Matriptase 2 inhibitors and uses thereof

Abstract

The present invention provides compounds for inhibiting matriptase 2 or its mutants, as well as compositions and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to compounds and methods for inhibiting Matriptase 2 ("Mat-2") or its mutants. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using the compositions to treat various disorders. Background Art

[0002] Matriptase-2 is a cell surface serine protease with a modular structure. Mutations in matriptase-2 cause iron-refractory iron deficiency anemia (IRIDA), an iron deficiency disorder in which hepcidin levels are inappropriately high. The enzymatic activity of matriptase-2 reduces hepcidin expression by inhibiting bone morphogenetic protein (BMP) / sons of mothers against decapentaplegic homologue protein (SMAD) signaling. Loss or inhibition of matriptase-2 activity leads to increased hepcidin production in the liver. Summary of the Invention

[0003] It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as Matriptase 2 inhibitors. In one aspect, the present invention provides a compound of formula I:

[0004]

[0005] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0006] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with relative or absolute hepcidin deficiency, or in which regulating iron metabolism by increasing hepcidin production in the liver may be therapeutically useful. Such diseases, disorders, or conditions include those described herein. DETAILED DESCRIPTION

[0007] 1. General Description of Certain Embodiments of the Invention:

[0008] The compounds of the present invention and their pharmaceutical compositions are useful as inhibitors of Matriptase 2 or its mutants. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention and their pharmaceutical compositions can inhibit the activity of Matriptase 2 or its mutants and thereby treat certain diseases, disorders or conditions associated with relative or absolute hepcidin deficiency, or in which regulating iron metabolism by increasing hepatic hepcidin production can be therapeutically useful, such as those described herein.

[0009] It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as Matripase 2 inhibitors. In one aspect, the present invention provides a compound of formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein

[0012] Each X is independently C or N;

[0013] L 1 is a bond or an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -C(O)- or -O-;

[0014] R 1 is H or an optionally substituted ring selected from phenyl, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0015] L 2 is an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O)2-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR- or -Cy-;

[0016] -Cy- is an optionally substituted divalent ring selected from phenyl, a 4-6 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 4-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0017] R 2is H or an optionally substituted ring selected from the group consisting of a 4-7 membered monocyclic carbocycle, a 4-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic carbocycle, a 7-10 membered bicyclic heterocarboxyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic ring, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and adamantyl;

[0018] R 3 H, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-OC 1-6 Aliphatic, C 1-6 Aliphatic or -C(O)-C 1-6 aliphatic, wherein the C 1-6 Aliphatic is optionally substituted;

[0019] L 3 is a bond or an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-;

[0020] R 4 is –NHR, -C(NR)-NHR, -NH-C(NR)-NHR, -F, or -OH; and

[0021] Each R is independently H, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C(O)-C 1-8 Alkyl, -C(O)-OC 1-8 alkyl, 4-7 membered monocyclic carbocyclyl, -O-(4-7 membered monocyclic carbocyclyl), -C(O)-(4-7 membered monocyclic carbocyclyl), -C(O)-O-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, 8-10 membered bicyclic aryl, -O-(8-10 membered bicyclic aryl), -C(O)-(8-10 membered bicyclic aryl) or -C(O)-O-(8-10 membered bicyclic aryl), wherein the C 1-8 Each of the alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl groups is optionally and independently substituted.

[0022] 2. Compounds and Definitions:

[0023] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For purposes of the present invention, the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Determination of Chemical Elements. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0024] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl"), which has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, which has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0025] As used herein, the term "bicycle" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or with one or more unsaturated units, with one or more atoms in common between the two rings of the ring system. Therefore, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicycle" is a subset of "bicyclic", which requires the presence of one or more heteroatoms in one or both rings of the bicyclic ring. Such heteroatoms can be present at the ring junction and are optionally substituted, and can be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic ring" refers to any bicyclic ring system with at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. According to IUPAC definition, "bridge" is a non-branched atomic chain or atom or valence bond connecting two bridgeheads, wherein "bridgehead" is any skeleton atom (excluding hydrogen) of the ring system combined with three or more skeleton atoms. In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulphur. Such bridged bicyclic groups are well known in the art and include those groups listed below, wherein each group is connected to the rest of the molecule on any substitutable carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted by one or more substituents as listed for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclic groups include:

[0026]

[0027] Exemplary bridged bicyclic rings include:

[0028]

[0029]

[0030] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0031] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched alkyl groups.

[0032] The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0033] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0034] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to straight or branched divalent alkylene, alkenylene and alkynylene chains as defined herein.

[0035] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0036] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0037] As used herein, the term "cyclopropenyl" refers to a divalent cyclopropyl radical having the following structure:

[0038] The term "halogen" means F, Cl, Br or I.

[0039] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.

