Pyrrolidine-indole compounds and compositions comprising the same which are modulators of 5- HT2a

Abstract

Provided herein are compounds of formula (I), (II), (III), (IV), (V) or pharmaceutically acceptable salts or deuterated forms thereof, wherein R1, R2, R3, R4, R5, R6, R7A, R7B, R8, R9, R10, n, and m are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), (III), (IV), (V) or pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of formula (I), (II), (III), (IV), (V) or pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of the treatment of a serotonin 5-HT2A receptor associated disease / disorder.

Description

Attorney Docket No.: COPA-058 / 01WO 337248-2468Pyrrolidine-Indole Compounds and Compositions Comprising the SameCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present Application claims priority to U.S. Provisional Patent Application No. 63 / 790,564 filed April 17, 2025, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Over 50% of adults in the United States will be diagnosed with a psychiatric disorder at some point in their lifetime. Nearly 1 in 5 suffer from mental illness, and nearly 1 in 25 are afflicted with severe mental illness, such as major depression, schizophrenia, or bipolar disorder.

[0003] Psychedelics show promising activity in treating mental illness. New psychedelic compounds are needed for treating mental illness.SUMMARY

[0004] In embodiments, the present disclosure provides a compound of formula (I):

[0005] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0006] wherein:

[0007] R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0008] R2is -halo, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, -O-C1-6 alkyl, -OH, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl;Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0009] R3is -halo, -O-Ci-6 alkyl, -OH, -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-CI-6 alkyl, -N(CI-6alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl;

[0010] R4is -Ci-6 alkyl, -aryl, -heteroaryl, -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -Ci-6 alkylene-OH, -OH, -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl;

[0011] n is 0, 1, 2, or 3; and

[0012] m is 0 or 1,

[0013] and wherein, R2and R3are not both -halo.

[0014] In embodiments, the present disclosure provides a compound of formula (II):R516H (II),

[0015] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0016] wherein:

[0017] R5is -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0018] R6is -O-Ci-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -N(CI-6 alkyl)2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, -C1-6 alkylene-OH, or -S(O)-Ci-6 alkyl;

[0019] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-Ci-6 alkyl;

[0020] n is 0, 1, 2, or 3; and

[0021] m is 0 or 1,

[0022] and wherein, the compound is not:Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0023] In embodiments, the present disclosure provides a compound of formula (III):R1

[0024] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0025] wherein:

[0026] R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0027] R7Aand R7Bare each independently -halo;

[0028] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0029] n is 0, 1, 2, or 3; and

[0030] m is 0 or 1,

[0031] In embodiments, the present disclosure provides a compound of formula (IV):Attorney Docket No.: COPA-058 / 01WO 337248-2468R1

[0032] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0033] wherein:

[0034] R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0035] R8is -halo or -methyl;

[0036] R9is -C1-6 alkyl;

[0037] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0038] n is 0, 1, 2, or 3; and

[0039] m is 0 or 1.

[0040] In embodiments, the present disclosure provides a compound of formula (V):R1N— 1 iR4)

[0041] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0042] wherein:

[0043] R1is -H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0044] R10is -halo, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -C1-6 alkylene-O-Ci-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6alkyl;

[0045] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0046] n is 0, 1, 2, or 3; and

[0047] m is 0 or 1.

[0048] In embodiments, the compound is selected from any one of the compounds in Tables A-L.DETAILED DESCRIPTION

[0049] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0050] Definitions

[0051] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0052] Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0053] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0054] “Alkyl” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moietiesAttorney Docket No.: COPA-058 / 01WO 337248-2468described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, secpropyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.

[0055] “Alkylene” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

[0056] “Alkenyl” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl is attached to the rest of the molecule by a single bond. Alkenyl comprising any number of carbon atoms from 2 to 12 are included. An alkenyl comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0057] “Alkynyl” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl is attached to the rest of the molecule by a single bond. Alkynyl comprising any number of carbon atoms from 2 to 12 are included. An alkynyl comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Nonlimiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like.

[0058] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.

[0059] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0060] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising one to thirteen carbon ring atoms, one to six heteroatoms as ring atoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring containing at least one heteroatom as a ring atom. For purposes of this disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl,Attorney Docket No.: COPA-058 / 01WO 337248-2468benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e. thienyl).

[0061] “Heterocyclyl” refers to a stable 3- to 20-membered non-aromatic, saturated or partially unsaturated ring radical which consists of two to twelve carbon ring atoms and from one to six heteroatoms as ring atoms selected from nitrogen, oxygen or sulfur, at least one non-aromatic, saturated or partially unsaturated ring containing at least one heteroatom as a ring atom. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl.

[0062] As used herein, the symbol “” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of XY — 1 which is not depicted as being attached to the point of attachment bond. For example, “5—’’indicates that the chemical entity “XY” is bonded to another chemical entity via the point ofAttorney Docket No.: COPA-058 / 01WO 337248-2468attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference.

[0063] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0064] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0065] The term “substituted” used herein means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, aryl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, di alkyl aryl silyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSChRh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In theAttorney Docket No.: COPA-058 / 01WO 337248-2468foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, A-heterocyclyl, heteroaryl, -heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, 7V-heterocyclyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In embodiments, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with halo, nitro, -CN, -Ci-Ce alkyl, NRARB, Ci-Ce-haloalkyl, -Ci-Ce-alkyl-NRARB, -Ci-C6-alkyl-0H, -C(=0)RD, -C(=0)N(RE)RF, -C(=0)-0RD, -N(RG)C(=0)RD, -N(RG)C(=0)N(RE)RF, -N(RG)C(=0)0RD, -N(RG)S(=0)RD, -N(RG)S(=0)2RD, N=S(=0)(RE)RF, -0RD, -0(C=0)RD, -0(C=0)N(RE)RF, -0(C=0)0RD, -C2-C6 alkenyl, or-C2-Ce alkynyl; wherein RAand RBare each independently -H, -Ci-Ce alkyl, cycloalkyl, aryl, heteroaryl, -C(0)Rc, -C(0)0Rc, -S(O)RC, or -S(O)2RC; Rcis H, -Ci-Ce alkyl, aryl, cycloalkyl, or heterocyclyl; and RD, RE, RF, RG, are each independently selected from -H, Ci-Ce-alkyl-, Ci-Ce-haloalkyl-, -Ci-Ce-alkyl-OH, cycloalkyl, C2-Ce-alkenyl-, heterocyclyl, aryl, or heteroaryl. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0066] The compounds of the disclosure, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0067] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0068] Compounds

[0069] The present disclosure provides compounds of formula (I), (II), (III) (IV), (V), (I-E), Table A-L, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

[0070] In embodiments, the present disclosure provides a compound of formula (I):R2R3AS mH (I),

[0071] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0072] wherein:

[0073] R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0074] R2is -halo, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, -O-C1-6 alkyl, -OH, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl;

[0075] R3is -halo, -O-C1-6 alkyl, -OH, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl;

[0076] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0077] n is 0, 1, 2, or 3; and

[0078] m is 0 or 1,

[0079] and wherein, R2and R3are not both -halo.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0080] In embodiments, the present disclosure provides a compound of formula (II):

[0081] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0082] wherein:

[0083] R5is -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0084] R6is -O-C1-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -N(CI-6 alkyl)2, -CN, -C(C=O)-C1-6 alkyl, -O(C=O)-Ci-6alkyl, -C1-6 alkylene-OH, or -S(O)-Ci-6 alkyl;

[0085] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0086] n is 0, 1, 2, or 3; and

[0087] m is 0 or 1,

[0088] and wherein, the compound is not:

[0089] In embodiments, the present disclosure provides a compound of formula (III):Attorney Docket No.: COPA-058 / 01WO 337248-2468R1

[0090] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0091] wherein:

[0092] R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0093] R7Aand R7Bare each independently -halo;

[0094] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0095] n is 0, 1, 2, or 3; and

[0096] m is 0 or 1.

[0097] In embodiments, the present disclosure provides a compound of formula (IV):R1

[0098] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0099] wherein:

[0100] R1is -H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0101] R8is -halo or -methyl;Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0102] R9is -Ci-6 alkyl;

[0103] R4is -Ci-6 alkyl, -aryl, -heteroaryl, -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -Ci-6 alkylene-OH, -OH, -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl;

[0104] n is 0, 1, 2, or 3; and

[0105] m is 0 or 1.

[0106] In embodiments, the present disclosure provides a compound of formula (V):

[0107] or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof

[0108] wherein:

[0109] R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;

[0110] R10is -halo, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -C1-6 alkylene-O-Ci-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6alkyl;

[0111] R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;

[0112] n is 0, 1, 2, or 3, and

[0113] m is 0 or 1.

[0114] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more substituents.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0115] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0116] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -C1-6 alkyl, -C2-6 alkenyl, or -C2-6 alkynyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, or -C2-6 alkynyl, are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0117] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, or -cycloalkyl; wherein the -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, or -cycloalkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0118] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -aryl, -heteroaryl; wherein the -aryl or -heteroaryl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0119] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, or -heterocyclyl; wherein the -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, or -heterocyclyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0120] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkylene-O-Ci-6 alkyl or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0121] In embodiments of formula (I), (III), (IV), and (V), R1is -H.

[0122] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-6 alkyl, wherein the -C1-6 alkyl is optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0123] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-6 alkyl.

[0124] In embodiments of formula (I), (III), (IV), and (V), R1is -methyl, -ethyl, -propyl, isopropyl or -butyl. In embodiments, R1is -methyl. In embodiments, R1is - ethyl. In embodiments, R1is - propyl. In embodiments, R1is - isopropyl. In embodiments, R1is - butyl.

[0125] In embodiments of formula (III), R1is methyl or butyl.

[0126] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-6 alkyl or -C1-6 alkylene-heteroaryl, wherein the heteroaryl is optionally substituted with -C1-6 alkyl.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0127] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-3 alkylene-5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with a methyl. In embodiments, the

[0128] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -C1-6 alkyl, or -C1-6 alkylene-heteroaryl .

[0129] In embodiments of formula (I), (III), (IV), and (V), R1is -heterocyclyl, -C1-6 alkyl, or -C1-6 alkylene-heteroaryl.

[0130] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-6 alkyl substituted with - OH.

[0131] In embodiments of formula (I), (III), (IV), and (V), R1is -CH2CH2OH.

[0132] In embodiments of formula (I), (III), (IV), and (V), R1is -CH2CH2CH3.

[0133] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-6 alkylene-heteroaryl.

[0134] In embodiments of formula (I), (III), (IV), and (V), R1is -C1-6 alkylene-heteroaryl,wherein the -C1-6 alkylene-heteroaryl isI

[0135] In embodiments of formula (I), (III), (IV), and (V), R1is -heterocyclyl. In embodiments, o V„ / / o —,0.the -heterocyclyl is , ' or '~i“v.

[0136] In embodiments of formula (I), (III), (IV), and (V), R1is -cycloalkyl. In embodiments,the -cycloalkylis 'zvyv.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0137] In embodiments of formula (I), (III), (IV), and (V), R1is -H, -heterocyclyl, -cycloalkyl, -Ci-6 alkyl, or -Ci-6 alkylene-heteroaryl, wherein the -Ci-6 alkyl is optionally substituted with -OH or -halo.

[0138] In embodiments of formula (I), (III), (IV), and (V), R1is -Ci-6 alkyl substituted with -halo.

[0139] In embodiments of formula (I), (III), (IV), and (V), R1is -Ci-6 alkyl substituted with -halo.

[0140] In embodiments of formula (I), (III), (IV), and (V), R1is -CH2CH2F.

[0141] In embodiments of formula (I), R1is -C1-6 alkyl, -C1-6 alkylene-heteroaryl or -heterocyclyl, wherein the heteroaryl is optionally substituted with -C1-6 alkyl.

[0142] In embodiments of formula (I), R1is methyl.

[0143] In embodiments of formula (I), R1is -C1-3 alkylene-5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with a methyl. In embodiments, the -C1-6HHalkylene-heteroarylis , 7" or

[0144] In embodiments of formula (I), R1is -heterocyclyl. In embodiments, the -heterocyclyl

[0145] In embodiments of formula (III), R1is -C1-6 alkyl.

[0146] In embodiments of formula (III), R1is methyl or butyl.

[0147] In embodiments of formula (IV), R1is -H, -C1-6 alkyl, or -C1-6 alkylene-heteroaryl. Inembodiments, the -C1-6 alkylene-heteroaryl is '"T

[0148] In embodiments of formula (V), R1is -H, -heterocyclyl, -cycloalkyl, -C1-6 alkyl, or -Ci-6 alkylene-heteroaryl, wherein the -C1-6 alkyl is optionally substituted with -OH or -halo.

[0149] In embodiments of formula (V), R1is -H, -heterocyclyl, -C1-6 alkyl, or -C1-6 alkylene-heteroaryl, wherein the -C1-6 alkyl is optionally substituted with -OH.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0150] . In embodiments, the -Ci-6 alkylene-heteroaryl is:

[0151] In embodiments of formula (V), R1is -C1-6 alkyl substituted with -OH.

[0152] In embodiments of formula (V), R1is -CH2CH2OH.

[0153] In embodiments of formula (V), R1is -CH2CH2CH3.

[0154] In embodiments of formula (V), R1is -C1-6 alkyl substituted with -halo.

[0155] In embodiments of formula (V), R1is -C1-6 alkyl substituted with -halo.

[0156] In embodiments or formula (V), R1is -CH2CH2F.R2

[0157] In embodiments of formula (I), R2is -halo, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -Ci-6 alkylene-O-Ci-6 alkyl, -O-C1-6 alkyl, -OH, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl.

[0158] In embodiments of formula (I), R2is -halo, -C1-6 alkyl, -C2-6 alkenyl, or -C2-6 alkynyl.

[0159] In embodiments of formula (I), R2is -aryl or -heteroaryl.

[0160] In embodiments of formula (I), R2is -C1-6 alkylene-aryl or -C1-6 alkylene-heteroaryl.

[0161] In embodiments of formula (I), R2is -heterocyclyl or -cycloalkyl.

[0162] In embodiments of formula (I), R2is -C1-6 alkylene-O-Ci-6 alkyl or -O-C1-6 alkyl.

[0163] In embodiments of formula (I), R2is -OH, -SH, -NH2, or-CN.

[0164] In embodiments of formula (I), R2is -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, or -SH.

[0165] In embodiments of formula (I), R2is -NH-C1-6 alkyl, -N(CI-6 alkyl)2, or -NH2.

[0166] In embodiments of formula (I), R2is -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6alkyl.

[0167] In embodiments of formula (I), R2is -halo.

[0168] In embodiments of formula (I), R2is -F, -Cl, -Br, or -I. In embodiments, R2is -Cl, -Br, or -I. In embodiments, R2is -F, -Br, or -I. In embodiments, R2is -Br or -I. In embodiments, R2is -F or -Cl.

[0169] In embodiments, of formula (I), R2is -F.

[0170] In embodiments, of formula (I), R2is -Cl.

[0171] In embodiments, of formula (I), R2is -Br.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0172] In embodiments, of formula (I), R2is -I. / C

[0173] In embodiments of formula (I), R3is -halo, -O-Ci-6 alkyl, -OH, -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-CI-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl.

[0174] In embodiments of formula (I), R3is -O-Ci-6 alkyl, -OH, -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-CI-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6alky.

[0175] In embodiments of formula (I), R3is -NH-CI-6 alkyl, -N(CI-6 alkyl)2, or -NH2.

[0176] In embodiments of formula (I), R3is -SH, -NH2, or-CN.

[0177] In embodiments of formula (I), R3is -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6alkyl.

[0178] In embodiments of formula (I), R3is -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, or -SH.

[0179] In embodiments of formula (I), R3is -halo or -OH.

[0180] In embodiments of formula (I), R3is -O-Ci-6 alkyl.

[0181] In embodiments of formula (I), R3is -O-Me, -O-ethyl, O-propyl, -O-isopropyl, or O-butyl.

[0182] In embodiments of formula (I), R3is -O-Me.

[0183] In embodiments of formula (I), R3is -O-ethyl.

[0184] In embodiments of formula (I), R3is - O-propyl.

[0185] In embodiments of formula (I), R3is -O-isopropyl.

[0186] In embodiments of formula (I), R3is O-butyl.R2and R3

[0187] In embodiments of formula (I), R3is -O-Ci-6 alkyl, -OH, -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-CI-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl, and R2is -halo, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -Ci-6 alkylene-O-Ci-6 alkyl, -O-Ci-6 alkyl, -OH, -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-CI-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl.

[0188] In embodiments of formula (I), R2and R3are not both -halo.

[0189] In embodiments of formula (I), R2and R3are not both -F, -Cl, -Br, or -I.

[0190] In embodiments of formula (I), R2and R3are not both -F.

[0191] In embodiments of formula (I), R2and R3are not both -Cl.

[0192] In embodiments of formula (I), R2and R3are not both -Br.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0193] In embodiments of formula (I), R2and R3are not both -I. / C

[0194] In embodiments of formula (I), (II), (III), (IV), or (V), R4is -Ci-6 alkyl, -aryl, -heteroaryl, -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -Ci-6 alkylene-OH, -OH, -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl.

[0195] In embodiments of formula (I), (II), (III), (IV), or (V), R4is -Ci-6 alkyl.

[0196] In embodiments of formula (I), (II), (III), (IV), or (V), R4is -OH.

[0197] In embodiments of formula (I), (II), (III), (IV), or (V), R4is -aryl or -heteroaryl.

[0198] In embodiments of formula (I), (II), (III), (IV), or (V), R4is -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, or -Ci-6 alkylene-OH.

[0199] In embodiments of formula (I), (II), (III), (IV), or (V), R4is -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl.

[0200] In embodiments, embodiments of formula (I), (II), (III), (IV), or (V), R4is -O-Ci-6 alkyl or -OH.

[0201] In embodiments, embodiments of formula (II), R4is -O-Ci-6 alkyl or -OH. / C

[0202] In embodiments of formula (II), R5is -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl are optionally substituted with one or more substituents.

[0203] In embodiments of formula (II), R5is -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0204] In embodiments of formula (II), R5is -C1-6 alkyl, -C2-6 alkenyl, or -C2-6 alkynyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, or -C2-6 alkynyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0205] In embodiments of formula (II), R5is -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, or -cycloalkyl; wherein the -aryl, -heteroaryl, -C1-6Attorney Docket No.: COPA-058 / 01WO 337248-2468alkylene-aryl, -Ci-6 alkylene-heteroaryl, -heterocyclyl, or -cycloalkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0206] In embodiments of formula (II), R5is -aryl or -heteroaryl; wherein the -aryl or -heteroaryl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0207] In embodiments of formula (II), R5is -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, or heterocyclyl; wherein the -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, or -heterocyclyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0208] In embodiments of formula (II), R5is C1-6 alkylene-O-Ci-6 alkyl or -O-C1-6 alkyl; wherein C1-6 alkylene-O-Ci-6 alkyl or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl.

[0209] In embodiments of formula (II), R5is -C1-6 alkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, or -heterocyclyl, each of which is optionally substituted with -halo or -OH.

[0210] In embodiments of formula (II), R5is -C1-6 alkyl, which is optionally substituted with -halo or -OH.

[0211] In embodiments of formula (II), R5is -CH2CH2F or -CH2CH2OH.

[0212] In embodiments of formula (II), R5is -CH2CH2F.

[0213] In embodiments of formula (II), R5is -CH2CH2OH.

[0214] In embodiments of formula (II), R5is -C1-6 alkylene-aryl,

[0215] In embodiments of formula (II), R5is "C

[0216] In embodiments of formula (II), R5is -C1-6 alkylene-heteroaryl.

[0217] In embodiments of formula (II), R5is -C1-6 alkylene-heteroaryl, wherein the -C1-6

[0218] In embodiments of formula (II), R5is -heterocyclyl.Attorney Docket No.: COPA-058 / 01WO 337248-24680

[0219] In embodiments of formula (II), R5is -heterocyclyl, wherein the is -heterocyclyl is olzo0, < / VW1, or s / vw i . / C

[0220] In embodiments of formula (II), R6is -O-Ci-6 alkyl, -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -N(CI-6alkyl)2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, -Ci-6 alkylene-OH, or -S(O)-Ci-6alkyl.

[0221] In embodiments of formula (II), R6is -S-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, or -SH.

[0222] In embodiments of formula (II), R6is -C(C=O)-Ci-6 alkyl or -O(C=O)-Ci-6 alkyl.

[0223] In embodiments of formula (II), R6is -N(CI-6 alkyl)2 or-CN.

[0224] In embodiments of formula (II), R6is -O-Ci-6 alkyl or -S-Ci-6 alkyl.

[0225] In embodiments of formula (II), R6is -O-Ci-6 alkyl, -S-Ci-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, or -Ci-6 alkylene-OH.

[0226] In embodiments of formula (II), R6is -O-Ci-6 alkyl.

[0227] In embodiments of formula (II), R6is -S-Ci-6 alkyl.

[0228] In embodiments of formula (II), R6is -S(O)-Ci-6 alkyl.

[0229] In embodiments of formula (II), R6is -S(O)2-Ci-6 alkyl.

[0230] In embodiments of formula (II), R6is -Ci-6 alkylene-OH.

[0231] In embodiments of formula (II), R6is -O-Me, -S-Me, -CH2-OH, -S(O)-Me, or -S(O)2-Me.

[0232] In embodiments of formula (II), R6is -S-Me.

[0233] In embodiments of formula (II), R6is -O-Me.R7AandR7B

[0234] In embodiments of formula (III), R7Aand R7Bare each independently -halo.

[0235] In embodiments of formula (III), R7Aand R7Bare each independently -F, -Cl, -Br, or -I.

[0236] In embodiments of formula (III), R7Aand R7Bare each independently -F, -Cl, or -Br.

[0237] In embodiments of formula (III), R7Aand R7Bare each independently -F or -Cl.

[0238] In embodiments of formula (III), R7Aand R7Bare each independently -F or -Br.

[0239] In embodiments of formula (III), R7Aand R7Bare both -F.

[0240] In embodiments of formula (III), R7Aand R7Bare both -Cl.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0241] In embodiments of formula (III), R7Aand R7Bare both -Br.

[0242] In embodiments of formula (III), R7Aand R7Bare both -I. / C

[0243] In embodiments of formula (IV), R8is -halo or -methyl.

[0244] In embodiments of formula (IV), R8is -halo.

[0245] In embodiments of formula (IV), R8is -methyl.

[0246] In embodiments of formula (IV), R8is -F, -Cl, -Br, or -I.

[0247] In embodiments of formula (IV), R8is -F, -Cl, or -Br.

[0248] In embodiments of formula (IV), R8is -F or -Cl.

[0249] In embodiments of formula (IV), R8is -F or -Br.

[0250] In embodiments of formula (IV), R8is -F.

[0251] In embodiments of formula (IV), R8is -Cl.

[0252] In embodiments of formula (IV), R8is -Br.

[0253] In embodiments of formula (IV), R8is -I.

[0254] In embodiments of formula (IV), R8is -F or -methyl. / C

[0255] In embodiments of formula (IV), R9is -Ci-6 alkyl.

[0256] In embodiments of formula (IV), R9is -methyl, -ethyl, -propyl, isopropyl or -butyl.

[0257] In embodiments of formula (IV), R9is -methyl.

[0258] In embodiments of formula (IV), R9is - ethyl.

[0259] In embodiments of formula (IV), R9is - propyl.

[0260] In embodiments of formula (IV), R9is - isopropyl.

[0261] In embodiments of formula (IV), R9is - butyl.

[0262] In embodiments of formula (V), R10is -halo, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -C1-6 alkylene-O-Ci-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6 alkyl.

[0263] In embodiments of formula (V), R10is -C2-6 alkenyl or -C2-6 alkynyl.

[0264] In embodiments of formula (V), R10is -aryl or -heteroaryl.

[0265] In embodiments of formula (V), R10is -C1-6 alkylene-aryl or -C1-6 alkylene-heteroaryl.

[0266] In embodiments of formula (V), R10is -aryl, -heteroaryl, or -heterocyclyl.

