is mono-substituted or poly-substituted with a substituent selected from 15. The saturated or unsaturated 3- to 14-membered cycloalkyl includes non-condensed or non-bridged, condensed, or bridged cycloalkyl, and is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, and in each case, unsubstituted, -F, -Cl, -Br, -I,, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y 、 -OR Y, -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself according to any one of clauses 1 to 5, or a compound for use, which is mono- or polysubstituted with a substituent selected from 16.5 to 14-membered aryl is unsubstituted, and independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SR Y , -S(=O)R Y , -S(=O)2R Y , -C(=O)R Y , -C(=O)OR Y , or -C(=O)NR Y R Z The compound itself according to any one of clauses 1 to 5, or a compound for use, which is phenyl or another 5- to 14-membered aryl and is mono- or polysubstituted with a substituent selected from 17.V C1-C6 alkyl or C1-C6 heteroalkyl represented by is saturated or unsaturated, unsubstituted, and independently of one another, -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, -R Y , -OR Y , -OC(=O)R Y , -NR Y R Z , -NR Y C(=O)R Z , -SRY 、 -S(=O)R Y 、 -S(=O)₂R Y 、 -C(=O)R Y 、 -C(=O)OR Y 、 or -C(=O)NR Y R Z The compound itself described in any one of clauses 1 to 6, or a compound for use, which is mono- or polysubstituted with a substituent selected from 18. V is unsubstituted and, independently of one another, -F, -Cl, -Br, -I, CF₃, -CF₂H, -CN, -C(=O)OH, -NH₂, -NO₂, -OH, =O, -SF₅; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -C 1-6 -alkyl; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -C(=O)O-C 1-6 -alkyl; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -NHC 1-6 -alkyl; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -N(C 1-6 -alkyl)₂; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -O-C 1-6 -alkyl; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -S(=O)₂-C 1-6 -alkyl; a saturated or unsaturated 3- to 14-membered cycloalkyl which is unsubstituted, mono- or polysubstituted, and the 3- to 14-membered cycloalkyl is optionally connected via -C₁-C₆-alkylene- or -C₁-C₆-heteroalkylene- (both being saturated or unsaturated, unsubstituted, mono- or polysubstituted), 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 connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted), and is monosubstituted or polysubstituted with a substituent selected from 3- to 14-membered heterocycloalkyl, the compound itself according to any one of the preceding paragraphs, or a compound for use. 19. V is unsubstituted and, independently of one another, -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2, -N(CH3)2, -cyclopropyl, or -O-cyclopropyl (preferably selected from -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2, or -N(CH3)2); 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, -C(=O)NH2, and -cyclopropyl, preferably selected from -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -alkenyl, -C 2-6 -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, and is monosubstituted or polysubstituted with a substituent selected from the group consisting of -C 1-6 -alkyl; 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is mono- or polysubstituted with a substituent selected from the group consisting of 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is 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-C(=O)OC mono- or polysubstituted with a substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2 1-6 -alkyl; 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 3- to 14-membered cycloalkyl mono- or polysubstituted with a substituent selected from the group consisting of -alkynyl, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2; 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, 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2, which is a 3- to 14-membered heterocycloalkyl mono- or polysubstituted with a substituent selected from the group consisting of; a compound as described in any one of the preceding paragraphs, or a compound for use, which is mono- or polysubstituted with a substituent selected from the group consisting of. 20. V is, unsubstituted, independently of one another, -F, -Cl, -CN, -OH, =O, -C 1-6 -alkyl, -CHF2, -CF3, -C 1-6 -alkylene-NH2, -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, -OCF3, -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 -alkyl substituted -piperazine, or unsubstituted, monosubstituted or polysubstituted oxetanyl, the compound itself according to any one of the preceding paragraphs, or a compound for use. 21. V is (i) unsubstituted, (ii) monosubstituted, (iii) disubstituted, (iv) trisubstituted, or (v) tetrasubstituted, the compound itself according to any one of the preceding paragraphs, or a compound for use. 22. R 1 is -H, -F, -Cl, -Br, -I; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-6-alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -O-C1-6-alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)C 1-6 -alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)NH C 1-6 -alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)N(C 1-6 -alkyl)2; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6-Alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -S(=O)2-C1-6-alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-heteroalkyl; or Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-membered cycloalkyl, where the 3- to 14-membered cycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (either saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), a 3- to 14-membered cycloalkyl as described in any one of the preceding clauses, the compound itself, or a compound for use. 23.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, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-CF2H, -C 1-6 -Alkylene-CFH2, -C 1-6 -Alkylene-NH-C 1-6 -Alkylene-CF3, -C 1-6 -Alkylene-N(C 1-6 -Alkyl)-C 1-6 -Alkylene-CF3, -C(=O)C 1-6 -Alkyl, -C(=O)OC 1-6 -Alkyl, -C(=O)NHC 1-6 -Alkyl, -C(=O)N(C 1-6 -Alkyl)2, -S(=O)-C 1-6 -Alkyl, -S(=O)2-C 1-6 -Alkyl, -O-C 1-6-Alkyl, -unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl, the compound itself as described in any one of the preceding clauses, or a compound for use. 24.R 1 is, -H, -C 1-6 -Alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -CH2F, -CHF2, -CF3, -unsubstituted cyclopentyl, or -unsubstituted cyclopropyl, preferably, R 1 is, -H, -C 1-6 -Alkyl, -C 1-6 -Alkylene-O-C 1-6 -Alkyl, -CH2F, -CHF2, -CF3, or -unsubstituted cyclopentyl, the compound itself as described in any one of the preceding clauses, or a compound for use. 25.R 1 is, -CH2F, -CHF2, -CH3, or -unsubstituted cyclopropyl, preferably, R 1 is, -CH2F, -CHF2, -CH3, or -CH2CH3, the compound itself as described in any one of the preceding clauses, or a compound for use. 26.R 2 is -H; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-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 -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in either case, saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), 3- to 14-membered cycloalkyl; or A saturated or unsaturated, unsubstituted, mono- or polysubstituted 3- to 14-membered heterocycloalkyl, wherein the 3- to 14-membered heterocycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (either being saturated or unsaturated, unsubstituted, mono- or polysubstituted), and is mono- or polysubstituted with a substituent selected from the group consisting of 3- to 14-membered heterocycloalkyl, the compound itself according to any one of the preceding clauses, or a compound for use. 27.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, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, or -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF3, the compound itself according to any one of the preceding clauses, or a compound for use. 28.R 2 is -H or -C 1-6 -alkyl, the compound itself according to any one of the preceding clauses, or a compound for use. 29.R 3 is -H; -OH; a saturated or unsaturated, unsubstituted, mono- or polysubstituted -C1-C6-alkyl; or The compound itself according to any one of the preceding clauses, or a compound for use, which represents saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-heteroalkyl. 30.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, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, or -C 1-6 -alkylene-N(C 1-6 -alkyl)-C 1-6 -alkylene-CF3, the compound itself according to any one of the preceding clauses, or a compound for use. 31.R 3 is -H, -OH, or saturated, unsubstituted, or -OH mono-substituted -C 1-6 -alkyl, the compound itself according to any one of the preceding clauses, or a compound for use. 32.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-C1-6-alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-alkyl; saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -C1-C6-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 -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), 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 -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), a 3- to 14-membered heterocycloalkyl; An unsubstituted, mono-substituted or multi-substituted 6- to 14-membered aryl, wherein the 6- to 14-membered aryl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), a 6- to 14-membered aryl; or An unsubstituted, mono-substituted or multi-substituted 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted), a 5- to 14-membered heteroaryl, the compound itself according to any one of the preceding paragraphs, or a compound for use. 33.R 4 is A saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 3 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 4 -alkyl)2, -NHC(=O)O-C1-6 -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-NH2, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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)2C 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-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C 1-6 -alkyl)2, -NHC(=O)O-C 1-6 -alkyl, -N(C1-6 -(alkyl)C(=O)O-C 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)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, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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(3- to 14-membered cycloalkyl); Saturated or unsaturated, unsubstituted, independently of one another, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -C1-6 -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, monosubstituted 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 monosubstituted 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-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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 in each case, 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 in each case, is unsubstituted, -F, -Cl, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -C 1-6 -alkylene-NH-C 1-6 -alkyl, -C 1-6 -alkylene-N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH-C1-6 -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, mono- 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-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -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-C1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocycloalkyl, and unsubstituted 5- to 14-membered heteroaryl, mono- 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 the 5- to 14-membered heteroaryl is in each case 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 is in each case unsubstituted, -F, -Cl, -CN, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -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-NH2, -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-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2, -S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- 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 the compound itself according to any one of the preceding clauses, or a compound for use. 34.R 4 is -H; saturated, unsubstituted, monosubstituted or polysubstituted with -F -S(=O)2C 1-6 -alkyl; saturated, unsubstituted -S(=O)2(3- to 14-membered cycloalkyl); saturated, unsubstituted, independently of one another, -OH, -OC 1-6 -alkyl, -N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-NH-C 1-6 -alkyl, -C monosubstituted or disubstituted with a substituent selected from the group consisting of unsubstituted phenyl1-6 -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 saturated, unsubstituted, and, independently of one another, -C 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-NH-C 1-6 -alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-NHC(=O)O-C 1-6 -alkyl, -OH, -OC 1-6 -alkyl, -NH2, -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), wherein -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, -C 1-6 -alkyl, -C 1-6-alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-O-C 1-6 -alkyl, -NH2, -N(C 1-6 -alkyl)2, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-N(C 1-6 -alkyl)2, -C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)O-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -S(=O)2C 1-6 -alkyl, oxetanyl, pyrimidinyl, -C 1-6 -alkylene-phenyl, which is mono- 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 mono-substituted 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 in each case is unsubstituted and, independently of one another, is mono- or di-substituted with a substituent selected from the group consisting of -C 1-6 -alkyl, -OH, of 5- to 14-membered heteroaryl or -C 1-6 -alkylene-(5- to 14-membered heteroaryl), represents the compound itself according to any one of the preceding clauses, or a compound for use. 35.R 3 and R 4The compound itself according to any one of the preceding paragraphs, or a compound for use, which together form a saturated or unsaturated, unsubstituted, or mono- or polysubstituted 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S. 36.R 3 and R 4 which 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, -C 1-6 -alkyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl-, C(=O)N(C 1-6 -alkyl)2, -C(=O)O-C 1-6 -alkyl, -NHC(=O)O-C 1-6 -alkyl, -unsubstituted pyridyl, and a substituent selected from the group consisting of unsubstituted or -C 1-6 -alkyl mono- or polysubstituted with a substituent selected from the group consisting of 1,2,4-oxadiazole substituted with -alkyl, the compound itself according to any one of the preceding paragraphs, or a compound for use. 37.R 3 and R 4 which together form an unsubstituted or -N(CH3)2 mono-substituted pyrrolidine ring; an unsubstituted or -C 1-6 -alkyl, -NH2, -N(CH3)2, -C(=O)NH-C 1-6 -alkyl, -C(=O)O-C 1-6 -alkyl, -NHC(=O)O-C 1-6 -alkyl, and an unsubstituted or -C 1-6 -alkyl mono-substituted with a substituent selected from the group consisting of 1,2,4-oxadiazole substituted with -alkyl, a piperidine ring; an unsubstituted morpholine ring; or an unsubstituted or -C 1-6 -alkyl and an N-substituted piperazine ring substituted with a substituent selected from the group consisting of -unsubstituted pyridyl, the compound itself according to any one of the preceding paragraphs, or a compound for use. 38.R 5 and R 5 ’ are, independently of one another, -H; saturated or unsaturated, unsubstituted, mono- or polysubstituted -C1-C6-alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -C1-C6-heteroalkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted 3- to 14-membered cycloalkyl, where the 3- to 14-membered cycloalkyl is optionally connected via -C1-C6-alkylene- or -C1-C6-heteroalkylene- (in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted), a compound as claimed in any one of the preceding claims, or a compound for use. 39.R 5 and R 5 ’ are, independently of one another, -H, -C1-C6-alkyl, or -C1-C6-alkylene-N(C1-C6-alkyl)2, a compound as claimed in any one of the preceding claims, or a compound for use. 40.R 5 and R 5 wherein at least one of ’ does not represent -H, a compound as claimed in any one of the preceding claims, or a compound for use. 41.R 6 , R 7 and R 8 are, independently of one another, -H; -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2; saturated or unsaturated, unsubstituted, mono- or polysubstituted -C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -O-C 1-6 -alkyl; saturated or unsaturated, unsubstituted, mono- or polysubstituted -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, a compound as described in any one of the preceding clauses itself, or a compound for use. 42.R 6 、R 7 and R 8 are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, -C 1-6 -alkyl, -CF3, -CHF2, -CH2F, -O-C 1-6 -alkyl, -OCF3, -OCHF2, -OCH2F, Unsubstituted, or independently of one another, -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, 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, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2, substituted with one or more substituents selected from -N(C 1-6 -alkyl)2; -C(=O)OC substituted, non-replaceably or independently of one another, with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2 1-6 -alkyl; -OC(=O)C substituted, non-replaceably or independently of one another, with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2 1-6 -alkyl; or -C substituted, non-replaceably or independently of one another, with one or more substituents selected from -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2 1-6 -heteroalkyl, a compound as described in any one of the preceding paragraphs per se, or a compound for use. 43.R 6 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl, a compound as described in any one of the preceding paragraphs per se, or a compound for use. 44.R 6 does not represent -H, a compound as described in any one of the preceding paragraphs per se, or a compound for use. 45.R 7 represents -H, -F, -Cl, -CN, or -C1-C6-alkyl, a compound as described in any one of the preceding paragraphs per se, or a compound for use. 46.R 7 does not represent -H, a compound as described in any one of the preceding paragraphs per se, or a compound for use. 47.R 8The compound as described in any one of the preceding clauses, or the compound for use, wherein [a certain group] represents -H, -F, -Cl, -CN, or -C1-C6-alkyl. 48.R 8 The compound as described in any one of the preceding clauses, or the compound for use, wherein [a certain group] does not represent -H. 49. (i) R 6 、R 7 、and R 8 each represents -H, or (ii) Two of R 6 、R 7 、and R 8 represent -H, and the remaining of R 6 、R 7 、and R 8 represents -F, -Cl, -CN, or -CH3, or (iii) One of R 6 、R 7 、and R 8 represents -H, and the remaining of R 6 、R 7 、and R 8 each independently represents -F, -Cl, -CN, or -CH3, the compound itself, or the compound for use as described in any one of the preceding clauses. 50. The compound as described in any one of the preceding clauses, or the compound for use, selected from the group consisting of the above-mentioned compounds 001 - 004, or compounds 005 - 046, and its physiologically acceptable salts. 51. The compound as described in any one of the preceding clauses, or the compound for use, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain. 52. The compound as described in any one of the preceding clauses, or the compound for use, wherein the pain is postoperative pain. 53. In the compound of formula (I), its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, (a - 1) Q represents -NR 3 R 4 、R 1 represents R W 、RW represents -C1-C6-alkyl and / or (a-2) Q is -NR 3 R 4 represents, R 5 and R 5 ’s at least one represents -H and / or (a-3) Q is -NR 3 R 4 represents, R 6 represents -H and / or (a-4) Q is -NR 3 R 4 represents, R 8 represents -H, or alternatively (b-1) (b-1) Q is -NR 3 R 4 represents, R 1 represents -CH2F, -CHF2, -CF3, -CN, -methyl, -ethyl, -propyl, or -cyclopropyl and / or (b-2) Q is -NR 3 R 4 represents, R 5 and R 5 ’s at least one does not represent -H and / or (b-3) Q is -NR 3 R 4 represents, R 3 represents -H, a compound of formula (I) defined by any one of the preceding clauses, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs. 54. A pharmaceutical composition or medicament comprising a compound according to any one of the preceding clauses. Further exemplary embodiments of the present invention are summarized as Items 1 to 68 below. 1. A compound of formula (I), its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chemical formula