[0040] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 shared pi electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0041] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. The term "nitrogen," when used with respect to a ring atom of a heterocycle, includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0042] The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazolidinyl ... Oxazolin oxazepinyl, thiazepinyl The term "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0043] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0044] As described herein, the compounds of the present invention may include "optionally substituted" moieties. Typically, regardless of whether or not the term "optionally" is present, the term "substituted" means that one or more hydrogens of a designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a designated group, the substituent may be the same or different at each position. The combination of substituents contemplated by the present invention is preferably one that results in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and, in some embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0045] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2); 0–4 R o ; –(CH2) 0–4 OR o ;-O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 CH(OR o )2;–(CH2) 0– 4SR o ; –(CH2) 0–4 Ph, which can be R o Substitution; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be R o Substitution; –CH=CHPh, which can be replaced by R o Substitution; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be replaced by R o Substitution; –NO2; –CN; –N3; -(CH2) 0–4 N(R o )2;–(CH2) 0–4 N(R o )C(O)R o ;–N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o2;–(CH2) 0–4 N(R o )C(O)OR o ;–N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;–(CH2) 0–4 C(O)R o ;–C(S)R o ;–(CH2) 0–4 C(O)OR o ;–(CH2) 0–4 C(O)SR o ;-(CH2) 0–4 C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ;–OC(O)(CH2) 0–4 SR–、SC(S)SR o ;–(CH2) 0–4 SC(O)R o ;–(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR o ;–SC(S)SR o ,-(CH2) 0–4 OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ;-(CH2) 0–4 SSR o ;–(CH2) 0–4 S(O)2R o ;–(CH2) 0–4 S(O)2OR o ;–(CH2) 0–4 OS(O)2R o ;–S(O)2NR o 2;–S(O)(NR o )Ro ; –S(O)2N=C(NR o 2)2;-(CH2) 0–4 S(O)R o ;-N(R o )S(O)2NR o 2;–N(R o )S(O)2R o ;–N(OR o )R o ;–C(NH)NR o 2;–P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;–OP(O)(OR o )2;SiR o 3;–(C 1–4 linear or branched alkylene)O–N(R o )2; or –(C 1–4 linear or branched alkylene) C(O)O–N(R o )2.

[0046] Each R o are independently hydrogen, C 1–6 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definitions, two independent occurrences of R o Together with one or more atoms therebetween, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted with a divalent substituent on a saturated carbon atom of R° selected from ═O and ═S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2) 0–2 R · 、–(halogen R · ),–(CH2) 0–2 OH, –(CH2) 0–2 OR · 、–(CH2) 0–2 CH(OR · )2;-O(halogen R · ), –CN, –N3, –(CH2) 0–2 C(O)R · 、–(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR ·、–(CH2) 0–2 SR · 、–(CH2) 0– 2SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR · 、–(CH2) 0–2 NR · 2. –NO2, –SiR · 3. –OSiR · 3. -C(O)SR · 、–(C 1–4 linear or branched alkylene)C(O)OR · or –SSR · .

[0047] Each R · Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or wherein R after halogen · substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents independently selected from the group consisting of: =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、–O(C(R * 2)) 2–3 O–or–S(C(R * 2)) 2–3 S-, or the divalent substituent attached to the ortho-substitutable carbon of the "optionally substituted" group is -O(CR * 2) 2–3 O–, where each independent occurrence of R * Selected from hydrogen, C 1–6 aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0048] When R * It is C 1–6 When aliphatic, R * Optionally substituted by: halogen, -R · 、-(halogen R · ),-OH, –OR ·、–O(halogen R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or wherein R after halogen · Substituted only with one or more halogens.

[0049] The optional substituents on the substitutable nitrogen are independently or Each of these are independently hydrogen, C 1–6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with one or more atoms therebetween, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when It is C 1–6 When aliphatic, Optionally substituted by: halogen, -R · 、-(halogen R · ),-OH, –OR · 、–O(halogen R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · Independently selected from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or wherein R after halogen · Substituted only with one or more halogens.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0051] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1–4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, where appropriate, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0052] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having a structure that includes replacement of hydrogen by deuterium or tritium, or by 13 C- or 14 Compounds of the present invention having a structure in which the carbon of the present invention is replaced by a carbon-enriched carbon are within the scope of the present invention. Such compounds according to the present invention are, for example, used as analytical tools, as probes in biological assays, or as therapeutic agents. In certain embodiments, the compounds of the present invention include one or more deuterium atoms.

[0053] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits Matriptase 2 or a mutant thereof with measurable affinity. In certain embodiments, the inhibitor has an IC 50 and / or a binding constant of less than about 100 μM, less than about 50 μM, less than about 20 μM, less than about 10 μM, or less than about 5 μM.

[0054] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in the activity of Matriptase 2 or a mutant thereof between a sample comprising a compound or composition of the invention and Matriptase 2 or a mutant thereof and an equivalent sample comprising Matriptase 2 or a mutant thereof in the absence of the compound or composition of the invention.

[0055] 3. Description of exemplary embodiments:

[0056] In one aspect, the present invention provides a compound of formula I:

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein

[0059] Each X is independently C or N;

[0060] L 1 is a bond or an optionally substituted divalent C 1-8a saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -C(O)- or -O-;

[0061] R 1 is H or an optionally substituted ring selected from phenyl, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0062] L 2 is an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O)2-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR- or -Cy-;

[0063] -Cy- is an optionally substituted divalent ring selected from phenyl, and a 4-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0064] R 2 is H or an optionally substituted ring selected from the group consisting of a 4-7 membered monocyclic carbocycle, a 4-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic carbocycle, a 7-10 membered bicyclic heterocarboxyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic ring, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and adamantyl;

[0065] R 3 H, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-OC 1-6 Aliphatic, C 1-6 Aliphatic or -C(O)-C 1-6 aliphatic, wherein the C 1-6 Aliphatic is optionally substituted;

[0066] L 3 is a bond or an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-;

[0067] R4 is –NHR, -C(NR)-NHR, -NH-C(NR)-NHR, -F, or -OH; and

[0068] Each R is independently H, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C(O)-C 1-8 Alkyl, -C(O)-OC 1-8 alkyl, 4-7 membered monocyclic carbocyclyl, -O-(4-7 membered monocyclic carbocyclyl), -C(O)-(4-7 membered monocyclic carbocyclyl), -C(O)-O-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, 8-10 membered bicyclic aryl, -O-(8-10 membered bicyclic aryl), -C(O)-(8-10 membered bicyclic aryl) or -C(O)-O-(8-10 membered bicyclic aryl), wherein the C 1-8 Each of the alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl groups is optionally and independently substituted.

[0069] Each X is independently C or N as generally defined above.

[0070] In some embodiments, X is C. In some embodiments, X is N.

[0071] In some embodiments, each X is independently C or N, such that Selected from the following

[0072] In some embodiments, each X is independently selected from those depicted in Table A below.

