KV1.3 potassium channel antagonists

Abstract

The present invention relates to KV1.3 potassium channel antagonists and their use in the treatment and management of inflammatory diseases, including neuroinflammatory diseases.

Description

[0001] KV1.3 potassium channel antagonists

[0002] Technical field

[0003] The present invention relates to Kv1.3 potassium channel antagonists and their use in the treatment and management of inflammatory diseases, including neuroinflammatory diseases.

[0004] Background

[0005] The Kv1.3 potassium channel, a voltage-gated potassium channel, is widely expressed in the immune and nervous systems, playing crucial roles in the function of T-cells and microglia.

[0006] The activation, proliferation, and effector functions of T-cells are tightly regulated by the interplay of ion channels, including the Kv1.3 channel. In T-cells, Kv1.3 channels are involved in the modulation of calcium signalling, which is critical for T-cell receptor (TCR) signalling and subsequent activation.

[0007] Upon TCR engagement, the membrane potential of T-cells becomes depolarized, leading to the opening of voltage-gated Kv1.3 channels. This results in the efflux of potassium ions, which stabilizes the membrane potential and promotes the opening of calcium channels. The influx of calcium activates the calcium-dependent signalling pathways that drive T-cell activation, differentiation, and proliferation. Consequently, the inhibition of Kv1.3 channels can prevent the activation and proliferation of T-cells, modulating immune responses and potentially ameliorating autoimmune and inflammatory conditions.

[0008] Microglia are the resident immune cells of the central nervous system (CNS), responsible for maintaining homeostasis and responding to injury or infection. In the context of neuroinflammation and neurodegenerative diseases, microglial activation can contribute to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS), ultimately exacerbating neuronal damage.

[0009] The Kv1.3 potassium channel has been found to play a critical role in microglial activation and function. Under resting conditions, microglia express low levels of Kv1.3 channels, but upon stimulation by pro-inflammatory signals, the expression and activity of these channels increase significantly. This upregulation of Kv1.3 channels enhances the production of ROS and pro-inflammatory cytokines, perpetuating the inflammatory response and amplifying neuronal injury.

[0010] The functional involvement of Kv1.3 channels in T-cells and microglia suggests that their selective antagonism could be a promising therapeutic strategy for mitigating inflammation, particularly neuroinflammation associated with neurodegenerative diseases such as Multiple Sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. In preclinical studies, the use of Kv1.3 channel antagonists has been shown to suppress T-cell activation and proliferation, reduce microglial activation, and decrease the production of pro-inflammatory mediators. These effects translate into reduced neuroinflammation and improved outcomes in animal models of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.

[0011] Summary

[0012] The present invention relates to Kv1.3 potassium channel antagonists.

[0013] In one aspect, the present invention relates to a compound of Formula (I),

[0014] Formula (I) wherein

[0015] R1is halogen or H;

[0016] R2is halogen;

[0017] R3is halogen;

[0018] R5is H or halogen;

[0019] R6is H or halogen;

[0020] R4is of Formula (II):

[0021] Formula (II) wherein

[0022] X1is C(R7)(R8);

[0023] X2is C(R9)(R10) or a bond;

[0024] X3is C(R11)(R12) or N(R13);

[0025] X4is C(R16)(R17), O or a bond;

[0026] X5is C(R18)(R19) or a bond;

[0027] X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14, R12and R14, R12and R27, R9and R13or R10and R13are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);

[0028] R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0029] R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0030] R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R9is joined together with R13or R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0031] R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R10is joined together with R13or R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0032] R11is -X7N(R14)(R15) or -X7-O-X8-R27;

[0033] X7is a bond or C1-3 alkanediyl;

[0034] X8is a bond or C1-3 alkanediyl;

[0035] R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F; or when R27is joined together with R12to form a ring together with the intervening atom(s), then R27is Ci-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0036] R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;

[0037] R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; or when R12is joined together with R14or R27to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R13is H or C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy; or when R13and R9or R10are joined together to form a ring together with the intervening atoms, then R13is -C1-3 alkanediyl-N(R28)-, wherein the C1- 3 alkanediyl is optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl, and R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0038] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0039] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0040] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0041] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0042] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X2is C(R9)(R10), X4is C(R16)(R17), and X5is C(R18)(R19), or a pharmaceutically acceptable salt thereof.

[0043] In one aspect, the present invention relates a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial. Definitions

[0044] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0045] The terms “approximately” and “about” as referred herein are synonymous. In some embodiments, “about” refer to the recited amount, value, or duration ±20%, ±10%, ± 5%, ± 4%, ±3%, ±2%, ±1 %, or ± 0.5%.

[0046] As used herein, the term "antagonist" refers to any compound which inhibits (e.g., antagonizes, reduces, decreases, blocks, reverses, or alters) the effect of a given agonist of a protein (including the protein itself). More particularly, an antagonist is capable of acting in a manner relative to the activity of the protein, such that the biological activity of the natural agonist, is decreased in a manner that is antagonistic (e.g., against, a reversal of, contrary to) to the natural action of the protein. The terms "antagonist", "inhibitor" and “blocker” are used herein interchangeably to refer to an agent that decreases or suppresses a biological activity, such as to repress an activity of an ion channel, such as Kv1.3.

[0047] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0048] The terms “C1-3 alkyl” and “C1-6 alkyl” as used herein refer to a straight or branched hydrocarbon chains containing from 1 to 3 and 1 to 6 carbon atoms, respectively. Representative examples of C1-3 alkyl and C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.

[0049] The term “C3-6 cycloalkyl” as used herein refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms. Representative examples of C3- 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “C1-3 alkoxy” as used herein refer to -OR#, wherein R#represents a C1-3 alkyl as defined herein. Representative examples of C1-3 alkoxy include methoxy, ethoxy, propoxy, and iso-propoxy.

[0050] The term “halogen” as used herein refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0051] In some embodiments, a chemical group is “a bond”, which may also be referred to as said chemical group is absent. For example, when Rain CH3-Ra-OH is “a bond”, it refers to CH3OH.

[0052] In some embodiments, two R groups are linked together to form a ring, i.e. a ring is formed by the two R groups and the intervening atom(s).

[0053] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0054] The term “spiro compound” as used herein refers to a compound having one atom (usually a quaternary carbon) as the only common member of two rings. The term “C5-8 spiroalkyl” as used herein refers to a bicyclic ring system comprising 5 to 8 carbon atoms, wherein the two rings are connected through a single common carbon atom. Representative examples of C5-8 spiroalkyl include, but are not limited to, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, and spiro[2.5]octanyl.

[0055] As described herein, compounds of the present invention may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position, i.e. the substituent may be individually / independently selected from a group of substituents. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0056] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0057] Detailed description

[0058] In one aspect, the present invention relates to a compound of Formula (I),

[0059] Formula (I) wherein

[0060] R1is halogen or H;

[0061] R2is halogen;

[0062] R3is H or halogen;

[0063] R5is H or halogen;

[0064] R6is H or halogen;

[0065] R4is of Formula (II):

[0066] Formula (II) wherein

[0067] X1is C(R7)(R8);

[0068] X2is C(R9)(R10) or a bond;

[0069] X3is C(R11)(R12) or N(R13);

[0070] X4is C(R16)(R17), O or a bond; X5is C(R18)(R19) or a bond;

[0071] X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14, R12and R14, R12and R27, R9and R13or R10and R13are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);

[0072] R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0073] R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0074] R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R9is joined together with R13or R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0075] R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R10is joined together with R13or R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0076] R11is -X7N(R14)(R15) or -X7-O-X8-R27;

[0077] X7is a bond or C1-3 alkanediyl;

[0078] X8is a bond or C1-3 alkanediyl;

[0079] R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F; or when R27is joined together with R12to form a ring together with the intervening atom(s), then R27is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0080] R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;

[0081] R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; or when R12is joined together with R14or R27to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R13is H or C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy; or when R13and R9or R10are joined together to form a ring together with the intervening atoms, then R13is -C1-3 alkanediyl-N(R28)-, wherein the C1- 3 alkanediyl is optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl, and R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0082] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0083] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0084] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0085] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0086] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X2is C(R9)(R10), X4is C(R16)(R17), and X5is C(R18)(R19), or a pharmaceutically acceptable salt thereof.

[0087] In one aspect, the present invention concerns a compound of Formula (I),

[0088] Formula (I) wherein

[0089] R1is halogen or H;

[0090] R2is halogen;

[0091] R3is H or halogen;

[0092] R5is H or halogen;

[0093] R6is H or halogen;

[0094] R4is of Formula (II):

[0095] Formula (II) wherein

[0096] X1is C(R7)(R8);

[0097] X2is C(R9)(R10) or a bond;

[0098] X3is C(R11)(R12) or N(R13);

[0099] X4is C(R16)(R17), O or a bond;

[0100] X5is C(R18)(R19) or a bond;

[0101] X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14or R12and R14are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0102] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0103] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or when R9is joined together with R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0104] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; ; or when R10is joined together with R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0105] R11is -X7N(R14)(R15) or -O-azetidinyl;

[0106] X7is a bond or C1-3 alkanediyl;

[0107] R14is H or C1-3 alkyl; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0108] R15is H or C1-3 alkyl; R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or when R12is joined together with R14to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0109] R13is H or C1-3 alkyl optionally substituted with NH2;

[0110] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0111] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0112] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0113] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X4is C(R11)(R12), or a pharmaceutically acceptable salt thereof.

[0114] In one aspect, the present invention relates to a compound of Formula (I),

[0115] Formula (I) wherein

[0116] R1is halogen or H;

[0117] R2is halogen;

[0118] R3is H or halogen;

[0119] R5is H or halogen;

[0120] R6is H or halogen;

[0121] R4is of Formula (II):

[0122] Formula (II) wherein

[0123] X1is C(R7)(R8);

[0124] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0125] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0126] X2is C(R9)(R10) or a bond;

[0127] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen, ; R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; X3is C(R11)(R12) or N(R13);

[0128] R11is -X7N(R14)(R15) or -O-azetidinyl;

[0129] X7is a bond or C1-3 alkanediyl; R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0130] R15is H or C1-3 alkyl;

[0131] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0132] X4is C(R16)(R17), O or a bond;

[0133] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0134] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0135] X5is C(R18)(R19) or a bond;

[0136] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0137] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0138] X6is a bond or C(R20)(R21);

[0139] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0140] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X4is C(R11)(R12), or a pharmaceutically acceptable salt thereof.

[0141] In one aspect, the present invention relates to a compound of Formula (I),

[0142] Formula (I) wherein

[0143] R1is halogen or H;

[0144] R2is halogen;

[0145] R3is H or halogen;

[0146] R5is H or halogen;

[0147] R6is H or halogen;

[0148] R4is of Formula (II):

[0149] Formula (II) wherein

[0150] X1is C(R7)(R8);

[0151] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0152] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0153] X2is C(R9)(R10) or a bond;

[0154] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0155] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0156] X3is C(R11)(R12) or N(R13);

[0157] R11is -X7N(R14)(R15) or -O-azetidinyl;

[0158] X7is a bond or C1-3 alkanediyl;

[0159] R14is H or C1-3 alkyl, or R14is a bond and R12is C1-3 alkyl and R14is linked to

[0160] R12to form a 4 or 5 membered ring;

[0161] R15is C1-3 alkyl;

[0162] R12is H or C1-3 alkyl;

[0163] R13is H or C1-3 alkyl optionally substituted with NH2;

[0164] X4is C(R16)(R17), O or a bond;

[0165] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0166] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0167] X5is C(R18)(R19) or a bond;

[0168] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0169] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0170] X6is a bond or C(R20)(R21);

[0171] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F; and

[0172] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F; with the proviso that when X3is N(R13), then X4is C(R11)(R12), or a pharmaceutically acceptable salt thereof.

[0173] Thus, in one aspect, the current invention relates to a compound of Formula (X):

[0174] Formula (X) wherein R1, R2, R3, R4, R5, R6, X1, X2, X3, X4, X5, and X6, are as defined herein, or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound is a Kv1.3 potassium channel inhibitor.

[0176] In some embodiments, R1is halogen. In some embodiments, R1is Cl. In some embodiments, R1is F. In some embodiments, R1is H. In some embodiments, R2is Cl. In some embodiments, R3is halogen. In some embodiments, R3is Cl. In some embodiments, R3is F. In some embodiments, R3is H. In some embodiments, R5is H. In some embodiments, R5is halogen. In some embodiments, R5is F. In some embodiments, R6is H. In some embodiments, R6is halogen. In some embodiments, R6is F. In some embodiments, R5is H and R6is H. In some embodiments, R1is halogen, and R2is halogen. In some embodiments, R2is halogen, and R3is halogen. In some embodiments, R1is halogen, R2is halogen, and R3is halogen. In some embodiments, R1is halogen, R2is halogen, R3is halogen, R5is H, and R6is H. In some embodiments, R1is halogen, R2is halogen, R3is H, R5is H, and R6is H. In some embodiments, R1is halogen, R2is halogen, R3is H, R5is halogen, and R6is H. In some embodiments, R1is halogen, R2is halogen, R3is H, R5is H, and R6is halogen. In some embodiments, R1is H, R2is halogen, R3is halogen, R5is H, and R6is H. In some embodiments, R1is F or Cl, R2is F or Cl, and R3is F or Cl. In some embodiments, R1is F, R2is Cl, and R3is Cl. In some embodiments, R1is Cl, R2is Cl, and R3is Cl. In some embodiments, R1is Cl, R2is Cl, and R3is F. In some embodiments, R1is F, R2is Cl, and R3is F. In some embodiments, R1is F or Cl, R2is Cl, R3is Cl, R5is H, and R6is H. In some embodiments, R1is F, R2is Cl, R3is Cl, R5is H, and R6is H. In some embodiments, R1is Cl, R2is Cl, R3is Cl, R5is H, and R6is H. In some embodiments, R1is Cl, R2is Cl, R3is F, R5is H, and R6is H. In some embodiments, R1is F, R2is Cl, R3is F, R5is H, and R6is H. In some embodiments, R1is Cl, R2is Cl, R3is H, R5is F, and R6is H. In some embodiments, R1is Cl, R2is Cl, R3 is H, R5is H, and R6is F. In some embodiments, R1is Cl, R2is Cl, R3is H, R5is H, and R6is H. In some embodiments, R1is F, R2is Cl, R3is H, R5is H, and R6is H. In some embodiments, R1is H, R2is Cl, R3is Cl, R5is H, and R6is H. In some embodiments, R1is F or Cl, R2is F or Cl, R3is F or Cl, R5is H, and R6is H.

[0177] In some embodiments, X2is C(R9)(R10); X3is N(R13); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond. In some embodiments, R4is of Formula (III):

[0178] Formula (III) wherein R7, R8, R9, R10, R16, R17, R18, R19, and X3are as defined herein.

[0179] In some embodiments, R4is of Formula (IV):

[0180] Formula (IV) wherein R7, R8, R9, R10, R16, R17, R18, R19, and X3are as defined herein.

[0181] In some embodiments, R7, R8, R9, R10, R16, R17, R18, and R19are H.

[0182] In some embodiments, R4is of Formula (XI):

[0183] Formula (XI) wherein R13is H, C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy;

[0184] R22is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and q is 0, 1 , 2, 3 or 4. In some embodiments, q is 0. In some embodiments, q is 1 . In some embodiments, q is 2.

[0185] In some embodiments, R22is C1-3 alkyl. In some embodiments, R22is -CH3. In some embodiments, R22is F.

[0186] In some embodiments, R4is of Formula (V):

[0187] Formula (V) wherein R7and R13are as defined herein.

[0188] In some embodiments, X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond. In some embodiments, X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond and X6is a bond. In some embodiments, R4is of Formula (XXXVI):

[0189] Formula (XXXVI) wherein R7, R8, R9, R10, R11, R12, R16, R17, and X5are as defined herein. In some embodiments, R4is of Formula (XXXVIa): Formula (XXXVIa) wherein R7, R8, R9, R10, R11, R12, R16, R17, and X5are as defined herein. In some embodiments, R4is of Formula (XXXVI) or Formula (XXXVIa), wherein

[0190] R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0191] R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0192] R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen;

[0193] R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen;

[0194] R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; R11is - X7N(R14)(R15);

[0195] X7is a bond or C1-3 alkanediyl;

[0196] R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F;

[0197] R15is H or C1-3 alkyl;

[0198] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0199] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0200] X5is a bond or C(R18)(R19);

[0201] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0202] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0203] In some embodiments, R7is H or F; R8is H or F; R9is H or F; R10is H or F; R12is H; R11is -X7N(R14)(R15); X7is a bond or C1-3 alkanediyl; R14is H or C1-3 alkyl; R15is H or C1-3 alkyl; R16is H or F; R17is H or F; X5is a bond or C(R18)(R19); R18is H or F; and R19is H or F. In some embodiments, R7is H; R8is H; R9is F; R10is H; R12is H; R11is - X7N(R14)(R15); X7is a bond or C1-3 alkanediyl; R14is H or C1-3 alkyl; R15is H or C1-3 alkyl; R16is H; R17is H; X5is a bond or C(R18)(R19); R18is H; and R19is H. In some embodiments, R7is H; R8is H; R9is F; R10is H; R12is H; R11is -NH2, -N(H)(CH3) or N(CH3)2; R16is H; R17is H; X5is a bond or C(R18)(R19); R18is H; and R19is H; or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, R4is of Formula (XII):

[0205] Formula (XII) wherein

[0206] R11is -X7N(R14)(R15);

[0207] X7is a bond or C1-3 alkanediyl;

[0208] R14is H or C1-3 alkyl ;

[0209] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4.

[0210] In some embodiments, R4is of Formula (XII):

[0211] Formula (XII) wherein

[0212] R11is -X7-O-X8-R27

[0213] X7is a bond or C1-3 alkanediyl;

[0214] X8is a bond or C1-3 alkanediyl;

[0215] R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F;

[0216] R14is H or C1-3 alkyl ;

[0217] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4.

[0218] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.

[0219] In some embodiments, R4is of Formula (Via):

[0220] Formula (Via) wherein R11and R12are as defined herein.

[0221] In some embodiments, R4is of Formula (Vlb):

[0222] Formula (Vlb) wherein R11and R12are as defined herein.

[0223] In some embodiments, X2is a bond; X3is C(R11)(R12); X4is C(R11)(R12) or O; X5is C(R18)(R19); and X6is C(R20)(R21). In some embodiments, R4is of Formula (XIII):

[0224] Formula (XIII) wherein R7, R8, R11, R12, R18, R19, R20, R21, and X4are as defined herein. In some embodiments, R4is of Formula (XIII), wherein

[0225] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0226] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0227] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0228] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0229] R11is -X7N(R14)(R15);

[0230] X7is a bond or C1-3 alkanediyl;

[0231] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, Ci-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0232] R15is H or C1-3 alkyl;

[0233] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0234] X4is C(R16)(R17) or O;

[0235] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0236] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0237] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0238] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0239] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0240] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0241] In some embodiments, R4is of Formula (XIII), wherein

[0242] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0243] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0244] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0245] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0246] R11is -X7N(R14)(R15);

[0247] X7is a bond or C1-3 alkanediyl;

[0248] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0249] R15is H or C1-3 alkyl;

[0250] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0251] X4is C(R16)(R17) or O;

[0252] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0253] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0254] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0255] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0256] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0257] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen. In some embodiments, R4is of Formula (XlVa). In some embodiments, R4is of Formula (XlVb).

[0258] Formula (XlVa) Formula (XlVb)

[0259] In some embodiments, R4is of Formula (XV):

[0260] Formula (XV) wherein R11, R12, and X4are as defined herein, R24is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and t is 0, 1 , 2, 3 or 4. In some embodiments, R4is of Formula (XV), wherein R11is -X7N(R14)(R15);

[0261] X7is a bond or C1-3 alkanediyl;

[0262] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0263] R15is H or C1-3 alkyl;

[0264] X4is C(R16)(R17) or O;

[0265] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0266] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0267] R24is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and t is O, 1 , 2, 3 or 4. In some embodiments, R4is of Formula (XV), wherein

[0268] R11is -X7N(R14)(R15);

[0269] X7is a bond or C1-3 alkanediyl;

[0270] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0271] R15is H or C1-3 alkyl;

[0272] X4is C(R16)(R17) or O;

[0273] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0274] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0275] R24is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and t is O, 1 , 2, 3 or 4.

[0276] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, R24is C1-3 alkyl. In some embodiments, R24is -CH3. In some embodiments, R24is F.

[0277] In some embodiments, R4is of Formula (Vila):

[0278] Formula (Vila) wherein X4, R11and R12are as defined herein.

[0279] In some embodiments, R4is of Formula (VI lb):

[0280] Formula (VI lb) wherein X4, R11and R12are as defined herein. In some embodiments, X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond. In some embodiments, R4is of Formula (XVI):

[0281] Formula (XVI) wherein R7, R8, R9, R10, R11, R12, R16, and R17are as defined herein. In some embodiments, R4is of Formula (XVI), wherein

[0282] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0283] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0284] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0285] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0286] R11is -X7N(R14)(R15);

[0287] X7is a bond or C1-3 alkanediyl;

[0288] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0289] R15is H or C1-3 alkyl;

[0290] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0291] X4is C(R16)(R17) or O;

[0292] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0293] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0294] In some embodiments, R4is of Formula (XVI), wherein

[0295] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0296] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0297] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0298] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0299] R11is -X7N(R14)(R15);

[0300] X7is a bond or C1-3 alkanediyl; R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0301] R15is H or C1-3 alkyl;

[0302] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0303] X4is C(R16)(R17) or O;

[0304] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0305] In some embodiments, R4is of Formula (XVIIa). In some embodiments, R4is of Formula (XVI lb).

[0306] Formula (XVIIa) Formula (XVI lb)

[0307] In some embodiments, R4is of Formula (XVIII):

[0308] Formula (XVIII) wherein R11and R12are as defined herein, R25is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and u is 0, 1 , 2, 3 or 4. In some embodiments, R4is of Formula (XVIII), wherein R11is -X7N(R14)(R15);

[0309] X7is a bond or C1-3 alkanediyl;

[0310] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0311] R15is H or C1-3 alkyl;

[0312] R25is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and u is 0, 1 , 2, 3 or 4.

[0313] In some embodiments, R4is of Formula (XVIII), wherein

[0314] R11is -X7N(R14)(R15);

[0315] X7is a bond or C1-3 alkanediyl;

[0316] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0317] R15is H or C1-3 alkyl;

[0318] R25is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and u is 0, 1 , 2, 3 or 4.

[0319] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, R25is C1-3 alkyl substituted with 1 to 3 F. In some embodiments, R25is -CF3 or a pharmaceutically acceptable salt thereof. In some embodiments, R25is C1-3 alkyl. In some embodiments, R25is -CH3. In some embodiments, R25is C1-3 alkoxy. In some embodiments, R25is -OCHs.ln some embodiments, R22is F.

[0320] In some embodiments, R4is of Formula (Villa):

[0321] Formula (Villa) wherein R9, R11and R12are as defined herein. In some embodiments, R4is of Formula (VII lb):

[0322] Formula (VI I lb) wherein R9, R11and R12are as defined herein.

[0323] In some embodiments, X2is a bond; X3is C(R11)(R12); X4is C(R16)(R17) or a bond; X5is C(R18)(R19); and X6is bond. In some embodiments, R12and R14are linked together to form a ring. In some embodiments, R14is a bond and R12is C1-3 alkyl and R14is linked to R12to form a 4 or 5 membered ring. In some embodiments, R14is Ci alkanediyl and R12is a bond or C1-3 alkyl and R14is linked to R12to form a 4 or 5 membered ring.

[0324] In some embodiments, R4is of Formula (XII):

[0325] Formula (XII) wherein R11and R12, are as defined herein, R23is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4. In some embodiments, R4is of Formula (XII), wherein

[0326] R11is -X7N(R14)(R15);

[0327] X7is a bond or C1-3 alkanediyl;

[0328] R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0329] R23is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4. In some embodiments, R4is of Formula (XII), wherein

[0330] R11is -X7N(R14)(R15);

[0331] X7is a bond or C1-3 alkanediyl;

[0332] R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0333] R23is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4.

[0334] In some embodiments, R4is of Formula (XII), wherein

[0335] R11is -X7-O-X8-R27;

[0336] X7is a bond or C1-3 alkanediyl;

[0337] X8is a bond or C1-3 alkanediyl;

[0338] R27is linked to R12to form a 4-6 membered ring, and R27is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0339] R23is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4.

[0340] In some embodiments, R12and R27are joined together to form a 4-6 membered ring together with the intervening atoms.

[0341] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, R23is C1-3 alkyl. In some embodiments, R23is -CH3. In some embodiments, R23is F.

[0342] In some embodiments, R14is linked to R12to form a 4-6 membered ring. In some embodiments, R14is linked to R12to form a 4 membered ring. In some embodiments, R14is linked to R12to form a 5 membered ring. In some embodiments, R14is linked to R12to form a 6 membered ring.

[0343] In some embodiments, R4is of Formula (XIX):

[0344] Formula (XIX) wherein

[0345] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; X5is C(R18)(R19) or a bond;

[0346] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0347] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0348] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0349] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0350] R26is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; m is 0 pr 1 ; p is 0, 1 or 2; v is 0, 1 , 2, 3 or 4.

[0351] In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2.

[0352] In some embodiments, R4is of Formula (IX):

[0353] Formula (IX) wherein m is 0 or 1 ; n is 0 or 1 ; and p is 0, 1 or 2, with the proviso that when m is 0 then p is 1 , and with the proviso that when p is 2, then m is 0. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, m is 0 and p is 1. In some embodiments, m is 1 and p is 1. In some embodiments, m is 1 and p is 0. In some embodiments, m is 0 and p is 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 0, n is 0 and p is 1. In some embodiments, m is 1 , n is 0 and p is 0. In some embodiments, m is 1 , n is 0 and p is 1. In some embodiments, m is 1 , n is 1 and p is 0. In some embodiments, m is 0, n is 1 and p is 1. In some embodiments, m is 1 , n is 1 and p is 1. In some embodiments, m is 0, n is 1 and p is 2.

[0354] In some embodiments, X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond. In some embodiments, R9and R14are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond; and R9and R14are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond; and R9and R14are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, R4is of Formula (XXIV):

[0355] Formula (XXIV) wherein

[0356] X5is C(R18)(R19) or a bond;

[0357] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0358] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0359] R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0360] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0361] X7is a bond or C1-3 alkanediyl;

[0362] R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;

[0363] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0364] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0365] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen,

[0366] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0367] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0368] In some embodiment, R4is of Formula (XX):

[0369] Formula (XX) wherein

[0370] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0371] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0372] R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0373] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0374] X7is a bond or C1-3 alkanediyl;

[0375] R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0376] R15is H or C1-3 alkyl;

[0377] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0378] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0379] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0380] In some embodiments, the moiety of Formula (XX) is of Formula (XXI):

[0381] Formula (XXI)

[0382] In some embodiments, R10and R14are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond; and R10and R14are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, R4is of Formula (XXII):

[0383] Formula (XXII) wherein

[0384] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0385] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0386] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0387] R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0388] R11is -X7N(R14)(R15);

[0389] X7is a bond or C1-3 alkanediyl;

[0390] R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0391] R15is H or C1-3 alkyl;

[0392] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0393] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0394] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen. In some embodiments, the moiety of Formula (XXII) is of Formula (XXIII):

[0395] Formula (XXIII)

[0396] In some embodiments, R10and R13are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, X1is C(R7)(R8); X2is C(R9)(R10); X3is N(R13); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond, and R9and R13are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, R9and R13are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, X1is C(R7)(R8); X2is C(R9)(R10); X3is N(R13); X4is C(R16)(R17); X5is a bond; and X6is a bond, and R9and R13are joined together to form a 4-6 membered ring together with the intervening atoms. In some embodiments, R4is of Formula (XXV):

[0397] Formula (XXV) wherein

[0398] X5is C(R18)(R19) or a bond;

[0399] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0400] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0401] R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0402] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0403] X9is C1-3 alkanediyl;

[0404] R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0405] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0406] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0407] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen.

[0408] In some embodiments, R7is H. In some embodiments, R7is halogen. In some embodiments, R7is F. In some embodiments, R7is C1-3 alkyl. In some embodiments, R7is CH3. In some embodiments, R7is C1-3 alkyl substituted with C1-3 alkoxy. In some embodiments, R7is -CH2OCH3.

[0409] In some embodiments, R8is H. In some embodiments, R8is halogen. In some embodiments, R8is F. In some embodiments, R8is C1-3 alkyl. In some embodiments, R8is CH3. In some embodiments, R8is C1-3 alkyl substituted with C1-3 alkoxy. In some embodiments, R8is -CH2OCH3.

