Oral complement factor D inhibitors

Abstract

Disclosed are compounds of formula (I), and pharmaceutically acceptable salts thereof, that are inhibitors of the complement system. Pharmaceutical compositions containing such compounds and methods of using the compounds and compositions in the treatment or prevention of diseases or conditions characterized by abnormal complement system activity are also provided. [Formula 1] JPEG2022552185000568.jpg52164

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 912,929, filed October 9, 2019. [Background technology]

[0002] The complement system is part of an organism's immune system that enhances the ability of antibodies and phagocytes to destroy and remove foreign bodies (e.g., pathogens) from the organism. The complement system includes a set of plasma proteins that act together to attack extracellular pathogens and induce a series of inflammatory responses to help fight infection. Complement activation can occur in several pathways. For example, complement activation can occur in response to a specific pathogen or spontaneously by antibodies binding to a pathogen. When a complement protein is activated, a cascade is triggered, with one complement protein inducing the activation of subsequent proteins in the sequence. The activation of a few complement proteins at the beginning of the pathway is greatly amplified by each successive enzymatic reaction, rapidly generating a disproportionately large complement response. (Non-Patent Document 1). Healthy organisms have regulatory mechanisms to prevent uncontrolled complement activation.

[0003] Once activated, complement proteins can bind to pathogens and opsonize them for phagocytosis by phagocytes that have complement receptors. Small fragments of some complement proteins then act as chemotactic agents to recruit more phagocytes to the site of complement activation and also activate these phagocytes. Complement proteins then create holes or pores in the invading organisms, destroying them. Complement plays an important role in protecting the body from foreign bodies, but it can also destroy healthy cells and tissues. Inappropriate activation of complement is involved in the pathology of many diseases that affect the immune, renal, cardiovascular, and nervous systems (Non-Patent Document 2). Thus, there is a need to develop additional complement inhibitors with therapeutic potential in the treatment of many disorders. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Marrides, S.Pharmacological Reviews 1998,Vol.50,pages 59-88 [Non-Patent Document 2] Morgan,B.Eur J Clin Invest 1994,Vol.24,pages 219-228 Summary of the Invention [Means for solving the problem]

[0005] In certain aspects, the present invention provides compounds having the structure of formula (I), and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, [ka] is arylene or heteroarylene; [ka] is arylene or heteroarylene; [ka] at two and only two adjacent positions [ka] condensed to; [ka] is aryl or heteroaryl; [ka] is aryl or heteroaryl; J is -CH 2 -, -NH-, -CH 2CH 2 -, -C(O)-, -O-, -S-, -S(O)-, -SO 2 -, -N(alkyl)-, -CH(alkyl)-, -CH(aryl)-, -C(alkyl) 2 -, -CH(cycloalkyl)-, or [ka] represents; K is a bond, -O-, -NH-, -C(O)-, -CH 2 -, -S-, -S(O)-, -SO 2 -, -N(alkyl)-, -CH(alkyl)-, or -CH(cycloalkyl)-; At least one of J and K is a bond, -C(O)-, or -CH 2 -, -CH 2 CH 2 -, -CH(alkyl)-, or -CH(aryl)-; L C is a bond, -CH 2 -, -CH(alkyl)-, -CH(cycloalkyl)-, -CH(hydroxyalkyl)-, -CH(haloalkyl)-, -CH 2 CH 2 -, -CF 2 -, -CH(F)-, -CF(alkyl)-, -C(O)-, -CD 2 -, or -CH(D)-; L D is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, -CH(F)-, -CD 2 -, -CH(D)-, -CH(alkyl)-, -CH(cycloalkyl)-, -CHNH 2 represents -, -CH(NH(alkyl))-, -CH(NH(cycloalkyl))-, or a bond; R Ais H, halo, hydroxyl, cyano, amino, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, -C(O)OH, -C(O)NH 2 -, -C(O)N(alkyl) 2 -, -CH 2 C(O)OH, -NO 2 , -CH 2 NH (optionally substituted alkyl), -CH 2 N(Boc)(optionally substituted alkyl), -CH 2 NH((cycloalkyl)alkyl), -CH 2 N(alkyl)(cycloalkyl), -CH 2 N(alkyl)((cycloalkyl)alkyl), -NH(optionally substituted alkyl), -NH(cycloalkyl), -NH((cycloalkyl)alkyl), -NH((heterocycloalkyl)alkyl), -N(alkyl) 2 , -N(alkyl)((cycloalkyl)alkyl, -N(alkyl)((heterocycloalkyl)alkyl, -NH(heteroarylalkyl), -CH 2 O(optionally substituted aryl), -C(O)O(alkyl), -C(O)NH(optionally substituted alkyl), -C(O)NH((cycloalkyl)alkyl), -NHC(O)O(alkyl), or -CH 2 N(alkyl) 2 represents; R B is H, -C(O)O(alkyl), halogen, cyano, amino, -C(O)OH, -CH 2 C(O)OH, -C(O)NH 2, -C(O)NH(cycloalkyl), -C(O)NH(alkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)(alkyl), alkylaminoalkyl, alkylaminocycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or is an optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, or heterocycloalkyl; R C represents H, halo, -OH, or amino, or is optionally substituted alkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy; R D is H, halo, hydroxyl, cyano, -NH 2 , -NH(Ac), -NH(alkyl), -N(alkyl) 2 , -NH(CO)(alkyl), -CH 2 NH 2 , -CH 2 NHC(O)(alkyl), -C(O)NH 2 , -C(O)OH, or -NHC(O)O(alkyl), or is optionally substituted alkyl, alkoxyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, haloalkoxyl, or haloalkyl; R 1 represents H or optionally substituted alkyl; and m, n, p, and q are each independently 0, 1, or 2.

[0006] In certain aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

[0007] In certain aspects, the present invention provides a method for treating a disease or condition characterized by abnormal complement system activity, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt thereof. In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immunological disorder. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease. In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome. In other particular aspects, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis. In further aspects, the disease or condition characterized by abnormal complement system activity is a blood disorder. In further aspects, the disease or condition characterized by abnormal complement system activity is an ocular disorder or disease. In yet another aspect, the disease or condition characterized by aberrant complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascular disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or post-operative inflammation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in the treatment of disorders of the immune system, renal system, cardiovascular system, and nervous system. Provided herein are compounds of formula (I) and pharma- ceutical acceptable salts thereof that are useful for the treatment or prevention of diseases or conditions characterized by abnormal activity of the complement system.

[0009] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0010] The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, or oxygen, nitrogen or sulfur.

[0011] The term "alkyl" as used herein is a term of the art and refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl group has about 30 or fewer carbon atoms in its backbone (e.g., C for straight chain). 1 -C 30 , C for branched chain 3 -C 30 ), or about 20 or less, or 10 or less carbon atoms. In certain embodiments, the term "alkyl" refers to 1 -C 10 In certain embodiments, the term "alkyl" refers to a C 1 -C 6 Alkyl groups, e.g., C 1 -C 6 In certain embodiments, the term "alkyl" refers to a straight chain alkyl group. 3 -C 12 In certain embodiments, the term "alkyl" refers to a branched chain alkyl group. 3 -C 8It refers to a branched chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0012] The term "cycloalkyl" means monocyclic or bicyclic or bridged saturated carbocyclic rings, each of which has from 3-12 carbon atoms. Particular cycloalkyls have from 5-12 carbon atoms in the ring structure, and can have from 6-10 carbons in the ring structure. Preferably, cycloalkyls are selected from the group consisting of (C 3 -C 7 ) cycloalkyl, which represents a monocyclic saturated carbocyclic ring having 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings include monocyclic cycloalkyl rings in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form -(CH 2 ) w- (wherein w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems include a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. A bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group is optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, where the fused bicyclic cycloalkyl is optionally substituted.

[0013] As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group substituted with one or more cycloalkyl groups. An example of a cycloalkylalkyl group is a cyclohexylmethyl group.

[0014] The term "heterocycloalkyl" as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which may be fully saturated or may contain one or more units of unsaturation (for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system), having from 3 to 12 atoms including at least one heteroatom such as nitrogen, oxygen, or sulfur. For illustrative purposes, which should not be construed as limiting the scope of the invention, the following are examples of heterocycles: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, Heterocycloalkyl groups include, but are not limited to, aryl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, trithianyl, and 2-azobicyclo[3.1.0]hexane. Heterocycloalkyl groups are optionally substituted by one or more substituents, as described below.

[0015] As used herein, the term "(heterocycloalkyl)alkyl" refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0016] The term "alkenyl" as used herein means a straight or branched chain hydrocarbon radical containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) in an alkenyl group can be located anywhere in the moiety and can have either the (Z) or (E) configuration with respect to the double bond(s).

[0017] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0018] The term "alkylene" is art-recognized and as used herein refers to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, aryl alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. That is, in one embodiment, "substituted alkyl" is "alkylene".

[0019] The term "amino" is a term of the art and, as used herein, refers to both unsubstituted and substituted amines, for example, moieties that can be represented by the general formula: [ka] In the formula, R a , R b , and R c are each independently hydrogen, alkyl, alkenyl, -(CH 2 ) x -R d , or R a and R b which, together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure; R d represents aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl; and x is zero or an integer ranging from 1 to 8. In certain embodiments, R a or R b Only one of the groups is a carbonyl, e.g., R a , R b and the nitrogens together do not form an imide. In other embodiments, R a and R b (and optionally R c ) are each independently a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) x -R d In certain embodiments, R a and R b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which may be further substituted (e.g., with halogen, alkyl, alkoxy, hydroxy, etc.). In certain embodiments, the term "amino" refers to -NH 2 Refers to...

[0020] In certain embodiments, the term "alkylamino" refers to -NH(alkyl).

[0021] In certain embodiments, the term "dialkylamino" refers to -N(alkyl) 2 Refers to...

[0022] As used herein, the term "amide" refers to -NHC(=O)-, where the amide group is attached to the parent molecular moiety through a nitrogen. An example of an amide is CH 3 C(=O)N(H)- and CH 3 CH 2 Examples of alkyl amides include C(=O)N(H)-.

[0023] The term "acyl" is a term of the art and as used herein refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0024] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group, i.e., -CH 2 NH 2 Refers to...

[0025] The term "aminoacyl" is a term of the art and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0026] As used herein, the term "aminothionyl" refers to the analog of aminoacyl in which the O of RC(O)-- has been replaced with sulfur, thus making it a RC(S)-- form.

[0027] The term "phosphoryl" is a term of the art and as used herein may generally be represented by the formula: [ka] wherein Q50 represents S or O, and R59 represents hydrogen, lower alkyl or aryl; e.g., -P(O)(OMe)- or -P(O)(OH). 2 For example, when used to substitute an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula: [ka] wherein Q50 and R59 are each independently as defined above, and Q51 is O, S, or N; for example, -OP(O)(OH)OMe or -NH-P(O)(OH). 2 When Q50 is S, the phosphoryl moiety is a "phosphorothioate".

[0028] As used herein, the term "aminophosphoryl" refers to a phosphoryl group substituted with at least one amino group, as defined herein; e.g., -P(O)(OH)NMe 2 Refers to...

[0029] As used herein, the term "azide" or "azido" refers to a -N 3 means a group.

[0030] The term "carbonyl" as used herein refers to -C(=O)-.

[0031] The term "thiocarbonyl" as used herein refers to -C(=S)-.

[0032] The term "alkylphosphoryl," as used herein, refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, --P(O)(OH)Me.

[0033] The term "alkylthio" as used herein refers to alkyl-S-. The term "(alkylthio)alkyl" refers to an alkyl group substituted with an alkylthio group.

[0034] As used herein, the term "carboxy" refers to -CO 2 H group.

[0035] The term "aryl" is a term of the art and, as used herein, includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene and pyrene. Typically, aryl groups contain 6 to 10 carbon ring atoms (i.e., (C 6 -C 10 ) aryl). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, and the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings with two or more carbons shared between two adjacent rings (these rings are "fused rings"), at least one of the rings being aromatic hydrocarbon, e.g., the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group.

[0036] The term "heteroaryl" is a term of the art and as used herein refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms in the ring structure, including one or more heteroatoms, such as nitrogen, oxygen, or sulfur. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. A "heteroaryl" may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared between two adjacent rings (these rings are "fused rings"), at least one of the rings being an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl.

[0037] The term "aralkyl" or "arylalkyl" is a term of the art and, as used herein, refers to an alkyl group substituted with an aryl group, the moiety being attached to the parent molecule through the alkyl group.

[0038] The term "heteroaralkyl" or "heteroarylalkyl" is a term of the art and, as used herein, refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through an alkyl group.

[0039] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0040] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0041] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, represented by -C(=O)-, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0042] The term "alkylcarbonyl" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0043] The term "arylcarbonyl" as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0044] As used herein, "alkylcarbonyloxy" and "arylcarbonyloxy" refer to an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to, phenylcarbonyloxy.

[0045] The term "alkenoxy" or "alkenoxyl" means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. A representative example of an alkenoxyl is 2-propene-1-oxyl (i.e., CH 2 =CH-CH 2 -O-) and vinyloxy (i.e., CH 2 =CH-O-).

[0046] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0047] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0048] As used herein, the term "carbocyclyl" means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms that is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.

[0049] The term "cyano" is a term of the art and, as used herein, refers to --CN.

[0050] The term "halo" is a term of the art and as used herein refers to -F, -Cl, -Br, or -I.

[0051] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with halogen atoms.

[0052] The term "hydroxy" is a term of the art and as used herein refers to --OH.

[0053] As used herein, the term "hydroxyalkyl" means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0054] As used herein, the term "silyl" refers to silyl (H 3 Hydrocarbyl derivatives of the (Si-) group (i.e., (hydrocarbyl) 3Si-), where a hydrocarbyl group is a univalent group formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl group can be a combination of different groups that can be altered to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0055] As used herein, the term "silyloxy" means that a silyl group, as defined herein, is attached to the parent molecule through an oxygen atom.

[0056] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis and trans isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof that are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0057] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, then separating the resulting diastereomeric mixture and cleaving the auxiliary group to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, the diastereomeric salt is formed with an appropriate optically active acid or base, followed by separation of the diastereomers by partial crystallization or chromatographic means well known in the art, and then the pure enantiomer is recovered.

[0058] "Substituted" or "substituting" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and it is understood that the substitution results in a stable compound that does not spontaneously undergo transformation, such as, for example, by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0059] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, the substituents described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0060] In certain embodiments, optional substituents contemplated in the present invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl, sulfonamide, ketone (e.g., -CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano.

[0061] As used herein, the terms "optionally substituted" or "substituted or unsubstituted" when preceding a list of chemical moieties means that the list of chemical moieties that follows is substituted or unsubstituted, respectively. For example, "substituted or unsubstituted aryl, heteroaryl, and cycloalkyl" or "optionally substituted aryl, heteroaryl, and cycloalkyl" means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0062] As used herein, the phrase "protecting group" refers to temporary substituents that protect potentially reactive functional groups from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2001). nd ed.; Wiley: New York, 1991. Protected forms of the compounds of the invention are included within the scope of the invention.

[0063] For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0064] Other chemical terms herein are intended to be used in accordance with conventional usage in the art as exemplified in the McGraw-Hill Dictionary of Chemical Terms (Parker, S. (ed.), 1985), McGraw-Hill, San Francisco, incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0065] The term "pharmaceutically acceptable salts" as used herein includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of salt-containing molecules is not 1:1. For example, a salt may contain more than one inorganic or organic acid molecule per molecule of base, e.g., two hydrochloric acid molecules per molecule of the compound of formula I. As another example, a salt may contain less than one inorganic or organic acid molecule per molecule of base, e.g., two molecules of the compound of formula I per molecule of tartaric acid.

[0066] The term "prodrug" as used herein refers to a compound that can be metabolized in vivo to provide a compound of formula I. Thus, prodrugs can include compounds prepared by modifying one or more functional groups in a compound of formula I to provide a corresponding compound that can be metabolized in vivo to provide a compound of formula I. Such modifications are known in the art. For example, one or more hydroxyl or amine groups in a compound of formula I can be acylated with an alkyl-C(=O)-group or a residue derived from an amino acid to provide a prodrug.

[0067] Prodrug forms of compounds with various nitrogen-containing functional groups (amino, hydroxyamino, amido, etc.) may include the following types of derivatives, where each R p The groups can be independently hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, arylalkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl. (a)-NHC(O)R p Carboxamide represented as (b)-NHC(O)OR p Carbamates represented as (c)NHC(O)OROC(O)R p (Acyloxy)alkyl carbamates represented by the following formula: (d)-NHCR(=CHCO 2 R p ) or -NHCR(=CHCONR p R p ) (e)-N=CR p R p The Schiff base is represented as (f) RCONHCH 2 NR p R p Mannich base (derived from carboximide compound) represented as

[0068] The preparation of such prodrug derivatives is described in a variety of literature sources (see, for example: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO0041531, p. 30).

[0069] Prodrug forms of carboxyl-containing compounds include esters (-CO 2 R m ), R m The group corresponds to any alcohol at a level that is pharma- ceutically acceptable for release in the body by enzymatic or hydrolytic processes. Another prodrug derived from the carboxylic acid form of the present disclosure may be a quaternary salt type structure as described in Bodor et al., J. Med. Chem. 1980, 23, 469.

[0070] The terms "carrier" and "pharmaceutical acceptable carrier" as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutical acceptable carriers include liquids such as water, saline, and oil; solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin, which is incorporated herein by reference in its entirety.

[0071] As used herein, the term "treat" refers to preventing, halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treat" refers to halting or slowing the progression of, or eliminating a disease or condition in a subject. In one embodiment, "treat" refers to reducing at least one objective symptom of a disease or condition in a subject.

[0072] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0073] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce a desired therapeutic effect.

[0074] As used herein, the term "inhibit" refers to reducing by an objectively measurable amount or extent. In various embodiments, "inhibit" refers to reducing by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, "inhibit" refers to reducing by 100 percent, i.e., stopping or eliminating.

[0075] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0076] compound The present invention provides compounds having the structure of formula (I), and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, [ka] is arylene or heteroarylene; [ka] is arylene or heteroarylene; [ka] at two and only two adjacent positions [ka] condensed to; [ka] is aryl or heteroaryl; [ka] is aryl or heteroaryl; J is -CH 2 -, -NH-, -CH 2 CH 2 -, -C(O)-, -O-, -S-, -S(O)-, -SO 2 -, -N(alkyl)-, -CH(alkyl)-, -CH(aryl)-, -C(alkyl) 2 -, -CH(cycloalkyl)-, or [ka] represents; K is a bond, -O-, -NH-, -C(O)-, -CH 2 -, -S-, -S(O)-, -SO 2 -, -N(alkyl)-, -CH(alkyl)-, or -CH(cycloalkyl)-; At least one of J and K is a bond, -C(O)-, or -CH 2 -, -CH 2 CH 2 -, -CH(alkyl)-, or -CH(aryl)-; L C is a bond, -CH 2 -, -CH(alkyl)-, -CH(cycloalkyl)-, -CH(hydroxyalkyl)-, -CH(haloalkyl)-, -CH 2 CH 2 -, -CF 2 -, -CH(F)-, -CF(alkyl)-, -C(O)-, -CD 2 -, or -CH(D)-; L D is -CH 2 -, -CH 2 CH 2 -, -CF 2 -, -CH(F)-, -CD 2 -, -CH(D)-, -CH(alkyl)-, -CH(cycloalkyl)-, -CHNH 2 represents -, -CH(NH(alkyl))-, -CH(NH(cycloalkyl))-, or a bond; R Ais H, halo, hydroxyl, cyano, amino, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, -C(O)OH, -C(O)NH 2 -, -C(O)N(alkyl) 2 -, -CH 2 C(O)OH, -NO 2 , -CH 2 NH (optionally substituted alkyl), -CH 2 N(Boc)(optionally substituted alkyl), -CH 2 NH((cycloalkyl)alkyl), -CH 2 N(alkyl)(cycloalkyl), -CH 2 N(alkyl)((cycloalkyl)alkyl), -NH(optionally substituted alkyl), -NH(cycloalkyl), -NH((cycloalkyl)alkyl), -NH((heterocycloalkyl)alkyl), -N(alkyl) 2 , -N(alkyl)((cycloalkyl)alkyl, -N(alkyl)((heterocycloalkyl)alkyl, -NH(heteroarylalkyl), -CH 2 O(optionally substituted aryl), -C(O)O(alkyl), -C(O)NH(optionally substituted alkyl), -C(O)NH((cycloalkyl)alkyl), -NHC(O)O(alkyl), or -CH 2 N(alkyl) 2 represents; R B is H, -C(O)O(alkyl), halogen, cyano, amino, -C(O)OH, -CH 2 C(O)OH, -C(O)NH 2, -C(O)NH(cycloalkyl), -C(O)NH(alkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)(alkyl), alkylaminoalkyl, alkylaminocycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or is an optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, or heterocycloalkyl; R C represents H, halo, -OH, or amino, or is optionally substituted alkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy; R D is H, halo, hydroxyl, cyano, -NH 2 , -NH(Ac), -NH(alkyl), -N(alkyl) 2 , -NH(CO)(alkyl), -CH 2 NH 2 , -CH 2 NHC(O)(alkyl), -C(O)NH 2 , -C(O)OH, or -NHC(O)O(alkyl), or optionally substituted alkyl, alkoxyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, haloalkoxyl, or haloalkyl; R 1 represents H or optionally substituted alkyl; and m, n, p, and q are each independently 0, 1, or 2.

[0077] In certain embodiments of the compounds of formula (I): J is -CH 2 -, -NH-, -CH 2 CH 2 - or -C(O)-; K represents a bond, -O-, -NH-, or -C(O)-; When J represents -NH-, K is a bond or -C(O)-; L C is -CH2 -, -CH(alkyl)-, or -CH(hydroxyalkyl)-; R A is H, halo, hydroxyl, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (heterocycloalkyl)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, -C(O)OH, -NO 2 , -CH 2 NH (optionally substituted alkyl), -CH 2 NH((cycloalkyl)alkyl), -NH((cycloalkyl)alkyl, -CH 2 O(optionally substituted aryl), -C(O)O(alkyl), -C(O)NH(optionally substituted alkyl), -C(O)NH((cycloalkyl)alkyl), -NHC(O)O(alkyl), or -CH 2 N(alkyl) 2 represents; R B is H, -C(O)O(alkyl), alkyl, -C(O)OH, hydroxyalkyl, tosyl, heterocycloalkyl, -C(O)NH 2 or -C(O)NH(cycloalkyl); R C represents H or halo; R D is H or halo, hydroxyl, alkyl, alkoxyl, -NH 2 , -C(O)NH 2 , -NHC(O)O(alkyl), or haloalkoxyl; and R 1 represents H or alkyl.

[0078] In certain embodiments, the compound has the structure of formula (Ia): [ka]

[0079] In certain embodiments, the compound has the structure of formula (Ia-1): [ka]

[0080] In certain embodiments, the compound has the structure of formula (Ia-2): [ka]

[0081] In certain embodiments, the compound has the structure of formula (Ib-1): [ka]

[0082] In certain embodiments, the compound has the structure of formula (Ib-2): [ka]

[0083] In certain embodiments, the compound has the structure of formula (Ic-1): [ka]

[0084] In certain embodiments, the compound has the structure of formula (Id-1): [ka]

[0085] In certain embodiments, the compound has the structure of formula (Id-2): [ka]

[0086] In certain embodiments, the compound has the structure of formula (Ie-1): [ka]

[0087] In certain embodiments, the compound has the structure of formula (Ie-2): [ka]

[0088] In certain embodiments, the compound has the structure of formula (If-1): [ka]

[0089] In certain embodiments, the compound has the structure of formula (If-2): [ka]

[0090] In certain embodiments, the compound has the structure of formula (Ig-1): [ka]

[0091] In certain embodiments, the compound has the structure of formula (Ig-2): [ka]

[0092] In certain embodiments, the compound has the structure of formula (Ih-1): [ka]

[0093] In certain embodiments, the compound has the structure of formula (Ih-2): [ka]

[0094] In certain embodiments, the compound has the structure of formula (Ij): [ka]

[0095] In certain embodiments, the compound has the structure of formula (Ij-1): [ka]

[0096] In certain embodiments, the compound has the structure of formula (Ij-2): [ka]

[0097] In certain embodiments, the compound has the structure of formula (Ik): [ka]

[0098] In certain embodiments, the compound has the structure of formula (Im): [ka]

[0099] In certain embodiments, the compound has the structure of formula (IIa): [ka]

[0100] In certain embodiments, the compound has the structure of formula (IIb): [ka]

[0101] In certain embodiments, the compound has the structure of formula (IIc): [ka]

[0102] In certain embodiments, the compound has the structure of formula (IId): [ka]

[0103] In certain embodiments, the compound has the structure of formula (IIe): [ka]

[0104] In certain embodiments, the compound has the structure of formula (IIf): [ka]

[0105] In certain embodiments, the compound has the structure of formula (IIg): [ka]

[0106] In certain embodiments, the compound has the structure of formula (IIh): [ka]

[0107] In certain embodiments, the compound has the structure of formula (IIj): [ka]

[0108] In certain embodiments, the compound has the structure of formula (IIk): [ka]

[0109] In certain embodiments, the compound has the structure of formula (IIm): [ka]

[0110] In certain embodiments, the compound has the structure of formula (IIn): [ka]

[0111] In certain embodiments, the compound has the structure of formula (IIo): [ka]

[0112] In certain embodiments, the compound has the structure of formula (IIp): [ka]

[0113] In certain embodiments, the compound has the structure of formula (IIq): [ka]

[0114] In certain embodiments, the compound has the structure of formula (IIr): [ka]

[0115] In certain embodiments, the compound has the structure of formula (IIs): [ka]

[0116] In certain embodiments, the compound has the structure of formula (IIt): [ka]

[0117] In certain embodiments, the compound has the structure of formula (IIu): [ka]

[0118] In certain embodiments, the compound has the structure of formula (IIv): [ka]

[0119] In certain embodiments, the compound has the structure of formula (IIw): [ka]

[0120] In certain embodiments, the compound has the structure of formula (IIx): [ka]

[0121] In certain embodiments, the compound has the structure of formula (IIy): [ka]

[0122] In certain embodiments, the compound has the structure of formula (IIz): [ka]

[0123] As described in the definitions above, aryl and heteroaryl moieties encompass bicyclic and polycyclic ring structures. Thus, in some embodiments, the heteroaryl moieties present in formula (I) include [ka] is a tricyclic ring system, such as one of the following tricyclic ring systems: [ka] In the formula, Z is O, NH, -CH-CH-, or -CH-N-. For example, [ka] may be a tricyclic ring structure such as any of the following: benzo[1,2-b:3,4-b']difuran, 6H-furo[2,3-e]indole, furo[2,3-f]quinoline, naphtho[1,2-b]furan, furo[3,2-h]quinoline, benzo[2,1-b:3,4-b']difuran, 8H-furo[3,2-g]indole, 1H-furo[2,3-g]indole, 1,6-dihydropyrrolo[2,3-e]indole, 1H-pyrrolo[2,3-f]quinoline, 1H-benzo[g]indole, 1H-pyrrolo[3,2-h]quinoline, 1,8-dihydropyrrolo[3,2-g]indole, 8H-furo[3 ,2-g]indole, thieno[2,3-e]benzofuran, 6H-thieno[2,3-e]indole, thieno[2,3-f]quinoline, naphtho[1,2-b]thiophene, thieno[3,2-h]quinoline, thieno[3,2-g]benzofuran, 8H-thieno[3,2-g]indole, 1H-furo[2,3-g]indazole, 1,6-dihydropyrrolo[2,3-g]indazole, 1H-pyrazolo[3,4-f]quinoline, 1H-benzo[g]indazole, 1H-pyrazolo[4,3-h]quinoline, 1,8-dihydropyrrolo[3,2-g]indazole, and 1H-furo[3,2-g]indazole. A and [ka] of, [ka] In any open position above [ka] may be bonded to R B and -J-, [ka] In any open position above [ka] It may also be bound to

[0124] In any of the preceding embodiments, [ka] may represent a 6-membered aryl or heteroaryl.

[0125] For example, in certain embodiments, [ka] teeth [ka] represents; X C1 represents CH or N; and X C2 represents CH or N.

[0126] In certain embodiments, [ka] teeth [ka] Represents.

[0127] In certain embodiments, [ka] teeth [ka] Represents.

[0128] In certain embodiments, L C Ha-CH 2 - represents.

[0129] In certain embodiments, R C represents H. Or, R C may represent halo, preferably F.

[0130] In certain embodiments, -JK- is -CH 2 -, -NH-, -CH 2 -O-, -CH 2 CH 2 -O-, -C(O)-NH-, or -NHC(O)-. Preferably, -JK- is -CH 2 It represents -O- or -C(O)-NH-.