[0073] As generally defined above, L 1 is a bond or an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -C(O)- or -O-.

[0074] In some embodiments, L 1 Yes key.

[0075] In some embodiments, L 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -C(O)- or -O-. 1 is an optionally substituted C 1-8A divalent hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is optionally replaced by -S(O)2-, -C(O)-, or -O-. 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein two methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -C(O)-, or -O-. In some embodiments, L 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein three methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -C(O)-, or -O-.

[0076] In some embodiments, L 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one methylene unit of the hydrocarbon chain is replaced by -S(O)2-. In some embodiments, L 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one methylene unit of the hydrocarbon chain is replaced by -C(O)-. 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain in which one methylene unit of the hydrocarbon chain is replaced by –O-.

[0077] In some embodiments, L 1 is -(CH2)-. In some embodiments, L 1 is -(CH2)2-. In some embodiments, L 1 is -(CH2)3-. In some embodiments, L 1 Is -S(O)2CH2-. In some embodiments, L 1 Is -S(O)2(CH2)2-. In some embodiments, L 1 Is -S(O)2-. In some embodiments, L 1 Is -CH2S(O)2-. In some embodiments, L 1 It is -(CH2)2-S(O)2-.

[0078] In some embodiments, L 1 Select from those depicted in Table A below.

[0079] As generally defined above, R 1 is H or an optionally substituted ring selected from phenyl, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0080] In some embodiments, R1 is H. In some embodiments, R 1 is an optionally substituted ring selected from phenyl, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0081] In some embodiments, R 1 is an optionally substituted phenyl group. 1 is unsubstituted phenyl. In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes wherein halogen is F, Cl or Br. In some embodiments, R 1 yes wherein halogen is F, Cl or Br. In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R1 yes

[0082] In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 is an optionally substituted 5-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 6-membered heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0083] In some embodiments, R 1 is an optionally substituted pyridinyl. 1 is unsubstituted pyridyl. In some embodiments, R 1 yes

[0084] In some embodiments, R 1 yes

[0085] In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. 1 is an optionally substituted 8-membered bicyclic aromatic carbocyclic ring. 1 is an optionally substituted 9-membered bicyclic aromatic carbocyclic ring. 1 is an optionally substituted 10-membered bicyclic aromatic carbocyclic ring. 1 It is a 10-membered bicyclic aromatic carbon ring, surrounded by –CH2-R 11 、–OR 11 ,–NR 11 ,–SR 11 、–NR-C(O)-R 11 、-C(O)-NR-R 11 、-C(O)-R 11 、-S(O)2-R 11 、-C(O)-OR 11 、-OC(O)-R 11 、-NR-S(O)2-R 11 or -S(O)2-NR-R 11 Optionally substituted, wherein R 11 is an optionally substituted phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 yes In some embodiments, R 1 yes

[0086] In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 9-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 10-membered bicyclic heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0087] In some embodiments, R 1 yes

[0088] In some embodiments, R 1 Select from those depicted in Table A below.

[0089] As generally defined above, L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O)2-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR- or -Cy-.

[0090] In some embodiments, L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one, two, or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, or -OC(O)-. 1-8 The divalent hydrocarbon chain is replaced by –OH.

[0091] In some embodiments, L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O)2-, -NR-S(O)2- or -S(O)2-NR-.

[0092] In some embodiments, L 2is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -Cy-.

[0093] In some embodiments, L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -NR-S(O)2- or -S(O)2-NR-.

[0094] In some embodiments, L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -C(O)- or -S(O)2-.

[0095] In some embodiments, L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -C(O)-O- or -OC(O)-.

[0096] In some embodiments, L 2 is –CH2-, –NH-, -NH-CH3-, -CH3-NH-, -NH-C(O)-, -N(CH3)-C(O)-, -S(O)2-, -CH2-NH-C(O)-, -(CH2)2-, -NH-CH(CH3)-, -NH-(CH2)2-, -NH-(CH2)4-NH- or -NH-(CH2)3-.

[0097] In some embodiments, L 2 Select from those depicted in Table A below.

[0098] As generally defined above, -Cy- is an optionally substituted bivalent ring selected from phenyl, a 4-6 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 4-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0099] In some embodiments, -Cy- is optionally substituted phenylene. In some embodiments, -Cy- is unsubstituted phenylene.

[0100] In some embodiments, -Cy- is optionally substituted pyridinylene. In some embodiments, -Cy- is unsubstituted pyridinylene.

[0101] In some embodiments, -Cy- is an optionally substituted 4-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 4-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 5 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, -Cy- is an optionally substituted 4-6 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 4-6 membered monocyclic heterocycle having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 5 membered monocyclic heterocycle having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 6 membered monocyclic heterocycle having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, -Cy- is an optionally substituted bivalent ring that is an oxadiazole. In some embodiments, -Cy- is an optionally substituted bivalent ring that is a thiadiazole.

[0104] In some embodiments, -Cy- is selected from those depicted in Table A below.

[0105] As generally defined above, R 2 is H or an optionally substituted ring selected from the group consisting of a 4-7 membered monocyclic carbocycle, a 4-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic carbocycle, a 7-10 membered bicyclic heterocarboxyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic ring, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and adamantyl.

[0106] In some embodiments, R 2 is H. In some embodiments, R 2is an optionally substituted ring selected from the group consisting of a 4-7 membered monocyclic carbocycle, a 4-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic carbocycle, a 7-10 membered bicyclic heterocarboxyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic ring, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and adamantyl.

[0107] In some embodiments, R 2 is an optionally substituted 4-7 membered monocyclic carbocycle.

[0108] In some embodiments, R 2 is an optionally substituted 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is an optionally substituted 4-membered monocyclic heterocyclic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is an optionally substituted 5-membered monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 6-membered monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 7-membered monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0109] In some embodiments, R 2 is an optionally substituted 7-10 membered bicyclic carbocycle.

