Indolizine derivatives modulating trpm3

Abstract

The present invention relates to compounds useful for the prevention or treatment of TRPM3 mediated disorders, more particularly disorders including pain and inflammatory hypersensitivity and epilepsy. The present invention also relates to a method for the prevention or treatment of said TRPM3 mediated disorders.

Description

[0001] Cross-references to related applications

[0002] This international patent application claims priority to U.S. Provisional Patent Application No. 63 / 601,266, filed November 21, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to compounds that can be used to prevent or treat TRPM3-mediated conditions, and more particularly to conditions selected from pain (such as migraines and inflammatory pain) or hypersensitivity reactions and epilepsy. The invention also relates to a method for preventing or treating said TRPM3-mediated conditions. Background Technology

[0004] The TRP superfamily consists of proteins with six transmembrane domains (6TM), which assemble in the form of homotetramers or heterotetramers to form cation-permeable ion channels. The name TRP originates from the Drosophila trp (transient receptor potential) mutant, characterized by transient receptor potentials in the Drosophila photoreceptor in response to continuous light. Over the past 15 years, trp-related channels have been identified in yeast, worms, 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.

[0005] Members of the TRP superfamily are likely expressed in all mammalian organs and cell types, and significant progress has been made in understanding their physiological roles in recent years. The specific selectivity of certain TRP channels allows them to... 2+ Mg 2+ TRP channels play a crucial role in the cellular uptake and / or transepithelial transport of trace metal ions. Furthermore, the sensitivity of TRP channels to a wide range of chemical and physical stimuli allows them to function as dedicated biosensors involved in processes ranging from vision to taste and touch. In particular, several members of the TRP superfamily exhibit very high sensitivity to temperature. These so-called thermal TRPs are highly expressed in sensory neurons and / or keratinocytes of the skin, where they act as primary thermal sensors for detecting harmless and harmful (painful) temperatures.

[0006] It is becoming increasingly clear that TRP channel dysfunction is directly involved in the etiology of a wide range of hereditary and acquired diseases. In fact, loss-of-function and gain-of-function mutations in TRP channel genes have been identified as direct causes of hereditary diseases, including shortness of breath, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, mucopolysaccharidosis type IV, and familial focal segmental glomerulosclerosis. Furthermore, TRP channel function / dysfunction has been directly associated with a broad range of pathological symptoms, including chronic pain, hypertension, cancer, and neurodegenerative diseases.

[0007] TRPM3 (transient receptor potential M-type 3) represents a promising pharmacological target. TRPM3 is expressed in large sub-concentrations of small-diameter sensory neurons from the dorsal root and trigeminal ganglion and is involved in heat perception. The neurosteroid pregnenolone sulfate is a known potent activator of TRPM3 (Wagner et al., 2008). Pregnenolone sulfate induces pain in wild-type mice but not in TRPM3 knockout mice. It has also recently been shown that CFA-induced inflammation and inflammatory pain are eliminated in TRPM3 knockout mice. Therefore, TRPM3 antagonists could be used as analgesics to combat pain, such as inflammatory pain (Vriens J. et al., *Neuron*, May 2011). The relationship between TRPM3 and epilepsy has also been established (see Eur J Hum Genet. Oct 2019; 27(10): 1611–1618; Elife. May 2020; 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.

[0008] Several TRPM3 antagonists are known, but none of them point to the compound disclosed herein (Straub I et al., *Molecular Pharmacocol*, November 2013). For example, liquiditigenin, a putative TRPM3 blocker, has been described as reducing mechanical and cold hyperalgesia in rat models of pain (Chen L et al., *Scientific Reports*, July 2014). A significant medical need remains for new, alternative, and / or better treatments for the prevention or treatment of TRPM3-mediated conditions, more specifically for pain (such as inflammatory pain) and epilepsy. There is an urgent need for therapeutics with good potency, low levels or no side effects (such as non-addictiveness compared to opioids, and non-toxicity) and / or good or better pharmacokinetic or kinetic properties for a particular type of pain.

[0009] This invention provides a novel class of compounds that are antagonists of TRPM3 and can be used as modulators of TRPM3-mediated diseases. Summary of the Invention

[0010] This invention provides indolezine derivatives and pharmaceutical compositions comprising such indolezine derivatives. The invention also provides indolezine derivatives for use as pharmaceuticals, more particularly for the prevention and / or treatment of TRPM3-mediated conditions, especially for the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy; and / or for combating pain and / or inflammatory hypersensitivity and / or epilepsy.

[0011] The present invention also provides the use of indolezine derivatives in the manufacture of pharmaceutical compositions or drugs for the prevention and / or treatment of TRPM3-mediated conditions, particularly for the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy; and / or for the treatment of pain and / or inflammatory hypersensitivity and / or epilepsy.

[0012] The present invention also provides a method for preventing or treating TRPM3-mediated conditions by administering an indoleazine derivative according to the invention to a subject in need. More particularly, the present invention relates to methods for preventing and / or treating pain and / or inflammatory hypersensitivity and / or epilepsy and / or seizures; and / or for combating pain and / or inflammatory hypersensitivity and / or epilepsy.

[0013] The present invention further provides a method for preparing the indoleazine derivative of the present invention. Detailed Implementation

[0014] The invention will be further described, and in some cases described with respect to specific embodiments, but the invention is not limited thereto.

[0015] The first aspect of the present invention provides compounds of formula (I), their stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs.

[0016] (I)

[0017] Optionally used for the treatment of pain or epilepsy, or methods for treating pain or epilepsy;

[0018] in

[0019] R 1 This represents -F, -Cl, -Br, -I, -CN, and -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 ;

[0020] R 3 Indicates -OH or -R Y ;

[0021] X represents the single bond between Cy and the carbon atom to which it is attached, or X represents -O-, -CR. 5 R 5 '-、-S-、-S(O)n-、-S-CR 5 R 5' -、-CR 5 R 5' -S-、-CR 5 R 5' -CR 4 R 4' -、-NR 5 -CR 4 R 4' -、-C=、-C≡C- or -CR 5 R 5' -NR 5- In each case, it is unsubstituted, monosubstituted, or polysubstituted, and the substituents are independently selected from -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 ;

[0022] R 4 and R 4Ꞌ Represented independently of each other -R Y ;

[0023] n is an integer in the range of 1 to 2;

[0024] R 5 and R 5 'Represented independently of each other - R Y , or R 5 and R 5' They together form carbonyl groups on the atoms to which they are attached, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered heterocycloalkyl groups.

[0025] R 6 R 7 and R 8 The following can be represented independently: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC(=O)R W -NR W R X -NR W C(=O)R X -SR W -S(=O)R W -S(=O)2R W -C(=O)R W -C(=O)OR W or -C(=O)NR W RX ;

[0026] Cy represents a saturated or unsaturated 3- to 14-membered heterocyclic alkyl group; a saturated or unsaturated 3- to 14-membered cycloalkyl group; a 5- to 14-membered aryl group; a -C1-C6 alkyl group, a -C1-C6 heteroalkyl group; or a 5- to 14-membered heteroaryl group; in each case, it is unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently 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 ;

[0027] in

[0028] R W and R X Represented independently of each other and independently in each case

[0029] -H;

[0030] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl;

[0031] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl;

[0032] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; or

[0033] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0034] R Y and R Z Represented independently of each other and independently in each case:

[0035] -H;

[0036] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl;

[0037] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl;

[0038] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0039] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0040] Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryl groups; wherein the 6- to 14-membered aryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or

[0041] Unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

[0042] Or 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.

[0043] Furthermore, "monosubstituted or polysubstituted" in each case independently means substituted by one or more substituents, such as 1, 2, 3, 4 or more, which are independently selected from -F, -Cl, -Br, -I, -CN, -C 1-6 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C1-6 -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)OC 1-6 -alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-C(=O)-NH(C) 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-C(=O)-N(C) 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6 -alkylene-C(=O)-NH(OH), -OH, -C 1-6 -alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -OC 1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-NH2, -OC 1-6 -alkylene-NH-C 1-6 -alkyl, -OC 1-6 -alkylene-N(C) 1-6-alkyl)2、-OC(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-C 1-6 -alkyl, -OC(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-OC 1-6 -alkyl, -OC(=O)-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-OC(=O)-NH(C) 1-6 -alkyl), -OC(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OC(=O)-N(C) 1-6 -alkyl)2, -OS(=O)2-NH2, -C 1-6 -alkylene-OS(=O)2-NH2, -OS(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-OS(=O)2-NH(C) 1-6 -alkyl), -OS(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OS(=O)2-N(C) 1-6 -alkyl)2, -NH2, -NO, -NO2, -C 1-6 -alkylene-NH2, -NH(C) 1-6 -alkyl), -N (3- 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)-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-C(=O)-OC 1-6 -alkyl, -NH-C(=O)-NH2, -C 1-6-alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C) 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-C(=O)-N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH2、-N(C 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -NH-S(=O)2OH, -C 1-6 -alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-C 1-6 -alkyl, -NH-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-OC 1-6 -alkyl, -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C1-6 -alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C) 1-6 -alkyl), -NH-S(=O)2N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-S(=O)2N(C 1-6 -alkyl)2, -N(C 1-6 -alkyl)-S(=O)2-OH, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OH, -N(C 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH2、-N(C 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 -alkyl, -C 1-6 -alkylene-SC 1-6 -alkyl, -S(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -C 1-6-alkylene-S(=O)2-C 1-6 -alkyl, -S(=O)2-OH, -C 1-6 -alkylene-S(=O)2-OH, -S(=O)2-OC 1-6 -alkyl 、 -C 1-6 -alkylene-S(=O)2-OC 1-6 -alkyl 、 -S(=O)2-NH2、-C 1-6 -alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-S(=O)2-NH(C) 1-6 -alkyl), -S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-S(=O)2-N(C) 1-6 -alkyl) 2, 3 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 heterocyclic alkyl groups), -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).

[0044] Typically, X is described such that the first atom listed in the symbol is bonded to the benzofuran ring system, i.e., the symbol -S-CR. 5 R 5' -、-CR 5 R 5' -S-、-CR 5 R 5' -CR 4 R 4' -、-NR 5 -CR 4 R 4' -or-CR 5 R 5' -NR5 The first atom in the symbol is bonded to the benzofuran ring system and the second atom in the symbol is bonded to Cy.

[0045] In one embodiment of the indoleazine derivative according to the present invention, R 1 Selected from -C1-C6-alkyl groups. In one embodiment, R 1 Selected from methyl, ethyl, and propyl. In one embodiment, R 1 It is a methyl group.

[0046] In one embodiment of the indoleazine derivative according to the present invention, R 3 Indicates -CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently for R Y or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl, optionally wherein R 9 R 9' and R 9'' The two components together form a 3- to 14-membered cycloalkyl, a 3- to 14-membered heterocycloalkyl, a 5- to 14-membered aryl, or a 5- to 14-membered heteroaryl, wherein the 3- to 14-membered cycloalkyl, 3- to 14-membered heterocycloalkyl, 5- to 14-membered aryl, or 5- to 14-membered heteroaryl is optionally substituted by one or more R Y Single or multiple substitutions.

[0047] In one embodiment, R 5 and R 5 Together they form saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 4-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 4-membered heterocycloalkyl groups. In one embodiment, R 5 and R 5 Together they form cyclopropyl, cyclobutyl, or oxetane.

[0048] In one embodiment of the indoleazine derivative according to the present invention, R 7 and R 8 Independently selected from H, C1-C6-alkyl, and C1-C6-heteroalkyl. In one embodiment, R 7 and R 8 Preferably, each is -H.

[0049] In one embodiment of the indoleazine derivative according to the present invention, R 6 Selected from H, halogens and C 1-6Haloalkyl. In one embodiment, R 6 Selected from H and F.

[0050] In one embodiment of the indoleazine derivative according to the present invention, R 6 It is selected from cyano, carbonyl, carboxylic acid, carboxylic acid ester, nitro, ammonium, aldehyde and sulfonyl.

[0051] In one embodiment of the indoleazine derivative according to the invention, Cy comprises one or more cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings, wherein, for Cy having more than one cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, the rings may share one or more atoms in a spirosystem or a fused system, or may optionally be linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case being saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted.

[0052] In some embodiments, the 5- to 14-membered heteroaryl or aryl groups within the definition of Cy are selected from chamomile, benzimidazole, benzisoxazole, benzoxazole, benzodioxane, benzofuran, benzothiadiazole, benzothiazol, benzothiophene, carbazole, zoline, dibenzofuran, furan, furazon, imidazole, imidazopyridine, indazole, indole, indoleazine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, hydroxyindole, phthalazine, purine, pyrazine. Pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazolium, thiadiazole, thiazole, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine; in each case, unsubstituted, monosubstituted, or polysubstituted, the substituents being independently 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 .

[0053] In some embodiments, the 5- to 14-membered heteroaryl groups within the definition of Cy are selected from the group consisting of: furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole, pyridine, isoquinoline, benzothiazole, pyridazine, pyrimidine, and imidazopyridine; in each case, they are unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, and -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 .

[0054] In some embodiments, the 5- to 14-membered heteroaryl groups within the definition of Cy are 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, thiazolyl-2-yl, thiazolyl-4-yl, thiazolyl-5-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, isoquinoline-1-yl, isoquinoline-5-yl, benzo[d]thiazolyl-2-yl, pyridazin-3-yl, pyrimidin-5-yl, and imidazo[1,2-a]pyridin-6-yl; in each case, unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently 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)ORY or -C(=O)NR Y R Z .

[0055] In some embodiments, the 5- to 14-membered heteroaryl groups within the definition of Cy are selected from the group consisting of: pyrazol-3-yl, pyrazol-4-yl, thiazolyl-4-yl, thiazolyl-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; in each case, they are unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6 alkyl, -CN, -NO, -NO2, =O, =S, -SF5, and -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 .

[0056] In one embodiment, the saturated or unsaturated 3- to 14-membered cycloalkyl group within the definition of Cy is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, including unfused or unbridged, fused or bridged cycloalkyl groups; in each case, it is unsubstituted, monosubstituted or polysubstituted, the substituents being independently 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 .

[0057] In one embodiment, the 5- to 14-membered aryl group within the definition of Cy is a phenyl group or another 5- to 14-membered aryl group that is unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently 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 。

[0058] In a further embodiment of the indoleazine derivative according to the invention, Cy represents a 3- to 14-membered heterocyclic alkyl group, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted, and the substituents are independently 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 .

[0059] In some embodiments, the 3- to 14-membered heterocyclic alkyl groups within the definition of Cy are selected from azetane, 1,4-oxazhetane, azetane, azetidine, aziridine, azetane, diazetane, dioxane, dioxolane, dithiopentane, dithiopentane, imidazoline, isothiazolane, isoxazolane, morpholine, oxazolane, hexane oxide, oxazolane, ethylene oxide, piperazine, piperidine, pyrazolane, pyrrolidine, quinine ring, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, thiazoline, thiohexane, thiohexane propane, thiohexane pentane, 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-pyrrolizine, hexahydrocyclopentadieno[c]pyrrole, octahydrocyclopentadieno[c]pyrrole and octahydropyrrolo[1,2-a]pyrazine; in each case unsubstituted, monosubstituted or polysubstituted, wherein the substituents are independently 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 .

[0060] In some embodiments, the 3- to 14-membered heterocyclic alkyl group within the definition of Cy is oxane, oxane-4-yl, oxetane, or oxetane-3-yl; in each case, it is unsubstituted, monosubstituted, or polysubstituted, the substituents being independently 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)RZ -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 .

[0061] In another preferred embodiment of the indoleazine derivative according to the invention, Cy represents a C1-C6 alkyl or C1-C6 heteroalkyl group, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted, and the substituents are independently 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 .

[0062] In some embodiments of the indoleazine derivatives according to the invention, Cy is unsubstituted, monosubstituted, or polysubstituted, the substituents being independently selected from each other.

[0063] -F, -Cl, -Br, -I, -CN, -C(=O)OH, -NH2, -NO2, -OH, =O, -SF5;

[0064] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 -alkyl;

[0065] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -alkyl;

[0066] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -NHC 1-6 -alkyl;

[0067] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -N(C)1-6 -alkyl)2;

[0068] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC 1-6 -alkyl;

[0069] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C 1-6 -alkyl;

[0070] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; or

[0071] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

[0072] In some embodiments, Cy is unsubstituted, monosubstituted, or polysubstituted, and the substituents are selected independently from each other.

[0073] -OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -CN, -NO2, -C(=O)OH, -NH2 or -N(CH3)2;

[0074] Saturated or unsaturated, unsubstituted, mono- or poly-substituted -C 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2;

[0075] Saturated or unsaturated, unsubstituted, mono- or poly-substituted -C 1-6 -Heteroalkyl, wherein the substituents are independently selected from the group consisting of: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2;

[0076] Unsubstituted, substituted, monosubstituted, or polysubstituted -OC 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2;

[0077] Unsubstituted, substituted, monosubstituted, or polysubstituted -O(C=O)C 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2;

[0078] Unsubstituted, substituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2;

[0079] Cycloalkyl groups ranging from 3 to 14 members, selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; in each case, unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, and -C. 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2;

[0080] 3- to 14-membered heterocyclic alkyl groups, selected from the group consisting of: azetane, 1,4-oxazhetane, azetane, azetidine, aziridine, azetane, diazetane, dioxane, dioxolane, dithiazolinone, isothiazolidine, isoxazolidine, morpholine, oxazolidine, hexane oxide, oxazolidine, ethylene oxide, piperazine, piperidine, pyrazolidine, pyrrolidine, quinine ring, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, thiazolinone, thiohexane, thiohexane propane, thiohexane pentane, thiomorpholine, indoline, dioxane ... Hydrobenzofuran, 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-pyrrolizine, hexahydrocyclopentadieno[c]pyrrole, octahydrocyclopentadieno[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine, in each case unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from the group consisting of: -F, -Cl, -Br, -I, -C 1-6 -alkyl, C 2-6 -Alkenyl, -C 2-6 -Alkyne, -OH, =O, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2 and -C(=O)NH2.

[0081] In some embodiments, Cy is unsubstituted, monosubstituted, or polysubstituted, and the substituents are independently selected from -F, -Cl, -CN, -OH, =O, and -C. 1-6 -alkyl, methyl, ethyl, -CHF2, -CF3, -C 1-6 -alkylene-NH2, -C1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-NHC(=O)-OC 1-6 -alkyl, -C(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-OC 1-6 -alkyl, -OCF3, -OC 1-6 -alkylene-N(C) 1-6 -alkyl)2、-S(=O)2-C 1-6 -alkyl, -azacyclobutane, -C 1-6 -alkylene-O-tetrahydropyran, or with -C 1-6 -alkyl-substituted piperazine.

[0082] In some embodiments of the indoleazine derivative according to the present invention, Cy is...

[0083] (i) Unreplaced;

[0084] (ii) Monosubstituted;

[0085] (iii) Disubstituted;

[0086] (iv) Trisubstituted; or

[0087] (v) tetrasubstituted, wherein the specific substituents of (iii) to (v) may be distinct from each other, or wherein one or more of the specific substituents of (iii) to (v) may be the same.

[0088] In some embodiments of the indoleazine derivative according to the present invention, Cy is...

[0089] (i) Unreplaced;

[0090] (ii) Monosubstituted; or

[0091] (iii) Disubstituted.

[0092] In some embodiments, Cy represents a C3-C8 cycloalkyl, phenyl, C5-C8 heterocycloalkyl, or C5-C8 heteroaryl group, optionally substituted with one or more of a halogen, C1-C3-haloalkyl, hydroxyl, acyl, formamide, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, butyl, cyclobutyl, oxetane, pyrrole, or diazole, wherein the formamide, acyl, cyclopropyl, cyclobutyl, oxetane, pyrrole, and diazole are optionally further substituted with a halogen, C1-C3-haloalkyl, hydroxyl, phenyl, methyl, methoxy, ethyl, ethoxy, or propyl group, optionally linked by a C1-C6-alkylene- or -C1-C6-heteroalkylene-.

[0093] Another aspect of the present invention provides compounds of formula (II), their stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs:

[0094] (II)

[0095] in:

[0096] R 3 Selected from -CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently for R Y ， Or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl, optionally wherein R 9 R 9' and R 9'' The two components together form a 3- to 14-membered cycloalkyl, a 3- to 14-membered heterocycloalkyl, a 5- to 14-membered aryl, or a 5- to 14-membered heteroaryl, wherein the 3- to 14-membered cycloalkyl, 3- to 14-membered heterocycloalkyl, 5- to 14-membered aryl, or 5- to 14-membered heteroaryl is optionally substituted by one or more R Y Mono- or poly-substituted;

[0097] R 6 Selected from H, halogens and C 1-6 Halogenated alkyl groups;

[0098] X represents the single bond between Cy and the carbon atom to which it is attached, or X represents -O-, -CR. 5 R 5 '、-S-、-S(O)n-,-S-CR 5 R 5' -、-CR 5 R 5'-S-、-CR 5 R 5' -CR 4 R 4' -、-NR 5 -CR 4 R 4' -、-C=、-C≡C- or -CR 5 R 5' -NR 5 - In each case, it is unsubstituted, monosubstituted, or polysubstituted, and the substituents are independently selected from -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 ;

[0099] n is an integer in the range of 1 to 2;

[0100] R 4 and R 4Ꞌ Represented independently of each other -R Y ;

[0101] R 5 and R 5 'Represented independently of each other - R Y , or R 5 and R 5' They together form carbonyl groups on the atoms to which they are attached, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered heterocycloalkyl groups.