[0131] In any of the preceding embodiments, [ka] may represent aryl.

[0132] For example, in certain embodiments, [ka] teeth [ka] Represents.

[0133] More specifically, in some embodiments, [ka] teeth [ka] Alternatively, in some embodiments, [ka] teeth [ka] Represents.

[0134] In certain embodiments, R 1 is H.

[0135] In certain embodiments, L D -CH 2 -, -CH 2 CH 2 - or a bond. Preferably, L D -CH 2 - represents.

[0136] In certain embodiments, R D represents H, halo, hydroxyl, alkyl, or alkoxyl. D represents H.

[0137] In certain embodiments, R B is H, -C(O)O(alkyl), halogen, cyano, amino, -C(O)OH, -CH 2 C(O)OH, -C(O)NH 2 , -C(O)NH(cycloalkyl), hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or is optionally substituted alkyl, cycloalkyl, or heterocycloalkyl.

[0138] In certain embodiments, R B represents H, alkyl, or -C(O)OH. B represents H.

[0139] In certain embodiments, RA is H, alkyl, alkoxyl, or -CH 2 O(optionally substituted aryl). In some embodiments, R A represents H.

[0140] In certain embodiments, the compound of formula (I) is selected from the compounds in the following table, and pharma- ceutically acceptable salts thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

[0141] Pharmaceutical Compositions The present invention provides pharmaceutical compositions each comprising one or more compounds of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention (which may include a pharma- ceutically acceptable salt thereof), and a pharma- ceutically acceptable carrier.

[0142] In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharma- ceutical active agent other than the compound of the present invention. The at least one additional pharma- ceutical active agent can be an agent useful in the treatment of a disease or condition characterized by abnormal complement system activity.

[0143] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharma- ceutically acceptable carrier and, optionally, one or more additional pharma- ceutical active agents.

[0144] How to use The present invention provides compounds, and pharma- ceutically acceptable salts thereof, that are useful for treating or preventing diseases or conditions characterized by abnormal complement system activity.

[0145] In certain aspects, the present invention provides a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0146] In certain aspects, the present invention provides a method for treating or preventing a disease or condition characterized by abnormal complement system activity. The method comprises the step of administering a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt thereof, to a subject in need of such treatment or prevention, thereby treating or preventing the disease or condition characterized by abnormal complement system activity. The disease or condition characterized by abnormal complement system activity is treated by reducing complement system activity in the subject.

[0147] Alternatively, in certain aspects, the present invention provides a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for treating a disease or condition characterized by abnormal complement system activity.

[0148] Alternatively, in certain aspects, the invention provides the use of a compound of the invention, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of a disease or condition characterized by abnormal complement system activity.

[0149] As used herein, a "disease or condition characterized by abnormal complement system activity" refers to any disease or condition in which it is desirable to reduce complement system activity. For example, it may be desirable to reduce complement system activity in settings of inappropriate or overactivation of the complement system.

[0150] In certain embodiments, the disease or condition characterized by abnormal complement system activity is an immunological disorder.

[0151] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a disease of the central nervous system.

[0152] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a renal disease.

[0153] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a cardiovascular disease.

[0154] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a neurodegenerative or neurological disease.

[0155] In certain embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome.

[0156] In certain embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

[0157] In certain embodiments, the disease or condition is atypical hemolytic uremic syndrome.

[0158] In certain embodiments, the disease or condition is organ transplant rejection.

[0159] In certain embodiments, the disease or condition is myasthenia gravis.

[0160] In certain embodiments, the disease or condition is neuromyelitis optica.

[0161] In certain embodiments, the disease or condition is membranoproliferative glomerulonephritis.

[0162] In certain embodiments, the disease or condition is dense deposit disease.

[0163] In certain embodiments, the disease or condition is cold agglutinin disease.

[0164] In certain embodiments, the disease or condition is fulminant antiphospholipid syndrome.

[0165] In other embodiments, the disease or condition characterized by abnormal complement system activity is adult respiratory distress syndrome, myocardial infarction, pulmonary inflammation, hyperacute rejection (transplant rejection), sepsis, cardiopulmonary bypass, burns, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barre syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer's disease, organ rejection (transplant), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis.

[0166] In other embodiments, the disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis.

[0167] In certain embodiments, the disease or condition characterized by abnormal complement system activity is a hematological disorder.

[0168] In another embodiment, the disease or condition characterized by abnormal complement system activity is an ocular disorder or disease.

[0169] In certain embodiments, the disease or condition characterized by aberrant complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascular disease, corneal graft rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or post-operative inflammation.

[0170] Formulations, Routes of Administration, and Dosing The compounds of the invention, and their pharma- ceutically acceptable salts, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the selected route of administration (e.g., orally, or parenterally by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes). Additional routes of administration are also contemplated by the present invention.

[0171] Thus, the compounds of the present invention may be administered systemically, for example, orally, in combination with a pharma- ceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations may, of course, be varied, but may conveniently be from about 2% to about 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0172] Tablets, troches, pills, capsules and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, fructose, lactose or aspartame, or flavorings such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, in addition to the above types of materials, liquid carriers such as vegetable oils or polyethylene glycols may be included. Various other materials may be present as coatings or to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, a dye, and a flavoring such as cherry or orange flavoring. Of course, any material used in preparing any unit dosage form should be pharma- ceutically acceptable and substantially non-toxic in the amounts employed.Furthermore, the active compounds may be incorporated into sustained-release preparations and devices.

[0173] The active compound may also be administered intravenously or intraperitoneally by infusion or injection.The solution of the active compound or its salt may be prepared in water or a physiologically acceptable aqueous solution, and may be mixed with a non-toxic surfactant, if desired.Dispersions may also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, and in oils.Under normal storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms.

[0174] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders that are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, and contain the active ingredient, optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be, for example, a solvent or liquid dispersion medium, including water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by forming liposomes, by maintaining the required particle size in the case of dispersions, or by using surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0175] Sterile injectable solutions are prepared by incorporating the required amount of active compound in a suitable solvent with various other ingredients as listed above as needed, and then sterilizing by filtration. In the case of sterile powders for preparing sterile injectable solutions, the preparation method can include vacuum drying and freeze-drying techniques, which results in a powder of the active ingredient plus any additional desired ingredients present in the previously sterile-filtered solution.

[0176] For topical administration, the compounds of the present invention may be applied in pure form, i.e., when they are liquids. However, it is generally desirable to administer them to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which may be a solid or liquid.

[0177] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohol or glycol, or water-alcohol / glycol blends, in which the compounds of the present invention can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antibacterial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

[0178] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral substances may also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like for application directly to the user's skin.

[0179] Examples of useful dermatological compositions that can be used to deliver the compounds of the invention to the skin are known in the art; see, e.g., Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; ​​incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

[0180] Useful dosages of the compounds of the invention can be determined, at least initially, by comparing their in vitro and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; see, for example, U.S. Patent No. 4,938,949, incorporated herein by reference.

[0181] The amount of the compound, or a pharma- ceutically acceptable salt thereof, required for therapeutic use will vary depending not only on the particular compound or salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or physician.

[0182] Generally, however, suitable dosages are in the range of about 0.5 to about 100 mg / kg of recipient body weight per day, e.g., about 3 to about 90 mg / kg of body weight per day, about 6 to about 75 mg / kg of body weight per day, about 10 to about 60 mg / kg of body weight per day, or about 15 to about 50 mg / kg of body weight per day.

[0183] The compounds of the invention, or pharma- ceutically acceptable salts thereof, may conveniently be formulated in unit dosage form; for example, containing 5-1000 mg, 10-750 mg, or 50-500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising the compounds of the invention, or pharma- ceutically acceptable salts thereof, formulated in such a unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses to be administered at appropriate intervals, for example, two, three, four or more sub-doses per day. The sub-dose itself may, for example, be further divided, into a number of discrete loosely spaced administrations.

[0184] The compounds of the present invention, or pharma- ceutically acceptable salts thereof, can also be administered in combination with other therapeutic agents, for example, other agents useful for the treatment or prevention of ischemia, blood loss, or reperfusion injury. In certain embodiments, the compounds of the present invention, and pharma- ceutically acceptable salts thereof, can also be administered in combination with one or more other therapeutic agents useful for the treatment or prevention of ocular disorders or diseases.

[0185] Other delivery systems may include sustained release, delayed release, or sustained release delivery systems well known in the art. Such systems can avoid repeated administration of active compounds, and increase convenience for subjects and physicians. Many types of release delivery systems are available and known to those skilled in the art. It may be desirable to use long-term sustained release implants. As used herein, long-term release means that delivery system or implant is constructed and arranged to deliver therapeutic levels of active ingredient for at least 30 days, preferably 60 days.

[0186] In certain embodiments, the compounds of the present invention are formulated for intraocular administration, for example, direct injection or insertion into or in relation to an intraocular medical device.In certain embodiments, the compounds of the present invention are formulated as eye drops.In certain embodiments, the compounds of the present invention can be administered via ocular delivery, for example, by local ocular administration, including topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, suprachoroidal, or subtenon administration.The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents via ocular delivery.

[0187] The compounds of the present invention may be formulated for deposition on a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other devices that may be placed or permanently implanted within a lumen of the body. As a specific example, it would be desirable to have devices and methods that can deliver the compounds of the present invention to areas of the body that have been treated by an interventional technique.

[0188] In an exemplary embodiment, the compounds of the invention may be deposited within a medical device, such as a stent, and delivered to a treatment site to treat a portion of the body.

[0189] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are typically permanently implanted in coronary or peripheral vessels. Stent designs include those in U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor). Such designs include both metallic and polymeric stents, and both self-expanding and balloon-expandable stents. Stents may also be used to deliver drugs to a site of contact with the vascular system, as disclosed, for example, in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and International Patent Applications WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center).

[0190] The term "deposited" means that the compound is coated, adsorbed, placed, or embedded in the device by methods known in the art. For example, the compound may be embedded in and released from a polymeric material that coats or covers the medical device ("matrix type"), or may be surrounded and released by a polymeric material ("reservoir type"). In the latter example, the compound may be entrapped within or attached to the polymeric material using one or more techniques for producing such materials known in the art. In other formulations, the compound may be attached to the surface of the medical device without the need for a coating, for example, by a detachable bond, and released over time, or may be removed by active mechanical or chemical processes. In other formulations, the compound may be in a permanently immobilized form that presents the compound at the implantation site.

[0191] In certain embodiments, the compounds may be incorporated into polymer compositions during the formation of biocompatible coatings for medical devices such as stents. The coatings produced from these components are typically homogeneous and are useful for coating many devices designed for implantation.

[0192] The polymer can be either a biostable or a bioabsorbable polymer, depending on the desired release rate or degree of polymer stability desired, although bioabsorbable polymers are often preferred for this embodiment because, unlike biostable polymers, bioabsorbable polymers do not persist long after implantation to cause adverse, chronic local reactions. Available bioabsorbable polymers include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoesters, polyphosphatides, and polyisobutenes. These include, but are not limited to, sphoester urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonates), copoly(ether esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, as well as biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable polymers known in the art.Also, biostable polymers with relatively low chronic tissue response such as polyurethanes, silicones, and polyesters can be used, provided they can be dissolved and cured or polymerized on the medical device, as well as other polymers such as polyolefins, polyisobutylene, and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, copolymers such as halogenated vinyl polymers and polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers such as polyvinyl methyl ether; halogenated polyvinylidenes such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics such as polystyrene, vinyl esters such as polyvinyl acetate; copolymers of vinyl monomers, and ethylene-methyl methacrylate. Also usable are olefins such as ethylene-vinyl acetate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymers; polyhydroxy-propyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0193] The polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubes, prostheses, and the like.

[0194] In certain embodiments of the invention, the compounds of the invention are attached to a polymer or semipermeable polymer matrix that is formed into a stent or stent-graft device.

[0195] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose. Spraying methods include conventional methods and microdeposition techniques using inkjet type dispensers. Additionally, the polymer can be deposited on the implantable device using photopatterning to place the polymer only on specific portions of the device. This coating of the device provides a uniform layer around the device and can improve the diffusion of various analytes through the device coating.

[0196] In certain embodiments of the present invention, the compound is formulated to be released from the polymer coating into the environment in which the medical device is placed. Preferably, at least one of several well-known techniques for polymeric carriers or layers to control elution is used to release the compound in a controlled manner over an extended time frame (e.g., several months). Some of these techniques are described in U.S. Patent Application 2004 / 0243225A1, the entire disclosure of which is incorporated herein in its entirety.

[0197] Additionally, the reagents and reaction conditions of the polymer composition can be manipulated to control the release of the compound from the polymer coating, for example, as described in U.S. Pat. No. 6,770,729, which is incorporated herein in its entirety. For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of the compound from the polymer coating. In a variation on this theme, the diffusion coefficient of one or more polymer coatings can be controlled to control the ability of an analyte present in the environment in which the medical device is placed (e.g., an analyte that promotes the degradation or hydrolysis of a portion of the polymer) to access one or more components within the polymer composition (and, for example, thereby, to control the release of the compound from the polymer coating). Yet another embodiment of the invention includes a device having multiple polymer coatings, each having multiple diffusion coefficients. In such an embodiment of the invention, the release of the compound from the polymer coating can be controlled by the multiple polymer coatings.

[0198] In yet another embodiment of the invention, the release of the compound from the polymer coating is controlled by the presence of one or more endogenous or exogenous compounds or by adjusting one or more properties of the polymer composition, such as the pH of the polymer composition. For example, a particular polymer composition can be designed to release a compound in response to a decrease in the pH of the polymer composition.

[0199] kit The invention also provides a kit comprising a compound of the invention or a pharma- ceutically acceptable salt thereof, at least one other therapeutic agent, packaging materials, and instructions for administering the compound of the invention or a pharma- ceutically acceptable salt thereof and the other therapeutic agent to a mammal to treat or prevent a disease or condition characterized by abnormal complement activity, hi one embodiment, the mammal is a human.

[0200] It will be appreciated by those of ordinary skill in the art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein in view of the information known to those of ordinary skill in the art, and may be made without departing from the scope of the invention or its embodiments. EXAMPLES

[0201] Having now described the invention in detail, it will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0202] Scheme 1 [ka] Preparation of 2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)benzoic acid (1f) Step-1: Preparation of methyl 2-((5-bromobenzofuran-3-yl)methoxy)benzoate (1c) To a solution of 5-bromo-3-(bromomethyl)benzofuran (1a) (250 mg, 0.862 mmol; CAS number 137242-43-4), potassium carbonate (477 mg, 3.45 mmol) in acetone (3 mL) was added methyl 2-hydroxybenzoate (1b) (157 mg, 1.035 mmol; CAS number 119-36-8). The resulting mixture was stirred at room temperature overnight. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-50%] to give methyl 2-((5-bromobenzofuran-3-yl)methoxy)benzoate (1c) (301 mg, 97% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6) δ 8.15 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 7.7, 1.8 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.55 (dd, J = 1.9, 1.1 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.34 (dd, J = 8.5, 1.0 Hz, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 5.36 (s, 2H), 3.76 (s, 3H); MS (ES+): 383.00 (M+Na).

[0203] Step-2: Preparation of methyl 2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)benzoate (1e) To a degassed solution of methyl 2-((5-bromobenzofuran-3-yl)methoxy)benzoate (1c) (300 mg, 0.83 mmol) in dioxane (3 mL), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (234 mg, 1.25 mmol; CAS no. 352525-94-1), K 3 PO 4 (0.71 mL, 1.41 mmol), tricyclohexylphosphine (93 mg, 0.33 mmol) and Pd 2 (dba) 3 (152 mg, 0.17 mmol) was added. The mixture was degassed and backfilled with argon, then heated in a microwave at 135 °C for 30 min. The mixture was diluted with EtOAc, washed with water, brine, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%] to give methyl 2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)benzoate (1e) (108 mg, 34% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6) δ 8.14 (s, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.73 - 7.63 (m, 4H), 7.63 - 7.58 (m, 1H), 7.58 - 7.50 (m, 2H), 7.44 - 7.37 (m, 2H), 7.33 (dd, J = 6.9, 2.0 Hz, 2H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 5.44 (s, 2H), 3.80 (s, 2H), 3.66 (s, 3H); MS (ES+): 388.1 (M+1).

[0204] Step-3: Preparation of 2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)benzoic acid (1f) To a solution of methyl 2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)benzoate (1e) (108 mg, 0.28 mmol) in THF (3 mL) was added a solution of lithium hydroxide hydrate (105 mg, 2.49 mmol) in water (1 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to remove the organic solvent. The aqueous mixture was acidified to pH 4-5 using 2 N HCl and purified by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0-100%] to give 2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)benzoic acid (1f) (46 mg, 15% yield) hydrochloride salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.68 (s, 1H, D 2 O replaceable), 8.44 (s, 3H, D 2O exchangeable), 8.18 (s, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.79 - 7.62 (m, 4H), 7.56 - 7.44 (m, 3H), 7.35 (d, J = 8.3 Analysis C 23 H 19 NO 4 .1.1HCl.H 2 Calculated for O: C, 64.02; H, 5.16; Cl, ​​9.04; N, 3.25; Found: C, 64.27; H, 5.25; Cl, ​​9.15; N, 3.41.

[0205] Scheme 2 [ka] Preparation of 3-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)propanoic acid (2d) Step-1: Preparation of ethyl 3-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)propanoate (2b) Compound 2b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (250 mg, 0.862 mmol) in acetone (3 mL) with ethyl 3-(2-hydroxyphenyl)propanoate (2a) (201 mg, 1.035 mmol; CAS number: 20921-04-4), K, according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (477 mg, 3.45 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 3-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)propanoate (2b) (287 mg, 83% yield) as a yellow oil; 1H NMR (300 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.26 - 7.09 (m, 3H), 6.89 (td, J = 7.2, 1.5 Hz, 1H), 5.29 (d, J = 1.0 Hz, 2H), 3.99 (q, J = 7.1 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H), 2.54 - 2.51 (m, 2H), 1.10 (t, J = 7.1 Hz, 3H);MS (ES+): 425.00 (M+Na).

[0206] Step-2: Preparation of ethyl 3-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)propanoate (2c) Compound 2c was prepared from ethyl 3-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)propanoate (2b) (287 mg, 0.712 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (200 mg, 1.068 mmol), K according to the procedure reported in Scheme 1, Step-2. 3 PO 4 (0.605 mL, 1.210 mmol), tricyclohexylphosphine (80 mg, 0.285 mmol), Pd 2 (dba) 3 (130 mg, 0.142 mmol) and heated in a microwave at 135 °C for 30 min, which gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0–70%], ethyl 3-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)propanoate (2c) (105 mg, 34% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6) δ 8.16 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.54 - 7.47 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.25 - 7.20 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.93 - 6.82 (m, 1H), 5.34 (s, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 2.86 - 2.77 (m, 2H), 2.58 - 2.51 (m, 2H), 1.02 (t, J = 7.1 Hz, 3H); MS (ES+): 430.2 (M+1).

[0207] Step-3: Preparation of 3-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)propanoic acid (2d) Compound 2d was prepared from ethyl 3-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)propanoate (2c) (105 mg, 0.244 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 3-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)propanoic acid (2d) (22 mg, 8% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.08 (s, 1H, D 2 O replaceable), 8.43 (s, 3H, D 2O exchangeable), 8.19 (s, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.86 (s, 1H), 7.77 - 7.65 (m, 3H), 7.56 - 7.41 (m, 2H), 7.25 - 7.11 (m, 3H), 6.94 - 6.84 (m, 1H), 5.34 (s, 2H), 4.10 (s, 2H), 2.80 (t, J = 7.7 Hz, 2H), 2.49 - 2.44 (m, 2H); MS (ES+): 402.1 (M+1).

[0208] Scheme 3 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(1-hydroxyethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (3l) Step-1: Preparation of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (3c) To a solution of methyl 4-hydroxy-3,5-diiodobenzoate (3a) (5 g, 12.38 mmol; CAS number 3337-66-4) in pyridine (10 mL) was added tert-butyldimethyl(prop-2-ynyloxy)silane (3b) (2.11 g, 12.38 mmol; CAS number 76782-82-6) and copper(I) oxide (0.89 g, 6.19 mmol). The mixture was degassed, backfilled with argon, stirred at room temperature for 10 min, and heated at 125 °C in a sealed flask for 4 h. The reaction was cooled to room temperature, diluted with EtOAc (250 mL) and diluted with cold 0.02 N KHSO. 4 The resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexanes 0-70%] to give methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (3c) (3.2 g, 58% yield) as a clear oil; 1H NMR (300 MHz, DMSO-d 6 ) δ 8.25 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.08 (s, 1H), 4.84 (s, 2H), 3.86 (s, 3H), 0.89 (s, 9H), 0.13 (s, 6H);MS (ES+): 469.1 (M+1).

[0209] Step-2: Preparation of methyl 2-(hydroxymethyl)-7-iodobenzofuran-5-carboxylate (3d) To a solution of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (3c) (4.3 g, 9.63 mmol) in THF (60 mL), TBAF (3.15 g, 12.04 mmol) was added at 0 °C, stirred at room temperature for 1 h, and then diluted with saturated NH 4 The mixture was quenched with Cl. The reaction mixture was extracted with EtOAc, and the organic layer was separated, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-70%] to give methyl 2-(hydroxymethyl)-7-iodobenzofuran-5-carboxylate (3d) (2.5 g, 78% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.25 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.04 (s, 1H), 5.64 (t, J = 5.9 Hz, 1H), 4.62 (d, 2H), 3.87 (s, 3H).

[0210] Step-3: Preparation of methyl 2-(bromomethyl)-7-iodobenzofuran-5-carboxylate (3e) To a stirred solution of triphenylphosphine (1.26 g, 4.82 mmol) in DCM (20 mL) was added bromine (0.25 mL, 4.82 mmol) at 0° C. The reaction mixture was warmed to room temperature, stirred for 10 min, and methyl 2-(hydroxymethyl)-7-iodobenzofuran-5-carboxylate (3d) (1 g, 3.01 mmol) in DCM (10 mL) was added over 5 min. The reaction was stirred for 10 min and saturated NaHCO 3 The mixture was quenched with 20 mL of ethyl acetate, diluted with DCM (50 mL), washed with water, brine, dried, filtered, and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography [silica gel (40 g), eluted with ethyl acetate and hexanes] to give methyl 2-(bromomethyl)-7-iodobenzofuran-5-carboxylate (3e) (0.72 g, 61% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.30 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.30 (s, 1H), 4.97 (s, 2H), 3.88 (s, 3H).

[0211] Step-4: Preparation of (2-(bromomethyl)-7-iodobenzofuran-5-yl)methanol (3f) To a stirred solution of DIBAL-H (1M in DCM, 26.6 mL, 26.6 mmol) in toluene (20 mL) was added a solution of methyl 2-(bromomethyl)-7-iodobenzofuran-5-carboxylate (3e) (5 g, 12.66 mmol) in DCM (40 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 3 h and acidified to pH 1 using HCl (1 M). The organic phase was separated, washed with water, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-50%] to give (2-(bromomethyl)-7-iodobenzofuran-5-yl)methanol (3f) (2.01 g, 43% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d6 ) δ 7.68 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.15 (s, 1H), 5.30 (s, 1H), 4.94 (s, 2H), 4.54 (s, 2H).

[0212] Step-5: Preparation of tert-butyl 2-(2-((5-(hydroxymethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3h) Compound 3h was prepared from (2-(bromomethyl)-7-iodobenzofuran-5-yl)methanol (3f) (1 g, 2.72 mmol) in acetone (15 mL) using tert-butyl 2-(2-hydroxyphenyl)acetate (3g) (0.681 g, 3.27 mmol), potassium carbonate (1.318 g, 9.54 mmol) and heating at 50 °C for 12 h according to the procedure reported in step-1 of scheme 1. This afforded tert-butyl 2-(2-((5-(hydroxymethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3h) (1.02 g, 76% yield) as a white solid after workup and purification by flash column chromatography [silica gel (40 g) eluted with ethyl acetate and hexanes 0-60%]; MS (ES+): 517.00 (M+Na).

[0213] Step-6: Preparation of tert-butyl 2-(2-((5-formyl-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3i) To a solution of tert-butyl 2-(2-((5-(hydroxymethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3h) (600 mg, 1.21 mmol) in DCM (15 mL) was added Dess-Martin periodinane (DMP) (1.09 g, 2.43 mmol) at room temperature and stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (100 mL), washed with 1 M NaHCO3 (50 mL), water (50 mL), dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (50 g), eluted with ethyl acetate in hexane 0-50%] to give tert-butyl 2-(2-((5-formyl-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3i) (530 mg, 89% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 8.30 - 8.18 (m, 2H), 7.33 (s, 1H), 7.29 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 7.21 (dt, J = 7.1, 1.8 Hz, 2H), 6.95 (td, J = 7.4, 1.2 Hz, 1H), 5.34 (s, 2H), 3.53 (s, 2H), 1.27 (s, 9H); MS (ES+): 515.00 (M+1).

[0214] Step-7: Preparation of tert-butyl 2-(2-((5-(1-hydroxyethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3j) To a solution of tert-butyl 2-(2-((5-formyl-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3i) (1.3 g, 2.64 mmol) in THF (20 mL) at -78 °C was added methyl magnesium bromide (1.4 M in THF, 2.075 mL, 2.90 mmol) and stirred at -78 °C for 1 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl solution and extracted with EtOAc (3x). The combined organic layers were washed with saturated NaHCO 3It was washed with aqueous solution, dried, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-60%] to give tert-butyl 2-(2-((5-(1-hydroxyethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3j) (0.86 g, 64% yield) as a yellow semi-solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.69 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.33 - 7.24 (m, 1H), 7.24 - 7.15 (m, 2H), 7.12 (s, 1H), 6.94 (td, J = 7.3, MS (ES+): 531.00 (M+1).

[0215] Step-8: Preparation of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(1-hydroxyethyl)benzofuran-2-yl)methoxy)phenyl)acetate (3k) A degassed solution of tert-butyl 2-(2-((5-(1-hydroxyethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3j) (250 mg, 0.49 mmol) in dioxane (5 mL) was treated with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (138 mg, 0.738 mmol), bis(triphenylphosphine)palladium(II) chloride (69.0 mg, 0.098 mmol) and KCl in water (1 mL). 2 CO 3A solution of (170 mg, 1.23 mmol) was added. The mixture was degassed, backfilled with argon and heated in an oil bath at 100 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water, brine, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%] to give tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(1-hydroxyethyl)benzofuran-2-yl)methoxy)phenyl)acetate (3k) (122 mg, 51% yield) as a clear oil; MS (ES+): 488.2 (M+1).

[0216] Step-9: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(1-hydroxyethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (3l) To a solution of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(1-hydroxyethyl)benzofuran-2-yl)methoxy)phenyl)acetate (3k) (122 mg, 0.25 mmol) in DCM (10 mL) was added TFA (0.57 mL, 7.38 mmol). The resulting mixture was stirred at room temperature for 3 h and concentrated to dryness under vacuum. The resulting residue was purified by reverse-phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%] to give 2-(2-((7-(3-(aminomethyl)phenyl)-5-(1-hydroxyethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (3l) (44 mg, 21% yield) hydrochloride salt as a white solid; 1 H NMR (300 MHz, DMSO-d 6) δ 12.13 (s, 1H), 8.49 (s, 3H), 7.98 - 7.87 (m, 2H), 7.63 - 7.48 (m, 4H), 7.31 - 7.16 (m, 3H), 7.05 (s, 1H), 6.94 (td, J = 7.2, MS (ES+): 432.1 (M+1); Analysis C 26 H 25 NO 5 .1.1(HCl).2(H 2 Calculated for 2,3-dichlorophenyl 2,4-dichlorophenyl 2,5-dichlorophenyl 2,6-dichlorophenyl 2,7 ...

[0217] Scheme 4 [ka] Preparation of 2-(3-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (4d) Step-1: Preparation of methyl 2-(3-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (4b) Compound 4b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (250 mg, 0.86 mmol) in acetone (3 mL) with methyl 2-(3-hydroxyphenyl)acetate (4a) (172 mg, 1.035 mmol; CAS number: 42058-59-3), K, according to the procedure reported in Scheme 1, Step-1. 2 CO 3(477 mg, 3.45 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded methyl 2-(3-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (4b) (170 mg, 53% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.7, 2.1 Hz, 1H), 7.30 - 7.19 (m, 1H), 7.00 - 6.94 (m, 2H), 6.87 (dt, J = 7.6, 1.2 Hz, 1H), 5.25 (s, 2H), 3.66 (s, 2H), 3.61 (s, 3H); MS (ES+): 397.00 (M+Na).