Chemical formula

Chemical formula

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 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 - diisopropylethylamine, DME - 1,2-dimethoxyethane, DMF - N,N-dimethylformamide, DMSO - dimethyl sulfoxide, 2,4-DNPH - 2,4-dinitrophenylhydrazine, 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, KOTMS - potassium trimethylsilanolate, LAH - lithium aluminum hydride, LG - leaving group, MeOH - methanol, MgSO4 - magnesium sulfate, min.-Min, Ms-Methanesulfonyl, Na2SO4-Sodium Sulfate, NBS-N-Bromosuccinimide, NMP-1-Methyl-2-pyrrolidinone, Pd(PPh3)4-Tetrakis-(triphenylphosphine)-palladium(0), Pd2(dba)3-Tris(dibenzylideneacetone)dipalladium, Pet ether-Petroleum ether, PPh3-Triphenylphosphine, PS-DIEA-Diisopropylethylamine supported on polystyrene, PS-PPh3-Triphenylphosphine supported on polystyrene, PyBop-Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, PTSA-p-Toluenesulfonic acid, RF: Ratio of frontiers, RM-Reaction mixture, RP-Reversed phase, RT-Room temperature, sat.-Saturated, SEM-[2-(Trimethylsilyl)ethoxy]methyl acetal, SFC-Supercritical fluid chromatography, SOR-Specific rotation, SPE-Solid phase extraction, TBDMS-tert-Butyldimethylsilyl, TBAF-Tetrabutylammonium fluoride, 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 2 , R 3 , R 4 , and R 5 are as described for the compounds of the present invention. In each occurrence of R 5 , at most two independent substituents (i.e., R5 and R 5’ ) are contemplated.

[0187] 5-(Benzyloxy)-2-methylpyridine of formula 1 can be condensed with a 2-bromoacetic acid derivative 2 (either commercially available or synthesized by procedures known to those skilled in the art) in a suitable solvent (such as ether, THF, etc.) to obtain a pyridinium salt of formula 3, where R2 is an ester protecting group (such as methyl, ethyl, t-Bu, etc.). The intermediate of formula 3 can be cyclized in acetic anhydride at a temperature in the range of 0 to 100 °C in the presence of a base (such as potassium acetate, etc.) to obtain an indolizine of formula 4. Subsequently, the ester derivative 4 can be converted to an intermediate compound of formula 5 via a hydrogenation reaction with a reducing agent (such as hydrogen gas, ammonium formate, cyclohexadiene, etc.) using a catalyst (more preferably Pd or Pt) in a solvent (such as THF, EtOH, etc.). Then, the intermediate of formula 5 can be converted to the desired compound of formula 7 via a nucleophilic substitution at a temperature in the range of 0 to 100 °C in a polar solvent (such as MeCN, DMF, NMP, etc.) in the presence of a base (such as DIPEA, DBU, triethylamine, Cs2CO3, etc.) with or without a chelating agent (such as 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.) using an intermediate of formula 6a (either a commercial product or a synthetic product) (where LG is a leaving group). Alternatively, the intermediate of formula 5 can be reacted with an intermediate of formula 6b (either a commercial product or a synthetic product) at a temperature in the range of 0 to 100 °C in the presence of an azodicarboxylate reagent (such as DEAD, DIAD, ADDP, etc.) and a phosphine (such as tributylphosphine, triphenylphosphine, etc.) in a solvent (such as THF, toluene, etc.) to obtain the desired compound of formula 7. Then, the ester derivative 7 can be converted to the desired compound of formula 8 via a standard saponification reaction. Alternatively, then, the benzyl derivative 4 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 (either 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 following examples, and then reacted with an amine of Formula 9 by procedures known to those skilled in the art or as described in the following examples to obtain the desired indolizine of Formula 10.

Chemical formula

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

[0189] 5-(Benzyloxy)-2-methylpyridine of formula 11 can be condensed with 2-bromoacetic acid derivative 12 (either commercially available or synthesized by procedures known to those skilled in the art) in a suitable solvent (such as ether, THF, etc.) to obtain a pyridinium salt of formula 13, where R2 is an ester protecting group (such as methyl, ethyl, t-Bu, etc.). The intermediate of formula 13 can be cyclized in acetic anhydride at a temperature in the range of 0 to 100 °C in the presence of a base (such as potassium acetate, etc.) to obtain indolizine of formula 14. Then, the ester derivative 14 can be converted to an intermediate compound of formula 15 via a hydrogenation reaction with a reducing agent (such as hydrogen gas, ammonium formate, cyclohexadiene, etc.) using a catalyst (more preferably Pd or Pt) in a solvent (such as THF, EtOH, etc.). Next, the intermediate of formula 15 is reacted with an intermediate of formula 16a (either a commercial product or a synthetic product) (where LG is a leaving group) in a polar solvent (such as MeCN, DMF, NMP, etc.) in the presence of a base (such as DIPEA, DBU, triethylamine, Cs2CO3, etc.) with or without a chelating agent (such as 18-crown-6, cis-anti-cis-dicyclohexano-18-crown-6, etc.) via nucleophilic substitution at a temperature in the range of 0 to 100 °C to give formula 17It can be converted into the desired compound. Alternatively, the intermediate of Formula 15 can be reacted with an intermediate of Formula 16b (commercially available or synthetic) in the presence of an azodicarboxylate reagent (such as DEAD, DIAD, ADDP, etc.) and a phosphine (such as tributylphosphine, triphenylphosphine, etc.) in a solvent (such as THF, toluene, etc.) at a temperature in the range of 0 to 100 °C to obtain the desired compound of Formula 17. Then, the ester derivative 17 can be converted into the desired compound of Formula 18 via a standard saponification reaction. Alternatively, the benzyl derivative 14 can then be converted into 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) in a polar aprotic solvent (such as DCM, DMF, etc.) under standard peptide coupling conditions (such as DCC, EDCI, HATU, PyBop, etc.). Alternatively, the carboxylic acid derivative of Formula 18 can be converted into 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 19 by procedures known to those skilled in the art or as described in the procedures of the following examples to obtain the desired indolizine of Formula 20.

Table 3

Table 4-1

Table 4-2

[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 compounds, and Part B represents pharmacological examples.

[0192] Part A All starting materials that are 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, etc. 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 N2) 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 + H] + and / or [M - H] - for m / z). In certain cases, for example, when positional isomers and / or diastereomers could have been formed / 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, a BRUKER 400MHz or BRUKER 500MHz machine (software Topspin), or alternatively, BRUKER AVANCE 300MHz and 400Mhz were used. For LC / MS analysis, for example, an Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI), or an Agilent 1200 SERIES, Mass: 6130 SQD (ESI / APCI) (software Chemistation) was used. Analytical HPLC was measured with, for example, Waters (software Empower), Agilent-1200-ELSD (software Chemistation), or Agilent-1260 (software OpenLAB). Analytical SFC was performed 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 performed 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 racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia 1 and Dia 2 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. If no suffix is attached after the compound code, it means that the compounds containing a stereocenter were obtained as racemic mixtures or mixtures of diastereomers respectively, unless the chemical name of the compound specifies the exact stereochemistry.