[0102] Cy represents a saturated or unsaturated 3- to 14-membered cycloalkyl group, a saturated or unsaturated 3- to 14-membered heterocycloalkyl group; a 5- to 14-membered aryl group or a 5- to 14-membered heteroaryl group; in each case, it is unsubstituted, monosubstituted, or polysubstituted, with the substituents independently selected from -F, -Cl, -Br, -I, -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 ;

[0103] in

[0104] R Y and R Z Represented independently of each other in each case.

[0105] -H;

[0106] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl;

[0107] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl;

[0108] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0109] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0110] Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryl groups; wherein the 6- to 14-membered aryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or

[0111] Unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

[0112] Or 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.

[0113] Furthermore, "monosubstituted or polysubstituted" in each case independently means substituted by one or more substituents, such as 1, 2, 3, 4 or more, which are independently selected from -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)OC 1-6 -alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-C(=O)-NH(C) 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-C(=O)-N(C) 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6 -alkylene-C(=O)-NH(OH), -OH, -C1-6 -alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -OC 1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-NH2, -OC 1-6 -alkylene-NH-C 1-6 -alkyl, -OC 1-6 -alkylene-N(C) 1-6 -alkyl)2、-OC(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-C 1-6 -alkyl, -OC(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-OC 1-6 -alkyl, -OC(=O)-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-OC(=O)-NH(C) 1-6 -alkyl), -OC(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OC(=O)-N(C) 1-6 -alkyl)2, -OS(=O)2-NH2, -C 1-6 -alkylene-OS(=O)2-NH2, -OS(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-OS(=O)2-NH(C) 1-6 -alkyl), -OS(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OS(=O)2-N(C) 1-6 -alkyl)2, -NH2, -NO, -NO2, -C 1-6 -alkylene-NH2, -NH(C) 1-6 -alkyl), -N (3- 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)-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-C(=O)-OC 1-6 -alkyl, -NH-C(=O)-NH2, -C 1-6 -alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C) 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-C(=O)-N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH2、-N(C 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -NH-S(=O)2OH, -C1-6 -alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-C 1-6 -alkyl, -NH-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-OC 1-6 -alkyl, -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C) 1-6 -alkyl), -NH-S(=O)2N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-S(=O)2N(C 1-6 -alkyl)2, -N(C 1-6 -alkyl)-S(=O)2-OH, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OH, -N(C 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH2、-N(C 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C)1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 -alkyl, -C 1-6 -alkylene-SC 1-6 -alkyl, -S(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-C 1-6 -alkyl, -S(=O)2-OH, -C 1-6 -alkylene-S(=O)2-OH, -S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-OC 1-6 -alkyl, -S(=O)2-NH2, -C 1-6 -alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-S(=O)2-NH(C) 1-6 -alkyl), -S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-S(=O)2-N(C) 1-6 -alkyl) 2, 3 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 heterocyclic alkyl groups), -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).

[0114] In one embodiment of the benzofuran derivative according to the present invention, R6 Selected from H, halogens and C 1-6 Haloalkyl. In one embodiment, R 6 Selected from H and F.

[0115] In one embodiment of the benzofuran derivative according to the present invention, R 6 It is selected from cyano, carbonyl, carboxylic acid, carboxylic acid ester, nitro, ammonium, aldehyde and sulfonyl.

[0116] In some embodiments of formulas (I) and (II), Cy represents a saturated or unsaturated, in each case unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl group (preferably 3-, 4-, 5-, or 6-membered cycloalkyl); optionally, a residue selected from the group consisting of:

[0117]

[0118] In some embodiments of formulas (I) and (II), Cy represents an unsubstituted, monosubstituted, or polysubstituted tert- to 14-membered aryl group in each case; optionally, a residue selected from the group consisting of:

[0119]

[0120] In some embodiments of formulas (I) and (II), Cy represents a saturated or unsaturated 3- to 14-membered heterocyclic alkyl group (preferably 3- to 5-membered heterocyclic alkyl group); a 5- to 14-membered heteroaryl group (preferably 5- to 6-membered heteroaryl group); a saturated or unsaturated 3- to 14-membered cycloalkyl group; a 5- to 14-membered aryl group; or a C1-C6 alkyl group; in each case unsubstituted, monosubstituted, or polysubstituted; preferably a residue selected from the group consisting of:

[0121]

[0122]

[0123] In one embodiment, Cy represents an unsubstituted, monosubstituted, or polysubstituted oxetane; preferably .

[0124] In some embodiments, Cy represents residues according to general formula (E).

[0125]

[0126] (E)

[0127] in

[0128] Y E1 Indicates -N=, -NR E2 -, S, O or -CRE3 =;Y E2 Indicates -N=, -NR E3 -, S, O or -CR E4 =; and Y E3 Indicates -N=, -NR E4 -, S, O or -CR E5 =; the condition is Y E1 Y E2 and Y E3 At least one of them is not -CR E3 =、-CR E4 = and -CR E5 =. In another preferred embodiment, V represents a residue according to general formula (E).

[0129] Where YE1 represents -N=, -NRE2-, S or -CRE3=; YE2 represents -N=, -NRE3-, S or -CRE4=; and YE3 represents -N=, -NRE4-, S or -CRE5=; the condition is that at least one of YE1, YE2 and YE3 is not -CRE3=, -CRE4= and -CRE5= respectively.

[0130] R E1 R E2 R E3 and R E4 Each can independently represent -H, -CH3, -CH2-cyclopropyl, -CH2CF3, -CH2CHF2, or -CF3; more specifically, R E1 R E2 R E3 and R E4 Each can be independently represented as -H, -CH3, or -CF3; preferably, the condition is R. E1 R E2 R E3 and R E4 Only one of them indicates that it is not a -H residue.

[0131] In some embodiments of formulas (I) and (II), Cy represents an unsubstituted, monosubstituted, or polysubstituted 2-pyridine. In some embodiments, Cy represents residues selected from the group consisting of:

[0132]

[0133] In some embodiments of formulas (I) and (II), Cy represents unsubstituted, monosubstituted, or polysubstituted 3-pyridine. In preferred embodiments, V represents residues selected from the group consisting of:

[0134]

[0135] In some embodiments of formulas (I) and (II), Cy represents an unsubstituted, monosubstituted, or polysubstituted 4-pyridine. In preferred embodiments, Cy represents residues selected from the group consisting of:

[0136] .

[0137] In some embodiments of formulas (I) and (II), Cy represents residues selected from the group consisting of:

[0138]

[0139] In some embodiments of formulas (I) and (II), Cy represents residues selected from the group consisting of:

[0140]

[0141] In some embodiments of formulas (I) and (II), Cy represents an unsubstituted, monosubstituted, or polysubstituted bicyclic heteroaryl group, preferably selected from the group consisting of:

[0142]

[0143] In some embodiments, Cy represents residues according to the general formula (F').

[0144]

[0145] (F')

[0146] in

[0147] Y F1 This indicates -N= or -CR F4 =; and Y F2 This indicates -N= or -CR F5 =; and Y F3 This indicates -N= or -CR F3 =; the condition is Y F1 and Y F2 At least one of them is not -CR F4 = and -CR F5 =;

[0148] R F1 R F2 R F3 R F4 and R F5 Independently representing -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, or -azacyclobutane; preferably, the condition is R F1 R F2 RF3 R F4 and R F5 Only one of them indicates that it is not a -H residue.

[0149] In another embodiment, Cy represents a residue according to general formula (F).

[0150]

[0151] (F)

[0152] in

[0153] Y F1 This indicates -N= or -CR F4 =; and Y F2 This indicates -N= or -CR F5 =; the condition is Y F1 and Y F2 At least one of them is not -CR F4 = and -CR F5 =;

[0154] R F1 R F2 R F3 R F4 and R F5 Independently representing -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, or -azacyclobutane; preferably, the condition is R F1 R F2 R F3 R F4 and R F5 Only one of them indicates that it is not a -H residue.

[0155] In some embodiments, Cy represents a residue according to the general formula (G) or (H).

[0156]

[0157] (G)(H)

[0158] Where R G1 and R H1 Choose from the group consisting of: -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, aziridine, -cyclopropyl, -O-cyclopropyl, and -CHF2; or R. G1 and R H1 Choose from the group consisting of: -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, and aziridine.

[0159] In other embodiments, V represents a residue according to the general formula (G') or (H').

[0160]

[0161] (G')(H')

[0162] Where R G1 and R H1 Choose from the group consisting of: -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, aziridine, -cyclopropyl, -O-cyclopropyl, and -CHF2; or R. G1 and R H1 Choose from the group consisting of: -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, and aziridine. 。

[0163] In one embodiment of the indoleazine derivative according to the present invention, R 1 express

[0164] -H, -F, -Cl, -Br, -I, -CN;

[0165] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-6-alkyl; saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -O-C1-6-alkyl;

[0166] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)C 1-6 -alkyl;

[0167] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC 1-6 -alkyl;

[0168] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)NHC 1-6 -alkyl;

[0169] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)N(C 1-6 -alkyl)2;

[0170] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -alkyl;

[0171] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl;

[0172] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; or

[0173] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

[0174] In some embodiments, R 1 Representing -H, -F, -Cl, -Br, -I, -C 1-6 -alkyl, -OC 1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-CF2H, -C 1-6 -alkylene-CFH2, -C 1-6 -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, -OC 1-6 -alkyl, unsubstituted -cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl or unsubstituted cyclohexyl.

[0175] In some embodiments, R 1 Indicates -H, -C 1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -CH2F, -CHF2, -CF3, unsubstituted -cyclopentyl or -cyclopropyl. Preferably, R 1 Indicates -H, -C1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -CH2F, -CHF2, -CF3, -cyclopentyl, or unsubstituted. In some embodiments, R 1 It represents -CH3.

[0176] In some embodiments, R 1 It represents -CH2F, -CHF2, -CH3, or -cyclopropyl. Preferably, R 1 This indicates -CH2F, -CHF2, or -CH3. In some embodiments, R 1 It represents -C(=O)NH2 or -CHF2.

[0177] In some embodiments, R 1 Indicates -H, -C 1-3 -alkyl, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -C 1-3 -alkylene-CFH2 or -cyclopropyl; preferably, R 1 Indicates -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.

[0178] In one embodiment, R 1 It indicates methyl, ethyl, or propyl.

[0179] In one embodiment, R 1 It indicates a methyl group.

[0180] In one embodiment of equations (I) and (II), R 3 Represents -H, -OH, -C 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)2, -CF3, -CF2H, -CFH2, -CF2Cl, -CFCl2, -C1-6 -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, optionally unsubstituted, monosubstituted or polysubstituted.

[0181] In some embodiments, R 3 It represents -H, -OH, or a saturated, unsubstituted, or monosubstituted -C. 1-6 -alkyl. Preferably, R 3 It represents -H.

[0182] In some embodiments, R 3 It represents -H.

[0183] In some embodiments of equations (I) and (II), R 3 R is attached to the N atom via a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C4-alkylene group or via a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C4-heteroalkylene group. In some embodiments of the benzofuran derivatives of formula (I) or (II), R 3 Alternative representation -CR 10 R 10' R 10'' (That is, R is specified therein) 10 In the embodiments of formula I or formula II, R 3 It can be represented as -CR 10 R 10' R 10'' In various embodiments, when R 10 R 10' and / or R 10'' When R represents one or more substituents in this paper independently, 10 R 10' and R 10'' One or more of them can be -H or for R 10 R 10' and R 10'' Any other substituents disclosed.

[0184] In one embodiment of the indoleazine derivative according to the present invention, R 10 R 10' and / or R 10'' Represent independently:

[0185] -H;

[0186] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)C 1-6 -alkyl;

[0187] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -S(=O)2-C1-6-alkyl;

[0188] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl;

[0189] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl;

[0190] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0191] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted;

[0192] Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryl groups; wherein the 6- to 14-membered aryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or

[0193] Unsubstituted, monosubstituted, or polysubstituted 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted.

[0194] In some embodiments, R 10 R 10' and / or R 10'' Independently represent

[0195] Saturated or unsaturated, unsubstituted, mono- or poly-substituted -S(=O)2C 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -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-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl;

[0196] -S(=O)2 (3- to 14-membered cycloalkyl), wherein the 3- to 14-membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in each case is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted, wherein the substituents are independently selected from the group consisting of -F, -Cl, and -C. 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6-alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl;

[0197] Saturated or unsaturated, unsubstituted, mono- or poly-substituted -C 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -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-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -alkylene-NH-C 1-6 -alkyl, -C1-6 -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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl;

[0198] 3- to 14-membered cycloalkyl or -C 1-6 -alkylene- (3- to 14-membered cycloalkyl), where -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 3- to 14-membered cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and is saturated or unsaturated in each case, and is unsubstituted, monosubstituted, or polysubstituted in each case, wherein the substituents are independently selected from the group consisting of -F, -Cl, and -C. 1-6 -alkyl, -C 1-6 -alkylene-CF3, -OH, =O, -OC 1-6 -alkyl, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl;

[0199] 3- to 14-membered heterocyclic alkyl groups or -C 1-6 -alkylene- (3- to 14-membered heterocyclic alkyl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 3- to 14-membered heterocyclic alkyl group is selected from the group consisting of: azetane, 1,4-oxazhetane, azetane, azetidine, aziridine, azetane, diazetane, dioxane, dioxolane, dithiopentane, dithiopentane, imidazoline, isothiazolane, isoxazolane, morpholine, oxazolane, hexane oxide, oxazolane, ethylene oxide, piperazine, piperidine, pyrazolane, pyrrolidine, quinine ring, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, thiazoline, thiohexane, thiohexane, thiohexane, thiohexane. Thiocyclopentane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiocyclohexane, 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-pyrrolizine, hexahydrocyclopentadieno[c]pyrrole, octahydrocyclopentadieno[c]pyrrole and octahydropyrrolo[1,2-a]pyrazine; in each case unsubstituted, monosubstituted or polysubstituted, wherein the substituents are independently selected from the group consisting of: -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-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C)1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl;

[0200] Unsubstituted, mono- or poly-substituted -phenyl groups, wherein the substituents are independently selected from the group consisting of: -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-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6 -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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl;

[0201] 5 to 14 yuan of heteroaryl or -C 1-6 -alkylene- (5- to 14-membered heteroaryl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 5- to 14-membered heteroaryl group is selected in each case from the group consisting of: benzimidazole, benzisoxazole, benzoxazole, benzodioxane, benzofuran, benzothiadiazole, benzothiazolium, carbazole, zoline, dibenzofuran, furan, furazonium, imidazole, imidazopyridine, indazole, indole, indoleazine, isobenzofuran, isoindole, isoquinoline, isothiazolium Isoxazole, naphthidine, oxadiazole, oxazole, hydroxyindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine; in each case, unsubstituted, monosubstituted, or polysubstituted, the substituents being independently selected from the group consisting of: -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-OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl, -N(C) 1-6 -alkyl)C(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NHC(=O)OC 1-6 -alkyl, -C 1-6 -alkylene-NH2, -C 1-6-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)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -C(=O)N(C 1-6 -alkyl)2、-S(=O)2C 1-6 -alkyl, -phenyl, -C 1-6 -alkylene-phenyl, saturated or unsaturated, unsubstituted 3- to 14-membered heterocyclic alkyl; and unsubstituted 5- to 14-membered heteroaryl.

[0202] In some embodiments, R 10 R 10' and / or R 10'' Independently represent

[0203] -H;

[0204] Saturated, unsubstituted, mono- or poly-substituted -S(=O)2C 1-6 -alkyl;

[0205] Saturated, unsubstituted -S(=O)2 (3- to 14-membered cycloalkyl);

[0206] Saturated, unsubstituted, monosubstituted, or disubstituted -C 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -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, unsubstituted -phenyl;

[0207] 3- to 14-membered cycloalkyl or -C 1-6 -alkylene- (3- to 14-membered cycloalkyl), where -C 1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein the 3- to 14-membered cycloalkyl group is saturated, unsubstituted, monosubstituted, or disubstituted, and the substituents are independently selected from the group consisting of: -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)OC 1-6 -alkyl, -OH, -OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl;

[0208] 3- to 14-membered heterocyclic alkyl groups or -C 1-6 -alkylene- (3- to 14-membered heterocyclic alkyl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 3- to 14-membered heterocyclic alkyl group is selected in each case from aziridine, 1,4-oxazetane, pyrrolidine, piperidine, azirane, diazirane, tetrahydrofuran, tetrahydropyran, oxazetane, morpholine, piperazine, hexahydrocyclopentadieno[c]pyrrole, octahydrocyclopentadieno[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 8-azabicyclo[ 3.2.1] Octane, 9-azabicyclo[3.3.1]nonane, quinine ring, hexahydro-1H-pyrrolizine, 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 1,1-dioxothiacyclohexane, in each case unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from the group consisting of: -F, -OH, =O, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2、-C 1-6 -alkylene-NH2, -C 1-6 -alkylene-N(C) 1-6 -alkyl)2、-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6-alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -S(=O)2C 1-6 -alkyl, oxetyl, pyrimidinyl, -C 1-6 -alkylene-phenyl;

[0209] Unsubstituted -phenyl;

[0210] 5 to 14 yuan of heteroaryl or -C 1-6 -alkylene- (5- to 14-membered heteroaryl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 5- to 14-membered heteroaryl group is selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, which is unsubstituted, monosubstituted, or disubstituted, wherein the substituents are independently selected from the group consisting of: -C 1-6 -alkyl, -OH.

[0211] In some embodiments, R 3 It forms residues selected from the group consisting of the nitrogen atom to which it is attached (excluding the -H on the nitrogen atom):

[0212]

[0213] In other embodiments, R 3 It represents -H.

[0214] In some embodiments, R 3 Residues selected from the group consisting of the following items:

[0215]

[0216]

[0217] In a further embodiment, R 3 This indicates the 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'' independently represent -H and -C. 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -C 1-3 -alkylene-CFH2, -C 1-3 -alkylene-OC 1-3 -alkyl, -C 1-3-alkylene-OH, -C(=O)-NH2 or C(=O)-NH-C 1-3 -alkyl; preferably -H, -CH3, -C 1-3 -alkylene-OH, -C(=O)-NH2 or C(=O)-NH-C 1-3 -alkyl. In one embodiment, at least R' or R'' does not represent -H. In an alternative embodiment, neither R' nor R'' represents -H.

[0218] In a further embodiment, R 10 R 10' and / or R 10'' Independently refers to saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl; or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl.

[0219] In a further embodiment, R 10 R 10' and / or R 10'' Independently refers to a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3-membered cycloalkyl group; or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3-membered heterocycloalkyl group. In some embodiments, R 10 R 10' and / or R 10'' Residues selected independently from the following groups:

[0220]

[0221] In some embodiments, R 3 R 10 R 10' and R 10'' Independently refers to a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 4-membered cycloalkyl group; or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl group (in some cases, a 4-membered heterocycloalkyl group). In some embodiments, R 3 R 10 R 10' and R 10'' Residues selected independently from the following groups:

[0222]

[0223] In some embodiments, R 3 R 10 R 10' and / or R 10'' Residues according to general formula (A) can be represented independently.

[0224]

[0225] (A)

[0226] in

[0227] m A It can be 0 or 1;

[0228] Y A Selected from -O-, -NR A6 -and-CR A7 R A8 -;and

[0229] R A1 R A2 R A3 R A4 R A5 R A6 R A7 and R A8 -H, F, and -C are represented independently of each other. 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-NH2, -C 1-3 -alkylene-NH(C) 1-3 -alkyl), -C 1-3 -alkylene-N(C) 1-3 -alkyl)2、-C 1-3 -alkylene-NH(C) 1-3 -alkylene-CF3), -C 1-3 -alkylene-C(=O)NH2, -C 1-3 -alkylene-NH-C(=O)OC 1-4 -alkyl, -C(=O)NH2, -C(=O)-NH-C 1-3 -alkyl, -C(=O)-N(C) 1-3 -alkyl)2, -3-oxetanebutyl or -CHF2; preferably, R A1 R A2 R A3 R A4 R A5 R A6 R A7 and R A8 -H, F, and -C are represented independently of each other. 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-NH2, -C 1-3 -alkylene-NH(C) 1-3 -alkyl), -C 1-3-alkylene-N(C) 1-3 -alkyl)2、-C 1-3 -alkylene-NH(C) 1-3 -alkylene-CF3), -C 1-3 -alkylene-C(=O)NH2, -C 1-3 -alkylene-NH-C(=O)OC 1-4 -alkyl, -C(=O)NH2, -C(=O)-NH-C 1-3 -alkyl, -C(=O)-N(C) 1-3 -alkyl)2 or -3-oxetanebutyl; or R A7 and R A8 They form a ring together with the carbon atoms to which they are attached and are represented as -CH2OCH2-, -CH2OCH2CH2-, or -CH2CH2OCH2CH2-, -CH2NHCH2-, -CH2NHCH2CH2-, or -CH2CH2NHCH2CH2-.

[0230] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently represent residues according to the general formula (A) as defined above, where

[0231] m A It can be 0 or 1;

[0232] Y A Selected from -O- and -CR A7 R A8 -;and

[0233] R A1 R A2 R A3 R A4 R A5 R A7 and R A8 -H and -C are represented independently of each other. 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C) 1-3 -alkyl)2, -C(=O)NH2 or -CHF2; preferably R A1 R A2 R A3 R A4 R A5 R A7 and R A8 -H and -C are represented independently of each other. 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C) 1-3-alkyl)2 or -C(=O)NH2; preferably, the condition is R A1 R A2 R A3 R A4 R A5 R A7 and R A8 Only one of them indicates that it is not a -H residue.