[0218] Step-2: Preparation of methyl 2-(3-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (4c) Compound 4c was prepared from methyl 2-(3-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (4b) (170 mg, 0.453 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (127 mg, 0.680 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.385 mL, 0.770 mmol), tricyclohexylphosphine (51 mg, 0.181 mmol), Pd 2 (dba) 3(83 mg, 0.091 mmol) and heated in a microwave at 135 °C for 30 min, which afforded, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0–70%], methyl 2-(3-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (4c) (95 mg, 52% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.54 - 7.48 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.5 Hz, MS (ES+): 402.1 (M+1).

[0219] Step-3: Preparation of 2-(3-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (4d) Compound 4d was prepared from methyl 2-(3-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (4c) (95 mg, 0.237 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (57 mg, 1.359 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the hydrochloride salt of 2-(3-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (4d) (30 mg, 17% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN (containing 0.1% HCl) in water 0-100%]; 1H NMR (300 MHz, DMSO-d 6 ) δ 12.36 (s, 1H, D 2 O replaceable), 8.40 (s, 3H, D 2 O exchangeable), 8.20 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.57 - 7.41 (m, 2H), 7.29 - 7.20 (m, Analysis C 24 H 21 NO 4 .(HCl).1.5(H 2 Calculated for 2,3-dichlorophenyl ether (CO): C, 63.93; H, 5.59; Cl, ​​7.86; N, 3.11; Found: C, 64.14; H, 5.61; Cl, ​​8.08; N, 3.28.

[0220] Scheme 5 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetic acid (5d) Step-1: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5b) Compound 5b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (450 mg, 1.552 mmol) in acetone (5 mL) using ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (5a) (354 mg, 1.785 mmol; CAS number 1261826-26-9), K, according to the procedure reported in Scheme 1, Step-1. 2 CO 3(751 mg, 5.43 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5b) (610 mg, 97% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.50 (dd, J = 8.8, 2.1 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.15 - 7.08 (m, MS (ES+): 397.00 (M+Na).

[0221] Step-2: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5c) Compound 5c was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5b) (310 mg, 0.761 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (214 mg, 1.142 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.647 mL, 1.294 mmol), tricyclohexylphosphine (85 mg, 0.304 mmol), Pd 2 (dba) 3(139 mg, 0.152 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5c) (68 mg, 21% yield) as a clear oil; MS (ES+): 434.1 (M+1).

[0222] Step-3: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetic acid (5d) Compound 5d was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5c) (68 mg, 0.157 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetic acid (5d) (9 mg, 3% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.26 (s, 1H, D 2 O replaceable), 8.33 (s, 3H, D 2O exchangeable), 8.12 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.53 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.26 - 7.17 (m, 1H), 7.16 - 7.05 (m, 2H), 5.31 (s, 2H), 4.11 (s, 2H), 3.55 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -123.82;MS (ES+): 406.1 (M+1).

[0223] Scheme 6 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetic acid (6e) Step-1: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6b) Compound 6b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (400 mg, 1.38 mmol) in acetone (5 mL) with ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (6a) (334 mg, 1.586 mmol; CAS no. 76322-29-7), K, according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (667 mg, 4.83 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6b) (500 mg, 86% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6) δ 8.14 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.7, 2.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 5.23 (s, 2H), 3.93 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.48 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H);MS (ES+): 441.00 (M+Na).

[0224] Step-2: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6d) Compound 6d was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6b) (250 mg, 0.596 mmol), 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (6c) (184 mg, 0.894 mmol), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.507 mL, 1.014 mmol), tricyclohexylphosphine (66.9 mg, 0.239 mmol), Pd 2 (dba) 3 (109 mg, 0.119 mmol) and heated in a microwave at 135 °C for 30 min, which gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6d) (121 mg, 44% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6) δ 8.14 (s, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.3, 2.3 Hz, 1H), 5.27 (s, 2H), 3.81 (s, 2H), 3.77 (s, 3H), 3.71 (q, J = 7.2 Hz, 2H), 3.46 (s, 2H), 0.87 (t, J = 7.1 Hz, 3H); MS (ES+): 464.1 (M+1).

[0225] Step-3: Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetic acid (6e) Compound 6e was prepared from ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6d) (121 mg, 0.261 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (75 mg, 1.789 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetic acid (6e) (58 mg, 22% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.94 (s, 1H, D 2 O replaceable), 8.50 (s, 3H, D 2O exchangeable), 8.15 (s, 1H), 7.88 (t, J = 1.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.67 - 7.48 (m, 3H), 7.37 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H), 5.30 (s, 2H), 4.14 (s, 2H), 3.75 (s, 3H), 3.44 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -122.31;MS (ES+): 436.1 (M+1);Analysis C 25 H 22 FNO 5 .1.1HCl.H 2 Calculated for O: C, 60.84; H, 5.13; Cl, ​​7.90; N, 2.84; Found: C, 60.56; H, 5.29; Cl, ​​7.70; N, 2.86.

[0226] Scheme 7 [ka] Preparation of 2,2'-((((7-(3-(aminomethyl)phenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (7f) Step-1: Preparation of (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (7a) To a solution of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate (3c) (268 g, 600 mmol) in THF (1200 mL) was added LiBH 4 (600 mL, 1201 mmol, 2 M solution in THF) and MeOH (48.6 mL, 1201 mmol) were added. The reaction mixture was stirred at room temperature for 6 h and saturated NH 4It was quenched with aqueous Cl and extracted with EtOAc, the organic layer was washed with brine, dried, filtered, concentrated in vacuo and used directly in the next step. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.62 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 6.93 (s, 1H), 5.29 (t, J = 5.8 Hz, 1H), 4.81 (s, 2H), 4.53 (d, J = 5.8 Hz, 2H), 0.89 (s, 9H), 0.12 (s, 6H).

[0227] Step-2: Preparation of (7-iodobenzofuran-2,5-diyl)dimethanol (7b) To a solution of (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (7a) (2 g, 4.78 mmol) in DCM (18 mL) was added HCl (4N in dioxane, 2.39 mL, 9.56 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated in vacuo, and the resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with EtOAc / MeOH (9:1) in hexanes 0-80%] to give (7-iodobenzofuran-2,5-diyl)dimethanol (7b) (1.42 g, 98% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.60 (d, J = 1.5 Hz, 1H), 7.55 - 7.48 (m, 1H), 6.92 - 6.84 (m, 1H), 5.53 (t, J = 5.8 Hz, 1H, D 2 O exchangeable), 5.27 (t, J = 5.8 Hz, 1H, D 2 MS (ES+): 326.9 (M+Na).

[0228] Step-3: Preparation of diethyl 2,2'-((((7-iodobenzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7d) To a solution of (7-iodobenzofuran-2,5-diyl)dimethanol (7b) (500 mg, 1.644 mmol), triphenylphosphine (949 mg, 3.62 mmol) and ethyl 2-(2-hydroxyphenyl)acetate (7c) (652 mg, 3.62 mmol; CAS number 41873-65-8) in DCM (30 mL) was added dropwise bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.33 g, 3.62 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 min. The suspension was filtered through a pad of Celite, and the filtrate was concentrated in vacuo and purified by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%] to give diethyl 2,2′-((((7-iodobenzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7d) (400 mg, 38.7% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.76 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.29 - 7.20 (m, 5H), 7.14 (s, 1H), 7.06 (dd, J = 8.3, 1.1 Hz, 1H), 6.99 - 6.87 MS (ES+): 651.1 (M+Na).

[0229] Step-4: 2,2'-((((7-(3-(aminomethyl)phenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diethyl diacetate (7e) Compound 7e was prepared from diethyl 2,2'-((((7-iodobenzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7d) (280 mg, 0.446 mmol) in dioxane (15 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (150 mg, 0.802 mmol), bis(triphenylphosphine)palladium(II) chloride (47 mg, 0.067 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (185 mg, 1.337 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with DMA-80 in DCM 0-50%], diethyl 2,2'-((((7-(3-(aminomethyl)phenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7e) (136 mg, 50% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.80 (s, 1H), 7.76 - 7.70 (m, 1H), 7.68 - 7.66 (m, 1H), 7.66 - 7.63 (m, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.48 - 7.39 (m, 3H), 7.29 - 7.20 (m, 5H), 7.13 - 7.08 (m, 1H), 7.06 (s, 1H), 6.98 - 6.87 (m, 2H), 5.30 (s, 2H), 5.24 (s, 2H), 3.95 - 3.86 (m, 4H), 3.80 (s, 2H), 3.63 (s, 2H), 3.59 (s, 2H), 1.01 - 0.92 (m, 6H); MS (ES+): 608.3 (M+1).

[0230] Step-5: Preparation of 2,2'-((((7-(3-(aminomethyl)phenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (7f) Compound 7f was prepared according to the procedure reported in Scheme 1, step-3 from diethyl 2,2'-((((7-(3-(aminomethyl)phenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7e) (136 mg, 0.224 mmol) in THF (5 mL) using a solution of lithium hydroxide hydrate (47 mg, 1.119 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (50 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2,2′-((((7-(3-(aminomethyl)phenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (7f) (46 mg, 37% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.81 (brs, 3H, D 2 O exchangeable), 8.03 - 7.99 (m, 1H), 7.96 - 7.91 (m, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.30 - MS (ES+): 552.2 (M+1);(ES-): 550.2 (M-1);Analysis C 33 H 29 NO 7 .HCl.1.25H 2 Calculated for O: C, 64.92; H, 5.37; Cl, ​​5.81; N, 2.29; Found: C, 64.84; H, 5.36; Cl, ​​5.93; N, 2.44.

[0231] Scheme 8 [ka] Preparation of 2-(2-((5,7-bis(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (8e) Step-1: Preparation of (5,7-dibromobenzofuran-2-yl)methanol (8b) To a solution of 5,7-dibromobenzofuran-2-carboxylic acid (8a) (850 mg, 2.66 mmol; CAS number 90415-17-1) and N-methylmorpholine (0.351 mL, 3.19 mmol) in THF (50 mL) was added isobutyl chloroformate (0.419 mL, 3.19 mmol) at -5 °C and stirred for 30 min. The reaction mixture was filtered through a pad of Celite and the precipitate was washed with THF (3 x 20 mL). The combined filtrate was cooled to 0 °C and diluted with NaBH in water (2 mL). 4 A solution of (302 mg, 7.97 mmol) was added. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×). The combined organics were dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), EtOAc / MeOH (9:1) in hexanes 0-50%] to give (5,7-dibromobenzofuran-2-yl)methanol (8b) (705 mg, 87% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.86 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 6.88 (d, J = 0.9 Hz, 1H), 5.63 (t, J = 5.9 Hz, 1H), 4.61 (dd, J = 5.9, 0.9 Hz, 2H).

[0232] Step-2: Preparation of ethyl 2-(2-((5,7-dibromobenzofuran-2-yl)methoxy)phenyl)acetate (8c) Compound 8c was prepared from (5,7-dibromobenzofuran-2-yl)methanol (8b) (400 mg, 1.307 mmol) in DCM (30 mL) using triphenylphosphine (377 mg, 1.438 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (259 mg, 1.438 mmol), a solution of bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (528 mg, 1.438 mmol) in DCM (20 mL) and stirred at room temperature for 30 min according to the procedure reported in step-3 of scheme 7. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-50%], ethyl 2-(2-((5,7-dibromobenzofuran-2-yl)methoxy)phenyl)acetate (8c) (210 mg, 0.449 mmol, 34% yield) as a yellow oil; MS (ES+): 488.90 (M+1).

[0233] Step-3: Preparation of ethyl 2-(2-((5,7-bis(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (8d) Compound 8d was prepared from ethyl 2-(2-((5,7-dibromobenzofuran-2-yl)methoxy)phenyl)acetate (8c) (210 mg, 0.449 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (210 mg, 1.121 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (104 mg, 0.09 mmol), K in water (3 mL) 2 CO 3 (155 mg, 1.121 mmol) and heated at 100 °C for 3 h. This afforded, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0–50%], ethyl 2-(2-((5,7-bis(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (8d) (121 mg, 52% yield) as a clear oil;1 H NMR (300 MHz, DMSO-d 6 ) δ 7.89 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.80 - 7.72 (m, 3H), 7.69 - 7.55 (m, 3H), 7.49 - 7.37 (m, 4H), 7.35 - 7.28 (m, 2H), 7.28 - 7.19 (m, 3H), 7.11 (s, 1H), 6.99 - 6.91 (m, 1H), 5.32 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 3.83 - 3.76 (m, 4H), 3.60 (s, 2H), 0.98 (t, J = 7.1 Hz, 3H);MS(ES+): 521.2 (M+1).

[0234] Step-4: Preparation of 2-(2-((5,7-bis(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (8e) Compound 8e was prepared from ethyl 2-(2-((5,7-bis(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (8d) (121 mg, 0.232 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (75 mg, 1.794 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5,7-bis(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (8e) (49 mg, 22% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.71 (s, 3H, D 2O exchangeable), 8.25 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 8.04 (dd, J = 7.5, 1.8 Hz, 2H), 7.99 (d, J = 1.7 Hz, 1H), 7.83 (dt, J = 7.5, 1.7 Hz, 1H), 7.62 - 7.45 (m, 4H), 7.25 (tt, J = 7.5, 1.6 Hz, 3H), 7.15 (s, 1H), 6.95 (td, J = 7.0, 1.8 Hz, 1H), 5.36 (s, 2H), 4.15 (d, J = 8.6 Hz, 4H), 3.57 (s, 2H);MS (ES+): 493.2 (M+1);(ES-): 491.2 (M-1);Analysis C 31 H 28 N 2 O 4 .2HCl.H 2 Calculated for O: C, 63.81; H, 5.53; Cl, ​​12.15; N, 4.80; Found: C, 63.45; H, 5.43; Cl, ​​12.09; N, 4.88.

[0235] Scheme 9 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (9e) Step-1: Preparation of (5-bromobenzofuran-3-yl)methanol (9b) Compound 9b was prepared from 5-bromobenzofuran-3-carboxylic acid (9a) (850 mg, 3.53 mmol; CAS number 461663-79-6) in THF (50 mL) with N-methylmorpholine (0.465 mL, 4.23 mmol), isobutyl chloroformate (0.556 mL, 4.23 mmol) and NaBH in water (2.0 mL) according to the procedure reported in Scheme 8, step-1. 4(400 mg, 10.58 mmol) solution, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc / MeOH (9:1) in hexanes 0–50%] afforded (5-bromobenzofuran-3-yl)methanol (9b) (705 mg, 88% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.97 - 7.83 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.7, 2.1 Hz, 1H), 5.21 (t, J = 5.6 Hz, 1H, D2O interchangeable), 4.61 (dd, J = 5.6, 1.1Hz, 2H).

[0236] Step-2: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (9c) Compound 9c was prepared according to the procedure reported in step-3 of scheme 7 from (5-bromobenzofuran-3-yl)methanol (9b) (350 mg, 1.541 mmol) in DCM (30 mL) using a solution of triphenylphosphine (445 mg, 1.696 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (306 mg, 1.696 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (623 mg, 1.696 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-50%], ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (9c) (255 mg, 43% yield) as a clear oil; MS (ES+): 413.00 (M+Na).

[0237] Step-3: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (9d) Compound 9d was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (9c) (250 mg, 0.642 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (181 mg, 0.963 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (111 mg, 0.096 mmol), K in water (3 mL) 2 CO 3 (222 mg, 1.606 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (9d) (88 mg, 33% yield) as a clear oil; MS (ES+): 416.1 (M+1).

[0238] Step-4: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (9e) Compound 9e was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (9d) (88 mg, 0.212 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (108 mg, 2.57 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (9e) (30 mg, 37% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.40 (s, 3H, D 2O exchangeable), 8.13 (s, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.89 (t, J = 1.8 Hz, 1H), 7.78 - 7.64 (m, 3H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 (dt, J = MS (ES+): 388.1 (M+1);(ES-): 386.1 (M-1);Analysis C 24 H 21 NO 4 .1.05HCl.0.75H 2 Calculated for O: C, 65.63; H, 5.40; Cl, ​​8.48; N, 3.19; Found: C, 66.03; H, 5.25; Cl, ​​8.50; N, 3.43.

[0239] Scheme 10 [ka] Preparation of 2-(2-(5-(3-(aminomethyl)phenyl)benzofuran-3-carboxamido)phenyl)acetic acid (10c) Step-1: Preparation of ethyl 2-(2-(5-bromobenzofuran-3-carboxamido)phenyl)acetate (10b) To a stirred solution of 5-bromobenzofuran-3-carboxylic acid (9a) (150 mg, 0.622 mmol; CAS number 461663-79-6) in DMF (5 mL) was added ethyl 2-(2-aminophenyl)acetate (10a) (139 mg, 0.778 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.272 mL, 1.556 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU) (296 mg, 0.778 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-100%] to give ethyl 2-(2-(5-bromobenzofuran-3-carboxamido)phenyl)acetate (10b) (225 mg, 90% yield) as a yellow oil; MS (ES+): 402.00 (M+1).

[0240] Step-2: Preparation of 2-(2-(5-(3-(aminomethyl)phenyl)benzofuran-3-carboxamido)phenyl)acetic acid (10c) Compound 10c was prepared from ethyl 2-(2-((5-bromobenzofuran-3-carboxamido)phenyl)acetate (10b) (225 mg, 0.559 mmol) in dioxane (10 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (157 mg, 0.839 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (97 mg, 0.084 mmol), K in water (3 mL) 2 CO 3(193 mg, 1.398 mmol) and heated at 100 °C for 3 h. This gave the HCl salt of 2-(2-(5-(3-(aminomethyl)phenyl)benzofuran-3-carboxamido)phenyl)acetic acid (10c) (35 mg, 16% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA80 in DCM 0–50%] followed by reverse-phase column chromatography [C18 column (30 g), eluting with ACN in water (containing 0.1% HCl) 0–100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.32 (s, 1H, D 2 O replaceable), 10.11 (s, 1H, D 2 O exchangeable), 8.78 (s, 1H), 8.39 (d, J = 1.9 Hz, 4H, 3H D 2 O exchangeable), 7.89 (t, J = 1.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.56 - 7.44 (m, 3H), 7.37 - 7.29 (m, 2H), 7.23 (td, J = 7.4, 1.5 Hz, 1H), 4.12 (s, 2H), 3.71 (s, 2H);MS (ES+): 401.2 (M+1);(ES-): 399.1 (M-1);Analysis C 24 H 20 N 2 O 4 .HCl.H 2 Calculated for O: C, 63.37; H, 5.10; Cl, ​​7.79; N, 6.16; Found: C, 62.95; H, 4.73; Cl, ​​7.53; N, 6.12.

[0241] Scheme 11 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (11d) Step-1: Preparation of tert-butyl 2-(2-((5-(((cyclopropylmethyl)amino)methyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (11b) To a solution of tert-butyl 2-(2-((5-formyl-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3i) (350 mg, 0.711 mmol) in DCM / MeOH (10 mL, 4:1) was added cyclopropylmethanamine (11a) (51 mg, 0.711 mmol), acetic acid (0.081 mL, 1.422 mmol) and stirred at room temperature for 10 minutes. 4 (54 mg, 1.42 mmol) was added, stirred at room temperature overnight, and saturated NaHCO 3 (10 mL). The reaction mixture was extracted with EtOAc (3×). The organic layers were combined, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-60%] to afford tert-butyl 2-(2-((5-(((cyclopropylmethyl)amino)methyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (11b) (140 mg, 36% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6) δ 7.69 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.27 (td, J = 7.8, 7.2, 1.7 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.10 (s, 1H), 6.94 (td, J = 7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 3.75 (s, 2H), 3.51 (s, 2H), 2.34 (d, J = 6.6 Hz, 2H), 1.28 (s, 9H), 0.93 - 0.81 (m, 1H), 0.44 - 0.33 (m, 2H), 0.11 - 0.02 (m, 2H); MS (ES+): 548.10 (M+1).

[0242] Step-2: Preparation of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (11c) Compound 11c was prepared from tert-butyl 2-(2-((5-(((cyclopropylmethyl)amino)methyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (11b) (140 mg, 0.256 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (72 mg, 0.384 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (44 mg, 0.038 mmol), K in water (3 mL) 2 CO 3 (88 mg, 0.639 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with DMA-80 in DCM 0-50%], tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (11c) (76 mg, 56% yield) as a clear oil; MS (ES+): 527.2 (M+1).

[0243] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (11d) Compound 11d was prepared from tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (11c) (76 mg, 0.144 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (43 mg, 1.023 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (11d) (53 mg, 78% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.20 (s, 1H, D 2 O replaceable), 9.53 (s, 2H, D 2 O replaceable), 8.59 (s, 3H, D 2O exchangeable), 8.12 (d, J = 1.8 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.84 (d, J = 1.6 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.32 - 7.18 (m, 3H), 7.13 (s, 1H), 6.94 (td, J = 7.2, 1.4 Hz, 1H), 5.35 (s, 2H), 4.28 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H), 2.83 (s, 2H), 1.23 - 1.07 (m, 1H), 0.61 - 0.52 (m, 2H), 0.42 - 0.31 (m, 2H);MS (ES+): 471.2 (M+1);(ES-): 469.2 (M-1);Analysis C 29 H 30 N 2 O 4 .2HCl.1.5H 2 Calculated for O: C, 61.05; H, 6.18; Cl, ​​12.43; N, 4.91; Found: C, 61.20; H, 6.12; Cl, ​​12.16; N, 4.92.

[0244] Scheme 12 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetic acid (12 g) Step-1: Preparation of (2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (12b) A solution of 4-ethyl-2-methoxybenzaldehyde (12a) (1.82 g, 11.08 mmol; CAS number 142224-35-9), methyl(methylsulfinylmethyl)sulfane (2.203 g, 17.73 mmol), and Triton B (40 wt% in MeOH) (2.317 g, 5.54 mmol) in THF (20 mL) was heated at 70 °C for 16 h. The reaction mixture was diluted with ethyl acetate (250 mL), washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexanes 0-40%] to give (2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (12b) (2.66 g, 89% yield) as a pale yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.01 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.93 - 6.83 (m, 1H), 3.84 (s, 3H), 2.71 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 2.28 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H); MS (ES+): 271 (M+1).

[0245] Step-2: Preparation of ethyl 2-(4-ethyl-2-methoxyphenyl)acetate (12c) To a solution of (2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (12b) (2.66 g, 9.84 mmol) in ethanol (20 mL) was added HCl (4 M HCl in dioxane, 12.30 mL, 49.2 mmol) and heated at 80° C. for 16 h. The reaction mixture was concentrated to remove ethanol and saturated NaHCO 3(20 mL) and extracted with EtOAc. The organic layer was washed with water, brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with ethyl acetate in hexanes 0-2%] to give ethyl 2-(4-ethyl-2-methoxyphenyl)acetate (12c) (1.61 g, 74% yield) as a clear, colorless liquid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.06 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.73 (dd, J = 7.5, 1.6 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.51 (s, 2H), 2.58 (q, J = 7.6 Hz, 2H), 1.22 - 1.13 (m, 6H); MS (ES+): 245 (M+Na).

[0246] Step-3: Preparation of ethyl 2-(4-ethyl-2-hydroxyphenyl)acetate (12d) To a stirred solution of ethyl 2-(4-ethyl-2-methoxyphenyl)acetate (12c) (1.61 g, 7.24 mmol) in DCM (15 mL) was added boron tribromide (10 M in DCM, 14.49 mL, 14.49 mmol) under nitrogen atmosphere at 0° C. and stirred at 0° C. for 2 h. The reaction mixture was diluted with NaHCO 3 (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with water, brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with EtOAc in hexanes 0-10%] to give ethyl 2-(4-ethyl-2-hydroxyphenyl)acetate (12d) (472 mg, 31% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6) δ 9.32 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 6.58 (dd, J = 7.6, 1.7 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.48 (s, MS (ES+): 209 (M+1).

[0247] Step-4: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (12e) Compound 12e was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (300 mg, 1.035 mmol) in acetone (5 mL) with ethyl 2-(4-ethyl-2-hydroxyphenyl)acetate (12d) (248 mg, 1.190 mmol), K according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (500 mg, 3.62 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (12e) (412 mg, 95% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6) δ 8.14 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.7, 2.1 Hz, 1H), 7.12 - 7.02 (m, 2H), 6.76 (dd, J = 7.6, 1.5 Hz, 1H), 5.23 (s, 2H), 3.93 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H).

[0248] Step-5: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (12f) Compound 12f was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (12e) (206 mg, 0.494 mmol) in dioxane (3 mL) with 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (6c) (152 mg, 0.740 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.420 mL, 0.839 mmol), tricyclohexylphosphine (55 mg, 0.197 mmol), Pd 2 (dba) 3 (90 mg, 0.099 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (12f) (79 mg, 35% yield) as a clear oil; MS (ES+): 462.2 (M+1).

[0249] Step-6: Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetic acid (12 g) Compound 12g was prepared according to the procedure reported in step-3 of scheme 1 from 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)ethyl acetate (12f) (79 mg, 0.171 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (62 mg, 1.481 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetic acid (12g) (22 mg, 30% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.50 (s, 1H, D 2 O exchangeable), 8.15 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.68 - 7.58 (m, 1H), 7.58 - 7.50 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.76 (dd, J = 7.6, 1.5 Hz, 1H), 5.30 (s, 2H), 4.15 (s, 2H), 3.47 (s, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -122.31;MS (ES+): 434.2 (M+1);Analysis C 26 H 24 FNO 4 .HCl.1.75H 2Calculated for O: C, 62.27; H, 5.73; N, 2.79; Found: C, 62.56; H, 5.84; N, 3.04.

[0250] Scheme 13 [ka] Preparation of 2,2'-((((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (13b) Step-1: Preparation of diethyl 2,2'-((((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (13a) Compound 13a was prepared from diethyl 2,2'-((((7-iodobenzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7d) (290 mg, 0.461 mmol) in dioxane (15 mL) using 3-(aminomethyl)-2-fluorophenylboronic acid (6c) (171 mg, 0.831 mmol), bis(triphenylphosphine)palladium(II) chloride (48.6 mg, 0.069 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (191 mg, 1.384 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], diethyl 2,2'-((((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (13a) (180 mg, 62% yield) as a yellow oil; MS (ES+): 626.2 (M+1).

[0251] Step-2: Preparation of 2,2'-((((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (13b) Compound 13b was prepared according to the procedure reported in step-3 of scheme 1 from diethyl 2,2'-((((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (13a) (180 mg, 0.288 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (155 mg, 3.69 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2,2′-((((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (13b) (34 mg, 21% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.73 (s, 1H, D 2 O exchangeable), 7.79 (d, J = 1.7 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.50 - 7.47 (m, 1H), 7.46 - 7.39 (m, 1H), 7.26 - 7.15 (m, 5H), 7.13 - 7.03 (m, 2H), 6.97 - 6.86 (m, 2H), 5.26 (d, J = 3.0 Hz, 4H), 4.17 (s, 2H), 3.58 (s, 2H), 3.54 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -118.59;MS (ES+): 570.2 (M+1);(ES-): 568.2 (M-1);Analysis C 33 H 28 FNO 7 .HCl.1.5H 2Calculated for O: C, 62.61; H, 5.09; Cl, ​​5.60; N, 2.21; Found: C, 62.57; H, 4.96; Cl, ​​5.80; N, 2.28.

[0252] Scheme 14 [ka] Preparation of 2-(2-(5-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)phenyl)acetic acid (14c) Step-1: Preparation of ethyl 2-(2-(5-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)phenyl)acetate (14b) Compound 14b was prepared according to the procedure reported in step-1 of scheme 10 from 5-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (14a) (350 mg, 1.452 mmol; CAS number 1167056-46-3) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate (10a) (325 mg, 1.815 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.634 mL, 3.63 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU) (690 mg, 1.815 mmol) and stirring at room temperature overnight. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-100%], ethyl 2-(2-(5-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)phenyl)acetate (14b) (140 mg, 24% yield) as a white solid; MS(ES+): 402.00 (M+1).