[0199] The LC / MS analysis mentioned in the experimental part was performed on an Alliance Waters HPLC (equipped with a PDA detector) connected to a Waters 3100 mass detector in ESI mode, or an Acquity UPLC Waters (equipped with a PDA detector) connected to an SQD2 detector in ESI mode, or an Acquity UPLC Waters (equipped with a PDA detector) connected to an Xevo TQS detector in ESI mode.

[0200] Synthesis of Methyl 6-Hydroxy-2-Methylindolizine-3-Carboxylate (Int-01) [Chemical formula]

[0201] Step 1: Methyl 2-bromoacetate (65 mL, 690 mmol) was added to a solution of 5-(benzyloxy)-2-methylpyridine (125 g, 627 mmol) in ethanol (1000 mL) at room temperature. The RM was stirred at 80 °C for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was triturated with pet ether (500 mL) and dried to give benzyloxy)-1-(2-methoxy-2-oxoethyl)-2-methylpyridinium bromide (210 g, 85%).

[0202] [Step 2: Sodium acetate (73.8 g, 900 mmol) was added to a solution of methyl 2-(5-(benzyloxy)-2-methyl-1H-pyridin-1-yl)acetate (105 g, 300 mmol) in acetic anhydride (500 mL) at room temperature. The reaction mixture (RM) was stirred at 150 °C for 24 h. The RM was cooled to room temperature, diluted with EtOAc (1000 mL), washed with saturated NaHCO3 (3 × 500 mL) and brine solution (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 20% EtOAc in Pet ether as the eluent to give methyl 6-(benzyloxy)-2-methylindolizine-3-carboxylate (19 g, 21%) as a pale yellow solid.] 1 1 1H NMR (400 MHz, CDCl3) δ ppm: 7.47 (d, 2H), 7.42 - 7.40 (m, 2H), 7.33 - 7.39 (m, 1H), 7.25 - 7.28 (m, 1H), 6.88 (dd, 1H), 6.26 (s, 1H), 5.07 (s, 2H), 3.91 (s, 3H), 2.51 (s, 3H).

[0203] [Step 3: Ammonium formate (11.31 g, 179.45 mmol) and 10% palladium on carbon (2.5 g) were added to a solution of methyl 6-(benzyloxy)-2-methylindolizine-3-carboxylate (5.3 g, 17.94 mmol) in methanol (500 mL) at room temperature. The RM was stirred at room temperature for 2 h. The RM was filtered through a Celite pad, washed with MeOH (100 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with water (250 mL), extracted with EtOAc (2 × 250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with n-pentane (100 mL) and dried to give methyl 6-hydroxy-2-methylindolizine-3-carboxylate (Int-01) as a pale yellow solid (2.2 g, 59%).] 11H NMR (400 MHz, DMSO-D6) δ ppm: 9.49 (s, 1H), 9.05 (s, 1H), 7.42 (d, 1H), 6.83 - 6.85 (m, 1H), 6.32 (s, 1H), 3.81 (s, 3H), 2.42 (s, 3H).

[0204] Synthesis of 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-02). [Chemical formula]

[0205] 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 then 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 under reduced pressure. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC using 10% EtOAc in hexane as eluent to give 3-(tert-butyl-dimethyl-silanyloxy)-2-(4-methoxy-benzylamino)-2-methyl-propionitrile (25 g, 57%) as a yellow liquid. 1 1H-NMR (400 MHz, DMSO-d6) 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).

[0206] 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 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 layer was dried over Na2SO4 and concentrated. The residue was purified by FCC on silica gel using 50% EtOAc in hexane as eluent to afford 3-(tert-butyl-dimethyl-silanyloxy)-2-(4-methoxy-benzylamino)-2-methyl-propionamide (3.4 g, 33%) as an oily liquid. 1 1H-NMR (400 MHz, DMSO-d6) 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).

[0207] 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 H2 gas balloon pressure for 4 h. The RM was filtered through a celite bed and washed with 10% MeOH-DCM. The filtrates were combined and concentrated to afford 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-02) (1.5 g, 76%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) 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).

[0208] Synthesis of Methyl 6-((2-fluorobenzyl)oxy)-2-methylindolizine-3-carboxylate (Int-03) and Potassium 6-((2-fluorobenzyl)oxy)-2-methylindolizine-3-carboxylate (Int-04)

Chemical Structure

[0209] Step 1: To a solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (2 g, 9.75 mmol) in THF (40 mL) were added ADDP (4.918 g, 19.492 mmol), P(nBu)3 (4.81 mL, 19.5 mmol), and (2-fluorophenyl)methanol (1.477 g, 11.7 mmol) at 0 °C. The reaction mixture (RM) was stirred at room temperature for 16 h. The RM was diluted with water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 10% EtOAc in pet ether as the eluent to give methyl 6-((2-fluorobenzyl)oxy)-2-methylindolizine-3-carboxylate (Int-03) as a pale yellow solid (2.0 g, 68.6%). 11H NMR (400 MHz, DMSO-D6) δ ppm: 9.18 (d, 1H), 7.57 - 7.61 (m, 1H), 7.53 (t, 1H), 7.45 - 7.47 (m, 1H), 7.41 - 7.43 (m, 2H), 7.24 (dd, 1H), 6.41 (s, 1H), 5.18 (d, 2H), 3.83 (s, 3H), 2.45 (s, 3H). Step 2: KOTMS (614 mg, 4.78 mmol) was added to a solution of methyl 6-((2-fluorobenzyl)oxy)-2-methylindolizine-3-carboxylate (Int-03) (300 mg, 0.957 mmol) in THF (10.0 mL) at room temperature. The RM was stirred at 70 °C for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was triturated with pentane to give methyl 6-((2-fluorobenzyl)oxy)-2-methylindolizine-3-carboxylate as the potassium salt (Int-04) (310 mg) as a brown solid.

[0210] Synthesis of ethyl 3-amino-2-oxopyrrolidine-3-carboxylate hydrochloride (Int-05).

Chemical formula

[0211] Step 1: Boc anhydride (35.8 mL, 155.9 mmol) was added to a solution of diethyl 2-aminomalonate hydrochloride (30 g, 141.7 mmol) and TEA (60.18 mL, 425.25 mmol) in DCM (400 mL) at 0 °C. The RM was stirred at room temperature for 16 h. The RM was diluted with ice water (500 mL), the organic layer was separated, the organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give diethyl 2-((tert-butoxycarbonyl)amino)malonate (35.8 g) as a colorless solid.

[0212] Step 2: A solution of nitroethene (6.64 g, 90.90 mmol) dissolved in diethyl ether (15 mL) was added to a solution of diethyl 2-((tert-butoxycarbonyl)amino)malonate (10 g, 36.36 mmol) and sodium ethoxide (1.97 g, 29.08 mmol) in ethanol (300 mL) at 0 °C. The reaction mixture (RM) was slowly allowed to reach room temperature. Subsequently, the RM was stirred for 2 hours. The RM was diluted with ice water (500 mL), the organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by RP flash chromatography using 0.1% FA in water and ACN as the eluent to obtain diethyl 2-((tert-butoxycarbonyl)amino)-2-(2-nitroethyl)malonate (4.1 g).

[0213] Step 3: Raney-Ni (5.3 g) was added to a solution of diethyl 2-((tert-butoxycarbonyl)amino)-2-(2-nitroethyl)malonate (4.0 g, 11.49 mmol) in ethanol (50 mL) in a Parr hydrogenation vessel under an inert atmosphere. The RM was stirred at room temperature for 16 hours under H2 (70 psi). The RM was filtered through a Celite pad, and the Celite pad was washed with ethanol. The combined filtrate was concentrated under reduced pressure to obtain ethyl 3-((tert-butoxycarbonyl)amino)-2-oxopyrrolidine-3-carboxylate (1.6 g) as a colorless oil.

[0214] Step 4: HCl (4 M in dioxane, 3.6 mL) was added to a stirred solution of ethyl 3-((tert-butoxycarbonyl)amino)-2-oxopyrrolidine-3-carboxylate (1.6 g, 5.9 mmol) in DCM (30 mL) at 0 °C. The RM was stirred at room temperature for 2 hours. The RM was concentrated under vacuum. The residue was triturated with diethyl ether (10 mL), filtered, and dried under vacuum to obtain ethyl 3-amino-2-oxopyrrolidine-3-carboxylate hydrochloride (Int-05) (1.03 g) as an off-white solid.

[0215] Synthesis of 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-06-En1) and (Int-06-En2).

Chemical Structure

[0216] Step 1: To a stirred solution of diethyl 2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)malonate (60 g, 179.99 mmol) in 1,4-dioxane (600 mL) was added TEA (49.90 mL, 359.99 mmol) at 0 °C. After 15 minutes, formaldehyde (29.18 g, 359.99 mmol) was added at 0 °C. The reaction mixture (RM) was warmed to room temperature and stirred at 80 °C for 16 hours. The RM was diluted with ice-cold water (200 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 40% EtOAc in pet ether to give diethyl 2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2-(hydroxymethyl)malonate (59 g, 90%) as a pale yellow gum. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.86 - 7.82 (m, 2 H), 7.74 - 7.69 (m, 2 H), 4.25 - 4.18 (m, 4 H), 4.07 (d, 2 H), 3.83 - 3.79 (m, 2 H), 2.79 (t, 1 H), 2.33 - 2.30 (m, 2 H), 1.28 (t, 6 H).

[0217] Step 2: Imidazole (25.48 g, 374.27 mmol) was added to a solution of diethyl 2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2-(hydroxymethyl)malonate (68 g, 187.13 mmol) in DCM (700 mL) at 0 °C. After 15 minutes, TBDMS chloride (33.84 g, 224.56 mmol) was added at 0 °C. The reaction mixture (RM) was stirred at room temperature for 16 h. The RM was diluted with ice-cold water (300 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 10% EtOAc in pet ether to give diethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)malonate (68 g, 77%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.84 - 7.82 (m, 2 H), 7.71 - 7.69 (m, 2 H), 4.18 - 4.11 (m, 6 H), 3.76 - 3.72 (m, 2 H), 2.41 - 2.37 (m, 2 H), 1.26 (t, 6 H), 0.89 (s, 9 H), 0.08 (s, 6 H).

[0218] Step 3: Hydrazine hydrate (10.69 g, 213.55 mmol) was added to a stirred solution of diethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)malonate (68 g, 142.37 mmol) in ethanol (700 mL) at 0 °C. The RM was stirred at room temperature for 16 h. The RM was diluted with ice-cold water (300 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 30% EtOAc in Pet. ether to give ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylate (30.7 g, 71%) as an off-white solid. 11H NMR (400 MHz, CDCl3) δ ppm: 5.76 (s, 1 H), 4.22 - 4.17 (m, 2 H), 4.06 (d, 1 H), 3.94 (d, 1 H), 3.46 - 3.42 (m, 1 H), 3.36 - 3.35 (m, 1 H), 2.59 - 2.55 (m, 1 H), 2.49 - 2.43 (m, 1 H), 1.27 (t, 3 H), 0.87 (d, 9 H), 0.06 (d, 6 H).