[0410] In some embodiments, R9is H. In some embodiments, R9is halogen. In some embodiments, R9is F. In some embodiments, R9is C1-3 alkyl. In some embodiments, R9is CH3. In some embodiments, R9is C1-3 alkyl substituted with C1-3 alkoxy. In some embodiments, R9is -CH2OCH3. In some embodiments, R9is C1-3 alkyl substituted with 1 to 3 F. In some embodiments, R9is -CF3. In some embodiments, R9is C1-3 alkyl substituted with azetidinyl optionally substituted with one or more halogens. In some embodiments, R9isF. In some embodiments, R9is C1-3 alkoxy. In some embodiments, R9is -OCH3.

[0411] In some embodiments, R10is H. In some embodiments, R10is halogen. In some embodiments, R10is F. In some embodiments, R10is C1-3 alkyl. In some embodiments, R10is CH3. In some embodiments, R10is C1-3 alkyl substituted with C1-3 alkoxy. In some embodiments, R10is -CH2OCH3. In some embodiments, R10is C1-3 alkyl substituted with 1 to 3 F. In some embodiments, R10is -CF3. In some embodiments, R10is C1-3 alkyl substituted with azetidinyl optionally substituted with one or more halogens. In some embodiments, R10isF. In some embodiments, R10is C1-3 alkoxy.

[0412] In some embodiments, R10is -OCH3. In some embodiments, R11is -X7N(R14)(R15), wherein X7, R14and R15are as defined herein. In some embodiments, R11is N(H)(CH3). In some embodiments, R11is N(CHa)2. In some embodiments, R11is NH2. In some embodiments, R11is C1-3 alkyl optionally substituted with NH2, N(H)(CH3), or N(CH3)2. In some embodiments, R11is CH2N(H)(CH3). In some embodiments, R11is CH2N(CH3)2. In some embodiments, R11is CH2NH2. In some embodiments, R11is . In some embodiments, R11is

[0413] R11isH. In some embodiments, R11is -X7-O-X8-R27. In some embodiments, R11 . In some embodiments, R11is . In some embodiments, In some embodiments, R11is -O-azetidinyl. In some embodiments, R11is

[0414] In some embodiments, R12is H. In some embodiments, R12is halogen. In some embodiments, R12is F. In some embodiments, R12is C1-3 alkyl. In some embodiments, R12is C1-3 alkyl substituted with 1 to 3 F. In some embodiments, R12is CF3.

[0415] In some embodiments, R13is H. In some embodiments, R13is C1-3 alkyl optionally substituted with NH2. In some embodiments, R13is C1-3 alkyl. In some embodiments, R13is CH3. In some embodiments, R13is C1-3 alkyl substituted with NH2. In some embodiments, R13is CH2NH2. In some embodiments, R13is -(CH2)2NH2. In some embodiments, R13is C1-3 alkyl substituted with -N(CH3)2. In some embodiments, R13is - (CH2)2N(CH3)2. In some embodiments, R13is C1-3 alkyl substituted with azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy. In some embodiments, R13is . In some embodiments,

[0416] In some embodiments, R14is H. In some embodiments, R14is C1-3 alkyl. In some embodiments, R14is CH3. In some embodiments, R14is C1-3 alkyl substituted with oxetanyl. In some embodiments, R14is . In some embodiments, R14is C1-3 alkyl substituted with C1-3 alkoxy. In some embodiments, R14is -(CP OCIp. In some embodiments, R14is C1-3 alkyl substituted with azetidinyl optionally substituted with one or more F. In some embodiments

[0417] In some embodiments,

[0418] In some embodiments, R15is H. In some embodiments, R15is C1-3 alkyl. In some embodiments, R15is CH3. In some embodiments, R16is H. In some embodiments, R16is F. In some embodiments, R17is H. In some embodiments, R17is F. In some embodiments, R18is H. In some embodiments, R18is F. In some embodiments, R19is H. In some embodiments, R19is F. In some embodiments, R20is H. In some embodiments, R20is F. In some embodiments, R21is H. In some embodiments, R21is F.

[0419] In some embodiments, R27is N(R14)(R15). In some embodiments, R27is NH2. In some embodiments, R27is azetidinyl optionally substituted with one or more F. In some embodiments, R27is . In some embodiments, R27is

[0420] In some embodiments, X1is CH2. In some embodiments, X1is C(CH3)(H). In some embodiments, X2is CH2. In some embodiments, X2is C(F)(H). In some embodiments, X2is CF2. In some embodiments, X2is a bond. In some embodiments, X3is a bond. In some embodiments, X3is C(NH2)(H). In some embodiments, X3is C(N(H)(CH3))(H). In some embodiments, X3is C(N(CH3)2)(H). In some embodiments, X3is C(CH2(NH2))(H). In some embodiments, X3is C(CH2(NH2))(F). In some embodiments, X3is C(CH2(N(H)(CH3)))(H). In some embodiments, X3is C(CH2(N(CH3)2))(H). In some embodiments, X4is a bond. In some embodiments, X4is O. In some embodiments, X4is CH2. In some embodiments, X5is CH2. In some embodiments, X6is CH2. In some embodiments, X6is a bond. In some embodiments, X7is a bond. In some embodiments, X7is C1-3 alkanediyl. In some embodiments, X7is CH2.

[0421] In some embodiments, R8, R10, R16, R17, R18, and R19are H.

[0422] In some embodiments, no more than two of X2, X5and X6are bonds, or a pharmaceutically acceptable salt thereof.

[0423] In some embodiments, halogen is individually selected from F, Cl and Br. In some embodiments, halogen is F. In some embodiments, the azetidinyl is azetidin-1-yl. In some embodiments, the azetidinyl is azetidin-3-yl. In some embodiments, the oxetanyl is oxetan-3-yl.

[0424] In some embodiments, R4is . In some embodiments, R4is , In some embodiments, , . In some embodiments, some embodiments, R4is , embodiments, R4is . In some embodiments,

[0425] In some embodiments, some embodiments, R4is . , In some embodiments, R4 some embodiments, some embodiments, R4is . In some embodiments, R is In some embodiments, , , some embodiments, some embodiments, some embodiments, R4is some embodiments, R4is . In some embodiments, R4is . In some embodiments, R4is . In some embodiments, R4is . In some embodiments, R4is . In some embodiments, R4is . In some embodiments, some embodiments, R4is . , some embodiments, some embodiments, R4is

[0426] In some embodiments, R4is In some embodiments, R4is , some embodiments, R4 , some embodiments, R4is o mens, s . In some embodiments, R4is In some embodiments, . In some embodiments, R4is In some embodiments, some embodiments, R4is

[0427] . In some embodiments, some embodiments, R4 In some embodiments, R4is In some embodiments, R4is . . .. , — , . In some embodiments, R4is . In some embodiments, R4is

[0428] . In some embodiments, R4is . In some embodiments, R4is , . In some embodiments, embodiments, In some embodiments, some embodiments, R4is , embodiments, some embodiments,

[0429] In some embodiments, R4is . In some embodiments, some embodiments, some embodiments, R4is some embodiments, some embodiments, some embodiments, R4is . In some embodiments, some embodiments, R4is . In some embodiments, some embodiments, In some embodiments, some embodiments, R4is some embodiments, R4

[0430] NH is2. In some embodiments, R4is In some embodiments, , .In some embodiments, R4is

[0431] NH2NHg

[0432] . In some embodiments, R4is . In some embodiments, R4is

[0433] . In some embodiments, R4is In some embodiments, R4is R4is . In some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, R4is

[0434] In some embodiments, R4is . In some embodiments, R4is

[0435] . In some embodiments, R4is . In some embodiments,

[0436] 5 In some embodiments, the compound is selected from Group A, which consists of: or a pharmaceutically acceptable salt thereof.

[0437] In one aspect, the present invention concerns a compound of Group A, or a pharmaceutically acceptable salt thereof.

[0438] In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)-[(3R)-3- (dimethylamino)pyrrolidin-1-yl]methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)-[(3S)-3- [(dimethylamino)methyl]pyrrolidin-1-yl]methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)-(4- methylpiperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)(1 ,7- diazaspiro[4.4]nonan-7-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2-yl)-[(2S)-2,4- dimethylpiperazin-1-yl]methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(3-(aminomethyl)pyrrolidin-1-yl)(4,5-dichloro- 1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2,7-diazaspiro[3.4]octan-2-yl-(4,5-dichloro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-aminopyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)- (3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)- (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2-methylpiperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)- (4,5-dichloro-1 H-indol-2-yl)(3-((methylamino)methyl)pyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5- dichloro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-5-fluoro-1 H- indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)(1 ,6- diazaspiro[3.4]octan-6-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(4,5-dichloro-1 H-indol-2-yl)(3- (methylamino)pyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)(1 ,6- diazaspiro[3.3]heptan-6-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4,5-dichloro-1 H-indol-2-yl)(2,6- diazaspiro[3.3]heptan-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro- 1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H- indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro- 5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (2-(aminomethyl)morpholino)(3,4-dichloro-5- fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2,6- diazaspiro[3.4]octan-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(piperazin-1- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-aminopiperidin-1-yl) (3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-(azetidin-3-yloxy)pyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-(2-aminoethyl)piperazin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H- indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)(3,4- dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((2S,4R)-4-amino-2-methylpyrrolidin- 1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-amino-3- (trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)- (3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5- fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-(2-aminoethoxy)piperidin-1-yl)(3,4-dichloro-5-fluoro- 1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2-yl)(piperazin-1- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-aminopiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-(aminomethyl)-4-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4R)-4-amino-3-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H- indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-amino-3,3-difluoropiperidin-1-yl)(3,4-dichloro-5- fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2-yl)((4aS,7aR)- hexahydropyrrolo[3,4-b][1 ,4]oxazin-6(2H)-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-(aminomethyl)- 3-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)- (3-(aminomethyl)-3-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(3-(aminomethyl)-3-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H- indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(4-amino-3,3-difluoropyrrolidin-1-yl)(3,4-dichloro-5- fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3-(aminomethyl)-3-fluoroazetidin-1-yl)(3,4-dichloro-5- fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)(4-chloro- 3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2-yl)((3aR,6aS)- 3a,6a-difluorohexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (1,4-diazepan-1- yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2- yl) (2,6-diazaspiro [3.4] octan-6-yl) methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-(2-aminoethyl)piperazin-1-yl)(4- chloro-3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2- yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2- yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(3-aminopyrrolidin-1-yl)(4-chloro- 3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3- methylpiperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4- chloro-3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(4-chloro-3,5-difluoro-1 H-indol-2- yl)(2-(methoxymethyl)piperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-amino-4-methylpiperidin-1-yl)(4- chloro-3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2- yl)(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(4-amino-3,3- difluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4- chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4- chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-6-azaspiro[3.4]octan-6-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4- (2-(azetidin-3-yloxy)ethyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-((azetidin-3-yloxy)methyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(4-((3-fluoroazetidin-3-yl) methoxy)piperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3- fluoro-4-((oxetan-3-ylmethyl)amino)pyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro- 1 H-indol-2-yl)(4-(2-(3-methoxyazetidin-1-yl)ethyl)piperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4- chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin-1-yl)ethyl)piperazin-1- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)piperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4- ((oxetan-3-ylmethyl) amino)piperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2- yl)((3R,4S)-3-fluoro-4-(methyl amino)pyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro- 1 H-indol-2-yl)((3S,4R)-3-((2-(3,3-difluoro azetidin-1-yl)ethyl)amino)-4-fluoropyrrolidin-1- yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (3S,4R)-1-[(4-chloro-3,5-difluoro-1 H-indol-2-yl)carbonyl]-4-fluoro-N-[2- (3-fluoroazetidin-1 -yl)ethyl]pyrrolidin-3-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-(4-chloro-3,5-difluoro-1 H-indol-2- yl)(3-(2-(3,3-difluoroazetidin-1-yl)ethyl)piperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-(4-chloro-3,5- difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1-yl)ethyl)piperazin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4- chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((2-methoxy ethyl)amino)pyrrolidin- 1-yl)methanone, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(dimethylamino)ethyl) piperazin-1 -yl)methanone, or a pharmaceutically acceptable salt thereof.

[0439] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Tautomeric forms can also include methyltropic tautomers, which result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a methyl group.

[0440] Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. In some embodiments, the compounds of the invention include one or more isotopes of atoms in an amount greater than the natural abundance of the isotope. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, a compound of the invention includes at least one deuterium atom in an amount that is greater than the natural abundance of deuterium (e.g., the compound is enriched in deuterium). All compounds described herein, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0441] In one aspect, the present invention is directed to an intermediate compound, or a pharmaceutically acceptable salt thereof, which can be used in the synthesis of the compounds of the present invention. For example, said intermediate compound is in some embodiments one of the intermediate compounds, or a pharmaceutically acceptable salt thereof, of any one of the working examples. In some embodiments the compound of the present invention is selected from any of the intermediate compounds, or a pharmaceutically acceptable salt thereof, disclosed in any one of examples 1 to 84 herein.

[0442] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist as stereoisomers, enantiomers and diastereomers. Accordingly, the scope of the instant invention is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form and stereoisomeric mixtures of any chemical structures disclosed herein, unless the stereochemistry is specifically identified. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.

[0443] The term “stereoisomer” or “stereoisomerically pure” compound as used herein refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0444] In some embodiments, the compound as defined herein is stereoisomerically pure.

[0445] Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents, for example as outlined in the example section.

[0446] Pharmaceutical composition

[0447] The present invention also relates to a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound as disclosed herein. In some embodiments, said pharmaceutical composition comprises a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0448] While a compound as disclosed herein for use in therapy may be administered in the form of the raw chemical compound, it is often preferred to introduce the active ingredient, optionally in the form of a pharmaceutically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0449] In some embodiments, the invention provides pharmaceutical compositions comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0450] A therapeutic amount or therapeutically effective amount or dose refers to that amount of active ingredient, i.e. the compounds or compositions as disclosed herein, which treats, alleviates, abates, or reduces the severity of symptoms of a disease in a subject, such as ameliorates one or more symptoms of the condition or the condition itself. A therapeutic amount of a compound as described herein may improve patient survival, increase survival time or rate, diminish symptoms, make an injury, disease, or condition (e.g. a neurodegenerative disease) more tolerable, slow the rate of degeneration or decline, or improve a patient’s physical or mental well-being.

[0451] Therapeutic efficacy and toxicity, e.g. ED50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred. In some embodiments, the therapeutically effective dose of a compound as disclosed herein is in the range of about 0.01 mg / kg to about 100 mg / kg bodyweight / day.

[0452] The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.

[0453] To administer refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[0454] Biological activity

[0455] As demonstrated in Example 85, compounds of the present invention are Kv1.3 potassium channel antagonists.

[0456] Medical use

[0457] Being Kv1.3 potassium channel antagonists, the compounds of the present invention are of use in the treatment of diseases and disorders of a living body, including human. As used herein, the term “treatment” includes treatment, prevention, and / or alleviation or amelioration of one or more diseases and disorders or one or more symptoms of a disease or disorder. In one aspect, the compound as described herein is for use as a medicament.

[0458] In one aspect, the present invention relates to a compound of Formula (I),

[0459] Formula (I) wherein

[0460] R1is halogen or H;

[0461] R2is halogen;

[0462] R3is H or halogen;

[0463] R5is H or halogen;

[0464] R6is H or halogen;

[0465] R4is of Formula (II):

[0466] Formula (II) wherein

[0467] X1is C(R7)(R8);

[0468] X2is C(R9)(R10) or a bond;

[0469] X3is C(R11)(R12) or N(R13);

[0470] X4is C(R16)(R17), O or a bond;

[0471] X5is C(R18)(R19) or a bond;

[0472] X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14, R12and R14, R12and R27, R9and R13or R10and R13are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);

[0473] R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen; R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0474] R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R9is joined together with R13or R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0475] R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R10is joined together with R13or R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0476] R11is -X7N(R14)(R15) or -X7-O-X8-R27;

[0477] X7is a bond or C1-3 alkanediyl;

[0478] X8is a bond or C1-3 alkanediyl;

[0479] R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F; or when R27is joined together with R12to form a ring together with the intervening atom(s), then R27is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0480] R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;

[0481] R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; or when R12is joined together with R14or R27to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R13is H or C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy; or when R13and R9or R10are joined together to form a ring together with the intervening atoms, then R13is -C1-3 alkanediyl-N(R28)-, wherein the C1- 3 alkanediyl is optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl, and R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0482] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0483] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0484] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0485] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X2is C(R9)(R10), X4is C(R16)(R17), and X5is C(R18)(R19), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial.

[0486] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as defined herein, for use in the treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial.

[0487] In one aspect, the present invention relates to a method for treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial comprising administering a compound, or a pharmaceutically acceptable salt thereof, as described herein to a subject in need thereof.

[0488] In one aspect, the present invention relates to use of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for treatment of disease or medical condition where inhibition of Kv1 .3 potassium channel is beneficial.

[0489] The compounds of the present invention may be utilized in any therapy where it is desired to treat, reduce or alleviate symptoms of Kv1 .3 mediated diseases such as inflammatory and autoimmune diseases, diabetes, obesity or cancers.

[0490] In one aspect, the present invention relates to the compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of Kv1.3 mediated conditions.

[0491] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a neurodegenerative disease. A "neurodegenerative disease" refers to a central nervous system characterized by progressive, normally gradual, loss of functional neural tissue.

[0492] In some embodiments, the neurodegenerative disease is a tauopathy. Tauopathies depicts some neurodegenerative disorders characterized by tau deposits in the brain, with symptoms of dementia and parkinsonism. In some embodiments, the neurodegenerative disease is a tauopathy selected from the group consisting of Primary age related tauopathy (PART), globular glial tauopathy, Chronic traumatic encephalopathy (CTE), Progressive supranuclear palsy, Corticobasal degeneration, diffuse neurofibrillary tangles with calcification (DNTC), Frontotemporal dementia (FTD), and FTD with parkinsonism-17 (FTD with parkinsonism linked to chromosome 17; FTDP-17).

[0493] In some embodiments, the neurodegenerative disease is a neurodegenerative disorders associated with TDP-43 (TDP-43 proteinopathies or TDP-43-opathies). Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases.

[0494] In some embodiments, the neurodegenerative disease is a TDP-43 proteinopathy selected from the group consisting of amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobar degeneration / disease (FTLD), Primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43 or FTLD-ll (types a, b and c), Facial onset sensory and motor neuronopathy (FOSMN), Limbic-predominant age-related TDP-43 encephalopathy (LATE), cerebral age-related TDP-43 with sclerosis (CARTS), Guam Parkinson-dementia complex (G-PDC) and ALS (G-ALS), Kii ALS / PDC, amyotrophic lateral sclerosis / parkinsonism-dementia complex of Guam (ALS-PDC), Multisystem proteinopathy (MSP; also referred to as inclusion body myopathy (IBM) associated with early-onset Paget disease of the bone and FTLD dementia), Perry disease, and disorders with concomitant TDP-43 pathology, including Alzheimer’s disease (AD) and Chronic traumatic encephalopathy (CTE). In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of muscular dystrophy such as myotonic dystrophy (DM) including Type 1 DM (DM1) and Type 2 DM (DM2).

[0495] In some embodiments, the neurodegenerative disease is Multisystem proteinopathy (MSP). MSP is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and / or the central nervous system. MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders (IBMPFD, IBMPFD / ALS).

[0496] In some embodiments, the neurodegenerative disease is a synucleinopathy. Synucleinopathies (also called a-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.

[0497] In some embodiments, the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), neuroaxonal dystrophies, Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD / ALB).

[0498] In some embodiments, the neurodegenerative disease is cognitive deficit and / or memory loss. In some embodiments, the neurodegenerative disease is dementia. In some embodiments, the neurodegenerative disease is dementia selected from the group consisting of Alzheimer’s disease, Parkinson’s disease dementia, Huntingtons disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, dementia with lewy bodies, prion disease dementia, argyrophilic grain dementia, dementia pugilistica, Guadeloupean parkinsonism with dementia, neurofibrillary tangle- predominant dementia, tangle only dementia, Down’s syndrome, semantic dementia, familial British dementia, familial Danish dementia, and other dementias caused by another medical condition such as brain tumors, subdural hematoma, endocrine disorders, nutritional deficiencies, infections, immune disorders, liver or kidney failure, metabolic disorders such as Kufs disease, some leukodystrophies, some neurological disorders such as epilepsy, and multiple sclerosis. Disorders of peripheral nerves (peripheral neuropathy) are the most common neurological complications of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).

[0499] In some embodiments, the neurodegenerative disease is a demyelinating disorder. In some embodiments, the neurodegenerative disease is a demyelinating disorder of the central nervous system, CNS. In some embodiments, the demyelinating disorder is a myelinoclastic or demyelinating disorder, such as selected from the group consisting of multiple sclerosis, neuromyelitis optica (Devic’s disease) and idiopathic inflammatorydemyelinating diseases. In some embodiments, the demyelinating disorder is a leukodystrophic or dysmyelinating disorder, such as selected from the group consisting of CNS neuropathies such as vitamin B12 deficiency, central pontine myelinolysis, myelopathies such as tabes dorsalis (syphilitic myelopathy), leukoencephalopathies and leukodystrophies.

[0500] In some embodiments, the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system, PNS. In some embodiments, the demyelinating disorder is selected from the group consisting of Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy; Anti-MAG peripheral neuropathy; Charcot-Marie-Tooth disease and its counterpart Hereditary neuropathy with liability to pressure palsy; Copper deficiency-associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy); and Progressive inflammatory neuropathy.

[0501] In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD) with the R47H mutation. In some embodiments, the neurodegenerative disease is early Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Frontotemporal lobar degeneration (FTLD). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (NHD). In some embodiments, the neurodegenerative disease is FTLD-like syndrome. In some embodiments, the neurodegenerative disease is Huntington disease. In some embodiments, the neurodegenerative disease is Amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the neurodegenerative disease is Guillain-Barre syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathies. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tooth disease. In some embodiments, the neurodegenerative disease is prion disease, such as prion protein cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is stroke. In some embodiments, the neurodegenerative disease is cerebral amyloid angiopathy (CAA). In some embodiments the neurodegenerative disease is fragile X-associated tremor ataxia syndrome (FXTAS). In some embodiments the neurodegenerative disease is herpes simplex virus (HSV) encephalitis. In some embodiments the neurodegenerative disease is HIV-associated neurocognitive disorders (HAND). In some embodiments the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments the neurodegenerative disease is corticobasal degeneration. In some embodiments the neurodegenerative disease is Hallevorden-Spatz disease. In some embodiments the neurodegenerative disease is pallido-ponto-nigral degeneration. In some embodiments the neurodegenerative disease is postencephalitic parkinsonism. In some embodiments the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE). In some embodiments the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).

[0502] In some embodiments the neurodegenerative disease is a Leukoencephalopathy. Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. In some embodiments the neurodegenerative disease is a Leukoencephalopathy selected from the group consisting of Progressive multifocal leukoencephalopathy, Toxic leukoencephalopathy, Leukoencephalopathy with vanishing white matter, Leukoencephalopathy with neuroaxonal spheroids, Reversible posterior leukoencephalopathy syndrome, Megalencephalic leukoencephalopathy with subcortical cysts, and Hypertensive leukoencephalopathy. In some embodiments, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). In some embodiments the neurodegenerative disease is selected from the group consisting of cerebral autosomal dominant arteriopathy with subcortical infarcts or leukoencephalopathy; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).

[0503] In some embodiments the neurodegenerative disease is a leukodystrophy. In some embodiments the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophies are a group of rare, genetic disorders that affect the white matter of the brain. In some embodiments the neurodegenerative disease is a leukodystrophy selected from the group consisting of metachromatic leukodystrophy (MLD, also known as globoid cell leukodystrophy), Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, hypomyelinating leukodystrophy type 7 (4H syndrome), Pelizaeus-Merzbacher disease, cerebrotendineous xanthomatosis and leukoendephalopathy with vanishing white matter. In some embodiments the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some embodiments the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some embodiments the neurodegenerative disease is Nasu-Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL).

[0504] In some embodiments, the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler- Scheinker disease (GSS), kuru, and fatal familial insomnia.

[0505] In one aspect, the present invention relates to a method for treatment of a neurodegenerative disease comprising administering a compound, or a pharmaceutically acceptable salt thereof, as described herein to a subject in need thereof.

[0506] In one aspect, the present invention relates to a method for treatment of a neurodegenerative disease comprising one or more steps of administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein to a subject in need thereof. In one aspect, the present invention relates to use of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for treatment of a neurodegenerative disease.

[0507] In one aspect, the present invention concerns a compound as defined herein, or pharmaceutically acceptable salt thereof, for use in a method of inhibiting or reducing inflammation. In one aspect, the present invention concerns a compound as defined herein, or pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory condition or disorder.

[0508] In some embodiments, said Kv1.3 mediated condition is selected from the group consisting of inflammatory conditions, allergies and allergic conditions, hypersensitivity reactions, autoimmune diseases, severe infections, and organ or tissue transplant rejection. Exemplary Kv1.3 mediated conditions include inflammatory conditions, immune and proliferative disorders, including but not limited to rheumatoid arthritis (RA), osteoarthritis, osteoporosis, uveitis, inflammatory fibrosis (e.g., scleroderma, lung fibrosis, and cirrhosis), inflammatory bowel disorders (e.g., Crohn's disease, ulcerative colitis and inflammatory bowel disease), multiple sclerosis, psoriasis, contact-mediated dermatitis, systemic lupus erythematosus (SLE) and other forms of lupus, diabetes, type I diabetes, cancer, lupus, scleroderma, Sjogren syndrome, and vasculitis.

[0509] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a lysosomal storage disorder (LSD). Most lysosomal storage disorders cause progressive neurodegeneration leading to early death. In some embodiments the LSD is a lipidoses, such as a lipidoses selected from the group consisting of cholesteryl ester storage disease, fucosidosis, Schindler disease and Wolman disease. In some embodiments the LSD is a sphingolipidoses, such as a sphingolipidoses selected from the group consisting of Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (Types A, B and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency and Tay- Sachs disease. In some embodiments the LSD is a mucopolysaccharidoses, such as a mucopolysaccharidoses selected from the group consinting of Hunter syndrome, Hurler syndomre, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome and Natowicz syndrome. In some embodiments the LSD is selected from the group consisting of Batten disease, cyctinosis, Danon disease and Pompe disease.

[0510] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder of the bones and / or joints. In some embodiments, said disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia and dysosteoplasia.

[0511] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of traumatic brain injuries (TBI) and spinal cord injuries. Traumatic brain injuries (TBI), may also be known as intracranial injuries. Traumatic brain injuries occur when an external force traumatically injures the brain. Spinal cord injuries (SCI) include any injury to the spinal cord that is caused by trauma instead of disease. In some embodiments the TBI is chronic traumatic encephalopathy (CTE).

[0512] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of inflammation. In some embodiments said inflammation is selected from the group consisting of inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain bowel conditions including Inflammatory bowel disease (IBD).

[0513] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from the group consisting of cancer, an immunological disorder, a central nervous system disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.

[0514] Kv1.3 channel expression is associated with the control of proliferation in multiple cell types, apoptosis, and cell survival. These processes are crucial for cancer progression. Thus, inhibitors of Kv1.3 channels may be used as anticancer agents. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In some embodiments, the cancer is selected from the group consisting of biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasms, leukemias, lymphomas, liver cancer, lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcomas, skin cancer, testicular cancer, and thyroid cancer.

[0515] Kv1.3 channel blockers are potential therapeutic agents as immunosuppressants or immune system modulators. The Kv1.3 channel is also considered as a therapeutic target for the treatment of obesity and for enhancing peripheral insulin sensitivity in patients with type II diabetes mellitus. These compounds can also be utilized in the prevention of graft rejection and the treatment of immunological (e.g., autoimmune) and inflammatory disorders. The term "autoimmune diseases" generally refers to diseases in which "self1components undergo attack by the immune system. Such diseases may affect a single organ, as in, for example, multiple sclerosis and type I diabetes mellitus, or may involve multiple organs, as in, for example, rheumatoid arthritis and systemic lupus erythematosus. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of an autoimmune disease. In some embodiments, the autoimmune disease is Graves’ disease. In some embodiments, the autoimmune disease is Hashimoto’s thyroiditis. In some embodiments, the autoimmune disease is myasthenia gravis.

[0516] Autoimmune encephalitis (AIE) is a type of encephalitis (inflammation of the brain) which can result from a number of autoimmune diseases including Rasmussen encephalitis, Systemic lupus erythematosus, Behget's disease, Hashimoto's encephalopathy, Autoimmune limbic encephalitis, and Sydenham's chorea. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of autoimmune encephalitis. In some embodiment, the AIE is selected from the group consisting of Anti-NMDAR encephalitis; Anti-AMPAR encephalitis; Anti-GABA encephalitis, such as Anti-GABA-AR encephalitis and Anti-GABA-BR encephalitis; Anti-LGI1 encephalitis; Anti-CASPR2 encephalitis; Anti-GAD encephalitis; Anti-GlyR encephalitis; Anti-DPPX encephalitis; Encephalopathy associated with anti-lgLON5 antibodies; Anti-mGluR1 encephalitis; and anti-mGluR5 encephalitis. In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of atopic dermatitis (eczema).