[0110] In some embodiments, R 2 is an optionally substituted 7-10 membered bicyclic heterocarboxyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 7-membered bicyclic heterocarboxyl ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 8-membered bicyclic heterocarboxyl ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 9-membered bicyclic heterocarboxyl ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 10-membered bicyclic heterocarboxyl ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0111] In some embodiments, R 2 is optionally substituted phenyl.

[0112] In some embodiments, R 2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is an optionally substituted 5-membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 6-membered monocyclic heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0113] In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic ring.

[0114] In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 8-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 9-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 10-membered bicyclic heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0115] In some embodiments, R 2 is an optionally substituted adamantyl group.

[0116] In some embodiments, R 2 Selected from

[0117]

[0118]

[0119] In some embodiments, R 2 Select from those depicted in Table A below.

[0120] As generally defined above, R 3 H, -OH, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-OC1-6 Aliphatic, C 1-6 Aliphatic or -C(O)-C 1-6 Aliphatic, where C 1-6 Aliphatics are optionally substituted.

[0121] In some embodiments, R 3 is H. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -C(O)H. In some embodiments, R 3 is -NH2. In some embodiments, R 3 In some embodiments, R 3 is -COOH. In some embodiments, R 3 In some embodiments, R 3 It is -NH-C(O)-OC 1-6 Aliphatic, where C 1-6 Aliphatic is optionally substituted. In some embodiments, R 3 It is C 1-6 Aliphatic, where C 1-6 Aliphatic is optionally substituted. In some embodiments, R 3 Yes-C(O)-C 1-6 Aliphatic, where C 1-6 Aliphatics are optionally substituted.

[0122] In some embodiments, R 3 In some embodiments, R 3 is -NH2. In some embodiments, R 3 In some embodiments, R 3 is -COOH. In some embodiments, R 3 Is -NH-C(O)-O-C2H5. In some embodiments, R 3 It is –CH2-OCH3.

[0123] In some embodiments, R 3 Select from those depicted in Table A below.

[0124] As generally defined above, L 3 is a bond or an optionally substituted C 1-8 A divalent hydrocarbon chain wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-.

[0125] In some embodiments, L 3 Yes key.

[0126] In some embodiments, L 3 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-. In some embodiments, L 3 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is optionally replaced by -CO-. In some embodiments, L 3 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein two methylene units of the hydrocarbon chain are optionally replaced by -CO-. In some embodiments, L 3 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein three methylene units of the hydrocarbon chain are optionally replaced by -CO-.

[0127] In some embodiments, L3 is -CH2-.

[0128] In some embodiments, L 3 Select from those depicted in Table A below.

[0129] As generally defined above, R 4 is –NHR, -C(NR)-NHR, -NH-C(NR)-NHR, -F, or –OH.

[0130] In some embodiments, R 4 is -NHR. In some embodiments, R 4 Is -C(NR)-NHR. In some embodiments, R 4 Is -NH-C(NR)-NHR. In some embodiments, R 4 is -F. In some embodiments, R 4 It is –OH.

[0131] In some embodiments, R 4 is -NH2. In some embodiments, R 4 Selected from:

[0132]

[0133] In some embodiments, R 4 Select from those depicted in Table A below.

[0134] As generally defined above, each R is independently H, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C(O)-C 1-8 Alkyl, -C(O)-OC 1-8alkyl, 4-7 membered monocyclic carbocyclyl, -O-(4-7 membered monocyclic carbocyclyl), -C(O)-(4-7 membered monocyclic carbocyclyl), -C(O)-O-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, 8-10 membered bicyclic aryl, -O-(8-10 membered bicyclic aryl), -C(O)-(8-10 membered bicyclic aryl) or -C(O)-O-(8-10 membered bicyclic aryl), wherein C 1-8 Each of the alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl groups is optionally and independently substituted.

[0135] In some embodiments, R is H. In some embodiments, R is -OH.

[0136] In some embodiments, R is optionally substituted -C 1-8 In some embodiments, R is optionally substituted -OC 1-8 In some embodiments, R is optionally substituted -C(O)-C 1-8 In some embodiments, R is optionally substituted -C(O)-OC 1-8 In some embodiments, C 1-8 Alkyl is C 1-6 In some embodiments, C 1-8 In some embodiments, C 1-8 In some embodiments, C 1-8 The alkyl group is neopentyl.

[0137] In some embodiments, R is an optionally substituted 4-7 membered monocyclic carbocyclyl. In some embodiments, R is an optionally substituted -O-(4-7 membered monocyclic carbocyclyl). In some embodiments, R is an optionally substituted -C(O)-(4-7 membered monocyclic carbocyclyl). In some embodiments, R is an optionally substituted -C(O)-O-(4-7 membered monocyclic carbocyclyl). In some embodiments, the 4-7 membered monocyclic carbocyclyl is cyclopentyl. In some embodiments, the 4-7 membered monocyclic carbocyclyl is cyclohexyl.

[0138] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted -O-phenyl. In some embodiments, R is optionally substituted -C(O)-phenyl. In some embodiments, R is optionally substituted -C(O)-O-phenyl.

[0139] In some embodiments, R is an optionally substituted 8-10 membered bicyclic aryl. In some embodiments, R is an optionally substituted -O-(8-10 membered bicyclic aryl). In some embodiments, R is an optionally substituted -C(O)-(8-10 membered bicyclic aryl). In some embodiments, R is an optionally substituted -C(O)-O-(8-10 membered bicyclic aryl).

[0140] In some embodiments, R is selected from those depicted in Table A below.

[0141] In some embodiments, the compound of Formula I is Formula II:

[0142]

[0143] Among them L 1 , L 2 , L 3 、R 1 、R 2 、R 3 、R 4 Each of -Cy-, -Cy-, and R, individually and in combination, are as defined above and described in the embodiments herein.