[0219] Step 4: To a solution of ethyl 3 - ((((tert - butyldimethylsilyl)oxy)methyl)-2 - oxopyrrolidine - 3 - carboxylate (29 g, 96.19 mmol) in EtOH (120 mL), THF (60 mL), and H2O (30 mL) was added LiOH·H2O (20.18 g, 480.99 mmol) portionwise at 0 °C. The RM was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with cold water (20 mL) and then acidified with saturated aqueous citric acid (pH ~4). The solid was filtered, washed with water (10 mL) and then water (10 mL), and dried under vacuum to give 3 - ((((tert - butyldimethylsilyl)oxy)methyl)-2 - oxopyrrolidine - 3 - carboxylic acid (16.7 g, 63%) as a white solid. 1 1H NMR (400 MHz, DMSO - d6) δ ppm: 7.82 (s, 1 H), 3.88 (d, 1 H), 3.70 (d, 1 H), 3.27 - 3.21 (m, 1 H), 3.17 - 3.12 (m, 1 H), 2.34 - 2.32 (m, 1 H), 2.24 - 2.22 (m, 1 H), 0.84 (s, 9 H), 0.01 (d, 6 H).

[0220] Step 5: To a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylic acid (9.5 g, 34.74 mmol) in THF (40 mL) and benzene (120 mL) was added TEA (14.65 mL, 104.24 mmol), followed by DPPA (19.12 g, 69.49 mmol) at room temperature. The reaction mixture (RM) was stirred at room temperature for 2 h. The RM was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 × 50 mL), brine solution (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (40 mL) and benzene (120 mL). Then, benzyl alcohol (7.51 g, 69.49 mmol) was added at room temperature. The RM was stirred at 55 °C for 16 h. The RM was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 40% EtOAc in Pet. ether to give benzyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate (9 g, 68%). 1 H NMR (400 MHz, CDCl3) δ ppm: 7.37 - 7.29 (m, 5 H), 5.84 (brs, 1 H), 5.42 (brs, 1 H), 5.07 (s, 2 H), 3.85 (d, 1 H), 3.67 (d, 1 H), 3.39 - 3.33 (m, 2 H), 2.63 - 2.62 (m, 1 H), 2.53 - 2.51 (m, 1 H), 0.88 (s, 9 H), 0.05 (d, 6 H).

[0221] Step 6: To a solution of benzyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate (11 g, 29.05 mmol) in MeOH (150 mL) was added PTSA monohydrate (2.21 g, 11.62 mmol) in MeOH (50 mL) at 0 °C over 2 h. The RM was stirred at room temperature for 16 h. The RM was concentrated under reduced pressure. Ice-cold water (50 mL) was added to the residue. The aqueous layer was extracted with 10% MeOH in DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with n-pentane (3 × 15 mL), followed by diethyl ether (15 mL), filtered, and dried under vacuum to give benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate (7 g, 91%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.66 (s, 1H), 7.38 - 7.29 (m, 5H), 7.08 (s, 1H), 4.98 - 4.95 (m, 3H), 3.46 - 3.38 (m, 2H), 3.18 - 3.15 (m, 1H), 3.13 - 3.07 (m, 1H), 2.28 - 2.25 (m, 2H). Chiral separation of 3.5 g of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate was carried out by chiral SFC preparative separation. [Preparative SFC conditions: Column: Chiral peak IF (250×30×5 μm), CO2%: 65%, co-solvent%: 35% (100% methanol), total flow rate: 90 g / min, back pressure: 100.0 bar, temperature: 30 °C, wavelength: 215 nm, stacking time: 7.2 min, solubility: 100 ml of MeOH.] The collected pure fractions were concentrated under reduced pressure to give two isomers En1 (first elution) and En2 (second elution).

[0222] Step 7: To a stirred solution of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate En1 (1.4 g, 5.297 mmol) in ethanol (30 mL) was added Pd / C (450 mg) at room temperature. The reaction mixture (RM) was stirred at room temperature for 16 h under H2 (70 psi). The RM was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (2 × 5 mL) and dried under reduced pressure to afford 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-06-En1) (610 mg, 88%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (s, 1 H), 4.73 (t, 1 H), 3.36 - 3.34 (m, 1 H), 3.18 - 3.12 (m, 2 H), 3.10 - 3.04 (m, 1 H), 2.22 - 2.15 (m, 1 H), 1.76 - 1.72 (m, 1 H), 1.56 (s, 2 H).

[0223] Step 8: To a stirred solution of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate En2 (1.2 g, 4.54 mmol) in ethanol (30 mL) was added Pd / C (350 mg) at room temperature. The reaction mixture (RM) was stirred at room temperature for 16 h under H2 (70 psi). The RM was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (2 × 5 mL) and dried under reduced pressure to afford 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-06-En2) (550 mg, 93%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (s, 1 H), 4.73 (brs, 1 H), 3.36 - 3.32 (m, 1 H), 3.18 - 3.12 (m, 2 H), 3.10 - 3.04 (m, 1 H), 2.22 - 2.15 (m, 1 H), 1.76 - 1.71 (m, 1 H), 1.57 (s, 2 H).

[0224] Synthesis of 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-07).

Chemical Structure

[0225] Step 1: To a solution of 1-((tert-butyldimethylsilyl)oxy)propan-2-one (20 g, 106.19 mmol) in EtOH (100 mL) were added (4-methoxyphenyl)methanamine (15.261 mL, 116.81 mmol), TMSCN (15.94 mL, 127.42 mmol), and NH4Cl (1.704 g, 31.857 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCO3 (100 ml) and brine solution (100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica gel using 10% EtOAc in pet ether solution as the eluent to give 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropanenitrile (20 g, 56.30%). 1 1H NMR (400 MHz, DMSO-D6) δH ppm: 7.25 (d, 2 H), 6.88 (d, 2 H), 3.72 (s, 5 H), 3.65 - 3.75 (m, 1 H), 3.45 - 3.51 (m, 1 H), 2.74 - 2.77 (m, 1 H), 1.36 (s, 3 H), 0.87 (s, 9 H), 0.77 (m, 6 H).

[0226] Step 2: To a solution of 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropanenitrile (10 g, 29.9 mmol) in DMSO (70 mL) were added K2CO3 (28.97 g, 209.6 mmol) and H2O2 (14.041 mL, 598.802 mmol) at 0 °C. The reaction mixture (RM) was stirred at room temperature for 16 h. The RM was cooled to room temperature and quenched with ice-cold water (100 mL). The aqueous layer was extracted with diethyl ether (3 × 100 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica gel using 40 - 50% EtOAc in pet ether as the eluent to give 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropanamide (3.8 g, 36%) as a pale yellow liquid. 1 1H NMR (400 MHz, DMSO-D6) δH ppm: 7.25 (d, 2 H), 7.24 (brs, 1 H), 7.07 (brs, 1 H), 6.86 (d, 2 H), 3.72 (s, 3 H), 3.68 - 3.71 (m, 1 H), 3.56 - 3.59 (m, 1 H), 3.51 (d, 2 H), 2.05 (brs, 1 H), 1.15 (s, 3 H), 0.85 (s, 9 H), 0.03 (s, 6 H).

[0227] Step 3: To a solution of 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropanamide (10 g, 28.365 mmol) in MeOH (200 mL) was added 10% palladium hydroxide (5.178 g, 36.874 mmol) at room temperature. The RM was stirred at room temperature for 48 h under H2 pressure (70 psi). The RM was filtered through a Celite pad, washed with 10% MeOH in DCM (200 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by FCC on silica gel using 80% EtOAc in Pet. ether as the eluent to give 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-07) (5.5 g) as an off-white solid.1 1H NMR (400 MHz, DMSO-D6) δ ppm: 7.25 (s, 1H), 6.95 (s, 1H), 3.76 (d, 1H), 3.25 (d, 1H), 1.77 (s, 2H), 1.04 (s, 3H), 0.85 (s, 9H), 0.02 (s, 6H).

[0228] Preparative chiral SFC was performed on the racemic mixture of Int-07 to obtain Int-07-En1 and Int-07-En2.

[0229] Synthesis of N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-2-methyl-1-oxopropan-2-yl)-6-hydroxy-2-methylindolizine-3-carboxamide (Int-08-En1) [Chemical formula]

[0230] Step 1: To a solution of methyl 6-(benzyloxy)-2-methylindolizine-3-carboxylate (1 g, 3.39 mmol) in THF (20 mL) was added KOTMS (1.08 g, 8.46 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 5 hours. The volatiles were removed under reduced pressure. The residue was triturated with n-pentane (20 mL) and dried to give potassium 6-(benzyloxy)-2-methylindolizine-3-carboxylate (1.01 g, 93%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.85 (s, 1H), 7.49 - 7.47 (m, 2H), 7.41 - 7.37 (m, 2H), 7.35 - 7.31 (m, 1H), 7.18 (d, 1H), 6.55 (dd, 1H), 6.07 (s, 1H), 4.98 (s, 2H), 2.45 (s, 3H).

[0231] Step 2: To a solution of 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-07-En-1) (0.9 g, 3.914 mmol) in DMF (20 mL) were added DIPEA (2.7 mL, 15.6 mmol), potassium 6-(benzyloxy)-2-methylindolizine-3-carboxylate (1.0 g, 3.13 mmol), and HATU (1.8 g, 4.7 mmol) at 0 °C. The reaction mixture (RM) was stirred at 65 °C for 16 h. The RM was poured into ice water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 50% EtOAc in Pet. ether to give N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-2-methyl-1-oxopropan-2-yl)-6-(benzyloxy)-2-methylindolizine-3-carboxamide (0.7 g, 45%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.41 (s, 1 H), 7.48 (d, 2 H), 7.41 - 7.37 (m, 2 H), 7.35 - 7.33 (d, 1 H), 7.26 - 7.37 (m, 1 H), 6.99 (brs, 1 H), 6.86 (s, 1 H), 6.81 (dd, 1 H), 6.25 (s, 1 H), 5.36 (s, 1 H), 5.06 (s, 2 H), 4.32 (d, 1 H), 3.77 (d, 1 H), 2.59 (s, 3 H), 1.73 (s, 3 H), 0.91 (s, 9 H), 0.13 (s, 6 H).

[0232] Step 3: To a solution of N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-2-methyl-1-oxopropan-2-yl)-6-(benzyloxy)-2-methylindolizine-3-carboxamide (600 mg, 1.210 mmol) in ethanol (20 mL) and EtOAc (5 mL) was added Pd / C (10%) (240 mg) at room temperature. The reaction mixture (RM) was stirred at room temperature for 5 h under a H2 balloon. The RM was filtered through a pad of celite and washed with ethanol (2 × 20 mL). The filtrate was concentrated under reduced pressure to afford N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-2-methyl-1-oxopropan-2-yl)-6-hydroxy-2-methylindolizine-3-carboxamide (Int-08-En1) (490 mg, 99%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.18 (s, 1 H), 9.06 (s, 1 H), 7.41 (s, 1 H), 7.33 (d, 1 H), 7.22 (s, 1 H), 7.14 (s, 1 H), 6.68 (dd, 1 H), 6.25 (s, 1 H), 4.13 (d, 1 H), 3.97 (d, 1 H), 2.55 (s, 3 H), 1.53 (s, 3 H), 0.85 (s, 9 H), 0.007 (s, 6 H).

[0233] Int-08-En2 was prepared in a similar manner as described for Int-08-En1 (using appropriate reagents (chiral or racemic)) and purification methods known to those skilled in the art (including chiral HPLC or chiral SFC).