[0234] In some embodiments, R 3 Or R 10 R 10' and / or R 10'' Independently represent residues according to the general formula (A) as defined above, where

[0235] m A It can be 0 or 1;

[0236] Y A Selected from -O- and -CR A7 R A8 -;and

[0237] R A1 Indicates -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C) 1-3 -alkyl)2, -C(=O)NH2 or -CHF2; preferably R A1 Indicates -C 1-3 -alkylene-OH, -C 1-3 -alkylene-N(C) 1-3 -alkyl)2 or -C(=O)NH2; and

[0238] R A2 R A3 R A4 R A5 R A7 and R A8 It represents -H.

[0239] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl (preferably 5-membered cycloalkyl); or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (in some cases, 5-membered heterocycloalkyl); or an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl (in some cases, 5-membered heteroaryl). In a preferred embodiment, R 3 R 10 R10' and / or R 10'' Residues selected independently from the following groups:

[0240]

[0241] In some embodiments, R 3 R 10 R 10' and / or R 10'' Residues according to general formula (B) can be represented independently.

[0242]

[0243] (B)

[0244] in

[0245] Y B Selected from -O-, -NR B8 -and-CR B9 R B10 -;and

[0246] R B1 R B2 R B3 R B4 R B5 R B6 R B7 R B8 R B9 and R B10 They can be represented independently of each other: -H, -F, -OH, -C. 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-OC 1-3 -alkyl, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CO2H, -C 1-3 -alkylene-C(=O)OC 1-3 -alkyl, -C(=O)NH2, -C(=O)NH-C 1-3 -alkyl or -C(=O)N(C 1-3 -alkyl)2; or R B2 and R B3 Together, it represents =O; or R. B4 and R B5 Together, it means =O.

[0247] In some embodiments, R 3 Or R 10 R 10' and / or R 10''Independently represent residues according to general formula (B) as defined above, where

[0248] Y B Selected from -O- and -NR B8 -;and

[0249] R B1 R B2 R B3 R B4 R B5 R B6 R B7 R B8 -H, -F, and -C can be represented independently of each other. 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-CF3 or -C(=O)NH2; or R B2 and R B3 Together, it represents =O; or R. B4 and R B5 Together, it represents = O; the preferred condition is R. A1 R A2 R A3 R A4 R A5 R A7 and R A8 Only one, two, or three of the residues in the text indicate residues that are not -H; the preferred condition is R. A1 R A2 R A3 R A4 R A5 R A7 and R A8 At least one of them indicates a residue that is not -H.

[0250] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl (in some cases, 6-membered cycloalkyl); or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl (in some cases, 6-membered heterocycloalkyl); or an unsubstituted, monosubstituted or polysubstituted 6- to 14-membered aryl (in some cases, 6-membered aryl); or an unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl (in some cases, 6-membered heteroaryl). In some embodiments, R 3 R 10 R 10' and / or R 10''Residues selected independently from the following groups:

[0251]

[0252] In some embodiments, R 3 R 10 R 10' and / or R 10'' Residues according to general formula (C) can be represented independently.

[0253]

[0254] (C)

[0255] in

[0256] Y C1 Selected from -O-, -S(=O)2-, -NR C8 -and-CR C9 R C10 -and Y C2 Indicates -CR C11 R C12 -; or Y C1 Indicates -CR C9 R C10 -and Y C2 Selected from -O-, -S(=O)2- and -NR C8 -;

[0257] 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 Representing each other independently

[0258] -H, -F, -OH, -C(=O)OC 1-3 -alkyl, -NH2, -NH(C) 1-3 -alkyl), -N(C 1-3 -alkyl)2、-C 1-3 -alkyl, -C 1-3 -alkylene-OH, -C 1-3 -alkylene-, -C(=O)NH2, -C(=O)NH-C 1-3 -alkyl or -C(=O)N(C 1-3 -alkyl)2: or R C2 and R C3Together, it represents =O; or R. C4 and R C5 Together means =O; or R C9 and R C10 Together, it represents =O; or R. C11 and R C12 Together, it means =O.

[0259] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently represent residues according to the general formula (C) as defined above, where

[0260] Y C1 Selected from -O- or -NR C8 -and Y C2 Indicates -CR C11 R C12 -; or Y C1 Indicates -CR C9 R C10 -and Y C2 Selected from -O- and -NR C8 -;

[0261] 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 -H, -F, and -C can be represented independently of each other. 1-3 -alkyl, -C 1-3 -alkylene-OH or -C(=O)NH2; preferably, the condition is 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 Only one, two, or three of the residues in the text indicate residues that are not -H; the preferred condition is R. C1 R C2 R C3 R C4 R C5 RC6 R C7 R C8 R C9 R C10 R C11 and R C12 At least one of them indicates a residue that is not -H.

[0262] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently refers to a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 7-membered cycloalkyl group; or a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 7-membered heterocycloalkyl group. In some embodiments, R 3 R 10 R 10' and / or R 10'' Residues are represented independently:

[0263] .

[0264] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently representing saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups (in some cases, 3-, 4-, 5-, or 6-membered cycloalkyl groups); wherein the 3- to 14-membered cycloalkyl group is connected by: saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene-; or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocycloalkyl groups (in some cases, 4-, 5-, or 6-membered heterocycloalkyl groups); wherein the 3- to 14-membered heterocycloalkyl group is connected by: saturated or unsaturated, unsubstituted, mono ... Substituted or multisubstituted -C1-C6-alkylene-; or unsubstituted, monosubstituted or multisubstituted 6- to 14-membered aryl groups (in some cases, 6-membered aryl groups); wherein the 6- to 14-membered aryl groups are linked by: saturated or unsaturated, unsubstituted, monosubstituted or multisubstituted -C1-C6-alkylene-; or unsubstituted, monosubstituted or multisubstituted 5- to 14-membered heteroaryl groups (in some cases, 5- or 6-membered heteroaryl groups); wherein the 5- to 14-membered heteroaryl groups are linked by: saturated or unsaturated, unsubstituted, monosubstituted or multisubstituted -C1-C6-alkylene-. In a preferred embodiment, R 3 R 10 R 10' and / or R 10'' Residues selected independently from the following groups:

[0265]

[0266] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently representing a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 5-membered heterocyclic alkyl group; wherein the 5-membered heterocyclic alkyl group is connected by: a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene-; or an unsubstituted, monosubstituted or polysubstituted 5-membered heteroaryl group; wherein the 5-membered heteroaryl group is connected by: a saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkylene-.

[0267] In some embodiments, R 3 R 10 R 10' and / or R 10'' Residues selected independently from the following groups:

[0268]

[0269] In some embodiments, R 3 R 10 R 10' and / or R 10'' Independently represent

[0270] (i) 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'' independently represent -H and -C. 1-3 -alkyl, -CF3, -CF2H, -CFH2, -C 1-3 -alkylene-CF3, -C 1-3 -alkylene-CF2H, -C 1-3 -alkylene-CFH2, -C 1-3 -alkylene-OC 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

[0271] (ii) Based on the residues of general formula (D),

[0272]

[0273] (D)

[0274] in

[0275] m D and n D Each is independently 0, 1, 2, or 3; preferably, the condition is m D +n D ≤3;

[0276] Y D1 Selected from -O-, -S(=O)2-, -S(=O)(=NH)-, -NR D8 -and-CR D9 R D10 -and Y D2 Indicates -CR D11 R D12 -; or Y D1 Selected from -O-, -S(=O)2-, -NR D8 -and-CR D9 R D10 -and Y D2 Indicates -CR D11 R D12 -; or Y D1 Indicates -CR D9 R D10 -and Y D2 Selected from -O-, -S(=O)2- and -NR D8 -;

[0277] R D1 R D2 R D3 R D4 R D5 R D6 R D7 R D8 R D9 R D10 R D11 and R D12 They can be represented independently of each other: -H, -F, -OH, -C. 1-3 -alkylene-OH, -C(=O)NH2, -C 1-3 -alkylene-C(O)NH2, -C(=O)OC 1-3 -alkyl, -NH2, -C 1-3 -alkylene-NH2, -NH(C) 1-3 -alkyl), -N(C 1-3 -alkyl)2, -NH(C 1-3 -alkylene-CF3), -C 1-3 -alkylene-OCH3, -C 1-3 -alkyl, -C 1-3 -alkylene-CF3: or RD2 and R D3 Together, it represents =O; or R. D4 and R D5 Together, it represents =O; or R. D9 and R D10 Together, it represents =O; or R. D11 and R D12 Together means = O;

[0278] Preferably, wherein

[0279] m D and n D Each is independently 0, 1, 2, or 3; preferably, the condition is m D +n D ≤3;

[0280] Y D1 Selected from -O-, -NR D8 -and-CR D9 R D10 -and Y D2 Indicates -CR D11 R D12 -; or Y D1 Indicates -CR D9 R D10 -and Y D2 Selected from -O- and -NR D8 -;

[0281] R D1 R D2 R D3 R D4 R D5 R D6 R D7 R D8 R D9 R D10 R D11 and R D12 They can be represented independently of each other: -H, -F, -OH, -C. 1-3 -alkylene-OH, -C(=O)NH2, -CH2NH2, -CH2N(CH3)2, -NHCH2CF3, -CH3 or -CH2CF3: or R D2 and R D3 Together, it represents =O; or R. D4 and R D5 Together, it represents =O; or R. D9 and R D10 Together, it represents =O; or R. D11 and R D12 Together, it represents = O; the preferred condition is R. D1 RD2 R D3 R D4 R D5 R D6 R D7 R D8 R D9 R D10 R D11 and R D12 Only one, two, or three of the residues in the text indicate residues that are not -H; the preferred condition is R. D1 R D2 R D3 R D4 R D5 R D6 R D7 R D8 R D9 R D10 R D11 and R D12 At least one of them indicates a residue that is not -H.

[0282] In some embodiments, R 3 R 10 R 10' and / or R 10'' Residues selected independently from the following groups:

[0283]

[0284]

[0285] In some embodiments of the indoleazine derivative according to the present invention, R 5 and R 5 'represented independently of each other'

[0286] -H;

[0287] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl;

[0288] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl;

[0289] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

[0290] In some embodiments, R 5 and R 5'Independently represent -H, -C1-C6-alkyl or -C1-C6-alkylene-N(C1-C6-alkyl)2.

[0291] In some embodiments of the indoleazine derivative according to the present invention, R 5 and R 5 At least one of them is not -H.

[0292] In some embodiments of the indoleazine derivative according to the present invention, R 5 and R 5 Both are -H.

[0293] In some embodiments, R 5 Indicates -H and R 5 'Indicates residues 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-CFH2 and -C 1-3 -alkylene-OH; preferably -H or C 1-3 -alkyl.

[0294] In some embodiments of the indoleazine derivative according to the present invention, R 6 R 7 and R 8 Representing each other independently

[0295] -H;

[0296] -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2;

[0297] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 -alkyl;

[0298] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC 1-6 -alkyl;

[0299] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -NHC 1-6 -alkyl;

[0300] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -N(C) 1-6 -alkyl)2;

[0301] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C(=O)OC1-6 -alkyl;

[0302] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -OC(=O)C 1-6 -alkyl;

[0303] Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C 1-6 - Heteroalkyl.

[0304] In some embodiments, R 6 R 7 and R 8 Representing each other independently

[0305] -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2,

[0306] -C 1-6 -alkyl, -CF3, -CHF2, -CH2F,

[0307] -OC 1-6 -alkyl, -OCF3, -OCHF2, -OCH2F,

[0308] Unsubstituted or substituted with one or more substituents -NHC 1-6 -alkyl, wherein the substituents are independently 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;

[0309] Unsubstituted or substituted with one or more substituents -N(C) 1-6 -alkyl)2, wherein the substituents are independently 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;

[0310] -C(=O)OC, either unsubstituted or substituted with one or more substituents 1-6 -alkyl, wherein the substituents are independently 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;

[0311] -OC (=O)C, either unsubstituted or substituted with one or more substituents. 1-6 -alkyl, wherein the substituents are independently 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; or

[0312] -C unsubstituted or substituted with one or more substituents 1-6 - Heteroalkyl, wherein the substituents are independently 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.

[0313] In some embodiments, R 6 R 7 and R 8 Residues selected independently from the following groups: -H, -F, -Cl, -Br, -I, -CN, C 1-3 -alkyl, -CF3, -CF2H and -CFH2; preferably -H or -F.

[0314] In some embodiments of the indoleazine derivative according to the present invention, R 6 It represents -H, -F, -Cl, -CN or -C1-C6-alkyl.

[0315] In some embodiments of the indoleazine derivative according to the present invention, R 6 It does not represent -H.

[0316] In some embodiments, R 6 The residues selected from the group consisting of the following: -H, -F, -Cl, -CN or -CH3; preferably -H, -F, -CN or -CH3.

[0317] In some embodiments of the indoleazine derivative according to the present invention, R 7 It represents -H, -F, -Cl, -CN or -C1-C6-alkyl.

[0318] In some embodiments of the indoleazine derivative according to the present invention, R 7 It does not represent -H.

[0319] In some embodiments of the indoleazine derivative according to the present invention, R 8It represents -H, -F, -Cl, -CN or -C1-C6-alkyl.

[0320] In some embodiments of the indoleazine derivative according to the present invention, R 8 It does not represent -H.

[0321] In some embodiments, R 8 Residues selected from the group consisting of: -H, -F, -Cl, -CN, or CH3; preferably -F 。

[0322] In some embodiments of the indoleazine derivative according to the present invention

[0323] (i)R 6 R 7 and R 8 Each represents -H; or

[0324] (ii)R 6 R 7 and R 8 Both in the text represent -H, and R 6 R 7 and R 8 The other one represents -F, -Cl, -CN, or -CH3; or

[0325] (iii)R 6 R 7 and R 8 One of them represents -H, and R 6 R 7 and R 8 The other one in the series can be represented independently as -F, -Cl, -CN, or -CH3.

[0326] In an exemplary embodiment of the present invention, the indoleazine derivative is selected from the group consisting of:

[0327] Cpd 001-N-((S)-1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-(trans-2-phenylcyclopropyl)indoleazine-3-carboxamide;

[0328] Cpd 002-N-((S)-1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-(cis-2-phenylcyclopropyl)indoleazine-3-carboxamide;

[0329] Cpd 003-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide;

[0330] Cpd 004-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide;

[0331] Cpd 005-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3-carboxamide;

[0332] Cpd 006-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3-carboxamide;

[0333] Cpd 007-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(m-tolyloxy)indoleazine-3-carboxamide;

[0334] Cpd 008-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(m-tolyloxy)indoleazine-3-carboxamide;

[0335] Cpd 009-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(p-tolyloxy)indoleazine-3-carboxamide;

[0336] Cpd 010-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(p-tolyloxy)indoleazine-3-carboxamide;

[0337] Cpd 011-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-6-(2-methoxyphenoxy)-2-methylindoleazine-3-carboxamide;

[0338] Cpd 012-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-6-(2-methoxyphenoxy)-2-methylindoleazine-3-carboxamide;

[0339] Cpd 013-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-6-(3-methoxyphenoxy)-2-methylindoleazine-3-carboxamide;

[0340] Cpd 014-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-6-(3-methoxyphenoxy)-2-methylindoleazine-3-carboxamide;

[0341] Cpd 015-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-6-(4-methoxyphenoxy)-2-methylindoleazine-3-carboxamide;

[0342] Cpd 016-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-6-(4-methoxyphenoxy)-2-methylindoleazine-3-carboxamide;

[0343] Cpd 017-(S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide;

[0344] Cpd 018-6-(2-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methylindoleazine-3-carboxamide;

[0345] Cpd 019-6-(3-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methylindoleazine-3-carboxamide;

[0346] Cpd 020-6-(4-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methylindoleazine-3-carboxamide;

[0347] Cpd 021-6-Benzyl-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methylindoleazine-3-carboxamide;

[0348] Cpd 022-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(phenylthio)indoleazine-3-carboxamide;

[0349] Cpd 023-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-((1S,2S)-2-(pyridin-2-yl)cyclopropyl)indoleazine-3-carboxamide;

[0350] Cpd 024-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methyl-6-(phenylsulfinyl)indoleazine-3-carboxamide and

[0351] Cpd 025-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(phenylsulfonyl)indoleazine-3-carboxamide, and physiologically acceptable salts of any of these indoleazine derivatives. Generally, "Cpd001" can be alternatively referred to as "Cpd 1" or "#1", "Cpd 002" can be referred to as "Cpd 2" or "#2", and so on.

[0352] The indoleazine derivatives according to the invention are used to treat pain, preferably selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain. The indoleazine derivatives according to the invention can also be used to treat epilepsy.

[0353] In some embodiments, the indolezine derivative is selected from the group consisting of compounds 001 to 025, which include their stereoisomers and pharmaceutically acceptable salts.

[0354] Including the disclosed substituents X, Cy, R X R Z R Y 、 R Z R 1 R 2 R 3 R 4 R 5 R 5 '、R 6 R 7 R 8 R 9 (including R) 9' and R 9'' ) and R 10 (including R) 10' and R 10'' All definitions, embodiments, and meanings thereof also apply similarly to the indoleazine derivatives according to the present invention, which are not necessarily limited to the treatment of pain. Furthermore, X, Cy, R X R Z R Y R Z R 1 R 3 R 4 R 4' R 5 R 5' R 6 R 7 R 8 、 R 9 and R 10The meaning is also explicitly considered to be the incorporation of any of the exemplified groups in the exemplified compounds at these positions according to Formulas I and II. Therefore, this aspect of the invention relates to such indoleazine derivatives, compositions comprising indoleazine derivatives, pharmaceuticals comprising indoleazine derivatives, and indoleazine derivatives for the prevention and / or treatment of TRPM3-mediated conditions such as pain and / or inflammatory hypersensitivity and / or epilepsy and / or seizures; and / or for the treatment of 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 or migraine.

[0355] In some embodiments of the invention, the indoleazine derivative is selected from the group consisting of: cpd001 to cpd025 as described above and their physiologically acceptable salts.

[0356] Another aspect of the present invention relates to pharmaceutical compositions or drugs comprising compounds according to the present invention as described above.

[0357] Throughout this specification, references to "an embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily refer to the same embodiment, but may refer to the same embodiment. Furthermore, in one or more embodiments, specific features, structures, or characteristics can be combined in any suitable manner, as will be apparent to those skilled in the art from this disclosure. Moreover, embodiments described with respect to one aspect of the invention can be used in another aspect of the invention and can be combined. When referring to singular nouns, the use of indefinite or definite articles, such as "a" or "an," or "the," includes the plural form of the noun, unless otherwise specified.

[0358] Similarly, it should be understood that in the description of exemplary embodiments of the present invention, various features of the invention may sometimes be combined in a single embodiment, drawing or description thereof for the purpose of simplifying the disclosure and aiding in the understanding of one or more aspects of the invention.

[0359] In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms that are generally optimally present in the substituent or linker; it should be understood that, where otherwise stated in this application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.

[0360] As used herein, the term "leaving group" or "LG" refers to a chemical group that is readily replaced, cleaved, or hydrolyzed by a nucleophile under basic or acidic conditions. In one specific embodiment, the leaving group is selected from halogen atoms (e.g., Cl, Br, I) or sulfonates (e.g., methanesulfonate, toluenesulfonate, trifluoromethanesulfonate).

[0361] The term "protecting group" refers to a part of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of protecting groups varies considerably. One function of protecting groups is as intermediates in the synthesis of parent drugs. Chemical protecting groups and protecting / deprotecting strategies are well known in the art. See *Protective Groups in Organic Chemistry*, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often used to mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. Protection of a compound's functional groups alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by commonly used analytical tools. Chemically protected intermediates can themselves be biologically active or inactive.

[0362] Protected compounds can also exhibit altered, and in some cases optimized, in vitro and in vivo properties, such as resistance to cell membrane degradation or chelation. In this role, the protected compound with the intended therapeutic effect may be referred to as a prodrug. Another function of the protecting group is to convert the parent drug into a prodrug, thereby releasing the parent drug during prodrug conversion in vivo. Because the active prodrug can be absorbed more efficiently than the parent drug, it can have greater potency in vivo. In the case of chemical intermediates, the protecting group is removed in vitro, or in the case of prodrugs, the protecting group is removed in vivo. For chemical intermediates, whether the product obtained after deprotection (e.g., an alcohol) is physiologically acceptable is not particularly important, although it is generally desirable for the product to be pharmacologically harmless.

[0363] As used herein, the term "heteroatom" means an atom selected from the following: nitrogen, which may be quaternized or exist as an oxide; oxygen; and sulfur, including sulfur oxides, including sulfoxides and sulfones, and in some cases sulfonates. In certain circumstances, compounds and / or synthetic intermediates may include heteroatoms such as boron, phosphorus (including phosphonates), and silicon.

[0364] As used herein, the term "saturated or unsaturated alkyl" encompasses both saturated alkyl groups and unsaturated alkyl groups, such as alkenyl and ynyl groups. The term "alkyl" as used herein refers to a straight-chain or branched n-, secondary, or tertiary hydrocarbon without unsaturated sites. However, it is generally contemplated that in the various embodiments in which "alkyl" is mentioned, other corresponding embodiments having "saturated or unsaturated alkyl" are also contemplated, and vice versa. Examples are 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" refers to a straight-chain or branched n-, secondary, or tertiary 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 cis or trans configuration. As used herein, the term "alkynyl" refers to a straight-chain or branched n-, secondary, or tertiary 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 (propynyl, -CH2C) CH).