[0517] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of coeliac disease.

[0518] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory disorder. In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy.

[0519] Kv1.3 channels play a role in gastroenterological disorders including, but not limited to, inflammatory bowel diseases, such as, but not limited to, ulcerative colitis and Crohn’s disease. Ulcerative colitis is a chronic inflammatory bowel disease characterized by excessive T cell infiltration and cytokine production. Kv1.3 channels are thought to serve as a marker of disease activity and pharmacological blockade might constitute an immunosuppressive strategy in ulcerative colitis. Crohn’s disease is a type of inflammatory bowel disease which may affect any part of the gastrointestinal tract. Crohn’s disease is thought to be the result of intestinal inflammation due to a T cell- driven process initiated by normally safe bacteria. Thus, Kv1.3 channel inhibition can be utilized in treating the Crohn’s disease. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a gastroenterological disorder. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease such as Crohn’s disease or ulcerative colitis.

[0520] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a immunological disorder. In some embodiments, the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes mellitus).

[0521] Expression of Kv1.3 channels is elevated in microglia of human Alzheimer’s disease brains, suggesting that Kv1.3 channel is a pathologically relevant microglial target in Alzheimer’s disease. Thus, the Kv1.3 channel may be a therapeutic target for Alzheimer’s disease. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer’s disease. In some embodiments, the central nervous system disorder is Alzheimer’s disease. In some embodiments, the metabolic disorder is obesity or type II diabetes mellitus. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[0522] Kv1.3 channel blockers can be useful for ameliorating pathology in cardiovascular disorders such as, but not limited to, ischemic stroke, where activated microglia significantly contributes to the secondary expansion of the infarct. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular disorder. In some embodiments, the cardiovascular disorder is an ischemic stroke.

[0523] In some embodiments, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, Alzheimer’s disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, inflammatory bowel disease, obesity, type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof.

[0524] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of bipolar disorder.

[0525] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of Major depressive disorder (MDD, also known as clinical depression). In some embodiments, said MDD is selected from the group consisting of melancholic depression; atypical depression; catatonic depression; depression with anxious distress; depression with peri-partum onset; and seasonal affective disorder.

[0526] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of schizophrenia. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, such as neuropathic pain or inflammatory pain.

[0527] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of CNS complications of COVID-19 infection and / or post-COVID-19 conditions (also known as post-COVID syndrome, long COVID-19, long-haul COVID-19, and post acute sequelae of SARS COV-2 infection (PASC)).

[0528] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of epilepsy, such as genetic epilepsy or sporadic epilepsy. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. Accordingly, the scope of the methods and uses herein is to be understood to encompass methods and uses employing all such forms.

[0529] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” In some embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents. In some embodiments, the method includes coadministering one or more additional therapeutic agent. Examples of therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu- Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. In some embodiments, the therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for a disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD). As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0530] The compounds of the present invention may be used to treat an animal patient belonging to any classification. Examples of such animals include mammals such as humans, rodents, dogs, cats, zoo animals and farm animals. In some embodiments, the subject referred to herein is a mammal, such as a human.

[0531] In one aspect, the present invention concerns a method of blocking Kv1.3 potassium channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound as defined herein.

[0532] In one aspect, the present invention relates to a method of modulating the activity of Kv1.3 in a biological tissue, the method comprising contacting a biological tissue expressing Kv1.3 with a Kv1.3 modulating amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0533] In one aspect, the present invention concerns a method of suppressing T cell activation in a subject having a condition associated with undesired T cell activation. T cell activation can be measured by well-known methods, such as measuring reduction of IL-2 production by T cells. "Suppressing T cell activation" as used herein refers to the ability of the compound as defined herein, or a pharmaceutically acceptable salt thereof, to inhibit and reduce T cell activation by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0534] In some embodiments, the condition associated with undesired T cell activation is an inflammatory condition, an immune and proliferative disorder, including but not limited to rheumatoid arthritis (RA), osteoarthritis, osteoporosis, uveitis, inflammatory fibrosis (e.g., scleroderma, lung fibrosis, and cirrhosis), inflammatory bowel disorders (e.g., Crohn's disease, ulcerative colitis and inflammatory bowel disease), multiple sclerosis, psoriasis, contact-mediated dermatitis, systemic lupus erythematosus (SLE) and other forms of lupus, diabetes, type I diabetes, cancer, lupus, scleroderma, Sjogren syndrome, and vasculitis.

[0535] Method of manufacturing

[0536] The compounds of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.

[0537] Substituted 2-indole carboxylic acids are made using known literature procedures and in some cases a R3 halogen group is introduced via a halogenation reaction using known procedures and reagents such as NCS for chlorination and Selectfluor™ for fluorination. In some cases an indole protecting group, such as SEM, may be introduced using known procedures, which is then removed later in the sequence using known procedures. In other cases no protecting group is used and the indole NH remains in place during subsequent steps.

[0538] Scheme 1 nd g group (e.g. SEM)

[0539] The appropriately substituted indole-2-carboxylic acids are coupled with amines using standard procedures and reagents such as EDC & HOBt, HATLI, TCFH & NMI, DIPEA & COMII (Scheme 1). In some cases a Y protecting group (e.g. SEM) is in place during amide bond formation, which is then removed using standard procedures to afford the desired product where Y = H. In some cases the amide bond formation is performed without protection, i.e. where Y = H. In some cases the indole amide substituent (NQW) includes a protected amine (e.g.

[0540] Boc protected) which is deprotected to afford final products using standard methods.

[0541] In some cases the indole amide substituent (NQW) contains a hydroxyl group that is subsequently alkylated with a reagent containing a protected amine (e.g. Boc protected). The protecting group is then cleaved using standard methods to produce the desired compound, an exemplar being shown in Scheme 2. This method can be applied to other cyclic or acylic hydroxyl-containing NQW substituents and also using other alkylating agents containing protected amines.

[0542] Scheme 2

[0543] In some cases the indole amide substituent (NQW) contains an amino group that is subsequently substituted using an alkylation reaction or a reductive amination, for example using an aldehyde and a reducing agent such as NaCNBH3 or STAB. An exemplar being shown in Scheme 3. This method can be applied to other cyclic or acylic amine-containing NQW substituents and also using other alkylating agents.

[0544] Scheme 3

[0545] All starting materials are either commercially available or known in the art and may be synthesised by using known procedures. Starting materials may also be synthesised using the procedures disclosed herein. Reaction conditions such as reaction temperature, solvent and reagents for the Schemes in this section may be found in the experimental section herein. In one aspect, the present invention relates to a method for manufacturing a compound of Formula (I):

[0546] Formula (I) wherein R1, R2, R3, R4, R5, and R6are as defined herein, and is R4as defined herein.

[0547] In one aspect, the present invention relates to a method for manufacturing a compound of Formula (I):

[0548] Formula (I) wherein

[0549] R1is halogen or H;

[0550] R2is halogen;

[0551] R3is H or halogen;

[0552] R4is as defined herein;

[0553] R5is H or halogen;

[0554] R6is H or halogen, said method comprising the steps of: a. providing a compound of Formula (SI),

[0555] Formula (SI) wherein R1is halogen or H;

[0556] R2is halogen;

[0557] R3is H or halogen;

[0558] R5is H or halogen;

[0559] R6is H or halogen; and

[0560] Y is H or a protecting group;

[0561] Q

[0562] H-N' b. reacting the compound of step a) with , wherein jSR4ASdefined herein or a precursor for R4as defined herein, to generate the compound of Formula (Sil):

[0563] Formula (Sil) wherein

[0564] R1is halogen or H;

[0565] R2is halogen;

[0566] R3is H or halogen;

[0567] R5is H or halogen;

[0568] R6is H or halogen;

[0569] Y is a H or a protecting group; and js R4as defined herein or a precursor for R4as defined herein.

[0570] In some embodiments, Y is a protecting group (e.g. SEM) and said method for manufacturing a compound of Formula (I) includes a step subsequent to step b) wherein the protecting group is removed. In some embodiments, Y is H. In some embodiments, jSR4 jS asc|efjnec| herein. In some embodiments,

[0571] . Q . Q

[0572] H H

[0573] W js a precursor for R4as defined herein. For example, Wmay be R4 including a protecting group, such as if R4includes an amine, said amine may be protected (e.g. Boc protected). Further, a precursor for R4also includes groups that are further modified to afford R4as defined herein. For example, a precursor for R4may contain a hydroxyl group that is subsequently alkylated with a reagent containing a protected amine (e.g. Boc protected). The protecting group is then cleaved using standard methods to afford R4as defined herein. When jS aprecursor for R4as defined herein, one or more steps are included subsequent to step b) to afford the compound of Formula (I).

[0574] In some embodiments, Y is a protecting group and is a precursor for R4as defined herein, and step b) is followed by step c-1), wherein the protecting group in position Y is removed to generate the compound of Formula (SHI):

[0575] Formula (SIH)

[0576] Step c-1) is then followed by step c-2), wherein is modified to R4to generate the compound of Formula (I). In some embodiments, step c-1) and step c-2) occur simultaneously. Alternatively, in some embodiments, Y is a protecting group and jS aprecursor for R4as defined herein, and step b) is followed by step d-1), wherein jSmodified to R4to generate the compound of Formula (SIV):

[0577] Formula (SIV)

[0578] Step d-1) is then followed by step d-2), wherein the protecting group in position Y is removed, and the compound of Formula (I) is generated. In some embodiments, step d-1) and step d-2) occur simultaneously.

[0579] In some embodiments, R3in Formula (SI) is H. In some embodiments, R3in Formula (SI) is H and step a) includes introducing a halogen in position R3of the compound of Formula (SI) via a halogenation reaction. In some embodiments, said halogenation reaction includes using known procedures and reagents such as for example NCS for chlorination and SelectfluorTM for fluorination.

[0580] Items

[0581] 1 . A compound of Formula (I),

[0582] Formula (I) wherein

[0583] R1is halogen or H;

[0584] R2is halogen; R3is H or halogen;

[0585] R5is H or halogen;

[0586] R6is H or halogen;

[0587] R4is of Formula (II):

[0588] Formula (II) wherein

[0589] X1is C(R7)(R8);

[0590] X2is C(R9)(R10) or a bond;

[0591] X3is C(R11)(R12) or N(R13);

[0592] X4is C(R16)(R17), O or a bond;

[0593] X5is C(R18)(R19) or a bond;

[0594] X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14, R12and R14, R12and R27, R9and R13or R10and R13are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);

[0595] R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0596] R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0597] R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R9is joined together with R13or R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0598] R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R10is joined together with R13or R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R11is -X7N(R14)(R15) or -X7-O-X8-R27;

[0599] X7is a bond or C1-3 alkanediyl;

[0600] X8is a bond or C1-3 alkanediyl;

[0601] R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F; or when R27is joined together with R12to form a ring together with the intervening atom(s), then R27is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;

[0602] R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; or when R12is joined together with R14or R27to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R13is H or C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy; or when R13and R9or R10are joined together to form a ring together with the intervening atoms, then R13is -C1-3 alkanediyl-N(R28)-, wherein the C1-3 alkanediyl is optionally substituted with one or more substituents individually selected from halogen, C1- 3 alkyl, and C1-3 haloalkyl, and R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0603] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0604] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0605] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0606] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0607] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X2is C(R9)(R10), X4is C(R16)(R17), and X5is C(R18)(R19), or a pharmaceutically acceptable salt thereof.

[0608] 2. A compound of Formula (I),

[0609] Formula (I) wherein

[0610] R1is halogen or H;

[0611] R2is halogen;

[0612] R3is H or halogen;

[0613] R5is H or halogen;

[0614] R6is H or halogen;

[0615] R4is of Formula (II):

[0616] Formula (II) wherein

[0617] X1is C(R7)(R8);

[0618] X2is C(R9)(R10) or a bond;

[0619] X3is C(R11)(R12) or N(R13);

[0620] X4is C(R16)(R17), O or a bond;

[0621] X5is C(R18)(R19) or a bond;

[0622] X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14or R12and R14are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0623] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0624] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or when R9is joined together with R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; ; or when R10is joined together with R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0625] R11is -X7N(R14)(R15) or -O-azetidinyl;

[0626] X7is a bond or C1-3 alkanediyl;

[0627] R14is H or C1-3 alkyl; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1- 3 alkyl, and C1-3 haloalkyl;

[0628] R15is H or C1-3 alkyl; R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or when R12is joined together with R14to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0629] R13is H or C1-3 alkyl optionally substituted with NH2;

[0630] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0631] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0632] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0633] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0634] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0635] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X4is C(R11)(R12), or a pharmaceutically acceptable salt thereof. A compound of Formula (I),

[0636] Formula (I) wherein

[0637] R1is halogen or H; R2is halogen;

[0638] R3is H or halogen;

[0639] R5is H or halogen;

[0640] R6is H or halogen;

[0641] R4is of Formula (II):

[0642] Formula (II) wherein

[0643] X1is C(R7)(R8);

[0644] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0645] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0646] X2is C(R9)(R10) or a bond;

[0647] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0648] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0649] X3is C(R11)(R12) or N(R13);

[0650] R11is -X7N(R14)(R15) or -O-azetidinyl;

[0651] X7is a bond or C1-3 alkanediyl;

[0652] R14is H or C1-3 alkyl, or R14is a bond and R12is C1-3 alkyl and R14is linked to

[0653] R12to form a 4 or 5 membered ring;

[0654] R15is C1-3 alkyl;

[0655] R12is H or C1-3 alkyl;

[0656] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0657] X4is C(R16)(R17), O or a bond;

[0658] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0659] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0660] X5is C(R18)(R19) or a bond;

[0661] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0662] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F;

[0663] X6is a bond or C(R20)(R21);

[0664] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F; and

[0665] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, or F; with the proviso that when X3is N(R13), then X4is C(R11)(R12), or a pharmaceutically acceptable salt thereof.

[0666] 4. The compound according to any one of the preceding items, wherein R1is halogen, or a pharmaceutically acceptable salt thereof.

[0667] 5. The compound according to any one of the preceding items, wherein R1is Cl, or a pharmaceutically acceptable salt thereof.

[0668] 6. The compound according to any one of the preceding items, wherein R1is F, or a pharmaceutically acceptable salt thereof.

[0669] 7. The compound according to any one of the preceding items, wherein R1is H, or a pharmaceutically acceptable salt thereof.

[0670] 8. The compound according to any one of the preceding items, wherein R2is Cl, or a pharmaceutically acceptable salt thereof.

[0671] 9. The compound according to any one of the preceding items, wherein R3is halogen, or a pharmaceutically acceptable salt thereof.

[0672] 10. The compound according to any one of the preceding items, wherein R3is Cl, or a pharmaceutically acceptable salt thereof.

[0673] 11 . The compound according to any one of the preceding items, wherein R3is F, or a pharmaceutically acceptable salt thereof.

[0674] 12. The compound according to any one of the preceding items, wherein R3is H, or a pharmaceutically acceptable salt thereof.

[0675] 13. The compound according to any one of the preceding items, wherein R5is H, or a pharmaceutically acceptable salt thereof.

[0676] 14. The compound according to any one of the preceding items, wherein R5is halogen, or a pharmaceutically acceptable salt thereof.

[0677] 15. The compound according to any one of the preceding items, wherein R5is F, or a pharmaceutically acceptable salt thereof.

[0678] 16. The compound according to any one of the preceding items, wherein R6is H, or a pharmaceutically acceptable salt thereof.

[0679] 17. The compound according to any one of the preceding items, wherein R6is halogen, or a pharmaceutically acceptable salt thereof.

[0680] 18. The compound according to any one of the preceding items, wherein R6is F, or a pharmaceutically acceptable salt thereof.

[0681] 19. The compound according to any one of the preceding items, wherein R5is H and R6is H, or a pharmaceutically acceptable salt thereof. 20. The compound according to any one of the preceding items, wherein R1is halogen, and R2is halogen, or a pharmaceutically acceptable salt thereof.

[0682] 21. The compound according to any one of the preceding items, wherein R2is halogen, and R3is halogen, or a pharmaceutically acceptable salt thereof.

[0683] 22. The compound according to any one of the preceding items, wherein R1is halogen, R2is halogen, and R3is halogen, or a pharmaceutically acceptable salt thereof.

[0684] 23. The compound according to any one of the preceding items, wherein R1is halogen, R2is halogen, R3is halogen, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0685] 24. The compound according to any one of the preceding items, wherein R1is halogen, R2is halogen, R3is H, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0686] 25. The compound according to any one of the preceding items, wherein R1is halogen, R2is halogen, R3is H, R5is halogen, and R6is H, or a pharmaceutically acceptable salt thereof.

[0687] 26. The compound according to any one of the preceding items, wherein R1is halogen, R2is halogen, R3is H, R5is H, and R6is halogen, or a pharmaceutically acceptable salt thereof.

[0688] 27. The compound according to any one of the preceding items, wherein R1is H, R2is halogen, R3is halogen, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0689] 28. The compound according to any one of the preceding items, wherein R1is F or Cl, R2is F or Cl, and R3is F or Cl, or a pharmaceutically acceptable salt thereof.

[0690] 29. The compound according to any one of the preceding items, wherein R1is F, R2is Cl, and R3is Cl, or a pharmaceutically acceptable salt thereof.

[0691] 30. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, and R3is Cl, or a pharmaceutically acceptable salt thereof.

[0692] 31. The compound according to any one of the preceding items, wherein R1is F, R2is Cl, and R3is F, or a pharmaceutically acceptable salt thereof.

[0693] 32. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, and R3is F, or a pharmaceutically acceptable salt thereof. 33. The compound according to any one of the preceding items, wherein R1is F or Cl, R2is F or Cl, R3is F or Cl, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0694] 34. The compound according to any one of the preceding items, wherein R1is F or Cl, R2is Cl, R3is Cl, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0695] 35. The compound according to any one of the preceding items, wherein R1is F, R2is Cl, R3is Cl, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0696] 36. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, R3is Cl, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0697] 37. The compound according to any one of the preceding items, wherein R1is F, R2is Cl, R3is F, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0698] 38. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, R3is F, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0699] 39. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, R3is H, R5is F, and R6is H, or a pharmaceutically acceptable salt thereof.

[0700] 40. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, R3is H, R5is H, and R6is F, or a pharmaceutically acceptable salt thereof.

[0701] 41. The compound according to any one of the preceding items, wherein R1is Cl, R2is Cl, R3is H, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0702] 42. The compound according to any one of the preceding items, wherein R1is F, R2is Cl, R3is H, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0703] 43. The compound according to any one of the preceding items, wherein R1is H, R2is Cl, R3is Cl, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

[0704] 44. The compound according to any one of the preceding items, wherein X2is C(R9)(R10); X3is N(R13); X4is C(R16)(R17); X5is C(R18)(R19); and

[0705] X6is a bond, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (III):

[0706] Formula (III) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (IV):

[0707] Formula (IV) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R7, R8, R9, R10, R16, R17, R18, and R19are H, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XI):

[0708] Formula (XI) wherein

[0709] R13is H, C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy;

[0710] R22is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and q is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

[0711] 49. The compound according to any one of the preceding items, wherein q is 0, or a pharmaceutically acceptable salt thereof.

[0712] 50. The compound according to any one of the preceding items, wherein q is 1 , or a pharmaceutically acceptable salt thereof.

[0713] 51 . The compound according to any one of the preceding items, wherein q is 2, or a pharmaceutically acceptable salt thereof.

[0714] 52. The compound according to any one of the preceding items, wherein R22is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0715] 53. The compound according to any one of the preceding items, wherein R22is - CH3, or a pharmaceutically acceptable salt thereof.

[0716] 54. The compound according to any one of the preceding items, wherein R22is F, or a pharmaceutically acceptable salt thereof.

[0717] 55. The compound according to any one of the preceding items, wherein R4is of Formula (V):

[0718] Formula (V) or a pharmaceutically acceptable salt thereof.

[0719] 56. The compound according to any one of the preceding items, wherein X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond, or a pharmaceutically acceptable salt thereof.

[0720] 57. The compound according to any one of the preceding items, wherein X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond and X6is a bond, or a pharmaceutically acceptable salt thereof.

[0721] 58. The compound according to any one of the preceding items, wherein R4is of Formula (XXXVI):

[0722] Formula (XXXVI) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XXXVI):

[0723] Formula (XXXVI) wherein

[0724] R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0725] R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;

[0726] R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen;

[0727] R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen;

[0728] R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen;

[0729] R11is -X7N(R14)(R15);

[0730] X7is a bond or C1-3 alkanediyl;

[0731] R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F;

[0732] R15is H or C1-3 alkyl;

[0733] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0734] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0735] X5is a bond or C(R18)(R19);

[0736] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0737] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or a pharmaceutically acceptable salt thereof. The compound according to item 59, wherein R4is of Formula (XXXVIa):

[0738] Formula (XXXVIa) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R7is H or F; R8is H or F; R9is H or F; R10is H or F; R12is H; R11is - X7N(R14)(R15); X7is a bond or C1-3 alkanediyl; R14is H or C1-3 alkyl; R15is H or C1-3 alkyl; R16is H or F; R17is H or F; X5is a bond or C(R18)(R19); R18is H or F; and R19is H or F; or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein

[0739] R7is H; R8is H; R9is F; R10is H; R12is H; R11is -X7N(R14)(R15); X7is a bond or C1-3 alkanediyl; R14is H or C1-3 alkyl; R15is H or C1-3 alkyl; R16is H; R17is H; X5is a bond or C(R18)(R19); R18is H; and R19is H; or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein

[0740] R7is H; R8is H; R9is F; R10is H; R12is H; R11is -NH2, -N(H)(CH3) or N(CH3)2; R16is H; R17is H; X5is a bond or C(R18)(R19); R18is H; and R19is H; or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XII):

[0741] Formula (XII) wherein

[0742] R11is -X7N(R14)(R15);

[0743] X7is a bond or C1-3 alkanediyl;

[0744] R14is H or C1-3 alkyl ;

[0745] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XII):

[0746] Formula (XII) wherein

[0747] R11is -X7-O-X8-R27

[0748] X7is a bond or C1-3 alkanediyl;

[0749] X8is a bond or C1-3 alkanediyl;

[0750] R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F;

[0751] R14is H or C1-3 alkyl ;

[0752] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein r is 0, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein r is 1 , or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein r is 2, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (Via):

[0753] Formula (Via) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (Vlb):

[0754] Formula (Vlb) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein X2is a bond; X3is C(R11)(R12); X4is C(R11)(R12) or O; X5is C(R18)(R19); and X6is C(R20)(R21), or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XIII):

[0755] Formula (XIII) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of

[0756] Formula (XIII):

[0757] Formula (XIII) wherein

[0758] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0759] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0760] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0761] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0762] R11is -X7N(R14)(R15); X7is a bond or C1-3 alkanediyl;

[0763] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0764] R15is H or C1-3 alkyl;

[0765] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0766] X4is C(R16)(R17) or O;

[0767] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0768] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0769] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0770] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0771] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0772] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or a pharmaceutically acceptable salt thereof.

[0773] 74. The compound according to item 71 , wherein R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0774] 75. The compound according to any one of the preceding items, wherein R4is of Formula (XlVa):

[0775] Formula (XlVa) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XlVb):

[0776] Formula (XlVb) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XV):

[0777] Formula (XV) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XV):

[0778] Formula (XV) wherein

[0779] R11is -X7N(R14)(R15);

[0780] X7is a bond or C1-3 alkanediyl;

[0781] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0782] R15is H or C1-3 alkyl;

[0783] X4is C(R16)(R17) or O;

[0784] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0785] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0786] R24is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and t is 0, 1 , 2, 3 or 4,

[0787] 79. The compound according to item 78, wherein R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0788] 80. The compound according to any one of the preceding items, wherein t is 0, or a pharmaceutically acceptable salt thereof.

[0789] 81 . The compound according to any one of the preceding items, wherein t is 1 , or a pharmaceutically acceptable salt thereof.

[0790] 82. The compound according to any one of the preceding items, wherein t is 2, or a pharmaceutically acceptable salt thereof.

[0791] 83. The compound according to any one of the preceding items, wherein R24is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0792] 84. The compound according to any one of the preceding items, wherein R24is - CH3, or a pharmaceutically acceptable salt thereof.

[0793] 85. The compound according to any one of the preceding items, wherein R24is F, or a pharmaceutically acceptable salt thereof.

[0794] 86. The compound according to any one of the preceding items, wherein R4is of Formula (Vila): Formula (Vila) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (VI lb):

[0795] Formula (VI lb) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XVI):

[0796] Formula (XVI) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XVI):

[0797] Formula (XVI) wherein

[0798] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0799] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0800] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0801] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R11is -X7N(R14)(R15);

[0802] X7is a bond or C1-3 alkanediyl;

[0803] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0804] R15is H or C1-3 alkyl;

[0805] R13is H or C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with NH2;

[0806] X4is C(R16)(R17) or O;

[0807] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0808] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or a pharmaceutically acceptable salt thereof.

[0809] 91. The compound according to item 90, wherein R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0810] 92. The compound according to any one of the preceding items, wherein R4is of Formula (XVI la):

[0811] Formula (XVI la) or a pharmaceutically acceptable salt thereof.

[0812] 93. The compound according to any one of the preceding items, wherein R4is of Formula (XVI lb):

[0813] Formula (XVI lb) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of

[0814] Formula (XVIII):

[0815] Formula (XVIII) wherein

[0816] R11is -X7N(R14)(R15);

[0817] X7is a bond or C1-3 alkanediyl;

[0818] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0819] R15is H or C1-3 alkyl;

[0820] R25is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and u is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R4is of Formula (XVIII):

[0821] Formula (XVIII) wherein

[0822] R11is -X7N(R14)(R15);

[0823] X7is a bond or C1-3 alkanediyl;

[0824] R14is H or C1-3 alkyl ; and R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; or R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0825] R15is H or C1-3 alkyl;

[0826] R25is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and u is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

[0827] 96. The compound according to any one of the preceding items, wherein u is 0, or a pharmaceutically acceptable salt thereof.

[0828] 97. The compound according to any one of the preceding items, wherein u is 1 , or a pharmaceutically acceptable salt thereof.

[0829] 98. The compound according to any one of the preceding items, wherein u is 2, or a pharmaceutically acceptable salt thereof.

[0830] 99. The compound according to any one of the preceding items, wherein R25is C1-3 alkyl substituted with 1 to 3 F, or a pharmaceutically acceptable salt thereof.

[0831] 100. The compound according to any one of the preceding items, wherein R25is -CF3 or a pharmaceutically acceptable salt thereof.

[0832] 101 . The compound according to any one of the preceding items, wherein R25is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0833] 102. The compound according to any one of the preceding items, wherein R25is -CH3, or a pharmaceutically acceptable salt thereof. 103. The compound according to any one of the preceding items, wherein R25is C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0834] 104. The compound according to any one of the preceding items, wherein R25is -OCH3, or a pharmaceutically acceptable salt thereof.

[0835] 105. The compound according to any one of the preceding items, wherein R22is F, or a pharmaceutically acceptable salt thereof.

[0836] 106. The compound according to any one of the preceding items, wherein R4is of Formula (Villa):

[0837] Formula (Villa) or a pharmaceutically acceptable salt thereof.

[0838] 107. The compound according to any one of the preceding items, wherein R4is of Formula (VI I lb):

[0839] Formula (VI I lb) or a pharmaceutically acceptable salt thereof.

[0840] 108. The compound according to any one of the preceding items, wherein X2is a bond; X3is C(R11)(R12); X4is C(R16)(R17) or a bond; X5is C(R18)(R19); and

[0841] X6is bond, or a pharmaceutically acceptable salt thereof.

[0842] 109. The compound according to any one of the preceding items, wherein R12and R14are linked together to form a ring, or a pharmaceutically acceptable salt thereof.

[0843] 110. The compound according to any one of the preceding items, wherein R14is a bond and R12is C1-3 alkyl and R14is linked to R12to form a 4 or 5 membered ring, or a pharmaceutically acceptable salt thereof.

[0844] 111. The compound according to any one of the preceding items, wherein R14is Ci alkanediyl and R12is a bond or C1-3 alkyl and R14is linked to R12to form a 4 or 5 membered ring, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R4is of Formula (XII):

[0845] Formula (XII) wherein

[0846] R11is -X7N(R14)(R15);

[0847] X7is a bond or C1-3 alkanediyl;

[0848] R14is linked to R12to form a 4-6 membered ring, and R14is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0849] R23is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof. . The compound according to item 112, wherein R14is linked to R12to form a 4-6 membered ring, and R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R12and R27are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R4is of Formula (XII): Formula (XII) wherein

[0850] R11is -X7-O-X8-R27;

[0851] X7is a bond or C1-3 alkanediyl;

[0852] X8is a bond or C1-3 alkanediyl;

[0853] R27is linked to R12to form a 4-6 membered ring, and R27is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; and R12is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0854] R23is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and r is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

[0855] 116. The compound according to any one of the preceding items, wherein r is 0, or a pharmaceutically acceptable salt thereof.