[0144] In some embodiments, the compound of Formula I is selected from Formula II-a to II-f:

[0145]

[0146] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , L 3 、R 1 、R 2 、R 3 、R 4 Each of -Cy-, -Cy-, and R, individually and in combination, are as defined above and described in the embodiments herein.

[0147] In some embodiments, the compound of Formula I is Formula III:

[0148]

[0149] Among them L 1 , L 2 , L 3 、R 1 、R 2 、R 3 、R 4 Each of -Cy-, -Cy-, and R, individually and in combination, are as defined above and described in the embodiments herein.

[0150] In some embodiments, the compound of Formula I is selected from Formula III-a to III-f:

[0151]

[0152] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , L 3 、R 1 、R 2 、R 3 、R 4 Each of -Cy-, -Cy-, and R, individually and in combination, are as defined above and described in the embodiments herein.

[0153] In some embodiments, the compound of Formula I is Formula IV:

[0154]

[0155] Among them L 1 , L 2 , L 3 、R 1 、R 2 、R 3 、R 4 Each of -Cy-, -Cy-, and R, individually and in combination, are as defined above and described in the embodiments herein.

[0156] In some embodiments, the compound of Formula I is selected from Formula IV-a to IV-f:

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , L 3 、R 1 、R 2 、R 3 、R 4 Each of -Cy-, -Cy-, and R, individually and in combination, are as defined above and described in the embodiments herein.

[0159] Exemplary compounds of the present invention are listed in Table A below.

[0160] Table A: Exemplary compounds

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] The % inhibition (I) range is defined at 1 uM:

[0296] 0%≤I<25%=A;

[0297] 25%≤I<50%=B;

[0298] 50%≤I<75%=C;

[0299] 75%≤I≤100%=D.

[0300] In some embodiments, the present invention provides compounds listed in Table A above, or pharmaceutically acceptable salts thereof.

[0301] In some embodiments, the present invention provides compounds described in the following examples or pharmaceutically acceptable salts thereof.

[0302] In some embodiments, the compounds of the present invention are not:

[0303]

[0304] 4. Usage, preparation and administration:

[0305] Pharmaceutically acceptable compositions

[0306] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is effective to measurably inhibit Matriptase 2 or a mutant thereof in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is effective to measurably inhibit Matriptase 2 or a mutant thereof in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0307] As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0308] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0309] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.

[0310] As used herein, the term "an inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of Matriptase 2 or a mutant thereof.

[0311] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable drug reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0312] In some embodiments, the present invention provides the pharmaceutical composition of the present invention.For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and glyceride derivatives thereof are used in injectable preparations, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly their polyoxyethylated forms. These oil solutions or suspensions can also include long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants that are generally used to prepare pharmaceutically acceptable dosage forms (including emulsions and suspensoids). For the purpose of preparation, other commonly used surfactants can also be used, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers, which are generally used to make pharmaceutically acceptable solids, liquids or other dosage forms.

[0313] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, conventional carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in the form of capsules, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0314] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0315] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. For each of these areas or organs, suitable topical formulations are readily prepared.

[0316] Topical application for the lower intestinal tract may be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0317] For topical application, the pharmaceutically acceptable composition provided can be formulated in a suitable ointment comprising an active component suspended or dissolved in one or more carriers. The carrier for the topical administration of the compound of the present invention includes but is not limited to mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated in a suitable lotion or cream comprising an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0318] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated in ointments such as petrolatum.

[0319] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0320] Most preferably, pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such preparations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, pharmaceutically acceptable compositions of the present invention are administered with food.

[0321] The amount of the compound of the invention that can be combined with the carrier materials to produce a single dosage form of the composition will vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0322] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0323] Uses of compounds and pharmaceutically acceptable compositions

[0324] The compounds and compositions described herein are generally useful for inhibiting Matriptase 2 or mutants thereof.

[0325] The activity of compounds used as inhibitors of Matriptase 2 or its mutants in the present invention can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of Matriptase 2 or its mutants. Alternative in vitro assays quantify the ability of an inhibitor to bind to Matriptase 2 or its mutants. Detailed conditions for assaying compounds used as inhibitors of Matriptase 2 or its mutants in the present invention are listed in the Examples below.

[0326] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0327] As used herein, the term "low hepcidin" disorder, disease and / or condition as used herein means any disease or other deleterious condition in which absolute or relative hepcidin deficiency is known to play a role or in which increasing hepcidin may be therapeutically useful.

[0328] Provided compounds are inhibitors of Matriptase 2 or its mutants and are therefore useful in treating low hepcidin conditions, diseases, and / or disorders. Thus, in certain embodiments, the present invention provides methods for treating low hepcidin conditions, diseases, and / or disorders, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0329] Without wishing to be bound by any particular theory, it was found that inhibition of Matriptase-2 resulted in increased hepcidin production by the liver. Thus, in some embodiments, the present invention provides a method for increasing hepcidin production by the liver of a patient, the method comprising the step of administering to the patient a compound of the present invention, or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method for treating absolute and / or relative hepcidin deficiency in a patient, the method comprising the step of administering to the patient a compound of the present invention, or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method for treating insufficient hepcidin production in a patient, the method comprising the step of administering to the patient a compound of the present invention, or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method for treating excess or increased iron absorption or accumulation in a patient, the method comprising the step of administering to the patient a compound of the present invention, or a pharmaceutically acceptable composition thereof, to increase hepcidin production by the liver. In some embodiments, the present invention provides a method for treating ineffective erythropoiesis in a patient, the method comprising the step of administering to the patient a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0330] In some embodiments, the present invention provides a method for treating one or more iron overload conditions, diseases, and / or disorders, comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0331] As used herein, the term "iron overload disorder, disease and / or condition" refers to a disorder, disease or condition associated with excess iron levels or iron overload. Large amounts of free iron in the bloodstream can cause cell damage, especially in the liver, heart and endocrine glands. The cause of excess iron may be genetic, for example, iron overload may be caused by genetic disorders such as hemochromatosis type 1 (classic hemochromatosis), hemochromatosis type 2A or 2B (juvenile hemochromatosis), hemochromatosis type 3, African iron overload, neonatal hemochromatosis, aceruloplasminemia or congenital transferrin deficiency (atransferrinemia). Examples of non-genetic causes of iron overload include dietary iron overload (including African iron overload), transfusional iron overload (due to transfusions given to patients with thalassemia or other congenital blood disorders), hemodialysis, chronic liver disease (such as hepatitis C, cirrhosis, nonalcoholic steatohepatitis), porphyria cutanea tarda, post-portacaval shunting, dysmetabolic overload syndrome, iron tablet overdose (such as caused by a child taking iron tablets intended for adults), or any other cause of acute or chronic iron overload.