[0365] As used herein, the term "saturated or unsaturated alkylene" encompasses both saturated and unsaturated alkylenes, such as alkenyl, alynyl, alynylynyl, etc. The term "alkylene" as used herein refers to a saturated, straight-chain, or branched hydrocarbon group having two monovalent groups derived from the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), etc. The term "alkenyl" as used herein refers to a straight-chain or branched hydrocarbon group having at least one unsaturated site (usually 1 to 3, preferably 1), i.e., a carbon-carbon sp2 double bond, and having two monovalent groups derived from the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. As used herein, the term "alynyl" refers to a straight-chain or branched hydrocarbon group having at least one unsaturated site (usually 1 to 3, preferably 1), namely a carbon-carbon sp triple bond and having two monovalent groups at the center derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne.

[0366] As used herein, the term "saturated or unsaturated heteroalkyl" encompasses both saturated and unsaturated heteroalkyl groups, such as heteroalkenyl, heteroynyl, heteroenynyl, etc. The term "heteroalkyl" as used herein refers to a straight-chain or branched alkyl group in which one or more carbon atoms (typically 1, 2, or 3) are replaced by heteroatoms (i.e., oxygen, nitrogen, or sulfur atoms), provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 groups of the alkyl group may be replaced by -NH2 and / or one or more -CH2- groups of the alkyl group may be replaced by -NH-, -O-, or -S-. The S atoms in the chain may optionally be oxidized by one or two oxygen atoms to provide sulfoxides and sulfones, respectively. Furthermore, the heteroalkyl groups in the indoleazine derivatives of the present invention may contain oxo or thio groups at any carbon or heteroatom, which will produce stable compounds. Exemplary heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers (such as, for example, -methoxy, -ethoxy, -butoxy…), primary, secondary, and tertiary alkylamines, amides, ketones, esters, alkyl sulfides, and alkyl sulfones. The term "heteroalkenyl" refers to a straight-chain or branched alkenyl group in which one or more carbon atoms (usually 1, 2, or 3) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. Therefore, the term heteroalkenyl includes imine, -O-alkenyl, -NH-alkenyl, -N(alkenyl)2, -N(alkyl)(alkenyl), and -S-alkenyl. The term "heteroyynyl" as used herein refers to a straight-chain or branched ynyl group in which one or more carbon atoms (usually 1, 2, or 3) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. Therefore, the term heteroyynyl includes -cyano, -O-ynyl, -NH-ynyl, -N(ynyl)2, -N(alkyl)(ynyl), -N(alkenyl)(ynyl), and -S-ynyl.

[0367] As used herein, the term "saturated or unsaturated heteroalkylene" encompasses both saturated and unsaturated heteroalkylene, such as heteroalkenyl, heteroynyl, and heteroenynyl. The term "heteroalkylene" as used herein refers to a straight-chain or branched alkylene where one or more carbon atoms (typically 1, 2, or 3) are replaced by heteroatoms (i.e., oxygen, nitrogen, or sulfur atoms), provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. The term "heteroalkenyl" as used herein refers to a straight-chain or branched alkenylene where one or more carbon atoms (typically 1, 2, or 3) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. The term "heterynyl" as used herein refers to a straight-chain or branched alynylene where one or more carbon atoms (typically 1, 2, or 3) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms.

[0368] As used herein, the term "saturated or unsaturated cycloalkyl" encompasses both saturated and unsaturated cycloalkyl groups, such as cycloalkenyl and cycloynyl groups. Unless otherwise stated, the term "cycloalkyl" as used herein refers to a saturated cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, flavyl, decahydronaphthyl, adamantyl, etc. The term "cycloalkenyl" as used herein refers to a non-aromatic cyclic alkyl group 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, cyclopentenyl and cyclohexenyl. The double bond may be in cis or trans configuration. The term "cycloynyl" as used herein refers to a non-aromatic cyclic alkyl group having at least one unsaturated site (usually 1 to 3, preferably 1), i.e., a carbon-carbon sp triple bond. An example is cycloheptyl-1-yne. The term "cycloalkyl" envisions fused systems of two cycloalkyl rings (two sharing ring atoms) and spiro systems (one sharing ring atom). Fused systems of cycloalkyl and heterocyclic alkyl rings are considered heterocyclic alkyl, regardless of the ring bonded to the core structure. Fused systems of cycloalkyl and aryl rings are considered aryl, regardless of the ring bonded to the core structure. Fused systems of cycloalkyl and heteroaryl rings are considered heteroaryl, regardless of the ring bonded to the core structure.

[0369] As used herein, the term "saturated or unsaturated heterocyclic alkyl" encompasses both saturated heterocyclic alkyl and unsaturated non-aromatic heterocyclic alkyl that includes at least one heteroatom, i.e., N, O, or S, as a ring member. Unless otherwise stated, the term "heterocyclic alkyl" as used herein means a "cycloalkyl" in which one or more carbon atoms (typically one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. Unless otherwise stated, the term "heterocyclic alkenyl" as used herein means a "cycloalkenyl" in which one or more carbon atoms (typically one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. Unless otherwise stated, the term "heterocyclic alkynyl" as used herein means a "cycloalkynyl" in which one or more carbon atoms (typically one, two, or three) are replaced by oxygen, nitrogen, or sulfur atoms, provided that the chain may not contain two adjacent O atoms or two adjacent S atoms. Examples of saturated and unsaturated heterocyclic alkyl groups include, but are not limited to, azetane, 1,4-oxazheptane, azetane, azetidine, aziridine, azetane, diazetane, dioxane, dioxolane, dithiopentane, dithiopentane, imidazolide, isothiazolidine, isoxazolidine, morpholine, oxazolidine, hexane oxide, oxazolidine, ethylene oxide, piperazine, piperidine, pyrazolidine, pyrrolidine, quinine ring, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, and thiazolide. Thionylbutane, thiocyclopropane, thiocyclopentane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiocyclohexane, 2-azaspiro[3.3]heptane, 2-oxazaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-1H-pyrrolizine, hexahydrocyclopentadieno[c]pyrrole, octahydrocyclopentadieno[c]pyrrole, and octahydropyrrolo[1,2-a]pyrazine.Other heterocyclic alkyl groups as understood in this invention are described in Paquette, Leo A., *Principles of Modern Heterocyclic Chemistry* (WA Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Son, New York, 1950 to present), particularly Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, CW, and Scriven, E., *Comprehensive Heterocyclic Chemistry* (Pergman Press, 1996); and *Journal of the American Chemical Society* (1960) 82:5566. When a heterocyclic alkyl group does not contain nitrogen as a ring member, it is typically bonded by carbon. When a heterocyclic alkyl group contains a nitrogen-containing ring member, it can be bonded via nitrogen or carbon. Fused systems of heterocyclic alkyl rings with cycloalkyl rings are considered heterocyclic alkyl, regardless of the ring bonded to the core structure. Fused systems of heterocyclic alkyl rings with aryl rings are considered heterocyclic alkyl, regardless of the ring bonded to the core structure. Fused systems of heterocyclic alkyl rings with heteroaryl rings are considered heteroaryl, regardless of the ring bonded to the core structure.

[0370] As used herein, the term "aryl" refers to an aromatic hydrocarbon. Typical aryl groups include, but are not limited to, one-membered rings (such as phenyl or others) or fused two- or three-membered rings derived from free radicals of benzene, naphthalene, anthracene, biphenyl, etc. Fused systems of aromatic rings with cycloalkyl rings are considered aryl, regardless of the ring bonded to the core structure. Fused systems of aryl rings with heterocyclic alkyl rings are considered heterocyclic alkyl, regardless of the ring bonded to the core structure. Therefore, indoline, dihydrobenzofuran, dihydrobenzothiophene, etc., are considered heterocyclic alkyl according to the present invention. Fused systems of aryl rings with heteroaryl rings are considered heteroaryl, regardless of the ring bonded to the core structure.

[0371] As used herein, the term "heteroaryl" refers to an aromatic ring system that includes at least one heteroatom (i.e., N, O, or S) as a ring member of the aromatic ring system. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzisoxazole, benzodioxazole, benzodioxane, benzofuran, benzothiadiazole, benzothiazol, benzothiophene, carbazole, zoline, dibenzofuran, furan, furazon, imidazole, imidazopyridine, indazole, indole, indoleazine, isobenzofuran, isoindole, isoquinoline, isothiazazole, isoxazole, naphthidine, oxadiazole, oxazole, hydroxyindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazine, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine.

[0372] For further examples, carbon-bonded heterocycles are bonded at positions 2, 3, 4, 5, or 6 of pyridine, positions 3, 4, 5, or 6 of pyridazine, positions 2, 4, 5, or 6 of pyrimidine, positions 2, 3, 5, or 6 of pyrazine, positions 2, 3, 4, or 5 of furan, tetrahydrofuran, thiophene, pyrrole, or tetrahydropyrrole, positions 2, 4, or 5 of oxazole, imidazole, or thiazole, positions 3, 4, or 5 of isoxazole, pyrazole, or isothiazole, positions 2 or 3 of aziridine, positions 2, 3, or 4 of aziridine, positions 2, 3, or 4 of aziridine, positions 2, 3, 4, 5, 6, 7, or 8 of quinoline, or positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline.

[0373] Carbon-bonded heterocycles include 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. For example, nitrogen-bonded heterocycles are bonded at the 1-position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrroleline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, and 1H-indazole, at the 2-position of isoindole or isoindoline, at the 4-position of morpholine, and at the 9-position of carbazole or β-carbline. Nitrogen-bonded heterocycles include 1-aziridinepropyl, 1-aziridinebutyl, 1-pyrroleyl, 1-imidazoyl, 1-pyrazolyl, and 1-piperidinyl. Other heteroaryl groups in the sense of this invention are described in Paquette, Leo A., *Principles of Modern Heterocyclic Chemistry* (WA Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Son Publishing, New York, 1950 to present), particularly Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, CW, and Scriven, E., *Comprehensive Heterocyclic Chemistry* (Pergman Press, 1996); and *Journal of the American Chemical Society* (1960) 82:5566.

[0374] As used herein with respect to substituents, and unless otherwise stated, the terms “monosubstituted,” “disubstituted,” “trisubstituted,” “polysubstituted,” etc., mean as defined herein, a chemical structure in which each part is substituted by one or more substituents, meaning that one or more hydrogen atoms of said part are each independently substituted by a substituent. For example, -C can be polysubstituted by -F. 1-6 -alkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, etc. Similarly, -C groups can be multisubstituted by substituents selected independently from -F and -Cl. 1-6-alkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CCl3, CCl2CCl3, -CHClF, -CClF2, -CCl2CF3, -CF2CCl3, -CClFCCl2F, etc. The name of any substituent found at more than one site in the compounds of this invention should be chosen independently.

[0375] In some embodiments, the compound is shown as having wedge-shaped stereochemical bonds. For example, the wedge-shaped stereochemical bond in cpd 1 (with one wedge pointing out of the plane and the other pointing in the plane) represents the trans configuration, and the wedge-shaped stereochemical bond in cpd 2 (with both wedges pointing out of the plane) represents the cis configuration. Neither the trans nor cis configurations are depicted with absolute stereochemistry at the ring junction stereocenter, but all possible absolute stereochemistry at the bonded chiral center is included. For example, cpd 1 as depicted in Table 1 includes both the (R,R) and (S,S) absolute configurations of the chiral center on the cyclopropyl group of the trans stereoisomer. Similarly, cpd 2 as depicted in Table 1 includes both the (S,R) and (R,S) absolute configurations of the chiral center on the cyclopropyl group of the cis stereoisomer.

[0376] Unless otherwise stated, the term "solvent" as used herein includes any combination that can be formed from derivatives of the present invention with suitable inorganic solvents (e.g., hydrates) or organic solvents (e.g., but not limited to alcohols, ketones, esters, ethers, nitriles, etc.).

[0377] As used in this article, the term "subject" refers to an animal, including humans, preferably mammals, and most preferably humans, that has been used as a subject of treatment, observation or experimentation.

[0378] As used herein, the term "therapeutic effective amount" refers to the amount of an active compound or agent that elicits a biological or medical response sought by a researcher, veterinarian, physician, or other clinician in an tissue system, animal, or human, including the reduction or partial reduction of symptoms of the disease or condition being treated.

[0379] As used herein, the term "composition" is intended to cover products containing a specific amount of a therapeutically effective ingredient, and any product obtained directly or indirectly from a combination of specific amounts of a specific ingredient.

[0380] As used herein, the terms "antagonist" or "inhibitor" refer to compounds that, depending on the circumstances, produce a functional antagonistic effect on the TRPM3 ion channel, including competitive antagonists, non-competitive antagonists, desensitizing agonists, and partial agonists. Generally, "antagonist" and "inhibitor" can be understood as regulating TRPM3.

[0381] For the purposes of this invention, the term "TRPM3-regulated" is used to refer to situations influenced by the regulation of TRPM3 ion channels, including states mediated by TRPM3 ion channels.

[0382] As used herein, the term "TRPM3-mediated condition" refers to a condition or disease that can be prevented, treated, (partially) alleviated, or improved with the use of TRPM3 antagonists or modulators and consists of pain, inflammatory hypersensitivity symptoms, and epilepsy. According to the International Association for the Study of Pain and for the purposes of this invention, pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Preferably, the TRPM3-mediated condition is pain, preferably selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain or migraine. For the purposes of this invention, the term "inflammatory hypersensitivity" is used to refer to a condition characterized by one or more inflammatory features (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).

[0383] The indolezine derivatives of the present invention have been shown as, or understood as, antagonists or modulators of TRPM3, and therefore the present invention provides compounds that are used as medicines, more specifically as medicines in the prevention or treatment of TRPM3-mediated conditions in a subject by using a therapeutically effective amount of the indolezine derivatives of the present invention.

[0384] In one embodiment of the invention, the indolezine derivative of the invention is the only pharmacologically active compound for therapeutic administration. In another embodiment of the invention, the indolezine derivative of the invention can be used in combination with other therapeutic agents to treat or prevent TRPM3-mediated conditions. Therefore, the invention also relates to the use of compositions comprising:

[0385] - One or more compounds of the chemical formula herein and examples, and

[0386] - One or more other therapeutic or preventive agents for the prevention or treatment of TRPM3-mediated conditions, which are bioactive agents used simultaneously, separately or sequentially in combination formulations.

[0387] The pharmaceutical compositions or combinations according to the invention may contain the indolezine derivative of the invention in a wide range of contents, depending on the intended use and expected effect of the formulation. Typically, the content of the indolezine derivative of the invention in the combination formulation is in the range of 0.1% by weight to 99.9% by weight, preferably 1% by weight to 99% by weight, and more preferably 5% by weight to 95% by weight.

[0388] Given this fact, when several active ingredients are used in combination, they do not necessarily produce their combined therapeutic effect simultaneously and directly in the mammal to be treated. The corresponding composition may also be in the form of a medical kit or package containing two ingredients in separate but adjacent reservoirs or compartments. In the latter case, each active ingredient can therefore be formulated in a manner suitable for a different route of administration than the others; for example, one may be in the form of an oral or parenteral preparation, while the other may be in the form of an ampoule or aerosol for intravenous injection.

[0389] Those skilled in the art will also recognize that the indoleazine derivatives of the present invention can exist in many different protonated states, depending in particular on the pH and other conditions of their environment. While the structural formulas provided herein depict compounds in only one of several possible protonated states, it should be understood that these structures are illustrative only, and the invention is not limited to any particular protonated state—any and all protonated forms of the compounds are intended to fall within the scope of the invention.

[0390] As used herein, the terms "pharmaceutically acceptable salt" or "physiologically acceptable salt" refer to the therapeutically active, non-toxic salt form that compounds of the chemical formulas herein can form. Therefore, the compounds of the present invention optionally comprise salts of the compounds herein, particularly pharmaceutically acceptable, non-toxic salts containing, for example, Na. + Li + K + Ca 2+ and Mg 2+Such salts can include those derived by combination of a suitable cation (such as alkali metal and alkaline earth metal ions or ammonium and quaternary amino ions) with an acid anionic moiety (typically a carboxylic acid). The indoleazine derivatives of the present invention can carry multiple positive or negative charges. The net charge of the indoleazine derivatives of the present invention can be positive or negative. Any associated counterions are typically determined by the synthetic and / or isolated methods used to obtain the compound. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetates, trifluoroacetates, and mixtures thereof. It should be understood that the identity of any associated counterion is not a key feature of the present invention, and the present invention covers compounds associated with any type of counterion. Furthermore, since compounds can exist in many different forms, the present invention aims to cover not only forms associated with counterions (e.g., dry salts) but also forms not associated with counterions (e.g., aqueous solutions or organic solutions). Metal salts are typically prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts prepared in this manner are those containing Li + Na + and K + Salts are salts of compounds with higher solubility. By adding a suitable metal compound, a metal salt with lower solubility can be precipitated from a salt solution with higher solubility. Additionally, salts can be formed by the addition of certain organic and inorganic acids to a basic center (usually an amine) or an acidic group. Examples of such suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as, for example, acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, etc. Furthermore, the term also includes solvates, such as hydrates, alcohols, etc., that compounds of the chemical formulas herein and their salts can form. Finally, it should be understood that the compositions herein comprise the indoleazine derivatives of the invention in their unionized and zwitterionic forms, and in their hydrated form in combination with a stoichiometric amount of water.

[0391] The scope of this invention also includes salts of parent compounds and one or more amino acids, particularly salts of naturally occurring amino acids found as protein components. Amino acids are typically those with side chains having basic or acidic groups (e.g., lysine, arginine, or glutamic acid) or neutral groups (e.g., glycine, serine, threonine, alanine, isoleucine, or leucine).

[0392] The indoleazine derivatives of the present invention also include their physiologically acceptable salts. Examples of physiologically acceptable salts of the indoleazine derivatives of the present invention include salts derived from suitable bases, such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and Nx4. + (where X is -C) 1-6 -alkyl). Physiologically acceptable salts of compounds containing hydrogen atoms or amino groups include salts of the following: organic carboxylic acids, such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, ethanesulfonic 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 aminosulfonic acid. Physiologically acceptable salts of compounds containing hydroxyl groups include those described above. The anion of the compound and a suitable cation (such as Na) + and NX4 + (where X is usually selected independently from -H or -C) 1-4 Combinations of alkyl groups. However, salts of acids or bases that are not physiologically acceptable may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of this invention.

[0393] Unless otherwise stated, the term “enantiomer” as used herein refers to each individual optically active form of the indoleazine derivative of the present invention having an optical purity of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98% (as determined by standard methods in the art).

[0394] As used herein, the term "isomer" refers to all possible isomers that a compound of the formula herein may have, including tautomers and stereochemical forms, but excluding positional isomers. Generally, the structures shown herein illustrate only one tautomer or resonance form of the compound, but corresponding alternative configurations are also contemplated. Unless otherwise stated, the chemical name of a compound represents a mixture of all possible stereochemical isomers, containing all diastereomers and enantiomers of the basic molecular structure (since compounds of the formula herein may have at least one chiral center), as well as stereochemically pure or enriched compounds. More specifically, the stereocenter may have an R- or S-configuration, and multiple bonds may have cis or trans configurations.

[0395] The pure isomer form of the compound is defined as an isomer that substantially does not contain other enantiomers or diastereomers of the same basic molecular structure. In particular, the terms "stereoisomerically pure" or "chirally pure" refer to a compound having a stereoisomeric excess of at least about 80% (i.e., at least 90% of one isomer and at most 10% of 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 enantiomeric and diastereomeric excesses of the mixture, respectively.

[0396] The separation of stereoisomers is accomplished by standard methods known to those skilled in the art. One enantiomer of the indoleazine derivative of the present invention can be separated by methods such as forming diastereomers using optically active resolving agents, substantially free of its opposite enantiomers (Stereochemistry of Carbon Compounds, (1962) EL Eliel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr., 113:3 283-302). The separation of isomers in a mixture can be achieved by any suitable method comprising: (1) forming an ionic diastereoisomeric salt with a chiral compound and separating it by fractional crystallization or other methods; (2) forming a diastereoisomeric compound with a chiral derivatizing agent, separating the diastereomer and converting it to a pure enantiomer; or (3) the enantiomers can be directly separated under chiral conditions. In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases (such as strychnine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine)) with asymmetric compounds containing acidic functional groups (such as carboxylic acids and sulfonic acids). The diastereomeric salts can be separated by fractional crystallization or ion chromatography. To separate the optical isomers of amino compounds, the addition of chiral carboxylic acids or sulfonic acids (such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid) can form diastereomeric salts. Alternatively, by method (2), the substrate to be resolved can react with one enantiomer of the chiral compound to form a diastereomer pair (Eliel, E. and Willen, S. (1994), *Stereochemistry of Organic Compounds*, John Wiley & Son Publishing Co., Ltd.). Page 322). Diasteremeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent (such as a menthyl derivative), followed by separation of the diastereomer and hydrolysis to produce a free enantiomer-enriched compound. Methods for determining optical purity involve preparing chiral esters, such as menthyl ester or mosher ester, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), and analyzing the presence of two trans-restricted diastereomers in the NMR spectrum. Stable diastereomers can be separated and isolated by normal-phase and reversed-phase chromatography according to the method for separating trans-restricted naphthyl-isoquinoline (Hoye, T., WO 96 / 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, particularly cellulose or amylose derivatives. A commercially available polysaccharide-based chiral stationary phase is ChiralCel. ® CA, OA, OB5, OC5, OD, OF, OG, OJ, and OK, as well as Chiralpak ® AD, AS, OP(+), and OT(+). Suitable eluents or mobile phases used in combination with the chiral stationary phase of the polysaccharide are alcohols such as hexane modified with alcohols (e.g., ethanol, isopropanol, etc.). "Chiral Liquid Chromatography" (1989), edited by W.J. Lough, Chapman and Hall, New York; Okamoto, Inc. (1990, "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", Journal of Chromatography 513:375-378).