[0267] In embodiments of formula (V), R10is -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, or -SH.

[0268] In embodiments of formula (V), R10is -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, or-CN.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0269] In embodiments of formula (V), R10is -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=O)-CI-6alkyl.

[0270] In embodiments of formula (V), R10is -halo.

[0271] In embodiments of formula (V), R10is -F, -Cl, -Br, or -I.

[0272] In embodiments of formula (V), R10is -F, -Cl, or -Br.

[0273] In embodiments of formula (V), R10is -F or -Cl.

[0274] In embodiments of formula (V), R10is -F or -Br.

[0275] In embodiments of formula (V), R10is -F.

[0276] In embodiments of formula (V), R10is -Cl.

[0277] In embodiments of formula (V), R10is -Br.

[0278] In embodiments of formula (V), R10is -I.

[0279] In embodiments of formula (I), (II), (III), (IV), or (V), n is 0.

[0280] In embodiments of formula (I), (II), (III), (IV), or (V), n is 1.

[0281] In embodiments of formula (I), (II), (III), (IV), or (V), n is 2.

[0282] In embodiments of formula (I), (II), (III), (IV), or (V), n is 3.m

[0283] In embodiments of formula (I), (II), (III), (IV), or (V), m is 0.

[0284] In embodiments of formula (I), (II), (III), (IV), or (V), m is 1.

[0285] In embodiments of formula (I):R1

[0286] R1is -Ci-6 alkyl, -cycloalkyl, -Ci-6 alkylene-heteroaryl or -heterocyclyl, wherein the heteroaryl is optionally substituted with -Ci-6 alkyl and the -Ci-6 alkyl is optionally substituted with -halo;

[0287] R2is -halo;

[0288] R3is -O-Ci-6 alkyl;

[0289] n is 0; and

[0290] m is 1.

[0291] In embodiments, formula (II) is not deuterated.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0292] In embodiments of formula (II), when R6is O-methyl, R5is not -methyl or

[0293] In embodiments of formula (II), when R6is O-methyl, R5is not -methyl.

[0294] In embodiments of formula (II), when R6is O-methyl, R5is not

[0295] In embodiments of formula (II):R X5R®H (II),

[0296] R4is -O-Ci-6 alkyl or -OH;

[0297] R5is -Ci-6 alkyl, -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, or -heterocyclyl, each of which is optionally substituted with -halo or -OH;

[0298] R6is -O-Ci-6 alkyl, -S-Ci-6 alkyl, -S(O)-Ci-6 alkyl, -S(O)2-Ci-6 alkyl, -Ci-6 alkylene-OH;

[0299] n is 0 or 1; and

[0300] m is 1.

[0301] In embodiments of formula (III):N

[0302] R1is -Ci-6 alkyl;

[0303] R7Aand R7Bare each independently -halo;

[0304] n is 0;

[0305] m is 1.

[0306] In embodiments of formula (IV):Attorney Docket No.: COPA-058 / 01WO 337248-2468R1nR9R8(IV),

[0307] R1is -H, -Ci-6 alkyl, or -Ci-6 alkylene-heteroaryl;

[0308] R8is -halo or -methyl;

[0309] R9is -Ci-6 alkyl;

[0310] n is 0; and

[0311] m is 1.

[0312] In embodiments of formula (V):NH (V),

[0313] R1is -H, -Ci-6 alkyl, or -Ci-6 alkylene-heteroaryl, wherein the -Ci-6 alkyl is optionally substituted with -OH;

[0314] R10is -halo;

[0315] n is 0; and

[0316] m is 1.

[0317] Table A. Various compounds of formula (I)Compound CompoundStructure Structure No. No.H HkkN—rVVr'N1 2X° T ! A i \\kf / F — \ / 0 1UO H r"s\ 3 . m A 4. m Q0T V kF / F / Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0318] Table B. Various compounds of formula (I)Compound CompoundStructure Structure No. No.HrAv JAVQHrrv Bv-N—1A IBT F V KF '"X J / H H JQJQ2A s W 1 2BFk.Q 'c'l l JuF / TQV- 3A fjO 3B ,° T "7ozOd> A\ LFi °^r v zkF / 0^0Hrs\4A 4B* / \O W■ -= OH H H CJN H5A 5BV ' . ' ^°Ar vF / H H° l ^ V z\6A F \ / 6BQ -NNO^ o— o—Attorney Docket No.: COPA-058 / 01WO 337248-2468A 7Bo<3A 8B\"z1A 1 9BzQ ZZA 10B / OHo H Q A 11B°^T V AF / H Hf^jQ\xo' Y yF A N—112B N—^£A 13B xw V • °4 0T V XF1Attorney Docket No.: COPA-058 / 01WO 337248-2468H H JOQ>14A 14BF'*‘X / N—1N—'H H15A015BFxN—1N— ' / / H HfXXjQ15CX15DF N— ' / / H16A0r V / ^ox16BN—1O OHjXXjQX16C 16DFN-Jb Q>H F H F17A 17B°^r v .k F 7 'O'" 'b" H F H F17C 17D0F JK ^ 4 yO"

[0319] Table C. Various compounds of formula (II)Attorney Docket No.: COPA-058 / 01WO 337248-2468 Compound CompoundStructure Structure No. No.Hr^Sr-NH18 19N— ' \ H / ~-Z O> 0IO,NH[O>- 20 JOO r "N' 21 I C )1Q> f "N^'^ V .NHOo>ON KOlO> r 'N 22 N— ' 23 'H° 0 ° O / N>8H F H QJ24 25 JOIQ I / oHH Q AA rrvIO,N- / °x 26 IOO rN27 ObCM \ ? / NH H \z— \xo'>JOx / IP\?xOQ> M i0\ z\ z 28 N— ' 29 N— ' 0 0H H JP- 30 31 x JQO rNNN HN— 'H32 33Attorney Docket No.: COPA-058 / 01WO 337248-24681 z H H rZ — rZkjQ JX / NH35 J z — \HrrN KIHOJP'N-JOO rN37 . XM ? / ^H H« A 39 JOIQ?H V0— \71 N— / H. x» A 41 JOQ>s\ ,N.N— ' / HJxZzlQ / ’ rn>9> JO§>43-s'b V> N— ' / HH / OYA fXXjQxXM 45N— ' / Hf^jQ"°'X"'' V / -rox47 JOQ>XNQ^NJr"NJSNHH ZN]49xD& / H H N<>\m 51Attorney Docket No.: COPA-058 / 01WO 337248-2468H JOIQ?53bV / NX o—H_ HH055N— 'Hlj57N—1H F j^jQ J 590" HJ^JQ\ H N7=N 61Q po—63Hx xW ,cxJAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0320] Table D. Various compounds of formula (II)Compoun CompounStructure Structure dNo. dNo.H H00Q18A 18BN— ' 0 019A 19B \ H Cu> cOO0JP' K>N0J0 rNNH20A 20B K )O fN HsO SHrrvH-J rp^>N- JO21A JOO rN21B JQO fNS■ AH. JOQ> N— '22A 0 22B N— '°6° 00 ONfOTO> < -N JOO r N 23A >H23BuJ_NJH F H FjQjQ J J^0jQ J 24A 24B° “ oAttorney Docket No.: COPA-058 / 01WO 337248-2468Ho A 25B . m ?H A IO^N'N—KjO O JO A 26 NN~B NHoH0 A vOO 27BbO / N> H H° VA ^ '■■0 28B N-J OA 0 ■° 0Ho J00Q / A 29B N— '°o08 H Hf^XjQA 30BN— ‘ N— ‘ HxJ .OAOjA r JPN^ H |O A 3 ^ JQONH1BH Hr-Av-NA , ,&? 32B J00Q’ 'AAttorney Docket No.: COPA-058 / 01WO 337248-2468r H jP.N A 33BSW° \^ NrAA H 1Q,N—Hrr>' A 34B J0^>H H r"NA 35B JO^> r^NH''° \^ NHrA A J AQOA r JPN'N-rAr^\ JP-N-36B . JOQ> <^NoX^ ^""OH HO _ H HO A 37B ? "OH HA JOC5 38B .jm AH HA 39BO 11N—10 / V / N-- ’1 / A 40Bs4Hb^*HZ^NHOJW Ho.jOq> A 41BN— ' / / Attorney Docket No.: COPA-058 / 01WO 337248-2468H / 0>AlA 42B . JW A H Ho. OQ>A 43B0""< J N— N-J / / H / O>> JOOA 44B OM*H HfXXjQA ^^^CyOH 45B x XMN— ' / N—7 / H HC 45D °^^ V^...OH ' / / », / 7*^ / M-— ' N— ' / H HxjgoAXN'N N-746BNLQ^XNN-N ,N iCpJH Hf^XjQC '°^ VyyOx46D\.rN N-7''NA J'|JLQ^h / Ooo A ^ JOJ» ON47BXOQ> OAttorney Docket No.: COPA-058 / 01WO 337248-2468<NS fO'N1 zHH H rrAQf> z A 48BJz— ' XOTZ^*H FAxOo> ? 49B yz) . XM / \ZN. "■■O H HA 50B. jm AHr<vJ^jjQ J©N—A 51BN"■■OH Hf^[QA 52B<Ko— o— HA 53B ucxhb^ / N> ^ "■■0H HA .sXXQ V> 54B / N— ' " / ON-JAttorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468z 1 60A 60B .XXL Jz— ' / c / <0OTZ^O o—Nh j o ONH yz> t! N^X 61A JC» O 61B . VAA rN°^ \ A'"OH rA OSN—62AXX» O' 62B■"'OON ooA JC*N 63A AW O' 63B ^Sjyo ^^ V.N H64A ...0X ”MX / 64B\, N °^^ON

[0321] Table E. Various compounds of formula (III)Compound CompoundStructure Structure No. No.F F1 H 1 H O)|Q65 66FF X' \ / N—7N—1 /

[0322] Table F. Various compounds of formula (III)Compound CompoundStructure StructureNo. No.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0323] Table G. Various compounds of formula (IV)Compound CompoundStructure Structure No. No.1 H67 X zW 1 681 H F1 H r7:^Ar'N69 70HN— '

[0324] Table H. Various compounds of formula (IV)Compound CompoundStructure Structure No. No.1 H 1 H 67A , OQ> i 67B - XW i ° ’"'O ° X 'i 1 H i H68A . m V 68B"■■OAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0325] Table I. Various compounds of formula (V)Compound CompoundStructure Structure No. No.HHwF71 N—172FN—1° (5H H73 74F '''X / VAN-_YH H75 F 76N-— ' FN-J0 HC) HH77 78Fq-Po—Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0326] Table J. Various compounds of formula (V)Compound CompoundStructure Structure No. H No. H 71A 9 F ^ CMN-— ' 71B,0o0 H H72A CMF 72B CMN—1Attorney Docket No.: COPA-058 / 01WO 337248-2468H HA 73BF J X...Q VAN-JHNVHN^irH HOo> A 74B F ,,..0H H CM A F 75BN—1^ ""0 0A 76BF M o N-7N— ' HO7HO7H H CM A F ''"M / 77B / ^\ N--7NC_J / —7NO^ o— o— H H^MA 78BF '"‘ x / FN-JN-JAttorney Docket No.: COPA-058 / 01WO 337248-2468H H79A F '"’ x / 79B F "-Q N-7o— o— H H80A 80B / N'-NH H81A 81B9^F AF"HO HN—7H H82A 82BFX"”<Z^7N-—7FN-—7 / / 83A Od> Y 83B Od>\ . | V Y Y . ^ N.F Y H H84A F 84AN—7N—7F F

[0327] Table K Various compounds of the present disclosureCompound CompoundStructure StructureNo. No.Attorney Docket No.: COPA-058 / 01WO 337248-2468HH0 xw85Cl\ z\ 86 XM V N— 'H H XVQ JOIQ87 88N— ' XM-N N—7HOZH H XXjQX 89 ,. XX , 90FN— ' / H91N—1 /

[0328] Table L. Various compounds of the present disclosureCompound CompoundStructure Structure No. No.H HOo> rVXjO85AClV Z\ 85BN—7N—7HO86A XX V 86B'■ 0Attorney Docket No.: COPA-058 / 01WO 337248-2468H H XXjQ87A 87BN-— ' N— ' HC> HOZH H88AClV z\ 88BXM-N N— \M--N N—7H H89A 89BjHjXXjQ90A 90B Br' y yFN—7N—7 / / H H91A 91B uOXN—7N-7 / /

[0329] Compositions

[0330] The present disclosure provides pharmaceutical compositions comprising at least one compound disclosed herein (e.g., of compound of formula (I), (II), (III), (IV), (V), or Tables A-L or pharmaceutically acceptable salt, deuterated versions, or stereoisomer thereof) and one or more pharmaceutically acceptable excipients.

[0331] The compounds provided herein (e.g., of compound of formula (I), (II), (III), (IV), (V), or Tables A-L or pharmaceutically acceptable salt, deuterated versions, or stereoisomer thereof) may be administered as compounds per se or may be formulated as pharmaceutical compositions. The pharmaceutical compositions may comprise one or more pharmaceuticallyAttorney Docket No.: COPA-058 / 01WO 337248-2468acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, and / or antioxidants.

[0332] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0333] Therapeutic Use

[0334] The disclosure further relates to compounds disclosed herein (e.g., of compound of formula (I), (II), (III), (IV), (V), or Tables A-L or pharmaceutically acceptable salt, deuterated versions, or stereoisomer thereof), or a pharmaceutical composition comprising at least one compound disclosed herein (e.g., of compound of formula (I), (II), (III), (IV), (V), or Tables A-L or pharmaceutically acceptable salt, deuterated versions, or stereoisomer thereof), for use in the treatment of a serotonin 5-HT2A receptor associated disease / disorder.

[0335] In embodiments, the compounds (e.g., of compound of formula (I), (II), (III), (IV), (V), or Tables A-L or pharmaceutically acceptable salt, deuterated versions, or stereoisomer thereof), may be used in the treatment of an anxiety disorder, attention deficit hyperactivity disorder (ADHD), depression (including treatment resistant depression), cluster headache, diminished drive, burn-out, bore-out, migraine, Parkinson's disease, schizophrenia, an eating disorder (including anorexia nervosa), psychotic disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar I disorder, bipolar II disorder, major depressive disorder, psychotic depression, delusional disorders, shared psychotic disorder, Shared paranoia disorder, brief psychotic disorder, paranoid personality disorder, schizoidAttorney Docket No.: COPA-058 / 01WO 337248-2468personality disorder, schizotypal personality disorder, social anxiety disorder, substance-induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

[0336] In embodiments, the 5-HT2A receptor associated disease or disorder is depression. In embodiments, the depression is treatment resistant depression.

[0337] In embodiments, the 5-HT2A receptor associated disease or disorder is an eating disorder. In embodiments, the eating disorder is anorexia nervosa.

[0338] In embodiments, the 5-HT2A receptor associated disease or disorder is an anxiety disorder.

[0339] In embodiments, the 5-HT2A receptor associated disease or disorder is bipolar I disorder.

[0340] In embodiments, the 5-HT2A receptor associated disease or disorder is bipolar II disorder.

[0341] In embodiments, the 5-HT2A receptor associated disease or disorder is major depressive disorder.

[0342] In embodiments, the 5-HT2A receptor associated disease or disorder is posttraumatic stress disorder (PTSD).EXAMPLES

[0343] The present disclosure is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the disclosure in any way.

[0344] In embodiments, compounds of the present disclosure can be synthesized using the following methods. General reaction conditions are given, and reaction products can be purified by generally known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0345] Example 1: Synthesis of (l?)-5-methoxy-3-((l-(oxetan-3-yl)pyrrolidin-2-yl jinethy I )- 1 / / -indole (25 A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0346] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0347] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0348] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0349] Step 2: Benzyl ( / ?)-2-(5-methoxy-l / / -indole-3-carbonyl)pyrrolidine-l-carboxylate

[0350] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0351] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0352] 1HNMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25Attorney Docket No.: COPA-058 / 01WO 337248-2468- 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0353] Step 3: (7?)-5-nietlioxy-3-prolyl-l / / -indole

[0354] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0355] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0356] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0357] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0358] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0359] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0360] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0361] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0362] Step 5: (l?)-5-methoxy-3-((l-(oxetan-3-yl)pyrrolidin-2-yl)methyl)-lZ7-indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0363] To a stirred solution of the product from step 4 above (70.0 mg, 1 Eq, 289 pmol) in dry THF (3.00 mL) atrtwas addedoxetan-3-one(31.2mg, 1.5 Eq, 433 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (184 mg, 3 Eq, 866 pmol) was added and the reaction mixture was left to stir for 72 h at rt. The reaction mixture was quenched with sat. aq NaHCCh (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80 % (3:1 EtOAcZEtOH + 2% NH4OH) in / .w-hexane) to afford (A)-5-methoxy-3-((l-(oxetan-3-yl)pyrrolidin-2-yl)methyl)-l / 7-indole (41.3 mg, 139 pmol, 48.0 %).

[0364] m / z 287.2 (M+H)+ (ES+ )

[0365] 'H NMR (500 MHz, DMSO) 5 10.61 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 4.65 - 4.57 (m, 3H), 4.54 (t, J = 6.6 Hz, 1H), 3.99 (p, J = 6.9 Hz, 1H), 3.75 (s, 3H), 2.99 - 2.93 (m, 1H), 2.77 - 2.69 (m, 2H), 2.49 - 2.42 (m, 1H), 2.37 (q, J = 7.9 Hz, 1H), 1.73 - 1.55 (m, 3H), 1.54 - 1.42 (m, 1H).

[0366] Example 2: Synthesis of ( / ?)-5-methoxy-3-(( l-(tetrahydro-2 / / -pyran-4-yl)pyrrolidin-2-yl)methyl)- 1 / / -indole (28B)STAB, THF

[0367] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0368] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in iso-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0369] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0370] Step 2: Benzyl (l?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0371] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / Ao-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0372] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0373] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0374] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0375] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0376] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0377] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0378] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0379] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / waterAttorney Docket No.: COPA-058 / 01WO 337248-2468(15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAc / EtOH + 2 % NFLOH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0380] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0381] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0382] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0383] Step 5: ( / ?)-5-methoxy-3-(( l-(tetr:iliydro-2 / / -pyr:iii-4-yl)pyrrolidin-2-yl)niethyl)-1 / / -indole

[0384] To a stirred solution of the product from step 4 above (70.0 mg, 1 Eq, 289 pmol) in dry THF (3.00 mL) at rt was added tetrahydro-4H-thiopyran-4-one 1,1-dioxide (64.2 mg, 1.5 Eq, 433 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (184 mg, 3 Eq, 866 pmol) was added and the reaction mixture left to stir for 72 h at rt. The reaction mixture was quenched with sat. aq. NaHCCh (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo.

[0385] The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80 % (1 :3 EtOHZEtOAc + 2% NH4OH) in / .w-hexane) to afford (RJ-5-methoxy-3-((l-(tetrahydro-2Z / -pyran-4-yl)pyrrolidin-2-yl)methyl)-l / / -indole (61.9 mg, 188 pmol, 65.2 %).

[0386] m / z 315.4 (M+H)+ (ES+ ); 313.5 (M-H)- (ES-)

[0387] 'H NMR (500 MHz, DMSO) 5 10.38 (s, IH), 7.22 (d, J = 8.7 Hz, IH), 7.06 (d, J = 2.4 Hz, IH), 6.98 (d, J = 2.4 Hz, IH), 6.72 (dd, J = 8.7, 2.4 Hz, IH), 3.95 - 3.86 (m, 2H), 3.76 (s, 3H), 3.32 (dtd, J = 21.2, 11.6, 2.2 Hz, 2H), 3.19 - 3.11 (m, IH), 2.91 - 2.78 (m, 3H), 2.62 -2.55 (m, IH), 2.53 (d, J = 9.3 Hz, IH), 1.80 - 1.71 (m, 2H), 1.71 - 1.57 (m, 4H), 1.57 - 1.45 (m, 2H).

[0388] Example 3: Synthesis of (l?)-4-(2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)tetr:ihydro-2 / / -thiopyran 1,1-dioxide (29B)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0389] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0390] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in iso-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0391] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0392] Step 2: benzyl ( / ?)-2-(5-methoxy-l / / -indole-3-carbonyl)pyrrolidine-l-carboxylate

[0393] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / / .w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0394] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0395] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25Attorney Docket No.: COPA-058 / 01WO 337248-2468- 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0396] Step 3: (7?)-5-nietlioxy-3-prolyl-l / / -indole

[0397] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0398] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0399] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0400] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0401] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0402] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0403] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0404] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0405] Step 5: ( / ?)-4-(2-((5-nielIioxy- 1 / / -indol-3-yl)met hyl)pyrrolidin- 1 -yl)let raliydro-2 / / -thiopyran-l .1 -diox ideAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0406] To a stirred solution of the product from step 4 above (70.0 mg, 1 Eq, 289 pmol) in dry THF (3.00 mL) at rt was added tetrahydro-4H-thiopyran-4-one 1,1-dioxide (64.2 mg, 1.5 Eq, 433 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (184 mg, 3 Eq, 866 pmol) was added and the reaction mixture left to stir for 72 h at rt. The reaction mixture was quenched with sat. aq. NaHCCh (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered and concentrated in vacuo.

[0407] The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80 % (1:3 EtOHZEtOAc + 2% NH4OH) in / .w-hexane) to afford (R)-4-(2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)tetrahydro-2H-thiopyran 1,1-dioxide (46.1 mg, 0.13 mmol, 44 %).

[0408] m / z 363.3(M+H)+ (ES+ ); 361.1(M-H)- (ES-)

[0409] 'H NMR (500 MHz, DMSO) 5 10.62 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.25 - 3.13 (m, 2H), 3.13 - 3.00 (m, 4H), 2.86 (dd, J = 14.2, 3.3 Hz, 1H), 2.81 (t, J = 8.0 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.45 (dd, J = 14.2, 9.8 Hz, 1H), 2.16 -2.03 (m, 3H), 2.03 - 1.92 (m, 1H), 1.71 - 1.56 (m, 3H), 1.54 - 1.43 (m, 1H).

[0410] Example 4: Synthesis of ( / ?)-3-((l-((l / / -pyrazol-5-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lZ / -indole (23 A)STAB, THF

[0411] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0412] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h.Attorney Docket No.: COPA-058 / 01WO 337248-2468The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0413] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0414] Step 2: Benzyl (l?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0415] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCOs (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0416] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0417] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0418] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0419] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0420] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0421] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0422] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0423] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in z.w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0424] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0425] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0426] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0427] Step 5: ( / ?)-3-(( l-(( l / / -pyr:izol- -yl)inetliyl)pyrrolidiii-2-yl)inethyl)- -niethoxy-1 / / -indole

[0428] To a stirred solution of the product from step 4 above (70.0 mg, 1 Eq, 289 pmol) in dry THF (3.00 mL) at rt was added lH-pyrazole-5-carbaldehyde (41.6 mg, 1.5 Eq, 433 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (184 mg, 3 Eq, 866 pmol) was added and the reaction mixture left to stir for 72 h at rt. The reaction mixture was quenched with sat. aq. NaHCCh (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80 % (1 :3 EtOHZEtOAc + 2% NH4OH) in z.w-hexane) to afford (A)-3-((l-((lZ / -pyrazol-5-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lZ7-indole (52.0 mg, 0.16 mmol, 57 %).

[0429] m / z 311.3(M+H)+ (ES+ ); 309.3(M-H)- (ES-)

[0430] 'H NMR (500 MHz, DMSO) 5 12.52 (s, IH) 10.59 (s, IH), 7.53 (s, IH), 7.19 (d, J = 8.7 Hz, IH), 7.09 (d, J = 2.3 Hz, IH), 6.95 (d, J = 2.4 Hz, IH), 6.69 (dd, J = 8.7, 2.5 Hz, IH), 6.17 (d, J = 2.0 Hz, IH), 4.01 (d, J = 13.7 Hz, IH), 3.75 (s, 3H), 3.55 (d, J = 13.6 Hz, IH), 3.02Attorney Docket No.: COPA-058 / 01WO 337248-2468(dd, J = 14.0, 3.7 Hz, 1H), 2.89 (t, J = 8.0 Hz, 1H), 2.70 (s, 1H), 2.47 (d, J = 9.5 Hz, 1H), 2.27 (d, J = 8.4 Hz, 1H), 1.70 - 1.60 (m, 1H), 1.60 - 1.50 (m, 2H), 1.50 - 1.41 (m, 1H).