[0856] 117. The compound according to any one of the preceding items, wherein r is

[0857] 1 , or a pharmaceutically acceptable salt thereof.

[0858] 118. The compound according to any one of the preceding items, wherein r is

[0859] 2, or a pharmaceutically acceptable salt thereof.

[0860] 119. The compound according to any one of the preceding items, wherein R23is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0861] 120. The compound according to any one of the preceding items, wherein R23is -CH3, or a pharmaceutically acceptable salt thereof.

[0862] 121 . The compound according to any one of the preceding items, wherein R23is F, or a pharmaceutically acceptable salt thereof.

[0863] 122. The compound according to any one of the preceding items, wherein R14is linked to R12to form a 4-6 membered ring, or a pharmaceutically acceptable salt thereof.

[0864] 123. The compound according to any one of the preceding items, wherein R14is linked to R12to form a 4 membered ring, or a pharmaceutically acceptable salt thereof.

[0865] 124. The compound according to any one of the preceding items, wherein R14is linked to R12to form a 5 membered ring, or a pharmaceutically acceptable salt thereof. 125. The compound according to any one of the preceding items, wherein R14is linked to R12to form a 6 membered ring, or a pharmaceutically acceptable salt thereof.

[0866] 126. The compound according to any one of the preceding items, wherein R4is of Formula (XIX):

[0867] Formula (XIX) wherein

[0868] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0869] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0870] X5is C(R18)(R19) or a bond;

[0871] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0872] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0873] R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0874] R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0875] R26is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; m is 0 pr 1 ; p is 0, 1 or 2; v is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

[0876] 127. The compound according to any one of the preceding items, wherein v is 0, or a pharmaceutically acceptable salt thereof.

[0877] 128. The compound according to any one of the preceding items, wherein v is

[0878] 1 , or a pharmaceutically acceptable salt thereof.

[0879] 129. The compound according to any one of the preceding items, wherein v is

[0880] 2, or a pharmaceutically acceptable salt thereof.

[0881] 130. The compound according to any one of the preceding items, wherein R4is of Formula (IX):

[0882] Formula (IX) wherein m is 0 or 1; n is 0 or 1 ; and p is 0, 1 or 2, with the proviso that when m is 0 then p is 1, and with the proviso that when p is 2, then m is 0, or a pharmaceutically acceptable salt thereof.

[0883] 131. The compound according to any one of the preceding items, wherein m is 0, or a pharmaceutically acceptable salt thereof.

[0884] 132. The compound according to any one of the preceding items, wherein m is 1 , or a pharmaceutically acceptable salt thereof.

[0885] 133. The compound according to any one of the preceding items, wherein p is 0, or a pharmaceutically acceptable salt thereof.

[0886] 134. The compound according to any one of the preceding items, wherein p is

[0887] 1 , or a pharmaceutically acceptable salt thereof.

[0888] 135. The compound according to any one of the preceding items, wherein p is

[0889] 2, or a pharmaceutically acceptable salt thereof.

[0890] 136. The compound according to any one of the preceding items, wherein m is 0 and p is 1 , or a pharmaceutically acceptable salt thereof.

[0891] 137. The compound according to any one of the preceding items, wherein m is 1 and p is 1 , or a pharmaceutically acceptable salt thereof.

[0892] 138. The compound according to any one of the preceding items, wherein m is 1 and p is 0, or a pharmaceutically acceptable salt thereof.

[0893] 139. The compound according to any one of the preceding items, wherein m is 0 and p is 2, or a pharmaceutically acceptable salt thereof.

[0894] 140. The compound according to any one of the preceding items, wherein n is 0, or a pharmaceutically acceptable salt thereof.

[0895] 141. The compound according to any one of the preceding items, wherein n is 1 , or a pharmaceutically acceptable salt thereof. 142. The compound according to any one of the preceding items, wherein m is 0, n is 0 and p is 1 , or a pharmaceutically acceptable salt thereof.

[0896] 143. The compound according to any one of the preceding items, wherein m is 1 , n is 0 and p is 0, or a pharmaceutically acceptable salt thereof.

[0897] 144. The compound according to any one of the preceding items, wherein m is 1 , n is 0 and p is 1 , or a pharmaceutically acceptable salt thereof.

[0898] 145. The compound according to any one of the preceding items, wherein m is 1 , n is 1 and p is 0, or a pharmaceutically acceptable salt thereof.

[0899] 146. The compound according to any one of the preceding items, wherein m is 0, n is 1 and p is 1 , or a pharmaceutically acceptable salt thereof.

[0900] 147. The compound according to any one of the preceding items, wherein m is 1 , n is 1 and p is 1 , or a pharmaceutically acceptable salt thereof.

[0901] 148. The compound according to any one of the preceding items, wherein m is 0, n is 1 and p is 2, or a pharmaceutically acceptable salt thereof.

[0902] 149. The compound according to any one of the preceding items, wherein R9and R14are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof.

[0903] 150. The compound according to any one of the preceding items, wherein R10and R14are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof.

[0904] 151 . The compound according to any one of the preceding items, wherein X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond, or a pharmaceutically acceptable salt thereof.

[0905] 152. The compound according to any one of the preceding items, wherein X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond; and R9and R14are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof.

[0906] 153. The compound according to any one of the preceding items, wherein X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond; and R9and R14are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof.

[0907] 154. The compound according to any one of the preceding items, wherein R4is of Formula (XXIV):

[0908] Formula (XXIV) wherein

[0909] X5is C(R18)(R19) or a bond;

[0910] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0911] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0912] R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0913] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0914] X7is a bond or C1-3 alkanediyl;

[0915] R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0916] R15is H or C1-3 alkyl;

[0917] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0918] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0919] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen,

[0920] R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0921] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R4is of Formula (XX):

[0922] Formula (XX) wherein R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0923] R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; X7is a bond or C1-3 alkanediyl;

[0924] R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0925] R15is H or C1-3 alkyl;

[0926] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0927] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen, or a pharmaceutically acceptable salt thereof.

[0928] 156. The compound according to item 154, wherein R4is of Formula (XXI):

[0929] Formula (XXI) or a pharmaceutically acceptable salt thereof.

[0930] 157. The compound according to any one of the preceding items, wherein X1is C(R7)(R8); X2is C(R9)(R10); X3is C(R11)(R12); X4is C(R16)(R17); X5is a bond; and X6is a bond; and R10and R14are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof.

[0931] 158. The compound according to any one of the preceding items, wherein R4is of Formula (XXII):

[0932] Formula (XXII) wherein

[0933] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0934] R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0935] R9is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0936] R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0937] R11is -X7N(R14)(R15) or -O-azetidinyl;

[0938] X7is a bond or C1-3 alkanediyl;

[0939] R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0940] R15is H or C1-3 alkyl;

[0941] R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0942] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0943] R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen, or a pharmaceutically acceptable salt thereof. . The compound according to item 158, wherein R4is of Formula (XXIII):

[0944] Formula (XXIII) or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R9and R13are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R10and R13are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein X1is C(R7)(R8); X2is C(R9)(R10); X3is N(R13); X4is C(R16)(R17); X5is a bond; and X6is a bond, and R9and R13are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein X1is C(R7)(R8); X2is C(R9)(R10); X3is N(R13); X4is C(R16)(R17); X5is C(R18)(R19); and X6is a bond, and R9and R13are joined together to form a 4-6 membered ring together with the intervening atoms, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R4is of Formula (XXV):

[0945] Formula (XXV) wherein

[0946] X5is C(R18)(R19) or a bond;

[0947] R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;

[0948] R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;

[0949] X9is C1-3 alkanediyl;

[0950] R28is H or C1-3 alkyl;

[0951] R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; and

[0952] R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen, or a pharmaceutically acceptable salt thereof.

[0953] 165. The compound according to any one of the preceding items, wherein R7is H, or a pharmaceutically acceptable salt thereof.

[0954] 166. The compound according to any one of the preceding items, wherein R7is halogen, or a pharmaceutically acceptable salt thereof.

[0955] 167. The compound according to any one of the preceding items, wherein R7is F, or a pharmaceutically acceptable salt thereof.

[0956] 168. The compound according to any one of the preceding items, wherein R7is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0957] 169. The compound according to any one of the preceding items, wherein R7is CH3, or a pharmaceutically acceptable salt thereof.

[0958] 170. The compound according to any one of the preceding items, wherein R7is C1-3 alkyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0959] 171. The compound according to any one of the preceding items, wherein R7is -CH2OCH3, or a pharmaceutically acceptable salt thereof.

[0960] 172. The compound according to any one of the preceding items, wherein R8is H, or a pharmaceutically acceptable salt thereof.

[0961] 173. The compound according to any one of the preceding items, wherein R8is halogen, or a pharmaceutically acceptable salt thereof.

[0962] 174. The compound according to any one of the preceding items, wherein R8is F, or a pharmaceutically acceptable salt thereof.

[0963] 175. The compound according to any one of the preceding items, wherein R8is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0964] 176. The compound according to any one of the preceding items, wherein R8is CH3, or a pharmaceutically acceptable salt thereof.

[0965] 177. The compound according to any one of the preceding items, wherein R8is C1-3 alkyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. 178. The compound according to any one of the preceding items, wherein R8is -CH2OCH3, or a pharmaceutically acceptable salt thereof.

[0966] 179. The compound according to any one of the preceding items, wherein R9is H, or a pharmaceutically acceptable salt thereof.

[0967] 180. The compound according to any one of the preceding items, wherein R9is halogen, or a pharmaceutically acceptable salt thereof.

[0968] 181 . The compound according to any one of the preceding items, wherein R9is F, or a pharmaceutically acceptable salt thereof.

[0969] 182. The compound according to any one of the preceding items, wherein R9is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0970] 183. The compound according to any one of the preceding items, wherein R9is CH3, or a pharmaceutically acceptable salt thereof.

[0971] 184. The compound according to any one of the preceding items, wherein R9is C1-3 alkyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0972] 185. The compound according to any one of the preceding items, wherein R9is -CH2OCH3, or a pharmaceutically acceptable salt thereof.

[0973] 186. The compound according to any one of the preceding items, wherein R9is C1-3 alkyl substituted with 1 to 3 F, or a pharmaceutically acceptable salt thereof.

[0974] 187. The compound according to any one of the preceding items, wherein R9is -CF3, or a pharmaceutically acceptable salt thereof.

[0975] 188. The compound according to any one of the preceding items, wherein R9is C1-3 alkyl substituted with azetidinyl optionally substituted with one or more halogens, or a pharmaceutically acceptable salt thereof.

[0976] 189. The compound according to any one of the preceding items, wherein R9 isF, or a pharmaceutically acceptable salt thereof.

[0977] 190. The compound according to any one of the preceding items, wherein R9is C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0978] 191 . The compound according to any one of the preceding items, wherein R9is -OCH3, or a pharmaceutically acceptable salt thereof.

[0979] 192. The compound according to any one of the preceding items, wherein R10is H, or a pharmaceutically acceptable salt thereof. 193. The compound according to any one of the preceding items, wherein R10is halogen, or a pharmaceutically acceptable salt thereof.

[0980] 194. The compound according to any one of the preceding items, wherein R10is F, or a pharmaceutically acceptable salt thereof.

[0981] 195. The compound according to any one of the preceding items, wherein R10is C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0982] 196. The compound according to any one of the preceding items, wherein R10is -OCH3, or a pharmaceutically acceptable salt thereof.

[0983] 197. The compound according to any one of the preceding items, wherein R10is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0984] 198. The compound according to any one of the preceding items, wherein R10is CH3, or a pharmaceutically acceptable salt thereof.

[0985] 199. The compound according to any one of the preceding items, wherein R10is C1-3 alkyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0986] 200. The compound according to any one of the preceding items, wherein R10is -CH2OCH3, or a pharmaceutically acceptable salt thereof.

[0987] 201 . The compound according to any one of the preceding items, wherein R10is C1-3 alkyl substituted with 1 to 3 F, or a pharmaceutically acceptable salt thereof.

[0988] 202. The compound according to any one of the preceding items, wherein R10is -CF3, or a pharmaceutically acceptable salt thereof.

[0989] 203. The compound according to any one of the preceding items, wherein R10is C1-3 alkyl substituted with azetidinyl optionally substituted with one or more halogens, or a pharmaceutically acceptable salt thereof.

[0990] 204. The compound according to any one of the preceding items, wherein R10 isF, or a pharmaceutically acceptable salt thereof.

[0991] 205. The compound according to any one of the preceding items, wherein R11is -X7N(R14)(R15), or a pharmaceutically acceptable salt thereof.

[0992] 206. The compound according to any one of the preceding items, wherein R11is N(H)(CH3), or a pharmaceutically acceptable salt thereof.

[0993] 207. The compound according to any one of the preceding items, wherein R11is N(CH3)2, or a pharmaceutically acceptable salt thereof. 208. The compound according to any one of the preceding items, wherein R11is NH2, or a pharmaceutically acceptable salt thereof.

[0994] 209. The compound according to any one of the preceding items, wherein R11is C1-3 alkyl optionally substituted with NH2, N(H)(CH3), or N(CH3)2, or a pharmaceutically acceptable salt thereof.

[0995] 210. The compound according to any one of the preceding items, wherein R11is CH2N(H)(CH3), or a pharmaceutically acceptable salt thereof.

[0996] 211. The compound according to any one of the preceding items, wherein R11is CH2N(CH3)2, or a pharmaceutically acceptable salt thereof.

[0997] 212. The compound according to any one of the preceding items, wherein R11is CH2NH2, or a pharmaceutically acceptable salt thereof.

[0998] 213. The compound according to any one of the preceding items, wherein R11iS or apharmaceutically acceptable salt thereof.

[0999] 214. The compound according to any one of the preceding items, wherein R11 isH, or a pharmaceutically acceptable salt thereof.

[1000] 215. The compound according to any one of the preceding items, wherein R11 is , or a pharmaceutically acceptable salt thereof.

[1001] 216. The compound according to any one of the preceding items, wherein R11

[1002] F isH, or a pharmaceutically acceptable salt thereof.

[1003] 217. The compound according to any one of the preceding items, wherein R11is -X7-O-X8-R27, or a pharmaceutically acceptable salt thereof.

[1004] 218. The compound according to any one of the preceding items, wherein R11is , or a pharmaceutically acceptable salt thereof.

[1005] 219. The compound according to any one of the preceding items, wherein R11 is , or a pharmaceutically acceptable salt thereof. 220. The compound according to any one of the preceding items, wherein R11 , or a pharmaceutically acceptable salt thereof.

[1006] 221 . The compound according to any one of the preceding items, wherein R11is -O-azetidinyl, or a pharmaceutically acceptable salt thereof.

[1007] 222. The compound according to any one of the preceding items, wherein R11 is , or a pharmaceutically acceptable salt thereof.

[1008] 223. The compound according to any one of the preceding items, wherein R12is H, or a pharmaceutically acceptable salt thereof.

[1009] 224. The compound according to any one of the preceding items, wherein R12is halogen, or a pharmaceutically acceptable salt thereof.

[1010] 225. The compound according to any one of the preceding items, wherein R12is F, or a pharmaceutically acceptable salt thereof.

[1011] 226. The compound according to any one of the preceding items, wherein R12is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[1012] 227. The compound according to any one of the preceding items, wherein R12is C1-3 alkyl substituted with 1 to 3 F, or a pharmaceutically acceptable salt thereof.

[1013] 228. The compound according to any one of the preceding items, wherein R12is CF3, or a pharmaceutically acceptable salt thereof.

[1014] 229. The compound according to any one of the preceding items, wherein R13is H, or a pharmaceutically acceptable salt thereof.

[1015] 230. The compound according to any one of the preceding items, wherein R13is C1-3 alkyl optionally substituted with NH2, or a pharmaceutically acceptable salt thereof.

[1016] 231 . The compound according to any one of the preceding items, wherein R13is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[1017] 232. The compound according to any one of the preceding items, wherein R13is CH3, or a pharmaceutically acceptable salt thereof

[1018] 233. The compound according to any one of the preceding items, wherein R13is C1-3 alkyl substituted with NH2, or a pharmaceutically acceptable salt thereof.

[1019] 234. The compound according to any one of the preceding items, wherein R13is -CH2NH2, or a pharmaceutically acceptable salt thereof. 235. The compound according to any one of the preceding items, wherein R13is - (CH2)2NH2, or a pharmaceutically acceptable salt thereof.

[1020] 236. The compound according to any one of the preceding items, wherein R13is C1-3 alkyl substituted with -N(CH3)2, or a pharmaceutically acceptable salt thereof.

[1021] 237. The compound according to any one of the preceding items, wherein R13is - (CH2)2N(CH3)2, or a pharmaceutically acceptable salt thereof.

[1022] 238. The compound according to any one of the preceding items, wherein R13is C1-3 alkyl substituted with azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[1023] 239. The compound according to any one of the preceding items, wherein R13

[1024] 240. The compound according to any one of the preceding items, wherein R13

[1025] 241 . The compound according to any one of the preceding items, wherein R14is H, or a pharmaceutically acceptable salt thereof.

[1026] 242. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[1027] 243. The compound according to any one of the preceding items, wherein R14is CH3, or a pharmaceutically acceptable salt thereof.

[1028] 244. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl substituted with oxetanyl, or a pharmaceutically acceptable salt thereof.

[1029] 245. The compound according to any one of the preceding items, wherein R14 , or a pharmaceutically acceptable salt thereof.

[1030] 246. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[1031] 247. The compound according to any one of the preceding items, wherein R14is -(CH2)2OCH3, or a pharmaceutically acceptable salt thereof. 248. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl substituted with azetidinyl optionally substituted with one or more F, or a pharmaceutically acceptable salt thereof.

[1032] 249. The compound according to any one of the preceding items, wherein R14 , or a pharmaceutically acceptable salt thereof.

[1033] 250. The compound according to any one of the preceding items, wherein R14 is , or a pharmaceutically acceptable salt thereof.

[1034] 251 . The compound according to any one of the preceding items, wherein R15is H, or a pharmaceutically acceptable salt thereof.

[1035] 252. The compound according to any one of the preceding items, wherein R15is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[1036] 253. The compound according to any one of the preceding items, wherein R15is CH3, or a pharmaceutically acceptable salt thereof.

[1037] 254. The compound according to any one of the preceding items, wherein R16is H, or a pharmaceutically acceptable salt thereof.

[1038] 255. The compound according to any one of the preceding items, wherein R16is F, or a pharmaceutically acceptable salt thereof.

[1039] 256. The compound according to any one of the preceding items, wherein R17is H, or a pharmaceutically acceptable salt thereof.

[1040] 257. The compound according to any one of the preceding items, wherein R17is F, or a pharmaceutically acceptable salt thereof.

[1041] 258. The compound according to any one of the preceding items, wherein R18is H, or a pharmaceutically acceptable salt thereof.

[1042] 259. The compound according to any one of the preceding items, wherein R18is F, or a pharmaceutically acceptable salt thereof.

[1043] 260. The compound according to any one of the preceding items, wherein R19is H, or a pharmaceutically acceptable salt thereof.

[1044] 261 . The compound according to any one of the preceding items, wherein R19is F, or a pharmaceutically acceptable salt thereof.

[1045] 262. The compound according to any one of the preceding items, wherein R20is H, or a pharmaceutically acceptable salt thereof. 263. The compound according to any one of the preceding items, wherein R20is F, or a pharmaceutically acceptable salt thereof.

[1046] 264. The compound according to any one of the preceding items, wherein R27is N(R14)(R15), or a pharmaceutically acceptable salt thereof.

[1047] 265. The compound according to any one of the preceding items, wherein R27is NH2, or a pharmaceutically acceptable salt thereof.

[1048] 266. The compound according to any one of the preceding items, wherein R27is azetidinyl optionally substituted with one or more F, or a pharmaceutically acceptable salt thereof.

[1049] 267. The compound according to any one of the preceding items, wherein R27 is , or a pharmaceutically acceptable salt thereof.

[1050] 268. The compound according to any one of the preceding items, wherein R27is , or a pharmaceutically acceptable salt thereof.

[1051] 269. The compound according to any one of the preceding items, wherein R21is H, or a pharmaceutically acceptable salt thereof.

[1052] 270. The compound according to any one of the preceding items, wherein R21is F, or a pharmaceutically acceptable salt thereof.

[1053] 271. The compound according to any one of the preceding items, wherein X1is CH2, or a pharmaceutically acceptable salt thereof.

[1054] 272. The compound according to any one of the preceding items, wherein X1is C(CH3)(H), or a pharmaceutically acceptable salt thereof.

[1055] 273. The compound according to any one of the preceding items, wherein X2is CH2, or a pharmaceutically acceptable salt thereof.

[1056] 274. The compound according to any one of the preceding items, wherein X2is C(F)(H), or a pharmaceutically acceptable salt thereof.

[1057] 275. The compound according to any one of the preceding items, wherein X2is CF2, or a pharmaceutically acceptable salt thereof.

[1058] 276. The compound according to any one of the preceding items, wherein X2is a bond, or a pharmaceutically acceptable salt thereof.

[1059] 277. The compound according to any one of the preceding items, wherein X3is a bond, or a pharmaceutically acceptable salt thereof. 278. The compound according to any one of the preceding items, wherein X3is C(NH2)(H), or a pharmaceutically acceptable salt thereof.

[1060] 279. The compound according to any one of the preceding items, wherein X3is C(N(H)(CH3))(H), or a pharmaceutically acceptable salt thereof.

[1061] 280. The compound according to any one of the preceding items, wherein X3is C(N(CH3)2)(H), or a pharmaceutically acceptable salt thereof.

[1062] 281 . The compound according to any one of the preceding items, wherein X3is C(CH2(NH2))(H), or a pharmaceutically acceptable salt thereof.

[1063] 282. The compound according to any one of the preceding items, wherein X3is C(CH2(NH2))(F), or a pharmaceutically acceptable salt thereof.

[1064] 283. The compound according to any one of the preceding items, wherein X3is C(CH2(N(H)(CH3)))(H), or a pharmaceutically acceptable salt thereof.

[1065] 284. The compound according to any one of the preceding items, wherein X3is C(CH2(N(CH3)2))(H), or a pharmaceutically acceptable salt thereof.

[1066] 285. The compound according to any one of the preceding items, wherein X4is a bond, or a pharmaceutically acceptable salt thereof.

[1067] 286. The compound according to any one of the preceding items, wherein X4is O, or a pharmaceutically acceptable salt thereof.

[1068] 287. The compound according to any one of the preceding items, wherein X4is CH2, or a pharmaceutically acceptable salt thereof.

[1069] 288. The compound according to any one of the preceding items, wherein X5is CH2, or a pharmaceutically acceptable salt thereof.

[1070] 289. The compound according to any one of the preceding items, wherein X6is CH2, or a pharmaceutically acceptable salt thereof.

[1071] 290. The compound according to any one of the preceding items, wherein X6is a bond, or a pharmaceutically acceptable salt thereof.

[1072] 291 . The compound according to any one of the preceding items, wherein X7is a bond, or a pharmaceutically acceptable salt thereof.

[1073] 292. The compound according to any one of the preceding items, wherein X7is C1-3 alkanediyl, or a pharmaceutically acceptable salt thereof.

[1074] 293. The compound according to any one of the preceding items, wherein X7is CH2, or a pharmaceutically acceptable salt thereof.

[1075] 294. The compound according to any one of the preceding items, wherein R8, R10, R16, R17, R18, and R19are H, or a pharmaceutically acceptable salt thereof. 295. The compound according to any one of the preceding items, wherein no more than two of X2, X5and X6are bonds, or a pharmaceutically acceptable salt thereof.

[1076] 296. The compound according to any one of the preceding items, wherein halogen is individually selected from F, Cl and Br.

[1077] 297. The compound according to any one of the preceding items, wherein halogen is F.

[1078] 298. The compound according to any one of the preceding items, wherein the azetidinyl is azetidin-1-yl, or a pharmaceutically acceptable salt thereof.

[1079] 299. The compound according to any one of the preceding items, wherein the azetidinyl is azetidin-3-yl, or a pharmaceutically acceptable salt thereof.

[1080] 300. The compound according to any one of the preceding items, wherein the oxetanyl is oxetan-3-yl, or a pharmaceutically acceptable salt thereof.

[1081] 301 . The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1082] 302. The compound according to any one of the preceding items, wherein R4is orapharmaceutically acceptable salt thereof.

[1083] 303. The compound according to any one of the preceding items, wherein R4is or apharmaceutically acceptable salt thereof.

[1084] 304. The compound according to any one of the preceding items, wherein R4is , or a pharmaceutically acceptable salt thereof.

[1085] 305. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof. 306. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1086] 307. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1087] 308. The compound according to any one of the preceding items, wherein R4is , or a pharmaceutically acceptable salt thereof.

[1088] 309. The compound according to any one of the preceding items, wherein R4 or a pharmaceutically acceptable salt thereof.

[1089] 310. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1090] 311. The compound according to any one of the preceding items, wherein R4is or a pharmaceutically acceptable salt thereof.

[1091] 312. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1092] 313. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof. 314. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1093] 315. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1094] 316. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1095] 317. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1096] 318. The compound according to any one of the preceding items, wherein R4 or a pharmaceutically acceptable salt thereof.

[1097] 319. The compound according to any one of the preceding items, wherein R4 , or a pharmaceutically acceptable salt thereof.

[1098] 320. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1099] 321. The compound according to any one of the preceding items, wherein R4 or a pharmaceutically acceptable salt thereof. 322. The compound according to any one of the preceding items, wherein R4iS orapharmaceutically acceptable salt thereof.

[1100] 323. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1101] 324. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1102] 325. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1103] 326. The compound according to any one of the preceding items, wherein R4is , or a pharmaceutically acceptable salt thereof.

[1104] 327. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1105] 328. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1106] 329. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof. 330. The compound according to any one of the preceding items, wherein R4 or a pharmaceutically acceptable salt thereof.

[1107] 331. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1108] 332. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1109] 333. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1110] 334. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1111] 335. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1112] 336. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. 337. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1113] 338. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1114] 339. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1115] 340. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1116] 341. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1117] 342. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1118] 343. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. 344. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1119] 345. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1120] 346. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1121] 347. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1122] 348. The compound according to any one of the preceding items, wherein R4

[1123] MI . is2, or a pharmaceutically acceptable salt thereof.

[1124] 349. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1125] 350. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. 351. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1126] 352. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1127] 353. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1128] 354. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1129] 355. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1130] 356. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1131] 357. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. he compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. he compound according to any one of the preceding items, wherein R4 , he compound according to any one of the preceding items, wherein R4

[1132] NH2

[1133] , or a pharmaceutically acceptable salt thereof. he compound according to any one of the preceding items, wherein R4

[1134] , or a pharmaceutically acceptable salt thereof. 365. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1135] 366. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1136] 367. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1137] 368. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1138] 369. The compound according to any one of the preceding items, wherein R4is , or a pharmaceutically acceptable salt thereof.

[1139] 370. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. 371. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1140] 372. The compound according to any one of the preceding items, wherein R4 , or a pharmaceutically acceptable salt thereof.

[1141] 373. The compound according to any one of the preceding items, wherein R4 , or a pharmaceutically acceptable salt thereof.

[1142] 374. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof.

[1143] 375. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1144] 376. The compound according to any one of the preceding items, wherein R4 compound according to any one of the preceding items, wherein R4 or a pharmaceutically acceptable salt thereof. compound according to any one of the preceding items, wherein R4 compound according to any one of the preceding items, wherein R4

[1145] NHo , or a pharmaceutically acceptable salt thereof. compound according to any one of the preceding items, wherein R4 or a pharmaceutically acceptable salt thereof. 385. The compound according to any one of the preceding items, wherein R4 isH, or a pharmaceutically acceptable salt thereof.

[1146] 386. The compound according to any one of the preceding items, wherein R4is , or a pharmaceutically acceptable salt thereof.

[1147] 387. The compound according to any one of the preceding items, wherein R4

[1148] I is , or a pharmaceutically acceptable salt thereof.

[1149] 388. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1150] 389. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1151] 390. The compound according to any one of the preceding items, wherein R4 pharmaceutically acceptable salt thereof. mpound according to any one of the preceding items, wherein R4 , or a pharmaceutically acceptable salt thereof. mpound according to any one of the preceding items, wherein R4 , mpound according to any one of the preceding items, wherein R4

[1152] NH

[1153] , or a pharmaceutically acceptable salt thereof. mpound according to any one of the preceding items, wherein R4 , or a pharmaceutically acceptable salt thereof. ound according to any one of the preceding items, wherein R4 ,

[1154] , or a pharmaceutically acceptable salt thereof. ound according to any one of the preceding items, wherein R4or a pharmaceutically acceptable salt thereof. ound according to any one of the preceding items, wherein R4

[1155] , or a pharmaceutically acceptable salt thereof. ound according to any one of the preceding items, wherein R4

[1156] , or a pharmaceutically acceptable salt thereof. ound according to any one of the preceding items, wherein R4

[1157] , or a pharmaceutically acceptable salt thereof. 405. The compound according to any one of the preceding items, wherein R4 is , or a pharmaceutically acceptable salt thereof.