[0397] The terms cis and trans are used herein according to Chemical Abstracts nomenclature and include reference to the position of the substituent on the ring moiety. Those skilled in the art can readily determine the absolute stereochemical configuration of compounds of the formulas described herein using known methods such as X-ray diffraction.

[0398] When a compound crystallizes from a solution or slurry, it can crystallize in different spatially arranged lattice sites (a property known as "polymorphism") to form crystals with different crystalline forms, each called a "polymorph". Therefore, as used herein, the term "polymorph" refers to the crystalline form of a compound of formula (I) in which the molecules reside in three-dimensional lattice sites. Different polymorphs of a 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, accumulation mode, fluidity, and / or solid-state stability, etc.

[0399] The indolezine derivatives of the present invention and their physiologically acceptable salts (hereinafter collectively referred to as the active ingredients) may be administered via any route suitable for the condition to be treated, including oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intranasal, intravenous, intraarterial, intradermal, intrathecal, and epidural). Preferred routes of administration may vary depending on, for example, the recipient's condition.

[0400] The therapeutically effective amount of a compound formulation, particularly for the treatment of TRPM3-mediated conditions in humans and other mammals or animals, is preferably the amount of TRPM3 ion channel inhibition of the compound as defined herein, and corresponds to an amount that ensures a plasma level between 1 µg / ml and 100 mg / ml.

[0401] Appropriate doses of the compounds or compositions of the present invention are applied to treat or prevent TRPM3-mediated conditions in a subject. Depending on the pathological state to be treated and the patient's condition, the effective dose may be divided into several subunits per day or may be administered at intervals of more than one day.

[0402] The present invention further provides (pharmaceutical) compositions comprising one or more indolezine derivatives of the present invention, more particularly all of formula (I) or formula (II) and other formulas and embodiments described herein, and their more particular aspects or embodiments. Furthermore, the present invention provides compounds or (pharmaceutical) compositions of the present invention for use as medicines, more particularly for the treatment of pain, more specifically having all of chemical formula (I) and other chemical formulas and embodiments described herein, and their more particular aspects or embodiments. TRPM3-mediated symptoms are selected from pain and inflammatory hypersensitivity symptoms and epilepsy.

[0403] The indolezine derivatives of this invention can be formulated with conventional carriers and excipients, which will be selected according to conventional practice. Tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are typically isotonic when intended for delivery by means other than oral administration. Formulations optionally contain excipients, such as those described in the Handbook of Pharmaceutical Excipients (1986).

[0404] Subsequently, the term "pharmaceutically acceptable carrier" as used herein means any material or substance formulated with the active ingredient to facilitate its application or dispersal to the site of treatment, for example by dissolving, dispersing, or diffusing the composition, and / or facilitating its storage, transport, or handling without impairing its effectiveness. A pharmaceutically acceptable carrier can be a solid or liquid or a gas that has been compressed to form a liquid; that is, the compositions of the present invention can suitably be used as concentrates, emulsions, solutions, granules, powders, sprays, aerosols, suspensions, ointments, creams, tablets, pills, or powders.

[0405] Suitable pharmaceutical carriers for the pharmaceutical compositions and formulations thereof are well known to those skilled in the art, and there are no particular limitations on their selection in this invention. They may also include additives such as wetting agents, dispersants, adhesives, binders, emulsifiers, surfactants, solvents, coatings, antibacterial and antifungal agents, isotonic agents, etc., provided that they are consistent with pharmaceutical practice, i.e., that the carrier and additives do not cause permanent harm to mammals. The pharmaceutical compositions of this invention can be prepared in any known manner, for example by uniformly mixing, coating, and / or grinding the active ingredient with a selected carrier material and, where appropriate, other additives (such as surfactants) in one or more steps. They can also be prepared by micronization, for example, to obtain them in the form of microspheres typically having a diameter of about 1 to 10 gm, i.e., for the preparation of microcapsules for controlled or sustained release of the active ingredient.

[0406] While indolezine derivatives can be administered alone, they are preferred as pharmaceutical formulations. The veterinary and human formulations of the present invention comprise at least one active ingredient as described above, as well as one or more pharmaceutically acceptable carriers and optional other therapeutic ingredients. The carrier is preferably "acceptable" in the sense of compatibility with the other components of the formulation and harmlessness to the recipient. Formulations include those suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. Formulations can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. These methods include the step of binding the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, formulations are prepared by uniformly and tightly bonding the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then shaping the product if necessary.

[0407] Formulations of the present invention suitable for oral administration can be presented as discrete units, such as capsules, sachets, 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 emulsions. The active ingredient may also be present in pellets, saccharides, or pastes.

[0408] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets can be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and optionally formulated to provide a slow or controlled release of the active ingredient therein. For infections of the eyes or other external tissues (e.g., the mouth and skin), the formulation is optionally applied as a topical ointment or cream containing, for example, 0.075% w / w to 20% w / w (including active ingredient in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2% w / w to 15% w / w, and most preferably 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations can ideally include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such transdermal penetration enhancers include dimethyl sulfoxide and related analogues.

[0409] The oil phase of the emulsion of the present invention can be composed of known ingredients in a known manner. Although this phase may contain only emulsifiers (also known as laxatives), it ideally contains at least one emulsifier with fats or oils, or with a mixture of both fats and oils. Optionally, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. Both oils and fats are also preferred. The emulsifiers, with or without stabilizers, constitute so-called emulsified waxes, and the waxes, together with the oils and fats, constitute a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

[0410] The selection of a suitable oil or fat for the formulation is based on achieving the desired cosmetic performance, as the active compound has very low solubility in most oils that may be used in pharmaceutical emulsion formulations. Therefore, the cream should optionally be a non-greasy, non-coloring, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched mono- or dialkyl esters, such as diisohexyl adipate, isohexadecanyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or blends of branched esters known as Crodamol CAP, the latter three being preferred, can be used. These can be used alone or in combination, depending on the desired performance. Alternatively, high-melting-point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.

[0411] Formulations suitable for topical ocular application also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solvent of the active ingredient. The active ingredient is optionally present in such formulations at a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w. Formulations suitable for topical oral application include: lozenges containing a flavoring matrix containing the active ingredient, typically sucrose and gum arabic or tragacanth; lozenges containing an inert matrix containing the active ingredient, such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing a suitable liquid carrier containing the active ingredient.

[0412] Formulations for rectal administration may exist as suppositories having a suitable matrix comprising, for example, cocoa butter or salicylates. Formulations suitable for nasal administration, wherein the carrier is solid, include coarse powder with a particle size, for example, in the range of 20 to 500 micrometers (including increments of 5 micrometers within the range of 20 to 500 micrometers, such as 30 micrometers, 35 micrometers, etc.), administered by nasal inhalation, i.e., rapid inhalation through the nasal passages from a powder container near the nose. Suitable formulations for administration as, for example, nasal sprays or drops, wherein the carrier is liquid, include aqueous or oily solutions 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.

[0413] Formulations suitable for vaginal application may be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays, which, in addition to the active ingredient, contain a suitable carrier as known in the art.

[0414] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners. Formulations may be available in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Temporary injectable solutions and suspensions can be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0415] Preferred unit-dose formulations are those containing the active ingredient at the daily dose or sub-daily dose or an appropriate fraction thereof as described above.

[0416] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art related to the type of formulation discussed, such as flavoring agents, those suitable for oral administration.

[0417] The indoleazine derivatives of the present invention can be used to provide controlled-release pharmaceutical formulations (“controlled-release formulations”) containing one or more indoleazine derivatives of the present invention as active ingredients, wherein the release of the active ingredient can be controlled and modulated to allow for lower frequency of administration or to improve the pharmacokinetic or toxicological characteristics of a given compound of the present invention. Controlled-release formulations suitable for oral administration, comprising discrete units of one or more indoleazine derivatives of the present invention, can be prepared according to conventional methods.

[0418] Another embodiment of the invention relates to various prodrug or "prodrug" forms of the indoleazine derivatives of the invention. It may be necessary to formulate the indoleazine derivatives of the invention into a form of a chemical substance that itself does not have significant biological activity, but when delivered to an animal, mammal, or human, it will undergo a chemical reaction catalyzed by normal bodily functions, particularly enzymes present in the stomach or serum, which has the effect of releasing a compound as defined herein. Therefore, the term "prodrug" refers to these substances that are converted into an active pharmaceutical ingredient in vivo.

[0419] The indoleazine derivative prodrugs of the present invention can have any form suitable to the formulation user; for example, esters are a common, non-limiting prodrug form. However, in this case, the prodrug may necessarily be present in a form in which the covalent bond is cleaved by the action of an enzyme present at the target locus. For example, the C-C covalent bond can be selectively cleaved by one or more enzymes at the target locus; therefore, prodrugs in forms other than readily hydrolyzable precursors, especially 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, and other structures known in the art.

[0420] For the purposes of this invention, the term "therapeutically suitable prodrug" is defined herein as "a compound modified in vivo to a therapeutically active form when in contact with tissues of an animal, mammal, or human to which a prodrug has been administered, whether by a single biotransformation or by multiple biotransformations, without undue toxicity, irritation, or allergic reaction, and achieving the desired therapeutic outcome."

[0421] More specifically, as used herein, the term "prodrug" refers to inactive or significantly reduced-activity derivatives of compounds represented by the structural formulas described herein, which undergo spontaneous or enzymatic conversion in vivo to release the pharmacologically active form of the compound. For review purposes, see Rautio J. et al. (Prodrugs: design and clinical applications, Nature Reviews Drug Discovery, 2008, doi: 10.1038 / nrd2468).

[0422] The representative indoleazine derivatives of the present invention can be synthesized according to the general synthetic methods described below and illustrated in the embodiments below. Since the embodiments are exemplary, the invention should not be construed as being limited to the specific chemical reactions and specific conditions described in the embodiments and examples. Various starting materials used in the embodiments are commercially available or can be prepared by methods well known to those skilled in the art. Variables are as defined herein and are within the skill of those skilled in the art.

[0423] Example

[0424] The following examples are provided to illustrate the invention and should not be construed as limiting the scope of the invention.

[0425] The representative compounds of this invention can be synthesized according to the general synthetic methods described below and illustrated in the embodiments below. Since the embodiments are exemplary, this invention should not be construed as being limited to the specific chemical reactions and specific conditions described in the embodiments and examples. Various starting materials used in the embodiments are commercially available or can be prepared by methods well known to those skilled in the art. Variables are as defined herein and are within the skill of those skilled in the art.

[0426] The abbreviations used in this specification, particularly in the schemes and examples, are as follows: ABC – ammonium bicarbonate aqueous solution, ACN – acetonitrile, AcOH – acetic acid, ADDP – 1,1'-(azodicarbonyl)piperidine, aq. – aqueous solution, AIBN – azobisisobutyronitrile, BrettPhos – 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, CAN – cerium ammonium nitrate, COMU – (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony 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, DMAP–4-dimethylaminopyridine, DME–1,2-dimethoxyethane, DMEDA–1,2-dimethylethylenediamine, DMF–N,N-dimethyl Formamide, DMSO – dimethyl sulfoxide, DPPA – diphenylphosphoazide, 2,4-DNPH – 2,4-dinitrophenylhydrazine, DTBAD – tert-butyl azodicarbonate, 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 – rapid column chromatography, h – hour, HATU – O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, HP LC – High Performance Liquid Chromatography, IPA – Isopropanol, LAH – Lithium Aluminum Hydrate, LG – Leaving Group, mCPBA – m-chloroperoxybenzoic acid, MeOH – Methanol, min. – minutes, Ms – Methanesulfonyl, NBS – N-bromosuccinimide, nBuLi – n-Butyllithium, NMP – 1-Methyl-2-pyrrolidone, Pd(PPh3)4 – Tetra-(triphenylphosphine)-Palladium(O), PdCl2(dppf).DCM – [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II), Pd2(dba)3 – Tris(dibenzylacetone)dipalladium, Pet ether – petroleum ether, PPh3 – triphenylphosphine, PS-DIEA – polystyrene-supported diisopropylethylamine, PS-PPh3 – polystyrene-supported triphenylphosphine, PyBop – benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, Pyr. – pyridine, PTSA – p-toluenesulfonic acid, RF: frontier orbital ratio, RM – reaction mixture, RP – reversed phase, RT – room temperature, sat.– Saturated, SEM – [2-(trimethylsilyl)ethoxy]methyl acetal, SFC – Supercritical fluid chromatography, SPE – Solid phase extraction, TBDMS – tert-butyl dimethylsilyl ether, TBAF – Tetrabutylammonium fluoride hydrate, TBAI – Tetrabutylammonium iodide, TEA – Triethylamine, Tf – Trifluoromethanesulfonate, THF – Tetrahydrofuran, TFA – Trifluoroacetic acid, TLC – Thin-layer chromatography, TPP – Triphenylphosphine, IPA – Isopropanol, TMS – Trimethylsilyl, T3P – Propylphosphonic anhydride, XPhos Pd G3 – (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate.

[0427] The compounds of interest have structures according to general formula (A), and all other formulas and their embodiments described herein can be prepared as outlined in General Chemical Scheme 1.

[0428]

[0429] Option 1: All R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 As described with respect to the compounds of the present invention.

[0430] In a solvent (e.g., DMF, toluene, dioxane, water, etc.), a bromo-indoleazine of Formula 1 (commercially available or synthesized by a process known to those skilled in the art or as described in the examples below) (where R' is an ester protecting group (e.g., methyl, ethyl, t-Bu, etc.)) can be reacted with a Pd catalyst (e.g., Pd(PPh3)4, PdCl2(dppf), etc.) and a salt (e.g., KF, K3PO4, Na2CO3, etc.) with a suitable boric acid derivative 2 (commercially available or synthesized by a process known to those skilled in the art or as described in the examples below) (where R'' is a hydrogen or alkyl group (e.g., methyl, butyl, etc.)) to provide an intermediate of Formula 3. Cyclopropanization of the olefin derivative 3 with a hydrazone derivative 4 (commercially available or synthesized by a process known to those skilled in the art or as described in the examples below) in a polar aprotic solvent (e.g., DCM, dioxane, etc.) in the presence of a base (e.g., NaH, K2CO3, etc.) can supply an intermediate of Formula 5. The ester derivative 5 can then be converted into the acid derivative of formula 6 via a standard saponification reaction. The desired compound of formula 8 can be obtained from the acid derivative of formula 6 by reacting it with the amine derivative of formula 7 (commercially available or synthesized by procedures known in the art or as described in the examples below) under standard peptide coupling conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.).

[0431] In a more specific embodiment, the compounds of the present invention may be synthesized as described in Scheme 2.

[0432]

[0433] Option 2: All R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 X and Cy are as described with respect to the compounds of the present invention.

[0434] The 6-hydroxyindoleazine-3-carboxylic acid derivative 10 (commercially available or synthesized by a procedure known to those skilled in the art or as described in the examples below) (where R' is an ester protecting group (e.g., methyl, ethyl, t-Bu, etc.)) can be converted to the desired compound of formula 12 by Ullmann coupling mediated by a copper catalyst (e.g., CuI) in the presence of a base (e.g., DIPEA, DBU, triethylamine, Cs2CO3, etc.) in a polar solvent (e.g., 1,4-dioxane, etc.) with a ligand (e.g., tetramethyl-3,5-heptanedione, etc.) at a temperature ranging from room temperature to 100°C. Compounds of interest having Formula 13 can be obtained by standard saponification of ester derivative 12 in a polar aprotic solvent (e.g., DCM, DMF, etc.) under standard peptide coupling conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) followed by reaction with an amine derivative of Formula 7 (commercially available or synthesized by procedures known in the art or as described in the examples below).

[0435] In a more specific embodiment, the compounds of the present invention may be synthesized as described in Scheme 3.

[0436]

[0437] Option 3: All R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 X and Cy are as described with respect to the compounds of the present invention.

[0438] 6-Hydroxyindoleazine-3-carboxylic acid derivative 10 (commercially available or synthesized by a procedure known to those skilled in the art or as described in the examples below) (where R' is an ester protecting group (e.g., methyl, ethyl, t-Bu, etc.)) can be reacted with a trifluoromethanesulfonating agent (e.g., N,N-bis(trifluoromethanesulfonyl)aniline, OTf2, etc.) in the presence of a base (e.g., DIPEA, DBU, TEA, etc.) with or without a nucleophilic catalyst (e.g., DMAP, Pyr., etc.) in a polar aprotic solvent (e.g., DCM, DMF, etc.) to provide an intermediate of formula 20. In solvents (e.g., DMF, toluene, dioxane, water, etc.), 6-(((trifluoromethyl)sulfonyl)oxy)indolazine-3-carboxylate derivative 20 can be reacted with a Pd catalyst (e.g., Pd(PPh3)4, PdCl2(dppf) etc.) and a salt (e.g., KF, K3PO4, Na2CO3, etc.) with a suitable boric acid derivative 21 (commercially available or synthesized by procedures known to those skilled in the art or as described in the examples below) (where R'' is hydrogen or an alkyl group (e.g., methyl, butyl, etc.)) to provide an intermediate of formula 22. Compounds of interest having formula 23 can be obtained by standard saponification of ester derivative 22 in a polar aprotic solvent (e.g., DCM, DMF, etc.) under standard peptide coupling conditions (e.g., DCC, EDCI, HATU, PyBop, etc.) followed by reaction with an amine derivative of formula 7 (commercially available or synthesized by procedures known to those skilled in the art or as described in the examples below).

[0439] Table 1: Exemplary Indoleazine Derivatives

[0440]

[0441] The following examples are provided to illustrate the invention and should not be construed as limiting the scope of the invention.

[0442] Part A represents the preparation of the compound, while part B represents a pharmacological example.

[0443] Part A

[0444] All starting materials not explicitly described are commercially available (details of suppliers such as ABCR, Apollo Scientific Combi-Blocks, Enamine, FluoroChem, Matrix Scientific, Maybridge, Merck, TCI, etc. can be found in databases such as SciFinder®) or their synthesis has been precisely described in professional literature (experimental guides can be found in databases such as Reaxys® or SciFinder®) or can be prepared using conventional methods known to those skilled in the art.

[0445] If desired, the reaction is carried out under an inert atmosphere (primarily argon and N2). The equivalence of reagents and the amount of solvent used, as well as the reaction temperature and time, can vary slightly between different reactions carried out using similar methods. Treatment and purification methods are tailored to the characteristic properties of each compound and can be slightly varied for similar methods. The yields of the prepared compounds have not been optimized.

[0446] The terms "equivalent" ("eq." or "eq" or "equiv.") refer to molar equivalents, "RT" or "rt" refers to room temperature (T, 23 ± 7 °C), "M" indicates concentration in mol / L, "sol." means solution, and "conc." means concentration. The mixing ratio of solvents is usually expressed as a volume / volume ratio.

[0447] pass 1 H-NMR spectroscopy and / or mass spectrometry (MS, for [M+H]) + and / or [MH] – The m / z values ​​were used to perform key analytical characterization of all exemplary compounds and selected intermediates. In some cases, where regioisomers and / or diastereomers may be formed during the reaction, additional analyses were performed, such as... 13 C NMR and NOE (nuclear Overhauser effect) NMR experiments.

[0448] The analytical instruments used were, for example, BRUKER 400MHz or BRUKER 500MHz machines (Software Topspin) for NMR analysis, with BRUKER AVANCE 300MHz and 400MHz used alternatively. For LC / MS analysis, Agilent 1290 Infinity, Mass:6150 SQD (ESI / APCI) or Agilent 1200 SERIES, Mass:6130SQD (ESI / APCI) (Software Chemistation) were used. Analytical HPLC was performed, for example, on Waters (Software Empower), Agilent-1200-ELSD (Software Chemistation), or Agilent-1260 (Software OpenLAB). SFC analysis was performed, for example, on PICsolution (Software: SFC PICLAB ONLINE), WATERS-X5 (Software MASSLYNX), or WATERS-UPC2 (Empower).

[0449] Preparative HPLC was performed, for example, on a Waters 2998 (Empower software) or YMC (K-Prep software). Preparative SFC was performed, for example, on a Waters SFC-200 (Chromscope or Superchrome software), a Waters SFC-80 (Superchrome) or a PIC PIC-175 (S10-100 software).

[0450] If the stereochemistry is known, draw the structure of the example compound containing the stereochemical center and name it with its absolute stereochemistry. In cases where the absolute stereochemistry is unknown, the compound may be a mixture of racemic diastereomers, a pure diastereomer with unknown stereochemistry, or a pure enantiomer with unknown stereochemistry. Dia 1 and Dia 2 indicate that the diastereomers have been isolated, but their stereochemistry is unknown. En 1 and En 2 indicate that both enantiomers have been isolated, but their absolute configuration is unknown. The absence of a suffix after the compound code indicates that the compound containing the stereochemical center was obtained as either a racemic mixture or a mixture of diastereomers, unless the chemical name of the compound specifies the exact stereochemistry.

[0451] (S)-2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionamide (Int-A001–En1) Synthesis of (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionamide (Int-A001–En2).