[0431] Example 5: Synthesis of (l?)-5-methoxy-3-((l-((2-methyl-2H-l,2,3-triazol-4-yl)niethyl)pyrrolidin-2-yl)niethyl)-l / / -indole (26A)

[0432] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0433] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0434] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0435] Step 2: benzyl (7?)-2-(5-metho y-lH-indole-3-carbonyl)pyrrolidine-l-carbo ylate

[0436] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 gAttorney Docket No.: COPA-058 / 01WO 337248-2468cartridge, 0-70 % EtOAc / / .w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0437] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0438] 'HNMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0439] Step 3: (7?)-5-methoxy-3-prolyl-l / / -indole

[0440] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0441] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0442] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0443] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0444] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAc / EtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0445] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0446] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0447] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0448] Step 5: ( / ?)-5-methoxy-3-(( l-((2-niethyl-2 / / -1.2.3-triazol-4-yl)niethyl)pyrrolidin-2-yl )inethy I )- 1 / / -indole

[0449] To a stirred solution of the product from step 4 above (84.0 mg, 1 Eq, 237 pmol) in dry THF (3.00 mL) at rt was added 2-methyl-2H-l,2,3-triazole-4-carbaldehyde (33.3 mg, 1.2 Eq, 284 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (151 mg, 3 Eq, 711 pmol) was added and the reaction mixture left to stir for 20 h at rt. The reaction mixture was quenched with sat. aq. NaHCOs (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80 % (1:3 EtOHZEtOAc + 2% NH4OH) in / .w-hexane) to afford (R)-5-methoxy-3-((l-((2-methyl-2H-l,2,3-triazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (21.0 mg, 61 pmol, 26 %).

[0450] m / z 326.6(M+H)+ (ES+ )

[0451] 'H NMR (500 MHz, DMSO) 5 10.59 (s, IH), 7.62 (s, IH), 7.20 (d, J = 8.7 Hz, IH), 7.10 (d, J = 2.4 Hz, IH), 6.99 (d, J = 2.4 Hz, IH), 6.70 (dd, J = 8.7, 2.4 Hz, IH), 4.11 (s, 3H), 4.06 (d, J = 13.8 Hz, IH), 3.75 (s, 3H), 3.59 (d, J = 13.9 Hz, IH), 3.04 (dd, J = 14.1, 3.8 Hz, IH), 2.89 (t, J = 8.0 Hz, IH), 2.73 - 2.65 (m, IH), 2.53 (s, IH), 2.27 (d, J = 8.8 Hz, IH), 1.72 - 1.61 (m, IH), 1.61 - 1.51 (m, 2H), 1.51 - 1.42 (m, IH). One proton obscured by DMSO peak, observed in HSQC.

[0452] Example 6: Synthesis of (l?)-4-fluoro-3-((l-((5-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (73A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0453] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0454] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0455] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0456] Step 2: Benzyl (l?)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0457] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0458] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0459] m / z 367.0 (M+H)+ (ES+)

[0460] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0461] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0462] m / z 233.0 (M+H)+ (ES+)

[0463] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0464] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0465] m / z 219.2 (M+H)+ (ES+ )

[0466] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0467] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0468] Step 5: (R)-4-fluoro-3-((l-((5-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0469] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (60.0 mg, 1 Eq, 275 pmol) and 5-methyl-lH-pyrazole-3-carbaldehyde (45.4 mg, 1.5 Eq, 412 pmol) in THF (2.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (175 mg, 3 Eq, 825 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0470] The reaction was quenched with sat. aq. NaHCOs (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5Attorney Docket No.: COPA-058 / 01WO 337248-2468mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (43.0 mg, 0.13 mmol, 48 %, 96% Purity).

[0471] m / z 313.2 (M+H)+ (ES+ ); m / z 311.2 (M-H)- (ES-).

[0472] 'HNMR (500 MHz, DMSO) 5 1.44 - 1.71 (m, 4H), 2.16 (s, 4H), 2.56 - 2.73 (m, 2H), 2.87 (s, 1H), 3.18 (d, J = 13.9 Hz, 1H), 3.94 (d, J= 13.6 Hz, 1H), 5.89 (s, 1H), 6.69 (dd, J = 11.6, 7.7 Hz, 1H), 6.94 - 7.03 (m, 1H), 7.06 - 7.25 (m, 2H), 11.08 (s, 1H), 12.09 (s, 1H) - 1H under the water residual peak.

[0473] 19F NMR (471 MHz, DMSO) 5 -124.33.

[0474] Example 7: Synthesis of (R)-4-fluoro-3-((l-((l-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (78A)FO

[0475] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0476] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0477] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0478] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0479] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred atAttorney Docket No.: COPA-058 / 01WO 337248-2468the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0480] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0481] m / z 367.0 (M+H)+ (ES+)

[0482] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0483] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0484] m / z 233.0 (M+H)+ (ES+)

[0485] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0486] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0487] m / z 219.2 (M+H)+ (ES+ )Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0488] 'H NMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0489] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0490] Step 5: (R)-4-fluoro-3-((l-((l-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0491] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (60.0 mg, 1 Eq, 275 pmol) and l-methyl-lH-pyrazole-3-carbaldehyde (45.4 mg, 1.5 Eq, 412 pmol) in THF (2.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (175 mg, 3 Eq, 825 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0492] The reaction was quenched with sat. aq. NaHCOs (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford (59.0 mg, 0.19 mmol, 67 %, 98% Purity).

[0493] m / z 313.2 (M+H)+ (ES+ ); m / z 311.0 (M-H)- (ES-).

[0494] ‘HNMR (500 MHz, DMSO) 5 1.45 - 1.71 (m, 4H), 2.16 - 2.20 (m, 1H), 2.56 - 2.65 (m, 1H), 2.65 -2.75 (m, 1H), 2.84 - 2.92 (m, 1H), 3.19 (d, J= 13.6 Hz, 1H), 3.78 (s, 3H), 3.95 (d,J= 13.3 Hz, 1H), 6.10 (s, 1H), 6.69 (dd, J= 11.6, 7.7 Hz, 1H), 6.95 - 7.03 (m, 1H), 7.12 -7.18 (m, 2H), 7.56 (s, 1H), 11.08 (s, 1H). - 1H under water residual peak.

[0495] 19F NMR (471 MHz, DMSO) 5 -124.35.

[0496] Example 8: Synthesis of (R)-4-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)tetrahydro-2H-thiopyran 1,1-dioxide (71 A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0497] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0498] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0499] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0500] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0501] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0502] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0503] m / z 367.0 (M+H)+ (ES+)

[0504] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0505] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0506] m / z 233.0 (M+H)+ (ES+)

[0507] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0508] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0509] m / z 219.2 (M+H)+ (ES+ )

[0510] 1H NMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0511] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0512] Step 5: (R)-4-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)tetrahydro-2H-thiopyran 1,1-dioxide

[0513] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (60.0 mg, 1 Eq, 275 pmol) and tetrahydro-4H-thiopyran-4-one 1,1-dioxide (48.9 mg, 1.2 Eq, 330 pmol) in THF (2.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (175 mg, 3 Eq, 825 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0514] The reaction was quenched with sat. aq. NaHCCh (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5Attorney Docket No.: COPA-058 / 01WO 337248-2468mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (54.0 mg, 0.15 mmol, 55 %, 98% Purity).

[0515] m / z 351.2 (M+H)+ (ES+ ); m / z 349.2 (M-H)- (ES-)

[0516] ‘HNMR (500 MHz, DMSO) 5 1.47 - 1.72 (m, 4H), 1.91 - 2.13 (m, 4H), 2.53 - 2.60 (m, 1H), 2.78 - 2.84 (m, 1H), 2.98 - 3.05 (m, 2H), 3.05 - 3.13 (m, 4H), 3.15 - 3.24 (m, 1H), 6.69 (dd, J= 11.6, 7.7 Hz, 1H), 6.95 - 7.03 (m, 1H), 7.13 - 7.18 (m, 2H), 11.10 (s, 1H) - 1H under the DMSO residual peak.

[0517] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0518] Example 9: Synthesis of (R)-4-fluoro-3-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)methyl)-lH-indole (75 A)

[0519] Step 1: Benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0520] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0521] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0522] Step 2: Benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0523] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred atAttorney Docket No.: COPA-058 / 01WO 337248-2468the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0524] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0525] m / z 367.0 (M+H)+ (ES+)

[0526] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0527] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0528] m / z 233.0 (M+H)+ (ES+)

[0529] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0530] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0531] m / z 219.2 (M+H)+ (ES+ )Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0532] 'H NMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0533] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0534] Step 5: (R)-4-fluoro-3-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)methyl)-lH-indole

[0535] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (60.0 mg, 1 Eq, 275 pmol) and tetrahydro-4H-pyran-4-one (33.0 mg, 30.5 pL, 1.2 Eq, 330 pmol) in THF (2.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (175 mg, 3 Eq, 825 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0536] The reaction was quenched with sat. aq. NaHCOs (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (53.0 mg, 0.17 mmol, 62 %, 97% Purity).

[0537] m / z 303.2 (M+H)+ (ES+ ); m / z 301.2 (M-H)- (ES-).

[0538] ‘HNMR (500 MHz, DMSO) 5 1.40 - 1.78 (m, 8H), 2.50 - 2.57 (m, 2H), 2.76 - 2.88 (m, 1H), 2.95 - 3.02 (m, 1H), 3.05 - 3.17 (m, 1H), 3.23 - 3.31 (m, 2H), 3.84 - 3.93 (m, 2H), 6.68 (dd, J= 11.7, 7.7 Hz, 1H), 6.95 - 7.02 (m, 1H), 7.12 - 7.16 (m, 2H), 11.08 (s, 1H). - 1H under the DMSO residual peak.

[0539] 19F NMR (471 MHz, DMSO) 5 -124.43.

[0540] Example 10: Synthesis of (R)-4-fluoro-3-((l-((2-methyl-2H-l,2,3-triazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (80A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0541] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0542] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0543] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0544] Step 2: Benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0545] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0546] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0547] m / z 367.0 (M+H)+ (ES+)

[0548] Step 3: (l?)-4-fluoro-3-prolyl-lH-indole

[0549] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0550] m / z 233.0 (M+H)+ (ES+)

[0551] Step 4: (l?)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0552] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0553] m / z 219.2 (M+H)+ (ES+ )

[0554] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0555] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0556] Step 5: (l?)-4-fluoro-3-((l-((2-methyl-2H-l,2,3-triazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0557] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (60.0 mg, 1 Eq, 275 pmol) and 2-methyl-2H-l,2,3-triazole-4-carbaldehyde (36.6 mg, 1.2 Eq, 330 pmol) in THF (2.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (175 mg, 3 Eq, 825 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0558] The reaction was quenched with sat. aq. NaHCOs (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the prduct (41.0 mg, 0.13 mmol, 47 %, 99% Purity) as a colourless oil.

[0559] m / z 314.4 (M+H)+ (ES+ ); m / z 312.2 (M-H)- (ES-).

[0560] XH NMR (500 MHz, DMSO) 5 1.45 - 1.70 (m, 4H), 2.17 - 2.26 (m, 1H), 2.61 (dd, J= 13.7, 9.1 Hz, 1H), 2.67 - 2.76 (m, 1H), 2.87 (ddd, J= 9.5, 6.9, 2.6 Hz, 1H), 3.18 (dd, J= 13.7, 3.6 Hz, 1H), 3.46 (d, J= 13.8 Hz, 1H), 4.04 (d, J= 13.8 Hz, 1H), 4.09 (s, 3H), 6.69 (ddd, J= 11.6, 7.8, 0.8 Hz, 1H), 6.99 (td, J= 7.9, 5.1 Hz, 1H), 7.13 - 7.19 (m, 2H), 7.57 (s, 1H), 11.08 (s, 1H).

[0561] 19F NMR (471 MHz, DMSO) 5 -124.37.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0562] Example 11: Synthesis of (R)-4-fluoro-3-((l-((5-methoxypyrimidin-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (79A)

[0563] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0564] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0565] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0566] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0567] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0568] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column,Attorney Docket No.: COPA-058 / 01WO 337248-24680-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0569] m / z 367.0 (M+H)+ (ES+)

[0570] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0571] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0572] m / z 233.0 (M+H)+ (ES+)

[0573] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0574] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0575] m / z 219.2 (M+H)+ (ES+ )

[0576] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0577] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0578] Step 5: (R)-4-fluoro-3-((l-((5-methoxypyrimidin-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0579] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (35.0 mg, 1 Eq, 160 pmol) and 5-methoxypyrimidine-4-carbaldehyde (24.0 mg, 1.08 Eq, 174 pmol) in THF (1.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (102 mg, 3 Eq, 481 pmol) was added and the mixture was stirred at room temperature for 16 hours.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0580] The reaction was quenched with sat. aq. NaHCCh (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (33.0 mg, 96 pmol, 60 %, 99% Purity) as a light yellow oil.

[0581] m / z 341.2 (M+H)+ (ES+ ); m / z 339.2 (M-H)- (ES-).

[0582] ‘HNMR (500 MHz, DMSO) 5 1.44 - 1.53 (m, 1H), 1.54 - 1.60 (m, 2H), 1.62 - 1.73 (m, 1H), 2.29 - 2.36 (m, 1H), 2.59 (dd, J= 14.0, 9.3 Hz, 1H), 2.78 - 2.88 (m, 1H), 2.94 - 3.00 (m, 1H), 3.20 - 3.28 (m, 1H), 3.46 (d, J= 13.4 Hz, 1H), 3.93 (s, 3H), 4.23 (d, J= 13.4 Hz, 1H), 6.68 (dd, J= 11.6, 7.7 Hz, 1H), 6.96- 7.02 (m, 1H), 7.12 - 7.17 (m, 2H), 8.52 (s, 1H), 8.74 (s, 1H), 11.07 (s, 1H).

[0583] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0584] Example 12: Synthesis of (R)-4-fluoro-3-((l-((l-methyl-lH-pyrazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (74 A)

[0585] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0586] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0587] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0588] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylateAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0589] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0590] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0591] m / z 367.0 (M+H)+ (ES+)

[0592] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0593] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0594] m / z 233.0 (M+H)+ (ES+)

[0595] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0596] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) inAttorney Docket No.: COPA-058 / 01WO 337248-2468di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0597] m / z 219.2 (M+H)+ (ES+ )

[0598] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0599] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0600] Step 5: (R)-4-fluoro-3-((l-((l-methyl-lH-pyrazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0601] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (40.0 mg, 1 Eq, 183 pmol) and 1 -methyl- lH-pyrazole-4-carbaldehy de (30.3 mg, 1.5 Eq, 275 pmol) in THF (2.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (117 mg, 3 Eq, 550 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0602] The reaction was quenched with sat. aq. NaHCOs (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (35.0 mg, 0.11 mmol, 59 %, 97% Purity).

[0603] m / z 313.2 (M+H)+ (ES+ ); m / z 311.2 (M-H)- (ES-).

[0604] ‘HNMR (500 MHz, DMSO) 5 1.44 - 1.67 (m, 4H), 2.08 - 2.17 (m, 1H), 2.56 - 2.67 (m, 2H), 2.82- 2.89 (m, 1H), 3.17 (d, J= 11.1 Hz, 1H), 3.23 (d, J= 13.5 Hz, 1H), 3.78 (s, 3H), 3.85 (d, = 13.5 Hz, 1H), 6.69 (dd, J= 11.7, 7.8 Hz, 1H), 6.95 - 7.03 (m, 1H), 7.13 - 7.18 (m, 2H), 7.27 (s, 1H), 7.52 (s, 1H), 11.07 (s, 1H).

[0605] 19F NMR (471 MHz, DMSO) 5 -124.30.

[0606] Example 13: Synthesis of (R)-2-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol (76A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0607] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0608] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0609] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0610] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0611] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0612] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0613] m / z 367.0 (M+H)+ (ES+)

[0614] Step 3: (R)-4-fluoro-3-prolyl-lH-indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0615] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0616] m / z 233.0 (M+H)+ (ES+)

[0617] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0618] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0619] m / z 219.2 (M+H)+ (ES+ )

[0620] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0621] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0622] Step 5: methyl (R)-2-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)acetate

[0623] To a mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (83.0 mg, 1 Eq, 380 pmol) and cesium carbonate (186 mg, 1.5 Eq, 570 pmol) in THF (2.00 mL) was added methyl bromoacetate (87.3 mg, 52.6 pL, 1.5 Eq, 570 pmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL). The aqueous phase was further extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure.

[0624] The crude product was loaded onto a SCX resin cartridge and the cartridge was washed with MeOH (4 CV). The product was eluted with 0.7 M NH3 in MeOH (4 CV), the solvent wasAttorney Docket No.: COPA-058 / 01WO 337248-2468removed under pressure to afford the product (84.0 mg, 0.26 mmol, 68 %, 90% Purity) as a colourless oil.

[0625] m / z 291.0 (M+H)+ (ES+); m / z 289.0 (M-H)- (ES-).

[0626] 19F NMR (471 MHz, DMSO) 5 -124.63.

[0627] Step 6: (R)-2-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol

[0628] To a mixture of methyl (R)-2-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)acetate (83.0 mg, 1 Eq, 286 pmol) in 2-Methyltetrahydrofuran (2.00 mL) at 0 °C was added lithium aluminum hydride (32.5 mg, 357 pL, 2.40 molar, 3 Eq, 858 pmol) dropwise and the mixture was stirred at the same temperature for 30 min and then the mixture was stirred at room temperature for 45 min. The reaction mixture was cooled to 0 °C, diluted with THF (10 mL) and quenched with H2O (1.5 mL), 2.0 M NaOH (0.5 mL) and Na2SO4 (ca 2 g). The mixture was stirred for 10 min before it was filtered and the organic solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-90% (10% (0.7 M NH3 in MeOH) in dichloromethane) in di chloromethane, liquid load (dichloromethane)) to afford the product (43.0 mg, 0.16 mmol, 56 %, 98% Purity) as a colourless oil.

[0629] m / z 263.4 (M+H)+ (ES+ ); m / z 261.2 (M-H)- (ES-).

[0630] XH NMR (500 MHz, DMSO) 5 1.39 - 1.53 (m, 1H), 1.53 - 1.67 (m, 3H), 2.12 - 2.20 (m, 1H), 2.25 - 2.33 (m, 1H), 2.59 - 2.72 (m, 1H), 2.95 - 3.04 (m, 1H), 3.06 - 3.13 (m, 2H), 3.43 - 3.57 (m, 2H), 4.40 (s, 1H), 6.68 (dd, J= 11.6, 7.7 Hz, 1H), 6.95 - 7.03 (m, 1H), 7.12 -7.17 (m, 2H), 11.06 (s, 1H) - 1H under DMSO residual peak.

[0631] 19F NMR (471 MHz, DMSO) 5 -124.43.

[0632] Example 14: Synthesis of (l?)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (81B)F

[0633] Step 1: Benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylateAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0634] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0635] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0636] Step 2: Benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0637] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0638] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0639] m / z 367.0 (M+H)+ (ES+)

[0640] Step 3: (l?)-4-fluoro-3-prolyl-lH-indole

[0641] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity) .

[0642] m / z 233.0 (M+H)+ (ES+)

[0643] Step 4: (l?)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0644] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0645] m / z 219.2 (M+H)+ (ES+ )

[0646] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0647] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0648] Example 15: Synthesis of ( / ?)-5-methoxy-3-((l-((l-methyl-l / / -pyrazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-lZ / -indole (34A)

[0649] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0650] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in iso-Attorney Docket No.: COPA-058 / 01WO 337248-2468hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0651] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0652] Step 2: Benzyl ( / ?)-2-(5-niethoxy-l / / -indole-3-carbonyl)pyrrolidine-l-carboxylate

[0653] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCOs (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / Ao-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0654] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0655] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0656] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0657] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0658] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0659] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0660] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0661] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M inAttorney Docket No.: COPA-058 / 01WO 337248-2468THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in z.w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0662] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0663] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0664] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78.

[0665] Step 5: ( / )-5-met hoxy-3-(( 1 -(( 1 -methyl- 1 / / -pyrazol-4-yl)nielhyl)pyrrolidin-2-yl)methyl)-TH- indole

[0666] To a stirred solution of the product from step 4 above (50.0 mg, 1 Eq, 217 pmol) in dry THF (2.00 mL) at rt was added l-methyl-lH-pyrazole-4-carbaldehyde (28.7 mg, 1.2 Eq, 261 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (138 mg, 3 Eq, 651 pmol) was added and the reaction mixture left to stir for 20 h at rt. The reaction mixture was quenched with sat. aq. NaHCCh (3 mL) and left to stir for 20 min. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.

[0667] The crude product was purified by chromatography on silica gel (12 g cartridge, 0-60 % (1:3 EtOHZEtOAc + 2 % NH4OH) in z.w-hexane) to afford title compound (37.1 mg, 0.11 mmol, 50 %) as a colourless gum.

[0668] m / z 325.0(M+H)+ (ES+)

[0669] XH NMR (500 MHz, DMSO) 5 10.59 (s, IH), 7.55 (s, IH), 7.32 (s, IH), 7.20 (d, J = 8.7 Hz, IH), 7.09 (d, J = 2.1 Hz, IH), 6.94 (d, J = 2.5 Hz, IH), 6.69 (dd, J = 8.7, 2.4 Hz, IH), 3.87 (d, J = 13.5 Hz, IH), 3.79 (s, 3H), 3.75 (s, 3H), 3.32 (d, J = 13.6 Hz, IH), 3.02 (dd, J = 14.0, 3.7 Hz, IH), 2.90 - 2.84 (m, IH), 2.66 - 2.58 (m, IH), 2.54 - 2.46 (m, IH), 2.21 - 2.14 (m,Attorney Docket No.: COPA-058 / 01WO 337248-24681H), 1.70 - 1.61 (m, 1H), 1.61 - 1.40 (m, 3H). One proton obscured by DMSO peak, one proton obscured by H2O peak, both observed on HSQC.

[0670] Example 16: Synthesis of ( / ?)-5-methoxy-3-((l-((l-methyl-l / / -pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lZ / -indole (36A)

[0671] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0672] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0673] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0674] Step 2: benzyl (7?)-2-(5-methoxy-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0675] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0676] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0677] 'HNMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0678] Step 3: 7?-5-methoxy-3-prolyl-lH-indole

[0679] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0680] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0681] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0682] Step 4: ( / ?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0683] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0684] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0685] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0686] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column,Attorney Docket No.: COPA-058 / 01WO 337248-24684.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0687] Step 5: ( / ?)-5-methoxy-3-(( l-(( l-methyl-l / / -pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-TH- indole

[0688] To a stirred solution of the product from step 4 above (84.0 mg, 1 Eq, 237 pmol) in dry THF (3.00 mL) at rt was added l-methyl-lH-pyrazole-3-carbaldehyde (33.0 mg, 1.2 Eq, 284 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (151 mg, 3 Eq, 711 pmol) was added and the reaction mixture left to stir for 20 h at rt. The reaction mixture was quenched with sat. aq. NaHCOs (5 mL) and left to stir for 20 min. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.

[0689] The crude product was dissolved in 1.7 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 20% MeCN; 0.5-10.5 min, ramped from 20% MeCN to 50% MeCN; 10.5-10.6 min, ramped from 50% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a freeze-dryer.

[0690] The clean fractions were dissolved in MeCN and transferred into a vial before concentrating in vacuo to afford ( ’)-5-methoxy-3-(( l-(( l-methyl- l7 / -pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-U / -indole (34.2 mg, 103 pmol, 43.3 %).