[0332] In some embodiments, the iron overload disorder, disease, and / or condition is hemochromatosis type 1. In some embodiments, the iron overload disorder, disease, and / or condition is hemochromatosis type 2a. In some embodiments, the iron overload disorder, disease, and / or condition is hemochromatosis type 2b. In some embodiments, the iron overload disorder, disease, and / or condition is hemochromatosis type 3.

[0333] In some embodiments, the iron overload disorder, disease, and / or condition is hepcidin deficiency. In some embodiments, the iron overload disorder, disease, and / or condition is transfusional iron overload. In some embodiments, the iron overload disorder, disease, and / or condition is African iron overload. In some embodiments, the iron overload disorder, disease, and / or condition is iron overload cardiomyopathy.

[0334] In some embodiments, the present invention provides a method for treating one or more iron-loading anemias, the method comprising administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof. In some embodiments, the iron-loading anemia is beta-thalassemia, HbE / beta-thalassemia, or other variants thereof, including but not limited to: major thalassemia, intermediate thalassemia, minor thalassemia, non-transfusion-dependent thalassemia, and transfusion-dependent thalassemia. In some embodiments, the iron-loading anemia is associated with and / or caused by alpha-thalassemia. In some embodiments, the iron-loading anemia is type I and / or type II congenital dyserythropoietic anemia. In some embodiments, the iron-loading anemia is pyruvate kinase deficiency. In some embodiments, the iron-loading anemia is bone marrow dysplasia, including but not limited to myelodysplastic syndrome (MDS), RARS, and / or SF3B1-related MDS.

[0335] In some embodiments, the present invention provides a method for treating one or more blood diseases, disorders, and / or conditions, comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the blood disease, disorder, and / or condition is sickle cell disease. In some embodiments, the blood disease, disorder, and / or condition is sickle cell anemia. In some embodiments, the blood disease, disorder, and / or condition is polycythemia vera. In some embodiments, the blood disease, disorder, and / or condition is sideroblastic anemia. In some embodiments, the blood disease, disorder, and / or condition is bone marrow transplantation.

[0336] In some embodiments, the present invention provides a method for treating one or more liver diseases, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the liver disease is hepatitis B. In some embodiments, the liver disease is hepatitis C or other forms of viral hepatitis. In some embodiments, the liver disease is alcoholic liver disease. In some embodiments, the liver disease is cirrhosis. In some embodiments, the liver disease is hepatocellular carcinoma. In some embodiments, the liver disease is non-alcoholic steatohepatitis (NASH).

[0337] In some embodiments, the present invention provides a method for treating one or more metabolic diseases, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof. In some embodiments, the metabolic disease is metabolic syndrome. In some embodiments, the metabolic disease is insulin resistance. In some embodiments, the metabolic disease is type II diabetes. In some embodiments, the metabolic disease is porphyria. In some embodiments, the metabolic disease is porphyria cutanea tarda. In some embodiments, the metabolic disease is Wilson's disease. In some embodiments, the metabolic disease is acute iron overload.

[0338] In some embodiments, the present invention provides a method for treating one or more neurodegenerative disorders, the method comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the neurodegenerative disorder is selected from the group consisting of Huntington's disease (HD); Parkinson's disease (PD); amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); corticobasal degeneration (CBD); progressive supranuclear palsy (PSP); dementia with Lewy bodies (DLB); and multiple sclerosis (MS).

[0339] In some embodiments, the present invention provides a method for treating one or more infectious diseases, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the infectious disease is a siderophilic infection.

[0340] The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route of administration that is effective in treating or reducing the severity of a low hepcidin disease, disorder, and / or condition, or in any amount and by any route of administration that is effective in increasing hepcidin production in the liver. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the specific agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physically discrete unit of dosage suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition and severity of the condition being treated; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination or concomitantly with the specific compound being used; and similar factors well known in the medical field. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0341] Depending on the severity of the disease or condition being treated, the pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral spray or nasal spray, etc. In certain embodiments, the compounds of the present invention can be administered orally or parenterally once or more a day at a dosage level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, to achieve the desired therapeutic effect.

[0342] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also include inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0343] Injectable preparations can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be adopted are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0344] The injectable formulations can be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0345] In order to prolong the effect of the compounds of the present invention, it is generally desirable to slow down the absorption of the compound injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, and the dissolution rate can then depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form for parenteral administration is achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir-type injectable formulations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0346] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0347] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite clays, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0348] Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as other coatings well-known in the field of enteric coatings and pharmaceutical formulations. They can optionally contain opacifiers and can also be compositions that only or preferentially release one or more active ingredients in a certain part of the intestinal tract in a delayed manner. Examples of operable embedded compositions include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0349] The active compound can also be in a microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well-known in the field of pharmaceutical formulations. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. According to conventional practice, such dosage forms may also include additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. They may optionally contain an opacifier and may also be a composition that releases one or more active ingredients only or preferentially in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0350] The dosage form of the topical or transdermal administration of the compound of the present invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Under aseptic conditions, active ingredient is mixed with a pharmaceutically acceptable carrier as may be needed and any required preservative or buffer. Ophthalmic preparations, ear drops and eye drops are also expected to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing the controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing compounds in appropriate media. Absorption enhancers can also be used to increase the flux of compounds through the skin. This rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or a gel.

