TRPM3-modulating indolizine derivatives

Abstract

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

Description

TRPM3-MODULATING INDOLIZINE DERIVATIVESCROSS-REFERENCE TO RELATED APPLICATION

[0001] This International Patent Application claims priority to United States Provisional Patent Application No. 63 / 601,266, filed November 21, 2023, which is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The invention relates to compounds that are useful for the prevention or treatment of TRPM3 mediated disorders, more in particular disorders selected from pain, such as migraine pain, inflammatory pain or hypersensitivity, and epilepsy. The invention also relates to a method for the prevention or treatment of said TRPM3 mediated disorders.BACKGROUND

[0003] The TRP superfamily consists of proteins with six transmembrane domains (6TM) that assemble as homo- or heterotetramers to form cation-permeable ion channels. The name TRP originates from the Drosophila tip (transient receptor potential) mutant, which is characterized by a transient receptor potential in the fly photoreceptors in the response to sustained tight. In the last 15 years, tip-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, TRP A, TRPP, TRPML and TRPN.

[0004] Members of the TRP superfamily are expressed in probably all mammalian organs and cell types, and in recent years great progress has been made in the understanding of their physiological role. The tailored selectivity of certain TRP channels enables them to play key roles in the cellular uptake and / or transepithelial transport of Ca2+, Mg2+and trace metal ions. Moreover, the sensitivity of TRP channels to a broad array of chemical and physical stimuli, allows them to function as dedicated biological sensors involved in processes ranging from vision to taste, and tactile sensation. In particular, several members of the TRP superfamily exhibit a very high sensitivity to temperature. These so-called thermoTRPs are highly expressed in sensory neurons and / or skin keratinocytes, where they act as primary thermosensors for the detection of innocuous and noxious (painful) temperatures.

[0005] It is becoming increasingly clear that TRP channel dysfunction is directly involved in the etiology of various inherited and acquired diseases. Indeed, both loss-of-function and gain-of-function mutations in the TRP channel genes have been identified as the direct cause of inherited diseases, including brachyolmia, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, mucolipidosis type IV and familial focal segmental glomerulosclerosis. Moreover, TRP channel function / dysfunction has been directly linked to a wide range of pathological conditions, including chronic pain, hypertension, cancer and neurodegenerative disorders.

[0006] TRPM3 (Transient receptor potential melastatin 3) represents a promising pharmacological target. TRPM3 is expressed in a large subset of small-diameter sensory neurons from dorsal root and trigeminal ganglia, and is involved in heat sensing. The neurosteroid pregnenolone sulfate is a potent known activator of TRPM3 (Wagner et al., 2008). The neurosteroid pregnenolone sulfate evoked pain in wild type mice but not in knock-out TRPM3 mice. It was also recently shown that CFA induced inflammation and inflammatory pain are eliminated in TRPM3 knock-out mice. Therefore, TRPM3 antagonists could be used as analgesic drugs to counteract pain,such as inflammatory pain (Vriens J. et al. Neuron, May 2011). A relationship between TRPM3 and epilepsy has also been established (see e.g. Eur J Hum Genet. 2019 Oct; 27(10): 1611-1618; Elife 2020 May 19;9:e57190. doi: 10.7554 / eLife.57190. DOI: 10.7554 / eLife.57190; Channels (Austin). 2021; 15(1): 386-397. TRPM3 is therefore also a potential target for the treatment of epilepsy.

[0007] A few TRPM3 antagonists are known, but none of them points towards the compounds disclosed herein (Straub I et al. Mol Pharmacol, November 2013). For instance, Liquiritigenin, a postulated TRPM3 blocker has been described to decrease mechanical and cold hyperalgesia in a rat pain model (Chen L et al. Scientific reports, July 2014). There is still a great medical need for novel, alternative and / or better therapeutics for the prevention or treatment of TRPM3 mediated disorders, more in particular for pain such as inflammatory pain and epilepsy. Therapeutics with good potency on a certain type of pain, low level or no side-effects (such as no possibilities for addiction as with opiates, no toxicity) and / or good or better pharmacokinetic or -dynamic properties are highly needed.

[0008] The invention provides a class of novel compounds which are antagonists of TRPM3 and can be used as modulators of TRPM3 mediated disorders.SUMMARY

[0009] The invention provides indolizine derivatives and pharmaceutical compositions comprising such indolizine derivatives. The invention also provides indolizine derivatives for use as a medicament, more in particular for use in the prevention and / or treatment of TRPM3 mediated disorders, especially for use in the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy; and / or for counteracting pain and / or inflammatory hypersensitivity and / or epilepsy.

[0010] The invention also provides the use of indolizine derivatives for the manufacture of pharmaceutical compositions or medicaments for the prevention and / or treatment of TRPM3 mediated disorders, especially for the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy; and / or for counteracting pain and / or inflammatory hypersensitivity and / or epilepsy.

[0011] The invention also provides a method for the prevention or treatment of a TRPM3 mediated disorder by administering the indolizine derivatives according to the invention to a subject in need thereof. More in particular, the invention relates to such method for the prevention and / or treatment of pain and / or inflammatory hypersensitivity and / or epilepsy and / or epileptic seizures; and / or for counteracting pain and / or inflammatory hypersensitivity and / or epilepsy.

[0012] The invention further provides a method for the preparation of the indolizine derivatives of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0013] The invention will be further described and in some instances with respect to particular embodiments, but the invention is not limited thereto.

[0014] The first aspect of the invention is the provision of a compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereofoptionally for use in the treatment of pain or epilepsy or methods of treating pain or epilepsy; whereinR1represents -F, -Cl, -Br, -I, -CN, -Rw, -ORW, -OC(=O)RW, -NRWRX, -NRWC(=O)RX, -SRW, -S(=O)RW, - S(=O)2RW, -C(=O)RW, -C(=O)ORW, or -C(=O)NRWRX;R3represents -OH or -RY;X represents a single bond between Cy and the carbon atom to which it is attached, or X represents -O-, -CR5R5'- , -S-, -S(O)n-, -S-CR5R5’-, -CR5R5-S-, -CR5R5-CR4R4-, -NR5-CR4R4-, -C=, -C = -. or -CR5R5-NR5-, in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -NO2, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, - S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ;R4and R4' independently of one another represent -RY; n is an integer ranging from 1 to 2;R5and R5' independently of one another represent -RY’ or R5and R5' together form a carbonyl, a 3-6-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted, or a 3 -6-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted, on the atom to which they are attached;R6, R7and R8independently of one another represent -F, -Cl, -Br, -I, -CN, -N02, -SF5, -Rw, -ORW, -OC(=O)RW, -NRWRX, -NRWC(=O)RX, -SRW, -S(=O)RW, -S(=O)2RW, -C(=O)RW, -C(=O)ORW, or -C(=O)NRWRX;Cy represents 3-14-membered heterocycloalkyl, saturated or unsaturated; 3-14-membered cycloalkyl, saturated or unsaturated; 5-14-membered aryl; -C1-C6alkyl, -C1-C6heteroalkyl; or 5-14-membered heteroaryl; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CF3, -CF2H, C1-C6alkyl, -CN, -NO, -N02, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ; whereinRwand Rxindependently of one another and in each case independently represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, ineach case saturated or unsaturated, unsubstituted, mono- or polysubstituted;RYand Rzindependently of one another and in each case independently represent:-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;6-14-membered aryl, unsubstituted, mono- or poly-substituted; wherein said 6-14-membered aryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or RYand Rztogether form a 4, 5, 6, 7 or 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated, unsubstituted or mono- or polysubstituted; and wherein "mono- or polysubstituted" in each case independently means substituted with one or more, e.g. 1, 2, 3, 4, or more substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -C1-6-alkyl, -CF3, - CF2H, -CFH2, -CF2CI, -CFCI2, -C1-C-a6lkylene-CFs, -C1-6-alkylene-CF2H, -C1-6-alkylene-CFH2, -C1-6-alkylene-O- CF3, -C1-6-alkylene-O-CF2H, -C1-6-alkylene-O-CFFF, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C1-6-alkylene-N(Ci-6-alkyl)-C1-6-alkylene-CF3, -C(=O)-C1-6-alkyl, -C1-6-alkylene-C(=O)-C1-6-alkyl, -C(=O)OH, -C1-6-alkylene- C(=O)-OH, -C(=O)-OC1-6-alkyl, -C1-6-alkylene-C(=O)-OC1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=O)-NH2, - C1-6-alkylene-C(=O)-NH2, -C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-C(=O)-NH(C1-6-alkyl), -C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-C(=O)-N(C1-6-alkyl)2, -C(=O)-NH(OH), -C1-6-alkylene-C(=O)-NH(OH), -OH, -C1-6-alkylene-OH, =0, -OCF3, -OCF2H, -OCFH2, -OCF2CI, -OCFCb, -O-C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl, -O-C1-6-alkylene- O-C1-6-alkyl, -O-C1-6-alkylene-NH2, -O-C1-6-alkylene-NH-C1-6-alkyl, -O-C1-6-alkylene-N(C1-6-alkyl)2, -0-C(=0)- C1-6-alkyl, -C1-6-alkylene-O-C(=O)-C1-6-alkyl, -0-C(=0)-0-C1-6-alkyl, -C1-6-alkylene-O-C(=O)-O-C1-6-alkyl, -O- C(=O)-NH( C1-6-alkyl), -C1-6-alkylene-O-C(=O)-NH( C1-6-alkyl), -O-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-O- C(=O)-N(C1-6-alkyl)2, -O-S(=O)2-NH2, -C1-6-alkylene-O-S(=O)2-NH2, -O-S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene- O-S(=O)2-NH(C1-6-alkyl), -O-S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-O-S(=O)2-N(C1-6-alkyl)2, -NH2, -NO, -NO2, - C1-6-alkylene-NH2, -NH(C1-6-alkyl), -N(3-14-membered cycloalkyl)(C1-6-alkyl), -N(C1-6-alkyl)-C1-6-alkylene-OH, -N(H)-C1-6-alkylene-0H, -C1-6-alkylene-NH(C1-6-alkyl), -N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)2, -NH- C(=O)-C1-6-alkyl, -C1-6-alkylene-NH-C(=O)-C1-6-alkyl, -NH-C(=O)-O-C1-6-alkyl, -C1-6-alkylene-NH-C(=O)-O- C1-6-alkyl, -NH-C(=0)-NH2, -C1-6-alkylene-NH-C(=O)-NH2, -NH-C(=0)-NH(C1-6-alkyl), -C1-6-alkylene-NH- C(=O)-NH(C1-6-alkyl), -NH-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C(=O)-N(C1-6-alkyl)2, -N(C1-6-alkyl)- C(=0)-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-O-C1-6-alkyl, -C1-6- alkylene-N(C1-6-alkyl)-C(=O)-O-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-NH2, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-NH2,-N(C1-6-alkyl)-C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-NH(C1-6-alkyl), -N(C1-6-alkyl)-C(=O)- N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-N(C1-6-alkyl)2, -NH-S(=O)2OH, -C1-6-alkylene-NH- S(=O)2OH, -NH-S(=O)2-C1-6-alkyl, -C1-6-alkylene-NH-S(=O)2-C1-6-alkyl, -NH-S(=O)2-O-C1-6-alkyl, -C1-6- alkylene-NH-S(=O)2-O-C1-6-alkyl, -NH-S(=O)2-NH2, -C1-6-alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C1-6- alkyl), -C1-6-alkylene-NH-S(=O)2-NH(C1-6-alkyl), -NH-S(=O)2N(C1-6-alkyl)2, -C1-6-alkylene-NH-S(=O)2N(C1-6- alkyl)2, -N(C1-6-alkyl)-S(=O)2-OH, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-OH, -N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, - C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, -N(C1-6-alkyl)-S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)- S(=O)2-O-C1-6-alkyl, -N(C1-6-alkyl)-S(=O)2-NH2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-NH2, -N(C1-6-alkyl)- S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-NH(C1-6-alkyl), -N(C1-6-alkyl)-S(=O)2-N(C1-6- alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-N(C1-6-alkyl)2, -SH, =S, -SFs, -SCF3, -SCF2H. -SCFH2, -S-C1-6-alkyl, -C1-6-alkylene-S-C1-6-alkyl, -S(=0)-C1-6-alkyl, -C1-6-alkylene-S(=O)-C1-6-alkyl, -S(=O)2-C1-6-alkyl, -C1-6- alkylene-S(=O)2-C1-6-alkyl, -S(=O)2-OH, -C1-6-alkylene-S(=O)2-OH, -S(=O)2-O-C1-6-alkyl, -C1-6-alkylene- S(=O)2-O-C1-6-alkyl, -S(=O)2-NH2, -C1-6-alkylene-S(=O)2-NH2, -S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-S(=O)2- NH(C1-6-alkyl), -S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-S(=O)2-N(C1-6-alkyl)2, 3-14-membered cycloalkyl, -C1-6- alkylene-(3- 14-membered cycloalkyl), 3 to 14-membered heterocycloalkyl, -C1-6-alkylene-(3 to 14-membered heterocycloalkyl), -phenyl, -C1-6-alkylene-phenyl, 5 to 14-membered heteroaryl, -C1-6-alkylene-(5 to 14-membered heteroaryl), -O-(3- 14-membered cycloalkyl), -O-(3 to 14-membered heterocycloalkyl), -O-phenyl, -O-(5 to 14- membered heteroaryl), -C(=O)-(3-14-membered cycloalkyl), -C(=O)-(3 to 14-membered heterocycloalkyl), - C(=O)-phenyl, -C(=O)-(5 to 14-membered heteroaryl), -S(=O)2-(3- 14-membered cycloalkyl), -S(=O)2-(3 to 14- membered heterocycloalkyl), -S(=O)2-phenyl, -S(=O)2-(5 to 14-membered heteroaryl).

[0015] Generally, X is described such that the first atom listed in the notation is bonded to the benzofuran ring system, i.e., the first atom in the notations -S-CR5R5-, -CR5R5-S-, -CR5R5-CR4R4-, -NR5-CR4R4-, or -CR5R5- NR5- is bonded to the benzofuran ring system and the second atom in the notation is bonded to Cy.

[0016] In an embodiment of the indolizine derivative according to the invention, R1is selected from -C1-C6- alkyl. In an embodiment, R1is selected from methyl, ethyl, and propyl. In an embodiment, R1is methyl.

[0017] In an embodiment of the indolizine derivative according to the invention, R3represents -CR9R9'R9", wherein R9, R9', and R9" are independently RY, or C1-6alkyl or C1-6heteroalkyl optionally substituted with one or more RY, optionally wherein two of R9, R9', and R9" together form a 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl, said 3-14-membered cycloalkyl, 3-14- membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl optionally monosubstituted or polysubstituted with one or more RY.

[0018] In an embodiment, R5and R5' together form a 3-4-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted, or a 3-4-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted. In an embodiment, R5and R5' together form cyclopropyl, cyclobutyl, or oxetane.

[0019] In an embodiment of the indolizine derivative according to the invention, R7and R8are independently selected from H, C1-C6-alkyl, and C1-C6-heteroalkyl. In an embodiment, R7and R8are preferably each -H.

[0020] In an embodiment of the indolizine derivative according to the invention, R6is selected from H, halogen, and C1-6haloalkyl. In an embodiment, R6is selected from H and F.

[0021] In an embodiment of the indolizine derivative according to the invention, R6is selected from cyano,carbonyl, carboxylic acid, carboxylic esters, nitro, ammonium, aldehyde, and sulfonyl.

[0022] In an embodiment of the indolizine derivative according to the invention, Cy includes one or more cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings, wherein, for Cy having more than one cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, said rings may share one or more atoms in a spiro or fused system, or may be optionally connected through -C1-C6-alkylene- or -C1-C6-hctcroalkylcnc-. in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0023] In some embodiments, the 5-14-membered heteroaryl or aryl within the definition of Cy is selected from azulene, benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furane, furazane, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [l,2,4]triazolo[4,3- a]pyrimidine; in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ.

[0024] In some embodiments, the 5-14-membered heteroaryl within the definition of Cy is selected from the group consisting of furane, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole, pyridine, isoquinoline, benzothiazole, pyridazine, pyrimidine, imidazopyridine; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, - S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ.

[0025] In some embodiments, the 5-14-membered heteroaryl within the definition of Cy is selected from the group consisting of furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-5-yl, isoxazol-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, l,2,4-triazol-3-yl, l,2,3-triazol-4-yl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, isoquinolin- 1-yl, isoquinolin-5-yl, benzo [d]thiazol-2-yl, pyridazin-3-yl, pyrimidin- 5-yl, and imidazo[l,2-a]pyridin-6-yl; in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, , CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, - SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ.

[0026] In some embodiments, the 5-14-membered heteroaryl within the definition of Cy is selected form the group consisting of pyrazol-3-yl, pyrazol-4-yl, thiazol-4-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridine- 4-yl; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, , CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ.

[0027] In an embodiment, the 3-14-membered cycloalkyl, saturated or unsaturated within the definition of Cy is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl including unfused or unbridged, fused, or bridged cycloalkyls; in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, , CF3, -CF2H, C1-C6alkyl, -CN, -NO, - NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, - C(=O)ORY, or -C(=O)NRYRZ-

[0028] In an embodiment, the 5-14-membered aryl within the definition of Cy is phenyl or another 5-14- membered aryl, unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ

[0029] In further embodiments of the indolizine derivatives according to the invention Cy represents 3-14- membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, - SF5, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ.

[0030] In some embodiments, the 3-14-membered heterocycloalkyl within the definition of Cy is selected from azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxane, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofurane, tetrahydropyrane, tetrahydrothiopyrane, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzo-thiophene, 1,1 -dioxothia-cyclohexane, 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- IH-pyrrolizine, hexa-hydro- cyclopenta[c]pyrrole, octahydro-cyclopenta[c]pyrrole, and octahydro-pyrrolo[l,2-a]pyrazine; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, - SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ

[0031] In some embodiments, the 3-14-membered heterocycloalkyl within the definition of Cy is oxane, oxan- 4-yl, oxetane, or oxetan-3-yl; in each case unsubstituted, mono- orpolysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, CF3, -CF2H. C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ

[0032] In another preferred embodiment of the indolizine derivatives according to the invention Cy represents C1-C6alkyl or C1-C6heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, CF3, -CF2H, C1-C6alkyl, -CN, -NO, -NO2, =0, =S, -SFs, -RY, -ORY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, - C(=O)ORY, or -C(=O)NRYRZ.

[0033] In some embodiments of the indolizine derivative according to the invention Cy is unsubstituted, mono- or poly substituted with substituents independently of one another selected from-F, -Cl, -Br, -I, -CN, -C(=O)OH, -NH2, -NO2, -OH, =0, -SFs; -C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-C(=0)0-C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-NHC1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-N(C1-6-alkyl)2, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-O-C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-S(=O)2-C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each casesaturated or unsaturated, unsubstituted, mono- or polysubstituted; or3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0034] In some embodiments, Cy is unsubstituted, mono- or polysubstituted with substituents independently of one another selected from-OH, -F, -Cl, -Br, -I, -SH, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F. SF5, -CN, -NO2, -C(=O)OH, -NH2, or -N(CH3)2; -C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted with substituents independently of one another , selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2-6-alkynyl, -OH, =0, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2;-C1-6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted with substituents independently of one another , selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2- e-alkynyl, -OH, =0, -SH, =S, -CN, -CF3, -CHF2, -CH2F. -OCF3, -OCHF2, -OCH2F, SF5, -N02, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2;-OC1-6-alkyl, unsubstituted, mono- or polysubstituted with substituents independently of one another, selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2-6-alkynyl, -OH, =0, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -N02, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2;-0(C=0)C1-6-alkyl, unsubstituted, mono- or polysubstituted with substituents independently of one another , selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2-6-alkynyl, -OH, =0, -SH, =S, - CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -N02, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=O)NH2; -C(=0)0C1-6-alkyl, unsubstituted, mono- or polysubstituted with substituents independently of one another , selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2-6-alkynyl, -OH, =0, -SH, =S, - CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -N02, -C(=O)OH, -NH2, C(=O)CHF2, and -C(=0)NH2; 3-14-membered cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; in each case unsubstituted, mono- or polysubstituted with substituents independently of one another , selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2-6-alkynyl, -OH, =0, - SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -N02, -C(=O)OH, -NH2, C(=O)CHF2, and - C(=0)NH2;3-14-membered heterocycloalkyl selected from the group consisting of azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 2-azaspiro- [3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo- [3.3.1]nonane, hexahydro- IH-pyrrolizine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[l,2-a]pyrazine, in each case unsubstituted, mono- or poly substituted with substituents independently of one another , selected from the group consisting of -F, -Cl, -Br, -I, -C1-6-alkyl, C2-e-alkenyl, -C2- e-alkynyl, -OH, =0, -SH, =S, -CN, -CF3, -CHF2, -CH2F. -OCF3, -OCHF2, -OCH2F, SF5, -N02, -C(=O)OH, -NH2,C(=O)CHF2, and -C(=O)NH2.