[0234] Synthesis of potassium 2-methyl-6-(pyridin-2-ylmethoxy)indolizine-3-carboxylate (Int-09)

Chemical Structure

[0235] Step 1: To a solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (2 g, 9.756 mmol) in dry THF (20 mL) were added ADDP (4.9 g, 19.512 mmol) and n-Bu3P (4.8 mL, 19.512 mmol) at 0 °C. After 10 minutes, pyridin-2-ylmethanol (1.2 g, 11.707 mmol) was added. The RM was stirred at room temperature for 2 h. The RM was diluted with cold water (50 mL) and extracted with EtOAc (2 × 70 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 20% EtOAc in hexane as the eluent to give methyl 2-methyl-6-(pyridin-2-ylmethoxy)indolizine-3-carboxylate (1.8 g, 62.26%) as a pale yellowish gum. 1 1H NMR (400 MHz, CDCl3) δ ppm: 9.37 (d, 1 H), 8.64 (d, 1 H), 7.76 - 7.72 (m, 1 H), 7.56 (d, 1 H), 7.30 - 7.23 (m, 2 H), 6.94 - 6.91 (dd, 1 H), 6.27 (s, 1 H), 5.21 (s, 2 H), 3.90 (s, 3 H), 2.50 (t, 3 H).

[0236] Step 2: To a solution of methyl 2-methyl-6-(pyridin-2-ylmethoxy)indolizine-3-carboxylate (400 mg, 1.350 mmol) in THF (7.0 mL) was added KOTMS (865 mg, 6.749 mmol). The RM was stirred at 70 °C for 16 h. The volatiles were removed under reduced pressure. The residue was triturated with diethyl ether (20 mL) and dried to give potassium 2-methyl-6-(pyridin-2-ylmethoxy)indolizine-3-carboxylate (Int-09) (350 mg) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ ppm: 9.83 (d, 1 H), 8.58 - 8.57 (m, 1 H), 7.86 - 7.82 (m, 1 H), 7.58 (d, 1 H), 7.36 (m, 1 H), 7.22 (d, 1 H), 6.62 - 6.59 (dd, 1 H), 6.08 (s, 1 H), 5.06 (d, 2 H), 2.44 (s, 3 H).

[0237] Synthesis of 3 - amino - 3 - (hydroxymethyl)pyrrolidin - 2 - one (Int - 10 - En1) and (Int - 10 - En2).

Chemical Structure

[0238] Step 1: To a stirred solution of diethyl 2-(2-(1,3 - dioxoisoindolin - 2 - yl)ethyl)malonate (60 g, 179.99 mmol) in 1,4 - dioxane (600 mL) was added TEA (49.90 mL, 359.99 mmol) at 0 °C. After 15 minutes, formaldehyde (29.18 g, 359.99 mmol) was added at 0 °C. The reaction mixture (RM) was warmed to room temperature and stirred at 80 °C for 16 h. The RM was diluted with ice - cold water (200 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 40% EtOAc in pet ether to give diethyl 2-(2-(1,3 - dioxoisoindolin - 2 - yl)ethyl)-2-(hydroxymethyl)malonate (59 g, 90%) as a pale yellow gum. 1 1H NMR (400 MHz, CDCl3) δ ppm: 7.86 - 7.82 (m, 2 H), 7.74 - 7.69 (m, 2 H), 4.25 - 4.18 (m, 4 H), 4.07 (d, 2 H), 3.83 - 3.79 (m, 2 H), 2.79 (t, 1 H), 2.33 - 2.30 (m, 2 H), 1.28 (t, 6 H).

[0239] Step 2: Imidazole (25.48 g, 374.27 mmol) was added to a stirred solution of diethyl 2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2-(hydroxymethyl)malonate (68 g, 187.13 mmol) in DCM (700 mL) at 0 °C. After 15 minutes, tert-butyldimethylsilyl chloride (33.84 g, 224.56 mmol) was added at 0 °C. The reaction mixture (RM) was stirred at room temperature for 16 h. The RM was diluted with ice-cold water (300 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 10% EtOAc in pet ether to give diethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)malonate (68 g, 77%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.84 - 7.82 (m, 2 H), 7.71 - 7.69 (m, 2 H), 4.18 - 4.11 (m, 6 H), 3.76 - 3.72 (m, 2 H), 2.41 - 2.37 (m, 2 H), 1.26 (t, 6 H), 0.89 (s, 9 H), 0.08 (s, 6 H).

[0240] Step 3: Hydrazine hydrate (10.69 g, 213.55 mmol) was added to a stirred solution of diethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)malonate (68 g, 142.37 mmol) in ethanol (700 mL) at 0 °C. The RM was stirred at room temperature for 16 h. The RM was diluted with ice-cold water (300 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 30% EtOAc in Pet. ether to give ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylate (30.7 g, 71%) as an off-white solid.1 1H NMR (400 MHz, CDCl3) δ ppm: 5.76 (s, 1H), 4.22 - 4.17 (m, 2H), 4.06 (d, 1H), 3.94 (d, 1H), 3.46 - 3.42 (m, 1H), 3.36 - 3.35 (m, 1H), 2.59 - 2.55 (m, 1H), 2.49 - 2.43 (m, 1H), 1.27 (t, 3H), 0.87 (d, 9H), 0.06 (d, 6H).

[0241] Step 4: To a solution of ethyl 3 - ((((tert - butyldimethylsilyl)oxy)methyl)-2 - oxopyrrolidine - 3 - carboxylate (29 g, 96.19 mmol) in EtOH (120 mL), THF (60 mL), and H2O (30 mL) was added LiOH·H2O (20.18 g, 480.99 mmol) at 0 °C. The RM was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. The residue was diluted with cold water (20 mL) and then acidified with saturated aqueous citric acid (pH ~ 4). The solid was filtered, washed with water (10 mL), followed by water (10 mL), and dried under vacuum to give 3 - ((((tert - butyldimethylsilyl)oxy)methyl)-2 - oxopyrrolidine - 3 - carboxylic acid (16.7 g, 63%) as a white solid. 1 1H NMR (400 MHz, DMSO - d6) δ ppm: 7.82 (s, 1H), 3.88 (d, 1H), 3.70 (d, 1H), 3.27 - 3.21 (m, 1H), 3.17 - 3.12 (m, 1H), 2.34 - 2.32 (m, 1H), 2.24 - 2.22 (m, 1H), 0.84 (s, 9H), 0.01 (d, 6H).

[0242] Step 5: To a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylic acid (9.5 g, 34.74 mmol) in THF (40 mL) and benzene (120 mL) was added TEA (14.65 mL, 104.24 mmol), followed by DPPA (19.12 g, 69.49 mmol) at room temperature. The reaction mixture (RM) was stirred at room temperature for 2 h. The RM was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 × 50 mL), brine solution (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (40 mL) and benzene (120 mL). Then, benzyl alcohol (7.51 g, 69.49 mmol) was added at room temperature. The RM was stirred at 55 °C for 16 h. The RM was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0 - 40% EtOAc in Pet. ether to give benzyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate (9 g, 68%). 1 H NMR (400 MHz, CDCl3) δ ppm: 7.37 - 7.29 (m, 5 H), 5.84 (brs, 1 H), 5.42 (brs, 1 H), 5.07 (s, 2 H), 3.85 (d, 1 H), 3.67 (d, 1 H), 3.39 - 3.33 (m, 2 H), 2.63 - 2.62 (m, 1 H), 2.53 - 2.51 (m, 1 H), 0.88 (s, 9 H), 0.05 (d, 6 H).

[0243] Step 6: To a stirred solution of benzyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate (11 g, 29.05 mmol) in MeOH (150 mL) was added PTSA monohydrate (2.21 g, 11.62 mmol) in MeOH (50 mL) at 0 °C over 2 h. The RM was stirred at room temperature for 16 h. The RM was concentrated under reduced pressure. The residue was quenched with ice-cold water (50 mL) and extracted with 10% MeOH in DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with n-pentane (3 × 15 mL), followed by diethyl ether (15 mL), filtered, and dried under vacuum to give benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate (7 g, 91%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.66 (s, 1H), 7.38 - 7.29 (m, 5H), 7.08 (s, 1H), 4.98 - 4.95 (m, 3H), 3.46 - 3.38 (m, 2H), 3.18 - 3.15 (m, 1H), 3.13 - 3.07 (m, 1H), 2.28 - 2.25 (m, 2H). 3.5 g of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate was purified by chiral SFC preparative separation. [Preparative SFC conditions: Column: Chiral peak IF (250 × 30 × 5 μm), CO2%: 65%, co-solvent%: 35% (100% methanol), total flow rate: 90 g / min, back pressure: 100.0 bar, temperature: 30 °C, wavelength: 215 nm, stacking time: 7.2 min, solubility: 100 ml of MeOH.] The collected pure fractions were concentrated under reduced pressure to give two isomers En1 (first elution) and En2 (second elution).

[0244] Step 7: To a stirred solution of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate En1 (1.4 g, 5.297 mmol) in ethanol (30 mL) was added Pd / C (450 mg) at room temperature. The reaction mixture (RM) was stirred at room temperature for 16 h under H2 (70 psi). The RM was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (2 × 5 mL) and dried under high vacuum to give 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-10-En1) (610 mg, 88%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (s, 1 H), 4.73 (t, 1 H), 3.36 - 3.34 (m, 1 H), 3.18 - 3.12 (m, 2 H), 3.10 - 3.04 (m, 1 H), 2.22 - 2.15 (m, 1 H), 1.76 - 1.72 (m, 1 H), 1.56 (s, 2 H). UPLC: Rt = 2.29 min (98%).

[0245] Step 8: To a stirred solution of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate En2 (1.2 g, 4.54 mmol) in ethanol (30 mL) was added Pd / C (350 mg) at room temperature. The reaction mixture (RM) was stirred at room temperature for 16 h under H2 (70 psi). The RM was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (2 × 5 mL) and dried under high vacuum to give 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-10-En2) (550 mg, 93%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (s, 1 H), 4.73 (brs, 1 H), 3.36 - 3.32 (m, 1 H), 3.18 - 3.12 (m, 2 H), 3.10 - 3.04 (m, 1 H), 2.22 - 2.15 (m, 1 H), 1.76 - 1.71 (m, 1 H), 1.57 (s, 2 H).

[0246] Synthesis of Potassium 6-(Cyclopropylmethoxy)-2-methylindolizine-3-carboxylate (Int-11)

Chem.

[0247] Step 1: Cesium carbonate (14.28 g, 43.857 mmol) was added to a solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (3 g, 14.61 mmol) and (bromomethyl)cyclopropane (2.96 g, 21.928 mmol) in ACN (50 mL) at room temperature. The reaction mixture (RM) was stirred at 70 °C for 16 h. The RM was diluted with EtOAc (50 mL), washed with water (2 × 50 mL) and brine (50 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica gel using 20% EtOAc in Pet. ether as the eluent to give methyl 6-(cyclopropylmethoxy)-2-methylindolizine-3-carboxylate (3.5 g, 92%) as an orange solid. 1 1H NMR (400 MHz, DMSO-D6) δ ppm: 9.06 (s, 1 H), 7.49 (d, 1 H), 6.97 (d, 1 H), 6.39 (s, 1 H), 3.82 (s, 3 H), 3.81 - 3.85 (m, 2 H), 2.50 (s, 3 H), 1.21 - 1.27 (m, 1 H), 0.56 - 0.61 (m, 2 H), 0.37 - 0.39 (m, 2 H).