[0691] m / z 325.4(M+H)+ (ES+)

[0692] 'H NMR (500 MHz, DMSO) 5 10.57 (s, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 3.94 (d, J = 13.4 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.46 (d, J = 13.4 Hz, 1H), 3.03 (dd, J = 13.9, 3.6 Hz, 1H), 2.92 - 2.86 (m, 1H), 2.73 - 2.65 (m, 1H), 2.49 - 2.43 (m, 1H), 2.30 -2.22 (m, 1H), 1.68 - 1.58 (m, 1H), 1.58 - 1.49 (m, 2H), 1.49 - 1.40 (m, 1H).

[0693] Example 17: Synthesis of ( / ?)-5-methoxy-3-((l-((5-methyl-l / / -pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lZ / -indole (38A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0694] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate (4235-103)

[0695] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in isohexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0696] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0697] Step 2: Benzyl (l?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0698] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / Ao-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0699] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0700] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25Attorney Docket No.: COPA-058 / 01WO 337248-2468- 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0701] Step 3: (7?)-5-nietlioxy-3-prolyl-l / / -indole

[0702] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0703] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0704] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0705] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0706] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0707] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0708] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0709] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0710] Step 5: ( / ?)-5-methoxy-3-(( l-((5-methyl-l / / -pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-TH- indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0711] To a stirred solution of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 237 pmol) in dry THF (3.00 mL) at rt was added 5-methyl-lH-pyrazole-3-carbaldehyde (33.0 mg, 1.2 Eq, 284 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (151 mg, 3 Eq, 711 pmol) was added and the reaction mixture left to stir for 20 h at rt. The reaction mixture was quenched with sat. aq. NaHCOs (5 mL) and left to stir for 20 min. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.

[0712] The crude product was dissolved in 1.7 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 20% MeCN; 0.5-10.5 min, ramped from 20% MeCN to 50% MeCN; 10.5-10.6 min, ramped from 50% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Freeze-dryer. The clean fractions were dissolved in MeCN and transferred into a vial before concentrating in vacuo to afford (R)-5-methoxy-3-((l-((5-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (31.1 mg, 92.3 pmol, 38.9 %) as a colourless foam.

[0713] m / z 325.3(M+H)+ (ES+)

[0714] ‘HNMR (500 MHz, DMSO) 5 12.15 (s, 1H), 10.58 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.69 (dd, J = 8.7, 2.5 Hz, 1H), 5.92 (s, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.75 (s, 3H), 3.47 (d, J = 13.6 Hz, 1H), 3.02 (dd, J = 14.1, 3.7 Hz, 1H), 2.92 - 2.85 (m, 1H), 2.69 (s, 1H), 2.48 - 2.43 (m, 1H), 2.33 - 2.22 (m, 1H), 2.17 (s, 3H), 1.69 - 1.49 (m, 3H), 1.49 - 1.38 (m, 1H).

[0715] Example 18: Synthesis of (l?)-5-methoxy-3-((l-((5-methoxypyrimidin-4-yl)methyl)pyrrolidin-2-yl)methyl)-l / / -indole. Formic Acid (42A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0716] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0717] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.

[0718] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0719] Step 2: Benzyl ( / ?)-2-(5-methoxy-l / / -indole-3-carbonyl)pyrrolidine-l-carboxylate

[0720] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0721] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0722] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0723] Step 3: ( / ?)-5-niethoxy-3-prolyl-l / / -indole

[0724] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0725] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0726] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0727] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0728] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0729] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0730] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0731] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0732] Step 5: (l?)-5-methoxy-3-((l-((5-methoxypyrimidin-4-yl)methyl)pyrrolidin-2-yl)methyl)- 1 / / -indole. Formic Acid

[0733] To a stirred solution of the product from step 4 above (50.0 mg, 0.990 Eq, 215 pmol) in dry THF (2.00 mL) at rt was added 5-methoxypyrimidine-4-carbaldehyde (30.0 mg, 1 Eq,Attorney Docket No.: COPA-058 / 01WO 337248-2468217 pmol). The reaction mixture was stirred for 1 h. Sodium triacetoxyhydroborate (138 mg, 3 Eq, 652 pmol) was added and the reaction mixture left to stir for 20 h at rt. The reaction mixture was quenched with sat. aq. NaHCCh (3 mL) and left to stir for 20 min. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.

[0734] The crude product was purified by chromatography on silica gel (12 g cartridge, 0-70% (1:3 EtOH / EtOAc + 2 % NH4OH) in z.w-hexane). The crude product was re-purified by chromatography on RP Flash C18 (12 g cartridge, 0-10% (MeCN + 0.1% formic acid) in (water + 0.1% formic acid)) to afford (R)-5-methoxy-3-((l-((5-methoxypyrimidin-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole, Formic Acid (16.4 mg, 39.6 pmol, 18.2 %).

[0735] m / z 353.2(M+H)+ (ES+)

[0736] ‘HNMR (500 MHz, DMSO) 5 10.59 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 4.22 (d, J = 13.5 Hz, 1H), 3.93 (s, 3H), 3.74 (s, 3H), 3.61 (d, J = 13.4 Hz, 1H), 3.06 (dd, J = 14.3, 3.7 Hz, 1H), 3.03 - 2.95 (m, 1H), 2.91 - 2.84 (m, 1H), 2.56 - 2.52 (m, 1H), 2.37 (q, J = 8.6 Hz, 1H), 1.74 - 1.62 (m, 1H), 1.62 - 1.52 (m, 2H), 1.50 - 1.40 (m, 1H). One exchangeable proton not observed.

[0737] Example 19: Synthesis of (R)-2-(2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol (37 A)

[0738] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate (4235-103)

[0739] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in iso-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0740] m / z 264.2 (M-Cl+MeOH)+(ES+)

[0741] Step 2: benzyl ( / ?)-2-(5-niethoxy-l / / -indole-3-carbonyl)pyrrolidine-l-carboxylate

[0742] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / Ao-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity).

[0743] m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-)

[0744] 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 - 2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0745] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0746] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %).

[0747] m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-)

[0748] 1H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0749] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0750] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / waterAttorney Docket No.: COPA-058 / 01WO 337248-2468(15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAc / EtOH + 2 % NFLOH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %).

[0751] m / z 231.2(M+H)+ (ES+ ); 229.2(M-H)- (ES-)

[0752] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 - 2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0753] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0754] Step 5: methyl ( / ?)-2-(2-((5-methoxy-l / / -indol-3-yl)methyl)pyrrolidin-l-yl)acetate

[0755] To a stirred solution of the product from step 4 above (70.0 mg, 1 Eq, 304 pmol) and cesium carbonate (198 mg, 2 Eq, 608 pmol) in dry THF (3.00 mL) at rt was added methyl 2-bromoacetate (43.2 pL, 1.5 Eq, 456 pmol). The reaction mixture was stirred for 18 h.

[0756] The reaction mixture was quenched with sat. aq. NaHCCh (5 mL). The resulting aqueous suspension was extracted with EtOAc (2 ^ 10 mL). The collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo.

[0757] The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NHi / MeOH) in DCM) to afford the sub-titled product (71.8 mg, 0.22 mmol, 73 %) as a colourless oil.

[0758] m / z 303.2(M+H)+ (ES+)

[0759] 'H NMR (500 MHz, DMSO) 5 10.60 (s, IH), 7.20 (d, J = 8.7 Hz, IH), 7.08 (d, J = 2.3 Hz, IH), 6.99 (d, J = 2.4 Hz, IH), 6.70 (dd, J = 8.7, 2.4 Hz, IH), 3.76 (s, 3H), 3.69 (d, J = 16.6 Hz, IH), 3.63 (s, 3H), 3.30 (d, J = 16.6 Hz, IH), 3.11 - 3.04 (m, IH), 2.94 (dd, J = 13.9, 3.9 Hz, IH), 2.91 - 2.84 (m, IH), 2.48 - 2.38 (m, 2H), 1.77 - 1.67 (m, IH), 1.67 - 1.56 (m, 2H), 1.52 - 1.42 (m, IH).

[0760] Step 6: ( / ?)-2-(2-((5-methoxy-l / / -indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol

[0761] To a stirred suspension of the product from step 5 above (71.8 mg, 1 Eq, 221 pmol) in dry 2-Methyltetrahydrofuran (3.00 mL) under a nitrogen atmosphere at 0 °C was added lithiumAttorney Docket No.: COPA-058 / 01WO 337248-2468aluminum hydride (2.4 M in THF) (460 pL, 2.40 molar, 5 Eq, 1.10 mmol). The reaction mixture was heated to 60 °C and stirred for 30 min.

[0762] The mixture was cooled to 0 °C and quenched with 3:1 THF / water mixture (4 mL). Na2SO4 (5 g) was added to the suspension and stirred at rt for 1 h. The suspension was filtered through celite, washing with EtOAc (100 mL). The filtrate was concentrated in vacuo.

[0763] The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7 M NHVMeOH) in DCM) to afford (R)-2-(2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol (30.9 mg, 0.11 mmol, 50 %) as a pale orange gum.

[0764] m / z 275.0(M+H)+ (ES+)

[0765] 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 4.41 (t, J = 5.4 Hz, 1H), 3.75 (s, 3H), 3.56 - 3.49 (m, 2H), 3.11 - 3.05 (m, 1H), 3.02 (dt, J = 12.0, 7.1 Hz, 1H), 2.95 (dd, J = 14.1, 3.5 Hz, 1H), 2.62 (s, 1H), 2.48 - 2.42 (m, 1H), 2.32 (dt, J = 12.1, 6.2 Hz, 1H), 2.16 (q, J = 8.5 Hz, 1H), 1.70 - 1.54 (m, 3H), 1.46 - 1.39 (m, 1H).

[0766] Example 20: Synthesis of (R)-4-fluoro-3-((l-((3-methoxypyridin-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (77A)

[0767] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0768] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0769] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0770] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0771] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.

[0772] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0773] m / z 367.0 (M+H)+ (ES+)

[0774] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0775] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0776] m / z 233.0 (M+H)+ (ES+)

[0777] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0778] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purifiedAttorney Docket No.: COPA-058 / 01WO 337248-2468by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0779] m / z 219.2 (M+H)+ (ES+ )

[0780] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0781] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0782] Step 5: (R)-4-fluoro-3-((l-((3-methoxypyridin-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0783] A mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (45.0 mg, 85% Wt, 1 Eq, 175 pmol) and 3-methoxyisonicotinaldehyde (31.0 mg, 1.29 Eq, 226 pmol) in THF (1.50 mL) was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (131 mg, 3.53 Eq, 618 pmol) was added and the mixture was stirred at room temperature for 16 hours.

[0784] The reaction was quenched with sat. aq. NaHCCh (10 mL) and the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-60% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product that did not meet the purity criteria, thus it was dissolved in 1.4 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min'1eluting with a 0.3% Ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min'1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 30% MeCN; 0.5-15.5 min, ramped from 30% MeCN to 60% MeCN; 15.5-15.6 min, ramped from 60% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Freeze-dryer to afford (R)-4-fluoro-3-((l-((3-methoxypyridin-4-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (9.00 mg, 26 pmol, 15 %, 99% Purity).

[0785] m / z 340.2 (M+H)+ (ES+).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0786] 'H NMR (500 MHz, DMSO) 5 1.50 - 1.75 (m, 2H), 2.09 - 2.18 (m, 1H), 2.62 (dd, J= 13.9, 9.1 Hz, 1H), 2.77 - 2.85 (m, 1H), 2.90 - 2.97 (m, 1H), 3.15 (dd, J = 14.0, 3.7 Hz, 1H), 3.44 (d, J = 15.5 Hz, 1H), 3.89 (s, 3H), 3.98 (d, J = 15.4 Hz, 1H), 6.68 (dd, J = 11.6, 7.8 Hz, 1H), 6.95 - 7.03 (m, 1H), 7.12 - 7.17 (m, 2H), 7.39 (d, J = 4.6 Hz, 1H), 8.18 (d, J = 4.7 Hz, 1H), 8.29 (s, 1H), 11.07 (s, 1H) - 2H under DMSO residual peak

[0787] 19F NMR (471 MHz, DMSO) 5 -124.40.

[0788] Example 21: Synthesis of (R)-4-fluoro-3-((l-propylpyrrolidin-2-yl)methyl)-lH-indole (72A)

[0789] Step 1: benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0790] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (1.90 g, 1 Eq, 7.62 mmol) in dry DCM (53.0 mL) under a nitrogen atmosphere at 0 °C was added oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) and catalytic DMF. The reaction mixture was stirred at 0 °C for 3 hours, oxalyl chloride (2.90 g, 2.00 mL, 3 Eq, 22.9 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then the solvent was removed under reduced pressure to afford the product (2.04 g, 7.62 mmol, 100 %, 100% Purity) as a yellow oil.

[0791] m / z 264.2 (M+MeOH-Cl+H)+ (ES+ )

[0792] Step 2: benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0793] To a stirred solution of 4-fluoro-lH-indole (2.00 g, 2 Eq, 14.8 mmol) in dry Toluene (100 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide (1.76 g, 4.93 mL, 3.00 molar, 2 Eq, 14.8 mmol) dropwise over 10 min and the mixture was stirred at the same temperature for 3 hours. Freshly synthesised benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.98 g, 1 Eq, 7.40 mmol) in Toluene (10.0 mL) was added dropwise to the stirring solution of the deprotonated indole and the reaction mixture was stirred at room temperature for 16 hours.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0794] The reaction mixture was quenched with sat. sodium bicarbonate (150 mL) at 0 °C and left to stir for 1 h, warming to room temperature. The two phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (40 g column, 0-70% EtOAc in hexanes, load (silica)) to afford the product (1.66 g, 4.0 mmol, 54 %, 88% Purity).

[0795] m / z 367.0 (M+H)+ (ES+)

[0796] Step 3: (R)-4-fluoro-3-prolyl-lH-indole

[0797] To a mixture of benzyl (R)-2-(4-fluoro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate (1.66 g, 88% Wt, 1 Eq, 3.99 mmol) in EtOH (25.0 mL) was added palladium on carbon (166 mg, 0.391 Eq, 1.56 mmol) and the mixture was placed under a 1 bar hydrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction was vented and purged with nitrogen. The mixture was filtered to remove the Pd and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-prolyl-lH-indole (0.920 g, 3.9 mmol, 98 %, 99% Purity).

[0798] m / z 233.0 (M+H)+ (ES+)

[0799] Step 4: (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0800] To a mixture of (R)-4-fluoro-3-prolyl-lH-indole (0.940 g, 1 Eq, 4.05 mmol) in 2-Methyltetrahydrofuran (13.5 mL) at 0 °C was added lithium aluminum hydride (2.4 M in THF) (614 mg, 6.75 mL, 2.40 molar, 4 Eq, 16.2 mmol) dropwise. After for 10 min, the reaction was stirred at 66 °C for 5 hours and then at room temperature for 12 hours. The mixture was cooled down to 0 °C, diluted with THF (20 mL) and water (0.5 mL), 2.0 M NaOH (0.5 mL) and water (1.5 mL) were added followed by Na2SO4 (ca 2 g). The mixture was stirred for 45 min and filtered. The filtrated was concentrated under reduced pressure and the crude product purified by flash chromatography on silica gel (12 g column, 0-100% (20% (0.7 M in MeOH) in di chloromethane) in dichloromethane, liquid load (dichloromethane)) to afford the product (430 mg, 1.9 mmol, 46 %, 94% Purity) after being triturated with MTBE.

[0801] m / z 219.2 (M+H)+ (ES+ )

[0802] ‘HNMR (500 MHz, DMSO) 5 1.26 - 1.37 (m, 1H), 1.52 - 1.73 (m, 3H), 2.65 - 2.80 (m, 2H), 2.81 - 2.91 (m, 2H), 3.19 - 3.26 (m, 1H), 6.64 - 6.70 (m, 1H), 6.95 - 7.01 (m, 1H), 7.14 (d, J= 8.3 Hz, 2H), 11.04 - 11.08 (m, 1H) - NH missing due to a fast solvent exchange

[0803] 19F NMR (471 MHz, DMSO) 5 -124.47.

[0804] Step 5: (R)-l-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)propan-l-oneAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0805] To a mixture of (R)-4-fluoro-3-(pyrrolidin-2-ylmethyl)-lH-indole (85.0 mg, 1 Eq, 389 pmol) and triethylamine (158 mg, 217 pL, 4 Eq, 1.56 mmol) in THF (4.00 mL) at 0 °C was added propionic anhydride (101 mg, 100 pL, 2 Eq, 779 pmol) and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL) and the mixture extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSCh, filtered and the solvent removed under reduced pressure to afford (R)-l-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)propan-l-one (111 mg, 0.36 mmol, 94 %, 90% Purity) as a brown oil. Product was taken to the next step without further purification.

[0806] m / z 340.2 (M+H)+ (ES+).

[0807] Step 6: (R)-4-fluoro-3-((l-propylpyrrolidin-2-yl)methyl)-lH-indole

[0808] To a mixture of (R)-l-(2-((4-fluoro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)propan-l-one (0.111 g, 1 Eq, 405 pmol) in 2-Methyltetrahydrofuran (4.00 mL) at 0 °C was added lithium aluminum hydride (61.4 mg, 674 pL, 2.40 molar, 4 Eq, 1.62 mmol) dropwise and the mixture was stirred at 66 °C for 2 hours. The mixture was cooled to 0 °C, diluted with THF (10 mL) and quenched with water (1.5 mL) and 2 M NaOH (0.5 mL) and Na2SO4. The mixture was stirred at that temperature for 10 min and filtered and washed with THF. The filtrate was concentrated under reduced pressure and the crude product was dissolved in 2 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min'1eluting with a 0.3% Ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min'1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 40% MeCN; 0.5-15.5 min, ramped from 40% MeCN to 70% MeCN; 15.5-15.6 min, ramped from 70% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Freeze-dryer. The sample was freeze dried and the residue was dissolved in dichloromethane (2 mL) and washed with water (2 mL). The organic phase was dried over MgSCh, filtered and the solvent removed under reduced pressure to afford (R)-4-fluoro-3-((l-propylpyrrolidin-2-yl)methyl)-lH-indole (28.0 mg, 0.10 mmol, 26 %, 97% Purity).

[0809] m / z 261.2 (M+H)+ (ES+).

[0810] 'H NMR (500 MHz, DMSO) 5 0.89 (t, J = 7.4 Hz, 3H), 1.38 - 1.68 (m, 4H), 2.03 -2.19 (m, 2H), 2.52 - 2.59 (m, 1H), 2.76 - 2.85 (m, 1H), 3.02 - 3.14 (m, 2H), 6.68 (dd, J= 11.6,Attorney Docket No.: COPA-058 / 01WO 337248-24687.8 Hz, 1H), 6.95 - 7.02 (m, 1H), 7.06 - 7.24 (m, 2H), 11.06 (s, 1H). 2H under the DMSO residual peak.

[0811] 19F NMR (471 MHz, DMSO) 5 -124.37.

[0812] Example 22: Synthesis of (l?)-5-chloro-3-((l-(oxetan-3-yl)pyrrolidin-2-yl)methyl)-IH-indole (27A)STAB, THF

[0813] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0814] To a stirred solution of ((benzyloxy)carbonyl)-£>-proline (1.70 g, 1 Eq, 6.83 mmol) in dry DCM (50 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride 2.60 g, 1.79 mL, 3 Eq, 20.5 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 2.5 h, concentrated in vacuo and the resulting crude suspended in z.w-hexane (3 x 20 mL), and concentrated in vacuo to afford sub-title compound (1.83 g, 6.5 mmol, 95%, 95% purity) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0815] Step 2: benzyl (l?)-2-(5-chloro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0816] To a stirred solution of 5-chloro-lH-indole (2.07 g, 2 Eq, 13.7 mmol) in dry Toluene (90 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (1.63 g, 4.55 mL, 3.00 molar, 2 Eq, 13.7 mmol) dropwise over 5 min. The reaction mixture was stirred at rt for 2.5 h, solution of product from step 1 above (1.83 g, 0.95 Eq, 6.49 mmol) in dry Toluene (10.0 mL) was added dropwise and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with sat. aq. NaHCCh (100 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL) and the collected organic layers were dried over MgSCh, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-75 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off toAttorney Docket No.: COPA-058 / 01WO 337248-2468afford sub-title compound (1.09 g, 2.85 mmol, 24 %, 100% Purity), m / z 383.00 (Cl37), 381.00 (Cl35) (M-H)- (ES’). 'H NMR (500 MHz, DMSO) 5 12.22 (s, 1H), 12.19 (s, 1H), 8.54 (d, J = 3.0 Hz, 1H), 8.50 (d, J = 3.0 Hz, 1H), 8.18 (s, 1H), 8.15 (s, OH), 7.54 - 7.49 (m, 2H), 7.40 -7.36 (m, 4H), 7.26 (td, J= 6.7, 3.5 Hz, 2H), 7.12 (t, J= 7.2 Hz, 1H), 7.07 - 6.98 (m, 4H), 5.24 - 5.13 (m, 2H), 5.11 - 5.02 (m, 2H), 5.01 - 4.86 (m, 2H), 3.58 - 3.47 (m, 4H), 2.35 (m, 2H), 1.93 - 1.79 (m, 6H). Product is present as a ~1:1 mixture of tautomers with the spectrum possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species.

[0817] Step 3: ( / ?)-5-chloro-3-prolyl-l / / -indole

[0818] To a solution of the product from step 2 above (1.09 g, 1 Eq, 2.85 mmol) in dry DCM (10.00 mL) under a nitrogen atmosphere at 0 °C was added BBn in heptane (2.14 g, 8.54 mL, 1.00 molar, 3 Eq, 8.54 mmol) drop-wise and the resulting suspension was stirred for 30 min then warmed to rt and stirred for a further 4 h. The solution was cooled down to 0 °C, a further 1 eq. of BBrs in heptane (0.71 g, 2.85 mL, 1.00 molar) added, and the reaction mixture then warmed to rt and left to stir overnight. MeOH (5 mL) was added drop-wise and the mixture was stirred for 30 min. The mixture was loaded onto a cartridge of Si-TsOH (ca 5.0 g) and washed with MeOH (3 x 10 mL). The product was eluted with 0.7 M NH3 in MeOH (4 x 10 mL) and concentrated under reduced pressure to sub-title compound (0.720 g, 2.8 mmol, 97 %, 95% Purity), m / z 251.2 (Cl37), 249.2 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 58.56 (d, J= 1.8 Hz, 1H), 8.15 (m, 1H), 7.54 (dd, J= 8.7, 1.7 Hz, 1H), 7.28 (m, 1H), 4.78 - 4.71 (m, 1H), 3.21 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.38 (q, J= 8.2 Hz, 1H), 1.90 - 1.82 (m, 1H), 1.82 - 1.72 (m, 2H). Note: 2 Exchangeable protons not observed.

[0819] Step 4: (7?)-5-chloro-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0820] To a stirred suspension of the product from step 3 (0.720 g, 95% Wt, 1 Eq, 2.75 mmol) in dry tetrahydrofuran (18.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlH4 in THF (546 mg, 6.00 mL, 2.40 molar, 5.24 Eq, 14.4 mmol). The reaction mixture was heated to 60 °C and stirred for 3 h. Following this, the reaction was cooled to 0 °C, diluted with TBME (15 mL) then water (0.32 mL) added followed by 2 M aq NaOH (0.32 mL), water (1.00 mL) and MgSCh. The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate was concentrated / / ? vacuo. The resulting product was dissolved in MeOH (ca 5 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHi / MeOH (3 x 10 mL) andAttorney Docket No.: COPA-058 / 01WO 337248-2468concentrated under reduced pressure to afford sub-title compound (0.324 g, 0.95 mmol, 35 %, 69% Purity), m / z 237.20 (Cl37), 235.20 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 10.98 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.04 (m, 1H), 3.22 - 3.15 (m, 1H), 2.91 - 2.83 (m, 1H), 2.68 (m, 2H), 1.76 - 1.61 (m, 2H), 1.61 - 1.51 (m, 3H), 1.32 - 1.21 (m, 1H). Exchangeable pyrrolidine NH not observed.