[0035] In some embodiments, Cy is unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -CN, -OH, =0, -C1-6-alkyl, methyl, ethyl, -CHF2, -CF3, -C1-6-alkylene-NH2, -Ci- 6-alkylene-NHC(=O)O-C1-6-alkyl, -C1-6-alkylene-OH, -C1-6-alkylene-NHC(=O)-O-C1-6-alkyl, -C(=O)O-C1-6- alkyl, -N(C1-6-alkyl)2, -OC1-6-alkyl, -OCF3, -O-C1-6-alkylene-N(C1-6-alkyl)2, -S(=O)2-C1-6-alkyl, -azetidine, -C1-6- alkylene-O-tetrahydropyran, or -piperazine substituted with -C1-6-alkyl.

[0036] In some embodiments of the indolizine derivative according to the invention Cy is(i) unsubstituted;(ii) monosubstituted;(iii) disubstituted;(iv) trisubstituted; or(v) tetrasubstituted, wherein the particular substituents of (iii)-(v) may be independently different from one another or where one or more of the particular substituents of (iii)-(v) may be the same.

[0037] In some embodiments of the indolizine derivatives according to the invention Cy is(i) unsubstituted;(ii) monosubstituted; or(iii) disubstituted.

[0038] In some embodiments, Cy represents C3-C3 cycloalkyl, phenyl, C5-C8heterocycloalkyl, or C5-C8heteroaryl, optionally substituted with one or more of halogen, Ci-Cs-haloalkyl, hydroxy, acyl, carboxamide, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, butyl, cyclobutyl, oxetane, pyrrole, or diazole, said carboxamide, acyl, cyclopropyl, cyclobutyl, oxetane, pyrrole and diazole optionally being further substituted with halogen, Ci- Cs-haloalkyl, hydroxy, phenyl, methyl, methoxy, ethyl, ethoxy, or propyl, optionally connected through C1-C6- alkylene- or -Ci-G-hctcroalkylcnc-.

[0039] A further aspect of the invention is the provision of a compound of Formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate, and / or polymorph thereof:wherein:R3is selected from -CR9R9'R9", wherein R9, R9', and R9" are independently RY, or Ci -ealkyl or C1-6heteroalkyl optionally substituted with one or more RY, optionally wherein two of R9, R9', and R9" together form a 3-14- membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl, said 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryloptionally monosubstituted or polysubstituted with one or more RY;R6is selected from H, halogen, and Ci -ehaloalky 1;X represents a single bond between Cy and the carbon atom to which it is attached, or X represents -O-, -CR5R5', -S-, -S(O)n-,-S-CR5R5-CR5R5-S-, -CR5R5-CR4R4-, -NR5-CR4R4-, -C=, -C C or -CR5R5’-NR5-, in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -NO2, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, - S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ; n is an integer ranging from 1 to 2;R4and R4' independently of one another represent -RY;R5and R5' independently of one another represent -RY, or R5and R5' together form a carbonyl, a 3-6-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted, or a 3 -6-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted, on the atom to which they are attached;Cy represents 3-14-membered cycloalkyl, saturated or unsaturated, 3-14-membered heterocycloalkyl, saturated or unsaturated; 5-14-membered aryl, or 5-14-membered heteroaryl; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -NO2, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=0)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, - C(=O)ORY, or -C(=O)NRYRZ; whereinRYand Rzindependently of one another in each case independently represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or RYand Rztogether form a 4, 5, 6, 7 or 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated, unsubstituted or mono- or polysubstituted; and wherein "mono- or polysubstituted" in each case independently means substituted with one or more, e.g. 1, 2, 3, 4, or more substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -C1-6-alkyl, -CF3, - CF2H, -CFH2, -CF2CI, -CFCI2, -C1-6-alkylene-CFs, -C1-6-alkylene-CF2H, -C1-6-alkylene-CFFF, -C1-6-alkylene-O- CF3, -C1-6-alkylene-O-CF2H, -C1-6-alkylene-O-CFFF, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C1-6-alkylene-N(Ci-6-alkyl)-C1-6-alkylene-CF3, -C(=0)-C1-6-alkyl, -C1-6-alkylene-C(=O)-C1-6-alkyl, -C(=O)OH, -C1-6-alkylene- C(=O)-OH, -C(=O)-OC1-6-alkyl, -C1-6-alkylene-C(=O)-OC1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=O)-NH2, - C1-6-alkylene-C(=O)-NH2, -C(=0)-NH(C1-6-alkyl), -C1-6-alkylene-C(=O)-NH(C1-6-alkyl), -C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-C(=O)-N(C1-6-alkyl)2, -C(=O)-NH(OH), -C1-6-alkylene-C(=0)-NH(0H), -OH, -C1-6-alkylene-OH, =0, -OCF3, -OCF2H, -OCFH2, -OCF2C1, -OCFCb, -O-C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl, -O-C1-6-alkylene- O-C1-6-alkyl, -O-C1-6-alkylene-NH2, -O-C1-6-alkylene-NH-C1-6-alkyl, -O-C1-6-alkylene-N(C1-6-alkyl)2, -0-C(=0)- C1-6-alkyl, -C1-6-alkylene-O-C(=O)-C1-6-alkyl, -0-C(=0)-0-C1-6-alkyl, -C1-6-alkylene-O-C(=O)-O-C1-6-alkyl, -O- C(=0)-NH(C1-6-alkyl), -C1-6-alkylene-O-C(=O)-NH(C1-6-alkyl), -O-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-O- C(=O)-N(C1-6-alkyl)2, -O-S(=O)2-NH2, -C1-6-alkylene-O-S(=O)2-NH2, -O-S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene- O-S(=O)2-NH(C1-6-alkyl), -O-S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-O-S(=O)2-N(C1-6-alkyl)2, -NH2, -NO, -N02, - C1-6-alkylene-NH2, -NH(C1-6-alkyl), -N(3-14-membered cycloalkyl)(C1-6-alkyl), -N(C1-6-alkyl)-C1-6-alkylene-OH, -N(H)-C1-6-alkylene-0H, -C1-6-alkylene-NH(C1-6-alkyl), -N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)2, -NH- C(=0)-C1-6-alkyl, -C1-6-alkylene-NH-C(=O)-C1-6-alkyl, -NH-C(=O)-O-C1-6-alkyl, -C1-6-alkylene-NH-C(=0)-0- C1-6-alkyl, -NH-C(=0)-NH2, -C1-6-alkylene-NH-C(=O)-NH2, -NH-C(=0)-NH(C1-6-alkyl), -C1-6-alkylene-NH- C(=0)-NH(C1-6-alkyl), -NH-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C(=O)-N(C1-6-alkyl)2, -N(C1-6-alkyl)- C(=0)-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-O-C1-6-alkyl, -C1-6- alkylene-N(C1-6-alkyl)-C(=O)-O-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-NH2, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-NH2, -N(C1-6-alkyl)-C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-NH(C1-6-alkyl), -N(C1-6-alkyl)-C(=0)- N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-N(C1-6-alkyl)2, -NH-S(=O)2OH, -C1-6-alkylene-NH- S(=O)2OH, -NH-S(=O)2-C1-6-alkyl, -C1-6-alkylene-NH-S(=O)2-C1-6-alkyl, -NH-S(=O)2-O-C1-6-alkyl, -C1-6- alkylene-NH-S(=O)2-O-C1-6-alkyl, -NH-S(=O)2-NH2, -C1-6-alkylene-NH-S(=O)2-NH2, -NH-S(=O)2-NH(C1-6- alkyl), -C1-6-alkylene-NH-S(=O)2-NH(C1-6-alkyl), -NH-S(=O)2N(C1-6-alkyl)2, -C1-6-alkylene-NH-S(=O)2N(C1-6- alkyl)2, -N(C1-6-alkyl)-S(=O)2-OH, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-OH, -N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, - C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, -N(C1-6-alkyl)-S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)- S(=O)2-O-C1-6-alkyl, -N(C1-6-alkyl)-S(=O)2-NH2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-NH2, -N(C1-6-alkyl)- S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-NH(C1-6-alkyl), -N(C1-6-alkyl)-S(=O)2-N(C1-6- alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-N(C1-6-alkyl)2, -SH, =S, -SF5, -SCF3, -SCF3H, -SCFH2, -S-C1-6-alkyl, -C1-6-alkylene-S-C1-6-alkyl, -S(=0)-C1-6-alkyl, -C1-6-alkylene-S(=O)-C1-6-alkyl, -S(=O)2-C1-6-alkyl, -C1-6- alkylene-S(=O)2-C1-6-alkyl, -S(=O)2-OH, -C1-6-alkylene-S(=O)2-OH, -S(=O)2-O-C1-6-alkyl, -C1-6-alkylene- S(=O)2-O-C1-6-alkyl, -S(=O)2-NH2, -C1-6-alkylene-S(=O)2-NH2, -S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-S(=O)2- NH(C1-6-alkyl), -S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-S(=O)2-N(C1-6-alkyl)2, 3-14-membered cycloalkyl, -C1-6- alkylene-(3- 14-membered cycloalkyl), 3 to 14-membered heterocycloalkyl, -C1-6-alkylene-(3 to 14-membered heterocycloalkyl), -phenyl, -C1-6-alkylene-phenyl, 5 to 14-membered heteroaryl, -C1-6-alkylene-(5 to 14-membered heteroaryl), -0-(3- 14-membered cycloalkyl), -0-(3 to 14-membered heterocycloalkyl), -O-phenyl, -0-(5 to 14- membered heteroaryl), -C(=O)-(3-14-membered cycloalkyl), -C(=0)-(3 to 14-membered heterocycloalkyl), - C(=O)-phenyl, -C(=0)-(5 to 14-membered heteroaryl), -S(=O)2-(3- 14-membered cycloalkyl), -S(=O)2-(3 to 14- membered heterocycloalkyl), -S(=O)2-phenyl, -S(=O)2-(5 to 14-membered heteroaryl).

[0040] In an embodiment of the benzofuran derivative according to the invention, R6is selected from H, halogen, and C1-6haloalkyl. In an embodiment, R6is selected from H and F.

[0041] In an embodiment of the benzofuran derivative according to the invention, R6is selected from cyano,carbonyl, carboxylic acid, carboxylic esters, nitro, ammonium, aldehyde, and sulfonyl.

[0042] In some embodiments of Formulas (I) and (II), Cy represents a 3-14-membered cycloalkyl (preferably 3,4, 5 or 6-membered cycloalkyl), saturated or unsaturated, in each case unsubstituted, mono- or polysubstituted; optionally a residue selected from the group consisting of:

[0043] In some embodiments of Formulas (I) and (II), Cy represents a 3-14-membered aryl, in each case unsubstituted, mono- or polysubstituted; optionally a residue selected from the group consisting of:

[0044] In some embodiments of Formulas (I) and (II), Cy represents a 3-14-membered heterocycloalkyl (preferably 3-5-membered heterocycloalkyl), saturated or unsaturated; 5-14-membered heteroaryl (preferably 5- 6-membered heteroaryl); 3-14-membered cycloalkyl, saturated or unsaturated; 5-14-membered aryl; or C1-C6alkyl; in each case unsubstituted, mono- or polysubstituted; preferably a residue selected from the group consisting of:

[0046] In some embodiments, Cy represents a residue according to general formula (E)whereinYE1represents -N=, -NRE2-, S, O, or -CRE3=; YE2represents -N=, -NRE3-, S, O, or -CRE4=; and YE3represent - N=, -NRE4-, S, O, or -CRE5=; with the proviso that at least one of YE1, YE2, and YE3is not -CRE3=, -CRE4=, and - CRE5=, respectively. In another preferred embodiment, V represents a residue according to general formula (E) wherein YE1 represents -N=, -NRE2-, S, or -CRE3=; YE2 represents -N=, -NRE3-, S, or -CRE4=; and YE3 represent -N=, -NRE4-, S, or -CRE5=; with the proviso that at least one of YE1, YE2, and YE3 is not -CRE3=, - CRE4=, and -CRE5=, respectively.RE1, RE2, RE3, and RE4independently of one another represent -H, -CH3,-CH2-cyclopropyl, -CH2CF3, -CH2CHF2 or -CF3; more in particular RE1, RE2, RE3, and RE4independently of one another represent -H, -CH3, or -CF3; preferably with the proviso that only one of RE1, RE2, RE3, and RE4represents a residue that is not -H.

[0047] In some embodiments of Formulas (I) and (II), Cy represents 2-pyridine, unsubstituted, mono- or polysubstituted. In some embodiments, Cy represents a residue selected from the group consisting of:

[0048] In some embodiments of Formulas (I) and (II), Cy represents 3-pyridine, unsubstituted, mono- or polysubstituted. In preferred embodiments, V represents a residue selected from the group consisting of:

[0049] In some embodiments of Formulas (I) and (II), Cy represents 4-pyridine, unsubstituted, mono- or polysubstituted. In preferred embodiments, Cy represents a residue selected from the group consisting of:

[0050] In some embodiments of Formulas (I) and (II), Cy represents a residue selected from the group consisting

[0051] In some embodiments of Formulas (I) and (II), Cy represents a residue selected from the group consisting of:

[0052] In some embodiments of Formulas (I) and (II), Cy represents a bicyclic heteroaryl, unsubstituted, mono- or polysubstituted, preferably selected from the group consisting of:

[0053] In some embodiments, Cy represents a residue according to general formula (F’)whereinYF1represents -N= or -CRF4=; and Y1'2represents -N= or -CRF5=; and YF3represents -N= or -CRF3=; with the proviso that at least one of YF1and Y1'2is not -CRF4= and -CRF5=, respectively;RF1, RF2, RF3, RF4, and RF5independently of one another represent -H, -CH3, -CF3,-OH, -OCH3, -OCH2CH3, -Cl, or -azetidinyl; preferably with the proviso that only one of RF1, RF2, RF3, RF4, and RF5represents a residue that isnot -H.In another embodiment, Cy represents a residue according to general formula (F)whereinYF1represents -N= or -CRF4=; and YF2represents -N= or -CRF5=; with the proviso that at least one of YF1and YF2is not -CRF4= and -CRF5=, respectively;RF1, RF2, RF3, RF4, and RF5independently of one another represent -H, -CH3, -CF3,-OH, -OCH3, -OCH2CH3, -Cl, or -azetidinyl; preferably with the proviso that only one of RF1, RF2, RF3, RF4, and RF5represents a residue that is not -H.

[0054] In some embodiments, Cy represents a residue according to general formula (G) or (H)(G) (H) wherein RG1and RH1are selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, azetidinyl, -cyclopropyl, -O-cyclopropyl, and -CHF2; or wherein RG1and RH1are selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, and azetidinyl.In other embodiments, V represents a residue according to general formula (G’) or (H’)wherein RG1and RH1are selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, azetidinyl, -cyclopropyl, -O-cyclopropyl, and -CHF2; or wherein RG1and RH1are selected from the group consisting of -H, -CH3, -CF3, -OH, -OCH3, -OCH2CH3, -Cl, and azetidinyl

[0055] In an embodiment of the indolizine derivatives according to the invention R1represents-H, -F, -Cl, -Br, -I, -CN; -C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted; -O-C1-6-alkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted;-C(=O)C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-C(=O)OC1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-C(=O)NHC1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-C(=O)N(C1-6-alkyl)2, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-S(=O)C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-S(=O)2-C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted; or3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0056] In some embodiments, R1represents -H, -F, -Cl, -Br, -I, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-alkylene-O-C1-6- alkyl, -C1-6-alkylene-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)2, -CF3, -CF2H, -CFH2, -CF2CI, -CFCI2, -C1-6- alkylene-CF3, -C1-6-alkylene-CF2H, -C1-6-alkylene-CFFF, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C1-6-alkylene- N(C1-6-alkyl)-C1-6-alkylene-CF3, -C(=O)C1-6-alkyl, -C(=O)OC1-6-alkyl, -C(=O)NH2, -C(=O)NHC1-6-alkyl, - C(=O)N(C1-6-alkyl)2, -S(=O)-C1-6-alkyl, -S(=O)2-C1-6-alkyl, -O-C1-6-alkyl, -cyclopropyl unsubstituted, cyclobutyl unsubstituted, cyclopentyl unsubstituted or cyclohexyl unsubstituted.

[0057] In some embodiments, R1represents -H, -C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl, -CH2F, -CHF2, -CF3, - cyclopentyl, unsubstituted, or -cyclopropyl. Preferably, R1represents -H, -C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl, -CH2F, -CHF2, -CF3, -cyclopentyl, or unsubstituted. In some embodiments, R1represents -CH3.

[0058] In some embodiments, R1represents -CH2F, -CHF2, -CH3, or -cyclopropyl. Preferably, R1represents - CH2F, -CHF2, or -CH3. In some embodiments, R1represents -C(=O)NH2, or -CHF2.

[0059] In some embodiments, R1represents -H, -Ci-3-alkyl, -CF3, -CF2H, -CFH2, -CF2CI, -CFCI2, -Ci-3-alkylene- CF3, -Ci-3-alkylene-CF2H, -Ci-3-alkylene-CFH2, or -cyclopropyl; preferably, R1represents -H, -Ci-3-alkyl, -CF3, - CF2H, -CFH2, -CF2CI, -CFCI2, -Ci-3-alkylene-CF3, -Ci-3-alkylene-CF2H, or -Ci-s-alkylene-CFFF; for example - CH3.

[0060] In an embodiment, R1represents methyl, ethyl, or propyl.

[0061] In an embodiment, R1represents methyl.

[0062] In an embodiment of Formulas (I) and (II), R3represents -H, -OH, -C1-6-alkyl, -C1-6-alkylene-OH, -C1-6- alkylene-O-C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)2, -CF3, - CF2H, -CFH2, -CF2CI, -CFCI2, -C1-6-alkylene-CF3, -C1-6-alkylene-CF2H, -C1-6-alkylene-CFH2, -C1-6-alkylene-NH- C1-6-alkylene-CF3, or -C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-CF3, optionally unsubstituted, monosubstituted, or poly substituted.

[0063] In some embodiments, R3represents -H, -OH, or -C1-6-alkyl, saturated, unsubstituted or monosubstituted with -OH. Preferably, R3represents -H.

[0064] In some embodiments, R3represents -H.

[0065] In some embodiments of Formulas (I) and (II), R3is connected to the N to which it is attached through a -Ci-C4-alkylene-, saturated or unsaturated, unsubstituted, monosubstituted, or poly substituted, or through a -Ci- C4-heteroalkylene-, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted. In some embodiments of the benzofuran derivative of Formula (I) or Formula (II), R3instead represents -CR10R10’R10’’(i.e., in embodiments of Formula I or Formula II where R10is specified, R3may represent -CR10R10R10”). In various embodiments, when R10, R10’, and / or R10” independently represent one or more substituents herein, one or more of R10, R10’, and R10’’ may be -H or any other substituent disclosed for R10, R10’ , and R10”.