[0248] Step 2: KOTMS (2.47 g, 19.28 mmol) was added to a solution of methyl 6-(cyclopropylmethoxy)-2-methylindolizine-3-carboxylate (1 g, 3.85 mmol) in THF (50 mL) at room temperature. The RM was stirred at 70 °C for 16 h. The volatiles were removed under reduced pressure. The residue was triturated with n-pentane (30 mL) and dried under vacuum to give potassium 6-(cyclopropylmethoxy)-2-methylindolizine-3-carboxylate (Int-11) (1.6 g, 90%) as a brown solid. 11H NMR (400 MHz, DMSO-D6) δ ppm: 9.68 (s, 1 H), 7.15 (d, 1 H), 6.48 (dd, 1 H), 6.04 (s, 1 H), 3.70 (d, 2 H), 2.43 (s, 3 H), 1.20 - 1.25 (m, 1 H), 0.54 - 0.59 (m, 2 H), 0.32 - 0.36 (m, 2 H).

[0249] Synthesis of Potassium 6-(2,2-difluoroethoxy)-2-methylindolizine-3-carboxylate (Int-12)

Chemical Structure

[0250] Step 1: To a solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (3.0 g, 0.015 mmol) in ACN (30 mL) was added Cs2CO3 (11.908 g, 0.037 mmol) and 1,1-difluoro-2-iodoethane (3.366 g, 0.018 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL), extracted with EtOAc (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 10% EtOAc in pet ether as the gradient to give methyl 6-(2,2-difluoroethoxy)-2-methylindolizine-3-carboxylate (2.3 g, 58.43%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-D6) δ ppm: 9.25 (s, 1 H), 7.26 - 7.30 (m, 1 H), 6.82 - 6.85 (td, 1 H), 6.29 (s, 1 H), 5.95 - 6.25 (tt, 1 H), 4.17 - 4.24 (m, 2 H), 3.91 - 3.93 (d, 3 H), 2.50 - 2.51 (m, 3 H).

[0251] Step 2: To a solution of methyl 6-(2,2-difluoroethoxy)-2-methylindolizine-3-carboxylate (400 mg, 1.486 mmol) in THF (10.0 mL) was added KOTMS (952 mg, 7.428 mmol) at room temperature, and the mixture was stirred at 70 °C for 16 h. After cooling to room temperature, the volatiles were removed under reduced pressure. The residue was triturated with n-pentane (3 × 5 mL) and dried under reduced pressure to afford potassium 6-(2,2-difluoroethoxy)-2-methylindolizine-3-carboxylate (Int-12) (300 mg, 79%). 1 H NMR (400 MHz, DMSO-D6) δ ppm: 9.81 (d, 1 H), 7.21 (d, 1 H), 6.54 - 6.57 (dd, 1 H), 6.23 - 6.38 (tt, 1 H), 6.11 (s, 1 H), 4.14 - 4.22 (m, 2 H), 2.45 (s, 3 H).

[0252] Synthesis of methyl 2-methyl-6-((2-methylthiazol-5-yl)methoxy)indolizine-3-carboxylate (Int-13)

Chemical Structure

[0253] Step 1: To a solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (2 g, 9.746 mmol) in DMF (10 mL) were added Cs2CO3 (9.52 g, 29.23 mmol) and methyl 2-methyl-6-((2-methylthiazol-5-yl)methoxy)indolizine-3-carboxylate (1.7 g, 11.69 mmol) at 0 °C. The reaction mixture (RM) was stirred at room temperature for 16 h. The RM was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 20% EtOAc in pet ether to afford methyl 2-methyl-6-((2-methylthiazol-5-yl)methoxy)indolizine-3-carboxylate (Int-13) as a brown solid (1.5 g, 48.65%). 11H NMR (400 MHz, DMSO-d6) δ ppm: 9.16 (d, 1 H), 7.73 (s, 1 H), 7.52 (d, 1 H), 7.01 (dd, 1 H), 6.41 (s, 1 H), 5.33 (s, 2 H), 3.84 (s, 3 H), 2.63 (s, 3 H), 2.44 (s, 3 H).

[0254] Synthesis of potassium 2-methyl-6-((2-methylthiazol-5-yl)methoxy)indolizine-3-carboxylate (Int-14)

Chemical Structure

[0255] Step 1: To a solution of methyl 2-methyl-6-((2-methylthiazol-5-yl)methoxy)indolizine-3-carboxylate (1.4 g, 4.425 mmol) in 1,4-dioxane / MeOH (25 mL) was added KOH (1.241 g, 22.126 mmol) at room temperature, and the mixture was stirred at 50 °C for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was triturated with n-pentane (50.0 mL) and dried to give potassium 2-methyl-6-((2-methylthiazol-5-yl)methoxy)indolizine-3-carboxylate (Int-14) (1.8 g) as a brown solid.

[0256] Synthesis of 2-amino-4,4-difluoro-2-methylbutan-1-ol (Int-15).

Chemical Structure

[0257] Step 1: Ethyl 2-((diphenylmethylene)amino)acetate (30 g, 112.22 mmol) was added to a solution of t-BuOK (13.2 g, 117.83 mmol) in DMF (150 mL) at 0 °C. After 30 minutes, 1,1-difluoro-2-iodoethane (24.9 g, 130.18 mmol) was added dropwise at 0 °C over 10 minutes. The reaction mixture (RM) was stirred at 0 °C for 1 hour. After completion of the reaction, the RM was diluted with 5% aqueous NH4Cl solution (100.0 mL) and extracted with EtOAc (3 × 50.0 mL). The combined organic layers were washed with brine (100.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 5% EtOAc in pet ether as the eluent to afford ethyl 2-((diphenylmethylene)amino)-4,4-difluorobutanoate (30 g, 80.67%) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.63 - 7.65 (m, 2 H), 7.39 - 7.48 (m, 4 H), 7.31 - 7.36 (m, 2 H), 7.18 - 7.20 (m, 2 H), 5.75 - 5.91 (m, 1 H), 4.27 - 4.30 (m, 1 H), 4.14 - 4.19 (m, 2 H), 2.45 - 2.53 (m, 2 H), 1.25 (t, 3 H).

[0258] Step 2: Ethyl N-(diphenylmethylene)glycinate (20 g, 331.36 mmol) was added to a solution of t-BuOK (7.450 g, 112.21 mmol) in DMF (30 mL) at 0 °C. After 30 minutes, iodomethane (42.83 g, 141.93 mmol) was added dropwise at 0 °C over 10 minutes. The RM was stirred at 0 °C for 1 hour. After completion of the reaction, the RM was diluted with 5% aqueous NH4Cl solution (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 10% EtOAc in pet ether as the eluent to afford ethyl 2-((diphenylmethylene)amino)-4,4-difluoro-2-methylbutanoate (16 g, 76.75%) as a pale yellow liquid. 11H NMR (400 MHz, CDCl3) δ ppm: 7.50 - 7.59 (m, 2H), 7.36 - 7.41 (m, 4H), 7.28 - 7.32 (m, 2H), 7.13 - 7.15 (m, 2H), 6.16 - 6.49 (m, 1H), 3.69 - 3.77 (m, 2H), 2.31 - 2.57 (m, 2H), 1.44 (s, 3H), 1.11 (t, 3H).

[0259] Step 3: To a solution of ethyl 2 - ((diphenylmethylene)amino)-4,4 - difluoro - 2 - methylbutanoate (16 g, 46.32 mmol) in Pet. ether (75 mL) was added 1N HCl (150 mL) at room temperature. The RM was stirred at room temperature for 16 h. The RM was washed with EtOAc (2 × 50 mL). The aqueous solution was basified with NaHCO3 (pH about 8) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give ethyl 2 - amino - 4,4 - difluoro - 2 - methylbutanoate (5.910 g, 70.42%) as a pale yellow liquid. 1 1H NMR (400 MHz, CDCl3) δ ppm: 5.87 - 6.15 (m, 1H), 4.17 - 4.12 (m, 2H), 2.04 - 2.33 (m, 2H), 1.39 (s, 3H), 1.27 (t, 3H).

[0260] Step 4: To a solution of ethyl 2 - amino - 4,4 - difluoro - 2 - methylbutanoate (5.6 g, 30.90 mmol) in EtOH (50 mL) was added sodium borohydride (3.508 mg, 92.72 mmol) at 0 °C. The RM was stirred at room temperature for 7 h. The RM was quenched with water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 2 - amino - 4,4 - difluoro - 2 - methylbutan - 1 - ol (2.3 g, 53%) as a colorless rubbery solid. 1 1H NMR (400 MHz, DMSO - D6) δ ppm: 6.02 - 6.33 (m, 1H), 4.76 (t, 1H), 3.09 - 3.19 (m, 2H), 1.75 - 1.87 (m, 2H), 1.48 (br, s, 2H), 0.95 (s, 3H).

[0261] Synthesis of Potassium 2-Methyl-6-(pyridin-3-ylmethoxy)indolizine-3-carboxylate (Int-15)

Chem.

[0262] Step 1: To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (400 mg, 1.949 mmol) in dry THF (5 mL) were added ADDP (0.984 g, 3.898 mmol), tri-n-butylphosphine (0.962 mL, 3.898 mmol), and pyridin-3-ylmethanol (0.2 mL, 2.144 mmol) at 0 °C. The RM was stirred at room temperature for 2 h. The RM was quenched with ice-cold water (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 30% EtOAc in Pet. ether as the eluent to afford methyl 2-methyl-6-(pyridin-3-ylmethoxy)indolizine-3-carboxylate (500 mg, 87%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.33 (s, 1 H), 8.72 (s, 1 H), 8.61 - 8.59 (m, 1 H), 7.82 - 7.79 (m, 1 H), 7.36 - 7.32 (m, 1 H), 7.29 (d, 1 H), 6.86 (dd, 1 H), 6.28 (s, 1 H), 5.09 (s, 2 H), 3.91 (s, 3 H), 2.51 (s, 3 H).

[0263] Step 2: Potassium trimethylsilanolate (KOTMS, 487 mg, 3.796 mmol) was added to a solution of methyl 2-methyl-6-(pyridin-3-ylmethoxy)indolizine-3-carboxylate (450 mg, 1.519 mmol) in THF (7 mL) at room temperature. The reaction mixture (RM) was stirred at 70 °C for 16 h. Volatiles were removed under reduced pressure. The residue was triturated with n-pentane (30 mL) and dried under reduced pressure to afford potassium 2-methyl-6-(pyridin-3-ylmethoxy)indolizine-3-carboxylate (Int-15, 500 mg) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.88 (d, 1 H), 8.69 (d, 1 H), 8.52 - 8.54 (m, 1 H), 7.92 - 7.89 (m, 1 H), 7.44 - 7.41 (m, 1 H), 7.18 (d, 1 H), 6.55 (dd, 1 H), 6.07 (s, 1 H), 5.03 (s, 2 H), 2.44 (s, 3 H).

[0264] Synthesis of potassium 6-((2-methoxypyridin-3-yl)methoxy)-2-methylindolizine-3-carboxylate (Int-16)

Chemical Structure

[0265] Step 1: To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (400 mg, 1.949 mmol) in dry THF (7 mL) were added ADDP (0.984 mg, 3.898 mmol), n-Bu3P (0.962 mL, 3.898 mmol), and (2-methoxypyridin-3-yl)methanol (298 mg, 2.144 mmol) at 0 °C. The RM was stirred at room temperature for 2 h. After the reaction was complete, the RM was diluted with cold water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 30% EtOAc in hexane as the eluent to afford methyl 6-((2-methoxypyridin-3-yl)methoxy)-2-methylindolizine-3-carboxylate (400 mg, 63%) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ ppm: 9.32 (d, 1 H), 8.14 (dd, 1 H), 7.80 - 7.77 (m, 1 H), 7.27 (t, 1 H), 6.94 - 6.88 (m, 2 H), 6.27 (s, 1 H), 5.06 (s, 2 H), 4.01 (s, 3 H), 3.91 (s, 3 H), 2.51 (s, 3 H).