[1158] 406. The compound according to any one of the preceding items, wherein R4is , or a pharmaceutically acceptable salt thereof.

[1159] 407. The compound according to any one of the preceding items, wherein the compound is: (4,5-dichloro-1 H-indol-2-yl)-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methanone; (4,5-dichloro-1 H-indol-2-yl)-[(3S)-3-[(dimethylamino)methyl]pyrrolidin-1- yl]methanone;

[1160] (4,5-dichloro-1 H-indol-2-yl)-(4-methylpiperazin-1-yl)methanone; (4,5-dichloro-1 H-indol-2-yl)(1,7-diazaspiro[4.4]nonan-7-yl)methanone;

[1161] (3,4-dichloro-5-fluoro-1 H-indol-2-yl)-[(2S)-2,4-dimethylpiperazin-1- yl]methanone;

[1162] (S)-(3-(aminomethyl)pyrrolidin-1-yl)(4,5-dichloro-1H-indol-2-yl)methanone; 2,7-diazaspiro[3.4]octan-2-yl-(4,5-dichloro-1 H-indol-2-yl)methanone;

[1163] (R)-(3-aminopyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2-yl)methanone;

[1164] (R)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;

[1165] (S)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone; (S)-(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2-methylpiperazin-1-yl)methanone;

[1166] (S)-(4,5-dichloro-1 H-indol-2-yl)(3-((methylamino)methyl)pyrrolidin-1- yl)methanone;

[1167] (4,5-dichloro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone; (4-chloro-5-fluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone;

[1168] (4,5-dichloro-1 H-indol-2-yl)(1,6-diazaspiro[3.4]octan-6-yl)methanone; (R)-(4,5-dichloro-1 H-indol-2-yl)(3-(methylamino)pyrrolidin-1-yl)methanone;

[1169] (4,5-dichloro-1 H-indol-2-yl)(1,6-diazaspiro[3.3]heptan-6-yl)methanone; (4,5-dichloro-1 H-indol-2-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone;

[1170] (R)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;

[1171] (S)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;

[1172] ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone; (2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;

[1173] (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone;

[1174] (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(piperazin-1-yl)methanone;

[1175] (4-aminopiperidin-1-yl) (3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;

[1176] (R)-(3-(azetidin-3-yloxy)pyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2-yl)methanone;

[1177] (4-(2-aminoethyl)piperazin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;

[1178] ((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1179] ((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1180] ((2S,4R)-4-amino-2-methylpyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1181] (R)-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1182] (S)-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1183] ((3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H- indol-2-yl)methanone;

[1184] (4-(2-aminoethoxy)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1185] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(piperazin-1-yl)methanone;

[1186] (R)-(2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1187] (S)-(2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;

[1188] (4-aminopiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone;

[1189] ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1190] (4-(aminomethyl)-4-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1191] ((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1192] ((3S,4R)-4-amino-3-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1193] (4-amino-3,3-difluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone; (3,4-dichloro-5-fluoro-1 H-indol-2-yl)((4aS,7aR)-hexahydropyrrolo[3,4- b][1 ,4]oxazin-6(2H)-yl)methanone;

[1194] (R)-(3-(aminomethyl)-3-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1195] (S)-(3-(aminomethyl)-3-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1196] (S)-(3-(aminomethyl)-3-fluoropiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1197] ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;

[1198] (S)-(4-amino-3,3-difluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1199] (3-(aminomethyl)-3-fluoroazetidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1200] ((3S,4R)-3-amino-4-methoxypyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;

[1201] (3,4-dichloro-5-fluoro-1 H-indol-2-yl)((3aR,6aS)-3a,6a- difluorohexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)methanone;

[1202] (1 ,4-diazepan-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;

[1203] (3,4-dichloro-5-fluoro-1 H-indol-2-yl) (2,6-diazaspiro [3.4] octan-6-yl) methanone;

[1204] (4-(2-aminoethyl)piperazin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone;

[1205] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone;

[1206] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone;

[1207] (R)-(3-aminopyrrolidin-1-yl)(4-chloro-3,5-difluoro-1H-indol-2-yl)methanone;

[1208] (R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-methylpiperazin-1-yl)methanone;

[1209] ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;

[1210] (R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-(methoxymethyl)piperazin-1- yl)methanone;

[1211] (4-amino-4-methylpiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone;

[1212] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(octahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methanone;

[1213] (S)-(4-amino-3,3-difluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;

[1214] ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-1 H-indol-2-yl)methanone; ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3-fluoro-1 H-indol-2- yl)methanone;

[1215] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-7-azaspiro[3.5]nonan-7- yl)methanone;

[1216] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-6-azaspiro[3.4]octan-6-yl)methanone;

[1217] (4-(2-(azetidin-3-yloxy)ethyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1218] (4-((azetidin-3-yloxy)methyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;

[1219] (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(4-((3-fluoroazetidin-3-yl) methoxy)piperidin- 1-yl)methanone;

[1220] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)pyrrolidin-1-yl)methanone;

[1221] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-methoxyazetidin-1- yl)ethyl)piperazin-1-yl)methanone;

[1222] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin-1-yl)ethyl)piperazin-1- yl)methanone;

[1223] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)piperidin- 1-yl)methanone;

[1224] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3-ylmethyl) amino)piperidin-1-yl)methanone;

[1225] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)pyrrolidin- 1-yl)methanone;

[1226] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4R)-3-((2-(3,3-difluoro azetidin-1- yl)ethyl)amino)-4-fluoropyrrolidin-1-yl)methanone;

[1227] (3S,4R)-1-[(4-chloro-3,5-difluoro-1 H-indol-2-yl)carbonyl]-4-fluoro-N-[2-(3- fluoroazetidin-1-yl)ethyl]pyrrolidin-3-amine;

[1228] (R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1- yl)ethyl)piperazin-1-yl)methanone;

[1229] (S)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1- yl)ethyl)piperazin-1-yl)methanone;

[1230] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((2-methoxy ethyl)amino)pyrrolidin-1-yl)methanone; or

[1231] (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(dimethylamino)ethyl) piperazin-1 - yl)methanone, or a pharmaceutically acceptable salt thereof.

[1232] 408. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is a Kv1.3 potassium channel inhibitor.

[1233] 409. A pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[1234] 410. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use as a medicament.

[1235] 411. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use in the treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial.

[1236] 412. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use in the treatment of a neurodegenerative disease.

[1237] 413. The compound or composition for use according to item 412, wherein said neurodegenerative disease is selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD).

[1238] 414. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use in the treatment of a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke.

[1239] 415. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use in the treatment of a disease selected from the group consisting of rheumatoid arthritis (RA), neuropathic pain, inflammatory pain, CNS complications of COVID-19 infection, post-COVID-19 conditions, Chronic Traumatic Encephalopathy, HIV-Associated Neurocognitive Disorder (HAND), Traumatic Brain Injury, Epilepsy, Autoimmune Encephalitis, Bipolar disorder, major depression disorder(MDD) and Schizophrenia.

[1240] 416. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use in the treatment of a disease selected from the group consisting of Psoriasis, Atopic dermatitis, Celiac Disease, Lupus, Type 1 diabetes, Sjogren’s syndrome, Vasculitis, IBD, Crohn’s disease, Graves’ disease, Hashimoto’s thyroiditis, Myasthenia gravis and Scleroderma.

[1241] 417. The compound according to any one of items 1 to 408, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 409, for use in the treatment of a condition selected from the group consisting of cancer, an immunological disorder, a central nervous system disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.

[1242] 418. The compound for use according to item 417, wherein the immunological disorder is transplant rejection or an autoimmune disease.

[1243] 419. The compound for use according to item 417, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes mellitus.

[1244] 420. The compound for use according to item 417, wherein the central nervous system disorder is Alzheimer’s disease.

[1245] 421. The compound for use according to item 417, wherein the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy.

[1246] 422. The compound for use according to item 417, wherein the gastroenterological disorder is an inflammatory bowel disease.

[1247] 423. The compound for use according to item 417, wherein the metabolic disorder is obesity or type II diabetes mellitus.

[1248] 424. The compound for use according to item 417, wherein the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

[1249] 425. The compound for use according to item 417, wherein the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, Alzheimer’s disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, Crohn’s disease, ulcerative colitis, obesity, type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof. . The compound or composition for use according to any one of items 410 to 425, wherein said compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg bodyweight / day. . The compound or composition for use according to any one of items 410 to 426, wherein said compound is administered via enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery. . A method of blocking Kv1.3 potassium channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound according to any one of items 1 to 408 or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of item 409. . The method according to any one of the preceding items, wherein the subject is a mammal, such as human. . A method for manufacturing the compound of Formula (I) according to any one of items 1 to 408. . The method according to item 430, wherein said method comprising the steps of: a. providing a compound of Formula (SI),

[1250] Formula (SI) wherein

[1251] R1is halogen or H;

[1252] R2is halogen;

[1253] R3is H or halogen; R5is H or halogen;

[1254] R6is H or halogen; and

[1255] Y is H or a protecting group;

[1256] Q

[1257] H— N b. reacting the compound of step a) with , wherein is R4or a precursor for R4, to generate the compound of Formula (SI I):

[1258] Formula (Sil) wherein

[1259] R1is halogen or H;

[1260] R2is halogen;

[1261] R3is H or halogen;

[1262] R5is H or halogen;

[1263] R6is H or halogen;

[1264] Y is a H or a protecting group; and precursor for R4.

[1265] 432. The method according to item 431 , wherein Y is a protecting group (e.g. SEM) and the method further includes a step subsequent to step b) wherein the protecting group in position Y is removed.

[1266] 433. The method according to item 431 , wherein Y is H.

[1267] , C

[1268] H

[1269] 434. The method according to any one of items 431 to 433, wherein W jSR4.

[1270] . H Q

[1271] 435. The method according to any one of items 431 to 433, wherein W jSa precursor for R4and the method further includes a step subsequent to step b) wherein the precursor for R4is modified to R4. . The method according to item 431 , wherein Y is a protecting group and

[1272] W js a precursor for R4, and step b) is followed by step c-1), wherein the protecting group in position Y is removed to generate the compound of Formula (SIH):

[1273] Formula (SIH)

[1274] . Q w and step c-1) is followed by step c-2), wherein is modified to R4to generate the compound of Formula (I). . The method according to item 436, wherein step c-1) and step c-2) occur simultaneously. . The method according to item 431 , wherein Y is a protecting group and js a precursor for R4, and step b) is followed by step d-1), wherein is modified to R4to generate the compound of Formula (SIV):

[1275] Formula (SIV) and step d-1) is followed by step d-2), wherein the protecting group in position Y is removed, and the compound of Formula (I) is generated. . The method according to item 438, wherein step d-1) and step d-2) occur simultaneously. 440. The method according to any one of items 431 to 439, wherein R3in Formula (SI) is H.

[1276] 441. The method according to any one of items 431 to 439, wherein R3in Formula (SI) is H and step a) includes introducing a halogen in position R3of the compound of Formula (SI) via a halogenation reaction.

[1277] Examples

[1278] Abbreviations

[1279] 1. Ac = Acetyl

[1280] 2. AcO = Acetate

[1281] 3. ACN = Acetonitrile

[1282] 4. Boc = tert-Butoxycarbonyl

[1283] 5. Bu = Butyl

[1284] 6. COMII = (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate

[1285] 7. DAST = Diethylaminosulfur trifluoride

[1286] 8. DCE = dichloroethane

[1287] 9. DCM = Dichloromethane

[1288] 10. DI PEA = Diisopropylethylamine

[1289] 11. DMAP = 4-Dimethylaminopyridine

[1290] 12. DMF = / V, / V-Dimethylformamide

[1291] 13. DMS = Dimethylsulfide

[1292] 14. DMSO = Dimethylsulphoxide

[1293] 15. EDC / EDCI = 1-Ethyl-3-(3-dimethylaminopropy)carbodiimide

[1294] 16. Et20 = Diethyl ether

[1295] 17. gm = grams

[1296] 18. HATLI = N-[(Dimethylamino)-1 H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide

[1297] 19. HPLC = High pressure liquid chromatography

[1298] 20. HOBt = 1 -Hydroxybenzotriazole

[1299] 21. LCMS = Liquid chromatography mass spectrometry

[1300] 22. Me = Methyl

[1301] 23. min = minutes

[1302] 24. Ms = methanesulfonyl

[1303] 25. mg = milligrams 26. NCS = / V-Chlorosuccinimide

[1304] 27. NMI = N-Methylimidazole

[1305] 28. NMR = Nuclear magnetic resonance

[1306] 29. OTf = Trifluoromethanesulfonate

[1307] 30. RM = reaction mixture

[1308] 31. RP = Reverse-phase

[1309] 32. RT = Retention time

[1310] 33. rt = room temperature

[1311] 34. Selectfluor™ = 1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1 ,4- diium ditetrafluoroborate

[1312] 35. SEM = 2-(Trimethylsilyl)ethoxymethyl

[1313] 36. STAB = Sodium triacetoxyborohydride

[1314] 37. SM = starting material

[1315] 38. TCFH = Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

[1316] 39. TEA = Triethylamine

[1317] 40. TFA = Trifluoroacetic acid

[1318] 41. TFAA = Trifluoroacetic anhydride

[1319] 42. THF = Tetrahydrofuran

[1320] 43. TLC = Thin later chromatography

[1321] 44. Ts = p-toluenesulfonyl

[1322] 1H NMR Spectroscopy:

[1323] 1H NMR was recorded at 400MHz, on a Bruker Advance, II & III spectrometer using solvents from Merck Laboratories. Chemical shifts (5, ppm) are reported relative to the solvent peak (CDCh: 7.25, DMSO-d6: 2.50). Proton resonances are annotated as: chemical shift (5), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad), coupling constant (J, Hz), and number of protons.

[1324] General Hydrolysis Condition:

[1325] To a stirred solution of carboxylic ester (1 equiv.) in THF-H2O (2:1, 3.0 mL / mmol) was added LiOH.H2O (1.2-2 equiv.) and stirred at rt for 6-16 h. The reaction was monitored by LCMS or, TLC. After completion, reaction mixture was concentrated under reduced pressure, diluted with 1 N HCI and extracted with organic solvent and concentrated. In case of precipitation, solid was filtered, washed with organic solvent and dried. Finally, crude material was triturated with pentane or, Et20 to get solid compound. General Amidation Condition:

[1326] Condition-A: To a stirred solution of carboxylic acid (1 equiv.) in DMF (3.0 mL / mmol) was added DI PEA (3 equiv. or, 5 equiv. for SM containing HCI salt) followed by EDC.HCI (1 .5 equiv.) and HOBt (1.5 equiv.) and stirred at rt for 30 minutes. Thereafter, amine (1.2- 2 equiv.) was added into the reaction mixture and allowed to stir at rt for 16 h. After completion (monitored by TLC or, LCMS), the reaction mixture was subjected to usual work-up. It was diluted with organic solvent (EtOAc / DCM) and H2O and taken in a separatory funnel. The organic layer was separated and aq. layer was back extracted with organic solvent three times. The combined organic layer was washed with H2O, brine and dried over anhyd. Na2SO4. Then, it was filtered and the filtrate was evaporated to dryness under reduced pressure to afford the crude compound, which was purified by reverse phase prep. HPLC or, combiflash chromatography.

[1327] Condition-B: To a stirred solution of carboxylic acid (1 equiv.) in DMF (3.0 mL / mmol) was added DI PEA (3 equiv. or, 5 equiv. for SM containing HCI salt) followed by HATLI (1.5 equiv.) and stirred at rt for 30 minutes. Thereafter, amine (1.2-2 equiv.) was added into the reaction mixture and allowed to stir at rt for 16 h. After completion (monitored by TLC or, LCMS), the reaction mixture was subjected to usual work-up. It was diluted with organic solvent (EtOAc / DCM) and H2O and taken in a separatory funnel. The organic layer was separated and aq. layer was back extracted with organic solvent three times. The combined organic layer was washed with H2O, brine and dried over anhyd. Na2SO4. Then, it was filtered and the filtrate was evaporated to dryness under reduced pressure to afford the crude compound, which was purified by reverse phase prep. HPLC or, combiflash chromatography.

[1328] Condition-C: To an ice cold stirred solution of acid (1 equiv) in acetonitrile (0.03 mmol / ml) was added TCFH (1.1 equiv) followed by NMI (5 equiv.) and the resulting reaction mixture was stirred for 30 minutes before addition of amine (1.1 equiv.). The reaction was continued at rt and monitored by LCMS / TLC. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution. The aqueous part was back extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by RP-prep HPLC or, combiflash chromatography. Condition-D: To a stirred solution of carboxylic acid (1 equiv.) in DMF (3.0 mL / mmol) was added DI PEA (3 equiv. or, 5 equiv. for SM containing HCI salt) followed by COMII (1.5 equiv.) and stirred at rt for 30 minutes. Thereafter, amine (1.2-2 equiv.) was added into the reaction mixture and allowed to stir at rt for 16 h. After completion (monitored by TLC or, LCMS), the reaction mixture was subjected to usual work-up. It was diluted with organic solvent (EtOAc / DCM) and H2O and taken in a separatory funnel. The organic layer was separated and aq. layer was back extracted with organic solvent three times. The combined organic layer was washed with H2O, brine and dried over anhyd. Na2SO4. Then, it was filtered and the filtrate was evaporated to dryness under reduced pressure to afford the crude compound, which was purified by reverse phase prep. HPLC or, combiflash chromatography.

[1329] Reverse Phase Prep. HPLC Purification Method:

[1330] Unless stated otherwise, purifications were carried out on a WATERS auto purification instrument operating at ambient temperature and flow rate of 16.0 mL / min.

[1331] Method-A: Column name: YMC-Actus Triart C18 (250 x 20 mm, 5p). Mobile phase: A= 20 mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B in 3 min., then to 25% A and 75% B in 24 min., then to 5% A and 95% B in 25 min., held this composition upto 27 min. for column washing, then returned to initial composition in 28 min. and held till 30 min.

[1332] Method-B: Column name: Hydrosphare C18 (250 x 20 mm, 5p). Mobile phase: A = 0.1% Formic acid in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then 80% A and 20% B in 3 min, then to 55% A and 45% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1333] Method-C: Column name: X-bridge C18 prep OBD (250 x 19mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B=MeOH; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 40% A and 60% B in 4 min., then to 10% A and 90% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 28 min. for column washing, then returned to initial composition in 29 min. and held till 32 mins.

[1334] Method-D: Column name: YMC-Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 50% A and 50% B in 3 min., then to 20% A and 80% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 28 min. for column washing, then returned to initial composition in 29 min. and held till 32 mins.

[1335] Method-E: Column name: YMC-Actus Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 65% A and 35% B in 5 min., then to 30% A and 70% B in 30 min., then to 5% A and 95% B in 31 min., held this composition up to 33 min. for column washing, then returned to initial composition in 34 min. and held till 36 mins.

[1336] Method-F: Column name: - YMC Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 70% A and 30% B in 3 min., then to 40% A and 60% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 28 min. for column washing, then returned to initial composition in 29 min. and held till 32 mins.

[1337] Method-G: Column name: YMC Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 55% A and 45% B in 3 min., then to 20% A and 80% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 28 min. for column washing, then returned to initial composition in 29 min. and held till 32 mins.

[1338] Method-H: Column name: YMC Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B in 3 min., then to 30% A and 70% B in 25 min., then to 5% A and 95% B in 26 min., held this composition up to 29 min. for column washing, then returned to initial composition in 30 min. and held till 33 mins.

[1339] Method-I: Column name: Chromcore 120 C18 (250 x 21.2mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B in 3 min., then to 25% A and 75% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 27 min. for column washing, then returned to initial composition in 28 min. and held till 30 mins.

[1340] Method-J: Column name: YMC-Actus C18 (250 x 20 mm, 5p). Mobile phase: A = ACN, B=20mM NH4HCO3 in water; Gradient Profile: Mobile phase initial composition of 30% A and 70% B, then 45% A and 55% B in 3 min, then to 56.9% A and 43.1% B in 12 min., then to 100% A and 0% B in 12.5 min., held this composition up to 16 min. for column washing, then returned to initial composition in 17 min. and held till 20 min.

[1341] Method-K: Column name: - YMC Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 80% A and 20% B in 3 min., then to 40% A and 60% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 28 min. for column washing, then returned to initial composition in 29 min. and held till 32 mins.

[1342] Method-L: Column name: Kinetex C18 (250 x 21.2 mm, 5p). Mobile phase: A = 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 70% A and 30% B, then 70% A and 30% B in 3 min, then to 30% A and 70% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1343] Method-M: Column name: - YMC Actus Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 70% A and 30% B in 3 min., then to 30% A and 70% B in 20 min, then to 0% A and 100% B in 21 min., held this composition up to 24 min. for column washing, then returned to initial composition in 25 min. and held till 28 mins.

[1344] Method-N: Column name: -YMC-Actus Triart C18 (250 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B=ACN; Gradient Profile: Mobile phase initial composition of 70% A and 30% B, then to 45% A and 55% B in 3 min., then to 10% A and 90% B in 24 min., then to 5% A and 95% B in 25 min., held this composition up to 28 min for column washing, then returned to initial composition in 29 min. and held till 32 mins.

[1345] Method-O: Column name: Xterra C18 (250 x 19 mm, 10p). Mobile phase: A = 20mM NH4HCO3 in water, B= ACN; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then 70% A and 30% B in 3 min, then to 40% A and 60% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1346] Method-P: Column name: Xterra C18 (250 x 19 mm, 10p). Mobile phase: A = 0.1 % Formic acid in water, B=Methanol; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 40% A and 60% B in 3 min, then to 10% A and 90% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1347] Method-Q: Column name: YMC-Actus C18 (250 x 20 mm, 5p). Mobile phase: A = 20mM NF HCOs in water, B= ACN; Gradient Profile: Mobile phase initial composition of 70% A and 30% B, then 50% A and 50% B in 3 min, then to 20% A and 80% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1348] Method-R: Preparative HPLC was done in Gilson auto purification instrument equipped with UV Detector set to 220nm. Column name: Chromcore 120 C18 (250 x 21.2 mm, 5p) operating at ambient temperature and flow rate of 18 ml / min. Mobile phase: A =20 mM NH4HCO3 in water, Mobile phase: B= ACN; Gradient Profile: Mobile phase initial composition of 65% A and 35% B , held it up to 3 min, then to 25% A and 75% B in 22 min, then to 5% A and 95% B in 22.5 min, held this composition up to 25 min. for column washing, then returned to initial composition in 25.5 min. and held till 28 min.

[1349] Method-S: Column name: Chromcore 120 C18 (250 x 21.2 mm, 5p). Mobile phase: A =20 mM NH4HCO3 in water, Mobile phase: B= ACN; Gradient Profile: Mobile phase initial composition of 40% A and 60% B, held this composition up to 3 min, then to 10% A and 90% B in 18 min, then to 5% A and 95% B in 18.5 min held this composition up to 19 min. for column washing, then returned to initial composition in 19.5 min. and held till 25 min.

[1350] Method-T: Column name: Xterra C18 (250 x 19 mm, 10p). Mobile phase: A = 20mM NH4HCO3 in water, B=ACN; Gradient Profile: Mobile phase initial composition of 70% A and 30% B, then 50% A and 50% B in 3 min, then to 20% A and 80% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min.

[1351] Method-U: Column name: Xbridge Prep. C18 OBD (250 x 19mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B=Acetonitrile Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 65% A and 35% B in 5 min., then to 50% A and 50% B in 30 min., then to 5% A and 95% B in 31 min., held this composition up to 34 min for column washing, then returned to initial composition in 35 min. and held till 38 mins.

[1352] Method-V: Column name: Sunfire C18 (150 x 19mm, 10p). Mobile phase: A= 0.1% Formic acid in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 90% A and 10% B, then to 90% A and 10% B in 3 min, then to 60% A and 40% B in 22 min, then to 0% A and 100% B in 23 min., held this composition up to 25 min. for column washing, then returned to initial composition in 26 min. and held till 28 mins.

[1353] Method-W: Column name: Luna Omega C8 (250 x 21.2mm, 5p). Mobile phase: A= 10mM Ammonium acetate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 45% A and 55% B, then to 35% A and 65% B in 22 min, then to 0% A and 100% B in 23 min., held this composition up to 25 min. for column washing, then returned to initial composition in 26 min. and held till 28 mins.

[1354] Method-X: Column name: GEMINI (150 x 20mm, 5p). Mobile phase: A= 20mM NH4HCO3 in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 65% A and 35% B in 3 min., then to 45% A and 55% B in 25 min., then to 5% A and 95% B in 28 min. held this composition up to 29 min. for column washing, then returned to initial composition in 30 min. and held till 33 mins.

[1355] Method-Y: Column name: Xbridge Prep C18 OBD (250 x 19mm, 10p). Mobile phase: A= 20mM NH4HCO3 in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 75% A and 25% B in 5 min., then to 58% A and 42% B in 21 min., then to 5% A and 95% B in 22 min., held this composition up to 27 min for column washing, then returned to initial composition in 28 min. and held till 31 mins.

[1356] Method-Z: Column name: Xbridge prep C18 OBD (250 x 19mm, 10p). Mobile phase: A= 20mM NH4HCO3 in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 70% A and 30% B in 3 min., then to 40% A and 60% B in 25 min., then to 5% A and 95% B in 26 min., held this composition up to 29 min for column washing, then returned to initial composition in 30 min. and held till 33 mins

[1357] Chiral SFC prep, purification:

[1358] Method-A: SFC prep has been completed in Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiralpak-IG (21.0 mm x 250mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 ml / min, using 65% CO2 in super critical state & 35% of 100% Methanol as Mobile phase. Run this isocratic mixture up to 10.0 minutes and also maintained the isobaric condition of 120 bar at 289 nm wavelength.

[1359] Method-B: SFC prep was done on Waters SFC150 instrument equipped with Waters 2489 UVA / iSible / / Detector by using Chiralpak lG(30.O

[1360] Column operating at 35 °C temperature, maintaining flow rate of 1O0 ml / mih, using 60% CO2 in super critical state and 40% [0.1 % NH3 in Methanol) aS Mobile phase, Ruh this isocratic mixture up to 9.0 minutes and maintained the isobaricf c bar at 290 nm wavelength:

[1361] Method-C: SFC prep was done on Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using Chiralpak-IG (30.0 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 60% CO2 in super critical state & 40% of (0.3% NH3 in Methanol) as Mobile phase. Run this isocratic mixture up to 15.0 minutes and maintained the isobaric condition of 120 bar at 220 nm wavelength. LCMS / UPLC Methods:

[1362] Method-A (UV 260 and 220 nm): Column: Xbridge C18 column (3.5 pm, 50 x 3 mm). Mobile phase: 95% [5 mM NH4OAC in water] and 5% [5 mM NH4OAC in ACN: Water (90:10)] held for 0.75 min, then 85% [5 mM NH4OAC in water] and 15% [5 mM NH4OAC in ACN: Water (90:10) ] in 1.25 min further 70% [5 mM NH4OAC in water] and 30% [5 mM NH4OAC in ACN: Water (90:10) ] in 2.50 min, and finally 2% [5 mM NH4OAC in water] and 98% [5 mM NH4OAC in ACN: Water (90:10)] in 3.75 min, held this mobile phase composition up to 4.25 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[1363] Method B (UV 260 and 220 nm): Column: Waters Acquity UPLC BEH C8 (2.1 x 50 mm, 1.7 micron). Mobile phase: 95% [0.05% HCOOH in water] and 5% [0.05% HCOOH in ACN: Water (90:10)] held for 0.75 min, then to 75% [0.05% HCOOH in water] and 25% [0.05% HCOOH in ACN: Water (90:10) ] in 1.5 min, further to 5% [0.05% HCOOH in water] and 95% [0.05% HCOOH in ACN: Water (90:10)] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[1364] Method C (UV 260 and 220 nm): Column: YMC TRIART C18 (33 x 2.1 mm, 3u). Mobile phase: 98% [0.05% HCOOH in water] and 2% [ACN] held for 0.75 min, then to 90% [0.05% HCOOH in water] and 10% [ACN] in 1.0 min, further to 2% [0.05% HCOOH in water] and 98% [ACN] in 2.0 min, held this mobile phase composition up to 2.25 min and finally back to initial condition in 3.0 min). Flow =1 .5 ml / min.

[1365] Method D (UV 260 and 220 nm): Column: Xbridge C18 (4.6 x 50 mm, 5 u). Mobile phase: 90 % [10 mM NH4OAc in Water] and 10 % [ACN] to 70% [10 mM NH4OAc in Water] and 30% [ACN] in 1.5 min, further to 10% [10 mM NH4OAC in Water] and 90% [ACN] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min. Flow =1.20 ml / min.