[0066] In an embodiment of the indolizine derivatives according to the invention R10, R10’, and / or R10’’ independently represent:-H;-S(=O)C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-S(=O)2-C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0067] In some embodiments, R10, R10’, and / or R10’’ independently represent-S(=O)2C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -Cl, -C1-6-alkyl, -C1-6-alkylcnc-CF ,. -OH, =0, -OC1-6-alkyl, -C1-6-alkylene-OH, -C1-6-alkylene-O-C1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2, - NHC(=O)O-C1-6-alkyl, -N(C1-6-alkyl)C(=O)O-C1-6-alkyl, -C1-6-alkylene-NHC(=O)O-C1-6-alkyl, -C1-6-alkylene- NH2, -C1-6-alkylene-NH-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C(=O)- C1-6-alkyl, -C(=O)OH, -C(=O)O-C1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=O)NH2, -C(=O)NH(C1-6-alkyl), - C(=O)N(C1-6-alkyl)2, -S(=O)2C1-6-alkyl, -phenyl, -C1-6-alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5-14-membered heteroaryl, unsubstituted;-S(=O)2(3- 14-membered cycloalkyl), wherein said 3-14-membered cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, in each case saturated or unsaturated, unsubstituted, mono- or poly substituted with substituents independently of one another selected from the group consisting of -F, -Cl, -C1-6-alkyl, -C1-6-alkylcnc-CFi. -OH, =0, -OC1-6-alkyl, -C1-6-alkylene-OH, -C1-6- alkylene-O-C1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2, -NHC(=O)O-C1-6-alkyl, -N(C1-6-alkyl)C(=O)O-C1-6- alkyl, -C1-6-alkylene-NHC(=O)O-C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6-alkyl, -C1-6-alkylene- N(C1-6-alkyl)2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C(=0)-C1-6-alkyl, -C(=O)OH, -C(=O)O-C1-6-alkyl, - C(=O)O-C1-6-alkylene-CF3, -C(=O)NH2, -C(=O)NH(C1-6-alkyl), -C(=O)N(C1-6-alkyl)2, -S(=O)2C1-6-alkyl, - phenyl, -C1-6-alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5-14-membered heteroaryl, unsubstituted; -C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -Cl, -C1-6-alkyl, -C1-6-alkylcnc-CF,. -OH, =0, -OC1-6-alkyl, -C1-6-alkylene-OH, -C1-6-alkylene-O-C1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2, -NHC(=O)O-C1-6-alkyl, - N(C1-6-alkyl)C(=O)O-C1-6-alkyl, -C1-6-alkylene-NHC(=O)O-C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH- C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C(=0)-C1-6-alkyl, -C(=O)OH, - C(=O)O-C1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=O)NH2, -C(=O)NH(C1-6-alkyl), -C(=O)N(C1-6-alkyl)2, - S(=O)2C1-6-alkyl, -phenyl, -C1-6-alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5-14-membered heteroaryl, unsubstituted;3-14-membered cycloalkyl or -C1-6-alkylene-(3-14-membered cycloalkyl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 3-14-membered cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, in each case saturated or unsaturated, in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -Cl, -C1-6-alkyl, -C1-6-alkylcnc-CF,. -OH, =0, -OC1-6-alkyl, -C1-6- alkylene-OH, -C1-6-alkylene-O-C1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2, -NHC(=O)O-C1-6-alkyl, -N(C1-6- alkyl)C(=0)0-C1-6-alkyl, -C1-6-alkylene-NHC(=O)O-C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6- alkyl, -C1-6-alkylene-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C(=0)-C1-6-alkyl, -C(=O)OH, - C(=O)O-C1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=0)NH2, -C(=O)NH(C1-6-alkyl), -C(=O)N(C1-6-alkyl)2, - S(=O)2C1-6-alkyl, -phenyl, -C1-6-alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5-14-membered heteroaryl, unsubstituted;3-14-membered heterocycloalkyl or -C1-6-alkylene-(3-14-membered heterocycloalkyl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 3-14-membered heterocycloalkyl in each case is selected from the group consisting of azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1-dioxothiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7- azaspiro[3.5]nonane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, hexahydro-lH-pyrrolizine, hexa- hydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[l,2-a]pyrazine; in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -Cl, -C1-6-alkyl, -C1-6-alkylcnc-CF,. -OH, =0, -OC1-6-alkyl, -C1-6-alkylene-OH, -C1-6-alkylene-O- C1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2, -NHC(=O)O-C1-6-alkyl, -N(C1-6-alkyl)C(=O)O-C1-6-alkyl, -C1-6- alkylene-NHC(=0)0-C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C(=O)-C1-6-alkyl, -C(=O)OH, -C(=O)O-C1-6-alkyl, -C(=O)O-C1-6- alkylene-CF3, -C(=0)NH2, -C(=O)NH(C1-6-alkyl), -C(=O)N(C1-6-alkyl)2, -S(=O)2C1-6-alkyl, -phenyl, -C1-6- alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5-14-membered heteroaryl, unsubstituted;-phenyl unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -Cl, -CN, -C1-6-alkyl, -C1-6-alkylcnc-CF,. -OH, =0, -OC1-6-alkyl, -C1-6-alkylene-OH, -Ci- 6-alkylene-O-C1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2, -NHC(=O)O-C1-6-alkyl, -N(C1-6-alkyl)C(=0)0-Ci-e-alkyl, -C1-6-alkylene-NHC(=O)O-C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6-alkyl, -C1-6-alkylene- N(C1-6-alkyl)2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C(=0)-C1-6-alkyl, -C(=O)OH, -C(=O)O-C1-6-alkyl, - C(=O)O-C1-6-alkylene-CF3, -C(=O)NH2, -C(=O)NH(Ci -e-alkyl), -C(=O)N(C1-6-alkyl)2, -S(=O)2C1-6-alkyl, - phenyl, -C1-6-alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5- 14-membered heteroaryl, unsubstituted;5-14-membered heteroaryl or -C1-6-alkylene-(5-14-membered heteroaryl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 5-14-membered heteroaryl in each case is selected from the group consisting of benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furane, furazane, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [l,2,4]triazolo[4,3-a]pyrimidine; in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -Cl, -CN, -C1-6-alkyl, -C1-6-alkylcnc-CF ,. - OH, =0, -OC1-6-alkyl, -C1-6-alkylene-OH, -C1-6-alkylene-O-Ci -e-alkyl, -NH2, -NHCi -e-alkyl, -N(C1-6-alkyl)2, - NHC(=O)O-Ci -e-alkyl, -N(C1-6-alkyl)C(=O)O-C1-6-alkyl, -C1-6-alkylene-NHC(=O)O-Ci -e-alkyl, -C1-6-alkylene- NH2, -CI -e-alkylene-NH -CI -e-alkyl, -C1-6-alkylene-N(C1-6-alkyl)2, -C1-6-alkylcnc-NH-C1-6-alkylcnc-CFi. -C(=0)- C1-6-alkyl, -C(=O)OH, -C(=O)O-Ci -e-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=O)NH2, -C(=O)NH(C1-6-alkyl), - C(=O)N(C1-6-alkyl)2, -S(=O)2Ci -e-alkyl, -phenyl, -C1-6-alkylene-phenyl, 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted; and 5-14-membered heteroaryl, unsubstituted.

[0068] In some embodiments, R10, R10’, and / or R10’’ independently represent-H;-S(=O)2C1-6-alkyl, saturated, unsubstituted, monosubstituted or polysubstituted with -F;-S(=O)2(3- 14-membered cycloalkyl), saturated, unsubstituted; -C1-6-alkyl, saturated, unsubstituted, monosubstituted or disubstituted with substituents independently of one another selected from the group consisting of -OH, =0, -NH2, -NHCi -e-alkyl, -N(C1-6-alkyl)2, -OC1-6-alkyl, -C1-6- alkylene-NH2, -C1-6-alkylene-NH-Ci -e-alkyl, -C(=O)NH2, -C(=O)-NH-Ci-3-alkyl, -C(=O)-N(Ci-3-alkyl)2, -phenyl unsubstituted;3-14-membered cycloalkyl or -C1-6-alkylene-(3-14-membered cycloalkyl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 3-14-membered cycloalkyl is saturated, unsubstituted, monosubstituted or disubstituted with substituents independently of one another selected from the group consisting of -C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C1-6-alkylene-OH, -C1-6-alkylene- NHC(=O)O-Ci -e-alkyl, -OH, -OC1-6-alkyl, -NH2, -N(C1-6-alkyl)2, -NHC(=O)O-C1-6-alkyl;3-14-membered heterocycloalkyl or -C1-6-alkylene-(3-14-membered heterocycloalkyl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 3-14-membered heterocycloalkyl in each case is selected from azetane, 1,4-oxazepane, pyrrolidine, piperidine, azepane, diazepane, tetrahydrofuran, tetrahydropyran, oxetane, morpholine, piperazine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, octahydro- pyrrolo[l,2-a]pyrazine, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, quinuclidine, hexahydro-lH- pyrrolizine, 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 1,1 -dioxothiacyclohexane, in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected fromthe group consisting of -F, -OH, =0, -C1-6-alkyl, -C1-6-alkylcnc-CF,. -C1-6-alkylene-OH, -C1-6-alkylene-O-C1-6- alkyl, -NH2, -N(C1-6-alkyl)2, -C1-6-alkylene-NH2, -C1-6-alkylene-N(C1-6-alkyl)2, -C(=0)-C1-6-alkyl, -C(=O)OH, - C(=0)0-C1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=0)NH2, -C(=0)NH(C1-6-alkyl), -S(=O)2C1-6-alkyl, oxetanyl, pyrimidinyl, -C1-6-alkylene-phenyl;-phenyl unsubstituted;5-14-membered heteroaryl or -C1-6-alkylene-(5-14-membered heteroaryl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 5-14-membered heteroaryl in each case is selected from the group consisting of pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [l,2,4]triazolo[4,3-a]pyrimidine, in each case unsubstituted, monosubstituted or disubstituted with substituents independently of one another selected from the group consisting of -C1-6-alkyl, -OH.

[0069] In some embodiments, R3, with the nitrogen atom to which it is attached (with removal of the -H on the nitrogen atom), forms a residue selected from the group consisting of:

[0070] In other embodiments, R3represents -H.

[0071] In some embodiments, R3represents a residue selected from the group consisting of:

[0072] In further embodiments, R3represents a residue -CR'R"-(CH2)m-OH, wherein m is an integer of from 1 to 6, preferably from 1 to 3; and wherein R' and R" independently of one another represent -H, -Ci-3-alkyl, -CF3,-CFzH, -CFH2, -Ci-3-alkylene-CF3, -Ci-3-alkylene-CF2H, -Ci-3-alkylene-CFH2, -Ci-3-alkylene-O-Ci-3-alkyl, -C1-3- alkylene-OH, -C(=0)-NH2, or C(=O)-NH-Ci-3-alkyl; preferably -H, -CH3, -Ci-3-alkylene-OH, -C(=0)-NH2, or C(=O)-NH-Ci-3-alkyl. In an embodiment, at least R' or R" does not represent -H. In alternative embodiments, neither R' nor R" represents -H.

[0073] In further embodiments, R10, R10’, and / or R10’’ independently represent a 3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0074] In further embodiments, R10, R10’, and / or R10’’ independently represent a 3 -membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted; or a 3 -membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted. In some embodiments, R10, R10’, and / or R10” independently represent a residue selected from the group consisting of:

[0075] In some embodiments, R3, R10, R10’, and R10’’ independently represent a 4-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3-14-membered heterocycloalkyl (in some cases a 4-membered heterocycloalkyl), saturated or unsaturated, unsubstituted, mono- or polysubstituted. In someembodiments, R3, R10, R10’, and R10’’ independently represent a residue selected from the group consisting of:

[0076] In some embodiments, R3,R10, R10’, and / or R10” independently represent a residue according to general formula (A),wherein mAis 0 or 1;YAis selected from -O-, -NRA6- and -CRA7RA8-; andRA1, RAIRA3R \4 RASRAS jndependen[|v ofoneanother represent -H, F, -Ci-3-alkyl, -C1-3- alkylene-OH, -Ci-3-alkylene-NH2, -Ci-3-alkylene-NH(Ci-3-alkyl), -Ci-3-alkylene-N(Ci-3-alkyl)2, -Ci-3-alkylene- NH(Ci-3-alkylene-CF3), -Ci-3-alkylene-C(=O)NH2, -Ci-3-alkylene-NH-C(=O)OCi-4-alkyl, -C(=O)NH2, -C(=O)- NH-Ci-3-alkyl, -C(=O)-N(Ci-3-alkyl)2, -3-oxetanyl, or -CHF2; preferably, RA1, RA2. RAJ. RA4, RAS, RA6, RA7, and RA8independently of one another represent -H, F, -Ci-3-alkyl, -Ci-3-alkylene-OH, -Ci-3-alkylene-NH2, -C1-3- alkylene-NH(Ci-3-alkyl), -Ci-3-alkylene-N(Ci-3-alkyl)2, -Ci-3-alkylene-NH(Ci-3-alkylene-CF3), -Ci-3-alkylene- C(=O)NH2, -Ci-3-alkylene-NH-C(=O)OCi-4-alkyl, -C(=O)NH2, -C(=O)-NH-Ci-3-alkyl, -C(=O)-N(Ci-3-alkyl)2, or -3-oxetanyl; or RA7and RA8together with the carbon atom to which they are attached form a ring and represent - CH2OCH2-, -CH2OCH2CH2- or -CH2CH2OCH2CH2-, -CH2NHCH2-, -CH2NHCH2CH2- or -CH2CH2NHCH2CH2-.

[0077] In some embodiments, R3R10, R10’, and / or R10” independently represent a residue according to general formula (A) as defined above, wherein mAis 0 or 1;YAis selected from -O- and -CRA7RA8-; andRA1, RA2. RA3, RA4, RAS, RA7, and RA8independently of one another represent -H, -Ci-3-alkylene-OH, -C1-3- alkylene-N(Ci-3-alkyl)2, -C(=O)NH2, or -CHF2; preferably RA1, RA2, RA3, RA4, RAS, RA7, and RA8independently of one another represent -H, -Ci-3-alkylene-OH, -Ci-3-alkylene-N(Ci-3-alkyl)2, or -C(=O)NH2; preferably with the proviso that only one of RA1, RA2. RAJ. RA4, RAS, RA7, and RA8represents a residue that is not -H.

[0078] In some embodiments, R3orR10, R10’, and / or R10” independently represent a residue according to general formula (A) as defined above, wherein mAis 0 or 1;YAis selected from -O- and -CRA7RA8-; andRA1represents -Ci-3-alkylene-OH, -Ci-3-alkylene-N(Ci-3-alkyl)2, -C(=O)NH2, or -CHF2; preferably RA1represents -Ci-3-alkylene-OH, -Ci-3-alkylene-N(Ci-3-alkyl)2, or -C(=O)NH2; andRA2, RA3, RA4, RAS, RA7, and RA8represent -H.

[0079] In some embodiments, R3, R10, R10’, and / or R10’’ independently represent a 3-14-membered cycloalkyl (preferably a 5-membered cycloalkyl), saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3- 14-membered heterocycloalkyl (in some cases, a 5-membered heterocycloalkyl), saturated or unsaturated, unsubstituted, mono- or poly substituted; or a 5-14-membered heteroaryl (in some cases, a 5-membered heteroaryl), unsubstituted, mono- or polysubstituted. In preferred embodiments, R3,R10, R10’, and / or R10” independently represent a residue selected from the group consisting of:

[0080] In some embodiments, R3, R10, R10’, and / or R10” independently represent a residue according to general formula (B),whereinYBis selected from -O-, -NRB8- and -CRB9RB10-; andRB1, RBI RBJ RIM, RBS RB6 RB7 RBS RB9anj j^Bio independentiy of one another represent -H, -F, -OH, -C1-3- alkyl, -Ci-3-alkylene-OH, -Ci-3-alkylene-O-Ci-3-alkyl, -Ci-3-alkylene-CF3, -Ci-s-alkylene-COzH, -Ci-3-alkylene- C(=O)O-Ci-3-alkyl, -C(=O)NH2, -C(=O)NH-Ci-3-alkyl, or -C(=O)N(Ci-3-alkyl)2; orRB2and RB3together represent =0; or RB4and RBStogether represent =0.

[0081] In some embodiments, R3or R10, R10’, and / or R10” independently represent a residue according to general formula (B) as defined above, whereinYBis selected from -O- and -NRB8-; andRB1, RB2, RB3, RB4, RBS, RB6, RB7, RB8independently of one another represent -H, -F, -Ci-3-alkyl, -Ci-3-alkylene- OH, -Ci-3-alkylene-CF3 or -C(=O)NH2; or RB2and RB3together represent =0; or RB4and RBStogether represent =0; preferably with the proviso that only 1, 2 or 3 of RA1, RA2, RA3, RA4, RAS, RA7, and RA8represent a residue that is not -H; preferably with the proviso that at least one of RA1, RA2, RA3, RA4, RAS, RA7, and RA8represent a residue that is not -H.

[0082] In some embodiments, R3, R10, R10’, and / or R10’’ independently represent a 3-14-membered cycloalkyl (in some cases, a 6-membered cycloalkyl), saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3-14-membered heterocycloalkyl (in some cases, a 6-membered heterocycloalkyl), saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 6-14-membered aryl (in some cases, 6-membered aryl), unsubstituted, mono- or poly substituted; or a 5-14-membered heteroaryl (in some cases, a 6-membered heteroaryl), unsubstituted, mono- or polysubstituted. In some embodiments, R3, R10, R10’, and / or R10” independently represent a residue selected from the group consisting of:

[0083] In some embodiments, R3, R10, R10’, and / or R10” independently represent a residue according to general formula (C),alkylene-, -C(=0)NH2, -C(=0)NH-Ci-3-alkyl, or -C(=O)N(Ci-3-alkyl)2: or RC2and RC3together represent =0; or RC4and Rcstogether represent =0; or RC9and RC1° together represent =0; or RC11and RC12together represent =0.

[0084] In some embodiments, R3, R10, R10’, and / or R10” independently represent a residue according to general formula (C) as defined above, whereinYC1is selected from -O- or -NRC8- and YC2represents -CRcllRcl2-; or YC1represents -CRC9RC1°- and YC2is selected from -0-, and -NRC8-;RC1, RC2, RC3, RC4, Rcs, RC6, RC7, RC8,RC9, Rcl°, Rcl1and RC12independently of one another represent -H, -F , -Ci-3-alkyl, -Ci-3-alkylene-OH, or -C(=0)NH2; preferably with the proviso that only 1, 2 or 3 of RC1, RC2, RC3, RC4, RC5, RC6, RC7, RC8,RC9, RC1°, Rcl1and RC12represent a residue that is not -H; preferably with the proviso that at least one of RC1, RC2, RC3, RC4, Rcs, RC6, RC7, RC8,RC9, RC1°, RC11and RC12represent a residue that is not -H.

[0085] In some embodiments, R3, R10, R10’, and / or R10” independently represent a 7-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 7-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted. In some embodiments, R3,R10, R10’, and / or R10” independently represent the residue:

[0086] In some embodiments, R3, R10, R10’, and / or R10’’ independently represent a 3-14-membered cycloalkyl (in some cases, a 3, 4, 5 or 6-membered cycloalkyl), saturated or unsaturated, unsubstituted, mono- or poly substituted; wherein said 3-14-membered cycloalkyl is connected through -Ci -Ce-alkylene-, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 3-14-membered heterocycloalkyl (in some cases, a 4, 5 or 6-membered heterocycloalkyl), saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is connected through -Ci -Ce-alkylene-, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 6-14-membered aryl (in some cases, a 6-membered aryl), unsubstituted, mono- or poly substituted; wherein said 6-14-membered aryl is connected through -Ci -Ce-alkylene-, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl (in some cases, a 5 or 6-membered heteroaryl), unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is connected through -C1-C6-alkylene-, saturated or unsaturated, unsubstituted, mono- or poly substituted. In preferred embodiments, R3, R10, R10’, and / or R10” independently represents a residue selected from the group consisting of:

[0087] In some embodiments, R3, R10, R10’, and / or R10’’ independently represent a 5-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 5-membered heterocycloalkyl is connected through -C1-C6-alkylene-, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5- membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-membered heteroaryl is connected through -C1-C6-alkylene-, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0088] In some embodiments, R3, R10, R10’, and / or R10” independently represent a residue selected from the group consisting of:

[0089] In some embodiments, R3, R10, R10’, and / or R10’’ independently represent(i) a residue -CR'R"-(CH2)m-OH, wherein m is an integer of from 1 to 6, preferably from 1 to 3; and wherein R' and R" independently of one another represent -H, -Ci-3-alkyl, -CF3, -CF2H, -CFH2, -Ci-3-alkylene-CF3, -Ci-3-alkylene-CF2H, -Ci-3-alkylene-CFH2, -Ci-3-alkylene-O-Ci-3-alkyl, or -Ci-3-alkylene-OH; preferably -H, -CH3, or -Ci-3-alkylene-OH. In an embodiment, at least R' or R" does not represent -H. In an embodiment,neither R' nor R" represents -H; or(ii) a residue according to general formula (D),wherein mDand nDindependently of one another are 0, 1, 2, or 3; preferably with the proviso that mD+ nD< 3;YD1is selected from -O-, -S(=O)2-, -S(=O)(=NH)-, -NRD8- and -CRD9RD10- and YD2represents -CRD11RD12- ; or YD1is selected from -O-, -S(=O)2-, -NRD8- and -CRD9RD1°- and YD2represents -CRD11RD12-; or YD1represents -CRD9RD1°- and YD2is selected from -O-, -S(=O)2-, and -NRD8-;independentiy of one another represent -H, -F , -OH, -Ci-3-alkylene-OH, -C(=O)NH2, -Ci-3-alkylene-C(O)NH2, -C(=O)O-Ci-3-alkyl, -NH2, -C1-3- alkylene-NH2, -NH(Ci-3-alkyl), -N(Ci-3-alkyl)2, -NH(Ci-3-alkylene-CF3), -Ci-3-alkylene-OCH3, -Ci-3-alkyl, - Ci-s-alkylene-CFs: or RD2and RD3together represent =0; or RD4and RDStogether represent =0; or RD9and RD1° together represent =0; or RD11and RD12together represent =0; preferably wherein mDand nDindependently of one another are 0, 1, 2 or 3; preferably with the proviso that mD+ nD< 3;YD1is selected from -0-, -NRD8- and -CRD9RD1°- and YD2represents -CRD11RD12-; or YD1represents - CRD9RD1°- and YD2is selected from -O- and -NRD8-;RD1, RD2, RD3, RD4, RDS, RD6, RD7, RD8,RD9, RD1°, RD11and RD12independently of one another represent -H, -F , -OH, -Ci-3-alkylene-OH, -C(=O)NH2, -CH2NH2, -CH2N(CH3)2, -NHCH2CF3, -CH3, or -CH2CF3: or RD2and RD3together represent =0; or RD4and RDStogether represent =0; or RD9and RD1° together represent =0; or RD11and RD12together represent =0; preferably with the proviso that only 1, 2 or 3 of RD1, RD2, RD3, RD4, RDS, RD6, RD7, RD8,RD9, RD1°, RD11and RD12represent a residue that is not -H; preferably with the proviso that at least one of RD1, RD2, RD3, RD4, RDS, RD6, RD7, RD8,RD9, RD1°, RD11and RD12represent a residue that is not -H.

[0090] In some embodiments, R3, R10, R10’, and / or R10” independently represent a residue selected from the group consisting of:

[0091] In some embodiments of the indolizine derivative according to the invention R5and R5' independently of one another represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14- membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

[0092] In some embodiments, R5and R5' independently of one another represent -H, -C1-C6-alkyl, or -C1-C6- alkylene-N(Ci -Ce-alkyl)2.

[0093] In some embodiments of the indolizine derivatives according to the invention, at least one of R5and R5' is not -H.