[0253] Step-2: Preparation of 2-(2-(5-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)phenyl)acetic acid (14c) Compound 14c was prepared from ethyl 2-(2-((5-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)phenyl)acetate (14b) (140 mg, 0.35 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (98 mg, 0.522 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (60.3 mg, 0.052 mmol), K in water (3 mL) 2 CO 3 (120 mg, 0.870 mmol) and heated at 100 °C for 3 h. This gave the HCl salt of 2-(2-(5-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamido)phenyl)acetic acid (14c) (40 mg, 29% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM 0–50%] followed by reverse-phase column chromatography [C18 column (30 g), eluting with ACN in water (containing 0.1% HCl) 0–100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.37 (d, J = 3.2 Hz, 1H, D 2 O replaceable), 10.54 (s, 1H, D 2 O replaceable), 8.48 (s, 3H, D 2 O exchangeable), 8.38 (d, J = 3.1 Hz, 1H), 8.21 (s, 1H), 8.17 - 8.05 (m, 2H), 7.97 (dd, J = 8.5, 1.4 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.62 - 7.51 (m, 2H), 7.38 - 7.25 (m, 2H), 7.16 (td, J = 7.4, 1.3 Hz, 1H), 4.13 (q, J = 5.8 Hz, 2H), 3.78 (s, 2H);MS (ES+): 401.1 (M+1);(ES-): 399.1 (M-1);Analysis C 23 H 20N 4 O 3 .2HCl.2.75H 2 Calculated for O: C, 52.83; H, 5.30; Cl, ​​13.56; N, 10.71; Found: C, 53.03; H, 5.19; Cl, ​​13.21; N, 10.70.

[0254] Scheme 15 [ka] Preparation of 3-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)propanoic acid (15e) Step-1: Preparation of ethyl 3-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15a) Compound 15a was prepared according to the procedure reported in step-3 of scheme 7 from (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (7a) (2 g, 4.78 mmol) in DCM (30 mL) using a solution of triphenylphosphine (1.379 g, 5.26 mmol), ethyl 3-(2-hydroxyphenyl)propanoate (2a) (1.021 g, 5.26 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.931 g, 5.26 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), elution with EtOAc in hexanes 0-50%], ethyl 3-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15a) (1.9 g, 67% yield) as a yellow oil.

[0255] Step-2: Preparation of ethyl 3-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15b) Compound 15b was prepared according to the procedure reported in step-2 of scheme 7 from ethyl 3-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15a) (1.9 g, 3.20 mmol) in DCM (20 mL) using 4N HCl (3.59 mL, 14.34 mmol) in dioxane and stirring at room temperature for 3 h. This afforded ethyl 3-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15b) (975 mg, 43% yield) as a clear oil after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-70%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.75 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.17 (t, J = 7.9 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.87 (td, J = 7.4, 1.1 Hz, 1H), 5.55 (t, J = 5.8 Hz, 1H), 5.18 (s, 2H), 4.59 (dd, J = 5.9, 0.8 Hz, 2H), 4.07 - 3.97 (m, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.59 - 2.53 (m, 2H), 1.22 - 1.06 (m, 3H).

[0256] Step-3: Preparation of ethyl 3-(2-((2-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15c) Compound 15c was prepared from ethyl 3-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15b) (800 mg, 1.67 mmol) in DCM (30 mL) using a solution of triphenylphosphine (481 mg, 1.832 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (330 mg, 1.832 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (673 mg, 1.832 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. according to the procedure reported in step-3 of scheme 7. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 3-(2-((2-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15c) (700 mg, 65% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.82 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.29 - 7.14 (m, 6H), 7.07 - 7.02 (m, 1H), 6.95 (td, J = 7.3, 1.3 Hz, 1H), 6.87 (td, J = 7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 5.19 (s, 2H), 4.07 - 3.96 (m, 4H), 3.61 (s, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.22 - 1.10 (m, 6H).

[0257] Step-4: Preparation of ethyl 3-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)propanoate (15d) Compound 15d was prepared from ethyl 3-(2-((2-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)propanoate (15c) (400 mg, 0.623 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (175 mg, 0.934 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (108 mg, 0.093 mmol), K in water (3 mL) 2 CO 3 (215 mg, 1.556 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], ethyl 3-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)propanoate (15d) (241 mg, 62% yield) as a clear oil; MS (ES+): 622.2 (M+1); (ES-): 620.2 (M-1).

[0258] Step-5: Preparation of 3-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)propanoic acid (15e) Compound 15e was prepared according to the procedure reported in Scheme 1, step-3 from ethyl 3-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)propanoate (15d) (241 mg, 0.388 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (131 mg, 3.11 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 3-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)propanoic acid (15e) (120 mg, 34% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.86 (s, 3H, D 2 O exchangeable), 7.99 (d, J = 1.9 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.29 - 7.15 (m, 5H), 7.13 - 7.06 (m, 2H), 6.94 (td, J = 7.2, 1.5 Hz, 1H), 6.88 (td, J = 7.3, 1.2 Hz, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H), 2.85 (t, J = 7.7 Hz, 2H), 2.57 - 2.51 (m, 2H);MS (ES+): 566.2 (M+1);(ES-): 564.2 (M-1);Analysis C 34 H 31 NO 7 .HCl.H 2Calculated for O: C, 65.86; H, 5.53; Cl, ​​5.72; N, 2.26; Found: C, 65.84; H, 5.61; Cl, ​​5.99; N, 2.39.

[0259] Scheme 16 [ka] Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (16e) Step-1: Preparation of methyl 2-(3-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (16a) Compound 16a was prepared according to the procedure reported in step-3 of scheme 7 from (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (7a) (2 g, 4.78 mmol) in DCM (30 mL) using a solution of methyl 2-(3-hydroxyphenyl)acetate (4a) (0.874 g, 5.26 mmol), triphenylphosphine (1.379 g, 5.26 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.931 g, 5.26 mmol) in DCM (20 mL) and stirred at room temperature for 90 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], methyl 2-(3-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (16a) (1.61 g, 59% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6) δ 7.76 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.24 (td, J = 7.5, 1.3 Hz, 1H), 6.97 (s, 1H), 6.95 - 6.89 (m, 2H), 6.87 - 6.80 (m, 1H), 5.12 (s, 2H), 4.82 (s, 2H), 3.64 (s, 2H), 3.60 (s, 3H), 0.89 (s, 9H), 0.13 (s, 6H).

[0260] Step-2: Preparation of methyl 2-(3-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (16b) Compound 16b was prepared according to the procedure reported in step-2 of scheme 7 from methyl 2-(3-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (16a) (1.61 g, 2.84 mmol, 59% yield) in DCM (20 mL) using 4N HCl (3.59 mL, 14.34 mmol) in dioxane and stirring at room temperature for 3 h. This afforded methyl 2-(3-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (16b) (1.05 g, 49% yield) as a colorless oil after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane 0-70%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.75 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.25 (td, J = 7.4, 1.3 Hz, 1H), 6.96 - 6.90 (m, 3H), 6.85 (dt, J = 7.6, 1.2 Hz, 1H), 5.57 (t, J = 5.8 Hz, 1H), 5.13 (s, 2H), 4.63 - 4.55 (m, 2H), 3.65 (s, 2H), 3.61 (s, 3H).

[0261] Step-3: Preparation of ethyl 2-(2-((7-iodo-5-((3-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (16c) Compound 16c was prepared from methyl 2-(3-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (16b) in DCM (30 mL) according to the procedure reported in step-3 of scheme 7 using a solution of ethyl 2-(2-hydroxyphenyl)acetate (7c) (373 mg, 2.067 mmol), triphenylphosphine (542 mg, 2.067 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (759 mg, 2.067 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((7-iodo-5-((3-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (16c) (540 mg, 47% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.81 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.31 - 7.19 (m, 4H), 7.15 (s, 1H), 6.99 - 6.91 (m, 3H), 6.85 (dt, J = 7.5, 1.2 Hz, 1H), 5.30 (s, 2H), 5.15 (s, 2H), 4.05 - 4.01 (m, 2H), 3.65 (s, 3H), 3.61 (d, J = 1.6 Hz, 4H), 1.04 (t, J = 7.1 Hz, 3H).

[0262] Step-4: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((3-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (16d) Compound 16d was prepared from ethyl 2-(2-((7-iodo-5-((3-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (16c) (400 mg, 0.651 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (183 mg, 0.977 mmol), Pd(PPh) in dioxane (10 mL) according to the procedure reported in Scheme 3, step-8. 3 ) 4 (113 mg, 0.098 mmol), K in water (3 mL) 2 CO 3 (225 mg, 1.628 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with DMA80 in DCM 0–50%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((3-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (16d) (223 mg, 58% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.80 (t, J = 1.8 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.29 - 7.19 (m, 4H), 7.08 (s, 1H), 6.99 - 6.93 (m, 3H), 6.87 - 6.82 (m, 1H), 5.30 (s, 2H), 5.23 (s, 2H), 3.88 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 3.63 (s, 2H), 3.60 (s, 5H), 0.96 (t, J = 7.1 Hz, 3H).

[0263] Step-5: Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (16e) Compound 16e was prepared according to the procedure reported in Scheme 1, step-3 from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((3-(2-methoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (16d) (223 mg, 0.376 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (137 mg, 3.26 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2-(3-((7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (16e) (120 mg, 58% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.99 (d, J = 1.8 Hz, 1H), 7.96 - 7.88 (m, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.30 - 7.18 (m, 4H), 7.10 (s, 1H), 7.01 - 6.90 (m, 3H), 6.85 (dt, J = 7.5, 1.2 Hz, 1H), 5.33 (s, 2H), 5.22 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H), 3.55 (s, 2H);MS (ES+): 552.2 (M+1);(ES-): 550.2 (M-1);Analysis C 33 H 29 NO 7 .HCl.H 2Calculated for O: C, 65.40; H, 5.32; Cl, ​​5.85; N, 2.31; Found: C, 65.50; H, 5.51; Cl, ​​6.17; N, 2.43.

[0264] Scheme 17 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)-7-methylbenzofuran-3-yl)methoxy)phenyl)acetic acid (17e) Step-1: Preparation of (5-bromo-7-methylbenzofuran-3-yl)methanol (17b) Compound 17b was prepared from 5-bromo-7-methylbenzofuran-3-carboxylic acid (17a) (750 mg, 2.94 mmol; CAS number 1492450-22-2) in THF (20 mL) with N-methylmorpholine (0.388 mL, 3.53 mmol), isobutyl chloroformate (0.463 mL, 3.53 mmol), NaBH in water (2.0 mL) according to the procedure reported in Scheme 8, step-1. 4 (334 mg, 8.82 mmol) solution, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc / MeOH (9:1) in hexanes 0–50%] afforded (5-bromo-7-methylbenzofuran-3-yl)methanol (17b) (602 mg, 85% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.91 (s, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 5.19 (t, J = 5.6 Hz, 1H), 4.59 (dd, J = 5.6, 1.1 Hz, 2H), 2.45 (s, 3H).

[0265] Step-2: Preparation of ethyl 2-(2-((5-bromo-7-methylbenzofuran-3-yl)methoxy)phenyl)acetate (17c) Compound 17c was prepared according to the procedure reported in Scheme 7, step-3 from (5-bromo-7-methylbenzofuran-3-yl)methanol (17b) (286 mg, 1.186 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (235 mg, 1.305 mmol) in DCM (30 mL) using a solution of triphenylphosphine (342 mg, 1.305 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (479 mg, 1.305 mmol) in DCM (20 mL) at room temperature for 30 min. This afforded, after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((5-bromo-7-methylbenzofuran-3-yl)methoxy)phenyl)acetate (17c) (242 mg, 51% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 2.0, 1.0 Hz, 1H), 7.29 (ddd, J = 9.0, 7.4, 1.8 Hz, 1H), 7.20 (td, J = 8.1, 1.4 Hz, 2H), 6.93 (td, J = 7.4, 1.2 Hz, 1H), 5.23 (d, J = 0.9 Hz, 2H), 3.95 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 2.47 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H);MS (ES-): 401.10 (M-1).

[0266] Step-3: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-7-methylbenzofuran-3-yl)methoxy)phenyl)acetate (17d) Compound 17d was prepared from ethyl 2-(2-((5-bromo-7-methylbenzofuran-3-yl)methoxy)phenyl)acetate (17c) (260 mg, 0.645 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (181 mg, 0.967 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.548 mL, 1.096 mmol), tricyclohexylphosphine (54.2 mg, 0.193 mmol) and Pd 2 (dba) 3 (59.0 mg, 0.064 mmol) and heated in a microwave at 120 °C for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-7-methylbenzofuran-3-yl)methoxy)phenyl)acetate (17d) (86 mg, 31% yield) as a colorless oil; MS (ES+): 430.2 (M+1).

[0267] Step-4: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)-7-methylbenzofuran-3-yl)methoxy)phenyl)acetic acid (17e) Compound 17e was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-7-methylbenzofuran-3-yl)methoxy)phenyl)acetate (17d) (86 mg, 0.20 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (81 mg, 1.934 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)-7-methylbenzofuran-3-yl)methoxy)phenyl)acetic acid (17e) (27 mg, 34% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (35 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1H NMR (300 MHz, DMSO-d 6 ) δ 12.16 (s, 1H, D 2 O replaceable), 8.41 (s, 3H, D 2 O exchangeable), 8.12 (s, 1H), 7.90 - 7.80 (m, 2H), 7.73 (dt, J = 7.6, 1.6 Hz, 1H), 7.57 - 7.41 (m, 3H), 7.31 - 7.16 (m, 3H), 6.92 (td, J = Analysis C 25 H 23 NO 4 .HCl.H 2 Calculated for O: C, 65.86; H, 5.75; Cl, ​​7.78; N, 3.07; Found: C, 65.70; H, 5.65; Cl, ​​7.82; N, 3.16.

[0268] Scheme 18 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetic acid (18e) Step-1: Preparation of (5-bromo-7-methoxybenzofuran-3-yl)methanol (18b) Compound 18b was prepared from 5-bromo-7-methoxybenzofuran-3-carboxylic acid (18a) (880 mg, 3.25 mmol; CAS number 1875597-44-6) in THF (20 mL) with N-methylmorpholine (0.428 mL, 3.90 mmol), isobutyl chloroformate (0.512 mL, 3.90 mmol), NaBH in water (2.0 mL) according to the procedure reported in Scheme 8, step-1. 4(368 mg, 9.74 mmol) solution, which after workup and purification by flash column chromatography [silica gel (24 g), 0-50% EtOAc / MeOH in hexanes] afforded (5-bromo-7-methoxybenzofuran-3-yl)methanol (18b) (458 mg, 55% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.89 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 5.20 (t, J = 5.6 Hz, 1H), 4.57 (dd, J = 5.6, 1.1 Hz, 2H), 3.94 (s, 3H).

[0269] Step-2: Preparation of ethyl 2-(2-((5-bromo-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetate (18c) Compound 18c was prepared according to the procedure reported in step-3 of scheme 7 from (5-bromo-7-methoxybenzofuran-3-yl)methanol (18b) (600 mg, 2.334 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (463 mg, 2.57 mmol) in DCM (30 mL) using a solution of triphenylphosphine (673 mg, 2.57 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (943 mg, 2.57 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This afforded, after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((5-bromo-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetate (18c) (800 mg, 82% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6) δ 8.10 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.24 - 7.18 (m, 2H), 7.16 (dd, J = 5.0, 1.5 Hz, 1H), 6.93 (td, J = 7.3, 1.1 Hz, 1H), 5.28 - 5.14 (m, 2H), 3.97 (d, J = 1.8 Hz, 3H), 3.94 (q, J = 2.9 Hz, 2H), 3.56 (s, 2H), 1.01 (t, J = 7.1 Hz, 3H).

[0270] Step-3: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetate (18d) Compound 18d was prepared from ethyl 2-(2-((5-bromo-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetate (18c) (369 mg, 0.880 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (247 mg, 1.320 mmol) in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1, K 3 PO 4 (0.748 mL, 1.496 mmol), tricyclohexylphosphine (74 mg, 0.264 mmol) and Pd 2 (dba) 3 (81 mg, 0.088 mmol) and heated in a microwave at 120 °C for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetate (18d) (122 mg, 31% yield); MS (ES+): 446.2 (M+1).

[0271] Step-4: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetic acid (18e) Compound 18e was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetate (18d) (122 mg, 0.274 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (111 mg, 2.64 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)-7-methoxybenzofuran-3-yl)methoxy)phenyl)acetic acid (18e) (41 mg, 36% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.18 (s, 1H, D 2 O replaceable), 8.58 (s, 3H, D 2 O exchangeable), 8.09 (s, 1H), 7.98 (s, 1H), 7.77 (dt, J = 7.2, 2.0 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.36 - 7.15 (m, Analysis C 25 H 23 NO 5 .HCl.H 2 Calculated for O: C, 63.63; H, 5.55; Cl, ​​7.51; N, 2.97; Found: C, 63.40; H, 5.59; Cl, ​​7.67; N, 3.07.

[0272] Scheme 19 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (19e) Step-1: Preparation of (7-bromobenzofuran-2-yl)methanol (19b) Compound 19b was prepared from 7-bromobenzofuran-2-carboxylic acid (19a) (3.5 g, 14.52 mmol; CAS number 550998-59-9) in THF (50 mL) with N-methylmorpholine (1.916 mL, 17.42 mmol), isobutyl chloroformate (2.288 mL, 17.42 mmol), NaBH in water (2.0 mL) according to the procedure reported in Scheme 8, step-1. 4 (1.648 g, 43.6 mmol) solution, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc / MeOH (9:1) in hexanes 0–50%] afforded (7-bromobenzofuran-2-yl)methanol (19b) (2.2 g, 67% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.62 (dd, J = 7.7, 1.1 Hz, 1H), 7.50 (dd, J = 7.8, 1.1 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.89 (t, J = 0.9 Hz, 1H), 5.57 (t, J = 5.9 Hz, 1H, D 2 O exchangeable), 4.61 (dd, J = 5.9, 0.8 Hz, 2H).

[0273] Step-2: Preparation of ethyl 2-(2-((7-bromobenzofuran-2-yl)methoxy)phenyl)acetate (19c) Compound 19c was prepared according to the procedure reported in step-3 of scheme 7 from (7-bromobenzofuran-2-yl)methanol (19b) (2 g, 9.69 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (1.746 g, 9.69 mmol) in DCM (30 mL) using a solution of triphenylphosphine (2.54 g, 9.69 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (3.56 g, 9.69 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This afforded ethyl 2-(2-((7-bromobenzofuran-2-yl)methoxy)phenyl)acetate (19c) (1.8 g, 53% yield) as a colorless oil after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane 0-50%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.68 (dd, J = 7.8, 1.1 Hz, 1H), 7.57 (dd, J = 7.8, 1.0 Hz, 1H), 7.32 - 7.17 (m, 4H), 7.13 (s, 1H), 6.95 (td, J = 7.3, 1.3 Hz, 1H), 5.30 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.03 (t, J = 7.1 Hz, 3H); MS (ES+): 410.9 (M+Na).

[0274] Step-3: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (19d) Compound 19d was prepared from ethyl 2-(2-((7-bromobenzofuran-2-yl)methoxy)phenyl)acetate (19c) (465 mg, 1.195 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (403 mg, 2.150 mmol), bis(triphenylphosphine)palladium(II) chloride (126 mg, 0.179 mmol) and K in water (3 mL) according to the procedure reported in Scheme 3, step-8.2 CO 3 (495 mg, 3.58 mmol) which, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], gave ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (19d) (212 mg, 43% yield) as a yellow oil; MS (ES+): 416.1 (M+1).

[0275] Step-4: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (19e) Compound 19e was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (19d) (212 mg, 0.510 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (201 mg, 4.78 mmol) in water (1 mL) and stirring at room temperature for 4 h according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (19e) (103 mg, 22% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.50 (s, 3H, D 2O exchangeable), 7.97 (s, 1H), 7.92 (dt, J = 7.2, 1.8 Hz, 1H), 7.67 (dd, J = 7.7, 1.2 Hz, 1H), 7.60 - 7.53 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.09 (s, 1H), 6.94 (td, J = 7.1, 1.5 Hz, 1H), 5.33 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H);MS (ES+): 388.1 (M+1);(ES-): 386.1 (M-1);Analysis C 24 H 21 NO 4 .HCl.0.5H 2 Calculated for O: C, 66.59; H, 5.36; Cl, ​​8.19; N, 3.24; Found: C, 66.30; H, 5.54; Cl, ​​8.12; N, 3.27.

[0276] Scheme 20 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-(2-(carboxymethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (20j) Step-1: Preparation of methyl 7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (20c) Compound 20c was prepared according to the procedure reported in step-1 of scheme 3 from methyl 3,5-dibromo-4-hydroxybenzoate (20a) (15 g, 48.4 mmol; CAS number 41727-47-3) in pyridine (500 mL) using but-3-yn-1-ol (20b) (3.39 g, 48.4 mmol), copper(I) oxide (3.46 g, 24.20 mmol) and heating at 120 °C for 3 h. This afforded methyl 7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (20c) (8.1 g, 56% yield) as a white solid after workup and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexane 0-80%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.21 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 6.94 - 6.90 (m, 1H), 4.95 - 4.82 (m, 1H, D 2 O exchangeable), 3.88 (s, 3H), 3.78 (t, J = 6.5 Hz, 2H), 2.99 (td, J = 6.4, 1.0 Hz, 2H).

[0277] Step-2: Preparation of methyl 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate (20d) To a solution of methyl 7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (20c) (6 g, 20.06 mmol) and imidazole (1.366 g, 20.06 mmol) in anhydrous DCM (120 mL) was added TBS-Cl (3.02 g, 20.06 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h and warmed to room temperature overnight. The reaction mixture was diluted with DCM and water and extracted with DCM (2x). The organic layers were combined, washed with water, brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexanes 0-50%] to give methyl 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate (20d) (7.5 g, 90% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.19 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 6.93 - 6.86 (m, 1H), 3.94 (t, J = 6.1 Hz, 2H), 3.85 (s, 3H), 3.02 (t, J = 6.1 Hz, 2H), 0.78 (s, 9H), -0.05 (s, 6H).

[0278] Step-3: Preparation of (7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol (20e) Compound 20e was prepared from methyl 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate (20d) (7.32 g, 17.71 mmol) in THF (60 mL) at −78° C. using LiBH according to the procedure reported in Scheme 7, Step-1. 4(3M in THF) (17.71 mL, 53.1 mmol), MeOH (2.149 mL, 53.1 mmol) and stirred at room temperature for 24 h, which after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–60%] afforded (7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol (20e) (6.36 g, 93% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.49 - 7.45 (m, 1H), 7.40 - 7.37 (m, 1H), 6.75 - 6.71 (m, 1H), 5.29 (t, J = 5.8 Hz, 1H, D 2 O exchangeable), 4.54 (d, J = 5.8 Hz, 2H), 3.94 (t, J = 6.1 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 0.79 (s, 9H), -0.04 (s, 6H).

[0279] Step-4: Preparation of ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20f) Compound 20f was prepared according to the procedure reported in step-3 of scheme 7 from (7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol (20e) (6.11 g, 15.85 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (2.86 g, 15.85 mmol) in DCM (100 mL) using a solution of triphenylphosphine (4.16 g, 15.85 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (5.82 g, 15.85 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–20%], ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20f) (6.5 g, 75% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.63 (s, 1H), 7.53 (s, 1H), 7.32 - 7.22 (m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.81 (s, 1H), 5.18 (s, 2H), 4.12 - 3.90 (m, 4H), 3.65 (s, 2H), 3.03 (t, J = 6.1 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H), 0.83 (d, J = 0.9 Hz, 9H), 0.00 (s, 6H).

[0280] Step-4: Preparation of ethyl 2-(2-((7-bromo-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20 g) Compound 20g was prepared from ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20f) (2.3 g, 4.20 mmol) according to the procedure reported in step-2 of scheme 7 using 4N HCl in dioxane (1.05 mL, 4.2 mmol) in DCM (30 mL) and stirring at room temperature for 3 h. This afforded ethyl 2-(2-((7-bromo-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20g) (1.7 g, 93% yield) as a clear oil after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc / MeOH (9:1) in hexanes 0-60%]; MS (ES+): 455.00 (M+Na).

[0281] Step-5: Preparation of ethyl 2-(2-((7-bromo-2-(2-(2-(2-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20h) Compound 20h was prepared according to the procedure reported in step-3 of scheme 7 from ethyl 2-(2-((7-bromo-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20g) (1.33 g, 3.07 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (0.608 g, 3.38 mmol) in DCM (30 mL) using a solution of triphenylphosphine (0.886 g, 3.38 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.240 g, 3.38 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), elution with EtOAc in hexanes 0-50%], ethyl 2-(2-((7-bromo-2-(2-(2-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20h) (800 mg, 82% yield) as a colorless oil; MS (ES+): 595.2 (M+1).

[0282] Step-6: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-(2-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20i) Compound 20i was prepared from ethyl 2-(2-((7-bromo-2-(2-(2-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20h) (150 mg, 0.233 mmol) in dioxane (15 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (79 mg, 0.420 mmol), bis(triphenylphosphine)palladium(II) chloride (25 mg, 0.035 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (97 mg, 0.700 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-(2-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20i) (101 mg, 70% yield) as a yellow oil; MS (ES+): 622.3 (M+1); (ES-): 656.8 (M+Cl).

[0283] Step-7: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-(2-(carboxymethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (20j) Compound 20j was prepared according to the procedure reported in Scheme 1, step-3 from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-(2-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (20i) (101 mg, 0.162 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (49 mg, 1.167 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-(2-(carboxymethyl)phenoxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (20j) (45 mg, 34% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.99 (s, 1H), 7.94 (dt, J = 7.1, 1.9 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.27 - 7.14 (m, 4H), 7.13 - 7.01 (m, 2H), 6.90 (t, J = 7.4 Hz, 2H), 6.81 (s, 1H), 5.24 (s, 2H), 4.35 (t, J = 6.4 Hz, 2H), 4.12 (s, 2H), 3.59 (s, 2H), 3.48 (s, 2H), 3.30 - 3.25 (m, 2H);MS (ES+): 566.2 (M+1);(ES-): 564.2 (M-1);Analysis C 34 H 31 NO 7 .1.05HCl.H 2 Calculated for O: C, 65.66; H, 5.52; Cl, ​​5.99; N, 2.25; Found: C, 65.56; H, 5.61; Cl, ​​6.06; N, 2.30.

[0284] Scheme 21 [ka] Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-2-carboxamido)phenyl)acetic acid (21b) Step-1: Preparation of ethyl 2-(2-(7-bromobenzofuran-2-carboxamido)phenyl)acetate (21a) Compound 21a was prepared according to the procedure reported in step-1 of scheme 10 from 7-bromobenzofuran-2-carboxylic acid (19a) (750 mg, 3.11 mmol) in DMF (10 mL) using ethyl 2-(2-aminophenyl)acetate (10a) (725 mg, 4.05 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (1.359 mL, 7.78 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU) (1420 mg, 3.73 mmol) and stirring at room temperature for 2 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g) eluted with EtOAc in hexanes 0-60%], ethyl 2-(2-(7-bromobenzofuran-2-carboxamido)phenyl)acetate (21a) (1.01 g, 81% yield) as a yellow oil; MS (ES+): 424.00 (M+Na).

[0285] Step-2: Preparation of 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-2-carboxamido)phenyl)acetic acid (21b) Compound 21b was prepared from ethyl 2-(2-(7-bromobenzofuran-2-carboxamido)phenyl)acetate (21a) (450 mg, 1.119 mmol) in dioxane (10 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (377 mg, 2.014 mmol), bis(triphenylphosphine)palladium(II) chloride (118 mg, 0.168 mmol) and K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3(464 mg, 3.36 mmol) solution, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0–80%] afforded 2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-2-carboxamido)phenyl)acetic acid (21b) (95 mg, 21% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.51 (s, 1H, D 2 O replaceable), 10.20 (s, 1H, D 2 O replaceable), 8.54 (s, 3H, D 2 O exchangeable), 8.13 (t, J = 1.7 Hz, 1H), 8.05 (dt, J = 7.3, 1.8 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.65 - 7.54 (m, MS (ES+): 401.1 (M+1);(ES-);399.1 (M-1);Analysis C 24 H 20 N 2 O 4 .HCl.0.75H 2 Calculated for O: C, 64.00; H, 5.04; Cl, ​​7.87; N, 6.22; Found: C, 64.06; H, 4.98; Cl, ​​7.66; N, 6.13.

[0286] Scheme 22 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (22e) Step-1: Preparation of ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (22a) Compound 22a was prepared according to the procedure reported in step-3 of scheme 7 from (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (7a) (49 g, 117 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (27.4 g, 152 mmol) in DCM (450 mL) using a solution of triphenylphosphine (39.9 g, 152 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (55.9 g, 152 mmol) in DCM (300 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (330 g), eluted with EtOAc in hexanes 0–8%], ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (22a) (44.7 g, 66% yield) as an off-white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.71 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.95 - 6.87 (m, 1H), 5.13 (s, 2H), 4.82 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.12 (s, 6H).