[1366] Method E (UV 260 and 220 nm): Column: Xbridge C18 column (3.5 pm, 50 x 3 mm). Mobile phase: 98% [5 mM NH4OAc in water] and 2% [5 mM NH4OAc in ACN: Water (90:10)] held for 1.00 min, then 50% [5 mM NH4OAc in water] and 50% [5 mM NH4OAc in ACN: Water (90:10) ] in 5.00 min and finally 2% [5 mM NH4OAc in water] and 98% [5 mM NH4OAc in ACN: Water (90:10) ] in 8.00 min, held this mobile phase composition up to 10.00 min and finally back to initial condition in 12.00 min and held this composition up to 12.10 min).

[1367] Method-F (UV 260 and 220 nm): Column: Xbridge C18 column (3.5 pm, 50 x 3 mm). Mobile phase: 95% [5 mM NH4OAC in water] and 5% [5 mM NH4OAC in ACN: Water (90:10)] held for 0.75 min, then to 70% [5 mM NH4OAC in water] and 30% [5 mM NH4OAC in ACN: Water (90:10) ] in 1.00 min, and finally 2% [5 mM NH4OAC in water] and 98% [5 mM NH4OAC in ACN: Water (90:10)] in 2.00 min, held this mobile phase composition up to 2.50 min and finally back to initial condition in 2.75 min and held this composition up to 3.0 min). Flow rate-1.20 ml / min.

[1368] Method G (DAD: 200 to 400 nm): Column Used: Xbridge C18 column (3.5 pm, 50 x 3 mm) (mobile phase: 95% [5 mM NH4OAc in water] and 5% [5 mM NH4OAc in ACN: Water (90:10)] held for 0.75 min, then 85% [5 mM NH4OAc in water] and 15% [5 mM NH4OAc in ACN: Water (90:10) ] in 1.25 min further 30% [5 mM NH4OAc in water] and 70% [5 mM NH4OAc in ACN: Water (90:10) ] in 2.50 min, and finally 2% [5 mM NH4OAc in water] and 98% [5 mM NH4OAc in ACN: Water (90:10) ] in 3.75 min, held this mobile phase composition up to 4.25 min and finally back to initial condition in 4.50 min and held this composition up to 5.10 min).

[1369] Preparations

[1370] Preparation 1 : Synthesis of 3,4 diCI,5-F-1 H-indole-2-carboxylic acid

[1371] Step-1 : Synthesis of ethyl (Z)-2-azido-3-(2-chloro-3-fluorophenyl)acrylate

[1372] To a stirred solution of 2-chloro-3-fluorobenzaldehyde (1.0 gm, 6.3 mmol) in EtOH (10.0 mL) at -30° C was added NaH (0.45 gm, 18.98 mmol) and stirred at -30° C for 30 mins. Ethyl 2-azidoacetate (3.2 gm, 25.3 mmol) was added at 0 °C and stirred for 1 h. The reaction mixture was quenched with ice cold water. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 30.0 mL) and combined organic part was dried over Na2SO4 and evaporated in vacuum. The crude mass was purified by combiflash chromatography, (eluent gradient: 0-20% EtOAc in hexane) to afford desired compound (400.0 mg, 20%) as white solid. 1 H NMR (400 MHz, DMSO-d6) 5 8.00 (d, J = 6.6 Hz, 1 H), 7.48 - 7.39 (m, 2H), 7.07 (s, 1 H), 4.34 (q, J = 7.8 Hz, 2H), 1.33 (t, J = 7.8 Hz, 3H).

[1373] Step-2: Synthesis of ethyl 4-chloro-5-fluoro-1 H-indole-2-carboxylate The stirred solution of ethyl (Z)-2-azido-3-(2-chloro-3-fluorophenyl)acrylate (500.0 mg, 1.88 mmol) in xylene (3.0 ml) was heated at 130 °C for 2 h. The reaction mixture was concentrated under rota vapour to get the crude material which was triturated with etherpentane to obtained 400.0 mg (87%) desired compound. 1 H NMR (400 MHz, DMSO-d6) 5 12.38 (s, 1 H) 7.44 (dd, J= 8.9, 3.8 Hz, 1 H), 7.31 (t, J = 9.3 Hz, 1 H), 7.1 (s, 1 H), 4.34 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[1374] Step-3: Synthesis of 4-chloro-5-fluoro-1 H-indole-2-carboxylic acid

[1375] To a stirred solution of carboxylic ester (2.0 g, 8.30 mmol) in THF-H2O (20.0 mL) was added UOH.H2O (1.5 equiv.) and stirred at rt for 16 h. The reaction was monitored by LCMS. After completion, reaction mixture was concentrated under reduced pressure, diluted with 1 N HCI and extracted with organic solvent and concentrated to afford desired compound (1.5 g), which was used in the next step without further purification. LCMS: 211.74 [M-H]-.

[1376] Step-4: Synthesis of 3,4-dichloro-5-fluoro-1 H-indole-2-carboxylic acid

[1377] To a stirred solution of 4-chloro-5-fluoro-1 H-indole-2-carboxylic acid (3.0 g, 14.1 mmol) in ACN (40.0 mL) was added NCS (2.26 g, 16.90 mmol) and heated to 60°C for 3 hrs. The reaction was monitored by TLC. The reaction was filtered and the filtrate was concentrated to get crude compound. The crude was then purified by combiflash to afford desired product (1.2 g, 35%) as off white solid. 1 H NMR (400 MHz, DMSO-d6) 5 13.70 (brs, 1 H), 12.48 (s, 1 H), 7.44 (dd, J= 9.0, 4.2 Hz, 1 H), 7.35 (t, J = 9.5 Hz, 1 H), LCMS: 246.0 [M-H]-.

[1378] Preparation 2: Synthesis of 4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- indole-2-carboxylic acid

[1379] Step-1 : Synthesis of ethyl 4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-indole-2- carboxylate

[1380] Under argon atmosphere to an ice cold stirred solution of ethyl 4,5-dichloro-1 H-indole-2- carboxylate (500 mg, 1.93 mmol) in THF (10 mL) was added NaH (77 mg, 1.93 mmol) and the reaction mixture was stirred for 30 minutes. To it was then SEM-CI (0.54 ml, 2.90 mmol) was added and the resulting reaction mixture was stirred for 5 hours at RT. After completion (monitored by LCMS / TLC), the reaction mixture was quenched by careful addition of saturated aqueous NH4CI solution until effervescence ceases. The reaction mixture was diluted with ethyl acetate and water and separated. The aqueous part was back extracted with ethyl acetate and the combiner organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. Purification over silica gel column chromatography furnished the desired compound as colourless viscous liquid. Yield: 88%. 1 H NMR (400 MHz, DMSO-d6): 7.77 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz 1 H), 7.29 (s, 1 H) 5.97 (s, 2H), 4.34 (q, J = 8.0 Hz, 2H) 3.43 (t, J = 8.0 Hz, 2H), 1.34 (t, J = 8.0 Hz, 2H), 0.76 (t, J = 8.0 Hz, 2H), -0.14 (9H, s).

[1381] Step-2: Synthesis of 4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-indole-2- carboxylic acid

[1382] To a stirred solution of ethyl 4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-indole- 2-carboxylate (660 mg, 1.7 mmol) in THF-H2O (2:1 , 3.0 mL / mmol) was added UOH.H2O (214 mg, 5.11 mmol) and stirred at rt for 6-16 h. The reaction was monitored by LCMS or, TLC. After completion, reaction mixture was concentrated under reduced pressure, diluted with 1 N HCI and extracted with organic solvent and concentrated. In case of precipitation, solid was filtered, washed with organic solvent and dried. Finally, crude material was triturated with pentane or, Et20 to get solid compound. Yield: 97%. 1 H NMR (400 MHz, DMSO-d6): 7.44 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz 1 H), 6.68 (s, 1 H), 6.20 (s, 2H), 3.43 (t, J = 8.0 Hz, 1 H), 0.74 (t, J = 8.0 Hz, 2H), -0.13 (s, 9H) LCMS (Method-A): RT 1.03 min; 360.2 [M+HJ+.

[1383] Preparation 3: Synthesis of 3,5-fluoro-5-chloro-1 H-indole-2-carboxylic acid

[1384] Protocol 1

[1385] In a sealed tube, to a solution of 4-chloro-5-fluoro-1 H-indole-2-carboxylic acid (Preparation 4, 2.5 g, 11.73 mmol) in dry ACN (25 mL) was added Selectfluor (4.57 g, 12.91 mmol) and the resulting suspension was stirred for 16 hours at rt. The crude material was diluted with ethyl acetate and washed subsequently with water and brine. After drying over anhydrous sodium sulfate, the organic layer was filtered and concentrated under reduced pressure. The crude material was triturated with etherpentane and used in the next step without further purification (~1 :1 ratio of desired product and unreacted starting material as observed by 1 H-NMR).

[1386] Protocol 2

[1387] Step-1 : 4-chloro-3,3,5-trifluoroindolin-2-one:

[1388] To a stirred solution 4-chloro-5-fluoro-2,3-dihydro-1 H-indole-2, 3-dione (14.0 g, 70.15 mmol) in DCM (160.0 mL) was added DAST (23.167 mL, 175.38 mmol) at 0 °C under N2 atmosphere. The reaction mixture (suspension) was stirred for 6 h at rt. By this time suspension turned into solution. The reaction mixture was poured into saturated aq. NaHCO3 solution (200.0 mL) and extracted with DCM (3 x 200.0 mL). The combined organic layer was washed with brine, dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by combiflash chromatography (0 - 5% EtOAc-Hex) to give 3,3-difluoroindolin-2-one (8.5 g, 49%) as redish solid.

[1389] Step-2: 4-Chloro-3,5-difluoro-1 H-indole:

[1390] To a stirred solution of 4-chloro-3,3,5-trifluoro-2,3-dihydro-1H-indol-2-one (10.0 g, 45.13 mmol) in dry THF (150.0 mL) was added BH3.DMS (2M in THF, 67.5 mL, 135.39 mmol) dropwise under nitrogen at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was quenched with 10% aq. citric acid solution (till gas evolution ceased), diluted with water and extracted with EtOAc (3 x 200.0 mL). Combined organic layer was washed with water (2 x 200.0 mL) and brine (200.0 mL). The organic layer was then dried over anhyd. Na2SC>4, filtered and filtrate was evaporated under reduced pressure to provide crude compound. The resulting crude was purified by combiflash chromatography (eluent: 10% ethyl acetate in hexane) to afford 4-chloro-3,5-difluoro-1H-indole (6 g, 71 %) as brown solid. 1 H NMR (400 MHz, DMSO-d6) 5 11.28 (brs, 1 H), 7.52 (t, J= 2.6 Hz, 1 H), 7.36 - 7.32 (m, 1 H), 7.15 (t, J = 9.4 Hz, 1 H). LCMS (Method C): RT 2.19 min; 186.01 [M-H]-.

[1391] Step-3: 4-Chloro-3,5-difluoro-1-tosyl-1H-indole:

[1392] To a stirred solution of 4-chloro-3,5-difluoro-1H-indole (3.6 g, 19.19 mmol) in dry DMF (40.0 mL) was added NaH (1.0 g, 21.11 mmol, 60% in mineral oil) portionwise at 0 °C over a period of 10 minutes. The mixture was stirred at same for 15 minutes. p-TsCI (5.4 g, 28.79 mmol) was added, and the mixture was stirred at rt for 2 h. After completion (monitored by TLC), the reaction mixture was quenched with satd. cold aq. NH4CI solution and subjected to usual work-up. The reaction mixture was diluted with EtOAc (100.0 mL) and H2O (100.0 mL) and taken in a separatory funnel. The organic layer was separated and aq. layer was back extracted with EtOAc (3 x 100.0 mL). The combined organic layer was washed with H2O, brine and then dried over anhyd. Na2SO4. Then, organic part was filtered and the filtrate was evaporated to dryness under reduced pressure to get crude compound, which was purified using silica gel column chromatography (eluent: 25% ethyl acetate in hexane) to get 4-chloro-3,5-difluoro-1-(4- methyl-1-sulfonylphenyl)-1H-indole (4.8 g, 73%) as white solid. 1 H NMR (400 MHz, DMSO-d6) 5 8.17 (s, 1 H), 7.98 (d, J = 8.6 Hz, 1 H), 7.89 (d, J = 7.9 Hz, 2 H), 7.48 (t, J = 9.5 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 2H), 2.34 (s, 3H).

[1393] Step-4: Ethyl 4-chloro-3,5-difluoro-1 -tosyl-1 H-indole-2-carboxylate: n-Butyllithium (2.5 M in hexane, 6.4 mL) was added dropwise to a stirred solution of 4- chloro-3,5-difluoro-1-[(4-methylbenzene)sulfonyl]-1H-indole (5.0 g, 14.63 mmol) in dry THF (80 mL) at -78 °C. The resulting mixture was stirred at same temperature for 30 minutes. Thereafter, ethyl chroroformate (1.67 mL, 17.56 mmol) was added dropwise into the reaction mixture at -78 °C. After 10 minutes, cooling bath was removed and the mixture warmed to rt. After 2-3 h, the reaction mixture was quenched with satd. aq. NH4CI solution and extracted with EtOAc (3 x 100.0 mL). The combined organic layer was washed with H2O (100.0 mL), brine and then dried over anhyd. Na2SO4. Organic part was then filtered and the filtrate was evaporated to dryness under reduced pressure. The resulting crude was purified by combiflash chromatography (eluent: 5% ethyl acetate in hexane) to get ethyl 4-chloro-3,5-difluoro-1-tosyl-1H-indole-2-carboxylate (4.2 g, 69%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) 5 8.07 (d, J = 7.6 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 2H), 7.63 (t, J = 9.5 Hz, 21 H), 7.44 (d, J = 8.2 Hz, 1 H), 4.42 (q, J = 7.0 Hz, 2H), 1.98 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). LCMS (Method C): RT 2.56 min; 414.1 [M+HJ+.

[1394] Step-5: 4-Chloro-3,5-difluoro-1H-indole-2-carboxylic acid:

[1395] To a stirred solution of ethyl 4-chloro-3,5-difluoro-1-tosyl-1H-indole-2-carboxylate (4.2 g, 10.149 mmol) in THF-H2O mixture (80.0 mL, 1 :3 ratio) was added UOH.H2O (4.26 g, 101.493 mmol). The resulting mixture was stirred for 6 h at 60 °C. After completion (monitored by TLC), THF was evaporated from the reaction mixture under reduced pressure. The aqueous layer was washed with EtOAc (100.0 mL) to eliminate any nonpolar impurity. Then, pH of the aqueous layer was adjusted to ~4-5 with 6N HCI. The resulting solution was then extracted with EtOAc (3 x 100.0 mL). The combined organic layer was washed with brine and dried over anhyd. Na2SO4, filtered and the filtrate was evaporated to dryness under reduced pressure to provide 4-chloro-3,5-difluoro-1 / 7- indole-2-carboxylic acid (2.0 g, 85%) as grey solid. 1 H NMR (400 MHz, DMSO-d6) 5 13.53 (brs, 1 H), 12.03 (s, 1 H), 7.48 - 7.32 (m, 2H). LCMS (Method A): RT 2.36 min; 230.2 [M-H]-.

[1396] Preparation 4: Synthesis of 3,4-dichloro-1 H-indole-2-carboxylic acid:

[1397] Step-1 : To a stirred suspension of 4-chloro-1 H-indole-2-carboxylic acid (250 mg, 1.0 eq) in acetonitrile (3 ml) was added N-chlorosuccinimide (260 mg, 1.5 eq) and resulting mixture was stirred at 70 °C for overnight. After completion of the reaction (monitored by TLC), reaction mixture was concentrated, ethyl acetate was added to it and the organic part was extracted with ethyl acetate, the organic part was washed with water 2 times followed by brine, dried over anhydrous Na2SC>4 and evaporated under reduced pressure to afford 3,4-dichloro-1 H-indole-2-carboxylic acid as yellow liquid, it was then purified using Combi-Flash chromatography to afford pure 3,4-dichloro-1 H-indole-2-carboxylic acid (product eluted at -10-12% MeOH in ethyl acetate) as light yellow solid. 1 H NMR (400 MHz, DMSO-d6) 5 12.16 (bs, 1 H), 7.41 (d, J = 8.2 Hz, 1 H), 7.22 (t, i = 7.7 Hz, J2= 8 Hz, 1 H), 7.12 (d, J = 7.4 Hz, 1 H) LCMS Method-A: RT 2.68 min; 227.5 [M-H]+.

[1398] Preparation 5: Synthesis of 4-chloro-3-fluoro-1H-indole-2-carboxylic acid:

[1399] Step 1 : Synthesis of 3,3-difluoro-4-chloroindolin-2-one

[1400] To a stirred solution 4-chloro-2,3-dihydro-1 H-indole-2, 3-dione (5.0 g, 27.53 mmol) in DCM (60.0 mL) was added DAST (9.1 mL, 68.8 mmol) at 0°C under argon atmosphere. The reaction mixture (suspension) was stirred for 6h at RT and it turned into a clear solution. The reaction mixture was carefully poured into saturated aq. NaHCO3 solution (200.0 mL) and extracted with DCM (3 x 60.0 mL). The combined organic layer was washed with brine, dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by combiflash chromatography eluting with (20-30%) EtOAc in Hexane to give 3,3-difluoro-4-chloroindolin-2-one (11.2 g, 67%) as reddish solid. 1 H-NMR (CDCI3, 400 MHz); 8.04 (bs, 1 H), 7.37 (t, J = 8.08 Hz, 1 H), 7.24 (s, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H). LCMS (Method-C): RT 1.54 min; 204.06 [M+HJ+.

[1401] Step 2: Synthesis of 4-chloro-3-fluoro-1 / - / -indole

[1402] To a stirred solution of 4-chloro-3,3,difluoro-2,3-dihydro-1 / 7-indol-2-one (3.4 g, 16.7 mmol) in dry THF (40 mL) was added BH3.DMS (2M in THF, 25.5 mL, 50 mmol) dropwise under nitrogen at 0 °C and the reaction mixture was stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was quenched with 10% aq. citric acid solution (till gas evolution ceased), diluted with water and extracted with EtOAc (3 x 40.0 mL). Combined organic layer was washed with water (2 x 20.0 mL) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and filtrate was evaporated under reduced pressure to provide crude compound. The resulting crude was purified by combiflash chromatography (eluent: 10% ethyl acetate in hexane) to afford 4-chloro-3-fluoro-1 / - / -indole (2.2 g. 77%) as white solid. 1 H-NMR (CDCI3, 400 MHz); 7.70 (bs, 1 H), 7.21-7.16 (m, 1 H), 7.12-7.07 (m, 1 H), 7.00 (t, J = 2.7 Hz, 1 H), 7.00- 6.99 (m, 1 H).

[1403] Step 3: Synthesis of 4-chloro-3-fluoro-1-(4-methyl-1-sulfonylphenyl)-1 / - / -indole

[1404] To a stirred solution of 4-chloro-3-fluoro-1 / - / -indole (2.2 g, 12.9 mmol) in dry DMF (20.0 mL) was added NaH (516 mg, 12.97 mmol, 60% in mineral oil) portion wise at 0 °C over a period of 10 minutes. The mixture was stirred at same temperature for 15 mins, p- TsCI (2.4 g, 12.97 mmol) was added and the mixture was stirred at rt for 2 h. After completion (monitored by TLC), the reaction mixture was quenched with satd. cold aq. NH4CI solution. The reaction mixture was diluted with EtOAc (30.0 mL) and H2O (30.0 mL) and taken in a separatory funnel. The organic layer was separated and aq. layer was back extracted with EtOAc (3 x 30.0 mL). The combined organic layer was washed with satd. aq. NaHCO3 solution, H2O, brine and then dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to dryness under reduced pressure to get crude compound, which was washed with pentane (2 x 20.0) to get pure 4-chloro-3-fluoro-1- (4-methyl-1-sulfonylphenyl)-1 / - / -indole as white solid (3.8g, 90%). 1 H-NMR (CDCI3, 400 MHz); 7.91 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 2.8 Hz, 1 H), 7.26-7.18 (m, 4H), 2.34 (s, 3H). LCMS (Method-B): RT 3.65 min; 322.1 [M-H]-.

[1405] Step 4: Synthesis of ethyl 4-chloro-3-fluoro-1-tosyl-1 H-indole-2-carboxylate n-Butyllithium (2.5 M in hexane, 1.9 mL) was added dropwise to a stirred solution of 4- chloro-3-fluoro-1-[(4-methylbenzene)sulfonyl]-1 H-indole (3.8 g, 11.74 mmol) in dry THF (80 mL) at -78 °C. The resulting mixture was stirred at same temperature for 30 minutes. Ethyl chroroformate (1.4 gm, 12.91 mmol) was added dropwise into the reaction mixture at -78 °C. After 10 minutes, cooling bath was removed and the mixture warmed to RT for 3 h, the reaction mixture was quenched with satd. aq. NH4CI solution and extracted with EtOAc (3 x 100.0 mL). The combined organic layer was washed with H2O (100.0 mL), brine and then dried over anhydrous Na2SO4. Organic part was filtered and the filtrate was evaporated to dryness under reduced pressure. The resulting crude was purified by combiflash chromatography (eluent: 5% ethyl acetate in hexane) to get ethyl 4-chloro-3-fluoro-1-tosyl-1 H-indole-2-carboxylate (2.8 g, 60%) as an off-white solid. 1 H- NMR (CDCI3, 400 MHz); 7.99 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.34 (t, J = 8.4 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.47 (d, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1 .43 (t, J = 7.2 Hz, 1 H). LCMS (Method-C): RT 2.51 min; 396.2 [M+H]+.

[1406] Step 4: Synthesis of 4-chloro-3-fluoro-1 H-indole-2-carboxylic acid

[1407] To a stirred solution of ethyl 4-chloro-3-fluoro-1-tosyl-1 H-indole-2-carboxylate (2.9 g, 7.33 mmol) in THF-H2O mixture (80.0 mL, 1 :3 ratio) was added LiOH.H2O (3.1 g, 73.26 mmol). The resulting mixture was stirred at 60 °C for 6 h. After completion (monitored by TLC), THF was evaporated from the reaction mixture under reduced pressure. The aqueous layer was washed with EtOAc (100.0 mL) to eliminate any non-polar impurity. Then, pH of the aqueous layer was adjusted to ~4-5 with 6N HCI. The resulting solution was then extracted with EtOAc (3 x 100.0 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to dryness under reduced pressure to provide 4-chloro-3-fluoro-1 / 7-indole-2-carboxylic acid (1.5 g, 95%) as grey solid. 1 H-NMR (DMSO-D6, 400 MHz); 13.46 (bs, 1 H), 11.90 (s, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.47 (d, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.43 (t, J = 7.2 Hz, 1 H). LCMS (Method- C): RT 1.53 min; 213.99 [M+H]+. Example 1

[1408] Synthesis of (4,5-dichloro-1 H-indol-2-yl)-[(3R)-3-(dimethylamino)pyrrolidin-1 - yl]methanone Step-1 : Amidation of 4,5-dichloro-1 H-indole-2-carboxylic acid was performed following general condition-B and (3R)-3-(dimethylamino)pyrrolidine to afford the title compound as an off-white solid. Purification was done by reverse phase prep. HPLC following method T. 1 H NMR (400 MHz, DMSO-d6, 100 °C) 5 12.03- 11.48(m, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 6.90 (s, 1 H), 4.03 - 3.38 (m, 4H), 2.88 (t, J = 7.2 Hz, 1 H), 2.24 (s, 6H), 2.19 - 2.06 (m, 1 H), 1.99 - 1.80 (m, 1 H). LCMS Method-B: RT 2.25 min; 326.2 [M+HJ+.

[1409] Examples 2-5

[1410] Examples 2-5 were synthesized using similar conditions to those described for Example 1 using the appropriate indole acid (described in the Preparation section) and in the general methods (Table 1).

[1411] Table 1

[1412] Table 2: Analytical data for Examples 2-5

[1413] Example 6 Synthesis of (S)-(3-(aminomethyl)pyrrolidin-1-yl)(4,5-dichloro-1H-indol-2- yl)methanone Step-1 : Synthesis of tert-butyl (S)-((1-(4,5-dichloro-1 H-indole-2-carbonyl)pyrrolidin-3- yl)methyl)carbamate Amidation of 4,5-dichloro-1 H-indole-2-carboxylic acid (400.0 mg, 1.75 mmol) and tertbutyl (R)-(pyrrolidin-3-ylmethyl)carbamate (524.0 mg, 2.62 mmol) was done following amidation condition-A to afford the title compound (250.0 mg, crude). The crude was used in the next step without further purification. LCMS (Method-D): RT 3.53 min; 412 [M+H]+.

[1414] Step-2: Synthesis of (S)-(3-(aminomethyl)pyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2- yl)methanone

[1415] To a stirred solution of tert-butyl (S)-((1-(4,5-dichloro-1 H-indole-2-carbonyl)pyrrolidin-3- yl)methyl)carbamate (200.0 mg, 0.49 mmol) in DCM (5 mL) ), was added 4M HCI in dioxane (2 mL). The resulting solution was stirred at rt for 16 h. After the completion of the reaction, which was monitored by LCMS, the reaction mixture was evaporated under reduced pressure to get the crude product. It was purified by reverse phase prep. HPLC (Method-H) to get pure compound as a white solid (18 mg, 11.9%). 1 H NMR (400 MHz, DMSO-d6, 100 °C): 5 7.46 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 6.91 (s, 1 H), 4.03 - 3.57 (m, 3H), 3.59 - 3.35 (m, 1 H), 3.32 - 3.04 (m, 2H), 2.66 (h, J = 6.4, 6.9 Hz, 2H), 2.34 - 2.23 (m, 1 H), 2.18 - 1.97 (m, 1 H), 1.83 - 1.65 (m, 1 H). LCMS (Method-A): RT 2.43 min; 312.2 [M+HJ+.

[1416] Examples 7-58

[1417] Examples 7-56 were made using similar methods described for Example 6.

[1418] Table 3

[1419] Table 4: Analytical data for Examples 7-58

[1420] Example 59 Synthesis of (R)-(3-(azetidin-3-yloxy)pyrrolidin-1 -yl)(4,5-dichloro-1 H-indol-2- yl)methanone Step 1 : Synthesis of (R)-(4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-indol-2- yl)(3-hydroxypyrrolidin-1-yl)methanone

[1421] Coupling of )-(4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-indol-2-carboxylic acid (300 mg, 0.83 mmol) and (R)-pyrrolidin-3-ol (109 mg, 1.25 mmol) using general method B was performed. Purification over silica gel column chromatography furnished the desired compound. Yield: 83%. 1 H NMR (400 MHz, DMSO-d6): 7.68-7.65 (m, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 6.94 (d, J = 8.4 Hz 1 H), 5.78-5.70 (m, 2H), 5.03 (d, J = 36 Hz, 1 H), 4.19 (d, J = 36 Hz, 1 H), 4.01-3.72 (m, 1 H), 3.76-3.56 (m, 2H), 1.89-1.85 (m, 1 H), 0.74 (t, 2H), -0.13 (s, 9H). LCMS: RT 2.17 min; 429.24 [M+HJ+. Step 2: Synthesis of tert-butyl (R)-3-((1-(4,5-dichloro-1-((2-

[1422] (trimethylsilyl)ethoxy)methyl)-1 H-indole-2-carbonyl)pyrrolidin-3-yl)oxy)azetidine-1- carboxylate

[1423] To an ice cold stirred solution of (R)-(4,5-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- indol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone (300 mg, 0.701 mmol) in DMF (2.5 ml) was added NaH (200 mg, 4.206 mmol) and the resulting reaction mixture was heated at room temp to 50°C for 30 minutes. Then the reaction mixture cooled down to 0°C followed by addition of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)azetidine-1-carboxylate (858 mg, 2.804 mmol), it was stirred at RT for 16h. After completion (monitored by LCMS / TLC) the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate three times and the combined organic layer was washed with H2O, brine and dried over anhydrous Na2SO4. Then, it was filtered and the filtrate was concentrated under reduced pressure to dryness. The compound was used in the next step without further purification. Yield: 54%. LCMS: RT 2.51 min; 584.30 [M+HJ+.

[1424] Step 3: Synthesis of (R)-(3-(azetidin-3-yloxy)pyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2- yl)methanone

[1425] To a stirred solution of tert-butyl (R)-3-((1-(4,5-dichloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-indole-2-carbonyl)pyrrolidin-3-yl)oxy)azetidine-1- carboxylate (225 mg, 0.385 mmol) in DCM (5.0 ml) was added TFA (0.6 ml, 7.705 mmol) at 0°C and the resulting reaction mixture was at rt for 16 hours. After completion (monitored by LCMS) the volatiles were removed under reduced pressure. The crude material was dissolved in methanol and the pH of the solution was brought to pH 8 by sequential addition of amberlyst A21 which was filtered later and the filtrate was concentrated. The crude material was purified by RP-prep HPLC (Method G) to get the desired product as white solid. Yield: 6%. 1 H NMR (400 MHz, DMSO-d6): 12.12 (bs, 1 H), 8.38 (s, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz 1 H), 6.95 (d, J = 16.0 Hz 1 H) 4.40 (t, J = 8.0 Hz, 1 H), 4.20-3.78 (m, 7H), 2.06-1.96 (m, 2H). LCMS (Method A): RT 2.28 min; 354.22 [M+H]+.