[0094] In some embodiments of the indolizine derivatives according to the invention, R5and R5' are both -H.

[0095] In some embodiments, R5represents -H and R5' represents a residue selected from the group consisting of -H, -Ci-3-alkyl, -CF3, -CF2H, -CFH2, -Ci-3-alkylene-CF3, -Ci-3-alkylene-CF2H, -Ci-3-alkylene-CFH2, and -C1-3- alkylene-OH; preferably -H or Ci-3-alkyl.

[0096] In some embodiments of the indolizine derivatives according to the invention R6, R7and R8independently of one another represent-H;-F, -Cl, -Br, -I, -OH, -SH, -SFs, -CN, -NO2, -C(=O)OH, -NH2; -C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-O-C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-NHC1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-N(C1-6-alkyl)2, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-C(=O)OC1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-OC(=O)C1-6-alkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;-C1-6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted.

[0097] In some embodiments, R6, R7and R8independently of one another represent-H, -F, -Cl, -Br, -I, -OH, -SH, -SFs, -CN, -NO2, -C(=O)OH, -NH2,-C1-6-alkyl, -CF3, -CHF2, -CH2F,-O-C1-6-alkyl, -OCF3, -OCHF2, -OCH2F,-NHC1-6-alkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, - C(=O)OH, -NH2, and -C(=O)NH2;-N(C1-6-alkyl)2 unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, - C(=O)OH, -NH2, and -C(=O)NH2;-C(=0)0C1-6-alkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2;-0C(=0)C1-6-alkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2; or-C1-6-heteroalkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, - C(=O)OH, -NH2, and -C(=O)NH2.

[0098] In some embodiments, R6, R7and R8independently of one another represents a residue selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, Ci-3-alkyl, -CF3, -CF2H, and -CFH2; preferably -H or -F.

[0099] In some embodiments of the indolizine derivatives according to the invention R6represents -H, -F, -Cl, - CN, or -C1-C6-alkyl.

[0100] In some embodiments of the indolizine derivatives according to the invention, R6does not represent -H.

[0101] In some embodiments, R6represents a residue selected from the group consisting of -H, -F, -Cl, -CN or - CH3; preferably -H, -F, -CN or -CH3

[0102] In some embodiments of the indolizine derivatives according to the invention R7represents -H, -F, -Cl, - CN, or -C1-C6-alkyl.

[0103] In some embodiments of the indolizine derivatives according to the invention R7does not represent -H.

[0104] In some embodiments of the indolizine derivatives according to the invention R8represents -H, -F, -Cl, - CN, or -C1-C6-alkyl.

[0105] In some embodiments of the indolizine derivatives according to the invention R8does not represent -H.

[0106] In some embodiments, R8represents a residue selected from the group consisting of -H, -F, -Cl, -CN or CH3; preferably -F

[0107] In some embodiments of the indolizine derivatives according to the invention(i) R6, R7and R8each represent -H; or(ii) two of R6, R7and R8represent -H and the other of R6, R7and R8represents -F, -Cl, -CN, or -CH3; or(iii) one of R6, R7and R8represents -H and the other of R6, R7and R8independently of one another represent - F, -Cl, -CN, or -CH3.

[0108] In exemplary embodiments of the invention, the indolizine derivative is selected from the group consisting of:Cpd 001 - N-((S)-l-amino-3 -hydroxy -2 -methyl- l-oxopropan-2-y l)-2-methy l-6-(trans-2- phenylcyclopropyl)indolizine-3-carboxamide;Cpd 002 - N-((S)-l-amino-3 -hydroxy -2 -methyl- l-oxopropan-2-y l)-2-methy l-6-(cis-2- phenylcyclopropyl)indolizine-3-carboxamide;Cpd 003 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-phenoxyindolizine-3-carboxamide;Cpd 004 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-yl)-2-methyl-6-phenoxyindolizine-3 -carboxamide;Cpd 005 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(o-tolyloxy)indolizine-3-carboxamide;Cpd 006 - N-(4,4-difluoro- 1 -hydroxy -2 -methylbutan-2-yl)-2-methyl-6-(o-tolyloxy)indolizine-3 -carboxamide;Cpd 007 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(m-tolyloxy)indolizine-3-carboxamide;Cpd 008 - N-(4,4-difluoro-l-hydroxy-2-methylbutan-2-yl)-2-methyl-6-(m-tolyloxy)indolizine-3-carboxamide;Cpd 009 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(p-tolyloxy)indolizine-3-carboxamide;Cpd 010 - N-(4,4-difluoro- 1 -hydroxy -2 -methylbutan-2-yl)-2-methyl-6-(p-tolyloxy)indolizine-3 -carboxamide;Cpd Oil - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-6-(2-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 012 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-y l)-6-(2 -metho xypheno xy)-2-methylindolizine-3 - carboxamide;Cpd 013 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-6-(3-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 014 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-y l)-6-(3 -metho xypheno xy)-2-methylindolizine-3 - carboxamide;Cpd 015 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-6-(4-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 016 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-y l)-6-(4-metho xypheno xy)-2-methylindolizine-3 - carboxamide;Cpd 017 - (S)-N-(l-amino-3 -hydroxy -2 -methyl- l-oxopropan-2-y l)-2-methy l-6-phenoxyindolizine-3- carboxamide;Cpd 018 - 6-(2-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 019 - 6-(3-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 020 - 6-(4-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 021 - 6-benzyl-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 022 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(phenylthio)indolizine-3-carboxamide;Cpd 023 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-((lS,2S)-2-(pyridin-2- yl)cyclopropyl)indolizine-3-carboxamide;Cpd 024 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(phenylsulfinyl)indolizine-3-carboxamide andCpd 025 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(phenylsulfonyl)indolizine-3-carboxamide, and physiologically acceptable salts of any of these indolizine derivatives. Generally, “Cpd 001” may be alternatively referred to as “Cpd 1” or “# 1”, “Cpd 002” may be referred to as “Cpd 2” or “# 2”, and so on.

[0109] The indolizine derivatives according to the invention is for use in the treatment of pain which is preferably selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is postoperative pain. The indolizine derivatives according to the invention are also for use in the treatment of epilepsy.

[0110] In some embodiments, the indolizine derivatives are selected from the group consisting of compounds001 - 025, including stereoisomers and pharmaceutically acceptable salts thereof.

[0111] All definitions, embodiments and meanings of X, Cy, Rx, Rz, RY, Rz, R1, R2, R3, R4, R5, R5', R6, R7, R8, R9(including R9’ and R9”), and R10(including R10’ and R10”) including the disclosed substituents also analogously apply the indolizine derivatives according to the invention, which are not necessarily restricted for use in the treatment of pain. Moreover, the meanings of X, Cy, Rx, Rz, RY,RZ, R1, R3, R4, R4' R5, R5, R6, R7, R8, R9, and R10are also expressly considered to incorporate any exemplified groups in the exemplified compounds at these positions according to Formula I and Formula II. Thus, this aspect of the invention relates to the indolizine derivatives as such, compositions comprising the indolizine derivatives, medicaments comprising the indolizine derivatives, and the indolizine derivatives for use in the prevention and / or treatment of TRPM3 mediated disorders such as pain and / or inflammatory hypersensitivity and / or epilepsy and / or epileptic seizures; and / or for counteracting pain and / or inflammatory hypersensitivity and / or epilepsy. Preferably, the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is post-operative pain or migraine pain.

[0112] In some embodiments of the invention, the indolizine derivative is selected from the group consisting of cpd 001 to cpd 025 as mentioned above and the physiologically acceptable salts thereof.

[0113] Another aspect of the invention relates to a pharmaceutical composition or a medicament comprising a compound according to the invention as described above.

[0114] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments. Also, embodiments described for an aspect of the invention may be used for another aspect of the invention and can be combined. Where an indefinite or definite article is used when referring to a singular noun e.g., "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

[0115] Similarly, it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.

[0116] In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.

[0117] The term “leaving group” or “LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, Inflate).

[0118] The term "protecting group" refers to a moiety 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 a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drugsubstance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See: "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0119] Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.

[0120] The term “heteroatom(s)” as used herein means an atom selected from nitrogen, which can be quatemized or present as an oxide; oxygen; and sulfur, including oxidized sulfurs including, sulfoxide and sulfone, and in some cases sulfonate. In certain instances, the compounds and / or synthetic intermediates may include heteroatoms such as boron, phosphorous (including phosphorates), and silicon.

[0121] The term “alkyl, saturated or unsaturated” as used herein encompasses saturated alkyl as well as unsaturated alkyl such as alkenyl, alkynyl, and the like. The term “alkyl” as used herein means normal, secondary, or tertiary, linear or branched hydrocarbon with no site of unsaturation. However, it is generally contemplated that in various embodiments reciting “alkyl,” further corresponding embodiments with “alkyl, saturated or unsaturated” are contemplated, and vice versa. Examples are methyl, ethyl, 1 -propyl (n-propyl), 2-propyl (iPr), 1 -butyl, 2- methyl-l-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-l -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. The term “alkenyl” as used herein means normal, secondary or tertiary, linear or branched hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely 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 the cis or trans configuration. The term “alkynyl” as used herein means normal, secondary, tertiary, linear or branched hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to: ethynyl (-C=CH). and 1-propynyl (propargyl, -CH2CACH).

[0122] The term “alkylene, saturated or unsaturated” as used herein encompasses saturated alkylene as well as unsaturated alkylene such as alkenylene, alkynylene, alkenynylene and the like. The term "alkylene" as used herein means saturated, linear or branched chain hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typicalalkylene radicals include, but are not limited to: methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (- CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like. The term "alkenylene" as used herein means linear or branched chain hydrocarbon radical with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. The term "alkynylene" as used herein means linear or branched chain hydrocarbon radical with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

[0123] The term “heteroalkyl, saturated or unsaturated” as used herein encompasses saturated heteroalkyl as well as unsaturated heteroalkyl such as heteroalkenyl, heteroalky nyl, heteroalkenynyl and the like. The term “heteroalkyl” as used herein means linear or branched chain alkyl wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by a heteroatom, i.e., an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. This means that one or more -CH3 of said alkyl can be replaced by -NH2 and / or that one or more -CH2- of said alkyl can be replaced by -NH-, -O- or -S-. The S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfoxides and sulfones, respectively. Furthermore, the heteroalkyl groups in the indolizine derivatives of the invention can contain an oxo or thio group at any carbon or heteroatom that will result in a stable compound. Exemplary heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers (such as for example -methoxy, -ethoxy, -butoxy ... ), primary, secondary, and tertiary alkyl amines, amides, ketones, esters, alkyl sulfides, and alkyl sulfones. The term “heteroalkenyl” means linear or branched chain alkenyl wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The term heteroalkenyl thus comprises imines, -O-alkenyl, -NH-alkenyl, - N(alkenyl)2, -N(alkyl)(alkenyl), and -S-alkenyl. The term “heteroalkynyl” as used herein means linear or branched chain alkynyl wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The term heteroalkynyl thus comprises -cyano, -O-alkynyl, -NH-alkynyl, -N(alkynyl)2, -N(alkyl)(alkynyl), - N(alkenyl)(alkynyl), and -S-alkynyl.

[0124] The term “heteroalkylene, saturated or unsaturated” as used herein encompasses saturated heteroalkylene as well as unsaturated heteroalkylene such as heteroalkenylene, heteroalkynylene, heteroalkenynylene and the like. The term “heteroalkylene” as used herein means linear or branched chain alkylene wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by a heteroatom, i.e., an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The term “heteroalkenylene” as used herein means linear or branched chain alkenylene wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The term “heteroalkynylene” as used herein means linear or branched chain alkynylene wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms.

[0125] The term “cycloalkyl, saturated or unsaturated” as used herein encompasses saturated cycloalkyl as well as unsaturated cycloalkyl such as cycloalkenyl, cycloalkynyl and the like. The term “cycloalkyl” as used herein and unless otherwise stated means a saturated cyclic hydrocarbon radical, such as for instance cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, fenchyl, decalinyl, adamantyl and the like. The term “cycloalkenyl” as used herein means a non-aromatic cyclic hydrocarbon radical with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to cyclopentenyl and cyclohexenyl. The double bond may be in the cis or trans configuration. The term “cycloalkynyl” as used herein means a non-aromatic cyclic hydrocarbon radical with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple. An example is cyclohept- 1-yne. Fused (two shared ring atoms) and spiro (one shared ring atom) systems of two cycloalkyl rings are contemplated under the term “cycloalkyl.” Fused systems of a cycloalkyl ring with a heterocycloalkyl ring are considered as heterocycloalkyl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0126] The term “heterocycloalkyl, saturated or unsaturated” as used herein encompasses saturated heterocycloalkyl as well as unsaturated non-aromatic heterocycloalkyl including at least one heteroatom, i.e., an N, O, or S as ring member. The term “heterocycloalkyl” as used herein and unless otherwise stated means “cycloalkyl” wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The term “heterocycloalkenyl” as used herein and unless otherwise stated means “cycloalkenyl” wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The term “heterocycloalkynyl” as used herein and unless otherwise stated means “cycloalkynyl” wherein one or more carbon atoms (usually 1, 2 or 3) are replaced by an oxygen, nitrogen or sulfur atom, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. Examples of saturated and unsaturated heterocycloalkyl include but are not limited to azepane, 1,4-oxazepane, azetane, azetidine, aziridine, azocane, diazepane, dioxane, dioxolane, dithiane, dithiolane, imidazolidine, isothiazolidine, isoxalidine, morpholine, oxazolidine, oxepane, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiazolidine, thietane, thiirane, thiolane, thiomorpholine, indoline, dihydrobenzofuran, dihydrobenzothiophene, 1,1 -dioxothiacyclohexane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 8- azabicyclo[3.2. l]octane, 9-azabicyclo[3.3. l]nonane, hexahydro- IH-pyrrolizine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, and octahydropyrrolo[l,2-a]pyrazine. Further heterocycloalkyls in the meaning of the invention are described in Paquette, Leo A. "Principles of Modem Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, AlanR., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566. When the heterocycloalkyl contains no nitrogen as ring member, it is typically bonded through carbon. When the heterocycloalkyl contains nitrogen as ring member, it may be bonded through nitrogen or carbon. Fused systems of heterocycloalkyl ring with a cycloalkyl ring are considered as heterocycloalkyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycloalkyl ring with an aryl ring are considered as heterocycloalkyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of thering that is bound to the core structure.

[0127] The term “aryl” as used herein means an aromatic hydrocarbon. Typical aryl groups include, but are not limited to 1 ring (such as phenyl or others), or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. Fused systems of an aryl ring with a cycloalkyl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycloalkyl ring are considered as heterocycloalkyl irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofuran, dihydrobenzothiophene and the like are considered as heterocycloalkyl according to the invention. Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0128] The term “heteroaryl” as used herein means an aromatic ring system including at least one heteroatom, i.e., N, O, or S as ring member of the aromatic ring system. Examples of heteroaryl include but are not limited to benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furane, furazane, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [l,2,4]triazolo[4,3- a]pyrimidine.

[0129] By further way of example, carbon bonded heterocyclic rings are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

[0130] Carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2- pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2- pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or B-carboline. Nitrogen bonded heterocycles include 1- aziridyl, 1-azetedyl, 1 -pyrrolyl, 1 -imidazolyl, 1-pyrazolyl, and 1-piperidinyl. Further heteroaryls in the meaning of the invention are described in Paquette, Leo A. “Principles of Modem Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0131] As used herein with respect to a substituting group, and unless otherwise stated, the terms “monosubstituted”, “disubstituted”, “trisubstituted”, “polysubstituted” and the like means chemical structures defined herein, wherein the respective moiety is substituted with one or more substituents, meaning that one or more hydrogen atoms of said moiety are each independently replaced with a substituent. For example, -C1-6-alkylthat may be polysubstituted with -F includes -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, and the like. Likewise, -Ci- e-alkyl that may be polysubstituted with substituents independently of one another selected from -F and -Cl includes -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2CI, -CHCI2, -CCI3, -CH2CCI3, CCI2CCI3, -CHC1F, -CCIF2, -CCI2CF3, -CF2CCI3, -CCIFCCI2F, and the like. Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.

[0132] In some embodiments, compounds are shown with wedge stereochemical bonds. For example, the wedge stereochemical bonds in cpd 1 (with one wedge pointing out of the plane and the other pointing into the plane) represent a trans configuration, and the wedge stereochemical bonds in cpd 2 (both wedges pointing out of the plane) represent a cis configuration. Neither trans nor cis configuration depicts absolute stereochemistry at the ring junction stereogenic centers, but are inclusive of all possible absolute stereochemistries at the bonded chiral center(s). For example, cpd 1 as depicted in Table 1 includes both the (R,R) and (S,S) absolute configurations of the chiral centers on the cyclopropyl group of the trans stereoisomer. Likewise, cpd 2 as depicted in Table 1 includes both the (S,R) and (R,S) absolute configurations of the chiral centers on the cyclopropyl group of the cis stereoisomer.

[0133] As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this invention with a suitable inorganic solvent (e.g., hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.

[0134] The term “subject” as used herein, refers to an animal including humans, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0135] The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated.

[0136] The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0137] The term “antagonist” or “inhibitor” as used herein refers to a compound capable of producing, depending on the circumstance, a functional antagonism of the TRPM3 ion channel, including competitive antagonists, noncompetitive antagonists, desensitizing agonists, and partial agonists. In general, “antagonists” and “inhibitors” can be understood to modulate TRPM3.

[0138] For purposes of the invention, the term “TRPM3 -modulated” is used to refer to the condition of being affected by the modulation of the TRPM3 ion channel, including the state of being mediated by the TRPM3 ion channel.

[0139] The term “TRPM3 mediated disorder” as used herein refers to disorders or diseases for which the use of an antagonist or modulator of TRPM3 would prevent, treat, (partially) alleviate or improve the symptoms and consist of pain and inflammatory hypersensitivity condition and epilepsy. According to the International Association for the Study of Pain and for the purpose of the 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 disorder is pain which is preferably selected from nociceptive pain, inflammatory pain, and neuropathic pain. More preferably, the pain is post-operative pain or migraine pain. For the purpose of theinvention, the term “inflammatory hypersensitivity” is used to refer to a condition that is characterized by one or more hallmarks of inflammation, including edema, erythema, hyperthermia and pain, and / or by an exaggerated physiologic or pathophysiologic response to one or more than one type of stimulation, including thermal, mechanical and / or chemical stimulation.

[0140] The indolizine derivatives of the invention have been shown to be or are understood to be antagonists or modulators of TRPM3 and the invention therefore provides the compounds as such, the compounds for use as a medicine, more specifically for use as a medicine in the prevention or treatment of TRPM3 mediated disorders in a subject with a therapeutically effective amount of an indolizine derivative of the invention.

[0141] In an embodiment of the invention, the indolizine derivative of the invention is the sole pharmacologically active compound to be administered for therapy. In another embodiment of the invention, the indolizine derivative of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of TRPM3 mediated disorders. The invention therefore also relates to the use of a composition comprising:- one or more compounds of the formulae and embodiments herein, and- one or more further therapeutic or preventive agents that are used for the prevention or treatment of TRPM3 mediated disorders as biologically active agents in the form of a combined preparation for simultaneous, separate or sequential use.

[0142] The pharmaceutical composition or combined preparation according to this invention may contain indolizine derivatives of the invention over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the content of the indolizine derivatives of the invention of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.

[0143] In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g., one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.

[0144] Those of skill in the art will also recognize that the indolizine derivatives of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state - any and all protonated forms of the compounds are intended to fall within the scope of the invention.

[0145] The terms “pharmaceutically acceptable salts” or “physiologically acceptable salts” as used herein means the therapeutically active non-toxic salt forms which the compounds of formulae herein are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca2+and Mg2+. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The indolizinederivatives of the invention may bear multiple positive or negative charges. The net charge of the indolizine derivatives of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and / or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counterions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvates which the compounds of formulae herein as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise indolizine derivatives of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

[0146] Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally -occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0147] The indolizine derivatives of the invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the indolizine derivatives of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4+(wherein X is -C1-6-alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said 42ompoundd in combination with a suitable cation such as Na+and NX4+(wherein X typically is independently selected from -H or a -Ci-4-alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the invention.

[0148] As used herein and unless otherwise stated, the term “enantiomer” means each individual optically activeform of an indolizine derivative of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

[0149] The term “isomers” as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S -configuration, and multiple bonds may have either cis- or trans-configuration.

[0150] Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term “stereoisomerically pure” or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (i.e., at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms “enantiomerically pure” and “diastereomerically pure” should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.

[0151] Separation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of an indolizine derivative of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:3 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compound. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a- methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, andanalyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96 / 15 l l l).Under 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, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCel® CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak® AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.“("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990“ "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513:375-378).

[0152] The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety. The absolute stereochemical configuration of the compounds of the formulae described herein may easily be determined by those skilled in the art while using well- known methods such as, for example, X-ray diffraction.

[0153] When a compound is crystallized from a solution or slurry, it canbe crystallized in a different arrangement lattice of spaces (this property is called“ "polymorphism") to form crystals with different crystalline forms, each of which is known a“ "polymorphs". The term “Polymorph” as used herein, therefore, refers to a crystal form of a compound of Formula (I), where the molecules are localized in the three-dimensional lattice sites. Different polymorphs of the compound of Formula (I) may be different from each other in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, accumulation mode, flowability and / or solid state stability, etc.