[0287] Step-2: Preparation of ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (22b) Compound 22b was prepared from ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (22a) (12 g, 20.67 mmol) in THF (180 mL) using TBAF (6.76 g, 25.8 mmol) and stirring at room temperature for 1.5 h according to the procedure reported in step-2 of scheme 3. This afforded ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (22b) (8.78 g, 91% yield) as a white solid after workup and purification by flash column chromatography [silica gel (220 g), eluted with EtOAc in hexane 0-45%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.70 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 - 6.86 (m, 2H), 5.57 - 5.50 (m, 1H, D 2 MS (ES+): 489.00 (M+Na).

[0288] Step-3: Preparation of tert-butyl 2-(2-((5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (22c) Compound 22c was prepared according to the procedure reported in step-3 of scheme 7 from ethyl 2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (22b) (1 g, 2.145 mmol), tert-butyl 2-(2-hydroxyphenyl)acetate (3g) (0.491 g, 2.359 mmol) in DCM (30 mL) using a solution of triphenylphosphine (0.619 g, 2.359 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (0.866 g, 2.359 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], tert-butyl 2-(2-((5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (22c) (650 mg, 46% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.76 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.28 - 7.18 (m, 5H), 7.15 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.98 - 6.88 (m, 2H), 5.29 (s, 2H), 5.15 (s, 2H), 4.05 - 3.98 (m, 2H), 3.62 (s, 2H), 3.52 (s, 2H), 1.28 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H).

[0289] Step-4: Preparation of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (22d) Compound 22d was prepared from tert-butyl 2-(2-((5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (22c) (995 mg, 1.516 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (511 mg, 2.73 mmol), bis(triphenylphosphine)palladium(II) chloride (160 mg, 0.227 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (628 mg, 4.55 mmol) and heated at 100 °C for 3 h, which gave, after workup and purification by flash column chromatography [silica gel (40 g), elution with DMA80 in DCM 0–50%], tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (22d) (820 mg, 85% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.81 (s, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.28 - 7.17 (m, 5H), 7.13 - 7.08 (m, 1H), 7.06 (s, 1H), 6.97 - 6.85 (m, 2H), 5.30 (s, 2H), 5.24 (s, 2H), 3.96 - 3.87 (m, 2H), 3.82 (s, 2H), 3.63 (s, 2H), 3.52 (s, 2H), 1.22 (s, 9H), 0.99 (t, J = 7.1 Hz, 3H); MS (ES+): 636.30 (M+1).

[0290] Step-5: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (22e) Compound 22e was prepared according to the procedure reported in Scheme 3, step-9 from tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (22d) (220 mg, 0.346 mmol) in DCM (5 mL) using TFA (0.533 mL, 6.92 mmol) and stirring at room temperature for 2 h. This gave the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (22e) (21 mg, 10% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0–50%] followed by reverse phase column chromatography [C18 (30 g), eluted with ACN in water (containing 0.1% HCl) 0–100%]. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.16 (s, 1H, D 2 O replaceable), 8.38 (s, 3H, D 2O exchangeable), 7.97 (t, J = 1.7 Hz, 1H), 7.92 (dt, J = 7.3, 1.7 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.63 - 7.53 (m, 3H), 7.29 - 7.19 (m, 5H), 7.14 - 7.07 (m, 2H), 6.98 - 6.87 (m, 2H), 5.33 (s, 2H), 5.24 (s, 2H), 4.14 (s, 2H), 3.93 (q, J = 7.1 Hz, 2H), 3.63 (s, 2H), 3.56 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H);MS (ES+): 580.3 (M+1);(ES-): 578.2 (M-1).

[0291] Scheme 23 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(methoxycarbonyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (23c) Step-1: Preparation of methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) Compound 23a was prepared according to the procedure reported in step-3 of scheme 7 from methyl 2-(hydroxymethyl)-7-iodobenzofuran-5-carboxylate (3d) (670 mg, 2.018 mmol), tert-butyl 2-(2-hydroxyphenyl)acetate (3g) (462 mg, 2.219 mmol) in DCM (30 mL) using a solution of triphenylphosphine (582 mg, 2.219 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (815 mg, 2.219 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) (400 mg, 38% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.30 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.23 - 7.17 (m, 2H), 6.95 (td, J = 7.3, 1.2 Hz, 1H), 5.32 (s, 2H), 3.88 (s, 3H), 3.52 (s, 2H), 1.27 (s, 9H).

[0292] Step-2: Preparation of methyl 7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-carboxylate (23b) Compound 23b was prepared from methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) (200 mg, 0.383 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (129 mg, 0.689 mmol) in dioxane (10 mL) with bis(triphenylphosphine)palladium(II) chloride (40.3 mg, 0.057 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (159 mg, 1.149 mmol) and heated at 100 °C for 6 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], methyl 7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-carboxylate (23b) (160 mg, 0.319 mmol, 83% yield) as a yellow oil; MS (ES+): 502.2 (M+1).

[0293] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(methoxycarbonyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (23c) Compound 23c was prepared from methyl 7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-carboxylate (23b) (160 mg, 0.319 mmol) in DCM (3 mL) using TFA (0.12 mL, 1.532 mmol) and stirring at room temperature for 4 h according to the procedure reported in step-9 of scheme 3. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(methoxycarbonyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (23c) (41 mg, 24% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.20 (s, 1H, D 2 O replaceable), 8.63 (s, 3H, D 2 O exchangeable), 8.32 (s, J = 1.5 Hz, 1H), 8.15 (s, J = 1.4 Hz, 1H), 7.99 (s, 1H), 7.96 - 7.89 (m, 1H), 7.67 - 7.55 (m, 2H), 7.31 - 7.19 (m, Analysis C 26 H 23 NO 6 .HCl.1.25H 2 Calculated for O: C, 61.91; H, 5.30; Cl, ​​7.03; N, 2.78; Found: C, 61.81; H, 5.26; Cl, ​​7.13; N, 2.90.

[0294] Scheme 24 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24a) Compound 24a was prepared according to the procedure reported in Scheme 1, step-3 from tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methoxy)phenyl)acetate (22d) (210 mg, 0.33 mmol) in THF (5 mL) using a solution of lithium hydroxide hydrate (7.91 mg, 0.33 mmol) in water (1 mL) and stirring at room temperature for 2 h. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (24a) (41 mg, 0.067 mmol, 20% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.21 (s, 1H, D 2 O replaceable), 8.43 (s, 3H, D 2 O exchangeable), 7.99 - 7.95 (m, 1H), 7.74 (s, 1H), 7.68 - 7.61 (m, 2H), 7.60 - 7.53 (m, 3H), 7.28 - 7.19 (m, 4H), 7.09 (d, J = 7.2 Hz, 2H), 6.99 - 6.86 (m, 2H), 5.32 (s, 2H), 5.27 (s, 2H), 4.13 (s, 2H), 3.60 (s, 2H), 3.52 (s, 2H), 1.22 (s, 9H);MS (ES+): 608.3 (M+1);(ES-): 606.2 (M-1);Analysis C 37 H 37 NO 7 .HCl.0.25H2 Calculated for O: C, 68.51; H, 5.98; Cl, ​​5.47; N, 2.16; Found: C, 68.59; H, 5.92; Cl, ​​5.11; N, 2.09.

[0295] Scheme 25 [ka] Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (25c) Step-1: Preparation of ethyl 2-(2-((4-bromobenzofuran-2-yl)methoxy)phenyl)acetate (25b) Compound 25b was prepared according to the procedure reported in step-3 of scheme 7 from (4-bromobenzofuran-2-yl)methanol (25a) (1.5 g, 6.61 mmol; CAS number 177735-23-8), ethyl 2-(2-hydroxyphenyl)acetate (7c) (1.190 g, 6.61 mmol) in DCM (30 mL) using a solution of triphenylphosphine (1.906 g, 7.27 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (2.67 g, 7.27 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((4-bromobenzofuran-2-yl)methoxy)phenyl)acetate (25b) (1.5 g, 58% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.64 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 7.7, 1.1 Hz, 1H), 7.33 - 7.16 (m, 4H), 7.00 - 6.91 (m, 2H), 5.29 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 3.60 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[0296] Step-2: Preparation of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (25c) Compound 25c was prepared from ethyl 2-(2-((4-bromobenzofuran-2-yl)methoxy)phenyl)acetate (25b) (1.5 g, 3.85 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (1.30 g, 6.94 mmol) in dioxane (20 mL) using bis(triphenylphosphine)palladium(II) chloride (0.541 g, 0.771 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (1.598 g, 11.56 mmol) and heated at 100 °C for 3 h. This gave the HCl salt of ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (25c) (502 mg, 31% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM 0–50%] followed by reverse-phase column chromatography [C18 (30 g), eluting with ACN in water (containing 0.1% HCl) 0–100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.60 (s, 3H, D 2 O exchangeable), 7.81 (s, 1H), 7.69 - 7.59 (m, 2H), 7.59 - 7.52 (m, 2H), 7.49 - 7.39 (m, 2H), 7.32 (s, 1H), 7.28 - 7.16 (m, 3H), 6.93 (t, J MS (ES+): 416.2 (M+1);(ES-): 414.2 (M-1);Analysis C 26 H 25 NO4 .HCl.0.5H 2 Calculated for O: C, 67.75; H, 5.90; Cl, ​​7.69; N, 3.04; Found: C, 67.77; H, 5.72; Cl, ​​7.58; N, 3.09.

[0297] Scheme 26 [ka] Preparation of 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (26a) Compound 26a was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (25c) (442 mg, 1.064 mmol) in THF (15 mL) using a solution of lithium hydroxide hydrate (0.323 g, 7.71 mmol) in water (5 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (26a) (404 mg, 98% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.19 (s, 1H, D 2 O replaceable), 8.63 (s, 3H, D 2 O exchangeable), 7.83 (s, 1H), 7.71 - 7.60 (m, 2H), 7.57 (d, J = 4.8 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.34 (s, 1H), 7.28 - 7.16 (m, 3H), 6.93 (t, J = 7.3 Hz, 1H), 5.30 (s, 2H), 4.13 (s, 2H), 3.55 (s, 2H);MS (ES+) 388.1 (M+1);(ES-) 386.1 (M-1);Analysis C24 H 21 NO 4 Calculated for HCl: C, 68.00; H, 5.23; Cl, ​​8.36; N, 3.30; Found: C, 68.02; H, 5.28; Cl, ​​8.20; N, 3.31.

[0298] Scheme 27 [ka] Preparation of 2,2'-((((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (27e) Step-1: Preparation of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (27 g) 4-Chloropicolinaldehyde (27f) (15 g, 106 mmol) and Cs in DCM (100 mL) 2 CO 3 (51.8 g, 159 mmol) was added with (S)-2-methylpropane-2-sulfinamide (14.77 g, 122 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with brine (3×200 mL). The organic layer was dried, filtered, and concentrated in vacuo to give N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (27 g) (25.9 g, 100% yield), which was used directly in the next step; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.75 (dd, J = 5.3, 0.6 Hz, 1H), 8.48 (s, 1H), 8.13 (dd, J = 2.1, 0.6 Hz, 1H), 7.76 (dd, J = 5.3, 2.1 Hz, 1H), 1.22 (s, 9H).

[0299] Step-2: Preparation of (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (27b) To a solution of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (27g) (18.5 g, 76 mmol) in methanol (300 mL) at 0 °C, NaBH 4 (2.86 g, 76 mmol) was added and stirred for 0.5 h. The reaction was quenched with acetone (20 mL) and concentrated in vacuo. The residue was purified by dilution with EtOAc and saturated NH 4 The mixture was transferred to aqueous Cl. The organic layer was separated, washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (120 g), eluted with a 9:1 mixture of ethyl acetate and methanol in hexanes] to give (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (27b) (15.7 g, 84%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.48 (dd, J = 5.3, 0.6 Hz, 1H), 7.58 (dd, J = 2.1, 0.7 Hz, 1H), 7.43 (dd, J = 5.4, 2.1 Hz, 1H), 5.97 (t, J = 6.3 Hz, 1H), 4.29 (dd, J = 6.3, 3.3 Hz, 2H), 1.16 (s, 9H);Optical rotation [α] D = +45.4 (0.81, MeOH).

[0300] Step-3: Preparation of 2,2'-((((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diethyl diacetate (27a) To a degassed solution of diethyl 2,2'-((((7-iodobenzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (7d) (1.5 g, 2.387 mmol), bis(pinacolato)diboron (BisPin) (1.515 g, 5.97 mmol) and potassium acetate (0.703 g, 7.16 mmol) in anhydrous dioxane (20 mL) was added PdCl2 (dppf)-CH 2 Cl 2 The adduct (0.390 g, 0.477 mmol) was added. The reaction mixture was degassed, backfilled with argon, and heated at 90° C. overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with water (100 mL), brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-40%] to give diethyl 2,2'-((((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27a) (1.3 g, 87% yield) as a brown oil; MS (ES+): 651.1 (M+Na).

[0301] Step-4: Preparation of 2,2'-((((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diethyl diacetate (27c) Compound 27c was prepared from diethyl 2,2'-((((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27a) (500 mg, 0.796 mmol), (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (27b) (294 mg, 1.193 mmol) in dioxane (10 mL) with bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.119 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3(330 mg, 2.387 mmol) and heated at 100 °C for 12 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with methanol in DCM 0-5%], diethyl 2,2'-((((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27c) (142 mg, 25% yield) as a sticky solid; MS (ES+): 713.3 (M+1).

[0302] Step-5: Preparation of diethyl 2,2'-((((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27d) Compound 27d was prepared according to the procedure reported in step-2 of scheme 7 from diethyl 2,2'-((((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27c) (142 mg, 0.199 mmol) in DCM / THF (100 mL; 1:1) using HCl (4N in dioxane, 0.398 mL, 1.591 mmol) and stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), elution with EtOAc in hexanes 0-100%], methyldiethyl 2,2'-((((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27d) (89 mg, 18% yield); MS (ES+): 609.3 (M+1).

[0303] Step-6: Preparation of 2,2'-((((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (27e) Compound 27e was prepared according to the procedure reported in Scheme 1, step-3 from diethyl 2,2'-((((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27d) (89 mg, 0.146 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (31 mg, 0.731 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2,2′-((((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (27e) (29 mg, 36% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.79 (d, J = 5.3 Hz, 1H), 8.59 (s, 3H, D 2 O exchangeable), 8.13 (s, 1H), 8.03 (d, J = 5.4 Hz, 1H), 7.85 (s, 2H), 7.24 (dd, J = 7.6, 5.7 Hz, 5H), 7.16 - 7.07 (m, 2H), 6.93 (dt, J = 14.4, MS (ES+): 553.2 (M+1);(ES-): 551.1 (M-1);Analysis C 32 H 28 N 2 O 7 .1.5HCl.1.25H 2 Calculated for O: C, 61.03; H, 5.12; Cl, ​​8.44; N, 4.45; Found: C, 60.85; H, 5.29; Cl, ​​8.64; N, 4.44.

[0304] Scheme 28 [ka] Preparation of 2,2'-((((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (28d) Step-1: Preparation of (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (28f) 4-Chloro-3-fluoropicolinaldehyde (28e) (6.73 g, 42.2 mmol; CAS number 1260878-78-1) and Cs in DCM (350 mL) 2 CO 3 (27.5 g, 84 mmol) was added with (S)-2-methylpropane-2-sulfinamide (5.88 g, 48.5 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with brine (3×200 mL). The organic layer was dried, filtered, and concentrated in vacuo to give (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (28f) (11.08 g, 100% yield), which was used in the next reaction without further purification; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.59 (d, J = 5.1 Hz, 1H), 8.56 (s, 1H), 7.97 (dd, J = 5.6, 5.0 Hz, 1H), 1.21 (s, 9H).

[0305] Step-2: Preparation of (+)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (28a) To a solution of (S)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (28f) (11.08 g, 42.2 mmol) in methanol (211 mL) at 0 °C was added NaBH 4(1.595 g, 42.2 mmol) was added and stirred for 0.5 h. The reaction was quenched with acetone (20 mL) and concentrated in vacuo. The residue was purified by dilution with EtOAc and saturated NH 4 The organic layer was separated, washed with brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (120 g), eluted with a 9:1 mixture of ethyl acetate and methanol in hexanes] to give (+)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (28a) (9.34 g, 84% yield) as a thick, clear syrup; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.36 (d, J = 5.2 Hz, 1H), 7.72 - 7.62 (m, 1H), 5.86 (t, J = 5.9 Hz, 1H), 4.34 (dd, J = 5.9, 2.2 Hz, 2H), 1.09 (s, 9H);Optical rotation [α]D = +53.88 (c = 0.49, MeOH).

[0306] Step-3: Preparation of 2,2'-((((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diethyl diacetate (28b) Compound 28b was prepared from diethyl 2,2'-(((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (27a) (800 mg, 1.273 mmol), (+)-N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (28a) (505 mg, 1.909 mmol) in dioxane (10 mL) with bis(triphenylphosphine)palladium(II) chloride (134 mg, 0.191 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2CO 3 (528 mg, 3.82 mmol) and heated at 100 °C for 3.5 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluting with methanol in DCM 0-5%], diethyl 2,2'-((((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (28b) (136 mg, 15% yield) as a brown sticky solid; MS (ES+): 731.2 (M+1).

[0307] Step-2: Preparation of diethyl 2,2'-((((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (28c) Compound 28c was prepared according to the procedure reported in step-2 of scheme 7 from diethyl 2,2'-((((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (28b) (136 mg, 0.186 mmol) in DCM / THF (100 mL; 1:1) using HCl (4N in dioxane, 0.636 mL, 2.55 mmol) after stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), elution with EtOAc in hexanes 0-100%], diethyl 2,2'-((((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (28c) (66 mg, 8% yield); MS (ES+): 627 (M+1).

[0308] Step-3: Preparation of 2,2'-((((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (28d) Compound 28d was prepared according to the procedure reported in step-3 of scheme 1 from diethyl 2,2'-((((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetate (28c) (66 mg, 0.105 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (22 mg, 0.527 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2,2′-((((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-2,5-diyl)bis(methylene))bis(oxy))bis(2,1-phenylene))diacetic acid (28d) (30 mg, 50% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.69 - 8.55 (m, 4H, 3H D 2 O exchangeable), 7.89 (s, 1H), 7.81 (t, J = 5.3 Hz, 1H), 7.62 (s, 1H), 7.29 - 7.15 (m, 5H), 7.14 - 7.07 (m, 2H), 6.98 - 6.87 (m, 2H), 5.29 (s, 2H), 5.28 (s, 2H), 4.36 (m, J = 5.7 Hz, 2H), 3.59 (s, 2H), 3.55 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -128.57;MS (ES+): 571.2 (M+1);(ES-): 569.2 (M-1);Analysis C 32 H 27 FN 2 O 7 .1.35HCl.H2 Calculated for O: C, 60.26; H, 4.80; Cl, ​​7.50; N, 4.39; Found: C, 59.93; H, 4.76; Cl, ​​7.48; N, 4.41.

[0309] Scheme 29 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(hydroxymethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (29b) Step-1: Preparation of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(hydroxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (29a) Compound 29a was prepared from tert-butyl 2-(2-((5-(hydroxymethyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (3h) (400 mg, 0.809 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (228 mg, 1.214 mmol) in dioxane (10 mL) with bis(triphenylphosphine)palladium(II) chloride (114 mg, 0.162 mmol) and K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (280 mg, 2.023 mmol) and heated at 100 °C for 3 h, which gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0–50%], 2-(2-((7-(3-(aminomethyl)phenyl)-5-(hydroxymethyl)benzofuran-2-yl)methoxy)phenyl)ethyl acetate 2 tert-butyl ester (29a) (286 mg, 75% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6) δ 7.78 (d, J = 1.8 Hz, 1H), 7.71 (dt, J = 7.4, 1.7 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.45 - 7.36 (m, 2H), 7.31 - 7.18 (m, 3H), 7.04 (s, 1H), 6.93 (td, J = 7.3, 1.3 Hz, 1H), 5.31 - 5.20 (m, 3H), 4.64 (d, J = 5.1 Hz, 2H), 3.81 (s, 2H), 3.52 (s, 2H), 1.84 (s, 2H), 1.23 (s, 9H);MS (ES+): 474.2 (M+1).

[0310] Step-2: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(hydroxymethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (29b) Compound 29b was prepared from tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(hydroxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (29a) (286 mg, 0.604 mmol) in DCM (10 mL) using TFA (0.62 mL, 8.09 mmol) and stirring at room temperature for 3 h according to the procedure reported in step-9 of scheme 3. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(hydroxymethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (29b) (8 mg, 2% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.18 (s, 1H, D 2 O replaceable), 8.50 (s, 3H, D 2O exchangeable), 7.96 (s, J = 2.3 Hz, 1H), 7.91 (dt, J = 6.7, 2.1 Hz, 1H), 7.62 - 7.49 (m, 4H), 7.30 - 7.17 (m, 3H), 7.05 (s, 1H), 6.94 (td, J = 7.2, 1.4 Hz, 1H), 5.39 - 5.23 (m, 3H, 1H D 2 O exchangeable), 4.64 (d, J = 4.3 Hz, 2H), 4.12 (s, 2H), 3.55 (s, 2H);MS (ES+): 418.1 (M+1);(ES-): 416.1 (M-1).

[0311] Scheme 30 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-2-yl)methoxy)phenyl)acetic acid (30d) Step-1: Preparation of ethyl 2-(2-((7-bromobenzo[b]thiophen-2-yl)methoxy)phenyl)acetate (30b) Compound 30b was prepared according to the procedure reported in step-3 of scheme 7 from (7-bromobenzo[b]thiophen-2-yl)methanol (30a) (1.5 g, 6.17 mmol; CAS number 1171926-64-9), triphenylphosphine (1.780 g, 6.79 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (1.223 g, 6.79 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (2.492 g, 6.79 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((7-bromobenzo[b]thiophen-2-yl)methoxy)phenyl)acetate (30b) (1.3 g, 52% yield) as a white solid; 1H NMR (300 MHz, DMSO-d 6 ) δ 7.88 (dd, J = 7.9, 1.0 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.60 (dd, J = 7.7, 0.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.15 (dd, J = 8.3, 1.2 Hz, 1H), 6.95 (td, J = 7.4, 1.1 Hz, 1H), 5.44 (d, J = 1.0 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H), 1.13 (t, J = 7.1 Hz, 3H).

[0312] Step-2: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-2-yl)methoxy)phenyl)acetate (30c) Compound 30c was prepared from ethyl 2-(2-((7-bromobenzo[b]thiophen-2-yl)methoxy)phenyl)acetate (30b) (400 mg, 0.987 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (333 mg, 1.776 mmol), bis(triphenylphosphine)palladium(II) chloride (104 mg, 0.148 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (409 mg, 2.96 mmol) and heated at 100 °C for 6 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-2-yl)methoxy)phenyl)acetate (30c) (98 mg, 23% yield) as a yellow oil; MS (ES+): 432.1 (M+1).

[0313] Step-3: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-2-yl)methoxy)phenyl)acetic acid (30d) Compound 30d was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-2-yl)methoxy)phenyl)acetate (30c) (98 mg, 0.227 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (166 mg, 3.95 mmol) in water (1 mL) and stirring at room temperature for 4 h according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-2-yl)methoxy)phenyl)acetic acid (30d) (49 mg, 12% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.23 (s, 3H, D 2 O exchangeable), 7.82 - 7.74 (m, 2H), 7.72 - 7.65 (m, 1H), 7.56 - 7.50 (m, 3H), 7.48 - 7.41 (m, 1H), 7.39 - 7.32 (m, 1H), 7.18 - 7.09 (m, MS (ES+): 404.1 (M+1);(ES-): 402.1 (M-1);Analysis C 24 H 21 NO 3 S.HCl.0.5H 2 Calculated for O: C, 64.21; H, 5.16; Cl, ​​7.90; N, 3.12; Found: C, 64.03; H, 5.21; Cl, ​​7.72; N, 3.06.

[0314] Scheme 31 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetic acid (31f) Step-1: Preparation of ((7-bromo-5-fluorobenzofuran-2-yl)methoxy)(tert-butyl)dimethylsilane (31b) Compound 31b was prepared from 2,6-dibromo-4-fluorophenol (31a) (5 g, 18.53 mmol; CAS number 344-20-7) in pyridine (30 mL) using tert-butyldimethyl(prop-2-ynyloxy)silane (3b) (3.16 g, 18.53 mmol) and copper(I) oxide (1.325 g, 9.26 mmol) by stirring at room temperature for 10 min and at 125 °C for 6 h according to the procedure reported in step-1 of scheme 3. This gave ((7-bromo-5-fluorobenzofuran-2-yl)methoxy)(tert-butyl)dimethylsilane (31b) (3.6 g, 54% yield) as a clear oil after workup and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexane 0-70%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.51 (s, 1H), 7.48 (s, 1H), 6.93 (s, 1H), 4.83 (s, 2H), 0.89 (d, J = 1.3 Hz, 9H), 0.11 (d, J = 1.1 Hz, 6H).

[0315] Step-2: Preparation of (7-bromo-5-fluorobenzofuran-2-yl)methanol (31c) Compound 31c was prepared from ((7-bromo-5-fluorobenzofuran-2-yl)methoxy)(tert-butyl)dimethylsilane (31b) according to the procedure reported in step-5 of scheme 20 using HCl in DCM (4N in dioxane, 4 mL) and stirring at room temperature for 1 h, which afforded (7-bromo-5-fluorobenzofuran-2-yl)methanol (31c) (1.6 g, 35% yield) as a white solid after workup and purification by flash column chromatography [silica gel (80 g), eluted with EtOAc in hexanes 0-70%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.49 (d, J = 1.1 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 6.89 (t, J = 0.9 Hz, 1H), 5.60 (t, J = 5.8 Hz, 1H, D 2 O exchangeable), 4.60 (d, J = 5.7 Hz, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -118.70.

[0316] Step-3: Preparation of ethyl 2-(2-((7-bromo-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetate (31d) Compound 31d was prepared from (7-bromo-5-fluorobenzofuran-2-yl)methanol (31c) (1.12 g, 4.57 mmol) in DCM (30 mL) using triphenylphosphine (1.319 g, 5.03 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (0.906 g, 5.03 mmol), bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.846 g, 5.03 mmol) in DCM (20 mL) at room temperature for 30 min. according to the procedure reported in step-3 of scheme 7. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((7-bromo-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetate (31d) (1.1 g, 59% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.56 (d, J = 8.8 Hz, 2H), 7.32 - 7.17 (m, 3H), 7.13 (s, 1H), 6.95 (t, J = 7.4 Hz, 1H), 5.31 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.04 (t, J = 7.1 Hz, 3H).

[0317] Step-4: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetate (31e) Compound 31e was prepared from ethyl 2-(2-((7-bromo-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetate (31d) (420 mg, 1.031 mmol) in dioxane (20 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (213 mg, 1.134 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (238 mg, 0.206 mmol), K in water (3 mL) 2 CO 3(428 mg, 3.09 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0–50%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetate (31e) (166 mg, 37% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.82 (s, 1H), 7.77 - 7.71 (m, 1H), 7.51 - 7.37 (m, 4H), 7.31 - 7.17 (m, 3H), 7.06 (s, 1H), 6.94 (t, J = 7.3 Hz, 1H), 5.30 (s, MS (ES+): 434.20 (M+1).

[0318] Step-5: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetic acid (31f) Compound 31f was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetate (31e) (98 mg, 0.227 mmol) in THF (6 mL) using a solution of lithium hydroxide hydrate (87 mg, 2.063 mmol) in water (2 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-fluorobenzofuran-2-yl)methoxy)phenyl)acetic acid (31f) (107 mg, 26% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1H NMR (300 MHz, DMSO-d 6 ) δ 12.17 (s, 1H, D 2 O replaceable), 8.54 (s, 3H, D 2 O exchangeable), 8.02 (s, 1H), 8.00 - 7.89 (m, 1H), 7.58 (d, J = 4.7 Hz, 2H), 7.53 - 7.41 (m, 2H), 7.30 - 7.16 (m, 3H), 7.08 (s, 1H), 6.94 (t, J = 7.2 Hz, 1H), 5.34 (s, 2H), 4.12 (s, 2H), 3.56 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -119.69;MS (ES+): 406.1 (M+1);(ES-): 404.1 (M-1).

[0319] Scheme 32 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-((cyclopropylmethyl)carbamoyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (32d) Step-1: Preparation of 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylic acid (32a) Compound 32a was prepared from methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylate (23a) (2.72 g, 5.21 mmol) in THF (10 mL) according to the procedure reported in step-3 of scheme 1, using a solution of lithium hydroxide hydrate (0.219 g, 5.21 mmol) in water (2 mL) and stirring at room temperature overnight. The reaction mixture was concentrated under vacuum and acidified to pH 4. The aqueous solution was diluted with EtOAc (200 mL), washed with water, brine, dried, filtered and concentrated. The resulting residue was purified by flash column chromatography [silica gel (80 g), eluted with EtOAc / MeOH (9:1) in hexanes 0-100%] to give 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylic acid (32a) (5.8 g, 11.41 mmol, 66% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.13 (s, 1H), 8.33 - 8.19 (m, 2H), 7.32 - 7.23 (m, 2H), 7.20 (dt, J = 7.0, 2.0 Hz, 2H), 6.94 (td, J = 7.3, 1.2 Hz, 1H), 5.32 (s, 2H), 3.52 (s, 2H), 1.27 (s, 9H).