[0821] Step 5: (l?)-5-chloro-3-((l-(oxetan-3-yl)pyrrolidin-2-yl)methyl)-lH-indole

[0822] To a solution of the product from step 4 above (100 mg, 70% Wt, 1 Eq, 298 pmol) in dry THF (3.00 mL) at rt was added oxetan-3-one (32.9 mg, 29.3 pL, 98% Wt, 1.5 Eq, 447 pmol). The reaction mixture was stirred for 1.5 h, sodium triacetoxyborohydride (190 mg, 3 Eq, 895 pmol) added, and left to stir overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir for 1 h. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% (1:3 EtOHZEtOAc + 2% NH4OH) in iso-hexane) to afford sub-title compound (56.01 mg, 0.18 mmol, 59 %, 92% Purity) .

[0823] Further purification was achieved by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 10% MeCN; 0.5-10.5 min, ramped from 10% MeCN to 32.5% MeCN; 10.5-10.6 min, ramped from 32.5% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac, dissolved in DCM, treated with Aq. saturated sodium hydrogen carbonate solution, and the DCM layer passed through a phase separator to afford sub-title compound (26.51 mg, 90 pmol, 30 %, 99% Purity), m / z 293.20 (Cl37), 291.20 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 11.00 (s, 1H), 7.50 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.7, 2.0 Hz, 1H), 4.61 (t, J = 6.4 Hz, 2H), 4.57 (t, J = 6.3 Hz, 1H), 4.52 (t, J = 6.6 Hz, 1H), 3.98 (p, J = 6.9 Hz, 1H), 2.96 (t, J = 8.3 Hz, 1H), 2.78 - 2.68 (m, 2H), 2.48 - 2.44 (m, 1H), 2.37 (q, J = 8.0 Hz, 1H), 1.70 - 1.57 (m, 3H), 1.46 (m, 1H).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0824] The sample was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 15% Methanol (28 mMNHs), 85% CO2. The flow rate was 4 mL / min. The run time was 9.0 mins. Sample is racemic.

[0825] Example 23: Synthesis of (l?)-2-(2-((5-chloro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol (26A)STAB, THF

[0826] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0827] To a stirred solution of ((benzyloxy)carbonyl)-£>-proline (1.70 g, 1 Eq, 6.83 mmol) in dry DCM (50 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride 2.60 g, 1.79 mL, 3 Eq, 20.5 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 2.5 h, concentrated in vacuo and the resulting crude suspended in z.w-hexane (3 x 20 mL), and concentrated in vacuo to afford sub-title compound (1.83 g, 6.5 mmol, 95%, 95% purity) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0828] Step 2: benzyl (l?)-2-(5-chloro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0829] To a stirred solution of 5-chloro-lH-indole (2.07 g, 2 Eq, 13.7 mmol) in dry Toluene (90 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (1.63 g, 4.55 mL, 3.00 molar, 2 Eq, 13.7 mmol) dropwise over 5 min. The reaction mixture was stirred at rt for 2.5 h, solution of product from step 1 above (1.83 g, 0.95 Eq, 6.49 mmol) in dry Toluene (10.0 mL) was added dropwise and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with sat. aq. NaHCCh (100 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL) and the collected organic layers were dried over MgSCh, filtered and concentrated inAttorney Docket No.: COPA-058 / 01WO 337248-2468vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-75 % EtOAc / / .w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.09 g, 2.85 mmol, 24 %, 100% Purity), m / z 383.00 (Cl37), 381.00 (Cl35) (M-H)- (ES’). 'H NMR (500 MHz, DMSO) 5 12.22 (s, 1H), 12.19 (s, 1H), 8.54 (d, J = 3.0 Hz, 1H), 8.50 (d, J = 3.0 Hz, 1H), 8.18 (s, 1H), 8.15 (s, OH), 7.54 - 7.49 (m, 2H), 7.40 -7.36 (m, 4H), 7.26 (td, J= 6.7, 3.5 Hz, 2H), 7.12 (t, J= 7.2 Hz, 1H), 7.07 - 6.98 (m, 4H), 5.24 - 5.13 (m, 2H), 5.11 - 5.02 (m, 2H), 5.01 - 4.86 (m, 2H), 3.58 - 3.47 (m, 4H), 2.35 (m, 2H), 1.93 - 1.79 (m, 6H). Product is present as a ~1:1 mixture of tautomers with the spectrum possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species.

[0830] Step 3: ( / ?)-5-chloro-3-prolyl-l / / -indole

[0831] To a solution of the product from step 2 above (1.09 g, 1 Eq, 2.85 mmol) in dry DCM (10.00 mL) under a nitrogen atmosphere at 0 °C was added BBr? in heptane (2.14 g, 8.54 mL, 1.00 molar, 3 Eq, 8.54 mmol) drop-wise and the resulting suspension was stirred for 30 min then warmed to rt and stirred for a further 4 h. The solution was cooled down to 0 °C, a further 1 eq. of BBrs in heptane (0.71 g, 2.85 mL, 1.00 molar) added, and the reaction mixture then warmed to rt and left to stir overnight. MeOH (5 mL) was added drop-wise and the mixture was stirred for 30 min. The mixture was loaded onto a cartridge of Si-TsOH (ca 5.0 g) and washed with MeOH (3 x 10 mL). The product was eluted with 0.7 M NH3 in MeOH (4 x 10 mL) and concentrated under reduced pressure to sub-title compound (0.720 g, 2.8 mmol, 97 %, 95% Purity), m / z 251.2 (Cl37), 249.2 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 58.56 (d, J= 1.8 Hz, 1H), 8.15 (m, 1H), 7.54 (dd, J= 8.7, 1.7 Hz, 1H), 7.28 (m, 1H), 4.78 - 4.71 (m, 1H), 3.21 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.38 (q, J= 8.2 Hz, 1H), 1.90 - 1.82 (m, 1H), 1.82 - 1.72 (m, 2H). 2 Exchangeable protons not observed.

[0832] The sample was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 15% Methanol (28 mMNHs), 85% CO2. The flow rate was 4 mL / min. The run time was 9.0 mins. Sample is racemic.

[0833] Step 4: (7?)-5-chloro-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0834] To a stirred suspension of the product from step 3 (0.720 g, 95% Wt, 1 Eq, 2.75 mmol) in dry tetrahydrofuran (18.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlH4 in THF (546 mg, 6.00 mL, 2.40 molar, 5.24 Eq, 14.4 mmol). The reaction mixture was heated toAttorney Docket No.: COPA-058 / 01WO 337248-246860 °C and stirred for 3 h. Following this, the reaction was cooled to 0 °C, diluted with TBME (15 mL) then water (0.32 mL) added followed by 2 M aq NaOH (0.32 mL), water (1.00 mL) and MgSCh. The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate was concentrated / / ? vacuo. The resulting product was dissolved in MeOH (ca 5 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHs / MeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (0.324 g, 0.95 mmol, 35 %, 69% Purity), m / z 237.20 (Cl37), 235.20 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 10.98 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.04 (m, 1H), 3.22 - 3.15 (m, 1H), 2.91 - 2.83 (m, 1H), 2.68 (m, 2H), 1.76 - 1.61 (m, 2H), 1.61 - 1.51 (m, 3H), 1.32 - 1.21 (m, 1H). Exchangeable pyrrolidine NH not observed.

[0835] Step 5: (l?)-2-(2-((5-chloro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol

[0836] To a solution of the product from step 4 above (100 mg, 70% Wt, 1 Eq, 298 pmol) in dry THF (3.00 mL) at rt was added 2-methyl-2H-l,2,3-triazole-4-carbaldehyde (33.1 mg, 1 Eq, 298 pmol). The reaction mixture was stirred for 1.5 h, sodium triacetoxyborohydride (190 mg, 3 Eq, 895 pmol) added, and then left to stir overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% (1:3 EtOHZEtOAc + 2% NH4OH) in iso-hexane) to afford sub-title compound (51.38 mg, 0.14 mmol, 47 %, 90% Purity) as an oil.

[0837] Further purification was achieved by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 32.5% MeCN; 0.5-10.5 min, ramped from 32.5% MeCN to 62.5% MeCN; 10.5-10.6 min, ramped from 62.5% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford sub-title compound (29.3 mg, 88 pmol, 29 %, 99% Purity). m / z 333.20 (Cl37), 330.20 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 10.98 (s, 1H),Attorney Docket No.: COPA-058 / 01WO 337248-24687.61 (s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.24 (s, 1H), 7.04 (dd, J = 8.6, 2.0 Hz, 1H), 4.14 (s, 3H), 4.04 (d, J = 14.0 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 3.05 (dd, J = 13.9, 3.7 Hz, 1H), 2.90 - 2.87 (m, 1H), 2.70 - 2.63 (m, 1H), 2.55 - 2.52 (m, 1H), 2.26 (q, J = 8.5 Hz, 1H), 1.66 - 1.39 (m, 4H).

[0838] Example 24: Synthesis of (R)-3-((l-((2H-l,2,3-triazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole (31 A)

[0839] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0840] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0841] Step 2: Benzyl (7?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0842] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 gAttorney Docket No.: COPA-058 / 01WO 337248-2468cartridge, 0-70 % EtOAc / / .w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). *HNMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0843] Step 3: (7?)-5-methoxy-3-prolyl-l / / -indole

[0844] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 1HNMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0845] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0846] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAc / EtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-).1H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0847] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %.

[0848] Step 5: (R)-3-((l-((2H-l,2,3-triazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole

[0849] A mixture of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 365 pmol) and in THF (2.00 mL) was stirred at room temperature for 30 min and sodium triacetoxyborohydride (232 mg, 3 Eq, 1.09 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with 0.7 M NH3 in MeOH (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-70% (10% (0.7 M NH3 in MeOH) in dichloromethane, in dichloromethane, liquid load (dichloromethane)), m / z 312.2(M+H)+ (ES+). 'HNMR (500 MHz, DMSO) 5 1.39 - 1.69 (m, 3H), 2.21 - 2.33 (m, IH), 2.67 - 2.78 (m, IH), 2.84 - 2.94 (m, IH), 2.99 - 3.07 (m, IH), 3.14 - 3.19 (m, 2H), 3.63 - 3.70 (m, IH), 3.76 (s, 3H), 4.09 (d, J = 14.1 Hz, IH), 6.69 (dd, J = 8.8, 2.4 Hz, IH), 6.98 (s, IH), 7.09 (s, IH), 7.19 (d, J= 8.7 Hz, IH), 7.68 (s, IH), 10.59 (s, IH) - NH triazole missing.

[0850] Example 25: Synthesis of (R)-3-((l-((lH-l,2,4-triazol-5-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole (33 A)

[0851] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0852] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h.Attorney Docket No.: COPA-058 / 01WO 337248-2468The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0853] Step 2: Benzyl (l?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0854] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCOs (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0855] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0856] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 'H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0857] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indoleAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0858] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-).1H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0859] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %.

[0860] Step 5: (R)-3-((l-((lH-l,2,4-triazol-5-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole

[0861] A mixture of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 365 pmol) and lH-l,2,4-triazole-5-carbaldehyde (42.5 mg, 1.2 Eq, 438 pmol) in THF was stirred at room temperature for 30 min and REACTANT was added and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with 0.7 M NH3 in MeOH (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-70% (10% (0.7 M NH3 in MeOH) in dichloromethane, in dichloromethane, liquid load (di chloromethane)) to afford (R)-3-((l-((lH-l,2,4-triazol-5-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole (55.0 mg, 0.16 mmol, 45 %, 92% Purity), m / z 312.1 (M+H)+ (ES+). 'HNMR (500 MHz, DMSO) 5 1.38 - 1.69 (m, 4H), 2.33 - 2.46 (m, 2H), 2.74 - 2.86 (m, IH), 2.88 - 2.98 (m, IH), 2.98 - 3.08 (m, IH), 3.71 - 3.84 (m, 4H), 4.00 - 4.14 (m, IH), 6.68 (dd, J = 8.7, 2.4 Hz, IH), 7.03 (s, IH), 7.09 (d, J = 2.1 Hz, IH), 7.19 (d, J= 8.7 Hz, IH), 7.88 (s, IH), 10.58 (s, IH), 13.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0862] Example 26: Synthesis of (R)-3-((l-((lH-pyrazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole (35A)

[0863] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0864] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0865] Step 2: Benzyl (7?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0866] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m,Attorney Docket No.: COPA-058 / 01WO 337248-24682H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0867] Step 3: (7?)-5-nietlioxy-3-prolyl-l / / -indole

[0868] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 'HNMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0869] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0870] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-).1H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0871] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0872] Step 5: (R)-3-((l-((lH-pyrazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy- IH-indole

[0873] A mixture of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 365 pmol) and lH-pyrazole-4-carbaldehyde (42.1 mg, 1.2 Eq, 438 pmol) in THF (2.00 mL) was stirred at room temperature for 30 min and sodium triacetoxyborohydride (232 mg, 3 Eq, 1.09 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with 0.7 M NH3 in MeOH (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-70% (10% (0.7 M NH3 in MeOH) in di chloromethane, in dichloromethane, liquid load (dichloromethane)) to afford (R)-3-((l-((lH-pyrazol-4-yl)methyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole (36.0 mg, 0.11 mmol, 30 %, 94% Purity), m / z 311.1 (M+H)+ (ES+). 'H NMR (500 MHz, DMSO) 5 1.40 - 1.70 (m, 4H), 2.13 - 2.26 (m, 1H), 2.58 - 2.73 (m, 1H), 2.82 - 2.96 (m, 1H), 3.04 (d, J= 13.8 Hz, 1H), 3.17 (d, J= 5.4 Hz, 1H), 3.38 (s, 1H), 3.75 (s, 3H), 3.92 (d, J= 13.5 Hz, 1H), 6.69 (dd, J= 8.7, 2.5 Hz, 1H), 6.93 (d, J= 2.4 Hz, 1H), 7.10 (s, 1H), 7.20 (d, J= 8.7 Hz, 1H), 7.39 - 7.64 (m, 2H), 10.60 (s, 1H) - NH pyrazole missing.

[0874] Example 27: Synthesis of (R)-5-methoxy-3-((l-((2-methoxypyridin-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (44A)

[0875] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0876] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in iso-Attorney Docket No.: COPA-058 / 01WO 337248-2468hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0877] Step 2: Benzyl (l?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0878] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCOs (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / Ao-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0879] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0880] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 'H NMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0881] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0882] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M inAttorney Docket No.: COPA-058 / 01WO 337248-2468THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-).1H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0883] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %.

[0884] Step 5: (R)-5-methoxy-3-((l-((2-methoxypyridin-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0885] A mixture of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 365 pmol) and 2-methoxynicotinaldehyde (60.0 mg, 1.2 Eq, 438 pmol) in THF (2.00 mL) was stirred at room temperature for 30 min and sodium triacetoxyborohydride (232 mg, 3 Eq, 1.09 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with 0.7 M NH3 in MeOH (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (4 g column, 0-70% (10% (0.7 M NH3 in MeOH) in di chloromethane, in dichloromethane, liquid load (dichloromethane)) to afford (R)-5-methoxy-3-((l-((2-methoxypyridin-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (43.0 mg, 0.12 mmol, 32 %, 96% Purity) as a colourless oil. m / z 352.1 (M+H)+ (ES+). 'HNMR (500 MHz, DMSO) 5 1.45 - 1.67 (m, 3H), 1.68 - 1.79 (m, IH), 2.12 -2.21 (m, IH), 2.56 (dd, J = 14.2, 9.0 Hz, IH), 2.74 -2.83 (m, IH), 2.85 - 2.96 (m, IH), 3.02 (dd, J= 14.1, 3.8 Hz, IH), 3.41 (d, J= 14.6 Hz, IH), 3.73 (s, 3H), 3.87 (s, 3H), 4.01 (d, J= 14.5 Hz, IH), 6.69 (dd, J= 8.7, 2.4 Hz, IH), 6.95 (d, J= 2.4 Hz, IH), 6.98 (dd, J= 7.2, 4.9 Hz, IH), 7.10 (d, J= 2.3 Hz, IH), 7.20 (d, J= 8.6 Hz, IH), 7.73 (dd, J= 7.3, 1.9 Hz, IH), 8.05 (dd, J= 4.8, 1.9 Hz, IH), 10.60 (s, IH).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0886] Example 28: Synthesis of (R)-3-((l-(2-Fluoroethyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole (49A)

[0887] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0888] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0889] Step 2: Benzyl (7?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0890] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4Attorney Docket No.: COPA-058 / 01WO 337248-2468(M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). ‘HNMR (500 MHz, DMSO) 5 1 E90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0891] Step 3: l?-5-Methoxy-3-prolyl-LH-indole

[0892] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 'HNMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0893] Step 4: ( / ?)-5-Methoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0894] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-). 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0895] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column,Attorney Docket No.: COPA-058 / 01WO 337248-24684.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %.

[0896] Step 5: Sodium 2-fluoroacetate

[0897] To a stirred solution of ethyl 2-fluoroacetate (500 mg, 455 pL, 1 Eq, 4.71 mmol) in EtOH (5.00 mL) at 0 °C was added NaOH (207 mg, 1.1 Eq, 5.18 mmol). The reaction mixture was stirred for 18 h, after which isohexane (30 mL) was added. The reaction was cooled to 0 °C and filtered to give the sub-title compound (391 mg, 3.9 mmol, 82 %).JH NMR (500 MHz, DMSO) 54.34 (d, J = 1.9 Hz, 1H), 4.24 (s, 1H).19F NMR (471 MHz, DMSO) 5 -210.70 - -210.82 (m)

[0898] Step 6: (R)-2-Fluoro-l-(2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-one

[0899] To a stirred solution of the product from step 4 above (200 mg, 93% Wt, 1 Eq, 808 pmol) in dry DCM (5.00 mL) under a nitrogen atmosphere was added HATU (461 mg, 1.5 Eq, 1.21 mmol), DIPEA (313 mg, 422 pL, 3 Eq, 2.42 mmol) and the product from step 5 above (121 mg, 1.5 Eq, 1.21 mmol). The reaction mixture was stirred over the weekend at rt. The reaction mixture was diluted DCM (20 mL), and the organic phase washed with IM HC1 (20 mL), sat. NaHCCh (20 mL) and brine (20 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% (2% NH4OH in 3:1 EtOAcZEtOH) in hexane) to afford the sub-title compound (168 mg, 0.50 mmol, 62 %). m / z 290.0 (M+H)+(ES+).

[0900] Step 7: (R)-3-((l-(2-Fluoroethyl)pyrrolidin-2-yl)methyl)-5-methoxy-lH-indole

[0901] To a stirred suspension of the product from step 6 above (168 mg, 87% Wt, 1 Eq, 503 pmol) in dry 2-Me-THF (5.00 mL) under a nitrogen atmosphere at 0 °C was added LiAlH4 (2.4 M in THF) (76.4 mg, 839 pL, 2.40 molar, 4 Eq, 2.01 mmol). The reaction mixture was heated to 60 °C and stirred for 1 h. The mixture was cooled to 0 °C and quenched with 3 : 1 THF / water mixture (4 mL). Na2SO4 (5 g) was added to the suspension and stirred at rt for 1 h. The suspension was filtered through celite, washing with EtOAc (-100 mL). The filtrate was filtered and concentrated / / ? vacuo. The crude material was dissolved in DMSO (1.9 mL), filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40Attorney Docket No.: COPA-058 / 01WO 337248-2468mL min-1 eluting with a 0.3 % ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 MeOH over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 22.5% MeCN; 0.5-15.5 min, ramped from 22.5% MeCN to 52.5 % MeCN; 15.5-15.6 min, ramped from 52.5 % MeCN to 100 % MeCN; 15.6-17.5 min, held at 100 % MeCN. The clean fractions were evaporated in a freeze-dryer. The fractions were re-concentrated in vacuo from MeCN to afford the title compound (11.5 mg, 38.9 pmol, 7.72 %) as an orange gum. m / z 277.0 (M+H)+(ES+); 275.0 (M-H)’ (ES-). 'H NMR (500 MHz, DMSO) 5 10.63 - 10.55 (m, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.55 -4.46 (m, 1H), 3.75 (s, 3H), 3.27 - 3.14 (m, 1H), 3.14 - 3.08 (m, 1H), 2.95 (dd, J = 14.2, 3.7 Hz, 1H), 2.68 (qd, J = 7.1, 3.5 Hz, 1H), 2.61 - 2.51 (m, 1H), 2.49 - 2.44 (m, 1H), 2.22 (q, J = 8.6 Hz, 1H), 1.72- 1.55 (m, 3H), 1.49- 1.42 (m, 1H).19F NMR (471 MHz, DMSO) 5 -217.52.

[0902] Example 29: Synthesis of (l?)-5-(methylthio)-3-((l-(oxetan-3-yl)pyrrolidin-2-yl)methyl)-lH-indole (27 A)

[0903] Step 1: tert-butyl (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0904] A solution of 5-methylthio-indole (4.17 g, 2 Eq, 24.8 mmol) in dry toluene (40.00 mL) at 0 °C was treated with MeMgBr in Et2O (2.96 g, 8.26 mL, 3.00 molar, 2 Eq, 24.8 mmol) and the mixture was stirred for 30 min before being warmed to rt and stirred for a further 30 min. Simultaneously, ((benzyloxy)carbonyl)-£>-proline (2.75 g, 1 Eq, 12.4 mmol) in DCM (40.00 mL) at rt was treated with l-chloro-A,A,2-trimethylprop-l-en-l -amine (1.82 g, 1.80 mL, 1.1 Eq, 13.6 mmol) and the resulting solution was stirred at rt for 45 min before being added dropwise to the solution of deprotonated indole. The reaction mixture was stirred at rt for 18 hAttorney Docket No.: COPA-058 / 01WO 337248-2468before the mixture was treated with sat. aq. NaHCCh solution (80mL). The aq. layer was extracted with EtOAc (3 x 75 mL) before the pooled organics were washed with brine (40 mL), dried (MgSCh) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / / .w-hexane) and the product then triturated from MTBE to afford the sub-title compound (1.06 g, 2.94 mmol, 24 %). m / z 260.82 (M+H-CO2 / Bu) (ES+)

[0905] 'H NMR 500 MHz, DMSO) 5 12.01 (s, 2H), 8.45 - 8.41 (m, 1H), 8.41 (m, 1H), 8.14 -8.11 (m, 1H), 8.11 - 8.08 (m, 1H), 7.45 - 7.43 (m, 1H), 7.44 - 7.42 (m, 1H), 7.21 - 7.18 (m, 1H), 7.19 - 7.17 (m, 1H), 5.10 (dd, J= 8.9, 3.7 Hz, 1H), 5.06 - 5.01 (m, 1H), 3.49 - 3.36 (m, 4H), 2.34 - 2.21 (m, 2H), 1.88 - 1.74 (m, 6H), 1.39 (s, 9H), 1.13 (s, 9H). Product is present as a ~1:1 mixture of tautomers with the spectra possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species. Due to overlap with residual DMSO peak, both tautomer’s SMe peaks are obscured.

[0906] Step 2: (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidin-l-ium

[0907] To a solution of the product from step 1 above (1.06 g, 1 Eq, 2.94 mmol) in DCM (30.0 mL) and MeOH at rt was added HC1 in IPA (1.07 g, 4.90 mL, 6.00 molar, 10 Eq, 29.4 mmol) dropwise. The reaction mixture was left to stir for 18 h and then concentrated in vacuo to afford sub-title compound (893 mg, 3.01 mmol, 102%). m / z 261.12 (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 12.51 - 12.47 (m, 1H), 8.58 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 5.06 (s, 1H), 3.29 (d, J= 11.1 Hz, 2H), 2.71 - 2.50 (m, 2H), 2.04 - 1.85 (m, 3H). SMe peak is not observed due to overlap with residual DMSO solvent peak.