[1426] Examples 60-71

[1427] Examples 60-71 were made using similar methods described for Example 1 or 6.

[1428] Table 5

[1429] Table 6: Analytical data for Examples 60-71

[1430] Example 72

[1431] Synthesis of (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(4-((3-fluoroazetidin-3-yl) methoxy)piperidin-1-yl)methanone:

[1432] Step-1 : Synthesis of tert-butyl 3-fluoro-3-(((methylsulfonyl)oxy)methyl)azetidine-1- carboxylate

[1433] To an ice cold stirred solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1- carboxylate (500.0 mg, 2.44 mmol) in DCM (10.0 ml) was added triethylamine (0.35 ml, 2.49 mmol) followed by MsCI (0.28 ml, 3.64 mmol) and the resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (10.0 mL) and washed with water (10.0 mL). The aqueous part was back extracted with DCM (2 X 10.0 mL). The combined organic layer was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered. The filtrate was evaporated to dryness to get tert-butyl 3-fluoro-3-(((methylsulfonyl)oxy)methyl)azetidine-1 -carboxylate (650.0 mg, 94%), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 54.65 (d, J = 22.6 Hz, 2H), 4.09 - 3.92 (m, 4H), 3.26 (s, 3H), 1.39 (s, 9H). LCMS (Method F): RT 1.77 min; 284.31 [M+HJ+. Step-2: Synthesis of tert-butyl 3-(bromomethyl)-3-fluoroazetidine-1-carboxylate r— NBoc Br

[1434] To a solution of tert-butyl 3-fluoro-3-[(methanesulfonyloxy)methyl]azetidine-1- carboxylate (650.0 mg, 2.30 mmol) in THF (10.0 mL) was added LiBr (998.0 mg, 11.47 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hour. After completion (Monitored by TCL), ethyl acetate (10.0 mL) was added to the reaction mixture and the organic layer was washed with water. The aqueous part was back extracted with ethyl acetate (2 X 10.0 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered. The filtrate was evaporated to get tertbutyl 3-(bromomethyl)-3-fluoroazetidine-1 -carboxylate (400.0 mg, 65%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) 5 (4.04 - 3.89 (m, 6H), 1.39 (s, 9H).

[1435] Step-3: Synthesis of benzyl 4-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methoxy) piperidine-1 -carboxylate

[1436] To a stirred solution of tert-butyl 3-(bromomethyl)-3-fluoroazetidine-1-carboxylate (400.0 mg, 1.49 mmol) in DMF (5.0 mL) was added NaH (54.0 mg, 2.24 mmol) and stirred at O °C for 30 minutes followed by addition of benzyl 4-hydroxypiperidine-1 -carboxylate (386.0 mg, 1.64 mmol) stirred at RT for 16 hours. After completion, ethyl acetate (15.0 mL) was added to the reaction mixture and the organic layer was washed with water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered. The filtrate was evaporated to get benzyl 4-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3- yl)methoxy)piperidine-1 -carboxylate ( 400 mg, 66% ), which was used in the next step without further purification. LCMS (Method G): RT 3.73 min; 423.57 [M+H]+.

[1437] Step-4: Synthesis of tert-butyl 3-fluoro-3-((piperidin-4-yloxy)methyl)azetidine-1- carboxylate

[1438] To a stirred solution of tert-butyl 3-fluoro-3-({[1-(2-oxo-2-phenylethyl)piperidin-4-yl]oxy} methyl)azetidine-1 -carboxylate (400.0 mg, 0.99 mmol) in ethanol (5.0 ml) was added PtO2 (200.0 mg ) and stirred at RT for 3 hours. After completion, the reaction mixture was filtered and concentrated to afford tert-butyl 3-fluoro-3-((piperidin-4-yloxy)methyl) azetidine-1 -carboxylate (200 mg, 70%), which was used for the next step without further purification. LCMS (Method G): RT 2.59 min; 289.48.

[1439] Step-5: Synthesis of tert-butyl 3-(((1-(3,4-dichloro-5-fluoro-1 H-indole-2-carbonyl) piperidin-4-yl)oxy)methyl)-3-fluoroazetidine-1 -carboxylate

[1440] Amidation of 3,4-dichloro-5-fluoro-1 H-indole-2-carboxylic acid (200.0 mg, 0.81 mmol) and tert-butyl 3-fluoro-3-[(piperidin-4-yloxy)methyl]azetidine-1 -carboxylate (302.0 mg, 1.05 mmol) was done following amidation condition-C to afford tert-butyl3-[({1 -[(3,4- dichloro-5-fluoro-1 H-indol-2-yl)carbonyl]piperidin-4-yl}oxy)methyl]-3-fluoroazetidine-1- carboxylate (300.0 mg, 72 %). It was purified by combiflash chromatography eluting with (20 -30%) EA in hexane. LCMS (Method A): RT 1.87 min; 518.0 [M+HJ+.

[1441] Step-6: Synthesis of3,4-dichloro-5-fluoro-2-({4-[(3-fluoroazetidin-3-yl)methoxy]piperidin- 1 -yljmethyl)- 1 H-indole

[1442] To a stirred solution of tert-butyl 3-[({1-[(3,4-dichloro-5-fluoro-1 H-indol-2-yl)carbonyl] piperidin-4-yl}oxy)methyl]-3-fluoroazetidine-1 -carboxylate (200.0 mg, 0.39 mmol) in dioxane (2.0 ml_) HCL in dioxane (4N, 5.0 ml_) was added and was stirred at RT for 16 hours. The solvent was removed in vacuo and the crude was purified by reverse phase prep HPLC (Method F) to provide 3,4-dichloro-5-fluoro-2-({4-[(3-fluoroazetidin-3- yl)methoxy]piperidin-1-yl}methyl)-1 H-indole (40 mg, 26%) as white solid.1H NMR (401 MHz, DMSO-cfe, 100 °C) 5 7.45 - 7.36 (m, 1 H), 7.21 (t, J = 9.6 Hz, 1 H), 3.86 - 3.67 (m, 5H), 3.64 - 3.30 (m, 6H), 1.97 - 1 .86 (m, 2H), 1.66 - 1 .53 (m, 2H). LCMS (Method B): RT 2.47 min; 418.29 [M+HJ+.

[1443] Example 73

[1444] Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)pyrrolidin-1-yl)methanone:

[1445] Step 1 : Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)pyrrolidin-1-yl)methanone

[1446] To a stirred solution of ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H -indol-2-yl)methanone (Example 46, 100.0 mg, 0.32 mmol) in MeOH at 0 °C was added Na(CN)BH3 (40.0 mg, 0.06 mmol) and stirred at 0 °C for 15 mins. Oxetane- 3-carbaldehyde (25.0 mg, 0.28 mmol)) was added and stirred at rt for 16h. The reaction was monitored by LCMS, concentrated under reduced pressure to obtain crude material, which was purified by reverse prep-HPLC (Method D) to afford (4-chloro-3,5-difluoro-1 H- indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3-ylmethyl)amino)pyrrolidin-1-yl)methanone (30.0 mg, 25%) as white solid.1H NMR (400 MHz, DMSO-d6, 100 °C) 5 9.30 (s, 1 H), 7.42 - 7.35 (m, 1 H), 7.24 (t, J = 9.5 Hz, 1 H), 5.28 (s, 1 H), 5.14 (s, 1 H), 4.63 (t, J = 6.7 Hz, 2H), 4.29 (s, 2H), 3.96 - 3.83 (m, 3H), 3.42 - 3.38 (m, 2H), 3.06 (s, 2H), 2.97 - 2.85 (m, 2H). Method A: RT 2.63 min; 388.2 [M+H]+.

[1447] Example 74

[1448] Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-methoxyazetidin-1 - yl)ethyl)piperazin-1-yl)methanone:

[1449] Step 1 : Synthesis of tert-butyl 4-(2-oxoethyl)piperazine-1-carboxylate

[1450] Boc 0

[1451] N

[1452] ^CHO

[1453] To a solution of (COCI)2 (1.9 g, 15.0 mmol) in dry DCM (10.0 mL) was added dropwise a solution of dry DMSO (2.34 g, 30.0 mmol) in dry DCM (60.0 mL) at -70 C under N2. The mixture was stirred at -70 C for 30 min, then was added the tert-butyl 4-(2- hydroxyethyl)piperazine-1-carboxylate (2.3 g, 10.0 mmol) in dry DCM (40 mL). The mixture was stirred at -70 C for 90 min, then added dry TEA (6.0 mL). The reaction mixture was stirred at -70 C for 90 min. The reaction mixture was quenched with H2O (50 mL) at -70 C and warmed to RT. The layers were separated and the aqueous layer was further extracted with DCM (2 x 200.0 mL). The combined organics were washed with 5% aqueous citric acid (3 x 40 mL), 5% aqueous Na2CO3 (3 x 50 mL), and brine (3 x 40 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to provide the crude product. The crude material was purified by column Chromatography eluting with (10-15%) EtOAc in hexane to afford tert-butyl 4-(2-oxoethyl)piperazine-1- carboxylate (1.6 gm, 70%) as colourless liquid. 1 H NMR (400 MHz, DMSO-de) 59.58 (s, 1 H), 3.35 - 3.28 (m, 6H), 2.43 2.38 (m, 4H), 1 .39 (s, 9H).

[1454] Step 2: Synthesis of tert-butyl 4-(2-(3-methoxyazetidin-1-yl)ethyl)piperazine-1- carboxylate u OMe

[1455] A slurry of the 3-methoxy-azetidine (912.0 mg, 4.0 mmol) and the tert-butyl 4-(2- oxoethyl) piperazine-1 -carboxylate (379.0 mg, 4.4 mmol) in methanol (3.0 mL) was stirred for 30 min then treated with NaCNBH3 (77.0 mg, 0.363 mmol). After stirring 16 h, EtOAc (15.0 mL) was added to the reaction mixture. The resulting solution was washed with saturated aqueous NaHCO3 solution, water, and brine. The organics were dried (Na2SO4) and concentrated in vacuo to provide the crude product, which was purified by column Chromatography eluting with (10-15%) EtOAc in hexane to afford tertbutyl 4-(2-(3-methoxyazetidin-1-yl)ethyl)piperazine-1 -carboxylate (598.0 mg, 50%) colourless liquid. (Method F): RT 1.45 min; 300.20 [M+H]+.

[1456] Step 3: Synthesis of 1-(2-(3-methoxyazetidin-1-yl)ethyl)piperazine

[1457] To a stirred solution of tert-butyl 4-(2-(3-methoxyazetidin-1-yl)ethyl)piperazine-1- carboxylate (500.0 mg, 1.65 mmol) in DCM (5.0 ml) was added TFA (5.0 mL) at 0°C and stirred at RT for 2 hours. After completion (monitored by LCMS) the volatiles were removed under reduced pressure. The crude material was dissolved in methanol and the pH of the solution was brought to pH 8 by sequential addition of amberlyst A21 , filtered and the filtrate was concentrated to get 1-(2-(3-methoxyazetidin-1-yl)ethyl)piperazine (335.0 mg, crude) as off white solid, which was used for next step without further purification. LCMS (Method F): RT 0.21 min; 200.2 [M+H]+.

[1458] Step 4: (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-methoxyazetidin-1-yl)ethyl)pipera zin-1 -yl)methanone Amidation of 4-chloro-3,5-difluoro-1 H-mdole-2-carboxyhc acid (231.0 mg, 1.0 mmol) and 1-(2-(3-methoxyazetidin-1-yl)ethyl)-4-piperazine (198.0 mg, 1.0 mmol) was done following amidation condition-A to afford 4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3- methoxyazetidin-1-yl)ethyl) piperazin-1 -yl)methanone (82.0 mg, 20%) as white solid. It was purified by reverse phase prep. HPLC (Method-D).1H NMR (401 MHz, DMSO-de) 5 11.91 (brs, 1 H), 7.41 - 7.32 (m, 1 H), 7.32 - 7.22 (m, 1 H), 3.98 - 3.85 (m, 1 H), 3.70 - 3.52 (m, 4H), 3.52 - 3.43 (m, 2H), 3.12 (s, 3H), 2.80 - 2.70 (m, 2H), 2.63 - 2.53 (m, 2H), 2.48 - 2.39 (m, 4H), 2.37 - 2.24 (m, 2H). LCMS (Method A): RT 2.29 min; 413.2 [M+HJ+.

[1459] Example 75

[1460] Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin-1 - yl)ethyl)piperazin-1-yl)methanone

[1461] Step 1 : (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin-1-yl)ethyl)piperazin- 1-yl)methanone

[1462] Amidation of 4-chloro-3,5-difluoro-1 H-indole-2-carboxylic acid (150.0 mg, 0.65 mmol) and 1-(2-(3-fluoroazetidin-1-yl)ethyl)piperazine (198.0 mg, 1.0 mmol) was done following amidation condition-A to get (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin- 1-yl)ethyl)piperazin-1-yl)methanone (35 mg, 13 %) It was purified by reverse phase prep. HPLC (Method-D).1H NMR (401 MHz, DMSO-d6) 5 11.85 (m, 1 H), 7.41 - 7.22 (m, 2H), 5.31 - 4.95 (m, 1 H), 3.75 - 3.43 (m, 6H), 3.14 - 2.98 (m, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.48 - 2.39 (m, 4H), 2.31 (t, J = 6.8 Hz, 2H). LCMS (Method A): RT 2.38 min; 401.2 [M+HJ+.

[1463] Example 76

[1464] Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)piperidin-1 -yl)methanone: Step-1 : Synthesis of tert-butyl (3R,4S)-3-fluoro-4-((2-methoxyethyl)amino)pyrrolidine-1- carboxylate

[1465] Amidation of 4-chloro-3,5-difluoro-1 H-indole-2-carboxylic acid (220.0 mg, 0.95 mmol) and tert-butyl ((3R,4S)-3-fluoropiperidin-4-yl)(methyl)carbamate (199.1 mg, 0.86 mmol) was done following amidation condition-C to afford tert-butyl (3R,4S)-3-fluoro-4-((2- methoxyethyl)amino)pyrrolidine-1-carboxylate (270.0 mg, 63%) as off white solid It was purified by Combi flash chromatography eluting with 50% EA: Hexane. LCMS (Method- F): RT 2.13 min; 444.17 [M-H]-.

[1466] Step-2: Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)piperidin-1-yl) methanone

[1467] To a stirred solution of tert-butyl ((3R,4S)-1-(4-chloro-3,5-difluoro-1 H-indole-2-carbonyl)- 3-fluoropiperidin-4-yl)(methyl)carbamate (250.0 mg, 0.56 mmol) in DCM (2.0 mL) was added HCI in Dioxane (3.0 ml) at RT and for 16h. The reaction was monitored by LCMS. The reaction mass evaporated using vacuum to get Crude. The Crude was purified by reverse phase prep. HPLC (Method I) to afford (4-chloro-3,5-difluoro-1 H-indol-2- yl)((3R,4S)-3-fluoro-4-(methylamino)piperidin-1-yl)methanone (25.0 mg, 13%) as off white solid. 1 H NMR (400 MHz, DMSO-d6, 100 °C) 5 11.65 (brs, 1 H), 7.41 - 7.33 (m, 1 H), 7.22 (t, J = 9.4 Hz, 1 H), 4.97 - 4.73 (m, 1 H), 4.38 - 4.34 (m, 1 H), 4.20 - 4.13 (m, 1 H), 3.45 (d, J = 14.5 Hz, 1 H), 3.36 (d, J = 14.6 Hz, 1 H), 3.16 (t, J = 12.6 Hz, 1 H), 2.82 - 2.67 (m, 1 H), 2.37 (s, 3H), 1.86 - 1.76 (m, 1 H), 1.67 - 1.53 (m, 1 H). LCMS (Method A): RT 2.23 min; 346.2 [M+H]+.

[1468] Example 77

[1469] Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl) amino)piperidin-1 -yl)methanone:

[1470] Step 1 : Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)piperidin-1-yl)methanone:

[1471] To a stirred solution of ((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3,5-difluoro-1 H- indol-2-yl)methanone (Example 61 , 90.0 mg, 0.27 mmol) in DCE (6.0 ml) was added cat. AcOH and oxetane-3-carbaldehyde (16.0 mg, 0.19 mmol) at 0°C. RM was stirred at 0°C for 15 mins, added STAB (69.0 mg, 0.33 mmol) and stirred at RT for 5h. The reaction was monitored by LCMS, diluted with 10% methanol in DCM (10.0 mL), washed with saturated NaHCO3 solution. Organic part was dried over anhydrous Na2SO4 and concentrated to crude residue, which was purified by reverse phase prep HPLC (Method Z) to afford (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)piperidin-1-yl)methanone (25.0 mg, 23%) as off white solid. 1 H NMR (400 MHz, DMSO-d6, 100 °C) 5 11.51 (m, 1 H), 7.40 - 7.32 (m, 1 H), 7.22 (t, J = 9.5 Hz, 1 H), 4.90 - 4.86 (m, 1 H), 4.78 - 4.74 (m, 1 H), 4.64 (t, J = 6.7 Hz, 3H), 4.39 - 4.34 (m, 1 H), 4.33 - 4.24 (m, 3H), 4.22 - 4.12 (m, 1 H), 3.49 - 3.30 (m, 2H), 3.15 (t, J = 12.7 Hz, 1 H), 1.86 - 1.75 (m, 1 H), 1.67 - 1.54 (m, 2H). LCMS (Method A): RT 2.35 min; 402.2 [M+H]+.

[1472] Example 78

[1473] Synthesis of (4-ch loro-3, 5-difluoro-1H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)pyrrolidin-1-yl)methanone: Step 1 : Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methy lamino) pyrrolidin-1-yl)methanone:

[1474] To a stirred sol of ((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H- indol-2-yl)methanone (Example 46, 275.0 mg, 0.06 mmol) in MeOH (3.0 mL) was cooled to 0 °C, added Na(CN)BH3 (109.0 mg, 1.73 mmol) and stirred at 0 °C for 15 mins. Then HCHO (35% Aq) (16.0 mg, 0.04 ml, 0.52 mmol)) was added and stirred at 0 °C for 2h. The reaction was monitored by LCMS. The reaction mixture was concentrated to crude residue, which was purified by reverse phase prep. HPLC (Method M) to afford to afford (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methylamino)-pyrrolidin-1- yl)methanone (19.0 mg, 7%) as white solid. 1 H NMR (400 MHz, DMSO-de, 100 °C) 5 7.42 - 7.34 (m, 1 H), 7.27 - 7.18 (m, 1 H), 5.31 (s, 1 H), 5.17 (s, 1 H), 3.97 - 3.83 (m, 3H), 3.45 - 3.27 (m, 2H), 2.41 (s, 3H). Method A: RT 2.35 min; 332.2 [M+HJ+.

[1475] Example 79

[1476] Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4 / ?)-3-((2-(3,3-difluoro azetidin-1 -yl)ethyl)amino)-4-fluoropyrrolidin-1 -yl)methanone:

[1477] Step-1 : Synthesis of tert-butyl (3S,4 / ?)-3-(2-chloroacetamido)-4-fluoropyrrolidine- 1 -carboxylate:

[1478] To stirred solution of tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1 gm, 4.89 mmol, 1.0 eq.) in DCM (12 ml) was added TEA (1.03 ml, 7.34 mmol, 1.5 eq.) at 0°C under inert atmosphere. Then chloroacetyl chloride (0.47 ml, 5.87 mmol, 1.2 eq.) was added at 0°C and the reaction mixture was stirred for 1 hr at 0°C under inert atmosphere. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into cold water and the mixture extracted with DCM. Organic layer was washed successively with water followed by brine, collected, dried over anhydrous Na2SO4 and concentrated to get the crude product. It was then purified using Combi-Flash Chromatography (eluted at -15% MeOH-EA solvent system) to give tert-butyl (3S,4R)- 3-(2-chloroacetamido)-4-fluoropyrrolidine-1-carboxylate as yellow gum (1 gm, 73%).

[1479] 1H NMR (400MHz DMSO-d6): 6 8.54 (d, J = 6.9 Hz, 1 H), 5.16-5.03 (m, 1 H), 4.45-4.38 (m, 1 H), 4.11 (s, 2H), 3.66-3.59 (m, 1 H), 3.59-3.48 (m, 2H), 3.10-3.04 (m, 1 H), 1.40 (s, 9H). LCMS: m / z [M+H]+= 281.2 (calc, m / z = 281.10); RT = 3.08 min.

[1480] Step-2: Synthesis of tert-butyl (3S,4 / ?)-3-(2-(3,3-difluoroazetidin-1-yl)acetamido)-4- fluoropyrrolidine-1 -carboxylate:

[1481] To stirred solution of 3,3-difluoroazetidine (HCI salt) (520 mg, 4 mmol, 1.5 eq.) in acetonitrile (5 ml) was added K2CO3 (922 mg, 6.68 mmol, 2.5 eq.) at 0°C under inert atmosphere in Sealed Tube. Then reaction mixture was stirred for 15 min at 0°C. Then tert-butyl (3S,4R)-3-(2-chloroacetamido)-4-fluoropyrrolidine-1-carboxylate (750 mg, 2.67 mmol, 1 .0 eq.) was added at 0°C under inert atmosphere. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into water and the mixture extracted with ethyl acetate. Organic layer was washed successively with water followed by brine, then organic layer collected, dried over anhydrous Na2SO4 and concentrated to provide the crude product. It was then purified using Combi-Flash Chromatography (eluted at 50% EA-Hex as solvent system) to give tert-butyl (3S,4R)-3-(2-(3,3- difluoroazetidin-1-yl)acetamido)-4-fluoropyrrolidine-1 -carboxylate as yellow oil (600 mg, 66%).

[1482] 1H NMR (400MHz DMSO-d6): 6 8.04 (t, J = 7.12 Hz, 1 H), 5.13-4.99 (m, 1 H), 4.43-4.36 (m, 1 H), 3.74-3.67 (m, 4H), 3.57-3.47 (m, 3H), 3.33-3.16 (m, 2H), 3.16-3.09 (m, 1 H), 1.40 (s, 9H)

[1483] LCMS: m / z [M+H]+= 338.2 (calc, m / z = 338.16); RT = 1.71 min.

[1484] Step-3: Synthesis of tert-butyl (3S,4 / ?)-3-((2-(3,3-difluoroazetidin-1-yl)ethyl)amino)- 4-fluoropyrrolidine-1 -carboxylate: tert-butyl (3S,4R)-3-(2-(3,3-difluoroazetidin-1-yl)acetamido)-4-fluoropyrrolidine-1- carboxylate (75 mg, 0.22 mmol, 1.0 eq.) was taken in THF (2 ml) and BH3-THF (0.11 ml, 1.11 mmol, 5.0 eq.) was added at 0°C, then the reaction mixture was stirred at rt for 1 hr then heated at 70°C for 16 hr, MeOH was added and the reaction was refluxed at 75°C for another 16 hr. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into cold water and the mixture extracted with ethyl acetate. Organic layer was washed successively with water followed by brine, collected, dried over anhydrous Na2SO4 and concentrated to get the crude product. It was then purified using Combi-Flash Chromatography (eluted at -20-25% EA-Hex solvent system) to give tertbutyl (3S,4F?)-3-((2-(3,3-difluoroazetidin-1-yl)ethyl)amino)-4-fluoropyrrolidine-1- carboxylate as yellow gum (52 mg, 72%).

[1485] LCMS: m / z [M+H]+= 324.2 (calc, m / z = 324.18); RT = 1.67 min.

[1486] Step-4: Synthesis of tert-butyl (3S,4 / ?)-3-(N-(2-(3,3-difluoroazetidin-1-yl)ethyl)- 2, 2, 2-trifluoroacetamido)-4-fluoropyrrolidine-1 -carboxylate: tert-butyl (3S,4R)-3-((2-(3,3-difluoroazetidin-1-yl)ethyl)amino)-4-fluoropyrrolidine-1- carboxylate (70 mg, 0.22 mmol, 1.0 eq.) was taken in DOM (1 ml) and TEA (0.1 ml, 0.65 mmol, 3.0 eq.) was added to it, the reaction was set up at -78°C and TFAA (0.05 ml, 0.28 mmol, 0.3 eq.) was added slowly. The reaction was monitored for 2-3 hr. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into water and the mixture extracted with ethyl acetate. Organic layer was washed successively with water followed by brine, collected, dried over anhydrous Na2SO4 and concentrated to get the crude product. It was then purified using Combi-Flash Chromatography (eluted at -20% EA-Hex solvent system) to give tert-butyl (3S,4R)-3-(N-(2-(3,3-difluoroazetidin- 1 -yl)ethyl)-2, 2, 2-trifluoroacetamido)-4-fluoropyrrolidine-1 -carboxylate as yellow gum (65 mg, 91 %). LCMS: m / z [M+H]+= 420.2 (calc, m / z = 420.16); RT = 3.65 min.

[1487] Step-5: Synthesis of N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2,2,2-trifluoro-N-

[1488] ((3S,4 / ?)-4-fluoropyrrolidin-3-yl)acetamide: tert-butyl (3S,4R)-3-(N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2,2,2-trifluoroacetamido)-4- fluoropyrrolidine-1 -carboxylate (120 mg, 0.29 mmol, 1.0 eq.) was taken in DCM (2 ml) and TFA (0.5 ml, 1.72 mmol, 6 eq.) was added to it at 0°C, the reaction was allowed to stir at rt for 16 hr. On completion of the reaction (monitored by TLC) the reaction mixture was concentrated to give N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2,2,2-trifluoro-N-((3S,4R)- 4-fluoropyrrolidin-3-yl)acetamide as yellowish gum (76 mg, 83%).

[1489] LCMS: m / z [M+H]+= 320.2 (calc, m / z = 320.11); RT = 2.58 min.

[1490] Step-6: Synthesis of N-((3S,4R)-1-(4-chloro-3,5-difluoro-1 H-indole-2-carbonyl)-4- fluoropyrrolidin-3-yl)-N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2,2,2- trifl uoroacetam ide :

[1491] To the stirred solution of 4-chloro-3,5-difluoro-1 H-indole-2-carboxylic acid (Preparation 3) (65 mg, 0.28 mmol, 1.0 eq.) in DMF (1 ml) was added EDCI (81 mg, 0.42 mmol, 1.5 eq.), HOBt (57 mg, 0.42 mmol, 1.5 eq.), DIPEA (0.3 ml, 1.4 mmol, 5.0 eq.) and stirred at rt for 30 min. Then N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2,2,2-trifluoro-N-((3S,4R)-4- fluoropyrrolidin-3-yl)acetamide (90 mg, 0.28 mmol, 1.0 eq.) was added and stirred the reaction mixture at rt for 16 hr. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into ice cold water and the mixture extracted with ethyl acetate. Organic layer was washed successively with water followed by brine, collected, dried over anhydrous Na2SO4 and concentrated to get the crude product. It was then purified using Combi-Flash Chromatography (eluted at -35-40% EA-Hex solvent system) to give N-((3S,4R)-1-(4-chloro-3,5-difluoro-1 H-indole-2-carbonyl)-4- fluoropyrrolidin-3-yl)-N-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2,2,2-trifluoroacetamide as yellow gum (123 mg, 82%).

[1492] LCMS: m / z [M+H]+= 533.0 (calc, m / z = 533.09); RT = 3.54 min.

[1493] Step-7: Synthesis of (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4R)-3-((2-(3,3- difluoroazetidin-1-yl)ethyl)amino)-4-fluoropyrrolidin-1-yl)methanone:

[1494] (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4R)-3-((2-(3,3-difluoroazetidin-1- yl)ethyl)amino)-4-fluoropyrrolidin-1-yl)methanone (400 mg, 0.75 mmol, 1 eq.) was taken in MeOH (3 ml) and water (0.75 ml), K2CO3 (210 mg, 1.5 mmol, 2 eq.) was added and the reaction mixture was stirred at rt for 16 hr. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into ice cold water and the mixture extracted with ethyl acetate. Organic layer was washed successively with water followed by brine, collected, dried over anhydrous Na2SO4 and concentrated to get the crude product. It was then purified using Combi-Flash Chromatography (eluted at -40% EA- Hex solvent system) to give (4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4R)-3-((2-(3,3- difluoroazetidin-1-yl)ethyl)amino)-4-fluoropyrrolidin-1-yl)methanone as yellow gum which was further purified using reverse phase prep-purification method.