[0452]

[0453] Step 1: At room temperature, a solution of 1-((tert-butyldimethylsilyl)oxy)prop-2-one (20 g, 106.19 mmol) in EtOH (100 mL) was treated with (4-methoxyphenyl)methylamine (15.3 mL, 116.81 mmol), TMSCN (15.94 mL, 127.42 mmol), and NH4Cl (1.7 g, 31.8 mmol). RM was stirred at 80 °C for 16 h. After the reaction was complete, the volatiles were removed under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica gel (using 10% EtOAc in petroleum ether as eluent) to give 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropionitrile (20 g, 56.30%) as a pale yellow liquid. ¹H NMR (400 MHz, DMSO-d6) δ 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).

[0454] Step 2: At 0 °C, a solution of 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropionitrile (10 g, 29.940 mmol) in DMSO (70 mL) was treated with K₂CO₃ (28.966 g, 209.581 mmol) and H₂O₂ (14.041 mL, 598.802 mmol). The RM was stirred at room temperature for 16 h. After completion, the RM was cooled to room temperature and quenched with ice-cold water (100 mL). The aqueous layer was extracted with Et₂O (3 x 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% to 50% EtOAc in petroleum ether as eluent) to give 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropionamide (3.8 g, 36%) as a pale yellow liquid. 1H NMR (400MHz, DMSO-d6) δ ppm: 7.25 (d, 2 H), 7.24 (br s, 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 (br s, 1 H), 1.15 (s, 3 H), 0.85 (s, 9 H), 0.03 (s, 6 H).

[0455] Step 3: At room temperature, a solution of 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropionamide (10 g, 28.365 mmol) in MeOH (200 mL) was treated with 10% palladium hydroxide (5.178 g, 36.874 mmol). The mixture was stirred at room temperature for 48 h under H2 pressure (70 psi). After completion, the reaction mixture was filtered through a diatomaceous earth pad, washed with a solution of 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 petroleum ether as eluent) to give 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionamide (5.5 g) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δppm: 7.25 (s, 1 H), 6.95 (s, 1 H), 3.76 (d, 1 H), 3.25 (d, 1H), 1.77 (s, 2 H), 1.04 (s, 3 H), 0.85 (s, 9 H), 0.02 (s, 6H).

[0456] Step 4: 5.5 g of Int-001 was separated by preparative SFC. Column [size]: Lux. Cellulose-4 [250 x 30 x 5µm], CO2%: 75%, Solvent%: 25% (0.5% diethylamine in ACN), Total flow rate: 90 g / min, Back pressure: 120.0 bar, Temperature: 30 °C, Wavelength: 215 nm, Stacking time: 18.0 min, Loading capacity: 44.0 mg / injection, Solubility: 70 mL of ACN, Number of injections: 93, Instrument details: Brand / Model: SFC-MASS. The collected fraction was concentrated and lyophilized to obtain two isomers: the first elution (Int-A001–En1), which was a pale yellow gel (1.7 g). ¹H NMR (400MHz, DMSO-d6) δ ppm: 7.24 (s, ¹H), 6.93 (s, ¹H), 3.76 (d, ¹H), 3.26 (d, ¹H), 1.77 (s, ²H), 1.04 (s, ³H), 0.85 (s, ⁹H), 0.02 (s, ⁶H). SOR: -28.62 (1.0%, in CHCl₃) and second elution (Int-A001–En₂), which was a pale yellow gel (1.5 g). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.24 (s, 1 H), 6.93 (s, 1 H), 3.76 (d, 1 H), 3.26 (t, 1 H), 1.77 (s, 2 H), 1.04 (s, 3 H), 0.85 (s, 9 H), 0.02 (t, 6H). SOR: +47.54 (1.0% in CHCl3).

[0457] Synthesis of 2-amino-4,4-difluoro-2-methylbut-1-ol (Int-A003).

[0458]

[0459] Step 1: At 0 °C, 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). After 30 min, 1,1-difluoro-2-iodoethane (24.9 g, 130.18 mmol) was added over 10 min at 0 °C. The RM was stirred at 0 °C for 1 h. After the reaction was complete, the RM was diluted with 5% NH4Cl aqueous solution (100 mL) and extracted with EtOAc (3 x 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 5% EtOAc in petroleum ether as eluent) to give ethyl 2-((diphenylmethylene)amino)-4,4-difluorobutyrate (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).

[0460] Step 2: At 0°C, N-(diphenylmethylene)glycine ethyl ester (20 g, 331.36 mmol) was added to a solution of t-BuOK (7.450 g, 112.21 mmol) in DMF (30 mL). After 30 min, iodomethane (42.83 g, 141.93 mmol) was added over 10 min at 0°C. The RM was stirred at 0°C for 1 h. After the reaction was complete, the RM was diluted with 5% NH4Cl aqueous solution (100 mL) and extracted with EtOAc (3 x 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 petroleum ether as eluent) to give ethyl 2-((diphenylmethylene)amino)-4,4-difluoro-2-methylbutyrate (16 g, 76.75%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ ppm: 7.50 - 7.59 (m, 2 H), 7.36 - 7.41 (m, 4 H), 7.28 - 7.32 (m, 2 H), 7.13 - 7.15 (m, 2 H), 6.16 - 6.49 (m, 1 H), 3.69 - 3.77 (m, 2H), 2.31 - 2.57 (m, 2H), 1.44 (s, 3H), 1.11 (t, 3H).

[0461] Step 3: At room temperature, 1N HCl (150 mL) was added to a solution of ethyl 2-((diphenylmethylene)amino)-4,4-difluoro-2-methylbutyrate (16 g, 46.32 mmol) in petroleum ether (75 mL). The RM was stirred at room temperature for 16 h. The RM was washed with EtOAc (2 x 50 mL). The aqueous solution was alkalized with NaHCO3 (pH ~8) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give ethyl 2-amino-4,4-difluoro-2-methylbutyrate (5.910 g, 70.42%) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl3) δ ppm: 5.87 - 6.15 (m, 1 H), 4.17 - 4.12 (m, 2 H), 2.04 - 2.33 (m, 2 H), 1.39 (s, 3 H), 1.27 (t, 3 H).

[0462] Step 4: At 0 °C, sodium borohydride (3.508 mg, 92.72 mmol) was added to a solution of ethyl 2-amino-4,4-difluoro-2-methylbutyrate (5.6 g, 30.90 mmol) in EtOH (50 mL). The RM was stirred at room temperature for 7 h. The RM was quenched with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 2-amino-4,4-difluoro-2-methylbut-1-ol (Int-A003) (2.3 g, 53%) as a colorless gel. 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.02 -6.33 (m, 1 H), 4.76 (t, 1 H), 3.09- 3.19 (m, 2 H), 1.75 - 1.87 (m, 2 H), 1.48 (br, s, 2 H), 0.95 (s, 3 H).

[0463] Synthesis of 3-amino-3-(hydroxymethyl)pyrrolidone-2-one (Int-A005–En1) and (Int-A005–En2).

[0464]

[0465] Step 1: At 0°C, TEA (49.90 mL, 359.99 mmol) was added to a stirred solution of diethyl 2-(2-(1,3-dioxoisoindoline-2-yl)ethyl)malonate (60 g, 179.99 mmol) in 1,4-dioxane (600 mL). After 15 minutes, formaldehyde (29.18 g, 359.99 mmol) was added at 0°C. The 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 to 40% EtOAc in petroleum ether) to give diethyl 2-(2-(1,3-dioxoisoindoline-2-yl)ethyl)-2-(hydroxymethyl)malonate (59 g, 90%), which was a pale yellow gel. 1 H NMR (400 MHz, CDCl3) δppm: 7.86–7.82 (m, 2 H), 7.74–7.69 (m, 2 H), 4.25–4.18 (m, 4 H), 4.07 (d, 2H), 3.83–3.79 (m, 2 H), 2.79 (t, 1 H), 2.33–2.30 (m, 2 H), 1.28 (t, 6 H).

[0466] Step 2: At 0°C, imidazole (25.48 g, 374.27 mmol) was added to a stirred solution of 2-(2-(1,3-dioxoisoindoline-2-yl)ethyl)-2-(hydroxymethyl)malonate (68 g, 187.13 mmol) in DCM (700 mL). After 15 min, tert-butyldimethylchlorosilane (33.84 g, 224.56 mmol) was added at 0°C. The RM was stirred at room temperature for 16 hours. 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 petroleum ether) to give diethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(1,3-dioxoisoindoline-2-yl)ethyl)malonate (68 g, 77%) as a grayish-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).

[0467] Step 3: At 0 °C, hydrazine hydrate (10.69 g, 213.55 mmol) was added to a stirred solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(1,3-dioxoisoindoline-2-yl)ethyl)malonate (68 g, 142.37 mmol) in ethanol (700 mL). RM was stirred at room temperature for 16 h. RM was diluted with ice-cold water (300 mL) and extracted with EtOAc (2 x 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 0 to 30% EtOAc in petroleum ether) to give ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylate (30.7 g, 71%) as a grayish-white solid. 1H 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, 9H), 0.06 (d, 6 H).

[0468] Step 4: At 0 °C, LiOH·H2O (20.18 g, 480.99 mmol) was added to a solution of ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylic acid (29 g, 96.19 mmol) in EtOH (120 mL), THF (60 mL), and H2O (30 mL). RM was stirred at room temperature for 16 h. Volatile substances were removed under reduced pressure. The residue was diluted with cold water (20 mL) and then acidified with a saturated aqueous citric acid solution (pH ~4). The solid was filtered, washed with water (10 mL), then with 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 H 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, 1H), 2.34–2.32 (m, 1 H), 2.24–2.22 (m, 1 H), 0.84 (s, 9 H), 0.01 (d, 6 H).

[0469] Step 5: At room temperature, TEA (14.65 mL, 104.24 mmol) was added 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), followed by DPPA (19.12 g, 69.49 mmol). The 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 sodium bicarbonate aqueous solution (2 × 50 mL) and brine solution (50 mL), 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. RM was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with a 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 to 40% EtOAc in petroleum ether) to give (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-yl)carbamate (9 g, 68%). 1 HNMR (400 MHz, CDCl3) δ ppm: 7.37–7.29 (m, 5 H), 5.84 (brs, 1 H), 5.42 (brs, 1H), 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).

[0470] Step 6: At 0 °C, a solution of PTSA monohydrate (2.21 g, 11.62 mmol) in MeOH (50 mL) was added to a stirred solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidone-3-yl)carbamate (11 g, 29.05 mmol) in MeOH (150 mL) 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 a solution of 10% MeOH in DCM (3 × 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was ground with n-pentane (3 × 15 mL), then with diethyl ether (15 mL), filtered, and dried under vacuum to give benzyl (3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)carbamate (7 g, 91%) as a grayish-white solid. 1 ¹H NMR (400 MHz, DMSO-d6) δ ppm: 7.66 (s, 1 H), 7.38–7.29 (m, 5 H), 7.08 (s, 1 H), 4.98–4.95 (m, 3 H), 3.46–3.38 (m, 2 H), 3.18–3.15 (m, 1 H), 3.13–3.07 (m, 1 H), 2.28–2.25 (m, 2 H). 3.5 g of (3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)carbamate was purified by preparative chiral SFC. [Preparative SFC conditions: column: Chiral peak IF (250 × 30 × 5µm), CO2%: 65%, cosolvent%: 35% (100% MeOH), total flow rate: 90 g / min, back pressure: 100.0 bar, temperature: 30℃, wavelength: 215 nm, stacking time: 7.2 min, solubility: 100 ml of MeOH.] The collected pure fraction was concentrated under reduced pressure to obtain two isomers, En1 (first elution) and En2 (second elution).

[0471] Step 7: Pd / C (450 mg) was added to a stirred solution of (3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)carbamate En1 (1.4 g, 5.297 mmol) in ethanol (30 mL) at room temperature. RM was stirred at room temperature for 16 h under H2 (70 psi). RM was filtered through a diatomaceous earth pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was ground with diethyl ether (2 × 5 mL) and dried under high vacuum to give 3-amino-3-(hydroxymethyl)pyrrolidone-2-one (Int-A005–En1) (610 mg, 88%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δppm: 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%).

[0472] Step 8: At room temperature, Pd / C (350 mg) was added to a stirred solution of (3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)carbamate En2 (1.2 g, 4.54 mmol) in ethanol (30 mL). RM was stirred at room temperature under H2 (70 psi) for 16 h. RM was filtered through a diatomaceous earth pad and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was ground with diethyl ether (2 × 5 mL) and dried under high vacuum to give 3-amino-3-(hydroxymethyl)pyrrolidone-2-one (Int-A005–En2) (550 mg, 93%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δppm: 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).

[0473] Synthesis of 3-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-2-one (Int-A006) become.

[0474]

[0475] A stirred solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-yl)carbamate (1.0 g, 2.642 mmol) in ethanol (10.0 mL) was treated with carbon-supported palladium (Pd / C, 200 mg) and stirred at room temperature for 4 h under hydrogen (balloon). The RM was filtered through a diatomaceous earth pad and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure, and the residue was ground with n-pentane (2 × 5 mL) and dried under reduced pressure to give -amino-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-2-one (Int-A006) (500 mg, 77%) as a grayish-white solid. 1 H NMR (400 MHz, CD3OD) δ ppm: 3.68 (d, 1 H), 3.50 (d, 1 H), 3.34 –3.31 (m, 2 H), 2.41 – 2.36 (m, 1 H), 2.05 – 1.97 (m, 1 H), 0.90 (s, 9 H),0.072 (d, 6 H).

[0476] Synthesis of methyl 6-bromo-2-methylindoleazine-3-carboxylate (Int-B001)

[0477]

[0478] Step 1: At room temperature, a stirred solution of 5-bromo-2-methylpyridine (10 g, 58.13 mmol) in ACN (100 mL) was treated with methyl 2-bromoacetate (16.67 mL, 174.39 mmol). The RM was stirred at 80 °C for 16 h. The RM was concentrated under reduced pressure. The residue was milled with EtOAc (2 × 100 mL). The solid was filtered, washed with EtOAc (3 × 30 mL), and dried under high vacuum to give 5-bromo-1-(2-methoxy-2-oxoethyl)-2-methylpyridine-1-onium bromide (15 g, yield: 79%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.37 (s, 1 H), 8.88 (dd, 1 H), 8.11 (d, 1 H), 5.67 (s, 2 H), 3.79 (s, 3 H), 2.73 (s, 3 H).

[0479] Step 2: At room temperature, a stirred solution of 5-bromo-1-(2-methoxy-2-oxoethyl)-2-methylpyridin-1-onium bromide (15 g, 46.15 mmol) in acetic anhydride (75 mL) was treated with sodium acetate (11.35 g, 138.46 mmol). The RM was stirred at 150 °C for 24 h. The RM was quenched with saturated NaHCO3 solution (300 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using a gradient of 5% EtOAc in petroleum ether) to give methyl 6-bromo-2-methylindoleazine-3-carboxylate (Int-B001) (3.4 g, 27.4%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.63 (s, 1 H), 7.27–7.24 (m, 1 H), 7.04 (dd, 1 H), 6.33 (s, 1 H), 3.92 (s, 3H), 2.51 (s, 3 H).

[0480] Synthesis of methyl 2-methyl-6-vinylindoleazine-3-carboxylate (Int-B002)

[0481]

[0482] A stirred solution of methyl 6-bromo-2-methylindoleazine-3-carboxylate (Int-B001) (3 g, 11.189 mmol) in 1,4-dioxane (30 mL) and water (10 mL) was treated with potassium trifluoro(vinyl)borate (1.874 g, 13.987 mmol) and sodium carbonate (2.95 g, 27.974 mmol). The RM was degassed with argon for 15 min. Then, the RM was treated with PdCl2(dppf)·DCM (0.9 g, 1.119 mmol) at room temperature. The RM was stirred at 90 °C for 6 h. The RM was filtered through a small diatomaceous earth mat and washed with EtOAc (100 mL). The filtrate was washed with a saline solution (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using a gradient of 0 to 10% EtOAc in petroleum ether) to give methyl 2-methyl-6-vinylindoleazine-3-carboxylate (1.75 g, 72.6%) as a pale brown solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.41 (s, ¹H), 7.31 (d, ¹H), 7.20 (dd, ¹H), 6.71–6.64 (m, ¹H), 6.29 (s, ¹H), 5.70 (d, ¹H), 5.24 (d, ¹H), 3.91 (s, ³H), 2.52 (s, ³H).

[0483] 2-Methyl-6-(trans-2-phenylcyclopropyl)indolazine-3-carboxylic acid methyl ester (Int-B003) and 2-methyl-6-(cis-) Synthesis of methyl 2-phenylcyclopropyl indoleazine-3-carboxylate (Int-B004)

[0484]

[0485] A stirred solution of methyl 2-methyl-6-vinylindoleazine-3-carboxylate (1 g, 4.646 mmol) in 1,4-dioxane (30 mL) was treated with K₂CO₃ (1.3 g, 9.291 mmol) and (E)-N'-benzyl-4-methylbenzenesulfonylhydrazine (1.15 g, 4.181 mmol) at room temperature. RM was stirred at 110 °C for 16 h. RM was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with a saline solution (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using a gradient of 0 to 5% ethyl acetate in petroleum ether as a gradient) to give methyl 2-methyl-6-(trans-2-phenylcyclopropyl)indolazine-3-carboxylate (Int-B003) (260 mg, 18%) as an off-white solid and methyl 2-methyl-6-(cis-2-phenylcyclopropyl)indolazine-3-carboxylate (Int-B004) (70 mg, 5%) as an off-white solid. 2-Methyl-6-(trans-2-phenylcyclopropyl)indolazine-3-carboxylate (Int-B003): ¹H NMR (400 MHz, DMSO-d6) δ ppm: 9.28 (s, 1 H), 7.51 (d, 1 H), 7.27 (t, 2 H), 7.20–7.15 (m, 3 H), 6.94 (dd, 1 H), 6.40 (s, 1 H), 3.81 (s, 3 H), 2.49 (s, 3 H), 2.30–2.25 (m, 1 H), 2.22–2.18 (m, 1 H), 1.48–1.45 (m, 2 H). 2-Methyl-6-(cis-2-phenylcyclopropyl)indolazine-3-carboxylate (Int-B004): 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.12 (s, 1 H), 7.24 (d, 1 H), 7.09–7.03 (m, 2 H), 7.01–6.97 (m, 3 H), 6.71 (dd, 1 H), 6.27 (s, 1 H), 3.82 (s, 3 H), 2.55–2.50 (m, 2 H), 2.40 (s, 3 H), 1.52–1.43 (m, 2 H).

[0486] Synthesis of potassium 2-methyl-6-(trans-2-phenylcyclopropyl)indoleazine-3-carboxylate (Int-B005)

[0487]

[0488] A stirred solution of methyl 2-methyl-6-((trans)-2-phenylcyclopropyl)indoleazine-3-carboxylate (520 mg, 1.703 mmol) in THF (15 mL) was treated with potassium trimethylsilanoate (550 mg, 4.257 mmol). The RM was stirred at 75 °C for 5 h. The RM was concentrated under reduced pressure and dried under high vacuum to give potassium 2-methyl-6-((trans)-2-phenylcyclopropyl)indoleazine-3-carboxylate (720 mg, 100%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm:9.84 (s, 1 H), 7.29–7.26 (m, 2 H), 7.20–7.13 (m, 4 H), 6.48 (dd, 1H), 6.06 (s, 1 H), 2.45 (s, 3 H), 2.12–2.06 (m, 2 H), 1.39–1.33 (m, 2 H).

[0489] Synthesis of methyl 6-hydroxy-2-methylindoleazine-3-carboxylate (Int-B006)

[0490]

[0491] Step 1: At room temperature, 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). RM was stirred at 80 °C for 16 h. After the reaction was complete, the volatiles were removed under reduced pressure. The residue was ground with petroleum ether (500 mL) and dried to give benzyloxy)-1-(2-methoxy-2-oxoethyl)-2-methylpyridinium bromide (210 g, 85%).

[0492] Step 2: At room temperature, sodium acetate (73.8 g, 900 mmol) was added to a solution of methyl 2-(5-(benzyloxy)-2-methyl-114-pyridin-1-yl)acetate (105 g, 300 mmol) in acetic anhydride (500 mL). The 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 x 500 mL), brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 20% ​​EtOAc in petroleum ether as eluent) to give methyl 6-(benzyloxy)-2-methylindoleazine-3-carboxylate (19 g, 21%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm: 7.47 (d, 2 H), 7.42- 7.40 (m, 2 H), 7.33 - 7.39 (m, 1 H), 7.25 - 7.28 (m, 1 H), 6.88 (dd, 1 H), 6.26 (s, 1 H), 5.07 (s, 2 H), 3.91 (s, 3 H), 2.51 (s, 3 H).

[0493] Step 3: At room temperature, ammonium formate (11.31 g, 179.45 mmol) and 10% carbon-supported palladium (2.5 g) were added to a solution of methyl 6-(benzyloxy)-2-methylindoleazine-3-carboxylate (5.3 g, 17.94 mmol) in MeOH (500 mL). The RM was stirred at room temperature for 2 h. The RM was filtered through a diatomaceous earth 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 ground with n-pentane (100 mL) and dried to give methyl 6-hydroxy-2-methylindoleazine-3-carboxylate (Int-B006) (2.2 g, 59%) as a pale yellow solid. 1HNMR (400 MHz, DMSO-d6) δ ppm: 9.49 (s, 1 H), 9.05 (s, 1 H), 7.42 (d, 1H), 6.83 - 6.85 (m, 1 H), 6.32 (s, 1 H), 3.81 (s, 3 H), 2.42 (s, 3 H).