[0908] Step 3: (l?)-5-(methylthio)-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0909] To a stirred suspension of the product from step 2 above (873 mg, 1 Eq, 2.94 mmol) in dry 2-methyltetrahydrofuran (30.00 mL) under a nitrogen atmosphere at 0 °C was added lithium aluminium hydride in THF (558 mg, 6.13 mL, 2.40 molar, 5 Eq, 14.7 mmol). The reaction mixture was heated to 60 °C and stirred for 5 hours. LCMS analysis indicated that all the starting material had been consumed but the reaction had stalled at the partially reduced indole.The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL) and water (1.5 mL). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate wasAttorney Docket No.: COPA-058 / 01WO 337248-2468concentrated in vacuo. The resulting product was dissolved in dry 2-Methyltetrahydrofuran (30.00 mL), cooled to 0 °C, and lithium aluminum hydride in THF (335 mg, 3.68 mL, 2.40 molar, 3 Eq, 8.82 mmol) added dropwise. The reaction mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL), water (1.5 mL), MgSCh (ca 2.0 g). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in MeOH (ca 10 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHVMeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (426.1 mg, 1.2 mmol, 45%, 72% Purity), m / z 247.00 (M+H)+. 'HNMR (500 MHz, DMSO) 5 10.83 (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 3.23 - 3.17 (m, 1H), 2.91 - 2.84 (m, 1H), 2.76 (dd, J = 14.2, 6.3 Hz, 1H), 2.72 - 2.64 (m, 2H), 2.45 (s, 3H), 1.77 - 1.52 (m, 4H), 1.34 - 1.22 (m, 1H).

[0910] Step 4: (l?)-5-(methylthio)-3-((l-(oxetan-3-yl)pyrrolidin-2-yl)methyl)-lH-indole

[0911] To a stirred solution of the product from step 3 above (84.0 mg, 72% Wt, 1 Eq, 245 pmol) in dry THF (3 mL) at rt was added oxetan-3-one (23.5 mg, 20.9 pL, 98% Wt, 1.3 Eq, 319 pmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyborohydride (156 mg, 3 Eq, 736 pmol) added, and then left to stir overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NHi / MeOH) in DCM) to afford sub-title compound (47.1 mg, 156 pmol, 63.4 %, 100% Purity), m / z 302.91 (M+H)+. 'HNMR (500 MHz, DMSO) 10.84 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 4.61 (dt, J = 16.0, 6.2 Hz, 3H), 4.53 (t, J = 6.6 Hz, 1H), 3.99 (p, J = 6.8 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.78 - 2.69 (m, 2H), 2.49 - 2.44 (m, 4H), 2.41 -2.33 (m, 1H), 1.72 - 1.57 (m, 3H), 1.52 - 1.42 (m, 1H).

[0912] Example 30: Synthesis of (l?)-4-(2-((5-(methylthio)-lH-indol-3-yl)methyl)pyrrolidin-l-yl)tetrahydro-2H-thiopyran 1,1-dioxide (22B)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0913] Step 1: / c / 7-butyl (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0914] A solution of 5-methylthio-indole (4.17 g, 2 Eq, 24.8 mmol) in dry toluene (40.00 mL) at 0 °C was treated with MeMgBr in Et2O (2.96 g, 8.26 mL, 3.00 molar, 2 Eq, 24.8 mmol) and the mixture was stirred for 30 min before being warmed to rt and stirred for a further 30 min. Simultaneously, ((benzyloxy)carbonyl)-£>-proline (2.75 g, 1 Eq, 12.4 mmol) in DCM (40.00 mL) at rt was treated with l-chloro-7V,7V,2-trimethylprop-l-en-l -amine (1.82 g, 1.80 mL, 1.1 Eq, 13.6 mmol) and the resulting solution was stirred at rt for 45 min before being added dropwise to the solution of deprotonated indole. The reaction mixture was stirred at rt for 18 h before the mixture was treated with sat. aq. NaHCCh solution (80mL). The aq. layer was extracted with EtOAc (3 x 75 mL) before the pooled organics were washed with brine (40 mL), dried (MgSCh) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / Ao-hexane) and the product then triturated from MTBE to afford the sub-title compound (1.06 g, 2.94 mmol, 24 %). m / z 260.82 (M+H-CO2 / Bu) (ES+). 'H NMR 500 MHz, DMSO) 5 12.01 (s, 2H), 8.45 - 8.41 (m, 1H), 8.41 (m, 1H), 8.14 - 8.11 (m, 1H), 8.11 - 8.08 (m, 1H), 7.45 - 7.43 (m, 1H), 7.44 - 7.42 (m, 1H), 7.21 - 7.18 (m, 1H), 7.19 - 7.17 (m, 1H), 5.10 (dd, J= 8.9, 3.7 Hz, 1H), 5.06 - 5.01 (m, 1H), 3.49 - 3.36 (m, 4H), 2.34 - 2.21 (m, 2H), 1.88 - 1.74 (m, 6H), 1.39 (s, 9H), 1.13 (s, 9H). Product is present as a ~1:1 mixture of tautomers with the spectra possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species. Due to overlap with residual DMSO peak, both tautomer’s SMe peaks are obscured.

[0915] Step 2: (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidin-l-iumAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0916] To a solution of the product from step 1 above (1.06 g, 1 Eq, 2.94 mmol) in DCM (30.0 mL) and MeOH at rt was added HC1 in IPA (1.07 g, 4.90 mL, 6.00 molar, 10 Eq, 29.4 mmol) dropwise. The reaction mixture was left to stir for 18 h and then concentrated in vacuo to afford sub-title compound (893 mg, 3.01 mmol, 102%). m / z 261.12 (M+H)+(ES+).JH NMR (500 MHz, DMSO) 5 12.51 - 12.47 (m, 1H), 8.58 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 5.06 (s, 1H), 3.29 (d, J= 11.1 Hz, 2H), 2.71 - 2.50 (m, 2H), 2.04 - 1.85 (m, 3H). SMe peak is not observed due to overlap with residual DMSO solvent peak.

[0917] Step 3: (l?)-5-(methylthio)-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0918] To a stirred suspension of the product from step 2 above (873 mg, 1 Eq, 2.94 mmol) in dry 2-methyltetrahydrofuran (30.00 mL) under a nitrogen atmosphere at 0 °C was added lithium aluminium hydride in THF (558 mg, 6.13 mL, 2.40 molar, 5 Eq, 14.7 mmol). The reaction mixture was heated to 60 °C and stirred for 5 hours. LCMS analysis indicated that all the starting material had been consumed but the reaction had stalled at the partially reduced indole.The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL) and water (1.5 mL). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in dry 2-Methyltetrahydrofuran (30.00 mL), cooled to 0 °C, and lithium aluminum hydride in THF (335 mg, 3.68 mL, 2.40 molar, 3 Eq, 8.82 mmol) added dropwise. The reaction mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL), water (1.5 mL), MgSO4 (ca 2.0 g). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in MeOH (ca 10 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHVMeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (426.1 mg, 1.2 mmol, 45%, 72% Purity), m / z 247.00 (M+H)+'H NMR (500 MHz, DMSO) 5 10.83 (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 3.23 - 3.17 (m, 1H), 2.91 - 2.84 (m, 1H), 2.76 (dd, J = 14.2, 6.3 Hz, 1H), 2.72 - 2.64 (m, 2H), 2.45 (s, 3H), 1.77 - 1.52 (m, 4H), 1.34 - 1.22 (m, 1H).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0919] Step 4: (l?)-4-(2-((5-(methylthio)-lH-indol-3-yl)methyl)pyrrolidin-l-yl)tetrahydro-2H-thio pyran 1 , 1-dioxide

[0920] To a stirred solution of the product from step 3 above (84.0 mg, 72% Wt, 1 Eq, 245 pmol) in dry THF (3 mL) atrt was added tetrahydro-4H-thiopyran-4-one 1, 1-dioxide (47.3 mg, 1.3 Eq, 319 pmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyhydroborate (156 mg, 3 Eq, 736 pmol) added, and left to stir overnight at rt. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NHVMeOH) in DCM) to afford sub-title compound (65.4 mg, 173 pmol, 70.4 %). m / z 379.28 (M+H)+ JH NMR (500 MHz, DMSO) 5 10.85 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.05 (dd, J = 8.5, 1.7 Hz, 1H), 3.24 - 3.13 (m, 2H), 3.12 - 3.00 (m, 4H), 2.88 (d, J = 14.2 Hz, 1H), 2.82 (d, J = 8.0 Hz, 1H), 2.58 - 2.53 (m, 1H), 2.46 (s, 3H), 2.16 - 2.02 (m, 3H), 2.02 - 1.88 (m, 2H), 1.67 - 1.56 (m, 3H), 1.52 - 1.45 (m, 1H).

[0921] Example 31: Synthesis of (R)-5-methoxy-3-((l-((4-methoxypyridin-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole, Formic Acid (47 A)

[0922] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0923] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in iso-Attorney Docket No.: COPA-058 / 01WO 337248-2468hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+)

[0924] Step 2: benzyl ( / ?)-2-(5-niethoxy-l / / -indole-3-carbonyl)pyrrolidine-l-carboxylate

[0925] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCOs (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / Ao-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4 (M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). 'H NMR (500 MHz, DMSO) 5 11.90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0926] Step 3: (7?)-5-niethoxy-3-prolyl-l / / -indole

[0927] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 1HNMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0928] Step 4: (7?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0929] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M inAttorney Docket No.: COPA-058 / 01WO 337248-2468THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-).1H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0930] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %

[0931] Step 5: (R)-5-methoxy-3-((l-((4-methoxypyridin-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole, Formic Acid

[0932] A mixture of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 365 pmol) and 4-methoxynicotinaldehyde (60.0 mg, 1.2 Eq, 438 pmol) in THF (2.00 mL) was stirred at room temperature for 30 min before sodium triacetoxyborohydride (232 mg, 3 Eq, 1.09 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with 0.7 M NH3 in MeOH (5 mL), filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography.

[0933] The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 5-50% (MeCN + 0.1% formic acid) in (water + 0.1% formic acid)) to afford (R)-5-methoxy-3-((l-((4-methoxypyridin-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole, Formic Acid (8.00 mg, 20 pmol, 5.5 %, 99% Purity) as a colourless oil. m / z 352.2 (M+H)+ (ES+). 'H NMR (500 MHz, DMSO) 5 1.41 - 1.64 (m, 2H), 1.66 - 1.77 (m, IH), 2.14 - 2.23 (m, IH), 2.56 (dd, J = 14.2, 8.8 Hz, IH), 2.73 - 2.80 (m, IH), 2.85 - 2.91 (m, IH), 3.04 (dd, J = 14.2, 3.7 Hz, IH), 3.24 - 3.40 (m, IH), 3.45 (d, J= 13.8 Hz, IH), 3.74 (s, 3H), 3.86 (s, 3H), 4.05 (d, J= 13.8 Hz,Attorney Docket No.: COPA-058 / 01WO 337248-24681H), 6.69 (dd, J= 8.7, 2.4 Hz, 1H), 6.97 (d, J= 2.4 Hz, 1H), 7.03 (d, J= 5.5 Hz, 1H), 7.10 (d, J= 2.2 Hz, 1H), 7.20 (d, J= 8.7 Hz, 1H), 8.29 - 8.47 (m, 2H), 10.60 (s, 1H).

[0934] Example 32: Synthesis of (R)-5-((2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)methyl)-lH-indazole, Formic Acid (48A)

[0935] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0936] To a stirred solution of ((benzyloxy)carbonyl)-D-proline (4.50 g, 1 Eq, 18.1 mmol) in dry DCM (125 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride (6.87 g, 4.74 mL, 3 Eq, 54.2 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the resulting crude suspended in z^o-hexane (3 x 30 mL), then concentrated in vacuo to afford sub-title compound (4.83 g, 18.0 mmol, 100%) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0937] Step 2: Benzyl (7?)-2-(5-methoxy-LH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0938] To a stirred solution of 5-methoxy-lH-indole (5.00 g, 2 Eq, 34.0 mmol) in dry Toluene (225 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (4.05 g, 11.3 mL, 3.00 molar, 2 Eq, 34.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 3 h. A solution of product from step 1 above (4.83 g, 1.06 Eq, 18.0 mmol) in dry Toluene (25.0 mL) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with sat. aq. NaHCCh (250 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL) and the collected organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-70 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.57 g, 4.1 mmol, 24 %, 99% Purity), m / z 401.4Attorney Docket No.: COPA-058 / 01WO 337248-2468(M+Na+H)+(ES+); 377.3 (M-H)’ (ES-). ‘HNMR (500 MHz, DMSO) 5 1 E90 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.42 - 7.35 (m, 3H), 7.35 - 7.12 (m, 1H), 7.11 - 7.00 (m, 2H), 6.89 - 6.82 (m, 1H), 5.25 - 5.14 (m, 1H), 5.07 (q, J = 12.8 Hz, 1H), 4.95 (q, J = 13.3 Hz, 1H), 3.78 (d, J = 5.2 Hz, 3H), 3.58 - 3.44 (m, 2H), 2.43 -2.26 (m, 1H), 1.95 - 1.78 (m, 3H).

[0939] Step 3: 7?-5-methoxy-3-prolyl-lH-indole

[0940] A stirred suspension of product from step 2 above (1.57 g, 1 Eq, 4.11 mmol) and Pd / C (87L) (353 mg, 5% Wt, 0.04 Eq, 166 pmol) in EtOH (20.0 mL) under a nitrogen atmosphere at rt was charged with Hydrogen (1 bar). The reaction mixture was stirred at rt for 19 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (200 mL). The solvent was removed in vacuo to afford sub-title compound (907 mg, 3.6 mmol, 89 %). m / z 245.2(M+H)+ (ES+ ); 243.2(M-H)- (ES-). 'HNMR (500 MHz, DMSO) 5 11.88 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 4.35 (dd, J = 8.5, 6.0 Hz, 1H), 3.78 (s, 3H), 3.05 (dt, J = 12.0, 6.0 Hz, 1H), 2.73 (dt, J = 10.5, 6.5 Hz, 1H), 2.26 - 2.05 (m, 1H), 1.77 - 1.67 (m, 1H), 1.67 - 1.52 (m, 2H). One exchangeable proton not observed.

[0941] Step 4: ( / ?)-5-niethoxy-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0942] To a stirred suspension of the product from step 3 above (907 mg, 1 Eq, 3.64 mmol) in dry 2-MeTHF (20.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlHi (2.4 M in THF) (6.96 mL, 2.40 molar, 4.59 Eq, 16.7 mmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and quenched with 3 : 1 THF / water (15 mL). Na2SO4(10 g) was added to the suspension and stirred atrtfor 15 min. The suspension was filtered through celite, washing with EtOAc (200 mL). The filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100 % (3 : 1 EtOAcZEtOH + 2 % NH4OH) in / .w-hexane) to afford the sub-title compound (742 mg, 2.79 mmol, 76 %). m / z 231 ,2(M+H)+ (ES+ ); 229.2(M-H)- (ES-). 'H NMR (500 MHz, DMSO) 5 10.59 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.21 (p, J = 6.8 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.79 -2.60 (m, 3H), 1.78 - 1.62 (m, 2H), 1.62 - 1.53 (m, 1H), 1.36 - 1.25 (m, 1H). One Exchangeable proton not observed.

[0943] The material was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column,Attorney Docket No.: COPA-058 / 01WO 337248-24684.6 x 250 mm, 5 pm, with mobile phase 20 % Methanol (28 mM NH3), 80 % CO2. The flow rate was 4 mL / min. The run time was 4.5 mins. EE of 97.78 %.

[0944] Step 5: (R)-5-((2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)methyl)-lH-indazole, Formic Acid

[0945] A mixture of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indole (84.0 mg, 1 Eq, 365 pmol) and lH-indazole-5-carbaldehyde (64.0 mg, 1.2 Eq, 438 pmol) in THF (2.00 mL) was stirred at room temperature for 30 min before sodium triacetoxyborohydride (232 mg, 3 Eq, 1.09 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with 0.7 M NH3 in MeOH (5 mL), filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography.

[0946] The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 5-50% (MeCN + 0.1% formic acid) in (water + 0.1% formic acid)) to afford (R)-5-((2-((5-methoxy-lH-indol-3-yl)methyl)pyrrolidin-l-yl)methyl)-lH-indazole, Formic Acid (22.0 mg, 52 pmol, 14 %, 96% Purity), m / z 361.3 (M+H)+ (ES+). 'H NMR (500 MHz, DMSO) 5 1.48 -1.68 (m, 3H), 1.71 - 1.81 (m, 1H), 2.23 - 2.32 (m, 1H), 2.61 (dd, J = 14.1, 9.2 Hz, 1H), 2.85 (s, 2H), 3.07 (dd, J = 14.0, 3.8 Hz, 1H), 3.48 (d, J = 12.9 Hz, 1H), 3.70 (s, 3H), 4.25 (d, J = 12.8 Hz, 1H), 6.69 (dd, J= 8.7, 2.4 Hz, 1H), 6.92 (d, = 2.4 Hz, 1H), 7.12 (d, J= 2.3 Hz, 1H), 7.20 (d, J= 8.7 Hz, 1H), 7.39 (d, J= 8.5 Hz, 1H), 7.49 (d, J= 8.6 Hz, 1H), 7.70 (s, 1H), 8.02 (s, 1H), 8.20 (s, 1H), 10.62 (s, 1H), 13.00 (s, 1H) - 1H extra due to salt formation with formic acid.

[0947] Example 33: Synthesis of methyl (l?)-2-(2-((5-chloro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)acetate (87A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0948] Step 1: Benzyl (l?)-2-(chlorocarbonyl)pyrrolidine-l-carboxylate

[0949] To a stirred solution of ((benzyloxy)carbonyl)-£>-proline (1.70 g, 1 Eq, 6.83 mmol) in dry DCM (50 mL) under a nitrogen atmosphere at 0 °C was added oxalyl dichloride 2.60 g, 1.79 mL, 3 Eq, 20.5 mmol) and catalytic DMF. The reaction mixture was stirred at rt for 2.5 h, concentrated in vacuo and the resulting crude suspended in z.w-hexane (3 x 20 mL), and concentrated in vacuo to afford sub-title compound (1.83 g, 6.5 mmol, 95%, 95% purity) as a pale-yellow oil. m / z 264.2 (M-Cl+MeOH)+(ES+).

[0950] Step 2: Benzyl (l?)-2-(5-chloro-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0951] To a stirred solution of 5-chloro-lH-indole (2.07 g, 2 Eq, 13.7 mmol) in dry Toluene (90 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr in diethyl ether (1.63 g, 4.55 mL, 3.00 molar, 2 Eq, 13.7 mmol) dropwise over 5 min. The reaction mixture was stirred at rt for 2.5 h, solution of product from step 1 above (1.83 g, 0.95 Eq, 6.49 mmol) in dry Toluene (10.0 mL) was added dropwise and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with sat. aq. NaHCCh (100 mL) at 0 °C and left to stir at rt for 30 min. The resulting suspension was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL) and the collected organic layers were dried over MgSCh, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-75 % EtOAc / z.w-hexane). The resulting product was triturated with MTBE and filtered off to afford sub-title compound (1.09 g, 2.85 mmol, 24 %, 100% Purity), m / z 383.00 (Cl37), 381.00 (Cl35) (M-H)- (ES’). 'H NMR (500 MHz, DMSO) 5 12.22 (s, 1H), 12.19 (s, 1H), 8.54 (d, J = 3.0 Hz, 1H), 8.50 (d, J = 3.0 Hz, 1H), 8.18 (s, 1H), 8.15 (s, OH), 7.54 - 7.49 (m, 2H), 7.40 -7.36 (m, 4H), 7.26 (td, J= 6.7, 3.5 Hz, 2H), 7.12 (t, J= 7.2 Hz, 1H), 7.07 - 6.98 (m, 4H), 5.24Attorney Docket No.: COPA-058 / 01WO 337248-2468- 5.13 (m, 2H), 5.11 - 5.02 (m, 2H), 5.01 - 4.86 (m, 2H), 3.58 - 3.47 (m, 4H), 2.35 (m, 2H), 1.93 - 1.79 (m, 6H). Product is present as a ~1:1 mixture of tautomers with the spectrum possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species.

[0952] Step 3: ( / ?)-5-chloro-3-prolyl-l / / -indole

[0953] To a solution of the product from step 2 above (1.09 g, 1 Eq, 2.85 mmol) in dry DCM (10.00 mL) under a nitrogen atmosphere at 0 °C was added BBn in heptane (2.14 g, 8.54 mL, 1.00 molar, 3 Eq, 8.54 mmol) drop-wise and the resulting suspension was stirred for 30 min then warmed to rt and stirred for a further 4 h. The solution was cooled down to 0 °C, a further 1 eq. of BBrs in heptane (0.71 g, 2.85 mL, 1.00 molar) added, and the reaction mixture then warmed to rt and left to stir overnight. MeOH (5 mL) was added drop-wise and the mixture was stirred for 30 min. The mixture was loaded onto a cartridge of Si-TsOH (ca 5.0 g) and washed with MeOH (3 x 10 mL). The product was eluted with 0.7 M NH3 in MeOH (4 x 10 mL) and concentrated under reduced pressure to sub-title compound (0.720 g, 2.8 mmol, 97 %, 95% Purity), m / z 251.2 (Cl37), 249.2 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 58.56 (d, J= 1.8 Hz, 1H), 8.15 (m, 1H), 7.54 (dd, J= 8.7, 1.7 Hz, 1H), 7.28 (m, 1H), 4.78 - 4.71 (m, 1H), 3.21 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.38 (q, J= 8.2 Hz, 1H), 1.90 - 1.82 (m, 1H), 1.82 - 1.72 (m, 2H). Note: 2 Exchangeable protons not observed.

[0954] The sample was dissolved in MeOH to 1 mg / mL and screened by SFC (Waters UPC2, with a PDA and a QDA detector). The optimal conditions are using a Chiralpak IH column, 4.6 x 250 mm, 5 pm, with mobile phase 15% Methanol (28 mMNHs), 85% CO2. The flow rate was 4 mL / min. The run time was 9.0 mins. Sample is racemic.

[0955] Step 4: (7?)-5-chloro-3-(pyrrolidin-2-ylmethyl)-l / / -indole

[0956] To a stirred suspension of the product from step 3 (0.720 g, 95% Wt, 1 Eq, 2.75 mmol) in dry tetrahydrofuran (18.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlH4 in THF (546 mg, 6.00 mL, 2.40 molar, 5.24 Eq, 14.4 mmol). The reaction mixture was heated to 60 °C and stirred for 3 h. Following this, the reaction was cooled to 0 °C, diluted with TBME (15 mL) then water (0.32 mL) added followed by 2 M aq NaOH (0.32 mL), water (1.00 mL) and MgSCh. The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate was concentrated / / ? vacuo. The resulting product was dissolved in MeOH (ca 5 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHi / MeOH (3 x 10 mL) andAttorney Docket No.: COPA-058 / 01WO 337248-2468concentrated under reduced pressure to afford sub-title compound (0.324 g, 0.95 mmol, 35 %, 69% Purity), m / z 237.20 (Cl37), 235.20 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 10.98 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.04 (m, 1H), 3.22 - 3.15 (m, 1H), 2.91 - 2.83 (m, 1H), 2.68 (m, 2H), 1.76 - 1.61 (m, 2H), 1.61 - 1.51 (m, 3H), 1.32 - 1.21 (m, 1H). Exchangeable pyrrolidine NH not observed.