[1495] Reverse phase prep-purification method: Method AA

[1496] LCMS method: Method A

[1497] 1 H NMR (400MHz DMSO-d6, 100°C): 58.19 (s, 1 H), 7.39-7.37 (m, 1 H), 7.26-7.22 (m, 1 H), 5.27-5.14 (m, 1 H), 3.93-3.82 (m, 3H), 3.62-3.55 (m, 4H), 3.49-3.40 (m, 1 H), 3.36- 3.21 (m, 2H), 2.70-2.64 (m, 4H)

[1498] LCMS: m / z [M+H]+ = 437.2 (calc, m / z = 437.11); RT = 2.52 min.

[1499] Example 80

[1500] Synthesis of (3S,4R)-1 -[(4-chloro-3,5-difluoro-1 H-indol-2-yl)carbonyl]-4-fluoro-N- [2-(3-fluoroazetidin-1-yl)ethyl]pyrrolidin-3-amine

[1501] Step-1 : Synthesis of tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1 -carboxylate :

[1502] To stirred solution of tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1 -carboxylate (1.0 gm, 4.896 mmol, 1 .0 eq.) in DCM was added EtsN (1.02 ml, 7.344 mmol, 1.5 eq.) at 0°C under inert atmosphere. Then chloroacetyl chloride (0.47ml, 5.875 mmol, 1.2 eq.) was added at 0°C. then reaction mixture was stirred for 1 hr at 0°C under inert atmosphere LCMS and TLC of reaction mixture shows formation of desired product. Then reaction mixture was extracted with DCM and washed with water and dried over anhydrous Na2SO4and concentrated to get crude product, which was purified by Combi-flash chromatography (20 % EA-Hex) to get tert-butyl (3S,4R)-3-(2-chloroacetamido)-4- fluoropyrrolidine-1 -carboxylate (1.0 gm, 72.76 %) as colourless liquid.

[1503] LCMS: m / z [M+H]+= 281.2 (calc, m / z = 281.1); RT = 3.08 min.

[1504] Step-2: Synthesis of tert-butyl (3 / ?,4S)-3-fluoro-4-[2-(3-fluoroazetidin-1- yl)acetamido]pyrrolidin-1 -yl formate:

[1505] To stirred solution of 3-fluoroazetidine (hydrochloride salt) (447 mg, 4.00 mmol, 1.5 eq.) in MeCN (6 ml) was added K2CO3 (922 mg, 6.680 mmol, 2.5 eq.) at 0°C under inert atmosphere in sealed tube. Then reaction mixture was stirred for 15 min at 0°C. Then tert-butyl (3S,4R)-3-(2-chloroacetamido)-4-fluoropyrrolidine-1 -carboxylate (750 mg, 2.672 mmol, 1.0 eq.) was added at 0°C under argon atmosphere. Then reaction mixture was stirred for 16h at 70°C. LCMS and TLC of reaction mixture shows formation of desired product. Then reaction mixture extracted with EA and washed with water, dried over anhydrous Na2SC>4. then reaction mixture was concentrated and purified by Combi- Flash Chromatography (60% EA-Hex) to afford tert-butyl (3R,4S)-3-fluoro-4-[2-(3- fluoroazetidin-1-yl)acetamido]pyrrolidin-1-yl formate (320 mg, 76 %) as a colourless liquid.

[1506] LCMS: m / z [M+H]+= 320.2 (calc, m / z =320.17 ); RT = 1.63 min. Step-3: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-{[2-(3-fluoroazetidin-1- yl)ethyl]amino}pyrrolidine-1 -carboxylate:

[1507] Boc

[1508] To stirred solution of tert-butyl (3R,4S)-3-fluoro-4-[2-(3-fluoroazetidin-1- yl)acetamido]pyrrolidine-1-carboxylate (700 mg, 2.035 mmol, 1.0 eq. ) in THF (10 ml) was added BH3.THF (12 ml, 10.17 mmol, 5 eq.)) at 0°C under inert atmosphere. Then reaction mixture was stirred for 16 h at 75°C temperature. LCMS and TLC of reaction mixture shows formation of boron complex of product. Then reaction mixture was quenched with MeOH at 0°C till effervescence gone and then reaction mixture was refluxed with MeOH at 75°C under inert atmosphere for overnight. LCMS of reaction mixture shows formation of desired product. Then reaction mixture was concentrated and extracted with EA and washed with water and dried over Na2SO4, Which was concentrated to afford tert-butyl (3R,4S)-3-fluoro-4-{[2-(3-fluoroazetidin-1- yl)ethyl]amino}pyrrolidine-1 -carboxylate as a colourless gum liquid (650 mg, 96 % ). LCMS: m / z [M+H]+ = 306.21 (calc, m / z = 306.19); RT = 1.52 min.

[1509] Step-4: Synthesis of tert-butyl (3R,4S)-3-fluoro-4-(2,2,2-trifluoro-N-(2-(3- fluoroazetidin-1 -yl)ethyl)acetamido)pyrrolidine-1 -carboxylate

[1510] To stirred solution of tert-butyl (3R,4S)-3-fluoro-4-{[2-(3-fluoroazetidin-1- yl)ethyl]amino}pyrrolidine-1 -carboxylate (650 mg,2.129 mmol, 1 eq.) in DCM was added TEA (0.9 ml, 6.386 mmol, 3.0 eq.) and DMAP (26 mg ,0.213 mmol, 0.1 eq.) at 0°C under inert atmosphere. Then (CF3CO)2O was added at 0°C under inert atmosphere. Then reaction mixture was stirred for 2 hr. TLC of reaction mixture shows formation of desired product. Then reaction mixture was quenched with water and extracted with DCM and dried over Na2SO4and concentrated to get crude product which was purified by Combi- Flash chromatography (50 % EA-Hex solvent system) and concentrated to afford tert- butyl (3R,4S)-3-fluoro-4-(2,2,2-trifluoro-N-(2-(3-fluoroazetidin-1-yl)ethyl)acetamido) pyrrolidine-1 -carboxylate (400mg ,50 %) as a colourless liquid. LCMS: m / z [M+H]+= 402.24 (calc, m / z = 402.17); RT = 1.92 min.

[1511] Step-5: Synthesis of 2,2,2-trifluoro-N-(2-(3-fluoroazetidin-1-yl)ethyl)-N-((3S,4R)-4- fluoropyrrolidin-3-yl)acetamide tert-butyl (3R,4S)-3-fluoro-4-(2,2,2-trifluoro-N-(2-(3-fluoroazetidin-1-yl)ethyl)acetamido) pyrrolidine-1 -carboxylate (310.0 mg, 0.77 mmol, 1.0 eq.) was taken in DCM (4.0 ml) and TFA (0.6 ml, 7.70 mmol, 10 eq.) was added to it at 0°C. Then reaction mixture was warmed to room temperature and stirred for 16 hrs. The completion of the reaction was monitored by TLC and crude LCMS. The reaction was evaporated to dryness. Crude compound was taken in DCM (10.0 mL) and treated with Amberlite resin to make free base. The resultant crude was dried under vacuo to afford 2,2,2-trifluoro-N-(2-(3- fluoroazetidin-1-yl)ethyl)-N-((3S,4R)-4-fluoropyrrolidin-3-yl)acetamide as a colourless gum (200.0 mg, crude ).

[1512] LCMS: m / z [M+H]+= 302.15 (calc, m / z = 302.12); RT = 1.40 min.

[1513] Step-6: Synthesis of N-((3S,4R)-1-(4-chloro-3,5-difluoro-1 H-indole-2-carbonyl)-4- fluoropyrrolidin-3-yl)-2,2,2-trifluoro-N-(2-(3-fluoroazetidin-1-yl)ethyl)acetamide

[1514] To the stirred solution of 4-chloro-3,5-difluoro-1 H-indole-2-carboxylic acid (150 mg , 0.648 mmol, 1.0 eq. in DMF (3 ml) was added DIPEA (0.5 ml, 2.591 mmol, 4.0 eq.), EDC.HCL (152mg, 0.972 mmol, 1.5 eq.) and HOBT(132 mg ,0972 mmol, 1.5 eq.) and stirred at rt for 30 min. 2,2,2-trifluoro-N-(2-(3-fluoroazetidin-1-yl)ethyl)-N-((3S,4R)-4- fluoropyrrolidin-3-yl)acetamide (235.0 mg, 0.77 mmol, 1 .2 eq.) was added and stirred the reaction mixture at rt for 16 hr. On completion of the reaction (monitored by TLC) the reaction mixture was cooled, poured into ice cold water and the mixture extracted with ethyl acetate. Organic layer was washed successively with water followed by brine, collected, dried over anhydrous Na2SO4 and concentrated to get the crude product. It was then purified using Combi-Flash Chromatography (eluted at -35-40% EA-Hex solvent system) to give N-((3S,4R)-1-(4-chloro-3,5-difluoro-1 H-indole-2-carbonyl)-4- fluoropyrrolidin-3-yl)-2,2,2-trifluoro-N-(2-(3-fluoroazetidin-1-yl)ethyl)acetamideas yellow gum (300.0 mg, 90%).

[1515] LCMS: m / z [M+H]+= 515.19 (calc, m / z = 515.10); RT = 1.99 min.

[1516] Step-7: Synthesis of (3S,4R)-1-[(4-chloro-3,5-difluoro-1H-indol-2-yl)carbonyl]-4- fluoro-N-[2-(3-fluoroazetidin-1 -yl)ethyl]pyrrolidin-3-amine :

[1517] To stirred solution of difluoromethyl-N-[(3S,4R)-1-[(4-chloro-3,5-difluoro-1 H-indol-2- yl)carbonyl]-4-fluoropyrrolidin-3-yl]-N-[2-(3-fluoroazetidin-1-yl)ethyl]carbamoyl fluoride (300 mg, 0.582 mmol, 1 eq.) in 4 ml MeOH and 1 ml H2O (4:1) was added K2CO3 (242 mg, 1.745 mmol, 3.0 eq.) at RT under argon atmosphere. Then reaction mixture was stirred for 5 hr under argon atmosphere. TLC and LCMS of reaction mixture shows formation of desired product. Then reaction mixture was concentrated and purified by Reverse Phase Prep. HPLC purification method (HPLC method: Method-AB) to afford (3S,4R)-1-[(4-chloro-3,5-difluoro-1 H-indol-2-yl)carbonyl]-4-fluoro-N-[2-(3-fluoroazetidin- 1-yl)ethyl]pyrrolidin-3-amine (100 mg, %) as off white solid.

[1518] LCMS: m / z [M+H]+= 419.33 (calc, m / z = 419.12); RT = 2.32 min.

[1519] 1H NMR (400 MHz, DMSO-d6, 100 °C): 5 11.55 (1 H, brs), 7.38 (1H, S), 7.26-7.22 (1H, m), 5.27-5.04 (m,2H), 3.93-3.78 (m,3H), 3.59-3.35 (m,4H), 3.15-3.09 (m,2H), 2.68-2.57 (m,5H). Example 81 and 82

[1520] Synthesis of (R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1 - yl)ethyl)piperazin-1 -yl)methanone: and (S)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3- (2-(3,3-difluoroazetidin-1 -yl)ethyl)piperazin-1 -yl)methanone:

[1521] Step-1 : Synthesis of: 1 -benzyl 4-(tert-butyl) 2-(2-methoxy-2-oxoethyl)piperazine- 1,4-dicarboxylate:

[1522] To a stirred solution of tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (2 g, 7.74 mmol) in DCM (50 mL) was treated with NEta (5.35 mL, 38.71 mmol) for 10 min at 0 °C under nitrogen atmosphere followed by the addition of Cbz-CI (1.76 mL, 15.48 mmol) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. the reaction mixture was quenched with cold water (100 mL and extracted with DCM (100 ml_x2). The combined organic layers were washed with brine, dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude was purified by combiflash chromatography (eluent: 10% ethyl acetate in hexane) to afford 1-benzyl 4-(tert-butyl) 2-(2-methoxy-2-oxoethyl)piperazine-1 ,4-dicarboxylate (2.5 g, 83%) as gum. LCMS (Method A): RT 3.49 min; 410.1 [M+18]+.

[1523] Step-2: Synthesis of: 1-benzyl 4-(tert-butyl) 2-(2-hydroxyethyl)piperazine-1,4- dicarboxylate:

[1524] DIBAL-H (1 M in Toluene, 2.5 mL) was added dropwise to a stirred solution of 1-benzyl 4-(tert-butyl) 2-(2-methoxy-2-oxoethyl)piperazine-1 ,4-dicarboxylate (500 mg, 1 .27 mmol) in dry THF (10 mL) at 0°C. The resulting mixture was stirred at warmed to and 4 h. The reaction was monitored LCMS and TLC. The reaction mixture was quenched with satd. aq. NH4CI solution as dropwise added at 0 °C and the reaction mixture was filtered with celite bed then filtrated part was extracted with EtOAc (3x). The combined organic layer was washed with H2O, brine and then dried over anhyd. Na2SO4. Organic part was then filtered and the filtrate was evaporated to dryness under reduced pressure. The resulting crude was purified by combiflash chromatography (eluent: 50% ethyl acetate in hexane) to get 1 -benzyl 4-(tert-butyl) 2-(2-hydroxyethyl)piperazine-1 ,4-dicarboxylate (300 mg, 65%) as gum. LCMS (Method A): RT 3.23 min; 365.2 [M+1]+.

[1525] Step-3: Synthesis of: 1 -benzyl 4-(tert-butyl) 2-(2-oxoethyl)piperazine-1,4- dicarboxylate:

[1526] Boc

[1527] Cbz

[1528] To a stirred solution of 1 -benzyl 4-(tert-butyl) 2-(2-hydroxyethyl)piperazine-1 ,4- dicarboxylate (440 mg, 1.20 mmol) in DCM (20 mL) was added Dess-Martin periodinane (614 mg, 1.44 mmol) at 0 °C. The resulting mixture wa...

Claims

Claims1 . A compound of Formula (I),whereinR1is halogen or H;R2is halogen;R3is halogen;R5is H or halogen;R6is H or halogen;R4is of Formula (II):Formula (II) whereinX1is C(R7)(R8);X2is C(R9)(R10) or a bond;X3is C(R11)(R12) or N(R13);X4is C(R16)(R17), O or a bond;X5is C(R18)(R19) or a bond;X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14, R12and R14, R12and R27, R9and R13or R10and R13are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R9is joined together with R13or R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R10is joined together with R13or R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R11is -X7N(R14)(R15) or -X7-O-X8-R27;X7is a bond or C1-3 alkanediyl;X8is a bond or C1-3 alkanediyl;R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F; or when R27is joined together with R12to form a ring together with the intervening atom(s), then R27is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; or when R12is joined together with R14or R27to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R13is H or C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy; or when R13and R9or R10are joined together to form a ring together with the intervening atoms, then R13is -C1-3 alkanediyl-N(R28)-, wherein the C1-3 alkanediyl is optionally substituted with one or more substituents individually selected from halogen, Ci-3 alkyl, and C1-3 haloalkyl, and R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; andR21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X2is C(R9)(R10), X4is C(R16)(R17), and X5is C(R18)(R19), or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R1is halogen, or a pharmaceutically acceptable salt thereof.

3. The compound according to any one of the preceding claims, wherein R1is F or Cl, R2is F or Cl, R3is F or Cl, R5is H, and R6is H, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of the preceding claims, wherein R4is of Formula (XXXVI):Formula (XXXVI) or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of the preceding claims, wherein R4is ofFormula (XVI):Formula (XVI) or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of the preceding claims, wherein R11isNH2, N(H)(CH3) or N(CH3)2, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 5, wherein R4is:pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 3, wherein R4is of Formula(HI):Formula (III) or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 3 or 8, wherein X3is N(R13), or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 3, wherein R4is11 . The compound according to any one of claims 1 to 3 or 8, wherein X3isC(R11)(R12), or a pgarmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 3, wherein R4isacceptable salt thereof.

13. The compound according to any one of claims 1 to 3, wherein R4is of Formula(XIII):Formula (XIII) or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 3 or 13, wherein X4is O, or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1 to 3 or 13, wherein X4is C(R16)(R17), or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 3, wherein R4is selected from the group consisting of:pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 3, wherein R4is of Formula (XIX):Formula (XIX) whereinR7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;X5is C(R18)(R19) or a bond;R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R26is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; m is 0 pr 1 ; p is 0, 1 or 2; v is 0, 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 3, wherein R4is:pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 1 to 3, wherein R4is of Formula (XXIV):Formula (XXIV) whereinX5is C(R18)(R19) or a bond;R7is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R8is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R10is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;X7is a bond or C1-3 alkanediyl;R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R15is H or C1-3 alkyl;R12is H or C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen,R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; andR19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen, or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1 to 3, wherein R4is:or , or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 , wherein the compound is selected from the group consisting of:(3,4-dichloro-5-fluoro-1 H-indol-2-yl)-[(2S)-2,4-dimethylpiperazin-1 - yl]methanone;(R)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;(S)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;(S)-(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2-methylpiperazin-1-yl)methanone;(R)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;(S)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1H-indol-2-yl)methanone;((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone;(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(piperazin-1-yl)methanone;(4-aminopiperidin-1-yl) (3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;(4-(2-aminoethyl)piperazin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;((2S,4R)-4-amino-2-methylpyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(R)-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(S)-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;((3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H- indol-2-yl)methanone;(4-(2-aminoethoxy)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-methylpiperazin-1-yl)methanone;((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;(R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-(methoxymethyl)piperazin-1- yl)methanone;(4-amino-4-methylpiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(octahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methanone;(S)-(4-amino-3,3-difluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-1 H-indol-2-yl)methanone;((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3-fluoro-1 H-indol-2- yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-7-azaspiro[3.5]nonan-7- yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-6-azaspiro[3.4]octan-6-yl)methanone;(4-(2-(azetidin-3-yloxy)ethyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(4-((azetidin-3-yloxy)methyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(4-((3-fluoroazetidin-3-yl) methoxy)piperidin- 1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)pyrrolidin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-methoxyazetidin-1- yl)ethyl)piperazin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin-1-yl)ethyl)piperazin-1- yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)piperidin- 1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3-ylmethyl) amino)piperidin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)pyrrolidin- 1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4R)-3-((2-(3,3-difluoro azetidin-1- yl)ethyl)amino)-4-fluoropyrrolidin-1-yl)methanone;(3S,4R)-1-[(4-chloro-3,5-difluoro-1 H-indol-2-yl)carbonyl]-4-fluoro-N-[2-(3- fluoroazetidin-1-yl)ethyl]pyrrolidin-3-amine;(R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1- yl)ethyl)piperazin-1-yl)methanone;(S)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1- yl)ethyl)piperazin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((2-methoxy ethyl)amino)pyrrolidin-1-yl)methanone; and (4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(dimethylamino)ethyl) piperazin-1 - yl)methanone, or a pharmaceutically acceptable salt thereof.

22. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a Kv1 .3 potassium channel inhibitor.

23. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

24. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 for use as a medicament.

25. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 for use in the treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial.

26. A compound of Formula (I),Formula (I) whereinR1is halogen or H;R2is halogen;R3is halogen or H;R5is H or halogen;R6is H or halogen;R4is of Formula (II):Formula (II) whereinX1is C(R7)(R8);X2is C(R9)(R10) or a bond;X3is C(R11)(R12) or N(R13);X4is C(R16)(R17), O or a bond;X5is C(R18)(R19) or a bond;X6is a bond or C(R20)(R21); wherein R9and R14, R10and R14, R12and R14, R12and R27, R9and R13or R10and R13are optionally joined together to form a 4-6 membered ring together with the intervening atom(s);R7is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;R8is H; C1-3 alkyl optionally substituted with 1 to 3 F or C1-3 alkoxy; C1-3 alkoxy; or halogen;R9is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R9is joined together with R13or R14to form a ring together with the intervening atoms, then R9is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R10is H; C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or azetidinyl optionally substituted with one or more halogens; C1-3 alkoxy; or halogen; or when R10is joined together with R13or R14to form a ring together with the intervening atoms, then R10is O, a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R11is -X7N(R14)(R15) or -X7-O-X8-R27;X7is a bond or C1-3 alkanediyl;X8is a bond or C1-3 alkanediyl;R27is N(R14)(R15) or azetidinyl optionally substituted with one or more F; or when R27is joined together with R12to form a ring together with the intervening atom(s), then R27is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R14is H or C1-3 alkyl optionally substituted with oxetanyl, C1-3 alkoxy, or azetidinyl optionally substituted with one or more F; or when R14is joined together with R9, R10or R12to form a ring together with the intervening atom(s), then R14is C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl; R15is H or C1-3 alkyl;R12is H; C1-3 alkyl optionally substituted with 1 to 3 F; C1-3 alkoxy; or halogen; or when R12is joined together with R14or R27to form a ring together with the intervening atom, then R12is a bond or C1-3 alkanediyl optionally substituted with one or more substituents individually selected from halogen, C1-3 alkyl, and C1-3 haloalkyl;R13is H or C1-3 alkyl optionally substituted with NH2, N(H)(CH3), N(CH3)2 or azetidinyl, wherein said azetidinyl is optionally substituted with one or more substituents selected from halogen and C1-3 alkoxy; or when R13and R9or R10are joined together to form a ring together with the intervening atoms, then R13is -C1-3 alkanediyl-N(R28)-, wherein the C1-3 alkanediyl is optionally substituted with one or more substituents individually selected from halogen, C1- 3 alkyl, and C1-3 haloalkyl, and R28is H or C1-3 alkyl; R16is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R17is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R18is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R19is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen;R20is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; andR21is H, C1-3 alkyl optionally substituted with 1 to 3 F, C1-3 alkoxy, or halogen; with the proviso that when X3is N(R13), then X2is C(R9)(R10), X4is C(R16)(R17), and X5is C(R18)(R19),or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial.

27. The compound for use according to claim 26, wherein R1is halogen, and R3is halogen.

28. The compound for use according to claim 26, wherein the compound is: (4,5-dichloro-1 H-indol-2-yl)-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methanone; (4,5-dichloro-1 H-indol-2-yl)-[(3S)-3-[(dimethylamino)methyl]pyrrolidin-1- yl]methanone;(4,5-dichloro-1 H-indol-2-yl)-(4-methylpiperazin-1-yl)methanone; (4,5-dichloro-1 H-indol-2-yl)(1 ,7-diazaspiro[4.4]nonan-7-yl)methanone; (3,4-dichloro-5-fluoro-1 H-indol-2-yl)-[(2S)-2,4-dimethylpiperazin-1- yl]methanone;(S)-(3-(aminomethyl)pyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2-yl)methanone; 2,7-diazaspiro[3.4]octan-2-yl-(4,5-dichloro-1 H-indol-2-yl)methanone;(R)-(3-aminopyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2-yl)methanone;(R)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;(S)-(3-aminopiperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone; (S)-(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2-methylpiperazin-1-yl)methanone;(S)-(4,5-dichloro-1 H-indol-2-yl)(3-((methylamino)methyl)pyrrolidin-1- yl)methanone;(4,5-dichloro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone;(4-chloro-5-fluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone;(4,5-dichloro-1 H-indol-2-yl)(1 ,6-diazaspiro[3.4]octan-6-yl)methanone; (R)-(4,5-dichloro-1 H-indol-2-yl)(3-(methylamino)pyrrolidin-1-yl)methanone;(4,5-dichloro-1 H-indol-2-yl)(1 ,6-diazaspiro[3.3]heptan-6-yl)methanone;(4,5-dichloro-1 H-indol-2-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone;(R)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;(S)-(3-aminopyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(2-(aminomethyl)morpholino)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone; (3,4-dichloro-5-fluoro-1 H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone;(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(piperazin-1-yl)methanone;(4-aminopiperidin-1-yl) (3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;(R)-(3-(azetidin-3-yloxy)pyrrolidin-1-yl)(4,5-dichloro-1 H-indol-2-yl)methanone;(4-(2-aminoethyl)piperazin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2-yl)methanone;((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;((2S,4R)-4-amino-2-methylpyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(R)-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(S)-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;((3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl)(3,4-dichloro-5-fluoro-1 H- indol-2-yl)methanone;(4-(2-aminoethoxy)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-methylpiperazin-1-yl)methanone;((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;(R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-(methoxymethyl)piperazin-1- yl)methanone;(4-amino-4-methylpiperidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(octahydro-2H-pyrazino[1,2-a]pyrazin-2- yl)methanone;(S)-(4-amino-3,3-difluoropyrrolidin-1-yl)(4-chloro-3,5-difluoro-1 H-indol-2- yl)methanone;((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)(3,4-dichloro-1 H-indol-2-yl)methanone;((3R,4S)-4-amino-3-fluoropiperidin-1-yl)(4-chloro-3-fluoro-1 H-indol-2- yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-7-azaspiro[3.5]nonan-7- yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(2-oxa-6-azaspiro[3.4]octan-6-yl)methanone;(4-(2-(azetidin-3-yloxy)ethyl)piperidin-1 -yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(4-((azetidin-3-yloxy)methyl)piperidin-1-yl)(3,4-dichloro-5-fluoro-1 H-indol-2- yl)methanone;(3,4-dichloro-5-fluoro-1 H-indol-2-yl)(4-((3-fluoroazetidin-3-yl) methoxy)piperidin- 1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3- ylmethyl)amino)pyrrolidin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-methoxyazetidin-1- yl)ethyl)piperazin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(3-fluoroazetidin-1-yl)ethyl)piperazin-1- yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)piperidin- 1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((oxetan-3-ylmethyl) amino)piperidin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-(methyl amino)pyrrolidin- 1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3S,4R)-3-((2-(3,3-difluoro azetidin-1- yl)ethyl)amino)-4-fluoropyrrolidin-1-yl)methanone;(3S,4R)-1-[(4-chloro-3,5-difluoro-1 H-indol-2-yl)carbonyl]-4-fluoro-N-[2-(3- fluoroazetidin-1-yl)ethyl]pyrrolidin-3-amine;(R)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1- yl)ethyl)piperazin-1-yl)methanone;(S)-(4-chloro-3,5-difluoro-1 H-indol-2-yl)(3-(2-(3,3-difluoroazetidin-1- yl)ethyl)piperazin-1-yl)methanone;(4-chloro-3,5-difluoro-1 H-indol-2-yl)((3R,4S)-3-fluoro-4-((2-methoxy ethyl)amino)pyrrolidin-1-yl)methanone; or(4-chloro-3,5-difluoro-1 H-indol-2-yl)(4-(2-(dimethylamino)ethyl) piperazin-1 - yl)methanone, or a pharmaceutically acceptable salt thereof.

29. The compound for use according to any one of claims 25 to 28, wherein the disease or medical condition is a neurodegenerative disease.

30. The compound for use according to any one of claims 25 to 28, wherein the disease or medical condition is Multiple Sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease31. The compound for use according to claim 29, wherein the neurodegenerative disease is a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE), or a lysosomal storage disorder (LSD).

32. The compound for use according to claim 29, wherein the neurodegenerative disease is Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease or stroke.

33. The compound for use according to any one of claims 25 to 28, wherein the disease or medical condition is rheumatoid arthritis (RA), neuropathic pain, inflammatory pain, CNS complications of COVID-19 infection, post-COVID-19 conditions, Chronic Traumatic Encephalopathy, HIV-Associated Neurocognitive Disorder (HAND), Traumatic Brain Injury, Epilepsy, Autoimmune Encephalitis, Bipolar disorder, major depression disorder(MDD) or Schizophrenia.

34. The compound for use according to any one of claims 25 to 28, wherein the disease or medical condition is Psoriasis, Atopic dermatitis, Celiac Disease, Lupus, Type 1 diabetes, Sjogren’s syndrome, Vasculitis, IBD, Crohn’s disease, Graves’ disease, Hashimoto’s thyroiditis, Myasthenia gravis or Scleroderma.

35. The compound for use according to any one of claims 25 to 28, wherein the disease or medical condition is cancer; an immunological disorder, such as transplant rejection or an autoimmune disease, for example rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes mellitus; a central nervous system disorder, such as Alzheimer’s disease; an inflammatory disorder, such as an inflammatory skin condition, arthritis,psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy; a gastroenterological disorder, such as an inflammatory bowel disease; a metabolic disorder, such as obesity or type II diabetes mellitus; a cardiovascular disorder; or a kidney disease, such as chronic kidney disease, nephritis, or chronic renal failure.

36. The compound for use according to any one of claims 25 to 28, wherein the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, Alzheimer’s disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, Crohn’s disease, ulcerative colitis, obesity, type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof.

37. Use of a compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 22 or 26 to 28 for the manufacture of a medicament for treatment of disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial.

38. A method for treatment of a disease or medical condition where inhibition of Kv1.3 potassium channel is beneficial comprising administering a compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 22 or 26 to 28 to a subject in need thereof.

39. A method of blocking Kv1.3 potassium channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one as defined in any one of claims 1 to 22 or 26 to 28, or a pharmaceutically acceptable salt thereof.

40. The method according to any one of claims 38 or 39, wherein the subject is a mammal, such as human.

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