[0154] Indolizine derivatives of the invention and their physiologically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intranasal, intravenous, intraarterial, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.

[0155] The therapeutically effective amount of the preparation of the compound(s), especially for the treatment of TRPM3 mediated disorders in humans and other mammals or in animals, preferably is a TRPM3 ion channel inhibiting amount of the compounds as defined herein and corresponds to an amount which ensures a plasma level of between Ipg / ml and 100 mg / ml.

[0156] Suitable dosages of the compounds or compositions of the invention should be used to treat or prevent the TRPM3 mediated disorders in a subject. Depending upon the pathologic condition to be treated and the patient’s condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.

[0157] The invention further provides (pharmaceutical) compositions comprising one or more indolizine derivatives of the invention, more in particular of all the Formula (I) or Formula (II) and other formulas and embodiments described herein and the more particular aspects or embodiments thereof. Furthermore, the invention provides the compounds or (pharmaceutical) compositions of the invention, more in particular of all the Formula(I) and other formulas and embodiments described herein and the more particular aspects or embodiments thereof, for use as a medicine, more in particular for use in the treatment of pain. The TRPM3 mediated disorders are selected from pain and an inflammatory hypersensitivity condition and epilepsy.

[0158] The indolizine derivatives of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986).

[0159] Subsequently, the term "pharmaceutically acceptable carrier" as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and / or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e., the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.

[0160] Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, surface-active agents, solvents, coatings, antibacterial and antifungal agents, isotonic agents and the like, provided the same are consistent with pharmaceutical practice, i.e., carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the invention may be prepared in any known manner, for instance by homogeneously mixing, coating and / or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents, may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.

[0161] While it is possible for the indolizine derivatives to be administered alone it is preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients. The carrier(s) optimally are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0162] Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder orgranules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0163] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g., mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w / w such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in 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 polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3 -diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

[0164] The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

[0165] The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0166] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w / w. Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0167] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.

[0168] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0169] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0170] Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0171] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0172] Indolizine derivatives of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more indolizine derivatives of the invention ("controlled release formulations") in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more indolizine derivatives of the invention can be prepared according to conventional methods.

[0173] Another embodiment of this invention relates to various precursor or “prodrug” forms of the indolizine derivatives of the invention. It may be desirable to formulate the indolizine derivatives of the invention in the form of a chemical species which itself is not significantly biologically -active, but which when delivered to the animal, mammal or human will undergo a chemical reaction catalyzed by the normal function of the body, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing a compound as defined herein. The term “prodrug” thus relates to these species which are converted in vivo into theactive pharmaceutical ingredient.

[0174] The prodrugs of the indolizine derivatives of the invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-dmg forms. In the present case, however, the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used. The counterpart of the active pharmaceutical ingredient in the pro-dmg can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.

[0175] For the purpose of the invention the term “therapeutically suitable pro-drug” is defined herein as “a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal, mammal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome ”.

[0176] More specifically the term “prodrug”, as used herein, relates to an inactive or significantly less active derivative of a compound such as represented by the structural formulae herein described, which undergoes spontaneous or enzymatic transformation within the body in order to release the pharmacologically active form of the compound. For a comprehensive review, reference is made to Rautio J. et al. (“Prodrugs: design and clinical applications” Nature Reviews Drug Discovery, 2008, doi: 10.1038 / nrd2468).

[0177] Representative indolizine derivatives of the invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the specific chemical reaction and specific conditions described in the schemes and examples. The various starting material used in the schemes are commercially available or may be prepared by methods well within the skill persons versed in the art. The variables are as defined herein and within the skill of persons verses in the art.EXAMPLES

[0178] The following examples are provided for the purpose of illustrating the invention and by no means should be interpreted to limit the scope of the invention.

[0179] Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the specific chemical reaction and specific conditions described in the schemes and examples. The various starting material used in the schemes are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein and within the skill of persons versed in the art.

[0180]

[0176] Abbreviations used in the instant specification, particularly in the schemes and examples, are as follows: ABC - Aqueous solution of Ammonium Bicarbonate, ACN - acetonitrile, AcOH - Acetic acid, ADDP - l,l'-(Azodicarbonyl)dipiperidide, aq. - Aqueous, AIBN - Azobisisobutyronitrile, BrettPhos - 2- (Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l,r-biphenyl, CAN - Ceric ammonium nitrate, COMU - (l-Cyano-2 -ethoxy -2 -oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate, DABCO - l,4-diazabicyclo[2.2.2]octane, DAST - Diethylaminosulfur trifluoride, DBU - l,8-Diazabicyclo[5.4.0]undec-7-ene, DCC - N,N'-dicyclohexylcarbodiimide, DCM - Dichloromethane, DEAD - Diethyl azodicarboxylate, DIA - Diastereomer, DIAD - Diisopropyl azodicarboxylate, DEA - Diethylamine, DIPEA - Diisopropyl-ethyl amine, DMAP -4-Dimethylaminopyridine, DME - 1,2-Dimethoxy ethane, DMEDA - 1,2-Dimethylethylenediamine, DMF - N,N-Dimethylformamide, DMSO - Dimethylsulfoxide, DPP A - Diphenylphosphoryl azide, 2,4-DNPH - 2,4-Dinitrophenylhydrazine, DTBAD - tert-Butylazodicarboxylate, EDCI or EDC - l-Ethyl-3-(3-dimethylaminopropyl)_,carbodiimide, En - Enantiomer, Et2O - Diethyl ether, EtOH - Ethanol, EtOAc - Ethyl acetate, Eq. - Equivalent, FA - Formic acid, FCC - Flash column chromatography, h - Hour, HATU - O-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HPLC - High performance liquid chromatography, IPA - isopropyl alcohol, LAH - Lithiumaluminiumhydrid, LG - Leaving group, mCPBA - meta-Chloroperoxybenzoic acid, MeOH - methanol, min. - Minute, Ms - Methanesulfonyl, NBS - N-Bromosuccinimide, nBuLi - n-Butyl lithium, NMP - l-Methyl-2-pyrrolidinone, Pd(PPh3)4 - Tetrakis- (triphenylphosphine)-palladium(O), PdC12(dppf).DCM - [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd2(dba)3 - Tris(dibenzylideneacetone)dipalladium, Pet ether - Petroleum ether, PPh3 - Triphenylphospine, PS-DIEA - Diisoprpropyl-ethyl amine supported on PolyStyrene, PS-PPh3 - Triphenylphospine supported on PolyStyrene, PyBop - Benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate, Pyr. - Pyridine, PTSA - p-Toluenesulfonic acid, RF : ratio of frontiers, RM - Reaction mixture, RP - Reverse phase, RT - Room temperature, sat. - Saturated, SEM - [2- (Trimethylsilyl)ethoxy]methyl acetal, SFC - Supercritical fluid chromatography, SPE - Solid Phase Extraction, TBDMS - Tert-Butyldimethylsilyl ether, TBAF - Tetrabutylammonium fluoride hydrate, TBAI - Tetrabutylammonium iodide, TEA - Triethylamine, Tf - Trifluoromethanesulfonate, THF - Tetrahydrofurane , TFA - Trifluoroacetic acid, TLC - thin layer chromatography, TPP - triphenyl phosphine, IPA - isopropyl alcohol, TMS - trimethyl silyl, T3P - Propylphosphonic anhydride, XPhos Pd G3 - (2-Dicyclohexylphosphino-2',4',6'- triisopropyl-1, l'-biphenyl)[2-(2'-amino-l, r-biphenyl)]palladium(II) methanesulfonate.

[0181] The compounds of interest having a structure according to the general formula (A) and all other formulas described herein and embodiments thereof can be prepared as outlined in the general chemical scheme 1.Scheme 1 : all R1, R2, R3, R4, R5, R6, R7and R8are as described for the compounds of the present invention.

[0182] Bromo-indolizine of formula 1 (commercially available or synthesized by procedures known to people skilled in the art or as set forth in the examples below), wherein R’ is an ester protecting group (e.g. methyl, ethyl, t-Bu and the like), may be reacted with appropriate boronic derivatives 2 (commercially available or synthesized by procedures known to people skilled in the art or as set forth in the examples below), wherein R’ ’ is an hydrogenor an alkyl group (e.g. methyl, butyl and the like), in combination with Pd catalyst (e.g. Pd(PPh3)4, PdCh(dppf) and the like) and a salt (e.g., KF, K3PO4, Na2COs and the like) in a solvent (e.g., DMF, toluene, dioxane, water, and the like) to provide intermediates of formula 3. Cyclopropanation of olefin derivatives 3 with hydrazone derivatives 4 (commercially available or synthesized by procedures known in the art or as set forth in the examples below), in the presence of a base (e.g. NaH, K2CO3 and the like) in a polar aprotic solvent (e.g. DCM, Dioxane and the like) may supply intermediates of formula 5. Ester derivatives 5 may then be converted into acid derivatives of formula 6 via standard saponification reactions. The desired compounds of formula 8 may be obtained from acid derivatives of formula 6 by reaction with amine derivatives of formula 7 (commercially available or synthesized by procedures known in the art or as set forth in the examples below) under standard peptide coupling conditions (e.g. DCC, EDCI, HATU, PyBop and the like) in a polar aprotic solvent (e.g. DCM, DMF and the like).

[0183] In a more particular embodiment, compounds of the present invention may be synthesized as depicted in scheme 2.Scheme 2: all R1, R2, R3, R4, R5, R6, R7, R8, X and Cy are as described for the compounds of the present invention.

[0184] 6-Hydroxyindolizine-3 -carboxylic acid derivatives 10 (commercially available or synthesized by procedures known to people skilled in the art or as set forth in the examples below), wherein R’ is an ester protecting group (e.g. methyl, ethyl, t-Bu and the like), may be converted into the desired compounds of formula 12 via Ullmann coupling mediated by copper catalyst (e.g., Cui) using intermediates of formula 11 (commercially available or synthesized), wherein Y is a Halogen (e.g., I and the like), in the presence of a base (e.g., DIPEA, DBU, triethylamine, CS2CO3, and the like) in a polar solvent (e.g., 1,4-dioxane and the like), with a ligand (e.g., Tetramethyl-3,5-heptanedione and the like) at a temperature ranging from RT to 100°C. Compounds of interest having a formula 13 may be obtained from a standard saponification reactions of ester derivatives 12 followed by reaction with amine derivatives of formula 7 (commercially available or synthesized by procedures known in the art or as set forth in the examples below) under standard peptide coupling conditions (e.g. DCC, EDCI, HATU,PyBop and the like) in a polar aprotic solvent (e.g. DCM, DMF and the like).

[0185] In a more particular embodiment, compounds of the present invention may be synthesized as depicted in scheme 3.Scheme 3 : all R1, R2, R3, R4, R5, R6, R7, R8, X and Cy are as described for the compounds of the present invention.

[0186] 6-Hydroxyindolizine-3 -carboxylic acid derivatives 10 (commercially available or synthesized by procedures known to people skilled in the art or as set forth in the examples below), wherein R’ is an ester protecting group (e.g. methyl, ethyl, t-Bu and the like), may be reacted with a tritiating reagent (e.g. N,N-bis(trifluoromethanesulfonyl)aniline, OTf2 and the like) in the presence of a base (e.g., DIPEA, DBU, TEA, and the like) with or without a nucleophilic catalyst (e.g., DMAP , Pyr. and the like) in a polar aprotic solvent (e.g. DCM, DMF and the like) to provide intermediates of formula 20. 6-(((Trifluoromethyl)sulfonyl)oxy)indolizine- 3 -carboxylate derivatives 20 may be reacted with appropriate boronic derivatives 21 (commercially available or synthesized by procedures known to people skilled in the art or as set forth in the examples below), wherein R’ ’ is an hydrogen or an alkyl group (e.g. methyl, butyl and the like), in combination with Pd catalyst (e.g. Pd(PPh3)4, PdC12(dppf) and the like) and a salt (e.g., KF, K3PO4, Na2COs and the like) in a solvent (e.g., DMF, toluene, dioxane, water, and the like) to provide intermediates of formula 22. Compounds of interest having a formula 23 may be obtained from a standard saponification reactions of ester derivatives 22 followed by reaction with amine derivatives of formula 7 (commercially available or synthesized by procedures known in the art or as set forth in the examples below) under standard peptide coupling conditions (e.g. DCC, EDCI, HATU, PyBop and the like) in a polar aprotic solvent (e.g. DCM, DMF and the like).Table 1: Exemplary indolizine derivatives

[0187] The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.

[0188] Part A represent the preparation of the compounds whereas Part B represents the pharmacological examples.Part A

[0189] All starting materials which are not explicitly described were either commercially available (the details of suppliers such as for example ABCR, Apollo Scientific Combi-Blocks, Enamine, FluoroChem, MatrixScientific, Maybridge, Merck, TCI etc. can be found in the SciFinder® Database for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database or the SciFinder® Database respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

[0190] The reactions were, if necessary, carried out under an inert amosphere (mostly argon and N2). The number of equivalents of reagents and the amounts of solvents employed as well as the reaction temperatures and times can vary slightly between different reactions carried out by analogous methods. The work-up and purification methods were adapted according to the characteristic properties of each compound and can vary slightly for analogous methods. The yields of the compounds prepared are not optimized.

[0191] The indication „equivalents“ ("eq." or “eq” or “equiv.”) means molar equivalents, “RT” or “rt” means room temperature T (23 ± 7 °C), “M” are indications of concentration in mol / 1, “sol.” means solution, "cone." means concentrated. The mixing ratios of solvents are usually stated in the volume / volume ratio.

[0192] Key analytical characterization was carried out by means of ' H-NMR spectroscopy and / or mass spectrometry (MS, m / z for [M+H]+and / or [M-H | ) for all the exemplary compounds and selected intermediate products. In certain cases, where e.g. regioisomers and / or diastereomers could be / were formed during the reaction, additional analytics, such as, e.g.13C NMR and NOE (nuclear Overhauser effect) NMR experiments were in some cases performed.

[0193] Analytical instruments employed were e.g. for NMR analysis a BRUKER 400MHz or a BRUKER 500MHz machine (Software Topspin), alternatively a BRUKER AVANCE 300MHz and 400Mhz was employed.For LC / MS analysis e.g. an Agilent 1290 infinity ,Mass:6150 SQD(ESI / APCI) or an Agilent 1200 SERIES, Mass:6130 SQD(ESI / APCI) (Software Chemistation) was employed. Analytical HPLCs were measured e.g. on Waters (Software Empower), an Agilent-1200-ELSD (Software Chemistation) or an Agilent-1260 (Software OpenLAB). Analytical SFC were performed e.g. on a PIC solution (Software: SFC PICLAB ONLINE), a WATERS-X5 (Software MASSLYNX) or a WATERS-UPC2 (Empower).

[0194] Preparative HPLC were performed e.g. on a Waters 2998 (Software Empower) or a YMC (Software K- Prep). Preparative SFC were performed e.g. on a Waters, SFC- 200 (Software Chromscope or Super chrome), a Waters, SFC-80 (Super chrome) or a PIC, PIC-175 (Software S10-100).

[0195] Structures of example compounds that contain stereocenters are drawn and named with absolute stereochemistry, if known. In case of unknown absolute stereochemistry the compounds can be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry. Dia 1 and Dia 2 means that diastereoisomers were separated but the stereochemistry is unknown. En 1 and En 2 means that both enantiomers were separated but the absolute configuration is unknown. No suffix given after the compound code means that a compound containing stereocenters was obtained as a racemic mixture or a mixture of diastereomers, respectively, unless the chemical name of the compound specifies the exact stereochemistry.Synthesis of (S)-2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-AOOl - Enl),and (R)-2- amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-AOOl - En2),

[0196] Step 1 : A solution of l-((tert-butyldimethylsilyl)oxy)propan-2-one (20 g, 106.19 mmol) in EtOH (100 mL) was treated with (4-methoxyphenyl)methanamine (15.3 mL, 116.81 mmol), TMSCN (15.94 mL, 127.42 mmol) and NH4C1 (1.7 g, 31.8 mmol) at RT. The RM was stirred at 80 °C for 16 h. After completion of the reaction, volatiles were removed under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCCh (100 ml), brine solution (100 mL), dried over MgSO i. filtered and evaporated under reduced pressure. The residue was purified by FCC on silica gel using 10% EtOAc in pet ether as an eluent to afford 3 -((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2 -methylpropanenitrile as a pale yellow liquid (20 g, 56.30%). 1H NMR (400 MHz, DMSO-de) 5 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).

[0197] Step 2 : A solution of 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2- methylpropanenitrile (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) at 0° C. The RM was stirred at RT for 16 h. After completion, the RM wascooled to RT and quenched with ice-cold water (100 mL). The aqueous layer was extracted with Et2O (3 x 100 mL). Combined organic phases was washed with brine (50 mL), dried over Na2SC>4, filtered and evaporated under reduced pressure. The residue was purified by FCC on silica gel using 40-50% EtOAc in pet ether as an eluent to afford 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2-methylpropanamide as a pale yellow liquid (3.8 g, 36%). 1H NMR (400 MHz, DMSO-de) 5 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).

[0198] Step 3 : A solution of 3-((tert-butyldimethylsilyl)oxy)-2-((4-methoxybenzyl)amino)-2- methylpropanamide (10 g, 28.365 mmol) in MeOH (200 mL) was treated with 10% palladium hydroxide (5.178 g, 36.874 mmol) at RT. The RM stirred at RT for 48 h under H2 pressure (70 psi). After completion, the reaction mixture was filtered through a celite pad, washed with 10% MeOH in DCM (200 mL), filtrate was concentrated under reduced pressure. The residue was purified by FCC on silica gel using 80% EtOAc in Pet. ether as an eluent to afford 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide as an off white solid (5.5 g). 1H NMR (400 MHz, DMSO-de) 5 ppm: 7.25 (s, 1 H), 6.95 (s, 1 H), 3.76 (d, 1 H), 3.25 (d, 1 H), 1.77 (s, 2 H), 1.04 (s, 3 H), 0.85 (s, 9 H), 0.02 (s, 6 H).

[0199] Step 4 : 5.5 g of Int-001 was separated by Prep. SFC. Column [Dimensions]: Lux. Cellulose-4 [250 x 30 x 5pm], % CO2: 75%, % solvent: 25% (0.5% Diethyl Amine in ACN), Total Flow: 90 g / min, Back Pressure: 120.0 bar, Temperature: 30°C, Wavelength: 215 nm, stack: 18.0 min, Loadability: 44.0 mg / injection, Solubility: 70 mL of ACN, No of Injection: 93, Instrument details: Make / Model: SFC-MASS. The collected fractions were concentrated and lyophilized to afford two isomers: First eluting (Int-AOOl - Enl) , as a pale yellow gummy (1.7 g). 1H NMR (400 MHz, DMSO-de) 5 ppm: 7.24 (s, 1 H), 6.93 (s, 1 H), 3.76 (d, 1 H), 3.26 (d, 1 H), 1.77 (s, 2 H), 1.04 (s, 3 H), 0.85 (s, 9 H), 0.02 (s, 6H). SOR: -28.62 (1.0% in CHCh) and second eluting (Int-AOOl - En2), as a pale yellow gummy (1.5 g,). 1H NMR (400 MHz, DMSO-de) 5 ppm: 7.24 (s, 1 H), 6.93 (s,l 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, 6 H). SOR: +47.54 (1.0% in CHCh).Synthesis of 2-amino-4,4-difluoro-2-methylbutan-l-ol (Int-A003),

[0200] Step 1 : To a solution of t-BuOK (13.2 g, 117.83 mmol) in DMF (150 mL) was added ethyl 2- ((diphenylmethylene)amino)acetate (30 g, 112.22 mmol) at 0 °C. After 30 min, l,l-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 completion of the reaction, the RM was diluted with 5% aq NH4CI (100 mL), extracted with EtOAc (3 x 50 mL). Combined organic layer was 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 pet ether as an eluent to afford ethyl 2-((diphenylmethylene)amino)-4,4-difluorobutanoate as a pale yellow liquid (30 g, 80.67%).1H NMR (400 MHz, CDCh) 5 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).

[0201] Step 2: To a solution of t-BuOK (7.450 g, 112.21 mmol) in DMF (30 mL) was added Ethyl N- (diphenylmethylene)glycinate (20 g, 331.36 mmol) at 0 °C. 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 completion of the reaction, the RM was diluted with 5% aq NH4CI (100 mL), extracted with EtOAc (3 x 50 mL). Combined organic layer was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 10% EtOAc in pet ether as an eluent to afford ethyl 2- ((diphenylmethylene)amino)-4,4-difluoro-2-methylbutanoateas a pale yellow liquid (16 g, 76.75%).1H NMR (400 MHz, CDCh) 5 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, 2 H), 2.31 - 2.57 (m, 2 H), 1.44 (s, 3 H), 1.11 (t, 3 H).

[0202] Step 3 : To a solution of ethyl 2-((diphenylmethylene)amino)-4,4-difluoro-2-methylbutanoate (16 g, 46.32 mmol) in Pet. ether (75 mL) was added IN HO (150 mL) at RT. The RM was stirred at RT for 16 h. The RM was washed with EtOAc (2 x 50 mL). The aqueous solution was basified with NaHCOs (pH ~8), extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford ethyl 2-amino-4,4-difluoro-2-methylbutanoate as a pale yellow liquid (5.910 g, 70.42%). ' H NMR (400 MHz, CDCh) 5 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).