[0320] Step-2: Preparation of tert-butyl 2-(2-((5-((cyclopropylmethyl)carbamoyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (32b) Compound 32b was prepared according to the procedure reported in step-1 of scheme 10 from 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylic acid (32a) (400 mg, 0.787 mmol) in DMF (10 mL) using cyclopropylmethanamine (11a) (61.6 mg, 0.866 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.344 mL, 1.967 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU) (329 mg, 0.866 mmol) and stirring at room temperature overnight. This gave, after workup and purification by flash column chromatography [silica gel (24 g), elution with EtOAc in hexanes 0–100%], tert-butyl 2-(2-((5-((cyclopropylmethyl)carbamoyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (32b) (250 mg, 57% yield) as a white solid; MS (ES+): 584.10 (M+Na).

[0321] Step-3: Preparation of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((cyclopropylmethyl)carbamoyl)benzofuran-2-yl)methoxy)phenyl)acetate (32c) Compound 32c was prepared from tert-butyl 2-(2-((5-((cyclopropylmethyl)carbamoyl)-7-iodobenzofuran-2-yl)methoxy)phenyl)acetate (32b) (250 mg, 0.445 mmol) in dioxane (10 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (125 mg, 0.668 mmol), bis(triphenylphosphine)palladium(II) chloride (62.5 mg, 0.089 mmol) and K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3(154 mg, 1.113 mmol) which, after workup and purification by flash column chromatography [silica gel (12 g), elution with DMA80 in DCM 0-50%], afforded tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((cyclopropylmethyl)carbamoyl)benzofuran-2-yl)methoxy)phenyl)acetate (32c) (131 mg, 54% yield) as a colorless oil; MS (ES+): 541.3 (M+1), (ES-): 539.2 (M-1).

[0322] Step-4: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-((cyclopropylmethyl)carbamoyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (32d) Compound 32d was prepared from tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-((cyclopropylmethyl)carbamoyl)benzofuran-2-yl)methoxy)phenyl)acetate (32c) (131 mg, 0.242 mmol) in DCM (15 mL) using TFA (0.343 mL, 4.45 mmol) and stirring at room temperature for 3 h according to the procedure reported in step-9 of scheme 3. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-((cyclopropylmethyl)carbamoyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (32d) (35 mg, 16% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.18 (s, 1H, D2O exchangeable), 8.78 (t, J = 5.7 Hz, 1H), 8.45 (s, 3H, D 2O exchangeable), 8.22 - 8.12 (m, 2H), 8.07 (d, J = 1.7 Hz, 1H), 7.98 (dt, J = 7.4, 1.7 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.31 - 7.16 (m, 4H), 6.95 (td, J = 7.1, 1.5 Hz, 1H), 5.35 (s, 2H), 4.16 (s, 2H), 3.56 (s, 2H), 3.19 (t, J = 6.2 Hz, 2H), 1.18 - 0.99 (m, 1H), 0.50 - 0.36 (m, 2H), 0.31 - 0.21 (m, 2H);MS (ES+) 485.2 (M+1);(ES-): 483.2 (M-1);Analysis C 29 H 28 N 2 O 5 .HCl.1.75H 2 Calculated for O: C, 63.04; H, 5.93; Cl, ​​6.42; N, 5.07; Found: C, 63.21; H, 5.95; Cl, ​​6.37; N, 5.07.

[0323] Scheme 33 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (33f) Step-1: Preparation of ((7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methoxy)dimethylsilane tert-butyl (33b) Compound 33b was prepared according to the procedure reported in step-3 of scheme 7 from (2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol (7a) (2 g, 4.78 mmol), triphenylphosphine (1.379 g, 5.26 mmol), phenol (33a) (0.495 g, 5.26 mmol; CAS number 108-95-2) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.931 g, 5.26 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], tert-butyl ((7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methoxy)dimethylsilane (33b) (2.1 g, 89% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.76 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.41 - 7.38 (m, 1H), 7.31 - 7.25 (m, 2H), 7.04 - 6.99 (m, 2H), 6.95 (d, J = 7.8 Hz, 1H), 5.15 (s, 2H), 4.84 - 4.79 (m, 2H), 0.89 (s, 9H), 0.13 (s, 6H).

[0324] Step-2: Preparation of (7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methanol (33c) Compound 33c was prepared from tert-butyl((7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methoxy)dimethylsilane (33b) (2.1 g, 4.25 mmol) according to the procedure reported in step-2 of scheme 7, using HCl (4N in dioxane, 5.98 mL, 23.90 mmol) in DCM (20 mL) and stirring the reaction mixture at room temperature for 3 h. This afforded (7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methanol (33c) (1.5 g, 83% yield) as a white solid after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane 0-50%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.74 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.06 - 6.98 (m, 2H), 6.98 - 6.88 (m, 2H), 5.57 (t, J = 5.8 Hz, 1H), 5.16 (s, 2H), 4.60 (dd, J = 5.9, 0.8 Hz, 2H); MS (ES+): 403.0 (M+Na).

[0325] Step-3: Preparation of tert-butyl 2-(2-((7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (33d) Compound 33d was prepared according to the procedure reported in step-3 of scheme 7 from (7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methanol (33c) (400 mg, 1.052 mmol), triphenylphosphine (304 mg, 1.157 mmol), tert-butyl 2-(2-hydroxyphenyl)acetate (3g) (0.241 g, 1.157 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (425 mg, 1.157 mmol) in DCM (20 mL) and stirring the reaction mixture at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-50%], tert-butyl 2-(2-((7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (33d) (220 mg, 37% yield) as a colorless oil.

[0326] Step-4: Preparation of tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (33e) Compound 33e was prepared from tert-butyl 2-(2-((7-iodo-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (33d) (220 mg, 0.386 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (108 mg, 0.579 mmol), bis(triphenylphosphine)palladium(II) chloride (54.1 mg, 0.077 mmol), and K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3(133 mg, 0.964 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), elution with DMA80 in DCM 0-50%], tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (33e) (102 mg, 48% yield) as a colorless oil; MS (ES+): 550.2 (M+1).

[0327] Step-5: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (33f) Compound 33f was prepared from tert-butyl 2-(2-((7-(3-(aminomethyl)phenyl)-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetate (33e) (102 mg, 0.186 mmol) in DCM (5 mL) using TFA (0.297 mL, 3.86 mmol) according to the procedure reported in step-9 of scheme 3. This afforded the hydrochloride salt of 2-(2-((7-(3-(aminomethyl)phenyl)-5-(phenoxymethyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (33f) (14 mg, 7% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.12 (s, 1H, D 2 O replaceable), 8.39 (s, 3H, D 2O exchangeable), 7.99 - 7.90 (m, 2H), 7.75 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.63 - 7.51 (m, 2H), 7.35 - 7.25 (m, 3H), 7.25 - 7.18 (m, 2H), 7.12 - 7.01 (m, 3H), 6.94 (td, J = 7.2, 1.3 Hz, 2H), 5.33 (s, 2H), 5.24 (s, 2H), 4.13 (s, 2H), 3.55 (s, 2H);MS (ES+): 494.2 (M+1);(ES-): 492.2 (M-1).

[0328] Scheme 34 [ka] Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (34c) Step-1: Preparation of methyl 2-(3-((7-bromobenzofuran-2-yl)methoxy)phenyl)acetate (34a) Compound 34a was prepared according to the procedure reported in step-3 of scheme 7 from (7-bromobenzofuran-2-yl)methanol (19b) (510 mg, 2.246 mmol), triphenylphosphine (648 mg, 2.471 mmol), methyl 2-(3-hydroxyphenyl)acetate (4a) (411 mg, 2.471 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (907 mg, 2.471 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This afforded methyl 2-(3-((7-bromobenzofuran-2-yl)methoxy)phenyl)acetate (34a) (404 mg, 48% yield) as a yellow oil after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexane 0-50%]; 1 H NMR (300 MHz, DMSO-d 6) δ 7.68 (dd, J = 7.8, 1.1 Hz, 1H), 7.57 (dd, J = 7.8, 1.1 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.19 (s, 1H), 7.02 - 6.97 (m, 2H), 6.88 (dt, J = 7.6, 1.2 Hz, 1H), 5.29 (s, 2H), 3.66 (s, 2H), 3.60 (s, 3H).

[0329] Step-2: Preparation of methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (34b) Compound 34b was prepared from methyl 2-(3-((7-bromobenzofuran-2-yl)methoxy)phenyl)acetate (34a) (400 mg, 1.066 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (300 mg, 1.599 mmol), bis(triphenylphosphine)palladium(II) chloride (150 mg, 0.213 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (368 mg, 2.67 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (34b) (125 mg, 29% yield) as a colorless oil; MS (ES+): 402.1 (M+1).

[0330] Step-3: Preparation of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (34c) Compound 34c was prepared from methyl 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetate (34b) (125 mg, 0.311 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (134 mg, 3.20 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)acetic acid (34c) (77 mg, 19% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.18 (s, 3H, D 2 O exchangeable), 7.95 (s, J = 1.9 Hz, 1H), 7.89 (dt, J = 6.8, 2.0 Hz, 1H), 7.68 (dd, J = 7.7, 1.2 Hz, 1H), 7.61 - 7.51 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.14 (s, 1H), 7.03 - 6.92 (m, 2H), 6.87 (dt, J = 7.6, 1.2 Hz, 1H), 5.30 (s, 2H), 4.11 (s, 2H), 3.54 (s, 2H);MS (ES+): 388.1 (M+1);(ES-): 386.1 (M-1);Analysis C 24 H 21 NO 4 .HCl.H 2 Calculated for O: C, 65.23; H, 5.47; Cl, ​​8.02; N, 3.17; Found: C, 65.38; H, 5.40; Cl, ​​7.78; N, 3.13.

[0331] Scheme 35 [ka] Preparation of 3-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)propanoic acid (35c) Step-1: Preparation of ethyl 3-(2-((7-bromobenzofuran-2-yl)methoxy)phenyl)propanoate (35a) Compound 35a was prepared according to the procedure reported in step-3 of scheme 7 from (7-bromobenzofuran-2-yl)methanol (19b) (500 mg, 2.202 mmol), triphenylphosphine (635 mg, 2.422 mmol), ethyl 3-(2-hydroxyphenyl)propanoate (2a) (470 mg, 2.422 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (889 mg, 2.422 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 3-(2-((7-bromobenzofuran-2-yl)methoxy)phenyl)propanoate (35a) (308 mg, 35% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.66 (dd, J = 7.8, 1.1 Hz, 1H), 7.55 (dd, J = 7.8, 1.0 Hz, 1H), 7.24 - 7.12 (m, 5H), 6.94 - 6.86 (m, 1H), 5.36 (s, 2H), 3.99 (q, J = 7.1 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.64 - 2.53 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H).

[0332] Step-2: Preparation of ethyl 3-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)propanoate (35b) Compound 35b was prepared from ethyl 3-(2-((7-bromobenzofuran-2-yl)methoxy)phenyl)propanoate (35a) (300 mg, 0.744 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (209 mg, 1.116 mmol), bis(triphenylphosphine)palladium(II) chloride (104 mg, 0.149 mmol), K in water (3 mL) according to the procedure reported in Scheme 3, step-8. 2 CO 3 (257 mg, 1.860 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], ethyl 3-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)propanoate (35b) (155 mg, 49% yield) as a colorless oil; MS (ES+): 430.2 (M+1); (ES-): 428.2 (M-1).

[0333] Step-3: Preparation of 3-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)propanoic acid (35c) Compound 35c was prepared from ethyl 3-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)propanoate (35b) (155 mg, 0.361 mmol) in THF (4 mL) using a solution of lithium hydroxide hydrate (125 mg, 2.98 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 3-(2-((7-(3-(aminomethyl)phenyl)benzofuran-2-yl)methoxy)phenyl)propanoic acid (35c) (90 mg, 30% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6) δ 12.11 (s, 1H, D 2 O replaceable), 8.54 (s, 3H, D 2 O exchangeable), 7.95 (s, 1H), 7.93 - 7.88 (m, 1H), 7.68 (dd, J = 7.7, 1.2 Hz, 1H), 7.59 - 7.53 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.23 - 7.15 MS (ES+): 402.1 (M+1);(ES-): 400.2 (M-1);Analysis C 25 H 23 NO 4 .HCl.0.75H 2 Calculated for O: C, 66.52; H, 5.69; Cl, ​​7.85; N, 3.10; Found: C, 66.97; H, 5.65; Cl, ​​7.99; N, 3.14.

[0334] Scheme 36 [ka] Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (36e) Step-1: Preparation of (7-bromobenzofuran-3-yl)methanol (36b) Compound 36b was prepared from 7-bromobenzofuran-3-carboxylic acid (36a) (600 mg, 2.489 mmol; CAS number 1374574-88-5) with N-methylmorpholine (0.328 mL, 2.99 mmol), isobutyl chloroformate (0.392 mL, 2.99 mmol) in THF (50 mL) and NaBH in water (2.0 mL) according to the procedure reported in Scheme 8, step-1. 4(283 mg, 7.47 mmol) solution, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc / MeOH (9:1) in hexanes 0–50%] afforded (7-bromobenzofuran-3-yl)methanol (36b) (438 mg, 77% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.01 (s, 1H), 7.71 (dd, J = 7.7, 1.1 Hz, 1H), 7.56 (dd, J = 7.8, 1.0 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 5.25 (t, J = 5.5 Hz, 1H), 4.64 (dd, J = 5.5, 1.1 Hz, 2H).

[0335] Step-2: Preparation of ethyl 2-(2-((7-bromobenzofuran-3-yl)methoxy)phenyl)acetate (36c) Compound 36c was prepared according to the procedure reported in Scheme 7, step-3 from (7-bromobenzofuran-3-yl)methanol (36b) (435 mg, 1.916 mmol), triphenylphosphine (553 mg, 2.107 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (380 mg, 2.107 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (774 mg, 2.107 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-50%], ethyl 2-(2-((7-bromobenzofuran-3-yl)methoxy)phenyl)acetate (36c) (260 mg, 35% yield) as a yellow oil; MS (ES+): 389.0 and 391.0 (M+1); (ES-): 387.0 and 390.0 (M-1).

[0336] Step-3: Preparation of ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (36d) Compound 36d was prepared from ethyl 2-(2-((7-bromobenzofuran-3-yl)methoxy)phenyl)acetate (36c) (260 mg, 0.668 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (188 mg, 1.002 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (154 mg, 0.134 mmol), K in water (3 mL) and dioxane (10 mL) 2 CO 3 (231 mg, 1.670 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (36d) (82 mg, 30% yield) as a colorless oil; MS (ES+): 416.1 (M+1).

[0337] Step-4: Preparation of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (36e) Compound 36e was prepared from ethyl 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (36d) (82 mg, 0.197 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (112 mg, 2.67 mmol) in water (1 mL) and stirring at room temperature overnight according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (36e) (5.2 mg, 2% yield) as an off-white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%];1 H NMR (300 MHz, DMSO-d 6 ) δ 12.17 (s, 1H, D 2 O replaceable), 8.33 (s, 3H, D 2 O exchangeable), 8.17 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.90 (dt, J = 7.6, 1.7 Hz, 1H), 7.74 (dd, J = 7.8, 1.3 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.43 (t. (ES+): 388.1 (M+1);(ES-): 386.1 (M-1).

[0338] Scheme 37 [ka] Preparation of 7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-carboxylic acid (37b) Step-1: Preparation of 7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-carboxylic acid (37a) Compound 37a was prepared from 2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)-7-iodobenzofuran-5-carboxylic acid (32a) (250 mg, 0.492 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (138 mg, 0.738 mmol), Pd(PPh) according to the procedure reported in Scheme 1, Step-2. 3 ) 4 (114 mg, 0.098 mmol), K in water (3 mL) 2 CO 3(170 mg, 1.230 mmol) and heated in a microwave at 120 °C for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], 7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-carboxylic acid (37a) (103 mg, 43% yield) as a semi-solid; MS (ES+): 488.2 (M+1); (ES-): 486.2 (M-1).

[0339] Step-2: Preparation of 7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-carboxylic acid (37b) Compound 37b was prepared from 7-(3-(aminomethyl)phenyl)-2-((2-(2-(tert-butoxy)-2-oxoethyl)phenoxy)methyl)benzofuran-5-carboxylic acid (37a) (103 mg, 0.0.211 mmol) in DCM (10 mL) using TFA (0.379 mL, 4.92 mmol) according to the procedure reported in step-9 of scheme 3. This afforded the HCl salt of (7-(3-(aminomethyl)phenyl)-2-((2-(carboxymethyl)phenoxy)methyl)benzofuran-5-carboxylic acid (37b) (48 mg, 23% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.67 (s, 1H, D 2 O replaceable), 8.47 (s, 3H, D 2O exchangeable), 8.29 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.63 - 7.54 (m, 2H), 7.31 - 7.18 (m, 4H), 6.95 (td, J = 7.1, 1.6 Hz, 1H), 5.36 (s, 2H), 4.15 (s, 2H), 3.56 (s, 2H);MS (ES+): 432.1 (M+1);(ES-): 430.1 (M-1);Analysis C 25 H 21 NO 6 .1HCl.1.75H 2 Calculated for O: C, 60.12; H, 5.15; Cl, ​​7.10; N, 2.80; Found: C, 60.42; H, 5.18; Cl, ​​6.82; N, 2.83.

[0340] Scheme 38 [ka] Preparation of 2-(2-((3-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (38e) Step-1: Preparation of (3-bromobenzofuran-5-yl)methanol (38b) Compound 38b was prepared from methyl 3-bromobenzofuran-5-carboxylate (38a) (500 mg, 1.960 mmol; CAS number 501892-90-6) in THF (10 mL) by the procedure reported in Scheme 7, Step-1, using LiBH 4 (2.94 mL, 5.88 mmol; 2 M solution in THF) and MeOH (0.238 mL, 5.88 mmol) and stirred at room temperature for 24 h, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with EtOAc in hexanes 0–60%] afforded (3-bromobenzofuran-5-yl)methanol (38b) (310 mg, 70% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6) δ 8.28 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 1.7, 0.8 Hz, 1H), 7.37 (dd, J = 8.6, 1.7 Hz, 1H), 5.31 (t, J = 5.8 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H); MS (ES+): 226.00 (M+1).

[0341] Step-2: Preparation of ethyl 2-(2-((3-bromobenzofuran-5-yl)methoxy)phenyl)acetate (38c) Compound 38c was prepared according to the procedure reported in step-3 of scheme 7 from (3-bromobenzofuran-5-yl)methanol (38b) (310 mg, 1.365 mmol), triphenylphosphine (394 mg, 1.502 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (271 mg, 1.502 mmol) in DCM (30 mL) using a solution of bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 551 mg, 1.502 mmol) in DCM (20 mL) and stirred at room temperature for 30 min. This afforded ethyl 2-(2-((3-bromobenzofuran-5-yl)methoxy)phenyl)acetate (38c) (210 mg, 40% yield) as a colorless oil after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexane 0-50%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.54 - 7.42 (m, 1H), 7.25 (m, J = 14.9, 7.3, 1.7 Hz, 2H), 7.10 (dd, J = 8.2, 1.1 Hz, 1H), 6.91 (td, J = 7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[0342] Step-3: Preparation of ethyl 2-(2-((3-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (38d) Compound 38d was prepared from ethyl 2-(2-((3-bromobenzofuran-5-yl)methoxy)phenyl)acetate (38c) (210 mg, 0.540 mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (152 mg, 0.809 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 4 (94 mg, 0.081 mmol), K in water (3 mL) 2 CO 3 (186 mg, 1.349 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA80 in DCM 0-50%], ethyl 2-(2-((3-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (38d) (108 mg, 48% yield) as a clear oil; MS (ES+): 416.1 ((M+1).

[0343] Step-4: Preparation of 2-(2-((3-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (38e) Compound 38e was prepared from ethyl 2-(2-((3-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate (38d) (108 mg, 0.260 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (68 mg, 1.619 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((3-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid (38e) (78 mg, 77% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.20 (s, 1H), 8.62 (s, 3H), 8.43 (s, 1H), 8.21 (s, J = 1.7 Hz, 1H), 7.98 (s, J = 1.7 Hz, 1H), 7.78 (dt, J = 7.1, 1.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.59 - 7.44 (m, 3H), 7.22 (m, J = 7.5 Hz, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.59 (s, 2H);MS (ES+): 388.1 (M+1);(ES-): 386.1 (M-1);Analysis C 24 H 21 NO 4 .1.1 Calculated for HCl: C, 67.42; H, 5.21; Cl, ​​9.12; N, 3.28; Found: C, 67.61; H, 5.38; Cl, ​​8.97; N, 3.59.

[0344] Scheme 39 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-fluorophenyl)acetic acid (39f) Step-1: Preparation of tert-butyl 3-(3-(hydroxymethyl)benzofuran-5-yl)benzylcarbamate (39b) Compound 39b was prepared from (5-bromobenzofuran-3-yl)methanol (9b) (6.4 g, 28.2 mmol) in dioxane (100 mL) using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (39a) (12.68 g, 38.1 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (23.96 mL, 47.9 mmol), tricyclohexylphosphine (2.371 mg, 8.46 mmol), Pd 2 (dba) 3 (2.58 g, 2.82 mmol) and heated at 110 °C overnight in an oil bath under argon atmosphere, which gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0–70%], tert-butyl 3-(3-(hydroxymethyl)benzofuran-5-yl)benzylcarbamate (39b) (7.6 g, 76% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.95 - 7.90 (m, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.61 - 7.52 (m, 3H), 7.52 - 7.38 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 5.22 (t, J = MS (ES+): 376.10 (M+Na).

[0345] Step-2: Preparation of tert-butyl 3-(3-(chloromethyl)benzofuran-5-yl)benzylcarbamate (39c) To a stirred solution of tert-butyl 3-(3-(hydroxymethyl)benzofuran-5-yl)benzylcarbamate (39b) (1.13 g, 3.20 mmol) in DCM (20 mL) was added thionyl chloride (0.467 mL, 6.39 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and saturated NaHCO 3 It was quenched with aqueous solution (100 mL) and extracted with DCM (2×100 mL). The combined organics were washed with brine, dried, filtered and concentrated in vacuo to give tert-butyl 3-(3-(chloromethyl)benzofuran-5-yl)benzylcarbamate (39c) (650 mg, 55% yield) as a thick oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.64 (dd, J = 8.6, 1.9 Hz, 1H), 7.57 (d, J = 5.7 Hz, 2H), 7.51 - 7.40 (m, 2H), 7.25 (d, J = 7.5 Hz, 1H), 5.04 (s, 2H), 4.23 (d, J = 6.2 Hz, 2H), 1.41 (s, 9H); MS (ES+): 394.10 (M+Na).

[0346] Step-3: Preparation of ethyl 2-(2-((5-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-3-yl)methoxy)-4-fluorophenyl)acetate (39e) Compound 39e was prepared from tert-butyl 3-(3-(chloromethyl)benzofuran-5-yl)benzylcarbamate (39c) (140 mg, 0.376 mmol) in acetone (10 mL) according to the procedure reported in Scheme 1, Step 1, with 2-(4-fluoro-2-hydroxyphenyl)ethyl acetate (39d) (97 mg, 0.489 mmol; CAS no. 1261751-44-3), K2 CO 3 (104 mg, 0.753 mmol) and refluxed for 12 h, which after workup and purification by flash column chromatography [silica gel (24 g), elution with EtOAc / MeOH (9:1) in hexanes 0-80%] gave ethyl 2-(2-((5-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-3-yl)methoxy)-4-fluorophenyl)acetate (39e) (145 mg, 72% yield); MS (ES+): 556.2 (M+Na).

[0347] Step-4: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-fluorophenyl)acetic acid (39f) To a solution of ethyl 2-(2-((5-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-3-yl)methoxy)-4-fluorophenyl)acetate (39e) (145 mg, 0.272 mmol) in DCM (10 mL) was added TFA (1.5 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and a solution of THF (3 mL) and lithium hydroxide hydrate (63 mg, 1.51 mmol) in water (1 mL) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove the major organic solvent, and the aqueous solution was acidified to pH 5 and purified by reverse-phase column chromatography [C18 column (30 g), elution with ACN (containing 0.1% HCl) in water 0–100%] to give the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-fluorophenyl)acetic acid (39f) (21 mg, 19% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.10 (s, 1H, D2O exchangeable), 8.39 (s, 3H, D 2O exchangeable), 8.15 (s, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.89 (s, J = 2.0 Hz, 1H), 7.79 - 7.65 (m, 3H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.23 (m, J = 8.4, 6.9 Hz, 1H), 7.15 (dd, J = 11.4, 2.5 Hz, 1H), 6.76 (td, J = 8.5, 2.5 Hz, 1H), 5.34 (s, 2H), 4.11 (s, 2H), 3.51 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -113.04;MS (ES+): 406.2 (M+1);Analysis C 24 H 20 FNO 4 .HCl.1.25H 2 Calculated for O: C, 62.07; H, 5.10; Cl, ​​7.63; N, 3.02; Found: C, 62.21; H, 5.00; Cl, ​​7.97; N, 3.18.

[0348] Scheme 40 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)-5-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (40c) and 2-(3-((5-(3-(aminomethyl)-5-fluorophenyl)benzofuran-3-yl)methyl)-2-hydroxyphenyl)acetic acid (40d) Step-1: Preparation of ethyl 2-(2-((5-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetate (40b) Compound 40b was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (9c) (600 mg, 1.54 mmol) in dioxane (10 mL) to tert-butyl 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (40a) (812 mg, 2.31 mmol), K, according to the procedure reported in step-2 of scheme 1. 3 PO 4 (1.54 mL, 3.08 mmol), tricyclohexylphosphine (130 mg, 0.46 mmol), Pd 2 (dba) 3 (212 mg, 0.23 mmol) and heated at 125° C. in a microwave for 40 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0-70%], ethyl 2-(2-((5-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetate (40b) (386 mg, 47% yield) as a colorless oil; MS (ES+): 556.2 (M+Na).

[0349] Step-2: Preparation of 2-(2-((5-(3-(aminomethyl)-5-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (40c) and 2-(3-((5-(3-(aminomethyl)-5-fluorophenyl)benzofuran-3-yl)methyl)-2-hydroxyphenyl)acetic acid (40d) Compound 40c was prepared from ethyl 2-(2-((5-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetate (40b) in DCM (10 mL) using TFA (1.19 mL, 15.41 mmol) and stirring at room temperature for 3 h according to the procedure reported in Scheme 39, step-4. Hydrolysis of the ester was achieved using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and THF (3 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2-(3-((5-(3-(aminomethyl)-5-fluorophenyl)benzofuran-3-yl)methyl)-2-hydroxyphenyl)acetic acid (40d) (37 mg, 6% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.21 (s, 1H, D 2 O replaceable), 8.91 (s, 1H, D 2 O replaceable), 8.50 (s, 3H, D 2 O exchangeable), 7.93 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 12.5 Hz, 3H), 7.54 (dt, J = 10.4, 2.1 Hz, 1H), 7.34 (dt, J = 9.6, 1.9 Hz, 1H), 7.00 (ddd, J = 14.3, 7.6, 1.7 Hz, 2H), 6.70 (t, J = 7.5 Hz, 1H), 4.12 (s, 2H), 4.05 (s, 2H), 3.58 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -112.67;MS (ES+): 406.1 (M+1);Calculated for C 24 H 23 ClFNO 5 .HCl.H 2Calculated for O: C, 62.68; H, 5.04; Cl, ​​7.71; N, 3.05; Found: C, 62.71; H, 4.80; Cl, ​​7.47; N, 3.11. The HCl salt of 2-(2-((5-(3-(aminomethyl)-5-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (40c) (12 mg, 2% yield) was subsequently obtained as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.06 (s, 1H, D 2 O replaceable), 8.47 (s, 3H, D 2 O exchangeable), 8.14 (s, 1H), 8.07 (s, 1H), 7.78 - 7.71 (m, 3H), 7.63 (dt, J = 10.4, 2.0 Hz, 1H), 7.36 (dt, J = 9.5, 1.9 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.24 - 7.17 (m, 2H), 6.92 (td, 1H), 5.32 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -112.69;MS (ES+): 406.1 (M+1).