[0957] Step 5: methyl (l?)-2-(2-((5-chloro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)acetate

[0958] To a solution of the product from step 4 above (94.0 mg, 69% Wt, 1 Eq, 276 pmol) and cesium carbonate (180 mg, 2 Eq, 553 pmol) in dry THF (3.00 mL) at rt was added methyl 2-bromoacetate (63.4 mg, 39.2 pL, 1.5 Eq, 414 pmol). The reaction mixture was stirred for 18 hours and then quenched with sat. sodium bicarbonate (5 mL). The resulting aqueous suspension was extracted with EtOAc (2 x 10 mL), the collected organic layers dried over MgSCh and concentrated in vacuo. The mixture was loaded onto a cartridge of Si-TsOH (ca 1.5 g) and washed with MeOH (3 x 10 mL). The product was eluted with 0.7 M NH3 in MeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (53.0 mg, 0.12 mmol, 43 %, 68% Purity) as a brown oil. m / z 309.01 (Cl37), 307. 12 (Cl35) (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 10.99 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 3.72 - 3.66 (m, 1H), 3.63 (s, 3H), 3.31 - 3.25 (m, 2H), 2.95 (dd, J = 14.0, 3.9 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.49 - 2.45 (m, 1H), 2.40 (q, J = 8.4 Hz, 1H), 1.74 - 1.56 (m, 3H), 1.49 - 1.40 (m, 1H).

[0959] Step 6: (l?)-2-(2-((5-chloro-lH-indol-3-yl)methyl)pyrrolidin-l-yl)ethan-l-ol

[0960] To a solution of the product from step 5 above (53.0 mg, 68% Wt, 1 Eq, 117 pmol) in 2-methyltetrahydrofuran (2.00 mL) at 0 °C was added lithium aluminium hydride (14 mg, 0.15 mL, 2.40 molar, 3.1 Eq, 0.36 mmol) dropwise. The mixture was stirred for 30 min, warmed to rt, and stirred for a further 45 minutes. The reaction mixture was cooled to 0 °C, diluted with THF (10 mL) and quenched with H2O (1.5 mL), 2.0 M NaOH (0.5 mL) and MgSCh (ca 2 g) added. The mixture was stirred for 10 min, filtered under gravity, then concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (12 g column, 0-90% (10% (0.7 M NH3 in MeOH) in dichloromethane) in dichloromethane) to afford sub-title compound (37.5 mg, 0.11 mmol, 95 %, 83% Purity) as a colourless oil.

[0961] Further purification was achieved by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector,Attorney Docket No.: COPA-058 / 01WO 337248-2468Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min'1eluting with a 0.3% Ammonia in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min'1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 27.5% MeCN; 0.5-10.5 min, ramped from 27.5% MeCN to 57.5% MeCN; 10.5-10.6 min, ramped from 57.5% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Freeze-dryer, to afford sub-title compound (4.95 mg, 17.8 pmol, 15.1 %, 100% Purity), m / z 281.09 (Cl37), 279.13 (Cl35) (M+H)+(ES+). ‘HNMR (500 MHz, DMSO) 5 10.99 (s, 1H), 7.53 - 7.49 (m, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.42 (t, J = 5.4 Hz, 1H), 3.59 - 3.47 (m, 2H), 3.10 - 3.04 (m, 1H), 3.04 - 2.92 (m, 2H), 2.49 - 2.44 (m, 1H), 2.31 (m, 1H), 2.20 - 2.11 (m, 1H), 1.68 - 1.53 (m, 3H), 1.44 - 1.34 (m, 1H). Exchangeable OH peak not observed.

[0962] Example 34: Synthesis of (l?)-5-(methylthio)-3-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)methyl)-lH-indole (21 A)

[0963] Step 1: tert-butyl (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0964] A solution of 5-methylthio-indole (4.17 g, 2 Eq, 24.8 mmol) in dry toluene (40.00 mL) at 0 °C was treated with MeMgBr in Et2O (2.96 g, 8.26 mL, 3.00 molar, 2 Eq, 24.8 mmol) and the mixture was stirred for 30 min before being warmed to rt and stirred for a further 30 min. Simultaneously, ((benzyloxy)carbonyl)-£>-proline (2.75 g, 1 Eq, 12.4 mmol) in DCM (40.00 mL) at rt was treated with 1 -chi oro-A,A,2-trimethylprop-l-en-l -amine (1.82 g, 1.80 mL, 1.1 Eq, 13.6 mmol) and the resulting solution was stirred at rt for 45 min before being addedAttorney Docket No.: COPA-058 / 01WO 337248-2468dropwise to the solution of deprotonated indole. The reaction mixture was stirred at rt for 18 h before the mixture was treated with sat. aq. NaHCCh solution (80mL). The aq. layer was extracted with EtOAc (3 x 75 mL) before the pooled organics were washed with brine (40 mL), dried (MgSCh) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / / .w-hexane) and the product then triturated from MTBE to afford the sub-title compound (1.06 g, 2.94 mmol, 24 %). m / z 260.82 (M+H-CO2 / Bu) (ES+). 'H NMR 500 MHz, DMSO) 5 12.01 (s, 2H), 8.45 - 8.41 (m, 1H), 8.41 (m, 1H), 8.14 - 8.11 (m, 1H), 8.11 - 8.08 (m, 1H), 7.45 - 7.43 (m, 1H), 7.44 - 7.42 (m, 1H), 7.21 - 7.18 (m, 1H), 7.19 - 7.17 (m, 1H), 5.10 (dd, J= 8.9, 3.7 Hz, 1H), 5.06 - 5.01 (m, 1H), 3.49 - 3.36 (m, 4H), 2.34 - 2.21 (m, 2H), 1.88 - 1.74 (m, 6H), 1.39 (s, 9H), 1.13 (s, 9H). Product is present as a ~1:1 mixture of tautomers with the spectra possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species. Due to overlap with residual DMSO peak, both tautomer’s SMe peaks are obscured.

[0965] Step 2: (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidin-l-ium

[0966] To a solution of the product from step 1 above (1.06 g, 1 Eq, 2.94 mmol) in DCM (30.0 mL) and MeOH at rt was added HC1 in IPA (1.07 g, 4.90 mL, 6.00 molar, 10 Eq, 29.4 mmol) dropwise. The reaction mixture was left to stir for 18 h and then concentrated in vacuo to afford sub-title compound (893 mg, 3.01 mmol, 102%). m / z 261.12 (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 12.51 - 12.47 (m, 1H), 8.58 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 5.06 (s, 1H), 3.29 (d, J= 11.1 Hz, 2H), 2.71 - 2.50 (m, 2H), 2.04 - 1.85 (m, 3H). SMe peak is not observed due to overlap with residual DMSO solvent peak.

[0967] Step 3: (l?)-5-(methylthio)-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0968] To a stirred suspension of the product from step 2 above (873 mg, 1 Eq, 2.94 mmol) in dry 2-methyltetrahydrofuran (30.00 mL) under a nitrogen atmosphere at 0 °C was added lithium aluminium hydride in THF (558 mg, 6.13 mL, 2.40 molar, 5 Eq, 14.7 mmol). The reaction mixture was heated to 60 °C and stirred for 5 hours. LCMS analysis indicated that all the starting material had been consumed but the reaction had stalled at the partially reduced indole.The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL) and water (1.5 mL). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate wasAttorney Docket No.: COPA-058 / 01WO 337248-2468concentrated in vacuo. The resulting product was dissolved in dry 2-Methyltetrahydrofuran (30.00 mL), cooled to 0 °C, and lithium aluminum hydride in THF (335 mg, 3.68 mL, 2.40 molar, 3 Eq, 8.82 mmol) added dropwise. The reaction mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL), water (1.5 mL), MgSCh (ca 2.0 g). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in MeOH (ca 10 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHVMeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (426.1 mg, 1.2 mmol, 45%, 72% Purity), m / z 247.00 (M+H)+'H NMR (500 MHz, DMSO) 5 10.83 (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 3.23 - 3.17 (m, 1H), 2.91 - 2.84 (m, 1H), 2.76 (dd, J = 14.2, 6.3 Hz, 1H), 2.72 - 2.64 (m, 2H), 2.45 (s, 3H), 1.77 - 1.52 (m, 4H), 1.34 - 1.22 (m, 1H).

[0969] Step 4: (l?)-5-(methylthio)-3-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)methyl)-lH-indole

[0970] To a stirred solution of the product from step 3 above (84.0 mg, 72% Wt, 1 Eq, 245 pmol) in dry THF (3 mL) atrt was added 2-methyl-2H-l,2,3-triazole-4-carbaldehyde (37.3 mg, 95% Wt, 1.3 Eq, 319 pmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyborohydride (156 mg, 3 Eq, 736 pmol) added, and then left to stir overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NHVMeOH) in DCM) to afford sub-title compound (52.9 mg, 0.15 mmol, 60 %, 95% Purity). m / z 341.97 (M+H)+ 1H NMR (500 MHz, DMSO) 5 10.84 (s, 1H), 7.61 (s, 1H), 7.52 (d, J= 1.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.07 (dd, J = 8.4, 1.8 Hz, lH), 4.14 (s, 3H), 4.05 (d, J = 13.9 Hz, 1H), 3.61 (d, J = 14.0 Hz, 1H), 3.07 (dd, J = 14.0, 3.8 Hz, 1H), 2.73 - 2.64 (m, 1H), 2.58 -2.48 (m, 2H), 2.46 (s, 3H), 2.31 - 2.22 (m, 1H), 1.71 - 1.42 (m, 4H).

[0971] Example 35: Synthesis of 5-Methoxy-3-(((2S)-4-methoxy-l-((l-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (46A)Attorney Docket No.: COPA-058 / 01WO 337248-2468BOC2O Mel Et3N Ag2O Ghosez DMAP MeMgBrHCIR-H°C

[0972] Step 1: l-(tert-Butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate

[0973] To a solution of methyl (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride (5.00 g, 1 Eq, 27.5 mmol) and Boc2O (7.21 g, 7.59 mL, 1.2 Eq, 33.0 mmol) in DCM (60.0 mL) was added drop-wise EtiN (6.13 g, 8.44 mL, 2.2 Eq, 60.6 mmol) followed by DMAP (336 mg, 0.1 Eq, 2.75 mmol) and the mixture was stirred at rt for 18 h. 10 wt% aq. Citric acid (50 mL) was added, the mixture was stirred for 15 min then the phases were separated and the aq. phase extracted with DCM (50 mL). The combined organics were washed with brine (50 mL), dried (MgSCh), filtered and concentrated in vacuo to afford the sub-title compound (6.71 g, 27 mmol, 98 %). 'H NMR (500 MHz, CDC13) 54.47 - 4.23 (m, 2H), 3.82 - 3.76 (m, 3H), 3.76 - 3.45 (m, 2H), 2.40 - 2.25 (m, 1H), 2.14 - 2.02 (m, 1H), 1.43 (app d, 9H). One exchangeable proton not observed.

[0974] Step 2: l-(tert-Butyl) 2-methyl (2R,4R)-4-methoxypyrrolidine-l,2-dicarboxylate

[0975] To a solution of the product from step 1 above (6.71 g, 1 Eq, 27.4 mmol) in MeCN (100.0 mL) were added Mel (11.6 g, 5.13 mL, 3 Eq, 82.1 mmol) and silver oxide (9.51 g, 1.5 Eq, 41.0 mmol). The mixture was stirred for 24 h then filtered through celite washing with MeCN (2 x 20 mL) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc in isohexane) to afford the subtitle compound (1.45 g, 5.3 mmol, 19 %) as a colourless oil. m / z 160.6 (M-Boc+H)+(ES+).JH NMR (500 MHz, CDC13) 54.45 - 4.37 (m, 0.4H), 4.30 (dd, J = 8.8, 4.0 Hz, 0.6H), 3.97 - 3.89 (m, 1H), 3.76 (d, J = 2.1 Hz, 5H), 3.72 (s, 52H), 3.65 (dd, J = 11.6, 5.5 Hz, 0.6H), 3.58 (dd, JAttorney Docket No.: COPA-058 / 01WO 337248-2468= 11.6, 5.4 Hz, 0.4H), 3.53 -3.43 (m, 1H), 3.27 (s, 3H), 2.39 -2.18 (m, 2H), 1.47 (s, 4H), 1.42 (s, 5H).

[0976] Step 3: (2R,4R)-l-(tert-Butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid

[0977] To a solution of the product from step 2 above (1.45 g, 1 Eq, 5.59 mmol) in THF (20.0 mL) was added a suspension of LiOH (670 mg, 5 Eq, 28.0 mmol) in water (2.00 mL) and the mixture was stirred at rt for 18 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (25 mL). The aq. phase was acidified to ph 1-2 by addition of 1 M aq. HC1 then extracted with EtOAc (3 x 25 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the sub-title compound (968 mg, 3.7 mmol, 67 %). 'HNMR (500 MHz, CDCh) 54.56 - 4.20 (m, 1H), 3.96 (s, 1H), 3.73 - 3.43 (m, 2H), 3.33 (s, 3H), 2.87 -2.63 (m, 0.5H), 2.34 (s, 1H), 2.17 -2.00 (m, 0.5H), 1.48 (s, 9H). Note: One exchangeable proton not observed.

[0978] Step 4: tert-Butyl (2R)-4-methoxy-2-(5-methoxy-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0979] To a stirred solution of 5-methoxy-lH-indole (1.16 g, 2.00 Eq, 7.88 mmol) in dry toluene (35.0 mL) under a nitrogen atmosphere at 0 °C was added MeMgBr (940 mg, 2.63 mL, 3.00 molar, 2.00 Eq, 7.88 mmol) dropwise over 5 min and left to stir. In a separate vial, the product from step 3 above (968 mg, 1 Eq, 3.95 mmol) dissolved in dry DCM (5.00 mL) under a nitrogen atmosphere was treated with 1 -chi oro-N,N,2-trimethylprop-l-en-l -amine (539 mg, 534 pL, 1.02 Eq, 4.04 mmol). After 30 minutes, the acid chloride solution was added dropwise to the stirring solution of the deprotonated indole at 0 °C. The reaction mixture was stirred for 18 h. The reaction mixture was quenched with sat. NaHCCh (50 mL) at 0 °C and left to stir for 1 h, warming to rt. The resulting suspension was extracted with EtOAc (3 x 50 mL) and the collected organic layers were dried (Na2SO4) and filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-100% (1:3 EtOH / EtOAc + 2% NH40H) in isohexane) to afford the sub-title compound (68.9 mg, 0.18 mmol, 4.5 %). m / z 274.9 (M-Boc+H)+(ES+); 373.2 (M-H)’ (ES-). 'H NMR (500 MHz, DMSO) 5 11.85 (s, 1H), 8.29 (d, J = 5.4 Hz, 1H), 7.69 (dd, J = 12.0, 2.6 Hz, 1H), 7.37 (dd, J = 8.8, 1.7 Hz, 1H), 6.85 (dt, J = 8.8, 2.4 Hz, 1H), 5.07 - 4.96 (m, 1H), 3.99 (p, J = 6.4 Hz, 1H), 3.80 -3.75 (m, 4H), 3.26 - 3.13 (m, 1H), 3.19 (s, 2H), 3.16 (s, 1H), 2.71 - 2.61 (m, 1H), 1.80 - 1.71 (m, 1H), 1.40 (s, 4H), 1.13 (s, 5H).

[0980] Step 5: (5-Methoxy-lH-indol-3-yl)(4-methoxypyrrolidin-2-yl)methanone, HC1Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0981] To a solution of the product from step 4 above (68.0 mg, 97% Wt, 1 Eq, 176 pmol) in DCM (2.50 mL) and MeOH (500 pL) at rt was added HC1 in IPA (65.6 mg, 300 pL, 6.00 molar, 10.2 Eq, 1.80 mmol) dropwise. The reaction mixture was left to stir for 18 h. The reaction mixture was concentrated in vacuo to afford the sub-title compound (65.6 mg, 0.19 mmol, 110 %). m / z 275.1 (M+H)+(ES+); 273.2 (M-H)’ (ES-), 'H NMR (500 MHz, DMSO) 5 12.31 (s, 1H), 9.87 (s, 1H), 8.79 (s, 1H), 8.42 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.92 (dd, J= 8.8, 2.5 Hz, 1H), 5.07 (dd, J = 10.5, 5.8 Hz, 1H), 4.13 (s, 1H), 3.80 (s, 3H), 3.48 (d, J= 19.1 Hz, 1H), 3.31 (d, J = 11.7 Hz, 1H), 3.16 (s, 3H), 2.84 (ddd, J = 15.3, 10.4, 5.4 Hz, 1H), 2.08 (d, J = 14.2 Hz, 1H).

[0982] Step 6: 5-Methoxy-3-(((2S)-4-methoxypyrrolidin-2-yl)methyl)-lH-indole

[0983] To a stirred suspension of the product from step 5 above (65.6 mg, 89% Wt, 1 Eq, 188 pmol) in dry 2-Me-THF (2.00 mL) under a nitrogen atmosphere at 0 °C was added LiAlH4 (2.4 M in THF) (28.5 mg, 313 pL, 2.40 molar, 4 Eq, 751 pmol). The reaction mixture was heated to 60 °C and stirred for 2.5 h. The mixture was cooled to 0 °C and quenched with 4: 1 THF / water mixture (10 mL). Na2SO4 (5 g) was added to the suspension and stirred at rt overnight. The suspension was filtered through celite, washing with EtOAc (-200 mL). The filtrate was filtered and concentrated in vacuo to afford a crude brown foam. The foam was triturated with MTBE to afford the sub-title compound (40.0 mg, 0.10 mmol, 54 %). m / z 261.3 (M+H)+(ES+).

[0984] Step 7: 5-methoxy-3-(((2S)-4-methoxy-l-((l-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole

[0985] To a stirred solution of the product from step 6 above (40.0 mg, 65% Wt, 1 Eq, 99.9 pmol) in dry THF (2.00 mL) at rt was added l-methyl-lH-pyrazole-3-carbaldehyde (17.4 mg, 95% Wt, 1.5 Eq, 150 pmol). The reaction mixture was stirred for 1 h. NaBH(OAc)s (63.5 mg, 3 Eq, 300 pmol) was added and the reaction mixture left to stir for 20 h at rt. The reaction mixture was quenched with sat. aq NaHCCh (5 mL) and left to stir for 20 min. The aq. suspension was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was dissolved in DMSO (1.4 mL), filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column,Attorney Docket No.: COPA-058 / 01WO 337248-2468130 , 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.3% ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 MeOH over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 15% MeCN; 0.5-15.5 min, ramped from 15% MeCN to 45% MeCN; 15.5-15.6 min, ramped from 45% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a freeze-dryer to the title compound (5.70 mg, 15 pmol, 15 %) as a gum. m / z 355.1 (M+H)+(ES+). 'HNMR (500 MHz, DMSO) 5 10.63 - 10.55 (m, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 6.14 (d, J = 2.0 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.70 - 3.63 (m, 1H), 3.44 (d, J = 13.5 Hz, 1H), 3.14 - 3.09 (m, 1H), 2.93 (d, J = 10.6 Hz, 1H), 2.70 -2.62 (m, 1H), 2.54 (dd, J= 13.9, 9.4 Hz, 1H), 2.39 (dd, J = 10.7, 6.2 Hz, 1H), 1.95 (dt, J = 13.9, 7.2 Hz, 1H), 1.44 (ddd, J = 12.9, 8.4, 4.0 Hz, 1H).

[0986] Example 36: Synthesis of (l?)-5-(methylthio)-3-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)methyl)-lH-indole (18B)

[0987] Step 1: tert-butyl (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0988] A solution of 5-methylthio-indole (4.17 g, 2 Eq, 24.8 mmol) in dry toluene (40.00 mL) at 0 °C was treated with MeMgBr in Et2O (2.96 g, 8.26 mL, 3.00 molar, 2 Eq, 24.8 mmol) and the mixture was stirred for 30 min before being warmed to rt and stirred for a further 30 min. Simultaneously, ((benzyloxy)carbonyl)-£>-proline (2.75 g, 1 Eq, 12.4 mmol) in DCM (40.00 mL) at rt was treated with l-chloro-A,A,2-trimethylprop-l-en-l -amine (1.82 g, 1.80 mL, 1.1 Eq, 13.6 mmol) and the resulting solution was stirred at rt for 45 min before being addedAttorney Docket No.: COPA-058 / 01WO 337248-2468dropwise to the solution of deprotonated indole. The reaction mixture was stirred at rt for 18 h before the mixture was treated with sat. aq. NaHCCh solution (80mL). The aq. layer was extracted with EtOAc (3 x 75 mL) before the pooled organics were washed with brine (40 mL), dried (MgSCh) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / / .w-hexane) and the product then triturated from MTBE to afford the sub-title compound (1.06 g, 2.94 mmol, 24 %). m / z 260.82 (M+H-CO2 / Bu) (ES+). 'H NMR 500 MHz, DMSO) 5 12.01 (s, 2H), 8.45 - 8.41 (m, 1H), 8.41 (m, 1H), 8.14 - 8.11 (m, 1H), 8.11 - 8.08 (m, 1H), 7.45 - 7.43 (m, 1H), 7.44 - 7.42 (m, 1H), 7.21 - 7.18 (m, 1H), 7.19 - 7.17 (m, 1H), 5.10 (dd, J= 8.9, 3.7 Hz, 1H), 5.06 - 5.01 (m, 1H), 3.49 - 3.36 (m, 4H), 2.34 - 2.21 (m, 2H), 1.88 - 1.74 (m, 6H), 1.39 (s, 9H), 1.13 (s, 9H). Product is present as a ~1:1 mixture of tautomers with the spectra possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species. Due to overlap with residual DMSO peak, both tautomer’s SMe peaks are obscured.

[0989] Step 2: (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidin-l-ium

[0990] To a solution of the product from step 1 above (1.06 g, 1 Eq, 2.94 mmol) in DCM (30.0 mL) and MeOH at rt was added HC1 in IPA (1.07 g, 4.90 mL, 6.00 molar, 10 Eq, 29.4 mmol) dropwise. The reaction mixture was left to stir for 18 h and then concentrated in vacuo to afford sub-title compound (893 mg, 3.01 mmol, 102%).m / z 261.12 (M+H)+(ES+). 'H NMR (500 MHz, DMSO) 5 12.51 - 12.47 (m, 1H), 8.58 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 5.06 (s, 1H), 3.29 (d, J= 11.1 Hz, 2H), 2.71 - 2.50 (m, 2H), 2.04 - 1.85 (m, 3H). SMe peak is not observed due to overlap with residual DMSO solvent peak.

[0991] Step 3: (l?)-5-(methylthio)-3-(pyrrolidin-2-ylmethyl)-lH-indole

[0992] To a stirred suspension of the product from step 2 above (873 mg, 1 Eq, 2.94 mmol) in dry 2-methyltetrahydrofuran (30.00 mL) under a nitrogen atmosphere at 0 °C was added lithium aluminium hydride in THF (558 mg, 6.13 mL, 2.40 molar, 5 Eq, 14.7 mmol). The reaction mixture was heated to 60 °C and stirred for 5 hours. LCMS analysis indicated that all the starting material had been consumed but the reaction had stalled at the partially reduced indole.The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL) and water (1.5 mL). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate wasAttorney Docket No.: COPA-058 / 01WO 337248-2468concentrated in vacuo. The resulting product was dissolved in dry 2-Methyltetrahydrofuran (30.00 mL), cooled to 0 °C, and lithium aluminium hydride in THF (335 mg, 3.68 mL, 2.40 molar, 3 Eq, 8.82 mmol) added dropwise. The reaction mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL), water (1.5 mL), MgSCh (ca 2.0 g). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in MeOH (ca 10 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHVMeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (426.1 mg, 1.2 mmol, 45%, 72% Purity), m / z 247.00 (M+H) 'H NMR (500 MHz, DMSO) 5 10.83 (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 3.23 - 3.17 (m, 1H), 2.91 - 2.84 (m, 1H), 2.76 (dd, J = 14.2, 6.3 Hz, 1H), 2.72 - 2.64 (m, 2H), 2.45 (s, 3H), 1.77 - 1.52 (m, 4H), 1.34 - 1.22 (m, 1H).