[0351] In some embodiments, the present invention relates to a method for inhibiting matriptase 2 activity or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0352] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0353] Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a specific disease or condition are considered "appropriate for the disease or condition being treated."

[0354] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two or more additional therapeutic agents. In some embodiments, the combination of the disclosed compound and one or more additional therapeutic agents acts synergistically. In some embodiments, the additional therapeutic agent is an iron chelating compound or a pharmaceutically acceptable salt thereof. In some embodiments, the iron chelating compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: deferasirox, deferiprone, and deferoxamine.

[0355] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an iron chelating compound or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a patient suffering from iron overload. In some embodiments, the patient is a patient suffering from cardiac iron overload or iron overload-related cardiomyopathy. In some embodiments, the iron chelating compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: deferasirox, deferiprone, and deferoxamine.

[0356] Example

[0357] General synthetic method

[0358] As depicted in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0359] General preparation mode:

[0360] The general synthetic methods used in each general procedure follow and include illustrations of compounds synthesized using the indicated general procedure. Specific conditions and reagents listed herein are not to be construed as limiting the scope of the invention and are provided for illustrative purposes only.

[0361] The compounds of the present invention can be made by synthetic chemistry methods, examples of which are shown herein. It should be understood that the order of the steps in the methods can be changed, reagents, solvents and reaction conditions can be substituted for those specifically mentioned, and vulnerable moieties can be protected and deprotected as needed.

[0362] Unless otherwise stated, work-up includes partitioning of the reaction mixture between the organic and aqueous phases indicated in brackets, separation of the layers and drying the organic layer over anhydrous sodium sulfate, filtering under reduced pressure and distilling the solvent. Unless otherwise stated, purification includes purification by silica gel chromatography techniques typically using ethyl acetate / petroleum ether mixtures of suitable polarity as mobile phases.

[0363] The following abbreviations refer to the following definitions:

[0364] ACN-acetonitrile; br-broad; °C-degrees Celsius; CHCl3-chloroform; CD3OD-deuterated methanol; DMSO-d 6-deuterated dimethyl sulfoxide; DCM – dichloromethane; DIPEA – diisopropylethylamine; DMF – N,N-dimethylformamide; d – doublet; dd – doublet of doublet; EDC.HCl – 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; mg – milligram; g – gram; h – hour; 1 H-proton; HCl-hydrochloric acid; HPLC-high performance liquid chromatography; H2-hydrogen; HOBt-1-hydroxybenzotriazole; K2CO3-potassium carbonate; LCMS-liquid chromatography-mass spectrometry; LiOH.H2O-lithium hydroxide monohydrate; M-mole; MHz-megahertz (frequency); MeOH-methanol; mL-milliliter; min-minute; mol-mole; M + - molecular ion; M - multiplet; N2 - nitrogen; NH3 - ammonia; NBS - N-bromosuccinimide; NCS - N-chlorosuccinimide; NMR - nuclear magnetic resonance; NaOH - sodium hydroxide; RT - room temperature; s - singlet; t - triplet; TLC - thin layer chromatography; TFA - trifluoroacetic acid; TEA - triethylamine; THF - tetrahydrofuran; % - percent; μ - micro; and δ - Delta; Zn - zinc; mmol - millimolar.

[0365] Unless otherwise mentioned, the analysis of the compounds of the present invention is carried out with general methods well known to those skilled in the art. The present invention has been described with reference to certain preferred embodiments, and other embodiments will become apparent to those skilled in the art by considering the description. The present invention is further defined by reference to the following examples that describe the analysis of the compounds of the present invention in detail.

[0366] Unless otherwise stated, LCMS data have been recorded in +ve mode.

[0367] It will be apparent to those skilled in the art that many modifications, both materials and methods, may be practiced without departing from the scope of the invention.

[0368] General synthetic scheme 1

[0369]

[0370] PG = optional protecting group; X = Br or Cl; X1, X2, R2 and R3 are as defined in formula (I)

[0371] Example 1: Synthesis of Compound I-1

[0372] N-(6-aminopyridin-3-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0373]

[0374] Step-1: Ethyl 6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylate

[0375] 1-(Bromomethyl)-4-(trifluoromethyl)benzene (6.14g, 25.67mmol) and potassium carbonate (3.55g, 25.67mmol) were added to 6-cyano-1H-indole-2-carboxylic acid ethyl ester (5.0g, 23.34mmol) dissolved in 150mL of N,N-dimethylformamide and stirred at room temperature for 8h. After completion of the reaction, the mixture was quenched with ice-cold water and the precipitated product was filtered out. Therefore, the solid obtained was further washed with water and dried under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with 30-40% ethyl acetate / hexane to obtain the title compound (7.4g). LCMS: 373.1 (M+1) + .

[0376] Step-2: 6-Cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylic acid

[0377] The product of step-1 of Example-1 (7.0 g, 18.8 mmol) was dissolved in a mixture of 100 mL of tetrahydrofuran / methanol / water (1:1:1), and lithium hydroxide (1.57 g, 65.8 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4 h. The mixture was acidified with a saturated aqueous citric acid solution and extracted with ethyl acetate, then washed with brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under vacuum to obtain the title compound (5.2 g). LCMS: 345.1 (M+1) + .