[0266] Step 2: To a stirred solution of methyl 6-((2-methoxypyridin-3-yl)methoxy)-2-methylindolizine-3-carboxylate (400 mg, 1.226 mmol) in THF (7 mL) was added KOTMS (393 mg, 3.064 mmol) at room temperature. The RM was stirred at 70 °C for 16 h. The volatiles were removed under reduced pressure. The residue was triturated with n-pentane (5 mL) and filtered to afford potassium 6-((2-methoxypyridin-3-yl)methoxy)-2-methylindolizine-3-carboxylate (Int-16) (500 mg) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ ppm: 9.85 (s, 1H), 8.15 (dd, 1H), 7.86 (dd, 1H), 7.19 (d, 1H), 7.05 - 7.02 (m, 1H), 6.56 (dd, 1H), 6.07 (s, 1H), 4.94 (s, 2H), 3.93 (s, 3H), 2.49 (s, 3H).

[0267] Synthesis of potassium 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indolizine-3-carboxylate (Int-17)

Chemical Structure

[0268] Step 1: To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (1.2 g, 5.848 mmol, 1 eq) in dry THF (20 mL) were added ADDP (2.951 g, 11.695 mmol), n-Bu3P (2.886 mL, 11.695 mmol), and (2-(trifluoromethyl)pyridin-3-yl)methanol (1.346 g, 7.602 mmol) at 0 °C. The reaction mixture (RM) was stirred at room temperature for 16 h. The RM was diluted with cold water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 30% EtOAc in Pet. ether as the eluent to give methyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indolizine-3-carboxylate (800 mg, 37%) as a gray solid. 1 1H NMR (400 MHz, CDCl3) δ ppm: 9.31 (d, 1H), 8.68 (d, 1H), 8.16 (dd, 1H), 7.58 - 7.54 (m, 1H), 7.31 (d, 1H), 6.88 (dd, 1H), 6.30 (s, 1H), 5.29 (s, 2H), 3.91 (s, 3H), 2.51 (s, 3H).

[0269] Step 2: Potassium trimethylsilanolate (KOTMS) (550 mg, 4.117 mmol) was added to a stirred solution of methyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indolizine-3-carboxylate (600 mg, 1.647 mmol) in THF (15 mL) at room temperature. The RM was stirred at 70 °C for 16 h. The volatiles were removed under reduced pressure. The residue was triturated with pentane (40 mL), filtered, and dried under high vacuum to give potassium 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)indolizine-3-carboxylate (Int-17) (850 mg) as an off-white solid. 1 H NMR (400 MHz, CD3OD) δ ppm: 9.42 (d, 1 H), 8.64 (d, 1 H), 8.28 (d, 1 H), 7.72 - 7.69 (m, 1 H), 7.24 (d, 1 H), 6.73 (dd, 1 H), 6.20 (s, 1 H), 5.26 (s, 2 H), 2.53 (s, 3 H).

[0270] Synthesis of potassium 6-((4-fluoro-1-methyl-1H-pyrazol-5-yl)methoxy)-2-methylindolizine-3-carboxylate (Int-18)

Chemical formula

[0271] Step 1: To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (400 mg, 1.95 mmol) in dry THF (7 mL) were added ADDP (0.983 g, 3.9 mmol), n-Bu3P (0.96 mL, 3.9 mmol), and (4-fluoro-1-methyl-1H-pyrazol-5-yl)methanol (0.304 g, 2.3 mmol) at 0 °C. The RM was stirred at room temperature for 2 h. The RM was diluted with cold water (40 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0–50% EtOAc in Pet. ether to give methyl 6-((4-fluoro-1-methyl-1H-pyrazol-5-yl)methoxy)-2-methylindolizine-3-carboxylate (500 mg, 81%) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ ppm: 9.34 (d, 1 H), 7.32 - 7.28 (m, 2 H), 6.81 (dd, 1 H), 6.29 (s, 1 H), 5.05 (s, 2 H), 3.92 (m, 3 H), 3.89 (s, 3 H), 2.51 (s, 3 H).

[0272] Step 2: To a stirred solution of methyl 6-((4-fluoro-1-methyl-1H-pyrazol-5-yl)methoxy)-2-methylindolizine-3-carboxylate (450 mg, 1.42 mmol) in THF (8 mL) was added KOTMS (455 mg, 3.55 mmol) at room temperature. The RM was stirred at 70 °C for 16 h. The volatiles were removed under reduced pressure. The residue was triturated with n-pentane (20 mL) and dried under vacuum to give potassium 6-((4-fluoro-1-methyl-1H-pyrazol-5-yl)methoxy)-2-methylindolizine-3-carboxylate (Int-18) (500 mg) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6) δ ppm: 9.88 (d, 1 H), 7.46 - 7.45 (d, 1 H), 7.20 (d, 1 H), 6.55 (dd, 1 H), 6.08 (s, 1 H), 5.03 (s, 2 H), 3.86 (s, 3 H), 2.44 (s, 3 H).

[0273] Synthesis of Potassium 2-Methyl-6-(pyrazin-2-ylmethoxy)indolizine-3-carboxylate (Int-19)

Chem.

[0274] Step 1: To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (0.8 g, 3.9 mmol) in ACN (20 mL) was added cesium carbonate (3.81 g, 11.7 mmol) at 0 °C. After 5 minutes, 2-(chloromethyl)pyrazine (0.752 g, 5.848 mmol) was added at 0 °C. The reaction mixture (RM) was stirred at 80 °C for 2 h. The RM was diluted with water (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (30 mL), dried over Na2SO4, filtered, and concentrated under reduce...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, 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 This represents, R ２ is, -R Ｙ This represents, R ３ is -OH or -R Ｙ This represents, R ４ is, -R Ｙ or -S (=O) ２ R Ｙ Does it represent, Alternatively, R ３ and R ４ Together, they form saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted 4, 5, 6, 7, or 8-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S. T represents -O-, and U represents -CR ５ R ５ '- represents, or T is -CR ５ R ５ ' represents -, and U represents -O-, R ５ and R ５ ' are independent of each other, -R Ｙ This represents, R ６ , R ７ , and R ８ These are -F, -Cl, -Br, -I, -CN, and -NO, which are independent of each other. 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 This represents, V is a saturated or unsaturated 3- to 14-membered heterocycloalkyl, a saturated or unsaturated 3- to 14-membered cycloalkyl, a 5- to 14-membered aryl, C １ -C ６ Represents an alkyl or 5- to 14-membered heteroaryl group, in all cases unsubstituted and independently of each other: -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 It is monosubstituted or polysubstituted with a substituent selected from the following: R Ｗ and R Ｘ They are independent of each other, and in each case, they are independent of each other. -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 group, wherein the 3- to 14-membered cycloalkyl group is optionally -C １ -C ６ -Alkylene- or -C １ -C ６ A 3- to 14-membered cycloalkyl group connected via a heteroalkylene (in any case, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted); or A saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted 3- to 14-member heterocycloalkyl, wherein the 3- to 14-member 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 connected via a 3- to 14-member heterocycloalkyl, This represents, R Ｙ and R Ｚ They are independent of each other, and in each case, they are independent of each other. -H; Saturated or unsaturated, unsubstituted, mono-substituted or multi-substituted -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 group, wherein the 3- to 14-membered cycloalkyl group is optionally -C １ -C ６ -Alkylene- or -C １ -C ６ 3- to 14-membered cycloalkyls connected via heteroalkylenes (which are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted in all cases); A saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group, wherein the 3- to 14-membered heterocycloalkyl group is optionally composed of -C １ -C ６ -Alkylene- or -C １ -C ６ 3- to 14-membered heterocycloalkyls connected via heteroalkylenes (which are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted in all cases); Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryls, wherein the 6- to 14-membered aryls are optionally -C １ -C ６ -Alkylene- or -C １ -C ６ - A 6- to 14-membered aryl linked via a heteroalkylene (in any case, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted); or Unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryls, wherein the 5- to 14-membered heteroaryl is optionally -C １ -C ６ -Alkylene- or -C １ -C ６ 5- to 14-membered heteroaryls connected via heteroalkylenes (which in all cases are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted). Does it represent, Alternatively, R Ｙ and R Ｚ Together, they form saturated or unsaturated, unsubstituted, or monosubstituted or polysubstituted 4, 5, 6, 7, or 8-membered heterocycles containing 1 to 3 heteroatoms selected from N, O, and S. Here, "single substitution or multiple substitution" refers to -F, -Cl, -Br, -I, -CN, and -C, independently in both cases. １－６ -Alkyl, -CF ３ , -CF ２ H, -CFH ２ , -CF ２ Cl, -CFCl ２ , -C １－６ -Alkilen-CF ３ , -C １－６ -Alkilen-CF ２ H, -C １－６ -Alkilen-CFH ２ , -C １－６ -Alkilen-O-CF ３ , -C １－６ -Alkilen-O-CF ２ H, -C １－６ -Alkylene-O-CFH ２ , -C １－６ - Alkilen-NH-C １－６ -Alkilen-CF ３ , -C １－６ -Alkylene-N(C) １－６ -Alkyl)-C １－６ -Alkilen-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 -Alkilen-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 -Alkilen-NH ２ , -O-C １－６ - Alkilen-NH-C １－６ -alkyl, -O-C １－６ -Alkylene-N(C) １－６ -Alkyl) ２ , -OC(=O)-C １－６ -Alkyl, -C １－６ -Alkylene-O-C(=O)-C １－６ -Alkyl, -O-C (=O)-O-C １－６ -Alkyl, -C １－６ -Alkylene-O-C(=O)-O-C １－６ -alkyl, -O-C(=O)-NH(C １－６ -Alkyl), -C １－６ -Alkylene-O-C(=O)-NH(C) １－６ -alkyl), -O-C(=O)-N(C １－６ -Alkyl) ２ , -C １－６ -Alkylene-O-C(=O)-N(C) １－６ -Alkyl) ２ , -O-S (=O) ２ -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 -Alkilen-NH ２ ,-NH(C １－６ -alkyl), -N (3-14 member cycloalkyl) (C １－６ -alkyl), -N(C １－６ -Alkyl)-C １－６ -Alkylene-OH, -N(H)-C １－６ -Alkylene-OH, -C １－６ -Alkilen-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 -Alkilen-NH-C(=O)-C １－６ -Alkyl, -NH-C(=O)-O-C １－６ -Alkyl, -C １－６ -Alkilen-NH-C(=O)-O-C １－６ -alkyl, -NH-C(=O)-NH ２ , -C １－６ -Alkilen-NH-C(=O)-NH ２ , -NH-C(=O)-NH(C １－６ -Alkyl), -C １－６ -Alkilen-NH-C(=O)-NH(C) １－６ -alkyl), -NH-C(=O)-N(C １－６ -Alkyl) ２ , -C １－６ -Alkylene-NH-C(=O)-N(C) １－６ -Alkyl) ２ , -N(C １－６ -Alkyl)-C(=O)-C １－６ -Alkyl, -C １－６ -Alkylene-N(C) １－６ -Alkyl)-C(=O)-C １－６ -alkyl, -N(C) １－６ -Alkyl)-C(=O)-O-C １－６ -Alkyl, -C １－６ -Alkylene-N(C) １－６ -Alkyl)-C(=O)-O-C １－６ -alkyl, -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 -alkyl), -N(C １－６ -alkyl)-C(=O)-N(C １－６ -Alkyl) ２ , -C １－６ -Alkylene-N(C) １－６ -alkyl)-C(=O)-N(C １－６ -Alkyl) ２ , -NH-S (=O) ２ OH, -C １－６ -Alkilen-NH-S(=O) ２ OH, -NH-S (=O) ２ -C １－６ -Alkyl, -C １－６ -Alkilen-NH-S(=O) ２ -C １－６ -alkyl, -NH-S (=O) ２ -O-C １－６ -Alkyl, -C １－６ -Alkilen-NH-S(=O) ２ -O-C １－６ -alkyl, -NH-S (=O) ２ -NH ２ , -C １－６ -Alkilen-NH-S(=O) ２ -NH ２ , -NH-S (=O) ２ -NH(C) １－６ -Alkyl), -C １－６ -Alkilen-NH-S(=O) ２ -NH(C) １－６ -alkyl), -NH-S (=O) ２ N(C) １－６ -Alkyl) ２ , -C １－６ -Alkilen-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 -Alkilen-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 -Alkilen-S (=O) ２ -C １－６ -alkyl, -S (=O) ２ -OH, -C １－６ -Alkilen-S (=O) ２ -OH, -S (=O) ２ -O-C １－６ -Alkyl, -C １－６ -Alkilen-S (=O) ２ -O-C １－６ -alkyl, -S (=O) ２ -NH ２ , -C １－６ -Alkilen-S (=O) ２ -NH ２ , -S (=O) ２ -NH(C) １－６ -Alkyl), -C １－６ -Alkilen-S (=O) ２ -NH(C) １－６ -alkyl), -S (=O) ２ -N(C) １－６ -Alkyl) ２ , -C １－６ -Alkilen-S (=O) ２ -N(C) １－６ -Alkyl) ２ , 3-14 member cycloalkyl, -C １－６ -Alkylene-(3-14 member cycloalkyl), 3-14 member heterocycloalkyl, -C １－６ -Alkylene-(3-14 member heterocycloalkyl), -phenyl, -C １－６ -alkylene-phenyl, 5-14 member heteroaryl, -C １－６ -alkylene-(5-14 member heteroaryl), -O-(3-14 member cycloalkyl), -O-(3-14 member heterocycloalkyl), -O-phenyl, -O-(5-14 member heteroaryl), -C(=O)-(3-14 member cycloalkyl), -C(=O)-(3-14 member heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5-14 member heteroaryl), -S(=O) ２ - (3-14 member cycloalkyl), -S (=O) ２ - (3-14 member heterocycloalkyl), -S (=O) ２ -phenyl, -S (=O) ２ - This means that it is substituted with one or more substituents independently selected from (5- to 14-membered heteroaryl groups). Compounds represented by, or their stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs.