[0993] Step 4: (l?)-5-(methylthio)-3-((l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)methyl)-lH-indole

[0994] To a stirred solution of the product from step 3 above (84.0 mg, 72% Wt, 1 Eq, 245 pmol) in dry THF (3 mL) at rt was added tetrahydro-4H-pyran-4-one (32.6 mg, 30.1 pL, 98% Wt, 1.3 Eq, 319 pmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyborohydride (156 mg, 3 Eq, 736 pmol) added and then left to stir overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was first purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NHs / MeOH) in DCM), and then further purified by chromatography on C18 (13 g cartridge, 5-20% (MeCN + 0.1% formic acid) in (water + 0.1% formic acid)) to afford sub-title compound (20.4 mg, 61.7 pmol, 25.1 %, 100% Purity), m / z 331.18 (M+H)+*HNMR (500 MHz, DMSO) 5 10.83 (s, 1H), 7.43 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 3.89 (d, J = 11.4 Hz, 2H), 3.38 - 3.26 (m, 2H), 3.12 - 3.04 (m, 1H), 2.88 - 2.76 (m, 3H), 2.57 -2.46 (m, 5H), 1.83 - 1.71 (m, 2H), 1.66 - 1.55 (m, 4H), 1.52 - 1.43 (m, 2H).

[0995] Example 37: Synthesis of (l?)-3-((l-((lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-5-(methylthio)-lH-indole (20A)Attorney Docket No.: COPA-058 / 01WO 337248-2468

[0996] Step 1: / c / 7-butyl (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidine-l-carboxylate

[0997] A solution of 5-methylthio-indole (4.17 g, 2 Eq, 24.8 mmol) in dry toluene (40.00 mL) at 0 °C was treated with MeMgBr in Et2O (2.96 g, 8.26 mL, 3.00 molar, 2 Eq, 24.8 mmol) and the mixture was stirred for 30 min before being warmed to rt and stirred for a further 30 min. Simultaneously, ((benzyloxy)carbonyl)-£>-proline (2.75 g, 1 Eq, 12.4 mmol) in DCM (40.00 mL) at rt was treated with l-chloro-7V,7V,2-trimethylprop-l-en-l -amine (1.82 g, 1.80 mL, 1.1 Eq, 13.6 mmol) and the resulting solution was stirred at rt for 45 min before being added dropwise to the solution of deprotonated indole. The reaction mixture was stirred at rt for 18 h before the mixture was treated with sat. aq. NaHCCh solution (80mL). The aq. layer was extracted with EtOAc (3 x 75 mL) before the pooled organics were washed with brine (40 mL), dried (MgSCh) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-100% EtOAc / Ao-hexane) and the product then triturated from MTBE to afford the sub-title compound (1.06 g, 2.94 mmol, 24 %). m / z 260.82 (M+H-CO2 / Bu) (ES+) 'H NMR 500 MHz, DMSO) 5 12.01 (s, 2H), 8.45 - 8.41 (m, 1H), 8.41 (m, 1H), 8.14 - 8.11 (m, 1H), 8.11 - 8.08 (m, 1H), 7.45 - 7.43 (m, 1H), 7.44 - 7.42 (m, 1H), 7.21 - 7.18 (m, 1H), 7.19 - 7.17 (m, 1H), 5.10 (dd, J= 8.9, 3.7 Hz, 1H), 5.06 - 5.01 (m, 1H), 3.49 - 3.36 (m, 4H), 2.34 - 2.21 (m, 2H), 1.88 - 1.74 (m, 6H), 1.39 (s, 9H), 1.13 (s, 9H). Product is present as a ~1:1 mixture of tautomers with the spectra possessing multiple regions of overlapping. Therefore, spectrum has been quoted as a mixture of both species. Due to overlap with residual DMSO peak, both tautomer’s SMe peaks are obscured.

[0998] Step 2: (l?)-2-(5-(methylthio)-lH-indole-3-carbonyl)pyrrolidin-l-iumAttorney Docket No.: COPA-058 / 01WO 337248-2468

[0999] To a solution of the product from step 1 above (1.06 g, 1 Eq, 2.94 mmol) in DCM (30.0 mL) and MeOH at rt was added HC1 in IPA (1.07 g, 4.90 mL, 6.00 molar, 10 Eq, 29.4 mmol) dropwise. The reaction mixture was left to stir for 18 h and then concentrated in vacuo to afford sub-title compound (893 mg, 3.01 mmol, 102%). m / z 261.12 (M+H)+(ES+)JH NMR (500 MHz, DMSO) 5 12.51 - 12.47 (m, 1H), 8.58 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 5.06 (s, 1H), 3.29 (d, J= 11.1 Hz, 2H), 2.71 - 2.50 (m, 2H), 2.04 - 1.85 (m, 3H). SMe peak is not observed due to overlap with residual DMSO solvent peak.

[1000] Step 3: (l?)-5-(methylthio)-3-(pyrrolidin-2-ylmethyl)-lH-indole

[1001] To a stirred suspension of the product from step 2 above (873 mg, 1 Eq, 2.94 mmol) in dry 2-methyltetrahydrofuran (30.00 mL) under a nitrogen atmosphere at 0 °C was added lithium aluminium hydride in THF (558 mg, 6.13 mL, 2.40 molar, 5 Eq, 14.7 mmol). The reaction mixture was heated to 60 °C and stirred for 5 hours. LCMS analysis indicated that all the starting material had been consumed but the reaction had stalled at the partially reduced indole.The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL) and water (1.5 mL). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2 x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in dry 2-Methyltetrahydrofuran (30.00 mL), cooled to 0 °C, and lithium aluminium hydride in THF (335 mg, 3.68 mL, 2.40 molar, 3 Eq, 8.82 mmol) added dropwise. The reaction mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to 0 °C, diluted with TBME (15 mL) then water (0.5 mL) was added followed by 2 M aq. NaOH (0.5 mL), water (1.5 mL), MgSO4 (ca 2.0 g). The mixture was warmed to rt and stirred for 30 min then filtered washing with EtOAc (2x 10 mL) and the filtrate was concentrated in vacuo. The resulting product was dissolved in MeOH (ca 10 mL) and loaded onto a cartridge of Si-TsOH (ca 5 g) washing with MeOH (3 x 10 mL). The cartridge was eluted with 0.7 M NHVMeOH (3 x 10 mL) and concentrated under reduced pressure to afford sub-title compound (426.1 mg, 1.2 mmol, 45%, 72% Purity), m / z 247.00 (M+H)+'H NMR (500 MHz, DMSO) 5 10.83 (s, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 3.23 - 3.17 (m, 1H), 2.91 - 2.84 (m, 1H), 2.76 (dd, J = 14.2, 6.3 Hz, 1H), 2.72 - 2.64 (m, 2H), 2.45 (s, 3H), 1.77 - 1.52 (m, 4H), 1.34 - 1.22 (m, 1H).Attorney Docket No.: COPA-058 / 01WO 337248-2468

[1002] Step 4: (l?)-3-((l-((lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-5- (methylthio)-lH-indole

[1003] To a stirred solution of the product from step 3 above (84.0 mg, 72% Wt, 1 Eq, 245 pmol) in dry THF (3 mL) at rt was added lH-pyrazole-3-carbaldehyde (31.6 mg, 97% Wt, 1.30 Eq, 0.319 mmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyhydroborate (156 mg, 2.99 Eq, 0.735 mmol) added, and then left to stir overnight. The reaction mixture was quenched with sat. sodium bicarbonate solution (5 mL) and left to stir. The aqueous suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered and concentrated in vacuo. The crude product was first purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NHVMeOH) in DCM) and then further purified by chromatography on C18 (13 g cartridge, 5-20% (MeCN + 0.1% formic acid) in (water + 0.1% formic acid)) to afford sub-title compound (25.6 mg, 78 pmol, 32 %, 99% Purity), m / z 327.21 (M+H)+'H NMR (500 MHz, DMSO) 5 12.59 (s, 1H), 10.83 (s, 1H), 7.53 (s, 1H), 7.49 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.05 (dd, J = 8.4, 1.8 Hz, 1H), 6.17 (d, J= 1.9 Hz, 1H), 4.02 (d, J= 13.6 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H), 3.05 (dd, J = 14.1, 3.7 Hz, 1H), 2.92 - 2.84 (m, 1H), 2.69 - 2.65 (m, 1H), 2.56 - 2.50 (m, 1H), 2.48 (s, 3H), 2.31 -2.21 (m, 1H), 1.69 - 1.62 (m, 1H), 1.61 - 1.50 (m, 2H), 1.45 (m, 1H).

[1004] Example 38: Synthesis of (R)-4-Fluoro-5-methoxy-3-((l-((5-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indole (3 A)LiOH

[1005] Step 1: Benzyl (R)-2-(4-fluoro-5-methoxy-lH-indole-3-carbonyl)pyrrolidine-l-carboxylateAttorney Docket No.: COPA-058 / 01WO 337248-2468

[1006] To a solution of 4-fluoro-5-methoxy-lH-indole (1.00 g, 1.25 Eq, 6.05 mmol) in toluene (20.00 mL) cooled to 0 °C was added drop-wise MeMgBr in Et2O (753 mg, 2.10 mL, 3.00 molar, 1.3 Eq, 6.31 mmol). After 30 min the mixture was warmed to rt and stirred for a further 90 min. A solution of benzyl (R)-2-(chlorocarbonyl)pyrrolidine-l -carboxylate (1.30 g, 1 Eq, 4.86 mmol) in toluene (5.00 mL) was added drop-wise and stirring was continued for a further Ih. The mixture was poured into sat. aq. NELCl (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (MgSCh), filtered and concentrated in vacuo to afford a brown gum. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc in isohexane, eluted at 80%) to afford the sub-title compound, contaminated with benzyl 2-(3-(((benzyloxy)carbonyl)-D-prolyl)-4-fluoro-5-methoxy-lH-indole-l-carbonyl)pyrrolidine-l-carboxylate (1.29 g, 3.25 mmol, 67.0 %). This material was dissolved in THF (20.0 mL) and water (4.0 mL) to which was added LiOH (390 mg, 5 Eq, 16.3 mmol) and the mixture was stirred at rt for 5 h. The mixture was poured into sat. aq. NELCl (200 mL) and extracted with EtOAc (3 x 25 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc in isohexane, eluted at 80%) to afford the sub-title compound (576 mg, 1.2 mmol, 25 %). Note: yield calculated over 2 steps, m / z 397.3 (M+H)+(ES+).

[1007] Step 2: (R)-4-Fluoro-5-methoxy-3-prolyl-lH-indole

[1008] A stirred suspension of the product from step 1 above (576 mg, 83% Wt, 1 Eq, 1.21 mmol) and Pd / C (87L) (128 mg, 5% Wt, 0.05 Eq, 60.3 pmol) in EtOH (7.50 mL) under a nitrogen atmosphere at rt and the vessel was charged with Eb (2.44 mg, 1 Eq, 1.21 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (250 mL). The resulting product was redissolved in MeOH (7.00 mL) and Pd / C (87L) (128 mg, 5% Wt, 0.05 Eq, 60.3 pmol) was added. Under a nitrogen atmosphere at rt, the vessel was charged with Eb (2.44 mg, 1 Eq, 1.21 mmol). The reaction mixture was stirred at rt for 6 h. The reaction mixture was filtered through glass microfibres, rinsing with MeOH (150 mL). The solvent was removed in vacuo to afford the sub-title compound (360 mg, 1.2 mmol, 100 %). m / z 263.0(M+H)+(ES+); 261.2 (M-H)’ (ES-). 'HNMR (500 MHz, DMSO) 58.36 (s, IH), 7.22 (d, J = 8.8 Hz, IH), 7.12 (dd, J = 8.7, 7.3 Hz, IH), 4.41 (dd, J = 8.6, 6.0 Hz, IH), 3.83 (s, 3H), 3.04 (dt, J = 10.3, 6.1 Hz, IH), 2.73 (dt, J = 10.4, 6.6 Hz, IH), 2.19 -2.09 (m, IH), 1.77- 1.66 (m, IH), 1.66- 1.56 (m, 2H). 2 exchangeable protons not observed.19F NMR (471 MHz, DMSO) 5 -131.67.Attorney Docket No.: COPA-058 / 01WO 337248-2468

[1009] Step 3: (R)-4-Fluoro-5-methoxy-3-(pyrrolidin-2-ylmethyl)-lH-indol

[1010] To a stirred suspension of the product from step 2 above (360 mg, 90% Wt, 1 Eq, 1.24 mmol) in dry 2-Me-THF (10.0 mL) under a nitrogen atmosphere at 0 °C was added LiAlEU (2.4 M in THF) (188 mg, 2.06 mL, 2.40 molar, 4 Eq, 4.94 mmol). The reaction mixture was heated to 70 °C and stirred. The mixture was cooled to 0 °C and quenched with 4: 1 THF / water mixture (10 mL). Na2SO4 (10 g) was added to the suspension and stirred at rt for 1 h. The suspension was filtered through celite, washing with EtOAc (-200 mL). The filtrate was filtered and concentrated in vacuo to afford the sub-title compound (383 mg, 0.77 mmol, 62 %) as a crude brown oil. m / z 249.3 (M+H)+(ES+).

[1011] Step 4: (R)-4-Fluoro-5-methoxy-3-((l-((5-methyl-lH-pyrazol-3-yl)methyl)pyrrolidin-2-yl)methyl)-lH-indo

[1012] To a stirred solution of the product from step 3 above (80.0 mg, 50% Wt, 1 Eq, 161 pmol) in dry THF (2.00 mL) at rt was added 5-methyl-lH-pyrazole-3-carbaldehyde (22.4 mg, 95% Wt, 1.2 Eq, 193 pmol). The reaction mixture was stirred for 30 min. NaBH(OAc)s (102 mg, 3 Eq, 483 pmol) was added and the reaction mixture left to stir for 18h at rt. The reaction mixture was quenched with sat. aq. NaHCCh (5 mL) and left to stir for 20 min. The aq. suspension was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (Na2SO4), filtered...

Claims

Attorney Docket No.: COPA-058 / 01WO 337248-2468CLAIMS1. A compound of Formula (I):or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof wherein:R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;R2is -halo, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, -O-C1-6 alkyl, -OH, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=0)-CI-6 alkyl;R3is -halo, -O-C1-6 alkyl, -OH, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=0)-CI-6 alkyl;R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;n is 0, 1, 2, or 3;m is 0 or 1,and wherein, R2and R3are not both -halo.

2. The compound of claim 1, wherein R1is -C1-6 alkyl, cycloalkyl, -C1-6 alkylene-heteroaryl, or - heterocyclyl, wherein the heteroaryl is optionally substituted with -C1-6 alkyl and the -C1-6 alkyl is optionally substituted with -halo.

3. The compound of claim 2, wherein R1is methyl.

4. The compound of claim 2, wherein R1is -C1-3 alkylene-5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with a methyl.Attorney Docket No.: COPA-058 / 01WO 337248-24685. The compound of claim 2, wherein the -Ci-6 alkylene-heteroaryl is6. The compound of claim 2, wherein the -heterocyclylis , ' or Y7. The compound of claim 2, wherein the cycloalkyl is-^V.

8. The compound of any one of claims 1-7, wherein R2is -halo.

9. The compound of claim 8, wherein R2is -F.

10. The compound of any one of claims 1-9, wherein R3is -O-Ci-6 alkyl.

11. The compound of claim 8, wherein R3is -O-Me.

12. The compound of any one of claims 1-11, wherein n is 0.

13. The compound of any one of claims 1-12, wherein m is 1.

14. The compound of any one of claims 1-12, whereinR1is -Ci-6 alkyl or -Ci-6 alkylene-heteroaryl, wherein the heteroaryl is optionally substituted with -Ci-6 alkyl;R2is -halo; andR3is -O-Ci-6 alkyl.

15. The compound of any one of claims 1-12, whereinR1is -Ci-6 alkyl or -Ci-6 alkylene-heteroaryl, wherein the heteroaryl is optionally substituted with -Ci-6 alkyl;R2is -F; andR3is -O-Me.

16. The compound of any one of claims 1-15, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246817. The compound of any one of claims 1-16, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246818. The compound of any one of claims 1-17, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-246819. A compound of Formula (II):or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof wherein:R4is -Ci-6 alkyl, -aryl, -heteroaryl, -Ci-6 alkylene-aryl, -Ci-6 alkylene-heteroaryl, -Ci-6 alkylene-OH, -OH, -Ci-6 alkylene-O-Ci-6 alkyl, or -O-Ci-6 alkyl;R5is -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6Attorney Docket No.: COPA-058 / 01WO 337248-2468alkyl; wherein the -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;R6is -O-C1-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -N(CI-6 alkyl)2, -CN, -C(C=O)-Ci-6alkyl, -O(C=O)-Ci-6 alkyl, -C1-6 alkylene-OH, or -S(O)-Ci-6 alkyl;n is 0, 1, 2, or 3m is 0 or 1,and wherein, the compound is not:

20. The compound of claim 19, wherein the compound is not deuterated.

21. The compound of claim 19 or 20, wherein R5is -C1-6 alkyl, -cycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, or -heterocyclyl, each of which is optionally substituted with -halo or -OH.

22. The compound of claim 21, wherein R5is -C1-6 alkyl substituted with -halo or -OH.

23. The compound of claim 22, wherein R5is -CH2CH2F or -CH2CH2OH.

24. The compound of claim 21, wherein R5is -C1-6 alkylene-aryl isAttorney Docket No.: COPA-058 / 01WO 337248-2468H 25. The compound of claim 21, wherein the -Ci-6 alkylene-heteroaryl is . JOSN27. The compound of claim 21, wherein the -cycloalkyl isM>n' .

28. The compound of any one of claims 19-27, wherein R6is -O-Ci-6 alkyl, -S-Ci-6 alkyl, -S(O)-Ci-6alkyl, -S(O)2-Ci-6 alkyl, -Ci-6 alkylene-OH.

29. The compound of claim 28, wherein R6is -O-Me, -S-Me, -CH2-OH, -S(O)-Me, or -S(O)2-Me.

30. The compound of claim 28, wherein R6is -S-Me.

31. The compound of claim 28, wherein R6is -O-Me.

32. The compound of any one of claims 19-31, wherein R4is -O-C1-6 alkyl or -OH.

33. The compound of any one of claims 19-32, wherein n is 1.

34. The compound of any one of claims 19-32, wherein n is 0.

35. The compound of any one of claims 19-33, wherein m is 1.

36. The compound of any one of claims 19-35, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246837. The compound of any one of claims 15-30, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246838. The compound of any one of claims 15-31, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246839. A compound of F ormula (III) :or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof wherein:R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;R7Aand R7Bare each independently -halo;R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;n is 0, 1, 2, or 3; andm is 0 or 1.

40. The compound of claim 39, wherein R1is -C1-6 alkyl.

41. The compound of claim 39 or 40, wherein R1is methyl or butyl.

42. The compound of any one of claims 39-41, wherein R7Aand R7Bare both -F.

43. The compound of any one of claims 39-42, wherein n is 0.

44. The compound of any one of claims 39-43, wherein m is 1.

45. The compound of any one of claims 39-44, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-246846. The compound of any one of claims 39-45, wherein the compound is:

47. The compound of any one of claims 39-45, wherein the compound is:

48. A compound of Formula (IV):or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof wherein:Attorney Docket No.: COPA-058 / 01WO 337248-2468R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;R8is -halo or -methyl;R9is -C1-6 alkyl;R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;n is 0, 1, 2, or 3; andm is 0 or 1.

49. The compound of claim 48, wherein R1is -H, -C1-6 alkyl, or -C1-6 alkylene-heteroaryl.

50. The compound of claim 49, wherein the -C1-6 alkylene-heteroaryl is T51. The compound of any one of claims 48-50, wherein R8is -halo.

52. The compound of any one of claims 48-50, wherein R8is -methyl.

53. The compound of any one of claims 48-52, wherein R9is -methyl.

54. The compound of any one of claims 48-53, wherein n is 0.

55. The compound of any one of claims 48-54, wherein m is 1.

56. The compound of any one of claims 48-55, wherein the compound is:

57. The compound of any one of claims 48-56, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-246858. The compound of any one of claims 48-57, wherein the compound is:

59. A compound of formula (V):R1or a pharmaceutically acceptable salt, deuterated form or stereoisomer thereof wherein:Attorney Docket No.: COPA-058 / 01WO 337248-2468R1is -H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl; wherein the -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylenearyl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -cycloalkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -O-C1-6 alkyl are optionally substituted with one or more -halo, oxo, -OH, -NH2, -CN, or -C1-6 alkyl;R4is -C1-6 alkyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 alkylene-OH, -OH, -C 1-6 alkylene-O-C 1-6 alkyl, or -O-C1-6 alkyl;R10is -halo, -C2-6 alkenyl, -C2-6 alkynyl, -aryl, -heteroaryl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -heterocyclyl, -C1-6 alkylene-O-C 1-6 alkyl, -S-C1-6 alkyl, -S(O)2-Ci-6 alkyl, -SH, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -NH2, -CN, -C(C=O)-Ci-6 alkyl, -O(C=O)-Ci-6 alkyl, or -NH(C=0)-CI-6 alkyl;n is 0, 1, 2, or 3; andm is 0 or 1.

60. The compound of claim 59, wherein R1is -H, -heterocyclyl, -cycloalkyl, -C1-6 alkyl, or -C1-6 alkylene-heteroaryl, wherein the -C1-6 alkyl is optionally substituted with -OH or -halo. 0 \V / 061. The compound of claim 60, wherein the -heterocyclyl is: Qor0 T' .

62. The compound of claim 60, wherein the -C1-6 alkylene-heteroaryl is: / N63. The compound of claim 60, wherein the ■cycloalkyl is64. The compound of claim 60, wherein R1is -C1-6 alkyl substituted with -OH.

65. The compound of claim 64, wherein R1is -CH2CH2OH.

66. The compound of claim 64, wherein R1is -CH2CH2CH3.

67. The compound of claim 60, wherein R1is -C1-6 alkyl substituted with -halo.

68. The compound of claim 67, wherein R1is -CH2CH2F.

69. The compound of any one of claims 59-67, wherein R10is -halo.

70. The compound of claim 69, wherein R10is -F.Attorney Docket No.: COPA-058 / 01WO 337248-246871. The compound of any one of claims 59-70, wherein n is 0.

72. The compound of any one of claims 59-71, wherein m is 1.

73. The compound of any one of claims 59-72, wherein:R1is -heterocyclyl, -cycloalkyl, -Ci-6 alkyl, or -Ci-6 alkylene-heteroaryl; R9is -halo; andn is 0.

74. The compound of any one of claims 59-73, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-246875.Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246876. The compound of any one of claims 59-75, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-2468Attorney Docket No.: COPA-058 / 01WO 337248-246877. A compound selected from:

78. The compound of claim 77, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-246879. The compound of claim 77 or 78, wherein the compound is:Attorney Docket No.: COPA-058 / 01WO 337248-246880. A pharmaceutical composition comprising a compound of any one of claims 1-79, or a pharmaceutically acceptable salt or deuterated form thereof.

81. The pharmaceutical composition of claim 80, wherein the pharmaceutical composition is formulated for oral or parenteral administration.

82. The pharmaceutical composition of claim 81, wherein the parenteral administration is intravenous administration or subcutaneous administration.

83. A method of treating 5-HT2A receptor associated disease or disorder, comprising administering a compound of any one of claims 1-79, or a pharmaceutically acceptable salt or deuterated form thereof.

84. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is an anxiety disorder, attention deficit hyperactivity disorder (ADHD), depression, cluster headache, diminished drive, burn-out, bore-out, migraine, Parkinson's disease, schizophrenia, an eating disorder, psychotic disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar I disorder, bipolar II disorder, major depressive disorder, psychotic depression, delusional disorders, shared psychotic disorder, Shared paranoia disorder, brief psychotic disorder, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, social anxiety disorder, substance-induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

85. The method of claim 84, wherein the 5-HT2A receptor associated disease or disorder is depression.

86. The method of claim 85, wherein the depression is treatment resistant depression.Attorney Docket No.: COPA-058 / 01WO 337248-246887. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is an eating disorder.

88. The method of claim 87, wherein the eating disorder is anorexia nervosa.

89. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is an anxiety disorder.

90. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is bipolar I disorder.

91. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is bipolar II disorder.

92. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is major depressive disorder.

93. The method of claim 83, wherein the 5-HT2A receptor associated disease or disorder is posttraumatic stress disorder (PTSD).

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