[0494] Synthesis of potassium 2-methyl-6-(o-tolyloxy)indoleazine-3-carboxylate (Int-B007)

[0495]

[0496] Step 1: A stirred solution of methyl 6-hydroxy-2-methylindoleazine-3-carboxylate (850 mg, 4.142 mmol) in dioxane (20 mL) was treated with 1-iodo-2-methylbenzene (2.258 g, 10.355 mmol), Cu(I)I (79.092 mg, 0.414 mmol), and Cs₂CO₃ (2.699 g, 8.284 mmol). The RM was degassed with N₂ gas for 10 min at room temperature and treated with 2,2,6,6-tetramethylheptane-3,5-dione (0.153 g, 0.828 mmol). The RM was stirred at 100 °C for 16 h. The RM was filtered through a diatomaceous earth mat, the filtrate was diluted with water (15 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with a saline solution (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 1% EtOAc in petroleum ether as a gradient) to give methyl 2-methyl-6-(o-tolyloxy)indolazine-3-carboxylate (650 mg, 53.13%). 1 H NMR (400 MHz, CDCl3) δ ppm: 9.24 (s, 1 H), 7.35 - 7.32 (m, 1 H), 7.23 (s, 1 H), 7.11 (t, 1 H), 7.01 (t, 1 H), 6.86 -6.79 (m, 2 H), 6.33 (s, 1 H), 3.87 (s, 3 H), 2.52 (s, 3 H), 2.32 (s, 3 H).

[0497] Step 2: At room temperature, a stirred solution of methyl 2-methyl-6-(o-tolyloxy)indolazine-3-carboxylate (600 mg, 2.032 mmol) in THF (10.0 mL) was treated with potassium trimethylsilanolate (651.57 mg, 5.079 mmol). The RM was stirred at 70 °C for 16 h. The RM was concentrated under reduced pressure. The residue was ground with n-pentane (20 mL). The resulting solid was filtered to give potassium 2-methyl-6-(o-tolyloxy)indolazine-3-carboxylate (Int-B007) (700 mg) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.79 (s, 1 H), 7.30 (d, 1 H), 7.25 (d, 1 H), 7.09 (t, 1 H), 6.97 (t, 1 H), 6.70 (d, 1 H), 6.53 - 6.50 (m, 1 H), 6.18 (s, 1H), 2.50 (s, 3H), 2.29 (s, 3H).

[0498] The following intermediates were prepared in a manner similar to that of Int-B007 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art):

[0499] Table 2: Exemplary intermediates.

[0500]

[0501] Synthesis of methyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)indoleazine-3-carboxylate (Int-B016)

[0502]

[0503] A stirred solution of methyl 6-hydroxy-2-methylindoleazine-3-carboxylate (Int-B006) (1 g, 4.873 mmol) in DCM (20 mL) at 0 °C was treated with DMAP (0.060 g, 0.487 mmol) and DIPEA (2.122 mL, 12.182 mmol), followed by dropwise treatment with trifluoromethanesulfonic anhydride (1.637 mL, 9.746 mmol). RM was stirred at room temperature for 4 h. RM was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 4% EtOAc in petroleum ether as a gradient) to give methyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)indolazine-3-carboxylate (Int-B016) (1.2 g, 73%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 9.65 (d, ¹H), 7.40 (d, ¹H), 6.97–6.94 (m, ¹H), 6.44 (s, ¹H), 3.94 (s, ³H), 2.54 (d, ³H).

[0504] Synthesis of potassium 6-benzyl-2-methylindoleazine-3-carboxylate (Int-B017)

[0505]

[0506] Step 1: A solution of methyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)indolazine-3-carboxylate (Int-B016) (1 g, 2.965 mmol), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.776 g, 3.558 mmol), and potassium phosphate (1.259 g, 5.930 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added. RM was degassed with argon for 5 min. PdCl2dppf.DCM (0.121 g, 0.148 mmol) was added to RM and degassed again with argon for 5 min. RM was stirred at 90 °C for 16 h. RM was diluted with water (25 mL), and the compound was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 35% to 40% EtOAc in petroleum ether as a gradient) to give methyl 3-chloro-3-phenylcyclobutane-1-carboxylate (610 mg, 73.65%) as a colorless liquid. 1 H NMR (400 MHz, CDCl3) δppm: 9.39 (s, 1 H), 7.30 - 7.26 (m, 3 H), 7.22 - 7.18 (m, 3 H), 6.82 - 6.79 (m, 1 H), 6.26 (s, 1 H), 3.93 (s, 2 H), 3.90 (d, 3 H), 2.52 (s, 3 H).

[0507] Step 2: At room temperature, a stirred solution of methyl 6-benzyl-2-methylindoleazine-3-carboxylate (500 mg, 1.790 mmol) in THF (20 mL) was treated with potassium trimethylsilanoate (459.263 mg, 3.580 mmol). The RM was stirred at 65 °C for 16 h. The RM was concentrated under reduced pressure and washed with pentane (20 mL) to give potassium 6-benzyl-2-methylindoleazine-3-carboxylate (Int-B017) (510 mg) as a pale yellow gelatinous solid. 1H NMR (400 MHz, MeOD) δ ppm:9.45 (s, 1 H), 7.27 - 7.22 (m, 4 H), 7.20 - 7.17 (m, 2 H), 6.62 - 6.59 (m, 1H), 6.18 (s, 1 H), 3.88 (s, 2 H), 2.56 (s, 3 H).

[0508] 2-Methyl-6-(phenylthio)indoleazine-3-carboxylate (Int-B018) and 2-methyl-6-(phenylthio)indole Synthesis of potassium azinon-3-carboxylate (Int-B019)

[0509]

[0510] Step 1: A stirred solution of diphenyl disulfide (1.25 g, 5.595 mmol) and Zn dust (914.5 mg, 13.987 mmol) in THF (40 mL) was degassed with N2 gas for 5 min. Then, RM was treated with Pd(dppf)Cl2 (341.138 mg, 0.466 mmol) at room temperature, followed by treatment with methyl 6-bromo-2-methylindoleazine-3-carboxylate (2.5 g, 9.325 mmol). RM was stirred at 75 °C for 16 h. RM was diluted with diethyl ether (50 mL), filtered through a diatomaceous earth bed, and the filtrate was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 0 to 30% EtOAc in hexane as a gradient) to give methyl 2-methyl-6-(phenylthio)indolazine-3-carboxylate (Int-B018) (1.2 g, 43%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.68(s, 1 H), 7.36 (dd, 1 H), 7.34 – 7.22 (m, 4 H), 7.17 – 7.14 (m, 1 H), 6.96(dd, 1 H), 6.34 (s, 1 H), 3.91 (s, 3 H), 2.54 (s, 3 H).

[0511] Step 2: At room temperature, a stirred solution of methyl 2-methyl-6-(phenylthio)indolazine-3-carboxylate (Int-B018) (250 mg, 0.841 mmol) in THF (15 ml) was treated with potassium trimethylsilanolate (269.6 mg, 2.102 mmol). The RM was stirred at 75 °C for 16 h. The RM was concentrated under reduced pressure, and the resulting residue was washed with n-pentane (2 × 20 mL) and dried under high vacuum to give potassium 2-methyl-6-(phenylthio)indolazine-3-carboxylate (Int-B019) (400 mg) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.24 (s, 1 H), 7.33 –7.25 (m, 3 H), 7.16 – 7.12 (m, 3 H), 6.62 (dd, 1 H), 6.20 (s, 1 H), 2.50 (s, 3 H).

[0512] Synthesis of potassium 2-methyl-6-(phenylsulfinyl)indoleazine-3-carboxylate (Int-B020)

[0513]

[0514] Step 1: At 0 °C, a stirred solution of methyl 2-methyl-6-(phenylthio)indoleazine-3-carboxylate (1.8 g, 6.053 mmol) in DCM (30 mL) was treated with mCPBA (65% to 70%, 1.6 g, 7.264 mmol). The RM was stirred at room temperature for 16 h. The RM was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution (50 mL) and aqueous sodium thiosulfate solution (50 mL), followed by washing with brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 0 to 50% EtOAc in hexane as a gradient) to give methyl 2-methyl-6-(phenylsulfinyl)indoleazine-3-carboxylate (1.25 g, 66%) as an off-white solid. 1 H NMR(400 MHz, CDCl3) δ ppm: 9.94 (s, 1 H), 7.67 – 7.64 (m, 2 H), 7.51 – 7.45 (m,3 H), 7.37 (d, 1 H), 6.98 (dd, 1 H), 6.37 (s, 1 H), 3.96 (s, 3H), 2.54 (s, 3H).

[0515] Step 2: At room temperature, a stirred solution of methyl 2-methyl-6-(phenylsulfinyl)indolazine-3-carboxylate (1.2 g, 3.829 mmol) in THF (35 mL) was treated with potassium trimethylsilanoate (1.23 g, 9.573 mmol). The RM was stirred at 75 °C for 6 h. The RM was concentrated under reduced pressure, and the resulting residue was ground with n-pentane (2 × 25 mL) and dried under vacuum to give potassium 2-methyl-6-(phenylsulfinyl)indolazine-3-carboxylate (Int-B020) (1.5 g, 100%) as a grayish-white solid. 1 H NMR (400 MHz, MeOD) δ ppm: 10.07 (s, 1 H), 7.58 – 7.56 (m, 2 H), 7.46 – 7.40 (m, 3 H), 7.24 (d, 1 H), 6.55 (dd, 1 H), 6.25 (s, 1 H), 2.47 (s, 3H).

[0516] Example 1 -N-((S)-1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-(trans-2-) Synthesis of phenylcyclopropylindoleazine-3-carboxamide (Cpd 001)

[0517]

[0518] Step 1: At 0 °C, a stirred solution of 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropionamide (Int-A001-En1) (620 mg, 2.656 mmol) in DMF (10 mL) was treated with DIPEA (1.8 mL, 10.624 mmol), followed by a solution of 2-methyl-6-((trans)-2-phenylcyclopropyl)indolazine-3-carboxylate (Int-B005) (700 mg, 2.125 mmol) in DMF (5 mL) and HATU (1.2 g, 3.187 mmol). The RM was stirred at 65 °C for 16 h. The RM was then poured into ice-cold water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (30 mL) and brine solution (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 to 50% EtOAc in petroleum ether) to give N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-2-methyl-1-oxopropane-2-yl)-2-methyl-6-((trans)-2-phenylcyclopropyl)indolazine-3-carboxamide (380 mg, 35%) as a brown gel. 1H NMR (400MHz, CDCl3) δ ppm:9.44 (s, 1 H), 7.30–7.21 (m, 3 H), 7.19–7.11 (m, 3 H), 7.04 (brs, 1 H), 6.85 (s, 1 H), 6.71 (dd, 1 H), 6.24 (s, 1 H), 5.42 (brs, 1 H), 4.34 (dd, 1 H), 3.77 (dd, 1 H), 2.59 (s, 3 H), 2.30–2.12 (m, 2 H), 1.55 (s, 3H), 1.48–1.40 (m, 1 H), 1.39–1.38 (m, 1 H), 0.91 (s, 9 H), 0.13 (s, 6 H).

[0519] Step 2: At 0 °C, a solution of pyridine (1 mL, 11.567 mmol) in THF (10 mL) was treated with a solution of pyridine (1 mL, 11.567 mmol) in HF and stirred for 10 min. At 0 °C, RM was treated with a solution of N-(1-amino-3-((tert-butyldimethylsilyl)oxy)-2-methyl-1-oxopropane-2-yl)-2-methyl-6-((trans)-2-phenylcyclopropyl)indoleazine-3-carboxamide (390 mg, 0.771 mmol) in THF (5 mL). RM was stirred at room temperature for 16 h. RM was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with a saline solution (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Preparative HPLC conditions: mobile phase: 10 mM ABC in water, mobile phase B: ACN, column: LUNA C18 (150 x 25 mm) x 5 µm, flow rate: 20 ml / min, method: (T (in min) / B %): 0 / 30, 2 / 30, 10 / 70, 14 / 70, 17.1 / 98, 18 / 98, 18.1 / 30, 21 / 30, temperature: room temperature.] The desired fractions were evaporated and lyophilized to give N-((S)-1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-(trans-2-phenylcyclopropyl)indoleazine-3-carboxamide (Cpd 001) (88 mg, 29%) as a grayish-white solid.

[0520] A preparative chiral SFC was performed on a racemic mixture of Cpd 001 to obtain Cpd 001–En1 and Cpd 002–En2.

[0521] The following compounds were prepared in a manner similar to that described for Cpd 001:Cpd 002 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art).

[0522] Example 2 -N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(o-tolyloxy)indole Synthesis of 3-azine-carboxamide (Cpd 006)

[0523]

[0524] A solution of potassium 2-methyl-6-(o-tolyloxy)indolazine-3-carboxylate (Int-B006) (300 mg, 0.939 mmol) in DMF (5 mL) was treated with HATU (535.701 mg, 1.409 mmol) and DIPEA (0.491 mL, 2.818 mmol) and stirred for 10 min, then treated with 2-amino-4,4-difluoro-2-methylbut-1-ol (Int-A003) (143.763 mg, 1.033 mmol). RM was stirred at 70 °C for 2 h. RM was diluted with ice water (5 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 10% NaHCO3 (2 x 10.0 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 26% EtOAc in petroleum ether as eluent) to give N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(o-tolyloxy)indolazine-3-carboxamide (Cpd 006) (140 mg), which was a pale yellow gel.

[0525] A preparative chiral SFC was performed on a racemic mixture of Cpd 006 to obtain Cpd 006–En1 and Cpd 006–En2.

[0526] The following compounds were prepared in a manner similar to that described for Cpd 006:Cpd 004–En1, Cpd 004–En2, Cpd 008–En1, Cpd 008–En2, Cpd010–En1, Cpd 010–En2, Cpd 012–En1, Cpd 012–En2, Cpd 014–En1, Cpd 014–En2, Cpd 016–En1, Cpd 016–En2 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art).

[0527] Example 3-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide Synthesis of (Cpd 003–En1)

[0528]

[0529] At room temperature, a stirred solution of potassium 2-methyl-6-phenoxyindoleazine-3-carboxylate (Int-B008) (170 mg, 0.557 mmol, 1 equivalent) in DMA (3 mL) was treated with HATU (275.181 mg, 0.724 mmol, 1.3 equivalent) and DIPEA (0.291 mL, 1.670 mmol, 3 equivalent). Then, RM was treated with a solution of 3-amino-3-(hydroxymethyl)pyrrolidone-2-one (Int-A005–En1) (86.943 mg, 0.668 mmol, 1.2 equivalent) in DMA (2 mL). RM was stirred at room temperature for 16 h. RM was diluted with ice-cold water (25 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with ice-cold water (2 × 5.0 mL) and ice-cold brine (5.0 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residues were purified by preparative HPLC [Preparative HPLC conditions: mobile phase: 10 mM ABC in water, mobile phase B: ACN, column: UNIHYBRID C18 (150 x 25 mm) x 8 µm, flow rate: 18 mL / min, method: (T (in min) / % of B): 0 / 30, 2 / 30, 10 / 75, 11.5 / 75, 11.7 / 98, 15 / 98, 15.2 / 30, 18 / 30, temperature: room temperature]. The desired fraction was evaporated and lyophilized to give N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide (Cpd 003–En1) (53.5 mg, 25%) as a grayish-white solid.

[0530] The following compounds were prepared in a manner similar to that described for Cpd 003–En1:Cpd 003–En2, Cpd 007–En1, Cpd 007–En2, Cpd 009–En1, Cpd 009–En2, Cpd 011–En1, Cpd 011–En2, Cpd 013–En1, Cpd 013–En2, Cpd 015–En1, and Cpd016–En2 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art).

[0531] Example 4 -N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3- Synthesis of formamide (Cpd 005)

[0532]

[0533] Step 1: A solution of potassium 2-methyl-6-(o-tolyloxy)indolazine-3-carboxylate (Int-B007) (300 mg, 0.939 mmol) in THF (10 mL) was treated with PyBroP (656.767 mg, 1.409 mmol) and DIPEA (0.664 mL, 3.757 mmol) at room temperature. Then, RM was treated with 3-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-2-one (Int-A006) (275.477 mg, 1.127 mmol). RM was stirred at room temperature for 16 h. RM was diluted with water (25 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 0 to 55% EtOAc in petroleum ether as a gradient) to give N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3-carboxamide (100 mg, 21%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.54 (d, 1 H), 7.30 (d, 1 H), 7.19 (d, 1 H), 7.05 (t, 1 H), 6.94 (t, 1 H), 6.73 (dd, 1 H), 6.67 (d, 1 H), 6.48(s, 1 H), 6.31 (s, 1 H), 5.66 (s, 1 H), 4.03 (d, 1 H), 3.73 (d, 1 H), 3.58 –3.48 (m, 1 H), 3.40 (q, 1 H), 2.75 – 2.51 (m, 2 H), 2.58 (s, 3 H), 2.32 (s, 3H), 0.90 (s, 9 H), 0.099 (d, 6 H).

[0534] Step 2: At 0 °C, a solution of hydrogen fluoride in pyridine (0.344 mL, 1.970 mmol) in THF (10 mL) was treated with pyridine (0.447 mL, 1.970 mmol). Then, RM was treated at 0 °C with a solution of N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-yl)-2-methyl-6-(o-tolyloxy)indolazine-3-carboxamide (100 mg, 0.197 mmol). RM was stirred at room temperature for 16 h. RM was concentrated at room temperature and diluted with water (10.0 mL), alkalized with an aqueous solution of NaHCO3 (pH ~8-9), and then extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (10.0 mL) and brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel (using 0 to 6% MeOH in DCM as a gradient) to give N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3-carboxamide (Cpd005) (75 mg, 94%) as a grayish-white solid.

[0535] A preparative chiral SFC was performed on a racemic mixture of Cpd 005 to obtain Cpd 005–En1 and Cpd 005–En2.

[0536] The following compounds were prepared in a manner similar to that described for Cpd 005:Cpd 017, Cpd 019–En1, Cpd 019–En2, Cpd 020–En1, Cpd 020–En2, Cpd 021–En1, Cpd 021–En2, Cpd 022–En1, Cpd 022–En2, Cpd 024–En1, Cpd 024–En2, Cpd 024–En3, and Cpd 024–En4 (using appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to those skilled in the art).

[0537] Table 3: Analysis data.

[0538]

[0539]

[0540]

[0541] Table 4: Chiral analysis data.

[0542]

[0543]

[0544]

[0545] Part B

[0546] Example 5 – Monitoring Ca2+ uptake driven by TRPM3 ion channels.

[0547] To monitor the inhibitory effect of the compounds of this invention on the mouse TRPM3α2 (mTRPM3) ion channel, a cell system utilizing a cell line overexpressing mTRPM3α2 or hTRPM3 (flip-in HEK293) was used. The TRPM3 channel was stimulated / opened with pregnenolone sulfate (PS) (50 µM), which led to Ca2+ inhibition. 2+ Inflow.

[0548] For mTRPM3, intracellular calcium was measured using the calcium-responsive dye Fluor-4 AM ester (Invitrogen). 2+ Cells were cultured to 80-90% confluence, washed with virginium (Ingenieur), and separated from the surface by brief incubation with 0.05% trypsin (Ingenieur). Trypsin digestion was terminated by adding complete cell culture medium (DMEM, glutamine, 10% FCS, NEAA, Pen-Strep). Cells were collected and resuspended in calcium-free Krebs buffer at room temperature.

[0549] Prior to cell seeding (±2000 cells / well seeded into black 384-well plates (Greiner), the diluted compound was added to the assay plate along with PS dissolved in calcium-containing Krebs buffer. This produced 2.4 mM Ca 2+ Assay solution. After cell addition, the solution was directly read on an Envision fluorescence reader (PerkinElmer) with excitation at 485 nM and emission at 535 nM.

[0550] The channel inhibition was calculated by comparing the non-PS-stimulated control with the condition stimulated with PS (50 µM) containing the medium. The ability of the compounds of the present invention to inhibit this activity was determined as follows: Inhibition percentage = [1 - ((RFU determined for the sample in the presence of the test compound - RFU determined for the sample with the positive control inhibitor) divided by (RFU determined in the presence of the medium - RFU determined for the sample with the positive control inhibitor))] * 100.

[0551] The activities of the example compounds cpd 001 to 025 tested are described in the table below. All tested compounds showed activity in the Fluo-4 AM assay. Activity ranges A, B, and C refer to the IC50 values ​​in the Fluo-4 AM assay, as follows: “A”: IC50 value. 50 <1 µM; “B”: 1 µM ≤ IC 50 ≤20 µM, and “C”: IC 50 > 20 µM.

[0552] Table 5: Activities of exemplary compounds.