[0350] Scheme 41 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)acetic acid (41d) Step-1: Preparation of ethyl 2-(2-((5-bromonaphthalen-2-yl)methoxy)phenyl)acetate (41b) Compound 41b was prepared according to the procedure reported in step-3 of scheme 7 from (5-bromonaphthalen-2-yl)methanol (41a) (1 g, 4.22 mmol; CAS number 128104-53-0), triphenylphosphine (1.217 g, 4.64 mmol), ethyl 2-(2-hydroxyphenyl)acetate (7c) (0.836 g, 4.64 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.704 g, 4.64 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This afforded, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 2-(2-((5-bromonaphthalen-2-yl)methoxy)phenyl)acetate (41b) (1.2 g, 71% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.15 (dt, J = 8.8, 0.8 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.96 (dt, J = 8.5, 1.0 Hz, 1H), 7.89 (dd, J = 7.4, 1.1 Hz, 1H), 7.72 (dd, J = 8.8, 1.7 Hz, 1H), 7.47 (dd, J = 8.2, 7.4 Hz, 1H), 7.29 - 7.21 (m, 2H), 7.11 (d, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H); MS (ES-): 397.00 (M-1).

[0351] Step-2: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)acetate (41c) Compound 41c was prepared from ethyl 2-(2-((5-bromonaphthalen-2-yl)methoxy)phenyl)acetate (41b) (320 mg, 0.801 mmol) in dioxane (10 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (270 mg, 1.443 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 2 Cl 2 (84 mg, 0.120 mmol), K in water (3 mL) 2 CO 3 (332 mg, 2.404 mmol) and heated at 100 °C for 3 h, which gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0–50%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)acetate (41c) (200 mg, 59% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.04 (d, J = 1.7 Hz, 1H), 7.92 (dt, J = 8.3, 1.1 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.47 - 7.40 (m, 4H), 7.33 - 7.27 (m, 1H), 7.26 - 7.21 (m, 2H), 7.15 - 7.07 (m, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.66 (s, 2H), 1.99 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[0352] Step-3: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)acetic acid (41d) Compound 41d was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)acetate (41c) (200 mg, 0.470 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (101 mg, 2.404 mmol) in water (1 mL) and stirring at room temperature for 6 h according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)acetic acid (41d) (57 mg, 18% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.18 (s, 1H, D 2 O replaceable), 8.58 (s, 2H, D 2 O exchangeable), 8.09 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.67 - 7.53 (m, 5H), 7.53 - 7.41 (m, 2H), 7.28 - 7.18 (m, 2H), 7.12 - 7.03 (m, 1H), 6.90 (td, J = 7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H);MS (ES+): 398.1 (M+1);(ES-): 396.2 (M-1);Analysis C 26 H 23 NO 3 .HCl.H 2 Calculated for O: C, 69.10; H, 5.80; N, 3.10; Found: C, 69.13; H, 5.71; N, 3.09.

[0353] Scheme 42 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (42b) and 2-(3-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methyl)-2-hydroxyphenyl)acetic acid (42c) Step-1: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetate (42a) Compound 42a was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (9c) (300 mg, 0.771 mmol) in dioxane (3 mL) using 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (6c) (237 mg, 1.156 mmol), Pd according to the procedure reported in Scheme 3, Step-8. 2 (dba) 3 (70.6 mg, 0.077 mmol), tricyclohexylphosphine (65 mg, 0.231 mmol), K 3 PO 4 (0.655 mL, 1.310 mmol) of a 2 M solution of 4-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)ethyl acetate (42a) (98 mg, 29% yield) was prepared as a clear oil after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%]; MS (ES+): 434.1 (M+1).

[0354] Step-2: Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (42b) and 2-(3-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methyl)-2-hydroxyphenyl)acetic acid (42c) Compound 42b was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetate (42a) (98 mg, 0.226 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (97 mg, 2.312 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(3-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methyl)-2-hydroxyphenyl)acetic acid (42c) (7.5 mg, 2% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.17 (s, 1H, D 2 O replaceable), 8.40 (s, 3H, D 2 O exchangeable), 7.82 (s, 1H), 7.73 - 7.65 (m, 2H), 7.55 (t, J = 7.4 Hz, 2H), 7.46 (dt, J = 8.6, 1.8 Hz, 1H), 7.42 - 7.31 (m, 1H), 6.97 (d, J = 7.5 Hz, 2H), 6.69 (t, J = 7.5 Hz, 1H), 4.13 (s, 2H), 4.02 (s, 2H), 3.55 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -122.24; MS (ES+): 406.1 (M+1). Subsequently, the HCl salt of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (42b) (21 mg, 7% yield) was obtained as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.57 (s, 2H, D 2O exchangeable), 8.15 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.67 - 7.49 (m, 3H), 7.37 (t, J = 7.7 Hz, 1H), 7.31 - 7.16 (m, 3H), 6.92 (td, J = 7.3, 1.3 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H), 3.53 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -122.32;MS (ES+): 406.1 (M+1);Analysis C 24 H 20 FNO 4 .HCl.1.25H 2 Calculated for O: C, 62.07; H, 5.10; Cl, ​​7.63; N, 3.02; Found: C, 62.21; H, 4.85; Cl, ​​7.81; N, 3.11.

[0355] Scheme 43 [ka] Preparation of 3-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)propanoic acid (43c) Step-1: Preparation of ethyl 3-(2-((5-bromonaphthalen-2-yl)methoxy)phenyl)propanoate (43a) Compound 43a was prepared according to the procedure reported in step-3 of scheme 7 from (5-bromonaphthalen-2-yl)methanol (41a) (928 mg, 3.91 mmol), triphenylphosphine (1.129 g, 4.30 mmol), ethyl 3-(2-hydroxyphenyl)propanoate (2a) (0.760 g, 3.91 mmol) in DCM (30 mL) using bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.580 g, 4.30 mmol) in DCM (20 mL) and stirring at room temperature for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–50%], ethyl 3-(2-((5-bromonaphthalen-2-yl)methoxy)phenyl)propanoate (43a) (0.820 g, 51% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.16 (d, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.99 (dt, J = 8.5, 1.0 Hz, 1H), 7.89 (dd, J = 7.5, 1.1 Hz, 1H), 7.77 (dd, J = 8.8, 1.7 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.22 - 7.13 (m, 2H), 7.08 (dd, J = 8.7, 1.2 Hz, 1H), 6.88 (td, J = 7.3, 1.2 Hz, 1H), 5.35 (s, 2H), 4.02 (q, J = 7.1 Hz, 2H), 2.92 (t, J = 7.6 Hz, 2H), 2.61 (t, J = 8.3, 7.0 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H).

[0356] Step-2: Preparation of ethyl 3-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)propanoate (43b) Compound 43b was prepared from ethyl 3-(2-((5-bromonaphthalen-2-yl)methoxy)phenyl)propanoate (43a) (345 mg, 0.835 mmol) in dioxane (6 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (282 mg, 1.503 mmol), Pd(PPh) according to the procedure reported in Scheme 3, Step-8. 3 ) 2 Cl 2 (88 mg, 0.125 mmol), K in water (3 mL) 2 CO 3 (346 mg, 2.504 mmol) and heated at 100 °C for 3 h. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], ethyl 3-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)propanoate (43b) (146 mg, 40% yield) as a yellow oil; MS (ES+): 440.2 (M+1), (ES-): 438.2 (M-1).

[0357] Step-3: Preparation of 3-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)propanoic acid (43c) Compound 43c was prepared from ethyl 3-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)propanoate (43b) (146 mg, 0.332 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (70.1 mg, 1.669 mmol) in water (1 mL) and stirring overnight at room temperature according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 3-(2-((5-(3-(aminomethyl)phenyl)naphthalen-2-yl)methoxy)phenyl)propanoic acid (43c) (35 mg, 26% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d6 ) δ 9.00 (s, 2H, D 2 O exchangeable), 8.11 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.67 - 7.55 (m, 5H), 7.54 - 7.48 (m, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 7.3 Hz, 1H), 5.33 (s, 2H), 4.13 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.61 - 2.52 (m, 2H);MS (ES+): 412.2 (M+1);(ES-): 410.2 (M-1).

[0358] Scheme 44 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetic acid (44d) Step-1: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44b) Compound 44b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (358 mg, 1.235 mmol) in acetone (5 mL) with ethyl 2-(3-fluoro-2-hydroxyphenyl)acetate (44a) (281 mg, 1.420 mmol; CAS number 1261451-84-6) and K according to the procedure reported in Scheme 1, Step-1. 2 CO 3(597 mg, 4.32 mmol) and stirred overnight at room temperature, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-50%] afforded ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44b) (433 mg, 86% yield) as a yellow oil; MS (ES-): 405.7 (M-1).

[0359] Step-2: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44c) Compound 44c was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44b) (200 mg, 0.491 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (138 mg, 0.737 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.417 mL, 0.835 mmol), tricyclohexylphosphine (55.1 mg, 0.196 mmol), Pd 2 (dba) 3 (90 mg, 0.098 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44c) (56 mg, 26% yield) as a clear oil; MS (ES+): 434.1 (M+1).

[0360] Step-3: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetic acid (44d) Compound 44d was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44c) (56 mg, 0.129 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (62 mg, 1.473 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetic acid (44d) (3.5 mg, 2% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.33 (s, 1H, D 2 O replaceable), 8.32 (s, 3H, D 2 O exchangeable), 8.13 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.85 (t, J = 1.8 Hz, 1H), 7.78 - 7.65 (m, 3H), 7.54 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.28 - 7.17 (m, 1H), 7.12 - 7.04 (m, 2H), 5.27 (s, 2H), 4.12 (s, 2H), 3.57 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -129.52;MS (ES+): 406.1 (M+1).

[0361] Scheme 45 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetic acid (45b) Step-1: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (45a) Compound 45a was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (5b) (310 mg, 0.761 mmol) in dioxane (3 mL) with 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (6c) (235 mg, 1.142 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.647 mL, 1.294 mmol), tricyclohexylphosphine (85 mg, 0.304 mmol), Pd 2 (dba) 3 (139 mg, 0.152 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (45a) (241 mg, 70% yield) as a clear oil; MS (ES+): 452.1 (M+1).

[0362] Step-2: Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetic acid (45b) Compound 45b was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetate (45a) (241 mg, 0.534 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-5-fluorophenyl)acetic acid (45b) (104 mg, 32% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.27 (s, 1H, D2O exchangeable), 8.54 (s, 3H, D 2 O exchangeable), 8.14 (s, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.66 - 7.49 (m, 3H), 7.37 (t, J = 7.7 Hz, 1H), 7.26 - 7.16 (m, 1H), 7.15 - 7.05 (m, 2H), 5.29 (s, 2H), 4.14 (s, 2H), 3.55 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -122.36, -123.62;MS (ES+): 424.1 (M+1);Analysis C 24 H 19 F 2 NO 4 .HCl.H 2 Calculated for O: C, 60.32; H, 4.64; Cl, ​​7.42; N, 2.93; Found: C, 60.36; H, 4.56; Cl, ​​7.17; N, 2.94.

[0363] Scheme 46 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetic acid (46b) Step-1: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (46a) Compound 46a was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (44b) (200 mg, 0.491 mmol) in dioxane (3 mL) with 3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (6c) (151 mg, 0.737 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.417 mL, 0.835 mmol), tricyclohexylphosphine (55.1 mg, 0.196 mmol), Pd 2 (dba) 3 (90 mg, 0.098 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (46a) (86 mg, 39% yield) as a clear oil; MS (ES+): 452.1 (M+1).

[0364] Step-2: Preparation of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetic acid (46b) Compound 46b was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetate (46a) (86 mg, 0.190 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (61.8 mg, 3.22 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)-2-fluorophenyl)benzofuran-3-yl)methoxy)-3-fluorophenyl)acetic acid (46b) (13 mg, 6% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.50 (s, 2H, D 2 O exchangeable), 8.15 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.65 - 7.49 (m, 3H), 7.38 (t, J = 7.7 Hz, 1H), 7.26 - 7.17 (m, 1H), 7.12 - 7.03 (m, 2H), 5.24 (s, 2H), 4.15 (s, 2H), 3.57 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -122.28, -129.59;MS (ES+): 424.1 (M+1).

[0365] Scheme 47 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methylphenyl)acetic acid (47d) Step-1: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methylphenyl)acetate (47b) Compound 47b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (300 mg, 1.035 mmol) in acetone (5 mL) with ethyl 2-(2-hydroxy-4-methylphenyl)acetate (47a) (221 mg, 1.138 mmol), K according to the procedure reported in Scheme 7, Step-3. 2 CO 3 (500 mg, 3.62 mmol) was used and the reaction mixture was stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methylphenyl)acetate (47b) (383 mg, 92% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.7, 2.1 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.03 (s, MS (ES+): 425 (M+Na).

[0366] Step-2: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methylphenyl)acetate (47c) Compound 47c was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methylphenyl)acetate (47b) (380 mg, 0.94 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (309 mg, 1.65 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4(0.942 mL, 1.885 mmol), tricyclohexylphosphine (106 mg, 0.377 mmol), Pd 2 (dba) 3 (173 mg, 0.188 mmol) and heated in a microwave at 135 °C for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (12 g), eluted with DMA-80 in DCM 0-50%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methylphenyl)acetate (47c) (201 mg, 50% yield) as a clear oil; MS (ES+): 430.2 (M+1).

[0367] Step-3: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methylphenyl)acetic acid (47d) Compound 47d was prepared from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methylphenyl)acetate (47c) (201 mg, 0.468 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (119 mg, 2.83 mmol) in water (1 mL) and stirring at room temperature overnight, according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methylphenyl)acetic acid (47d) (93 mg, 25% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.14 (s, 1H, D2O exchangeable), 8.67 - 8.44 (bs, 3H, D 2O exchangeable), 8.12 (s, 1H), 8.03 (s, J = 1.2 Hz, 1H), 7.92 (s, J = 1.9 Hz, 1H), 7.78 - 7.65 (m, 3H), 7.56 - 7.44 (m, 2H), 7.08 (m, 2H), 6.78 - 6.69 (d, 1H), 5.31 (s, 2H), 4.10 (s, 2H), 3.49 (s, 2H), 2.32 (s, 3H);MS (ES+): 402.1 (M+1);Analysis C 25 H 23 NO 4 .HCl.0.75H 2 Calculated for O: C, 66.52; H, 5.69; Cl, ​​7.85; N, 3.10; Found: C, 66.60; H, 5.86; Cl, ​​8.02; N, 3.27.

[0368] Scheme 48 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetic acid (48b) Step-1: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (48a) Compound 48a was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (6b) (250 mg, 0.596 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (168 mg, 0.894 mmol), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.507 mL, 1.014 mmol), tricyclohexylphosphine (66.9 mg, 0.239 mmol), Pd 2 (dba) 3(109 mg, 0.119 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (48a) (124 mg, 47% yield) as a clear oil; MS (ES+): 446.1 (M+1).

[0369] Step-2: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetic acid (48b) Compound 48b was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetate (48a) (124 mg, 0.278 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (75 mg, 1.789 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-methoxyphenyl)acetic acid (48b) (45 mg, 18% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.12 (s, 1H, D 2 O replaceable), 8.38 (s, 3H, D 2O exchangeable), 8.12 (s, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.88 (t, J = 1.8 Hz, 1H), 7.78 - 7.65 (m, 3H), 7.57 - 7.41 (m, 2H), 7.10 (d, J = 8.3 MS (ES+): 418.1 (M+1);Analysis C 25 H 23 NO 5 .HCl.0.5H 2 Calculated for O: C, 64.86; H, 5.44; Cl, ​​7.66; N, 3.03; Found: C, 64.90; H, 5.32; Cl, ​​7.92; N, 3.16.

[0370] Scheme 49 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetic acid (49b) Step-1: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (49a) Compound 49a was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (12e) (206 mg, 0.49 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (139 mg, 0.74 mmol), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.42 mL, 0.84 mmol), tricyclohexylphosphine (55.4 mg, 0.20 mmol), Pd 2 (dba) 3(90 mg, 0.099 mmol) and heated in a microwave at 135 °C for 30 min, which after workup and purification by column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0-70%] afforded ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (49a) (88 mg, 0.198 mmol) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.71 - 7.59 (m, 3H), 7.53 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.09 (dd, J = 4.6, 3.0 Hz, 2H), 6.77 (d, J = 7.5 Hz, 1H), 5.29 (s, 2H), 3.77 (s, 2H), 3.71 (q, J = 7.1 Hz, 2H), 3.51 (s, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H); MS (ES+): 444.2 (M+1).

[0371] Step-2: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetic acid (49b) Compound 49b was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetate (49a) (88 mg, 0.198 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (62.1 mg, 1.48 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-ethylphenyl)acetic acid (49b) (35 mg, 17% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.06 (s, 1H, D 2 O replaceable), 8.47 (s, 3H, D 2 O exchangeable), 8.13 (s, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.90 (t, J = 1.7 Hz, 1H), 7.79 - 7.65 (m, 3H), 7.56 - 7.42 (m, 2H), 7.12 - 7.05 (m, MS (ES+): 416.2 (M+1);Analysis C 26 H 25 NO 4 .HCl.H 2 Calculated for O: C, 66.45; H, 6.01; Cl, ​​7.54; N, 2.98; Found: C, 66.77; H, 5.89; Cl, ​​7.62; N, 3.16.

[0372] Scheme 50 [ka] Preparation of 2-(2-((5-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetic acid (50d) Step-1: Preparation of ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) Compound 50a was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)phenyl)acetate (9c) in anhydrous dioxane (15 mL) using BisPin (1 g, 2.57 mmol), potassium acetate (0.756 g, 7.71 mmol), PdCl according to the procedure reported in Scheme 27, Step-1. 2 (dppf)-CH 2 Cl 2 The adduct (0.315 g, 0.39 mmol) was used to prepare the product by heating at 90° C. for 6.5 h, which after workup and purification by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0–40%] afforded ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) (1.01 g, 90% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.13 - 7.98 (m, 2H), 7.72 - 7.53 (m, 2H), 7.34 - 7.14 (m, 3H), 6.94 (td, J = 7.3, 1.3 Hz, 1H), 5.29 (d, J = 2.4 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.62 - 3.50 (m, 2H), 1.31 (s, 12H), 0.99 - 0.92 (m, 3H).

[0373] Step-2: Preparation of ethyl 2-(2-((5-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50c) Compound 50c was prepared from ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) (300 mg, 0.688 mmol), N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (50b) (273 mg, 1.031 mmol), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.584 mL, 1.169 mmol), tricyclohexylphosphine (57.8 mg, 0.206 mmol), Pd 2 (dba) 3 (63 mg, 0.069 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA80 in DCM 0-70%], ethyl 2-(2-((5-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50c) (210 mg, 57% yield) as a yellow oil; MS (ES+): 539.2 (M+1).

[0374] Step-3: Preparation of 2-(2-((5-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetic acid (50d) Compound 50d was prepared from ethyl 2-(2-((5-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50c) (210 mg, 0.390 mmol) in DCM (10 mL) using HCl (4 M solution in dioxane, 0.52 mL, 2.063 mmol) and stirring at room temperature for 2 h according to the procedure reported in step-4 of scheme 39. The ester was hydrolyzed using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and THF (3 mL) and stirred at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetic acid (50d) (81 mg, 29% yield) as a white solid after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.61 (t, J = 5.7 Hz, 3H, D2O interchangeable), 8.55 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.67 (dt, J = 8.6, 1.8 Hz, 1H), 7.33 - 7.14 (m, 3H), 6.93 (td, J = 7.3, 1.3 Hz, 1H), 5.33 (s, 2H), 4.39 - 4.28 (m, 2H), 3.54 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -132.79;MS (ES+): 407.1 (M+1);Analysis C 23 H 19 FN 2 O 4 .1.5HCl.2.25H 2Calculated for O: C, 55.07; H, 5.02; Cl, ​​10.60; N, 5.58; Found: C, 55.18; H, 4.36; Cl, ​​10.21; N, 5.64.

[0375] Scheme 51 [ka] Preparation of (S)-2-(2-((5-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (51c) Step-1: Preparation of (S)-ethyl 2-(2-((5-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (51b) Compound 51b was prepared from ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) (300 mg, 0.688 mmol), (S)-2-amino-2-(3-chlorophenyl)ethanol (51a) (177 mg, 1.03 mmol; CAS no. 663611-73-2), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.584 mL, 1.17 mmol), tricyclohexylphosphine (57.8 mg, 0.206 mmol), Pd 2 (dba) 3 (63 mg, 0.069 mmol) and heated in a microwave at 135 °C for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], (S)-ethyl 2-(2-((5-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (51b) (162 mg, 53% yield) as a clear oil; MS (ES+): 446.1 (M+1).

[0376] Step-2: Preparation of (S)-2-(2-((5-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (51c) Compound 51c was prepared from (S)-ethyl 2-(2-((5-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (51b) (162 mg, 0.364 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and stirring overnight at room temperature according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of (S)-2-(2-((5-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (51c) (82 mg, 29% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.16 (s, 1H, D 2 O replaceable), 8.68 (s, 3H, D 2 O exchangeable), 8.12 (s, 1H), 8.08 - 8.00 (m, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.55 - 7.43 (m, 2H), 7.31 - 7.16 (m, 3H), 6.93 (td, J = 7.2, 1.4 Hz, 1H), 5.62 (s, 1H, D 2 O exchangeable), 5.34 (s, 2H), 4.36 (t, J = 6.0 Hz, 1H), 3.81 (d, J = 5.9 Hz, 2H), 3.56 (s, 2H);MS (ES+): 418.2 (M+1);Analysis C 25 H 23 NO 5 .HCl.1.5H 2Calculated for O: C, 62.43; H, 5.66; Cl, ​​7.37; N, 2.91; Found: C, 62.41; H, 5.33; Cl, ​​7.26; N, 2.93; Optical rotation [α]D = +15.56 (c = 0.09, MeOH).

[0377] Scheme 52 [ka] Preparation of (R)-2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (52c) Step-1: Preparation of (R)-ethyl 2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (52b) Compound 52b was prepared from ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) (350 mg, 0.80 mmol), (R)-1-(3-bromophenyl)ethanamine (52a) (241 mg, 1.20 mmol, CAS no. 176707-77-0), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.68 mL, 1.36 mmol), tricyclohexylphosphine (67.5 mg, 0.24 mmol), Pd 2 (dba) 3 (73.5 mg, 0.08 mmol) and heated in a microwave at 135 °C for 30 min. This gave, after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], (R)-ethyl 2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (52b) (166 mg, 48% yield) as a yellow oil; MS (ES+): 430.2 (M+1).

[0378] Step-2: Preparation of (R)-2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (52c) Compound 52c was prepared from (R)-ethyl 2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (52b) (166 mg, 48% yield) in THF (3 mL) using a solution of lithium hydroxide hydrate (101 mg, 2.41 mmol) in water (1 mL) and stirring overnight at room temperature according to the procedure reported in step-3 of scheme 1. This afforded the HCl salt of (R)-2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (52c) (67 mg, 21% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.17 (s, 1H, D 2 O replaceable), 8.67 (s, 3H, D 2 O exchangeable), 8.12 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.72 (s, 3H), 7.52 (m, J = 4.6 Hz, 2H), 7.33 - 7.15 (m, 3H), 6.92 (td, J = 7.2, Analysis C 25 H 23 NO 4 .HCl.H 2 Calculated for O: C, 65.86; H, 5.75; Cl, ​​7.78; N, 3.07; Found: C, 65.71; H, 5.58 Cl, 7.66; N, 3.08.

[0379] Scheme 53 [ka] Preparation of 2-(2-((5-(2-(aminomethyl)pyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetic acid (53b) Step-1: Preparation of ethyl 2-(2-((5-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetate (53a) Compound 53a was prepared from ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) (350 mg, 0.80 mmol), (+)-N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (27b) (297 mg, 1.203 mmol), K in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.68 mL, 1.36 mmol), tricyclohexylphosphine (67.5 mg, 0.24 mmol), Pd 2 (dba) 3 (73.5 mg, 0.080 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetate (53a) (232 mg, 0.446 mmol, 55% yield) as a clear oil; MS (ES+): 521.2 (M+1).

[0380] Step-2: Preparation of 2-(2-((5-(2-(aminomethyl)pyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetic acid (53b) Compound 53b was prepared according to the procedure reported in Scheme 39, step-4 from ethyl 2-(2-((5-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetate (53a) (232 mg, 0.446 mmol) in DCM (10 mL) using HCl (4N in dioxane, 0.60 mL, 2.41 mmol) and stirring at room temperature for 2 h. The ester was hydrolyzed using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and THF (3 mL) and stirred at room temperature overnight. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 2-(2-((5-(2-(aminomethyl)pyridin-4-yl)benzofuran-3-yl)methoxy)phenyl)acetic acid (53b) (81 mg, 47% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.72 (d, J = 5.4 Hz, 1H), 8.55 (s, 3H, D 2 O exchangeable), 8.22 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.93 - 7.87 (m, 1H), 7.86 - 7.78 (m, 2H), 7.32 - 7.26 (m, 1H), 7.25 - 7.19 (m, 2H), 6.94 (td, J = 7.3, 1.3 Hz, 1H), 5.35 (s, 2H), 4.36 - 4.22 (m, 2H), 3.55 (s, 2H);MS (ES+): 389.1 (M+1);Analysis C 23 H 20 N 2 O 4 . 1.85HCl. 2.5H 2 Calculated for O: C, 55.15; H, 5.40; Cl, ​​13.09; N, 5.59; Found: C, 55.11; H, 5.09; Cl, ​​13.03; N, 5.63.

[0381] Scheme 54 [ka] Preparation of (S)-2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (54c) Step-1: Preparation of (S)-ethyl 2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (54b) Compound 54b was prepared from ethyl 2-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methoxy)phenyl)acetate (50a) (350 mg, 0.80 mmol), (S)-1-(3-bromophenyl)ethanamine (54a) (241 mg, 1.20 mmol, CAS no. 139305-96-7), K, in dioxane (3 mL) according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.68 mL, 1.36 mmol), tricyclohexylphosphine (67.5 mg, 0.24 mmol), Pd 2 (dba) 3 (73.5 mg, 0.080 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], (S)-ethyl 2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetate (54b) (167 mg, 49% yield) as a clear oil; MS (ES+): 430.2 (M+1).

[0382] Step-2: Preparation of (S)-2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (54c) Compound 54c was prepared according to the procedure reported in step-3 of scheme 1 from (S)-ethyl 2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (54b) (167 mg, 0.389 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of (S)-2-(2-((5-(3-(1-aminoethyl)phenyl)benzofuran-3-yl)methoxy)phenyl)acetic acid (54c) (52 mg, 16% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.11 (s, 1H, D 2 O replaceable), 8.50 (s, 3H, D 2 O exchangeable), 8.06 (s, 1H), 7.97 (t, J = 1.2 Hz, 1H), 7.86 (s, J = 1.9 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.50 - 7.39 (m, 2H), 7.24 - 7.11 (m, MS (ES+): 402.1 (M+1);Analysis C 25 H 23 NO 4 .HCl.H 2 Calculated for O: C, 65.86; H, 5.75; Cl, ​​7.78; N, 3.07; Found: C, 65.76; H, 5.61; Cl, ​​7.59; N, 3.18.

[0383] Scheme 55 [ka] Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (55d) Step-1: Preparation of ethyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (55b) Compound 55b was prepared from ethyl 5-bromo-3-(bromomethyl)benzofuran-2-carboxylate (55a) (500 mg, 1.381 mmol; CAS number 565192-82-7) in acetone (10 mL) with ethyl 2-(2-hydroxyphenyl)acetate (7c) (286 mg, 1.588 mmol), K according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (668 mg, 4.83 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (55b) (586 mg, 92% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.06 (d, J = 1.9 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.34 - 7.26 (m, 1H), 7.23 (dd, J = 7.4, 1.7 Hz, 1H), 7.17 (dd, J = 8.3, 1.1 Hz, 1H), 6.95 (td, J = 7.4, 1.1 Hz, 1H), 5.59 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H).

[0384] Step-2: Preparation of ethyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (55c) Compound 55c was prepared from ethyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (55b) (250 mg, 0.54 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (152 mg, 0.81 mmol), K according to the procedure reported in Scheme 1, Step-2. 3 PO 4 (0.46 mL, 0.92 mmol), tricyclohexylphosphine (60.8 mg, 0.22 mmol), Pd 2 (dba) 3 (99 mg, 0.11 mmol) and heated in a microwave at 135 °C for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (55c) (121 mg, 46% yield) as a clear oil; MS (ES+): 488.2 (M+1).