2. R ３ The compound described in claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, which represent -H.

3. The compound according to Claim 2, or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, wherein R4 represents a residue other than -H.

4. R １ The compound according to claim 1 or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, which represent -methyl or ethyl.

5. T represents -O-, and U represents -CR ５ R ５ A compound according to claim 1 or its stereoisomer, physiologically acceptable salt, solvate and / or polymorph representing '-'.

6. R ５ and R ５’ Each of the above R represents Ｙ The compound according to claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein H is present.

7. V is a 5- to 14-membered heteroaryl selected from (i) benzimidazole, benzisoxazole, benzoazole, benzodioxol, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furan, furazan, imidazole, imidazopyridine, indazole, indole, indidine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxiindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, in all cases being unsubstituted and independently of each other -F, -Cl, -CN, -OH, =O, -C １－６ -alkyl, -CHF ２ , -CF ３ , -C １－６ -Alkilen-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 -Alkilen-CF ３ , -C １－６ -alkylene-cyclopropyl, -cyclopropyl, -O-cyclopropyl, -C １－６ -Alkilen-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 -It is monosubstituted or polysubstituted with substituents selected from alkyl-substituted -piperazines, and in particular, in both cases, it is unsubstituted, and independently of each other, -F, -Cl, -CN, -OH, =O, -C １－６ -alkyl, -CHF ２ , -CF ３ , -C １－６ -Alkilen-NH ２ , -C １－６ -Alkylene-NHC(=O)O-C １－６ -Alkyl, -C １－６ -Alkylene-OH, -C １－６ -Alkilen-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 The compound according to claim 1, or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, representing a 5- to 14-membered heteroaryl compound monosubstituted or polysubstituted with substituents selected from alkyl-substituted piperazines, or (ii) an unsubstituted, monosubstituted or polysubstituted oxetanyl compound.

8. The saturated or unsaturated 3- to 14-membered cycloalkyl groups within the definition of V include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, which are uncondensed, uncrosslinked, condensed, or crosslinked cycloalkyl groups, and in all cases are unsubstituted and independently of each other -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 claim 1 or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, which are monosubstituted or polysubstituted with substituents selected from the above.

9. The 5-14 member aryls in the definition of V are unsubstituted and independent of each other, -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 claim 1 or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, which are phenyl or other 5- to 14-membered aryl compounds that are monosubstituted or polysubstituted with substituents selected from the above.

10. The 3-14 member heterocycloalkyls in the definition of V are 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, thiethane, thiran, thiolane, thiomorpholine, indoline, dihy Selected from dilobenzofuran, dihydrobenzothiophene, 1,1-dioxotiacyclohexane, 2-azabispiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azabispiro[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, in all cases unsubstituted and independently of each other, -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 claim 1 or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, which are monosubstituted or polysubstituted with substituents selected from the above.

11. V is saturated or unsaturated, unsubstituted, and independently of each other, -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 C is monosubstituted or polysubstituted with substituents selected from the above. １ -C ６ Alkyl or C １ -C ６ A compound according to claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs representing a heteroalkyl group.

12. The compound according to claim 1 or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, wherein V is a residue selected from the group consisting of the following. 【Chemistry 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 -Alkilen-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 -Alkilen-CF ３ , -C １－６ -Alkilen-CF ２ H, -C １－６ -Alkilen-CFH ２ , -C １－６ - Alkilen-NH-C １－６ -Alkilen-CF ３ , -C １－６ -Alkylene-N(C) １－６ -Alkyl)-C １－６ -Alkilen-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 A compound according to claim 1, or a stereoisomer, physiologically acceptable salt, solvate, and / or polymorph thereof, representing an alkyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl.

14. R ３ However, -H, -OH, -C １－６ -Alkyl, -C １－６ -Alkylene-OH, -C １－６ -Alkylene-O-C １－６ -Alkyl, -C １－６ -Alkilen-NH ２ , -C １－６ -Alkilen-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 -Alkilen-CF ３ , -C １－６ -Alkilen-CF ２ H, -C １－６ -Alkilen-CFH ２ , -C １－６ - Alkilen-NH-C １－６ -Alkilen-CF ３ , or -C １－６ -Alkylene-N(C) １－６ -Alkyl)-C １－６ -Alkilen-CF ３ The compound described in claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs.

15. R ４ but, -H; Saturated, unsubstituted, monosubstituted or polysubstituted with -F -S (=O) ２ C １－６ - Alkyl; Saturated, unsubstituted -S (=O) ２ (3-14 member cycloalkyl); Saturated, unsubstituted, monosubstituted, or polysubstituted -C １－６ - Alkyl; Each is an unsubstituted, monosubstituted, or polysubstituted 3- to 14-membered cycloalkyl or -C group. １－６ -Alkylene-(3-14 member cycloalkyl); Unsubstituted, monosubstituted, or polysubstituted 3- to 14-membered heterocycloalkyl or -C １－６ -Alkylene-(3-14 member heterocycloalkyl); Each is an unsubstituted, monosubstituted, or polysubstituted -phenyl or -C. １－６ -alkylene-phenyl; or Each is an unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl or -C compound. １－６ -Alkilen- (5-14 member heteroaryl) The compound described in claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs.

16. R ４ However, the 3-14 member cycloalkyl group is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted, and the 3-14 member cycloalkyl group is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ A 3- to 14-membered cycloalkyl group connected via an alkylene; or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group (preferably a 4, 5, or 6-membered heterocycloalkyl group), wherein the 3- to 14-membered heterocycloalkyl group is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ A 3- to 14-membered heterocycloalkyl group connected via an alkylene; or an unsubstituted, monosubstituted or polysubstituted 6- to 14-membered aryl group (preferably a 6-membered aryl group), wherein the 6- to 14-membered aryl group is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ A 6- to 14-membered aryl group connected via an alkylene; or an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl group (preferably a 5 or 6-membered heteroaryl group), wherein the 5- to 14-membered heteroaryl group is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C １ -C ６ A compound according to claim 1 or a stereoisomer, physiologically acceptable salt, solvate and / or polymorph thereof, representing a 5- to 14-membered heteroaryl linked via an alkylene.

17. R ３ However, H is R ４ The compound according to claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein the residue is selected from the group consisting of the following. 【Chemistry 3-1】 【Chemistry 3-2】

18. R ３ and R ４ These combine to form a heterocycle selected from the group consisting of pyrrolidine, piperidine, morpholine, and piperazine, in all cases unsubstituted and independently of each other, -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)OC １－６ -Alkyl, -NHC(=O)O-C １－６ -alkyl, -unsubstituted pyridyl, and unsubstituted or -C １－６ The compound according to claim 1, or its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs, which are monosubstituted or polysubstituted with substituents selected from the group consisting of 1,2,4-oxadiazole monosubstituted with alkyl.

19. R ５ and R ５ 'But, independently of each other, -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 group, wherein the 3- to 14-membered cycloalkyl group is optionally -C １ -C ６ -Alkylene- or -C １ -C ６ 3- to 14-membered cycloalkyl groups connected via heteroalkylenes (which in all cases are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted). The compound described in claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs.

20. R ６ , R ７ , and R ８ However, they are independent of each other. -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 ien-CH ２ F, -O-C １－６ -Alkyl, -OCF ３ , -OCHF ２ , -OCH ２ F, Non-substituted, or independently of each other: -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ -NHC substituted with one or more substituents selected from １－６ - Alkyl; Non-substituted, or independently of each other: -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ -N(C) substituted with one or more substituents selected from １－６ -Alkyl) ２ ; Non-substituted, or independently of each other: -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ -C(=O)OC substituted with one or more substituents selected from １－６ - Alkyl; Non-substituted, or independently of each other: -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ -OC(=O)C substituted with one or more substituents selected from １－６ - Alkyl; or Non-substituted, or independently of each other: -OH, =O, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF ３ ,-CHF ２ ien-CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, SF ５ , -NO ２ , -C(=O)OH, -NH ２ , and -C(=O)NH ２ -C substituted with one or more substituents selected from １－６ - Heteroalkyl, The compound described in claim 1 or its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs.

21. A compound according to claim 1, or a stereoisomer, physiologically acceptable salt, solvate, and / or polymorph thereof, selected from the group consisting of compounds 001 to 004 shown in the table below. 【Chemistry 4】

22. A compound according to claim 1, or a stereoisomer, physiologically acceptable salt, solvate, and / or polymorph thereof, selected from the group consisting of compounds 005 to 046 shown in the table below. 【Chemistry 5-1】 【Chemistry 5-2】

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a stereoisomer thereof, a physiologically acceptable salt, solvate, and / or polymorph.

24. A pharmaceutical composition according to claim 23 for use in the treatment of pain.

25. The pharmaceutical composition according to claim 24, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain, preferably postoperative pain.

26. The pharmaceutical composition according to claim 23 for use in the treatment of epilepsy.

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