[0203] Step 4 : To a solution of ethyl 2-amino-4,4-difluoro-2-methylbutanoate (5.6 g, 30.90 mmol) in EtOH (50 mL) was added sodium borohydride (3.508 mg, 92.72 mmol) at 0 °C. The RM was stirred at RT for 7 h. The RM was quenched with water (10 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 2-amino-4,4-difluoro-2-methylbutan-l-ol (Int-A003) as a colorless gum (2.3 g, 53%). ' H NMR (400 MHz, DMSO-de) 5 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).Synthesis of 3-Amino-3-(hvdroxymethyl)pyrrolidin-2-one (Int-A005 - Enl) and (Int-A005 - En2),

[0204] Step 1 : To a stirred solution of diethyl 2-(2-(l,3-dioxoisoindolin-2-yl)ethyl)malonate (60 g, 179.99 mmol) in 1,4-Dioxane (600 mL) was added TEA (49.90 mL, 359.99 mmol) at 0 °C. After 15 minutes, formaldehyde (29.18 g, 359.99 mmol) was added at 0 °C. The RM was warmed to RT and stirred at 80 °C for 16h. The RM was diluted with ice-cold water (200 mL) and extracted with EtOAc (2 x 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 pet ether to afford diethyl 2-(2-(l,3-dioxoisoindolin-2-yl)ethyl)-2-(hydroxymethyl)malonate (59 g, 90%) as pale yellow gummy.1H NMR (400 MHz, CDCh) 5 ppm: 7.86-7.82 (m, 2 H), 7.74-7.69 (m, 2 H), 4.25-4.18 (m, 4 H), 4.07 (d, 2 H), 3.83- 3.79 (m, 2 H), 2.79 (t, 1 H), 2.33-2.30 (m, 2 H), 1.28 (t, 6 H).

[0205] Step 2: To a stirred solution of diethyl 2-(2-(l,3-dioxoisoindolin-2-yl)ethyl)-2-(hydroxymethyl)malonate (68 g, 187.13 mmol) in DCM (700 mL) was added Imidazole (25.48 g, 374.27 mmol) at 0 °C . After 15 min., tert- Butyldimethylsilyl chloride (33.84 g, 224.56 mmol) at 0 °C was added. The RM was stirred for 16 h at RT. The RM was diluted with ice cold water (300 mL) and extracted with DCM (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 10% EtOAc in pet ether to afford diethyl 2-(((tert- butyldimethylsilyl)oxy)methyl)-2-(2-(l,3-dioxoisoindolin-2-yl)ethyl)malonate (68 g, 77%) as an off-white solid. ' H NMR (400 MHz, CDCh) 5 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).

[0206]

[0209] Step 3 : To a stirred solution of diethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(l,3- dioxoisoindolin-2-yl)ethyl)malonate (68 g, 142.37 mmol) in Ethanol (700 mL) was added Hydrazine hydrate (10.69 g, 213.55 mmol) at 0 °C. The RM was stirred for 16 h at RT. The 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 solution (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0-30% EtOAc in Pet. ether to afford ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)- 2 -oxopyrrolidine-3 -carboxylate (30.7 g, 71%) as an off white solid.1H NMR (400 MHz, CDCh) 5 ppm: 5.76 (s, 1 H), 4.22-4.17 (m, 2 H), 4.06 (d, 1 H), 3.94 (d, 1 H), 3.46-3.42 (m, 1 H), 3.36-3.35 (m, 1 H), 2.59-2.55 (m, 1 H), 2.49-2.43 (m, 1 H), 1.27 (t, 3 H), 0.87 (d, 9 H), 0.06 (d, 6 H).

[0207] Step 4 : To a solution of ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylate (29 g, 96.19 mmol) in EtOH (120 mL), THF (60 mL) and H2O (30 mL) was added LiOH.H2O (20.18 g, 480.99 mmol) at 0 °C. The RM was stirred for 16 h at RT. The volatiles were removed under reduced pressure. The residue was diluted with cold water (20 mL) and then acidified with saturated aqueous Citric acid solution (pH~4). The solid was filtered, washed with water (10 mL) followed by water (10 mL), dried under vacuum to afford 3- (((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidine-3-carboxylic acid (16.7 g, 63%) as a white solid.1H NMR (400 MHz, DMSO-de) 5 ppm: 7.82 (s, 1 H), 3.88 (d, 1 H), 3.70 (d, 1 H), 3.27-3.21 (m, 1 H), 3.17-3.12 (m, 1 H), 2.34-2.32 (m, 1 H), 2.24-2.22 (m, 1 H), 0.84 (s, 9 H), 0.01 (d, 6 H).

[0208] Step 5 : To a stirred solution of 3 -(((tert-butyldimethylsilyl)oxy)methyl)-2 -oxopyrrolidine-3 -carboxy lie acid (9.5 g, 34.74 mmol) in THF (40 mL) and benzene (120 mL) were added TEA (14.65 mL, 104.24 mmol) followed by DPPA (19.12 g, 69.49 mmol) at RT. The RM was stirred at RT for 2 h. The RM was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 50 mL), brine solution (50 mL), then dried over Na2SO i. filtered, and concentrated under reduced . The residue was dissolved in THF (40 mL) and benzene (120 mL). Then, Benzylalcohol (7.51 g, 69.49 mmol) was added at RT. The RM was stirred at 55 °C for 16 h. The RM was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0-40% EtOAc in Pet. ether to afford benzyl (3-(((tert- butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate (9 g, 68%). ' H NMR (400 MHz, CDCL) 5 ppm: 7.37-7.29 (m, 5 H), 5.84 (brs, 1 H), 5.42 (bis, 1 H), 5.07 (s, 2 H), 3.85 (d, 1 H), 3.67 (d, 1 H), 3.39-3.33 (m, 2 H), 2.63-2.62 (m, 1 H), 2.53-2.51 (m, 1 H), 0.88 (s, 9 H), 0.05 (d, 6 H).

[0209] Step 6 : To a stirred solution of benzyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3- yl)carbamate (11 g, 29.05 mmol) in MeOH (150 mL) was added PTSA monohydrate (2.21 g, 11.62 mmol) in MeOH (50 mL) over 2 h at 0 °C. The RM was stirred for 16 h at RT. The RM was concentrated under reduced pressure. The residue was quenched with ice-cold water (50 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with n-pentane (3 x 15 mL) followed by diethyl ether (15 mL), filtered and dried under vacuum to afford benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate (7 g, 91%) as an off white solid.1H NMR (400 MHz, DMSO-de) 5 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 benzyl (3-(hydroxymethyl)- 2-oxopyrrolidin-3-yl)carbamate was purified by chiral SFC prep.[ Preparative SFC Conditions: Column: Chiral peak IF (250 x 30 x 5pm), %CO2: 65%, %Co-solvent: 35% (100% MeOH), Total Flow: 90 g / min, Back Pressure: 100.0 bar, Temperature: 30 °C, Wavelength: 215 nm, Stack time: 7.2 min, Solubility: 100 ml of MeOH.] The collected pure fractions were concentrated under reduced pressure to afford two isomers Enl (the first eluting) and En2 (the second eluting).

[0210] Step 7 : To a stirred solution of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate Enl (1.4 g, 5.297 mmol) in Ethanol (30 mL) was added Pd / C (450 mg) at RT. The RM was stirred under H2 (70 psi) at RT for 16 h. The RM was filtered through a pad of Celite, and washed with MeOH (50 mL). The filtrate concentrated under reduced pressure. The residue was triturated with diethyl ether (2 x 5 mL) and dried under high vacuum to afford 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-A005 - Enl) (610 mg, 88%) as an off-white solid. ' H NMR (400 MHz, DMSO-de) 5 ppm: 7.54 (s, 1 H), 4.73 (t, 1 H), 3.36-3.34 (m, 1 H), 3.18-3.12 (m, 2 H), 3.10- 3.04 (m, 1 H), 2.22-2.15 (m, 1 H), 1.76-1.72 (m, 1 H), 1.56 (s, 2 H). UPLC: Rt = 2.29 min (98%).

[0211]

[0214] Step 8 : To a stirred solution of benzyl (3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)carbamate En2 (1.2 g, 4.54 mmol) in Ethanol (30 mL) was added Pd / C (350 mg) at RT. The RM was stirred under H2 (70 psi) at RT for 16 h. The RM was filtered through a pad of Celite, and washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (2 x 5 mL) and dried under high vacuum to afford 3-amino-3-(hydroxymethyl)pyrrolidin-2-one (Int-A005 - En2) (550 mg, 93%) as an off-white solid. ' H NMR (400 MHz, DMSO-de) 5 ppm: 7.54 (s, 1 H), 4.73 (brs, 1 H), 3.36-3.32 (m, 1 H), 3.18-3.12 (m, 2 H), 3.10-3.04 (m, 1 H), 2.22-2.15 (m, 1 H), 1.76-1.71 (m, 1 H), 1.57 (s, 2 H).Synthesis of 3-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (Int-A006),

[0212] A stirred solution of benzyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate (1.0 g, 2.642 mmol) in Ethanol (10.0 mL) was treated with Palladium on carbon (Pd / C, 200 mg) and stirred under hydrogen gas (balloon) at RT for 4 h. The RM was filtered through a pad of Celite and washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure and the residue was triturated with n-pentane (2 ^ 5 mL) and dried under reduced pressure to afford -amino-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (Int-A006) (500 mg, 77%) as an off-white solid. ' H NMR (400 MHz, CD3OD) 5 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).Synthesis of methyl 6-bromo-2-methylindolizine-3-carboxylate (Int-BO

[0213] Step 1 : 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) at RT. The RM was stirred at 80 °C for 16 h. The RM was concentrated under reduced pressure. The residue was triturated with EtOAc (2 x 100 mL). The solid was filtered, washed with EtOAc (3 x 30 mL) and dried under high vacuum to afford 5-bromo-l-(2-methoxy-2-oxoethyl)-2- methylpyridin-l-ium bromide (15 g, Yield: 79%) as a brown solid. ' H NMR (400 MHz, DMSO-de) 5 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).

[0214] Step 2 : A stirred solution of 5-bromo-l-(2-methoxy-2-oxoethyl)-2-methylpyridin-l-ium bromide (15 g, 46.15 mmol) in acetic anhydride (75 mL) was treated with sodium acetate (11.35 g, 138.46 mmol) at RT. The RM was stirred at 150 °C for 24 h. The RM was quenched with sat. NaHCOa solution (300 mL) and extracted with EtOAc (2 x 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 Pet. ether as a gradient to afford methyl 6-bromo-2-methylindolizine-3-carboxylate (Int-BOOl) (3.4 g, 27.4%) as a pale-yellow solid. ' H NMR (400 MHz, CDCh) 5 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, 3 H), 2.51 (s, 3 H).Synthesis of methyl 2-methyl-6-vinylindolizine-3-carboxylate (Int-B002)lnt-B001 lnt-B002

[0215] A stirred solution of methyl 6-bromo-2-methylindolizine-3-carboxylate (Int-BOOl) (3 g, 11.189 mmol) in 1,4-dioxane (30 mL) and water (10 mL) were 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 PdC12(dppf).DCM (0.9 g, 1.119 mmol) at RT. The RM was stirred at 90° C for 6 h. The RM wasfiltered through a small pad of Celite, washed with EtOAc (100 mL). The filtrate was washed with brine 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 0-10% EtOAc in Pet. ether as a gradient to afford methyl 2- methyl-6-vinylindolizine-3-carboxylate (1.75 g, 72.6%) as light brown solid. 1H NMR (400 MHz, CDC13) 5 ppm: 9.41 (s, 1 H), 7.31 (d, 1 H), 7.20 (dd, 1 H), 6.71-6.64 (m, 1 H), 6.29 (s, 1 H), 5.70 (d, 1 H), 5.24 (d, 1 H), 3.91 (s, 3 H), 2.52 (s, 3 H).Synthesis of methyl 2-methyl-6-(trans-2-phenylcvclopropyl)indolizine-3-carboxylate (Int-B003) and methyl 2- methyl-6-(cis-2-phenylcyclopropyl)indolizine-3-carboxylate (Int-B004)

[0216] A stirred solution of methyl 2-methyl-6-vinylindolizine-3-carboxylate (1 g, 4.646 mmol) in 1,4-dioxane (30 mL) were treated with K2CO3 (1.3 g, 9.291 mmol) and (E)-N'-benzylidene-4-methylbenzenesulfonohydrazide (1.15 g, 4.181 mmol) at RT. The RM was stirred at 110 °C for 16 h. The RM was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine 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 0-5% ethyl acetate in Pet. ether as a gradient to afford methyl 2-methyl-6-(trans-2- phenylcyclopropyl)indolizine-3-carboxylate (Int-B003) (260 mg, 18%) as an off-white solid and methyl 2-methyl- 6-(cis-2-phenylcyclopropyl)indolizine-3 -carboxylate (Int-B004) (70 mg, 5%) as an off-white solid. Methyl 2- methyl-6-(trans-2-phenylcyclopropyl)indolizine-3-carboxylate (Int-B003) : 1H NMR (400 MHz, DMSO-d6) 5 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). Methyl 2-methyl-6-(cis-2- phenylcyclopropyl)indolizine-3-carboxylate (Int-B004) : 1H NMR (400 MHz, DMSO-d6) 5 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).Synthesis of potassium 2 -methyl-6-(trans-2-phenylcvclopropyl)indolizine-3 -carboxylate (Int-B005)

[0217] A stirred solution of methyl 2-methyl-6-((trans)-2 -phenylcyclopropyl) indolizine-3 -carboxylate (520 mg, 1.703 mmol) in THF (15 mL) was treated with Potassium trimethylsilanolate (550 mg, 4.257 mmol) at RT. The RM was stirred at 75 °C for 5 h. The RM was concentrated under reduced pressured and dried under high vacuum to afford potassium 2-methyl-6-((trans)-2 -phenylcyclopropyl) indolizine-3 -carboxylate (720 mg, 100%) as brown solid. ' H NMR (400 MHz, DMSO-de) 5 ppm: 9.84 (s, 1 H), 7.29-7.26 (m, 2 H), 7.20-7.13 (m, 4 H), 6.48 (dd, 1 H), 6.06 (s, 1 H), 2.45 (s, 3 H), 2.12-2.06 (m, 2 H), 1.39-1.33 (m, 2 H).Synthesis of methyl 6-hy droxy -2 -methylindolizine-3 -carboxylate (Int-B006)

[0218] Step 1 : To a solution of 5-(benzyloxy)-2-methylpyridine (125 g, 627 mmol) in ethanol (1000 mL) was added methyl 2-bromoacetate (65 mL, 690 mmol) at RT. The RM was stirred at 80 °C for 16 h. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was triturated with pet ether (500 mL) and dried to afford benzyloxy)-! -(2 -methoxy -2 -oxoethyl)-2 -methylpyridinium bromide (210 g, 85%).

[0219] Step 2 : To a solution of methyl 2-(5-(benzyloxy)-2-methyl-114-pyridin-l-yl)acetate (105 g, 300 mmol) in acetic anhydride (500 mL) was added sodium acetate (73.8 g, 900 mmol) at RT. The RM was stirred at 150 °C for 24 h. The RM was cooled to RT, diluted with EtOAc (1000 mL), washed with sat. NaHCCh (3 x 500 mL), brine solution (400 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 20% EtOAc in Pet ether as an eluent to afford methyl 6-(benzyloxy)-2- methylindolizine-3 -carboxylate as a pale yellow solid (19 g, 21%).1H NMR (400 MHz, CDCL) 5 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).

[0220] Step 3 : To a solution of methyl 6-(benzyloxy)-2-methylindolizine-3-carboxylate (5.3 g, 17.94 mmol) in MeOH (500 mL) was added ammonium formate (11.31 g, 179.45 mmol) and 10% Palladium on carbon (2.5 g) at RT. The RM was stirred at RT for 2 h. The RM was filtered through a celite pad, washed with MeOH (100 mL) and the filtrate was concentrated under reduced pressure. The residue was diluted with water (250 mL), extracted with EtOAc (2 x 250 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with n-pentane (100 mL) and dried to afford methyl 6-hydroxy-2-methylindolizine-3-carboxylate methyl 6-hydroxy-2-methylindolizine-3-carboxylate (Int-B006) as a pale yellow solid (2.2 g, 59%). 1H NMR (400 MHz, DMSO-de) 5 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).Synthesis of potassium 2-methyl-6-(o-tolyloxy)indolizine-3-carboxylate (Int-B007)

[0221] Step 1 : To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (850 mg, 4.142 mmol) in dioxane (20 mL) was treated with l-iodo-2-methylbenzene (2.258 g, 10.355 mmol), Cu(I)I (79.092 mg, 0.414 mmol), CS2CO3 (2.699 g, 8.284 mmol). The RM was degassed with N2 gas for 10 min and treated with 2,2,6,6-Tetramethylheptane-3,5-dione (0.153 g, 0.828 mmol) at RT. The RM was stirred at 100 °C for 16 h. The RM was filtered through celite pad, filtrate was diluted with water (15 mL) and extracted with EtOAc (2 x 50 mL). Combined organic layer was washed with brine 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 pet ether as a gradient to afford methyl 2-methyl-6-(o-tolyloxy)indolizine-3-carboxylate (650 mg, 53.13%).1H NMR (400 MHz, CDCL) 5 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).

[0222] Step 2 : To a stirred solution of methyl 2-methyl-6-(o-tolyloxy)indolizine-3-carboxylate (600 mg, 2.032 mmol) inTHF (10.0 mL) was treated with Potassium trimethylsilanolate (651.57 mg, 5.079 mmol) atRT. The RM was stirred at 70 °C for 16 h. The RM was concentrated under reduced pressure. The residue was triturated with n-pentane (20 mL). The resulting solid was filtered to afford potassium 2-methyl-6-(o-tolyloxy)indolizine-3- carboxylate (Int-B007) (700 mg) as pale brown solid.1H NMR (400 MHz, DMSO-de) 5 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, 1 H), 2.50 (s, 3 H), 2.29 (s, 3 H).

[0223] The following intermediates were prepared in a maimer similar to Int-B007 (use of appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to the person skilled in the art):Table 2: Exemplary intermediates.Synthesis of methyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)indolizine-3-carboxylate (Int-B016)

[0224] To a stirred solution of methyl 6-hydroxy-2-methylindolizine-3-carboxylate (Int-B006) (1 g, 4.873 mmol) in DCM (20 mL) was treated with DMAP (0.060 g, 0.487 mmol) and DIPEA (2.122 mL, 12.182 mmol) then followed by Trifluoromethanesulfonic anhydride (1.637 mL, 9.746 mmol) dropwise at 0 °C. The RM was stirred at RT for 4 h. The RM was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). Combined organic layers were washed with water (20 mL), brine solution (20 mL) and dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 4% EtO Ac in pet ether as a gradient to afford methyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)indolizine-3-carboxylate (Int-B016) (1.2 g, 73%) as a pale yellow solid. 1H NMR (400 MHz, CDCh) 5 ppm: 9.65 (d, 1 H), 7.40 (d, 1 H), 6.97 - 6.94 (m, 1 H), 6.44 (s, 1 H), 3.94 (s, 3 H), 2.54 (d, 3 H).Synthesis of potassium 6-benzyl-2-methylindolizine-3-carboxylate (Int-B017)

[0225] Step 1 : To a solution of methyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)indolizine-3-carboxylate (Int-B016) (1 g, 2.965 mmol), 2-benzyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (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). The RM was degassed with Argon for 5 minutes. PdChdppf. DCM (0.121 g, 0.148 mmol) was added to the RM and again degassed with Argon for 5 minutes. The RM was stirred at 90 °C for 16 h. The RM was diluted with water (25 mL) and compound extracted with EtO Ac (2 x 100 mL). Combined organic layers were washed with brine (20 mL), dried over MySO i. filtered and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 35-40% EtO Ac in pet. ether as a gradient to afford methyl 3 -chloro-3 -phenylcyclobutane- 1 -carboxylate (610 mg, 73.65%) as colorless liquid.!H NMR (400 MHz, CDCh) 5 ppm: 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).

[0226] Step 2 : To a stirred solution of methyl 6-benzyl-2-methylindolizine-3-carboxylate (500 mg, 1.790 mmol) in THF (20 mL) was treated with potassium trimethylsilanolate (459.263 mg, 3.580 mmol) at RT. The RM was stirred at 65 °C for 16 h. The RM was concentrated under reduced pressure and washed with pentane (20 mL) to afford potassium 6-benzyl-2-methylindolizine-3-carboxylate (Int-B017) (510 mg) as a pale yellow gummy solid. 1H NMR (400 MHz, MeOD) 5 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, 1 H), 6.18 (s, 1 H), 3.88 (s, 2 H), 2.56 (s, 3 H).Synthesis of methyl 2-methyl-6-(phenylthio)indolizine-3-carboxylate (Int-B018) and potassium 2-methyl-6- (phenylthio)indolizine-3-carboxylate (Int-B019)

[0227] 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 withN2 gas for 5 min. Then, the RM was treated with Pd(dppf)C12 (341.138 mg, 0.466 mmol) followed by methyl 6-bromo-2-methylindolizine-3-carboxylate (2.5 g, 9.325 mmol) at RT. The RM was stirred at 75 °C for 16 h. The RM was diluted with diethyl ether (50 mL), filtered on celite bed, and filtrate was washed with brine (50 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 0-30% EtOAc in hexane as a gradient to afford methyl 2-methyl-6- (phenylthio)indolizine-3-carboxylate (Int-B018) (1.2 g, 43%) as an off-white solid.1H NMR (400 MHz, CDCL) 5 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).