[0553]

Claims

1. A compound of formula (I), its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs. (I) in R 1 represents -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 ; R 3 Indicates -R Y ; X represents the single bond between Cy and the carbon atom to which it is attached, or X represents -O-, -CR. 5 R 5 '-、-S-、-S(O)n-、-S-CR 5 R 5' -CR 5 R 5' -S-、-CR 5 R 5' -CR 4 R 4' -、-NR 5 -CR 4 R 4' -、-O-CR 5 R 5' -、-C=、-C≡C- or -CR 5 R 5' -NR 5 - In each case, the substituent is unsubstituted, monosubstituted, or polysubstituted, and the substituents are independently selected from -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 ; R 4 and R 4' Represented independently of each other -R Y ; n is an integer in the range of 1 to 2; R 5 and R 5 'Represented independently of each other - R Y , or R 5 and R 5' They together form carbonyl groups on the atoms to which they are attached, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered heterocycloalkyl groups. R 6 R 7 and R 8 The following can be represented independently: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC(=O)R W -NR W R X -NR W C(=O)R X -SR W -S(=O)R W -S(=O)2R W -C(=O)R W -C(=O)OR W or -C(=O)NR W R X ; Cy represents a saturated or unsaturated 3- to 14-membered cycloalkyl group, a saturated or unsaturated 3- to 14-membered heterocycloalkyl group; a 5- to 14-membered aryl group or a 5- to 14-membered heteroaryl group; in each case, it is unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from -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 ; in R W and R X Represented independently of each other in each case. -H； Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; or Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; R Y and R Z Represented independently of each other in each case. -H； Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryl groups; wherein the 6- to 14-membered aryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or Unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. Or 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. Furthermore, "monosubstituted or polysubstituted" in each case independently means substituted by one or more substituents, which are independently selected from -F, -Cl, -Br, -I, -CN, and -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)OC 1-6 -alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-C(=O)-NH(C) 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-C(=O)-N(C) 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6 -alkylene-C(=O)-NH(OH), -OH, -C 1-6 -alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -OC 1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-NH2, -OC 1-6 -alkylene-NH-C 1-6 -alkyl, -OC 1-6 -alkylene-N(C) 1-6 -alkyl)2、-OC(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-C 1-6 -alkyl, -OC(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-OC 1-6 -alkyl, -OC(=O)-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-OC(=O)-NH(C) 1-6 -alkyl), -OC(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OC(=O)-N(C) 1-6 -alkyl)2, -OS(=O)2-NH2, -C 1-6 -alkylene-OS(=O)2-NH2, -OS(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-OS(=O)2-NH(C) 1-6 -alkyl), -OS(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OS(=O)2-N(C) 1-6 -alkyl)2, -NH2, -NO, -NO2, -C 1-6 -alkylene-NH2, -NH(C) 1-6 -alkyl), -N (3- 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)-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-C(=O)-OC 1-6 -alkyl, -NH-C(=O)-NH2, -C 1-6 -alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C) 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-C(=O)-N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH2、-N(C 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -NH-S(=O)2OH, -C 1-6 -alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-C 1-6 -alkyl, -NH-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-OC 1-6 -alkyl, -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C) 1-6 -alkyl), -NH-S(=O)2N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-S(=O)2N(C 1-6 -alkyl)2, -N(C 1-6 -alkyl)-S(=O)2-OH, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OH, -N(C 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH2、-N(C 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 -alkyl, -C 1-6 -alkylene-SC 1-6 -alkyl, -S(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-C 1-6 -alkyl, -S(=O)2-OH, -C 1-6 -alkylene-S(=O)2-OH, -S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-OC 1-6 -alkyl, -S(=O)2-NH2, -C 1-6 -alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-S(=O)2-NH(C) 1-6 -alkyl), -S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-S(=O)2-N(C) 1-6 -alkyl) 2, 3 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 heterocyclic alkyl groups), -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).

2. The compound of formula (I) as defined in claim 1, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 1 C represents 1-3 alkyl.

3. The compound of formula (I) as defined in claim 2, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 1 It indicates methyl.

4. The compound of formula (I) as defined in any one of claims 1 to 3, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 3 Indicates CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently for R Y ， Or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl groups.

5. The compound of formula (I) as defined in any one of claims 1 to 3, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 3 Indicates CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' One of them is R Y ， Or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl, and wherein R 9 R 9' and R 9'' The two components together form a 3- to 14-membered cycloalkyl, a 3- to 14-membered heterocycloalkyl, a 5- to 14-membered aryl, or a 5- to 14-membered heteroaryl, wherein the 3- to 14-membered cycloalkyl, 3- to 14-membered heterocycloalkyl, 5- to 14-membered aryl, or 5- to 14-membered heteroaryl is optionally substituted by one or more R Y Single or multiple substitutions.

6. The compound of formula (I) as defined in any one of claims 1 to 3, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 3 Indicates CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently -H, -C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl groups -O-CH3, -(C=O)-NH2, -(C=O)-NH-CH3, (C=O)-N(CH3)2, -C 1-6 Alkyl-CF2H and -C 1-6 Alkyl-CF3.

7. The compound of formula (I) as defined in any one of claims 1 to 6, its stereoisomer, physiologically acceptable salt, solvate and / or polymorph, wherein Cy represents a C3-C8 cycloalkyl, phenyl, C5-C8 heterocycloalkyl or C5-C8 heteroaryl, optionally substituted with one or more of a halogen, C1-C3-haloalkyl, hydroxyl, acyl, formamide, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, butyl, cyclobutyl, oxetane, pyrrole or diazole, wherein the formamide, acyl, cyclopropyl, cyclobutyl, oxetane, pyrrole and diazole are optionally further substituted with a halogen, C1-C3-haloalkyl, hydroxyl, phenyl, methyl, methoxy, ethyl, ethoxy or propyl, optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-.

8. The compound of formula (I) as defined in any one of claims 1 to 6, its stereoisomer, physiologically acceptable salt, solvate, and / or polymorph, wherein Cy represents a residue selected from:

9. The compound of formula (I) as defined in any one of claims 1 to 8, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 3 Indicates -CR 10 R 10' R 10'' And R 10 R 10' and R 10'' Independently represent -H； Saturated, unsubstituted, mono- or poly-substituted -S(=O)2C 1-6 -alkyl; Saturated, unsubstituted -S(=O)2 (3- to 14-membered cycloalkyl); Saturated, unsubstituted, monosubstituted, or disubstituted -C 1-6 -alkyl, wherein the substituents are independently selected from the group consisting of: -OH, =O, -OC 1-6 -alkyl, -NH2, -NHC 1-6 -alkyl, -N(C) 1-6 -alkyl)2、-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, unsubstituted -phenyl; 3- to 14-membered cycloalkyl or -C 1-6 -alkylene- (3- to 14-membered cycloalkyl), where -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 3- to 14-membered cycloalkyl group is saturated, unsubstituted, monosubstituted, or disubstituted, and the substituents are independently selected from the group consisting of: -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)OC 1-6 -alkyl, -OH, -OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2、-NHC(=O)OC 1-6 -alkyl; 3- to 14-membered heterocyclic alkyl groups or -C 1-6 -alkylene- (3- to 14-membered heterocyclic alkyl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 3- to 14-membered heterocyclic alkyl group is selected in each case from aziridine, 1,4-oxazetane, pyrrolidine, piperidine, azirane, diazirane, tetrahydrofuran, tetrahydropyran, oxazetane, morpholine, piperazine, hexahydrocyclopentadieno[c]pyrrole, octahydrocyclopentadieno[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 8-azabicyclo[ 3.2.1] Octane, 9-azabicyclo[3.3.1]nonane, quinine ring, hexahydro-1H-pyrrolizine, 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 1,1-dioxothiacyclohexane, in each case unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from the group consisting of: -F, -OH, =O, -C 1-6 -alkyl, -C 1-6 -alkylene-CF3, -C 1-6 -alkylene-OH, -C 1-6 -alkylene-OC 1-6 -alkyl, -NH2, -N(C) 1-6 -alkyl)2、-C 1-6 -alkylene-NH2, -C 1-6 -alkylene-N(C) 1-6 -alkyl)2、-C(=O)-C 1-6 -alkyl, -C(=O)OH, -C(=O)OC 1-6 -alkyl, -C(=O)OC 1-6 -alkylene-CF3, -C(=O)NH2, -C(=O)NH(C 1-6 -alkyl), -S(=O)2C 1-6 -alkyl, oxetyl, pyrimidinyl, -C 1-6 -alkylene-phenyl; Unsubstituted -phenyl; or 5 to 14 yuan of heteroaryl or -C 1-6 -alkylene- (5- to 14-membered heteroaryl), wherein -C 1-6 -alkylene- is unsubstituted or monosubstituted with -OH, wherein the 5- to 14-membered heteroaryl group is selected in each case from the group consisting of: pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [1,2,4]triazolo[4,3-a]pyrimidine, and in each case is unsubstituted, monosubstituted, or disubstituted, wherein the substituents are independently selected from the group consisting of: -C 1-6 -alkyl, -OH.

10. The compound of formula (I) as defined in any one of claims 1 to 9, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 5 and R 5 'represented independently of each other' -H； Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

11. The compound of formula (I) as defined in any one of claims 1 to 9, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 5 and R 5 Together they form saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- or 4-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- or 4-membered heterocycloalkyl groups.

12. The compound of formula (I) as defined in any one of claims 1 to 11, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 6 R 7 and R 8 Representing each other independently -H, -F, -Cl, -Br, -I, -OH, -SH, -SF5, -CN, -NO2, -C(=O)OH, -NH2, -C 1-6 -alkyl, -CF3, -CHF2, -CH2F, -OC 1-6 -alkyl, -OCF3, -OCHF2, -OCH2F, Unsubstituted or substituted with one or more substituents -NHC 1-6 -alkyl, wherein the substituents are independently 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; Unsubstituted or substituted with one or more substituents -N(C) 1-6 -alkyl)2, wherein the substituents are independently 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, either unsubstituted or substituted with one or more substituents 1-6 -alkyl, wherein the substituents are independently 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, either unsubstituted or substituted with one or more substituents. 1-6 -alkyl, wherein the substituents are independently 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; or -C unsubstituted or substituted with one or more substituents 1-6 - Heteroalkyl, wherein the substituents are independently 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.

13. The compound of formula (I) as defined in any one of claims 1 to 12, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 7 and R 8 It represents -H.

14. The compound of formula (I) as defined in any one of claims 1 to 12, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 6 It indicates -H or -F.

15. A compound, its stereoisomer, physiologically acceptable salt, solvate and / or polymorph, selected from the group consisting of: Cpd 001-N-((S)-1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-(trans-2-phenylcyclopropyl)indoleazine-3-carboxamide; Cpd 002-N-((S)-1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-(cis-2-phenylcyclopropyl)indoleazine-3-carboxamide; Cpd 003-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide; Cpd 004-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide; Cpd 005-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3-carboxamide; Cpd 006-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(o-tolyloxy)indoleazine-3-carboxamide; Cpd 007-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(m-tolyloxy)indoleazine-3-carboxamide; Cpd 008-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(m-tolyloxy)indoleazine-3-carboxamide; Cpd 009-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(p-tolyloxy)indoleazine-3-carboxamide; Cpd 010-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-2-methyl-6-(p-tolyloxy)indoleazine-3-carboxamide; Cpd 011-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-6-(2-methoxyphenoxy)-2-methylindoleazine-3-carboxamide; Cpd 012-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-6-(2-methoxyphenoxy)-2-methylindoleazine-3-carboxamide; Cpd 013-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-6-(3-methoxyphenoxy)-2-methylindoleazine-3-carboxamide; Cpd 014-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-6-(3-methoxyphenoxy)-2-methylindoleazine-3-carboxamide; Cpd 015-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-6-(4-methoxyphenoxy)-2-methylindoleazine-3-carboxamide; Cpd 016-N-(4,4-difluoro-1-hydroxy-2-methylbutane-2-yl)-6-(4-methoxyphenoxy)-2-methylindoleazine-3-carboxamide; Cpd 017-(S)-N-(1-amino-3-hydroxy-2-methyl-1-oxopropane-2-yl)-2-methyl-6-phenoxyindoleazine-3-carboxamide; Cpd 018-6-(2-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methylindoleazine-3-carboxamide; Cpd 019-6-(3-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methylindoleazine-3-carboxamide; Cpd 020-6-(4-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methylindoleazine-3-carboxamide; Cpd 021-6-Benzyl-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methylindoleazine-3-carboxamide; Cpd 022-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-(phenylthio)indoleazine-3-carboxamide; Cpd 023-N-(3-(hydroxymethyl)-2-oxopyrrolidone-3-yl)-2-methyl-6-((1S,2S)-2-(pyridin-2-yl)cyclopropyl)indoleazine-3-carboxamide; Cpd 024-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methyl-6-(phenylsulfinyl)indoleazine-3-carboxamide and Cpd 025-N-(3-(hydroxymethyl)-2-oxopyrrolidine-3-yl)-2-methyl-6-(phenylsulfonyl)indoleazine-3-carboxamide.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.

17. A compound of formula (I) as defined in any one of claims 1 to 15, its stereoisomer, physiologically acceptable salt, solvate and / or polymorph, or a pharmaceutical composition according to claim 16, for the treatment of pain or epilepsy.

18. The compound or pharmaceutical composition for treating pain according to claim 17, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain; preferably postoperative pain or migraine.

19. A method for treating pain or epilepsy, the method comprising administering to a patient in need a therapeutically effective amount of a compound as defined in any one of claims 1 to 15 or a pharmaceutical composition as claimed in claim 16.

20. The method of claim 19, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain; preferably postoperative pain or migraine.

21. A compound of formula (II), its stereoisomers, physiologically acceptable salts, solvates and / or polymorphs. Formula II in R 3 Indicates CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently for R Y ， Or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl; or R in which 9 R 9' and R 9'' One of them is R Y ， Or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl, and wherein R 9 R 9' and R 9'' The two components together form a 3- to 14-membered cycloalkyl, a 3- to 14-membered heterocycloalkyl, a 5- to 14-membered aryl, or a 5- to 14-membered heteroaryl, wherein the 3- to 14-membered cycloalkyl, 3- to 14-membered heterocycloalkyl, 5- to 14-membered aryl, or 5- to 14-membered heteroaryl is optionally substituted by one or more R Y Mono- or poly-substituted; R 6 Selected from H, halogens and C 1-6 Halogenated alkyl groups; X represents the single bond between Cy and the carbon atom to which it is attached, or X represents -O-, -CR. 5 R 5 '-、-S-、-S(O)n-、-S-CR 5 R 5' -CR 5 R 5' -S-、-CR 5 R 5' -CR 4 R 4' -、-NR 5 -CR 4 R 4' -、-O-CR 5 R 5' -、-C=、-C≡C-、-CR 5 R 5' -NR 5 - In each case, the substituent is unsubstituted, monosubstituted, or polysubstituted, and the substituents are independently selected from -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 ; n is an integer in the range of 1 to 2; R 4 and R 4' Represented independently of each other -R Y ; R 5 and R 5 'Represented independently of each other - R Y , or R 5 and R 5' They together form carbonyl groups on the atoms to which they are attached, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 6-membered heterocycloalkyl groups. Cy represents a saturated or unsaturated 3- to 14-membered cycloalkyl group, a saturated or unsaturated 3- to 14-membered heterocycloalkyl group; a 5- to 14-membered aryl group or a 5- to 14-membered heteroaryl group; in each case, it is unsubstituted, monosubstituted, or polysubstituted, wherein the substituents are independently selected from -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 ; in: R Y and R Z Represented independently of each other in each case. -H； Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered heterocyclic alkyl groups; wherein the 3- to 14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; Unsubstituted, monosubstituted, or polysubstituted 6- to 14-membered aryl groups; wherein the 6- to 14-membered aryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or Unsubstituted, monosubstituted or polysubstituted 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. Or 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. Furthermore, "monosubstituted or polysubstituted" in each case independently means substituted by one or more substituents, such as 1, 2, 3, 4 or more, wherein the substituents are independently selected from -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)OC 1-6 -alkylene-CF3, -C(=O)-NH2, -C 1-6 -alkylene-C(=O)-NH2, -C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-C(=O)-NH(C) 1-6 -alkyl), -C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-C(=O)-N(C) 1-6 -alkyl)2, -C(=O)-NH(OH), -C 1-6 -alkylene-C(=O)-NH(OH), -OH, -C 1-6 -alkylene-OH, =O, -OCF3, -OCF2H, -OCFH2, -OCF2Cl, -OCFCl2, -OC 1-6 -alkyl, -C 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-OC 1-6 -alkyl, -OC 1-6 -alkylene-NH2, -OC 1-6 -alkylene-NH-C 1-6 -alkyl, -OC 1-6 -alkylene-N(C) 1-6 -alkyl)2、-OC(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-C 1-6 -alkyl, -OC(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-OC(=O)-OC 1-6 -alkyl, -OC(=O)-NH(C) 1-6 -alkyl), -C 1-6 -alkylene-OC(=O)-NH(C) 1-6 -alkyl), -OC(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OC(=O)-N(C) 1-6 -alkyl)2, -OS(=O)2-NH2, -C 1-6 -alkylene-OS(=O)2-NH2, -OS(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-OS(=O)2-NH(C) 1-6 -alkyl), -OS(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-OS(=O)2-N(C) 1-6 -alkyl)2, -NH2, -NO, -NO2, -C 1-6 -alkylene-NH2, -NH(C) 1-6 -alkyl), -N (3- 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)-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-C(=O)-OC 1-6 -alkyl, -NH-C(=O)-NH2, -C 1-6 -alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-C(=O)-NH(C) 1-6 -alkyl), -NH-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-C(=O)-N(C) 1-6 -alkyl)2, -N(C 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-C(=O)-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH2、-N(C 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-C(=O)-N(C 1-6 -alkyl)2, -NH-S(=O)2OH, -C 1-6 -alkylene-NH-S(=O)2OH, -NH-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-C 1-6 -alkyl, -NH-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-NH-S(=O)2-OC 1-6 -alkyl, -NH-S(=O)2-NH2, -C 1-6 -alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-NH-S(=O)2-NH(C) 1-6 -alkyl), -NH-S(=O)2N(C 1-6 -alkyl)2、-C 1-6 -alkylene-NH-S(=O)2N(C 1-6 -alkyl)2, -N(C 1-6 -alkyl)-S(=O)2-OH, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OH, -N(C 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-C 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-OC 1-6 -alkyl, -N(C) 1-6 -alkyl)-S(=O)2-NH2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH2、-N(C 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-NH(C 1-6 -alkyl), -N(C 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-N(C) 1-6 -alkyl)-S(=O)2-N(C 1-6 -alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -SC 1-6 -alkyl, -C 1-6 -alkylene-SC 1-6 -alkyl, -S(=O)-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)-C 1-6 -alkyl, -S(=O)2-C 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-C 1-6 -alkyl, -S(=O)2-OH, -C 1-6 -alkylene-S(=O)2-OH, -S(=O)2-OC 1-6 -alkyl, -C 1-6 -alkylene-S(=O)2-OC 1-6 -alkyl, -S(=O)2-NH2, -C 1-6 -alkylene-S(=O)2-NH2, -S(=O)2-NH(C 1-6 -alkyl), -C 1-6 -alkylene-S(=O)2-NH(C) 1-6 -alkyl), -S(=O)2-N(C 1-6 -alkyl)2、-C 1-6 -alkylene-S(=O)2-N(C) 1-6 -alkyl) 2, 3 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 heterocyclic alkyl groups), -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).

22. The compound of formula (II) as defined in claim 21, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 3 Indicates CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently for R Y or optionally by one or more R Y Replacement C 1-6 Alkyl or C 1-6 Heteroalkyl groups.

23. The compound of formula (II) as defined in any one of claims 21 to 22, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 3 Indicates CR 9 R 9' R 9'' , where R 9 R 9' and R 9'' Independently -H, -C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl groups -O-CH3, -(C=O)-NH2, -(C=O)-NH-CH3, -(C=O)-N(CH3)2, -C 1-6 Alkyl-CF2H and -C 1-6 Alkyl-CF3.

24. The compound of formula (II) as defined in any one of claims 21 to 23, its stereoisomer, physiologically acceptable salt, solvate, and / or polymorph, wherein Cy represents a C3-C8 cycloalkyl, phenyl, C5-C8 heterocycloalkyl, or C5-C8 heteroaryl group, optionally substituted with one or more of a halogen, C1-C3-haloalkyl, hydroxyl, acyl, formamide, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, butyl, cyclobutyl, oxetane, pyrrole, or diazole, wherein the formamide, acyl, cyclopropyl, cyclobutyl, oxetane, pyrrole, and diazole are optionally further substituted with a halogen, C1-C3-haloalkyl, hydroxyl, phenyl, methyl, methoxy, ethyl, ethoxy, or propyl group, optionally linked by a -C1-C6-alkylene- or -C1-C6-heteroalkylene-.

25. The compound of formula (II) as defined in any one of claims 21 to 23, its stereoisomer, physiologically acceptable salt, solvate, and / or polymorph, wherein Cy represents residues selected from:

26. The compound of formula (II) as defined in any one of claims 21 to 25, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 5 and R 5 'represented independently of each other' -H； Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-alkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted -C1-C6-heteroalkyl; Saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- to 14-membered cycloalkyl groups; wherein the 3- to 14-membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, and in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted.

27. The compound of formula (II) as defined in any one of claims 21 to 25, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 5 and R 5 Together they form saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- or 4-membered cycloalkyl groups, or saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted 3- or 4-membered heterocycloalkyl groups.

28. The compound of formula (II) as defined in any one of claims 21 to 27, its stereoisomers, physiologically acceptable salts, solvates, and / or polymorphs, wherein R 6 It represents -H, -Cl, or -F.

29. A pharmaceutical composition comprising the compound according to any one of claims 21 to 28.

30. A compound of formula (II) as defined in any one of claims 21 to 28, its stereoisomer, physiologically acceptable salt, solvate and / or polymorph, or a pharmaceutical composition according to claim 29, for the treatment of pain or epilepsy.

31. The compound or pharmaceutical composition for treating pain according to claim 30, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain; preferably postoperative pain or migraine.

32. A method for treating pain or epilepsy, the method comprising administering to a patient in need a therapeutically effective amount of a compound as defined in any one of claims 21 to 28 or a pharmaceutical composition as described in claim 29.

33. The method of claim 32, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain; preferably postoperative pain or migraine.

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