[0385] Step-3: Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (55d) Compound 55d was prepared according to the procedure reported in Scheme 1, step-3 from ethyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (55c) (121 mg, 0.248 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (136 mg, 3.25 mmol) in water (1 mL) and stirring at room temperature overnight. This gave the HCl salt of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (55d) (52 mg, 22% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%] followed by flash column chromatography [silica (12 g), eluted with MeOH in DCM 0-40%]; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.52 (s, 1H, D 2 O replaceable), 8.48 (s, 3H, D 2 O exchangeable), 8.13 (s, 1H), 7.92 - 7.81 (m, 3H), 7.73 (dt, J = 7.0, 2.0 Hz, 1H), 7.57 - 7.45 (m, 2H), 7.31 - 7.14 (m, 3H), 6.97 - 6.87 (m, 1H), 5.69 (s, 2H), 4.10 (s, 2H), 3.55 (s, 2H);MS (ES+): 432.1 (M+1);Analysis C 25 H 21 NO 6 .HCl.2.25H 2 Calculated for O: C, 59.06; H, 5.25; Cl, ​​6.97; N, 2.75; Found: C, 58.82; H, 5.13; Cl, ​​6.78; N, 2.80.

[0386] Scheme 56 [ka] Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylic acid (56d) Step-1: Preparation of ethyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylate (56b) Compound 56b was prepared from ethyl 5-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (56a) (500 mg, 1.322 mmol; CAS number 31310-31-3) in acetone (12 mL) with ethyl 2-(2-hydroxyphenyl)acetate (7c) (274 mg, 1.521 mmol), K according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (640 mg, 4.63 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylate (56b) (478 mg, 76% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.25 (d, J = 1.9 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.73 (dd, J = 8.7, 1.9 Hz, 1H), 7.31 (td, J = 7.8, 7.3, 1.7 Hz, 1H), 7.25 - 7.16 (m, 2H), 6.94 (td, J = 7.4, 1.2 Hz, 1H), 5.69 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.80 (q, J = 7.1 Hz, 2H), 3.46 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H).

[0387] Step-2: Preparation of ethyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylate (56c) Compound 56c was prepared from ethyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylate (56b) (250 mg, 0.52 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (147 mg, 0.786 mmol), K according to the procedure reported in Scheme 1, Step-2. 3 PO 4 (0.45 mL, 0.89 mmol), tricyclohexylphosphine (58.7 mg, 0.21 mmol), Pd 2 (dba) 3 (96 mg, 0.11 mmol) and heated in a microwave at 135 °C for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylate (56c) (88 mg, 33% yield) as a clear oil; MS (ES+): 504.2 (M+1).

[0388] Step-3: Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylic acid (56d) Compound 56d was prepared according to the procedure reported in Scheme 1, step-3 from ethyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylate (56c) (88 mg, 0.175 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (1 mL) and stirring at room temperature overnight. This gave, after workup and purification by reverse phase column chromatography [C18 column (30 g), eluting with ACN in water (containing 0.1% HCl) 0-100%] followed by flash column chromatography [silica (12 g), eluting with MeOH in DCM 0-40%], 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzo[b]thiophene-2-carboxylic acid (56d) (42 mg, 54% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.20 (s, 2H, D 2 O exchangeable), 8.17 (d, J = 1.7 Hz, 1H), 8.04 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.66 (dd, J = 8.4, 1.7 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.19 - 7.06 (m, 2H), 6.83 (t, J = 7.3 Hz, 1H), 5.85 (s, 2H), 4.12 (s, 2H), 3.42 (s, 2H);MS (ES+): 448.1 (M+1);Analysis C 25 H 21 NO 5 S.1.25H 2 Calculated for O: C, 63.88; H, 5.04; N, 2.98; Found: C, 63.82; H, 4.88; N, 3.09.

[0389] Scheme 57 [ka] Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-cyanophenyl)acetic acid (57d) Step-1: Preparation of ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-cyanophenyl)acetate (57b) Compound 57b was prepared from 5-bromo-3-(bromomethyl)benzofuran (1a) (300 mg, 1.035 mmol) in acetone (5 mL) with ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (57a) (244 mg, 1.190 mmol), K according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (500 mg, 3.62 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-cyanophenyl)acetate (57b) (235 mg, 55% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 8.8, 2.1 Hz, 1H), 7.45 (s, 2H), 5.33 (s, 2H), 3.93 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 0.96 (t, J = 7.1 Hz, 3H); MS (ES+): 447.9 (M+Cl).

[0390] Step-2: Preparation of ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-cyanophenyl)acetate (57c) Compound 57c was prepared from ethyl 2-(2-((5-bromobenzofuran-3-yl)methoxy)-4-cyanophenyl)acetate (57b) (235 mg, 0.57 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (159 mg, 0.85 mmol), K according to the procedure reported in step-2 of scheme 1. 3 PO 4 (0.48 mL, 0.96 mmol), tricyclohexylphosphine (63.6 mg, 0.23 mmol), Pd 2 (dba) 3 (104 mg, 0.11 mmol) and heated in a microwave at 135 °C for 30 min. This gave, after workup and purification by column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%], ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-cyanophenyl)acetate (57c) (96 mg, 38% yield) as a clear oil; MS (ES+): 444.1 (M+1).

[0391] Step-3: Preparation of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-cyanophenyl)acetic acid (57d) Compound 57d was prepared according to the procedure reported in step-3 of scheme 1 from ethyl 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-cyanophenyl)acetate (57c) (96 mg, 0.218 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (71 mg, 1.70 mmol) in water (1 mL) and stirring at room temperature overnight. This afforded the HCl salt of 2-(2-((5-(3-(aminomethyl)phenyl)benzofuran-3-yl)methoxy)-4-cyanophenyl)acetic acid (57d) (15 mg, 6% yield) as a white solid after workup and purification by reverse phase column chromatography [C18 column (30 g), eluted with ACN in water (containing 0.1% HCl) 0-100%]; 1H NMR (300 MHz, DMSO-d 6 ) δ 12.37 (s, 1H, D 2 O replaceable), 8.36 (s, 3H, D 2 O exchangeable), 8.17 (s, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.88 (t, J = 1.8 Hz, 1H), 7.79 - 7.68 (m, 4H), 7.54 (t, J = 7.6 Hz, 1H), 7.50 - 7.42 (m, 3H), 5.43 (s, 2H), 4.12 (s, 2H), 3.65 (s, 2H);MS (ES+): 413.1 (M+1);IR: 2228.9 cm -1 .

[0392] Scheme 58 [ka] Preparation of 5,7-bis(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (58f) Step-1: Preparation of tert-butyl 7-bromo-5-chloro-3-methylbenzofuran-2-carboxylate (58b) A solution of 1-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone (58a) (5 g, 20.04 mmol; CAS no. 59443-15-1) in DMF (50 mL) was diluted with tert-butyl 2-bromoacetate (4.30 g, 22.05 mmol), K 2 CO 3(4.15 g, 30.1 mmol) was added and stirred at 50 °C for 2 h. To this mixture was added DBU (6.04 mL, 40.1 mmol) which was heated at 100 °C for 3 h, quenched with a cold solution of 1N HCl (50 mL), and extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (24 g), eluted with EtOAc in DCM 0-70%] to give tert-butyl 7-bromo-5-chloro-3-methylbenzofuran-2-carboxylate (58b) (4.1 g, 59% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.97 (d, J = 1.9 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H), 2.49 (s, 3H), 1.59 (s, 9H).

[0393] Step-2: Preparation of tert-butyl 7-bromo-3-(bromomethyl)-5-chlorobenzofuran-2-carboxylate (58c) To a solution of tert-butyl 7-bromo-5-chloro-3-methylbenzofuran-2-carboxylate (58b) (300 mg, 0.868 mmol) in carbon tetrachloride (10 mL) was added NBS (170 mg, 0.955 mmol), benzoyl peroxide (31.5 mg, 0.130 mmol). The reaction mixture was heated to reflux for 24 h. The solids were removed by filtration and eluted with CH. 2 Cl 2 The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 5-10%] to give tert-butyl 7-bromo-3-(bromomethyl)-5-chlorobenzofuran-2-carboxylate (58c) (350 mg, 0.824 mmol, 95% yield) as a clear oil; 1HNMR (300 MHz, DMSO-d6) δ 8.11 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 5.07 (s, 2H), 1.62 (s, 9H).

[0394] Step-3: Preparation of tert-butyl 7-bromo-5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58d) Compound 58d was prepared from tert-butyl 7-bromo-3-(bromomethyl)-5-chlorobenzofuran-2-carboxylate (58c) (3 g, 7.07 mmol) in acetone (30 mL) with ethyl 2-(2-hydroxyphenyl)acetate (7c) (1.464 g, 8.13 mmol), K according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (3.42 g, 24.73 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded tert-butyl 7-bromo-5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58d) (1.7 g, 46% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.97 - 7.91 (m, 2H), 7.30 (td, J = 7.7, 1.7 Hz, 1H), 7.22 (dd, J = 7.5, 1.7 Hz, 1H), 7.15 (dd, J = 8.3, 1.1 Hz, 1H), 6.95 (td, J = MS (ES+): 544.90 (M+Na).

[0395] Step-4: Preparation of tert-butyl 5,7-bis(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58e) Compound 58e was prepared from tert-butyl 7-bromo-5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58d) (500 mg, 0.955 mmol) in dioxane (3 mL) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (492 mg, 2.63 mmol), K according to the procedure reported in Scheme 1, Step-2. 3 PO 4 (0.811 mL, 1.623 mmol), tricyclohexylphosphine (107 mg, 0.382 mmol), Pd 2 (dba) 3 (175 mg, 0.191 mmol) and heated in a microwave at 135° C. for 30 min. This gave, after workup and purification by column chromatography [silica (24 g), eluted with DMA80 in DCM 0-70%], tert-butyl 5,7-bis(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58e) (85 mg, 14% yield) as a clear oil; MS (ES+): 621.2 (M+1).

[0396] Step-5: Preparation of 5,7-bis(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (58f) Compound 58f was prepared according to the procedure reported in Scheme 1, step-3 from tert-butyl 5,7-bis(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58e) (85 mg, 0.137 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (120 mg, 2.86 mmol) in water (1 mL) and heating at 60° C. for 1 h. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 5,7-bis(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)benzofuran-2-carboxylic acid (58f) (37.5 mg, 51% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.55 (s, 6H, D 2 O exchangeable), 8.23 ​​(s, 1H), 8.21 - 8.11 (m, 3H), 8.08 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.68 - 7.45 (m, 4H), 7.30 - 7.17 (m, Analysis C 32 H 28 N 2 O 6 .2HCl.2.5H 2 Calculated for O: C, 58.72; H, 5.39; Cl, ​​10.83; N, 4.28; Found: C, 58.69; H, 5.29; Cl, ​​10.50; N, 4.62.

[0397] Scheme 59 [ka] Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylic acid (59 g) Step-1: Preparation of tert-butyl 2-(2-acetyl-4-bromo-6-nitrophenoxy)acetate (59b) A solution of 1-(5-bromo-2-hydroxy-3-nitrophenyl)ethanone (59a) (5 g, 19.23 mmol; CAS no. 70978-54-0) in DMF (50 mL) was diluted with tert-butyl 2-bromoacetate (4.50 g, 23.07 mmol), K 2 CO 3 (3.99 g, 28.8 mmol) was added and heated at 50 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (300 mL), washed with water (3x), brine, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-100%] to give tert-butyl 2-(2-acetyl-4-bromo-6-nitrophenoxy)acetate (59b) (5.9 g, 82% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.37 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.5 Hz, 1H), 4.56 (s, 2H), 2.62 (s, 3H), 1.40 (s, 9H).

[0398] Step-2: Preparation of tert-butyl 5-bromo-3-methyl-7-nitrobenzofuran-2-carboxylate (59c) To a solution of tert-butyl 2-(2-acetyl-4-bromo-6-nitrophenoxy)acetate (59b) (2.67 g, 7.14 mmol) in DMF (15 mL) was added DBU (1.613 mL, 10.70 mmol) and heated at 120 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), washed with water (3x), brine, dried, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel (40 g), eluted with EtOAc in hexanes 0-100%] to give tert-butyl 5-bromo-3-methyl-7-nitrobenzofuran-2-carboxylate (59c) (1.6 g, 63% yield) as a yellow solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.58 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 2.55 (s, 3H), 1.60 (s, 9H).

[0399] Step-3: Preparation of tert-butyl 5-bromo-3-(bromomethyl)-7-nitrobenzofuran-2-carboxylate (59d) Compound 59d was prepared from tert-butyl 5-bromo-3-methyl-7-nitrobenzofuran-2-carboxylate (59c) (500 mg, 1.404 mmol) in carbon tetrachloride (10 mL) using NBS (300 mg, 1.685 mmol), benzoyl peroxide (51.0 mg, 0.211 mmol) and refluxing for 30 h according to the procedure reported in step-2 of scheme 58. This afforded tert-butyl 5-bromo-3-(bromomethyl)-7-nitrobenzofuran-2-carboxylate (59d) (284 mg, 47% yield) as a white solid after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0-100%]; 1 H NMR (300 MHz, DMSO-d 6) δ 8.72 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 1.63 (s, 9H); MS (ES+): 455.80 (M+Na).

[0400] Step-4: Preparation of tert-butyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylate (59e) Compound 59e was prepared from tert-butyl 5-bromo-3-(bromomethyl)-7-nitrobenzofuran-2-carboxylate (59d) (1 g, 2.29 mmol) in acetone (10 mL) with ethyl 2-(2-hydroxyphenyl)acetate (7c) (0.476 g, 2.64 mmol), K according to the procedure reported in Scheme 1, Step-1. 2 CO 3 (1.11 g, 8.04 mmol) and stirred at room temperature overnight, which after workup and purification by flash column chromatography [silica gel (12 g), eluted with EtOAc in hexanes 0–50%] afforded tert-butyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylate (59e) (1.05 g, 85% yield) as a clear oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.54 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 7.35 - 7.26 (m, 1H), 7.26 - 7.14 (m, 2H), 7.01 - 6.91 (m, 1H), 5.60 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 1.57 (s, 9H), 0.98 (t, J = 7.1 Hz, 3H); MS (ES+): 555.9 and 558.0 (M+Na).

[0401] Step-5: Preparation of tert-butyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylate (59f) Compound 59f was prepared from tert-butyl 5-bromo-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylate (59e) (295 mg, 0.552 mmol) in dioxane / THF (5 mL, 1:1) with 3-(aminomethyl)phenylboronic acid hydrochloride (1d) (207 mg, 1.104 mmol), K according to the procedure reported in Scheme 3, Step-8. 3 PO 4 (1.104 mL, 2.208 mmol), tricyclohexylphosphine (46.4 mg, 0.166 mmol), Pd 2 (dba) 3 (50.6 mg, 0.055 mmol), PdCl 2 (dppf)-CH 2 Cl 2 The adduct (45 mg, 0.055 mmol) was used to prepare the product by heating at 90 °C for 1 h, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0–70%] afforded tert-butyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylate (59f) (202 mg, 65% yield) as a yellow semi-solid; 1 H NMR (300 MHz, DMSO-d 6) δ 8.58 (s, 2H), 7.79 (s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.53 - 7.45 (m, 2H), 7.45 - 7.39 (m, 1H), 7.36 - 7.27 (m, 1H), 7.26 - 7.18 (m, 2H), 6.95 (t, J = 7.3 Hz, 1H), 5.67 (s, 2H), 3.82 (s, 2H), 3.65 (q, J = 6.5, 6.0 Hz, 2H), 3.54 (s, 2H), 1.58 (s, 9H), 0.81 (t, J = 7.1 Hz, 3H); MS (ES+): 561.1 (M+1); (ES-): 559.1 (M-1).

[0402] Step-6: Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylic acid (59 g) Compound 59g was prepared according to the procedure reported in Scheme 1, step-3 from tert-butyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylate (59f) (202 mg, 0.360 mmol) in THF (3 mL) using a solution of lithium hydroxide hydrate (70 mg, 1.656 mmol) in water (1 mL) and stirring at 50° C. for 2 h. This gave, after workup and purification by reverse-phase column chromatography [C18 column (30 g), elution with ACN in water (containing 0.1% HCl) 0–100%], the HCl salt of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)-7-nitrobenzofuran-2-carboxylic acid (59 g) (35 mg, 13% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.32 (s, 1H, D 2 O exchangeable), 8.59 (d, J = 2.1 Hz, 2H), 8.49 (s, 3H, D 2O exchangeable), 7.99 (s, 1H), 7.89 - 7.81 (m, 1H), 7.57 (d, J = 4.9 Hz, 2H), 7.29 - 7.16 (m, 3H), 6.93 (td, J = 7.1, 1.8 Hz, 1H), 5.73 (s, 2H), 4.14 (s, 2H), 3.52 (s, 2H);MS (ES+): 477.0 (M+1);(ES-): 475.0 (M-1);Analysis C 25 H 20 N 2 O 8 .0.9HCl.1.25H 2 Calculated for O: C, 56.47; H, 4.44; Cl, ​​6.00; N, 5.27; Found: C, 56.21; H, 4.50; Cl, ​​5.99; N, 5.11.

[0403] Scheme 60 [ka] Preparation of 5-(3-(aminomethyl)phenyl)-3-((2-(carboxymethyl)phenoxy)methyl)-7-(1-methyl-1H-pyrazol-4-yl)benzofuran-2-carboxylic acid (60d) Step-1: Preparation of tert-butyl 5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-(1-methyl-1H-pyrazol-4-yl)benzofuran-2-carboxylate (60b) Compound 60b was prepared from tert-butyl 7-bromo-5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylate (58d) (980 mg, 1.871 mmol) in THF (10 mL) according to the procedure reported in Scheme 3, step-8, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60a) (1.17 g, 5.61 mmol; CAS number 761446-44-0), K 3 PO 4(3.74 mL, 7.48 mmol), tricyclohexylphosphine (105 mg, 0.374 mmol), Pd 2 (dba) 3 (171 mg, 0.187 mmol), PdCl 2 (dppf)-CH 2 Cl 2 The adduct (153 mg, 0.187 mmol) was used to prepare the product by heating at 80 °C for 2 h, which after workup and purification by flash column chromatography [silica gel (24 g), eluted with DMA-80 in DCM 0-70%] gave tert-butyl 5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-(1-methyl-1H-pyrazol-4-yl)benzofuran-2-carboxylate (60b) (729 mg, 74% yield) as a yellow oil; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 8.22 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.30 (td, J = 7.8, 7.4, 1.7 Hz, 1H), 7.25 - 7.14 (m, 2H), 6.95 (t, J = 7.4 Hz, 1H), 5.56 (s, 2H), 3.95 (s, 3H), 3.90 (q, J = 7.0 Hz, 2H), 3.56 (s, 2H), 1.59 (s, 9H), 0.95 (t, J = 7.1 Hz, 3H);MS (ES+): 525.0 and 527.0 (M+1).

[0404] Step-2: Preparation of tert-butyl 5-(3-(aminomethyl)phenyl)-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-(1-methyl-1H-pyrazol-4-yl)benzofuran-2-carboxylate (60c) Compound 60c was prepared from tert-butyl 5-chloro-3-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-7-(1-methyl-...

Claims

1. A compound of formula (Ia), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, 【Chemistry 2】 is arylene or heteroarylene; 【Chemistry 3】 teeth, 【Chemistry 4】 or 【Chemistry 5】 represents; 【Chemistry 6】 teeth, 【Chemistry 7】 represents; J is -CH ２ -, -NH-, -CH ２ CH ２ -, -C(O)-, -O-, -S-, -S(O)-, -SO ２ -, -N(alkyl)-, -CH(alkyl)-, -CH(aryl)-, -C(alkyl) ２ -, -CH(cycloalkyl)-, or 【Chemistry 8】 represents; K is a bond, -O-, -NH-, -C(O)-, -CH ２ -, -S-, -S(O)-, -SO ２ -, -N(alkyl)-, -CH(alkyl)-, or -CH(cycloalkyl)-; However, at least one of J and K is a bond, —C(O)—, or —CH ２ --, --CH ２ CH ２ -, -CH(alkyl)-, or -CH(aryl)-; L Ｃ is a bond, -CH ２ -, -CH(alkyl)-, -CH(cycloalkyl)-, -CH(hydroxyalkyl)-, -CH(haloalkyl)-, -CH ２ CH ２ -, -CF ２ -, -CH(F)-, -CF(alkyl)-, -C(O)-, -CD ２ -, or -CH(D)-; L Ｄ is -CH ２ --, --CH ２ CH ２ -, -CF ２ -, -CH(F)-, -CD ２ -, -CH(D)-, -CH(alkyl)-, -CH(cycloalkyl)-, -CHNH ２ represents -, -CH(NH(alkyl))-, -CH(NH(cycloalkyl))-, or a bond; R Ａ is H, halo, hydroxyl, cyano, amino, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, -C(O)OH, -C(O)NH ２ , -C(O)N(alkyl) ２ , -CH ２ C(O)OH, -NO ２ , -CH ２ NH(optionally substituted alkyl), -CH ２ N(Boc)(optionally substituted alkyl), -CH ２ NH((cycloalkyl)alkyl), -CH ２ N(alkyl)(cycloalkyl), -CH ２ N(alkyl)((cycloalkyl)alkyl), -NH(optionally substituted alkyl), -NH(cycloalkyl), -NH((cycloalkyl)alkyl), -NH((heterocycloalkyl)alkyl), -N(alkyl) ２ , -N(alkyl)((cycloalkyl)alkyl, -N(alkyl)((heterocycloalkyl)alkyl, -NH(heteroarylalkyl), -CH ２ O(optionally substituted aryl), -C(O)O(alkyl), -C(O)NH(optionally substituted alkyl), -C(O)NH((cycloalkyl)alkyl), -NHC(O)O(alkyl), or -CH ２ N(alkyl) ２ represents; R Ｂ is H, -C(O)O(alkyl), halogen, cyano, amino, -C(O)OH, -CH ２ C(O)OH, -C(O)NH ２ , -C(O)NH(cycloalkyl), -C(O)NH(alkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)(alkyl), alkylaminoalkyl, alkylaminocycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, or heterocycloalkyl; R Ｃ represents H, halo, -OH, or amino, or represents optionally substituted alkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy; R Ｄ is H, halo, hydroxyl, cyano, -NH ２ , -NH(Ac), -NH(alkyl), -N(alkyl) ２ , -NH(CO)(alkyl), -CH ２ N.H. ２ , -CH ２ NHC(O)(alkyl), -C(O)NH ２ , -C(O)OH, or -NHC(O)O(alkyl), or optionally substituted alkyl, alkoxyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, haloalkoxyl, or haloalkyl; R １ represents H or optionally substituted alkyl; m, n, p, and q are each independently 0, 1, or 2.

2. J is -CH ２ -, -NH-, -CH ２ CH ２ -, or -C(O)-; K represents a bond, —O—, —NH—, or —C(O)—; With the proviso that when J represents -NH-, K is a bond or -C(O)-; L Ｃ is -CH ２ -, -CH(alkyl)-, or -CH(hydroxyalkyl)-; R Ａ is H, halo, hydroxyl, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (heterocycloalkyl)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, -C(O)OH, -NO ２ , -CH ２ NH(optionally substituted alkyl), -CH ２ NH((cycloalkyl)alkyl), -NH((cycloalkyl)alkyl), -CH ２ O(optionally substituted aryl), -C(O)O(alkyl), -C(O)NH(optionally substituted alkyl), -C(O)NH((cycloalkyl)alkyl), -NHC(O)O(alkyl), or -CH ２ N(alkyl) ２ represents; R Ｂ is H, -C(O)O(alkyl), alkyl, -C(O)OH, hydroxyalkyl, tosyl, heterocycloalkyl, -C(O)NH ２ or -C(O)NH(cycloalkyl); R Ｃ represents H or halo; R Ｄ is H or halo, hydroxyl, alkyl, alkoxyl, -NH ２ , -C(O)NH ２ , -NHC(O)O(alkyl), or haloalkoxyl; R １ 2. The compound of claim 1, wherein represents H or alkyl.

3. Formula (Ia-1): 【Chemistry 9】 having the structure: or Formula (Ia-2): 【Chemistry 10】 having the structure: or Formula (IIb): 【Chemistry 11】 having the structure: or Formula (IIc): 【Chemistry 12】 having the structure: or Formula (IId): 【Chemistry 13】 having the structure: or Formula (IIe): 【Chemistry 14】 having the structure: or Formula (IIf): 【Chemistry 15】 having the structure: or Formula (IIg): 【Chemistry 16】 having the structure: or Formula (IIh): 【Chemistry 17】 having the structure: or Formula (IIj): 【Chemistry 18】 having the structure: or Formula (IIm): 【Chemistry 19】 having the structure: or Formula (IIo): 【Chemistry 20】 having the structure: or Formula (IIp): 【Chemistry 21】 having the structure: or Formula (IIr): 【Chemical 22】 having the structure: or Formula (IIt): 【Chemistry 23】 having the structure: or Formula (IIu): 【Chemistry 24】 having the structure: or Formula (IIv): 【Chemistry 25】 having the structure: or Formula (IIw): 【Chemistry 26】 having the structure: or Formula (IIy): 【Chemistry 27】 3. The compound of claim 1 or 2 having the structure:

4. L Ｃ Ga-CH ２ The compound according to any one of claims 1 to 3, wherein

5. R Ｃ A compound according to any one of claims 1 to 4, wherein represents H or halo.

6. R Ｃ The compound according to claim 5 , wherein represents F.

7. -J-K- is -CH ２ -, -NH-, -CH ２ -O-, -CH ２ CH ２ The compound according to any one of claims 1 to 6, which represents -O-, -C(O)-NH-, or -NHC(O)-.

8. -J-K- is -CH ２ A compound according to any one of claims 1 to 7, which represents -O- or -C(O)-NH-.

9. 【Chemical 28】 but, 【Chemical 29】 or 【Chemistry 30】 The compound according to any one of claims 1 to 8, which represents

10. R １ The compound according to any one of claims 1 to 9, wherein is H.

11. L Ｄ But -CH ２ --, --CH ２ CH ２ A compound according to any one of claims 1 to 10, wherein R represents - or a bond.

12. L Ｄ Ga-CH ２ The compound according to any one of claims 1 to 11, wherein

13. R Ｄ A compound according to any one of claims 1 to 12, wherein represents H, halo, hydroxyl, alkyl, or alkoxyl.

14. R Ｄ A compound according to any one of claims 1 to 13, wherein represents H.

15. R Ｂ A compound according to any one of claims 1 to 14, wherein represents H, alkyl, or -C(O)OH.

16. R Ｂ A compound according to any one of claims 1 to 15, wherein represents H.

17. R Ａ is H, alkyl, alkoxyl, or -CH ２ A compound according to any one of claims 1 to 16, which represents O(optionally substituted aryl).

18. R Ａ A compound according to any one of claims 1 to 17, wherein represents H.

19. 2. The compound according to claim 1 selected from the following table: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】

20. 2. The compound according to claim 1 selected from the following table: 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】 【Table 2-15】 【Table 2-16】 【Table 2-17】 【Table 2-18】 【Table 2-19】 【Table 2-20】

21. 2. The compound according to claim 1 selected from the following table: 【Table 3-1】 【Table 3-2】 【Table 3-3】 【Table 3-4】 【Table 3-5】 【Table 3-6】 【Table 3-7】

22. 2. The compound according to claim 1 selected from the following table: 【Table 4】

23. 2. The compound according to claim 1 selected from the following table: 【Table 5】

24. 2. The compound according to claim 1 selected from the following table: 【Table 6-1】 【Table 6-2】 【Table 6-3】 【Table 6-4】 【Table 6-5】 【Table 6-6】 【Table 6-7】

25. 2. The compound according to claim 1 selected from the following table: 【Table 7】

26. 2. The compound according to claim 1 selected from the following table: 【Table 8】

27. 2. The compound according to claim 1 selected from the following table: 【Table 9】

28. 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

29. A composition for treating or preventing a disease or condition characterized by abnormal complement system activity, comprising a compound according to any one of claims 1 to 27 or a pharma- ceutically acceptable salt thereof.

30. 30. The composition of claim 29, wherein the disease or condition characterized by abnormal complement system activity is an immunological disorder, a disease of the central nervous system, a neurodegenerative or neurological disease, a renal disease, a cardiovascular disease, a blood disorder, or an ocular disorder or disease.

31. the disease or condition characterized by abnormal complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense deposit disease, cold agglutinin disease, and fulminant antiphospholipid syndrome; or The disease or condition characterized by abnormal complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis; or 30. The composition of claim 29, wherein the disease or condition characterized by abnormal complement system activity is macular degeneration, age-related macular degeneration (AMD), macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet's uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, corneal neovascular disease, corneal transplant rejection, corneal dystrophic disease, autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren's syndrome, environmental dry eye disease, Fuchs endothelial dystrophy, retinal vein occlusion, or post-operative inflammation.

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