[0228] Step 2 : A stirred solution of methyl 2-methyl-6-(phenylthio)indolizine-3-carboxylate (Int-B018) (250 mg, 0.841 mmol) in THF (15 ml) was treated with potassium trimethylsilanolate (269.6 mg, 2.102 mmol) at RT. 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 x 20 mL) and dried under high vacuum to afford potassium 2-methyl-6- (phenylthio)indolizine-3-carboxylate (Int-B019) (400 mg) as an off-white solid.1H NMR (400 MHz, DMSO-de) 5 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).Synthesis of potassium 2 -methyl-6-(phenylsulfinyl)indolizine-3 -carboxylate (Int-B020)

[0229] Step 1 : A stirred solution of methyl 2-methyl-6-(phenylthio) indolizine-3 -carboxylate (1.8 g, 6.053 mmol) in DCM (30 mL) was treated with mCPBA (65-70%, 1.6 g, 7.264 mmol) at 0 °C. The RM was stirred at RT for 16 h. The RM was diluted with DCM (50 mL) and the organic layer was washed with Sat. aq. sodium bicarbonate solution (50 mL) and aq. sodium thiosulfate solution (50 ml) followed by brine (50 mL). The organic layer was dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 0-50% EtOAc in hexane as a gradient to afford methyl 2-methyl-6-(phenylsulfinyl) indolizine- 3-carboxylate (1.25 g, 66%) as an off-white solid. ' H NMR (400 MHz, CDCL) 5 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, 3 H), 2.54 (s, 3 H).

[0230] Step 2 : A stirred solution of methyl 2-methyl-6-(phenylsulfinyl) indolizine-3 -carboxylate (1.2 g, 3.829 mmol) in THF (35 mL) was treated with potassium trimethylsilanolate (1.23 g, 9.573 mmol) at RT. The RM was stirred at 75 °C for 6 h. The RM was concentrated under reduced pressure and the obtained residue was triturated with n-Pentane (2 x 25 mL), and dried under vacuum to afford potassium 2-methyl-6-(phenylsulfinyl)indolizine- 3-carboxylate (Int-B020) (1.5 g, 100%) as an off-white solid.1H NMR (400 MHz, MeOD) 5 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, 3 H).Example 1 - Synthesis of N-((S)-l-amino-3-hvdroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-6-(trans-2- phenylcvclopropyl)indolizine-3-carboxamide (Cpd 001)

[0231] Step 1 : A stirred solution of 2-amino-3-((tert-butyldimethylsilyl)oxy)-2-methylpropanamide (Int-AOOl- Enl) (620 mg, 2.656 mmol) in DMF (10 ml) was treated with DIPEA (1.8 mL, 10.624 mmol) followed by a solution of potassium 2-methyl-6-((trans)-2-phenylcyclopropyl)indolizine-3 -carboxylate (Int-B005) (700 mg, 2.125 mmol) in DMF (5 mL) and HATU (1.2 g, 3.187 mmol) at 0 °C. The RM was stirred at 65°C for 16 h. The RM was poured into ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated NaHCCL solution (30 mL), brine solution (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using a gradient of 0-50% EtOAc inPet. etherto afford N-(l-amino-3-((tert-butyldimethylsilyl) oxy)-2-methyl-l-oxopropan-2-yl)-2-methyl- 6-((trans)-2-phenylcyclopropyl) indolizine-3 -carboxamide (380 mg, 35%) as a brown gummy. ' H NMR (400 MHz, CDCh) 5 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, 3 H), 1.48-1.40 (m, 1 H), 1.39-1.38 (m, 1 H), 0.91 (s, 9 H), 0.13 (s, 6 H).

[0232] Step 2 : A solution of Pyridine (1 mL, 11.567 mmol) in THF (10 mL) was treated with HF in Pyridine (1 mL, 11.567 mmol) at 0 °C and stirred for 10 min. The RM was treated with a solution of N-(l-amino-3-((tert- butyldimethylsilyl)oxy)-2-methyl-l-oxopropan-2-yl)-2-methyl-6-((trans)-2-phenylcyclopropyl)indolizine-3- carboxamide (390 mg, 0.771 mmol) in THF (5 mL) at 0 °C. The RM was stirred at RT for 16 h. The RM was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep. HPLC [Prep. HPLC conditions: Mobile phase: lOmM ABC in water, Mobile phase B: ACN, Column: LUNA C18 (150 x 25 mm) x 5 pm, FLOW: 20 ml / min, Method: (T in min. / % of B): 0 / 30, 2 / 30, 10 / 70, 14 / 70, 17.1 / 98, 18 / 98, 18.1 / 30, 21 / 30, Temperature: RT.] The desired fractions were evaporated and lyophilized to afford N-((S)-l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-6-(trans-2- phenylcyclopropyl)indolizine-3-carboxamide (Cpd 001) (88 mg, 29%) as an off white solid.

[0233] A preparative chiral SFC was performed on the racemic mixture of Cpd 001 to afford Cpd 001 - Enl and Cpd 002 - En2.

[0234] The following compound was prepared in a similar manner (use of appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to the person skilled in the art) as described for Cpd 001 : Cpd 002.Example 2 - Synthesis of N-(4,4-difluoro-l -hydro xy-2-methylbutan-2-yl)-2-methyl-6-(o-tolyloxy)indolizine-3- carboxamide (Cpd 006)

[0235] A solution of potassium 2-methyl-6-(o-tolyloxy)indolizine-3-carboxylate (Int-B006) (300 mg, 0.939mmol) in DMF (5 mL) was treated with HATU (535.701 mg, 1.409 mmol), DIPEA (0.491 mL, 2.818 mmol), stirred for 10 min, then treated with 2-amino-4,4-difluoro-2-methylbutan-l-ol (Int-A003) (143.763 mg, 1.033 mmol). The RM was stirred at 70 °C for 2 h. The RM was diluted with ice water (5 mL), extracted with EtOAc (2 x 50 mL). Combined organic layer was washed with 10% NaHCCL (2x 10.0 mL) and brine solution (10 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 26% of EtOAc in pet. ether as an eluent, to afford N-(4,4-difluoro-l-hydroxy-2-methylbutan-2-yl)-2-methyl-6- (o-tolyloxy)indolizine-3-carboxamide (Cpd 006) (140 mg) as pale yellow gummy.

[0236] A preparative chiral SFC was performed on the racemic mixture of Cpd 006 to afford Cpd 006 - Enl and Cpd 006 - En2.

[0237] The following compounds were prepared in a similar manner (use of appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to the person skilled in the art) as described for Cpd 006 : Cpd 004 - Enl, Cpd 004 - En2, Cpd 008 - Enl, Cpd 008 - En2, Cpd 010 - Enl, Cpd 010 - En2, Cpd 012 - Enl, Cpd 012 - En2, Cpd 014 - Enl, Cpd 014 - En2, Cpd 016 - Enl, Cpd 016 - En2.Example 3 - Synthesis of N-(3-(hvdroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-phenoxyindolizine-3- carboxamide (Cpd 003 - Enl)

[0238] To a stirred solution of potassium 2-methyl-6-phenoxyindolizine-3-carboxylate (Int-B008) (170 mg, 0.557 mmol, 1 equiv.) in DMA (3 mL) was treated with HATU (275.181 mg, 0.724 mmol, 1.3 equiv.) DIPEA (0.291 mL, 1.670 mmol, 3 equiv) at RT. Then, the RM was treated with a solution of 3-amino-3- (hydroxymethyl)pyrrolidin-2-one (Int-A005 - Enl) (86.943 mg, 0.668 mmol, 1.2 equiv.) in DMA (2 mL). The RM was stirred at RT for 16 h. The RM was diluted with ice cold water (25 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed ice cold water (2 x 5.0 mL), ice cold brine (5.0 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by Prep. HPLC [Prep. HPLC conditions: Mobile phase: lOmM ABC in water, Mobile phase B: ACN, Column: UNIHYBRID C18 (150 x 25 mm) x 8 pm, FLOW: 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: RT.] The desired fractions were evaporated and lyophilized to afford N-(3-(hydroxymethyl)- 2-oxopyrrolidin-3-yl)-2-methyl-6-phenoxyindolizine-3-carboxamide (Cpd 003 - Enl) (53.5 mg, 25%) as an off white solid.

[0239] The following compounds were prepared in a similar manner (use of appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to the person skilled in the art) as described for Cpd 003 - Enl : Cpd 003 - En2, Cpd 007 - Enl, Cpd 007 - En2, Cpd 009 - Enl, Cpd 009 - En2, Cpd Oil - Enl, Cpd Oil - En2, Cpd 013 - Enl, Cpd 013 - En2, Cpd 015 - Enl, Cpd 016 - En2.Example 4 - Synthesis of N-(3 -(hydro xymethyl)-2-oxopyrro lidin-3 -yl)-2 -methyl-6-(o-tolyloxy)indolizine-3- carboxamide (Cpd 005)

[0240] Step 1 : A solution of Potassium 2-methyl-6-(o-tolyloxy)indolizine-3-carboxylate (Int-B007) (300 mg, 0.939 mmol) in THF (10 mL) was treated with PyBroP (656.767 mg, 1.409 mmol), DIPEA (0.664 mL, 3.757 mmol) at RT. Then, the RM was treated with 3-amino-3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (Int-A006) (275.477 mg, 1.127 mmol) . The RM was stirred at RT for 16 h. The RM was diluted with water (25 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by FCC on silica gel using 0-55% of EtOAc in Pet. ether as a gradient to afford N-(3-(((tert- butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(o-tolyloxy)indolizine-3-carboxamide (100 mg, 21%) as an off-white solid.!H NMR (400 MHz, CDCh) 5 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, 3 H), 0.90 (s, 9 H), 0.099 (d, 6 H).

[0241] Step 2 : A solution of Hydrogenfluoride in pyridine (0.344 mL, 1.970 mmol) in THF (10 mL) was treated with pyridine(0.447 mL, 1.970 mmol) at 0 °C. Then, the RM was treated with a solution of N-(3-(((tert- butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(o-tolyloxy)indolizine-3-carboxamide (100 mg, 0.197 mmol) at 0 °C. The RM was stirred at RT for 16 h. The RM was concentrated at RT and diluted with water (10.0 mL), basified with aq. NaHCCL solution (pH ~8-9), and then extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with water (10.0 mL), brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. . The residue was purified by FCC on silica gel using 0-6% of MeOH in DCM as a gradient to afford N-(3 -(hydro xymethyl)-2 -oxopyrro lidin-3 -yl)-2-methy l-6-(o-tolyloxy)indolizine-3- carboxamide (Cpd 005) (75 mg, 94%) as an off-white solid.

[0242] A preparative chiral SFC was performed on the racemic mixture of Cpd 005 to afford Cpd 005 - Enl and Cpd 005 - En2.

[0243] The following compounds were prepared in a similar manner (use of appropriate reagents (chiral or racemic) and purification methods (including chiral HPLC or chiral SFC) known to the person skilled in the art) as described for Cpd 005 : Cpd 017, Cpd 019 - Enl, Cpd 019 - En2, Cpd 020 - Enl, Cpd 020 - En2, Cpd 021 - Enl, Cpd 021 - En2, Cpd 022 - Enl, Cpd 022 - En2, Cpd 024 - Enl, Cpd 024 - En2, Cpd 024 - En3, Cpd 024 - En4.Table 3 : Analytical data.Table 4: Chiral analytical data.Part BExample 5 - Monitoring the TRPM3 ion channel driven Ca2+ uptake.

[0244] In order to monitor the inhibition of the mouse TRPM3a2 (mTRPM3) ion channel by the compounds of the invention, a cellular system making use of an mTRPM3alpha2 or hTRPM3 overexpressing cell line (flip-in HEK293) was used. The TRPM3 channel was stimulated / opened with Pregnenolone sulfate (PS) (50pM) which results in Ca2+influx.

[0245] For mTRPM3, the intracellular Ca2+was measured with a Calcium responsive dye, Fluor-4 AM ester (Invitrogen). Cells were cultured until a confluence of 80-90%, washed with Versene (Invitrogen) and detached from the surface by a short incubation with 0.05% Trypsin (Invitrogen). The trypsination process was stopped by the addition of complete cell culture medium (DMEM, glutamax, 10%FCS,NEAA, Pen-Strep). Cells were collected and resuspended in Krebs buffer without Calcium at RT.

[0246] Prior the cell seeding (±2000 cells / well into a black, 384 well plate (Greiner)) the diluted compound was added in the assay plate, together with the PS dissolved in Krebs buffer containing Calcium. This resulted in a 2.4mM Ca2+assay solution. Directly after cell addition the plates were read on an Envision fluorescence reader (Perkin Elmer) by an Excitation of 485nM and emission at 535nM.

[0247] Channel inhibition was calculated compared to a non-PS stimulated control versus a condition stimulated with PS (50pM) with vehicle. The ability of the compounds of the invention to inhibit this activity was determined as: Percentage inhibition = [1-((RFU determined for sample with test compound present - RFU determined for sample with positive control inhibitor) divided by (RFU determined in the presence of vehicle - RFU determined for sample with positive control inhibitor))] * 100.

[0248] The activities of the Example compounds cpd 001-025 tested are depicted in the table below. All tested compounds show an activity in the Fluo-4 AM assay. The activity ranges A, B and C refer to IC50 values in the Fluo-4 AM assay as follows: “A”: ICso <1 pM; “B” : 1 pM < ICso <20 pM and “C” : ICso > 20 pM.Table 5: Activities of exemplary compounds.

Claims

CLAIMS1. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereofwhereinR1represents -F, -Cl, -Br, -I, -CN, -Rw, -ORW, -OC(=O)RW, -NRWRX, -NRWC(=O)RX, -SRW, -S(=O)RW, -S(=O)2RW, -C(=O)RW, -C(=O)ORW, or -C(=O)NRWRX;R3represents -RY;X represents a single bond between Cy and the carbon atom to which it is attached, or X represents -O-, - CR5R5'-, -S-, -S(O)n-, -S-CR5R5, -CR5R5-S-, -CR5R5-CR4R4-, -NR5-CR4R4-, -O-CR5R5-, -C=, -C=C-, or -CRSRS'-NR5-, in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -NO2, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ;R4and R4' independently of one another represents -RY; n is an integer ranging from 1 to 2;R5and R5' independently of one another represent -RY, or R5and R5' together form a carbonyl, a 3-6- membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted, or a 3 -6-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted, on the atom to which they are attached;R6, R7and R8independently of one another represent -F, -Cl, -Br, -I, -CN, -N02, -SF5, -Rw, -ORW, - OC(=O)RW, -NRWRX, -NRWC(=O)RX, -SRW, -S(=O)RW, -S(=O)2RW, -C(=O)RW, -C(=O)ORW, or - C(=O)NRWRX;Cy represents 3-14-membered cycloalkyl, saturated or unsaturated, 3-14-membered heterocycloalkyl, saturated or unsaturated; 5-14-membered aryl, or 5-14-membered heteroaryl; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -N02, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=0)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ; whereinRwand Rxindependently of one another in each case independently represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6- heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or 3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -Ci- C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;RYand Rzindependently of one another in each case independently represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6- heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -Ci- C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or RYand Rztogether form a 4, 5, 6, 7 or 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated, unsubstituted or mono- or polysubstituted; and wherein "mono- or polysubstituted" in each case independently means substituted with one or more substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -C1-6-alkyl, -CF3, -CF2H, - CFH2, -CF2CI, -CFCI2, -C1-6-alkylene-CFs, -C1-6-alkylene-CF2H, -C1-6-alkylene-CFFF, -C1-6-alkylene-O- CF3, -C1-6-alkylene-O-CF2H, -C1-6-alkylene-O-CFFF, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C1-6-alkylene- N(C1-6-alkyl)-C1-6-alkylene-CF3, -C(=O)-C1-6-alkyl, -C1-6-alkylene-C(=O)-C1-6-alkyl, -C(=O)OH, -C1-6- alkylene-C(=O)-OH, -C(=O)-OC1-6-alkyl, -C1-6-alkylene-C(=O)-OC1-6-alkyl, -C(=O)O-C1-6-alkylene-CF3, -C(=O)-NH2, -C1-6-alkylene-C(=O)-NH2, -C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-C(=O)-NH(C1-6-alkyl), - C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-C(=O)-N(C1-6-alkyl)2, -C(=O)-NH(OH), -C1-6-alkylene-C(=O)- NH(OH), -OH, -C1-6-alkylene-OH, =0, -OCF3, -OCF2H, -OCFH2, -OCF2CI, -OCFCI2, -O-C1-6-alkyl, -C1-6- alkylene-O-C1-6-alkyl, -O-C1-6-alkylene-O-C1-6-alkyl, -O-C1-6-alkylene-NH2, -O-C1-6-alkylene-NH-C1-6- alkyl, -O-C1-6-alkylene-N(C1-6-alkyl)2, -0-C(=0)-C1-6-alkyl, -C1-6-alkylene-O-C(=O)-C1-6-alkyl, -O- C(=0)-0-C1-6-alkyl, -C1-6-alkylene-O-C(=O)-O-C1-6-alkyl, -0-C(=0)-NH(C1-6-alkyl), -C1-6-alkylene-O- C(=O)-NH(C1-6-alkyl), -O-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-O-C(=O)-N(C1-6-alkyl)2, -O-S(=O)2-NH2, -C1-6-alkylene-O-S(=O)2-NH2, -O-S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-O-S(=O)2-NH(C1-6-alkyl), -O- S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-O-S(=O)2-N(C1-6-alkyl)2, -NH2, -NO, -NO2, -C1-6-alkylene-NH2, -NH(C1-6-alkyl), -N(3-14-membered cycloalkyl)(C1-6-alkyl), -N(C1-6-alkyl)-C1-6-alkylene-OH, -N(H)-C1-6- alkylene-OH, -C1-6-alkylene-NH(C1-6-alkyl), -N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)2, -NH-C(=O)-Ci- e-alkyl, -C1-6-alkylene-NH-C(=O)-C1-6-alkyl, -NH-C(=O)-O-C1-6-alkyl, -C1-6-alkylene-NH-C(=O)-O-C1-6- alkyl, -NH-C(=O)-NH2, -C1-6-alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-NH- C(=O)-NH(C1-6-alkyl), -NH-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C(=O)-N(C1-6-alkyl)2, -N(C1-6- alkyl)-C(=O)-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-O-C1-6- alkyl, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-O-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-NH2, -C1-6-alkylene-N(C1-6- alkyl)-C(=O)-NH2, -N(C1-6-alkyl)-C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-NH(C1-6- alkyl), -N(C1-6-alkyl)-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-N(C1-6-alkyl)2, -NH- S(=O)2OH, -C1-6-alkylene-NH-S(=O)2OH, -NH-S(=O)2-C1-6-alkyl, -C1-6-alkylene-NH-S(=O)2-C1-6-alkyl, - NH-S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-NH-S(=O)2-O-C1-6-alkyl, -NH-S(=O)2-NH2, -C1-6-alkylene-NH- S(=O)2-NH2, -NH-S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-NH-S(=O)2-NH(C1-6-alkyl), -NH-S(=O)2N(CI-6- alkyl)2, -C1-6-alkylene-NH-S(=O)2N(C1-6-alkyl)2, -N(C1-6-alkyl)-S(=O)2-OH, -C1-6-alkylene-N(C1-6-alkyl)- S(=O)2-OH, -N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, -N(C1-6- alkyl)-S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-O-C1-6-alkyl, -N(C1-6-alkyl)-S(=O)2-NH2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-NH2, -N(C1-6-alkyl)-S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-N(C1-6- alkyl)-S(=O)2-NH(C1-6-alkyl), -N(C1-6-alkyl)-S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2- N(C1-6-alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -S-C1-6-alkyl, -C1-6-alkylene-S-C1-6-alkyl, -S(=O)- C1-6-alkyl, -C1-6-alkylene-S(=O)-C1-6-alkyl, -S(=O)2-C1-6-alkyl, -C1-6-alkylene-S(=O)2-C1-6-alkyl, -S(=O)2- OH, -C1-6-alkylene-S(=O)2-OH, -S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-S(=O)2-O-C1-6-alkyl, -S(=O)2-NH2, - C1-6-alkylene-S(=O)2-NH2, -S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-S(=O)2-NH(C1-6-alkyl), -S(=O)2-N(CI- 6-alkyl)2, -C1-6-alkylene-S(=O)2-N(C1-6-alkyl)2, 3-14-membered cycloalkyl, -C1-6-alkylene-(3-14- membered cycloalkyl), 3 to 14-membered heterocycloalkyl, -C1-6-alkylene-(3 to 14-membered heterocycloalkyl), -phenyl, -C1-6-alkylene-phenyl, 5 to 14-membered heteroaryl, -C1-6-alkylene-(5 to 14- membered heteroaryl), -O-(3-14-membered cycloalkyl), -O-(3 to 14-membered heterocycloalkyl), -O- phenyl, -O-(5 to 14-membered heteroaryl), -C(=O)-(3-14-membered cycloalkyl), -C(=O)-(3 to 14- membered heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5 to 14-membered heteroaryl), -S(=O)2-(3-14- membered cycloalkyl), -S(=O)2-(3 to 14-membered heterocycloalkyl), -S(=O)2-phenyl, -S(=O)2-(5 to 14- membered heteroaryl).

2. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in claim 1, wherein R1represents C1-3 alkyl.

3. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in claim 2, wherein R1represents methyl.

4. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 3, wherein R3represents C-R’R’R9', where R9, R9', and R9" are independently RY, or C1-6alkyl or C1-6heteroalkyl optionally substituted with one or more RY5. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 3, wherein R3represents C-R9R9'R9", where one of R9, R9', and R9" is RY, or Ci -ealkyl or C1-6heteroalkyl optionally substituted with one or more RY, and where two of R9, R9', and R9" together form a 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5- 14-membered aryl, or 5-14-membered heteroaryl, said 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl optionally monosubstituted or polysubstituted with one or more RY.

6. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 3, wherein R3represents C-R’R’R9', where R9, R9', and R9" are independently -H, -C1-6alkyl, -Ci -ealky 1-OH, -C1-6alkyl-O-CHe,. -(C=0)-NH2, -(C=O)-NH- CH3, (C=O)-N(CH3)2, -C1-6alkyl-CF2H, and -C1-6alkyl-CF3.

7. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 6, wherein Cy represents C3-Cs cycloalkyl, phenyl, C5-C8heterocycloalkyl, or C5-C8heteroaryl, optionally substituted with one or more of halogen, Ci-C3- haloalkyl, hydroxy, acyl, carboxamide, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, butyl, cyclobutyl, oxetane, pyrrole, or diazole, said carboxamide, acyl, cyclopropyl, cyclobutyl, oxetane, pyrrole and diazole optionally being further substituted with halogen, Ci-C3-haloalkyl, hydroxy, phenyl, methyl, methoxy, ethyl, ethoxy, or propyl optionally connected through -C1-C6-alkylene- or -Ci -Ce-hctcroalky lenc-.

8. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 6, wherein Cy represents a residue selected from:

9. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 8, wherein R3represents -C-R10R10’R10”, and wherein R10, R10’, and R10’’ independently represent-H;-S(=O)2C1-6-alkyl, saturated, unsubstituted, monosubstituted or polysubstituted with -F;-S(=O)2(3- 14-membered cycloalkyl), saturated, unsubstituted; -C1-6-alkyl, saturated, unsubstituted, monosubstituted or disubstituted with substituents independently of one another selected from the group consisting of -OH, , =0, -OC1-6-alkyl, -NH2, -NHC1-6-alkyl, -N(C1-6- alkyl)2, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6-alkyl, -C(=0)NH2, -C(=0)-NH-Ci-3-alkyl, - C(=O)N(Ci-3-alkyl)2, -phenyl unsubstituted;3-14-membered cycloalkyl or -C1-6-alkylene-(3-14-membered cycloalkyl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 3-14-membered cycloalkyl is saturated, unsubstituted, monosubstituted or disubstituted with substituents independently of one another selected from the group consisting of -C1-6-alkyl, -C1-6-alkylene-NH2, -C1-6-alkylene-NH-C1-6-alkylene-CF3, -C1-6- alkylene-OH, -C1-6-alkylene-NHC(=O)O-C1-6-alkyl, -OH, -OC1-6-alkyl, -NH2, -N(C1-6-alkyl)2, - NHC(=0)0-C1-6-alkyl;3-14-membered heterocycloalkyl or -C1-6-alkylene-(3- 14-membered heterocycloalkyl), wherein -C1-6- alkylene- is unsubstituted or monosubstituted with -OH, wherein said 3-14-membered heterocycloalkyl in each case is selected from azetane, 1,4-oxazepane, pyrrolidine, piperidine, azepane, diazepane, tetrahydrofuran, tetrahydropyran, oxetane, morpholine, piperazine, hexahydrocyclopenta[c]pyrrole, octahydrocyclopenta[c]pyrrole, octahydropyrrolo[l,2-a]pyrazin, 8-azabicyclo[3.2.1]octane, 9-azabicyclo- [3.3.1]nonane, quinuclidine, hexahydro-lH-pyrrolizine, 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 7- azaspiro[3.5]nonane, 1,1-dioxothiacyclohexane, in each case unsubstituted, mono- or polysubstituted with substituents independently of one another selected from the group consisting of -F, -OH, =0, -C1-6-alkyl, - C1-6-alkylene-CF3, -C1-6-alkylene-OH, -C1-6-alkylene-O-C1-6-alkyl, -NH2, -N(C1-6-alkyl)2, -C1-6-alkylene- NH2, -C1-6-alkylene-N(C1-6-alkyl)2, -C(=O)-C1-6-alkyl, -C(=O)OH, -C(=O)O-C1-6-alkyl, -C(=O)O-C1-6- alkylene-CF3, -C(=0)NH2, -C(=0)NH(C1-6-alkyl), -S(=O)2C1-6-alkyl, oxetanyl, pyrimidinyl, -C1-6- alkylene-phenyl;-phenyl unsubstituted; or5-14-membered heteroaryl or -C1-6-alkylene-(5-14-membered heteroaryl), wherein -C1-6-alkylene- is unsubstituted or monosubstituted with -OH, wherein said 5-14-membered heteroaryl in each case is selected from the group consisting of pyridine, pyridazine, pyrazine, pyrazole, isoxazole, triazole, and [l,2,4]triazolo[4,3-a]pyrimidine, in each case unsubstituted, monosubstituted or disubstituted with substituents independently of one another selected from the group consisting of -C1-6-alkyl, -OH.

10. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 9, wherein R5and R5' independently of one another represent -H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, ineach case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

11. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 9, wherein R5and R5' together form a 3-4- membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted, or a 3 -4-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

12. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 11, wherein R6, R7and R8independently of one another represent-H, -F, -Cl, -Br, -I, -OH, -SH, -SFs, -CN, -NO2, -C(=O)OH, -NH2,-C1-6-alkyl, -CF3, -CHF2, -CH2F,-O-C1-6-alkyl, -OCF3, -OCHF2, -OCH2F,-NHC1-6-alkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2;-N(C1-6-alkyl)2 unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2;-C(=0)0C1-6-alkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2;-0C(=0)C1-6-alkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2; or-C1-6-heteroalkyl unsubstituted or substituted with one or more substituents independently of one another selected from -OH, =0, -F, -Cl, -Br, -I, -SH, =S, -CN, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, SF5, -NO2, -C(=O)OH, -NH2, and -C(=O)NH2.

13. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 12 wherein R7and R8represent -H.

14. A compound of formula (I), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 1 to 12 wherein R6represents -H or -F.

15. A compound a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof selected from the group consisting ofCpd 001 - N-((S)-l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-6-(trans-2- phenylcyclopropyl)indolizine-3-carboxamide;Cpd 002 - N-((S)-l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-6-(cis-2-phenylcyclopropyl)indolizine-3-carboxamide;Cpd 003 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-phenoxyindolizine-3-carboxamide;Cpd 004 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-yl)-2-methyl-6-phenoxyindolizine-3 -carboxamide;Cpd 005 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(o-tolyloxy)indolizine-3-carboxamide;Cpd 006 - N-(4,4-difluoro- 1 -hydroxy -2 -methylbutan-2-yl)-2-methyl-6-(o-tolyloxy)indolizine-3 -carboxamide;Cpd 007 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(m-tolyloxy)indolizine-3-carboxamide;Cpd 008 - N-(4,4-difluoro-l-hydroxy-2-methylbutan-2-yl)-2-methyl-6-(m-tolyloxy)indolizine-3-carboxamide;Cpd 009 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(p-tolyloxy)indolizine-3-carboxamide;Cpd 010 - N-(4,4-difluoro- 1 -hydroxy -2 -methylbutan-2-yl)-2-methyl-6-(p-tolyloxy)indolizine-3 -carboxamide;Cpd Oil - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-6-(2-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 012 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-yl)-6-(2 -metho xyphenoxy)-2 -methylindolizine-3- carboxamide;Cpd 013 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-6-(3-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 014 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-yl)-6-(3 -metho xyphenoxy)-2 -methylindolizine-3- carboxamide;Cpd 015 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-6-(4-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 016 - N-(4,4-difluoro-l -hydroxy -2 -methylbutan-2-y l)-6-(4-methoxyphenoxy)-2-methylindolizine-3- carboxamide;Cpd 017 - (S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-6-phenoxyindolizine-3- carboxamide;Cpd 018 - 6-(2-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 019 - 6-(3-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 020 - 6-(4-fluorophenoxy)-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 021 - 6-benzyl-N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methylindolizine-3-carboxamide;Cpd 022 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(phenylthio)indolizine-3-carboxamide;Cpd 023 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-((lS,2S)-2-(pyridin-2- yl)cyclopropyl)indolizine-3-carboxamide;Cpd 024 - N-(3 -(hydro xymethyl)-2-oxopyrrolidin-3 -yl)-2-methyl-6-(phenylsulfinyl)indolizine-3-carboxamide andCpd 025 - N-(3-(hydroxymethyl)-2-oxopyrrolidin-3-yl)-2-methyl-6-(phenylsulfonyl)indolizine-3-carboxamide.

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

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

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

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

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

21. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereofwhereinR3represents C-R9R9'R9", where R9, R9', and R9" are independently RY, or Ci -ealkyl or C1-6heteroalkyl optionally substituted with one or more RY; or wherein one of R9, R9', and R9" is RY, or C1-6alkyl or Ci- eheteroalkyl optionally substituted with one or more RY, and where two of R9, R9', and R9" together form a 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl, said 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5- 14-membered heteroaryl optionally monosubstituted or polysubstituted with one or more RY;R6is selected from H, halogen, and C1-6haloalkyl;X represents a single bond between Cy and the carbon atom to which it is attached, or X represents -O-, - CR5R5'-, -S-, -S(O)n-, -S-CR5R5, -CR5R5-S-, -CR5R5-CR4R4'-, -NR5-CR4R4-, -O-CR5R5-, -C=, -C=C-, -CRSRS'-NR5-, in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -NO2, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, - NRYC(=O)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ; n is an integer ranging from 1 to 2;R4and R4' independently of one another represents -RY;R5and R5' independently of one another represent -RY, or R5and R5' together form a carbonyl, a 3-6- membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted, or a 3 -6-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted, on the atom to which they are attached;Cy represents 3-14-membered cycloalkyl, saturated or unsaturated, 3-14-membered heterocycloalkyl, saturated or unsaturated; 5-14-membered aryl, or 5-14-membered heteroaryl; in each case unsubstituted, mono- or poly substituted with substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -NO, -NO2, =0, =S, -SF5, -RY, -0RY, -OC(=O)RY, -NRYRZ, -NRYC(=0)RZ, -SRY, -S(=O)RY, -S(=O)2RY, -C(=O)RY, -C(=O)ORY, or -C(=O)NRYRZ; wherein:RYand Rzindependently of one another in each case independently represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;3-14-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered heterocycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6- heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted;6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted; or RYand Rztogether form a 4, 5, 6, 7 or 8 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, saturated or unsaturated, unsubstituted or mono- or polysubstituted; and wherein "mono- or polysubstituted" in each case independently means substituted with one or more, e.g. 1, 2, 3, 4, or more substituents independently of one another selected from -F, -Cl, -Br, -I, -CN, -C1-6- alkyl, -CF3, -CF2H, -CFH2, -CF2C1, -CFC12, -C1-6-alkylene-CF3, -C1-6-alkylene-CF2H, -C1-6-alkylene-CFH2, -C1-6-alkylene-O-CF3, -C1-6-alkylcnc-O-CF2H. -C1-6-alkylene-O-CFH2, -C1-6-alkylene-NH-C1-6-alkylene- CF3, -C1-6-alkylene-N(C1-6-alkyl)-C1-6-alkylene-CF3, -C(=0)-C1-6-alkyl, -C1-6-alkylene-C(=O)-C1-6-alkyl, - C(=O)OH, -C1-6-alkylene-C(=O)-OH, -C(=O)-OC1-6-alkyl, -C1-6-alkylene-C(=O)-OC1-6-alkyl, -C(=O)O-Ci-6-alkylene-CF3, -C(=O)-NH2, -C1-6-alkylene-C(=O)-NH2, -C(=0)-NH(C1-6-alkyl), -C1-6-alkylene-C(=0)- NH(C1-6-alkyl), -C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-C(=O)-N(C1-6-alkyl)2, -C(=0)-NH(0H), -C1-6- alkylene-C(=O)-NH(OH), -OH, -C1-6-alkylene-OH, =0, -OCF3, -OCF2H. -OCFH2, -OCF2C1, -OCFCI2, -O- C1-6-alkyl, -C1-6-alkylene-O-C1-6-alkyl, -O-C1-6-alkylene-O-C1-6-alkyl, -O-C1-6-alkylene-NH2, -O-C1-6- alkylene-NH-C1-6-alkyl, -O-C1-6-alkylene-N(C1-6-alkyl)2, -0-C(=0)-C1-6-alkyl, -C1-6-alkylene-0-C(=0)-Ci- e-alkyl, -O-C(=O)-O-C1-6-alkyl, -C1-6-alkylene-O-C(=O)-O-C1-6-alkyl, -O-C(=O)-NH(C1-6-alkyl), -C1-6-alkylene-0-C(=0)-NH(C1-6-alkyl), -O-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-O-C(=O)-N(C1-6-alkyl)2, -O- S(=O)2-NH2, -C1-6-alkylene-O-S(=O)2-NH2, -O-S(=O)2-NH(CI -e-alkyl), -C1-6-alkylene-O-S(=O)2-NH(C1-6- alkyl), -O-S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-O-S(=O)2-N(C1-6-alkyl)2, -NH2, -NO, -NO2, -C1-6-alkylene- NH2, -NH(C1-6-alkyl), -N(3-14-membered cycloalkyl)(C1-6-alkyl), -N(C1-6-alkyl)-C1-6-alkylene-OH, -N(H)- C1-6-alkylene-OH, -C1-6-alkylene-NH(C1-6-alkyl), -N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)2, -NH- C(=O)-C1-6-alkyl, -C1-6-alkylene-NH-C(=O)-C1-6-alkyl, -NH-C(=O)-O-C1-6-alkyl, -C1-6-alkylene-NH- C(=O)-O-Ci -e-alkyl, -NH-C(=O)-NH2, -C1-6-alkylene-NH-C(=O)-NH2, -NH-C(=O)-NH(C1-6-alkyl), -C1-6- alkylene-NH-C(=O)-NH(C1-6-alkyl), -NH-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-NH-C(=O)-N(C1-6-alkyl)2, -N(C1-6-alkyl)-C(=O)-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-O- C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-O-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-NH2, -C1-6-alkylene- N(Ci -6-alkyl)-C(=O)-NH2, -N(Ci -6-alkyl)-C(=O)-NH(Ci -e-alkyl), -C1-6-alkylene-N(C1-6-alkyl)-C(=O)- NH(Ci -e-alkyl), -N(C1-6-alkyl)-C(=O)-N(C1-6-alkyl)2, -C1-6-alkylene-N(C1-6-alkyl)-C(=O)-N(C1-6-alkyl)2, - NH-S(=O)2OH, -C1-6-alkylene-NH-S(=O)2OH, -NH-S(=O)2-C1-6-alkyl, -C1-6-alkylene-NH-S(=O)2-C1-6- alkyl, -NH-S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-NH-S(=O)2-O-C1-6-alkyl, -NH-S(=O)2-NH2, -C1-6-alkylene- NH-S(=O)2-NH2, -NH-S(=O)2-NH(C1-6-alkyl), -C1-6-alkylene-NH-S(=O)2-NH(C1-6-alkyl), -NH- S(=O)2N(C1-6-alkyl)2, -C1-6-alkylene-NH-S(=O)2N(C1-6-alkyl)2, -N(C1-6-alkyl)-S(=O)2-OH, -C1-6-alkylene- N(C1-6-alkyl)-S(=O)2-OH, -N(C1-6-alkyl)-S(=O)2-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-C1-6- alkyl, -N(C1-6-alkyl)-S(=O)2-O-C1-6-alkyl, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-O-C1-6-alkyl, -N(C1-6- alkyl)-S(=O)2-NH2, -C1-6-alkylene-N(C1-6-alkyl)-S(=O)2-NH2, -N(C1-6-alkyl)-S(=O)2-NH(C1-6-alkyl), -C1-6- alkylene-N(Ci -e-alkyl)-S(=O)2-NH(Ci -e-alkyl), -N(Ci -e-alkyl)-S(=O)2-N(Ci -e-alkyl)2, -C1-6-alkylene-N(Ci- e-alkyl)-S(=O)2-N(C1-6-alkyl)2, -SH, =S, -SF5, -SCF3, -SCF2H, -SCFH2, -S-C1-6-alkyl, -C1-6-alkylene-S-Ci- e-alkyl, -S(=O)-C1-6-alkyl, -C1-6-alkylene-S(=O)-C1-6-alkyl, -S(=O)2-Ci -e-alkyl, -C1-6-alkylene-S(=O)2-C1-6- alkyl, -S(=O)2-OH, -C1-6-alkylene-S(=O)2-OH, -S(=O)2-O-Ci -e-alkyl, -C1-6-alkylene-S(=O)2-O-C1-6-alkyl, - S(=O)2-NH2, -C1-6-alkylene-S(=O)2-NH2, -S(=O)2-NH(CI -e-alkyl), -C1-6-alkylene-S(=O)2-NH(C1-6-alkyl), - S(=O)2-N(C1-6-alkyl)2, -C1-6-alkylene-S(=O)2-N(C1-6-alkyl)2, 3-14-membered cycloalkyl, -C1-6-alkylene-(3- 14-membered cycloalkyl), 3 to 14-membered heterocycloalkyl, -C1-6-alkylene-(3 to 14-membered heterocycloalkyl), -phenyl, -C1-6-alkylene-phenyl, 5 to 14-membered heteroaryl, -C1-6-alkylene-(5 to 14- membered heteroaryl), -O-(3- 14-membered cycloalkyl), -O-(3 to 14-membered heterocycloalkyl), -O- phenyl, -O-(5 to 14-membered heteroaryl), -C(=O)-(3-14-membered cycloalkyl), -C(=O)-(3 to 14- membered heterocycloalkyl), -C(=O)-phenyl, -C(=O)-(5 to 14-membered heteroaryl), -S(=O)2-(3-14- membered cycloalkyl), -S(=O)2-(3 to 14-membered heterocycloalkyl), -S(=O)2-phenyl, -S(=O)2-(5 to 14- membered heteroaryl).

22. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in claim 21, wherein R3represents C-R9R9'R9', where R9, R9', and R9" are independently RY, or Ci -ealkyl or C1-6heteroalkyl optionally substituted with one or more RY.

23. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 21 to 22, wherein R3represents C-R’R’R9', whereR9, R9', andR9" are independently -H, -Ci -ealkyl, -C1-6alkyl-OH, -C1-6alkyl-O-CHi. -(C=O)-NH2, -(C=O)- NH-CH3, -(C=O)-N(CH3)2, -C1-6alkyl-CF2H, and -C1-6alkyl-CF3.

24. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 21 to 23, wherein Cy represents Ca-Cx cycloalkyl, phenyl, C5-C8heterocycloalkyl, or C5-C8heteroaryl, optionally substituted with one or more of halogen, C1-C3-haloalkyl, hydroxy, acyl, carboxamide, methyl, methoxy, ethyl, ethoxy, propyl, cyclopropyl, butyl, cyclobutyl, oxetane, pyrrole, or diazole, said carboxamide, acyl, cyclopropyl, cyclobutyl, oxetane, pyrrole and diazole optionally being further substituted with halogen, C-C, -haloalky I. hydroxy, phenyl, methyl, methoxy, ethyl, ethoxy, or propyl optionally connected through -C1-C6-alkylene- or-Ci -Ce-heteroalkylene-.

25. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 21 to 23, wherein Cy represents a residue selected from:

26. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 21 to 25, wherein R5and R5' independently of one another represent-H;-C1-C6-alkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;-C1-C6-heteroalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted;3-14-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-14-membered cycloalkyl is optionally connected through -C1-C6-alkylene- or -C1-C6-heteroalkylene-, in each case saturated or unsaturated, unsubstituted, mono- or polysubstituted.

27. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 21 to 25, wherein R5and R5' together form a 3-4- membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or poly substituted, or a 3-4- membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

28. A compound of formula (II), a stereo-isomeric form, a physiologically acceptable salt, solvate and / or polymorph thereof, as defined in any one of claims 21 to 27 wherein R6represents -H, -Cl, or -F.

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

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

31. The compound or the pharmaceutical composition for use in the treatment of pain according to claim 30, wherein the pain is selected from nociceptive pain, inflammatory pain, and neuropathic pain; preferably post-operative pain or migraine pain.

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

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

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