[0378] Step-3: tert-Butyl (5-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)pyridin-2-yl)carbamate

[0379] To obtain a reaction mixture, to the product of step-2 of Example-1 (350 mg, 1.01 mmol) dissolved in 5 mL of N,N-dimethylformamide was added (5-aminopyridin-2-yl)butylcarbamate (234 mg, 1.1 mmol), EDCI.HCl (292 mg, 1.52 mmol), HOBt (137 mg, 1.01 mmol) and DIEA (526 mg, 4.066 mmol), and the resulting solution was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with ethyl acetate, then washed with brine and water, and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with 20% ethyl acetate / hexane to obtain the title compound (380 mg). LCMS: 536.2 (M+1) + .

[0380] Step-4: Ethyl 2-((6-aminopyridin-3-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0381] The product of step 3 of Example 1 (350 mg, 0.65 mmol) was dissolved in 50 mL of ethanol-HCl (ethanol was saturated with HCl gas at -20°C) and kept in a glass sealed tube at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under vacuum to obtain the title compound (205 mg). LCMS: 482.2 (M+1) + .

[0382] Step-5: N-(6-aminopyridin-3-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0383] The product of step-4 of Example-1 (200 mg, 0.41 mmol) was dissolved in 50 mL of ethanol-ammonia (ethanol was saturated with ammonia gas at -70 ° C) and kept overnight in a steel bomb at room temperature. After the reaction was completed, the solvent was evaporated under vacuum to obtain a crude product, which was purified by a preparative high performance liquid chromatography instrument with an Agilent XDB C18 reverse phase column (21.2x150 mm, 5 microns). The mobile phase was 30% acetonitrile to 100% acetonitrile (0.1% TFA) in water (0.1% TFA), providing the title compound (110 mg). LCMS: 452.2 (M+1) + , 1H NMR (300MHz, DMSO-d6): δ5.98(s,2H),6.93(d,2H),7.22(d,1H),7.51(m,4H),7.81(brs,1 H),8.05(m,2H),8.41(s,1H),8.41(s,1H),9.11(brs,2H),9.25(brs,2H),10.75(brs,1H).

[0384] The following compounds listed in Table-1, Table-2 and Table-3 were prepared according to Scheme-1 by following a similar procedure as described above for Example-1 using appropriate reagents with suitable modifications known to those skilled in the art.

[0385] Table-1:

[0386]

[0387]

[0388]

[0389]

[0390]

[0391] Table–2:

[0392]

[0393]

[0394]

[0395] Table–3:

[0396]

[0397] Example 2: Synthesis of compound I-6.

[0398] N-(1-(3-aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0399]

[0400] Step-1: tert-Butyl 4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)-piperidine-1-carboxylate

[0401] The product of step-2 of Example 1 was treated with tert-butyl 4-aminopiperidine-1-carboxylate according to the procedure described in step-3 of Example 1 to obtain the title compound. LCMS: 527.2 (M+1) + .

[0402] Step-2: 6-Cyano-N-(piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0403] The product of step-1 of example-2 (884 mg, 1.68 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 665 mg of the title compound, except that the reaction was carried out at 0°C for 2 h. LCMS: 427.2 (M+1) + .

[0404] Step-3: tert-Butyl (3-(4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)-piperidin-1-yl)propyl)carbamate

[0405] The product of step-2 of example-2 (550 mg, 1.28 mmol) was treated with tert-butyl (3-bromopropyl)carbamate (305 mg, 1.28 mmol) according to the procedure described in step-1 of example-1 to obtain 525 mg of the title compound. LCMS: 584.3 (M+1) + .

[0406] Step-4: Ethyl 2-((1-(3-aminopropyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0407] The product of step-3 of example-2 (450 mg, 0.77 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 215 mg of the title compound. LCMS: 530.3 (M+1) + .

[0408] Step-5: N-(1-(3-aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0409] According to the procedure described in step-5 of example-1, the product of step-4 of example-2 (200 mg, 0.37 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 95 mg of the title compound. LCMS: 501.2 (M+1) + ,1 H NMR (300 MHz, DMSO-d6): δ 1.72 (m, 2H), 1.91 (m, 4H), 2.83 (m, 2H), 3.45 (m, 2H), 3.92 (m, 1H), 5.95 (s, 2H), 7.21 (d, 2H), 7.35 (s, 1H), 7.52 (d, 1H), 7.62 (d, 2H), 7.91 (m, 4H), 8.21 (s, 1H), 8.82 (d, 1H), 9.15 (brs, 2H), 9.24 (brs, 2H), 9.89 (brs, 1H); HPLC: 95.18% (retention time = 6.081 min).

[0410] Example 3: Synthesis of Compound I-7

[0411] 6-Carbamimidoyl-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0412]

[0413] Step-1: N-(1-(3-aminopropyl)piperidin-4-yl)-6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0414] According to the procedure described in Step-2 of Example-2, the product of Step-3 of Example-2 (550 mg, 1.28 mmol) was treated with 20 mL of ethanol-HCl to obtain 520 mg of the title compound. LCMS: 484.2 (M+1) + .

[0415] Step-2: 6-Cyano-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0416] The product of step 1 of Example 3 (498 mg, 1.03 mmol) was dissolved in 15 mL of N, N-dimethylformamide and treated with 1H-pyrazole-1-carboximidazole hydrochloride (329 mg, 2.25 mmol) and N, N-diisopropylethylamine (452 ​​mg, 3.50 mmol), and the resulting mixture was stirred at room temperature for 24 h. The solvent was evaporated under vacuum to give 250 mg of the title compound, which was used as is without further purification. LCMS: 526.2 (M+1) + .

[0417] Step-3: Ethyl 2-((1-(3-guanidinopropyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0418] According to the procedure described in Step-4 of Example-1, the product of Step-2 of Example-3 (250 mg, 0.47 mmol) was treated with 50 mL of ethanol-HCl to obtain 180 mg of the title compound. LCMS: 572.3 (M+1) + .

[0419] Step-4: 6-Carbamimidoyl-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0420] According to the procedure described in step-5 of example-1, the product of step-3 of example-3 (170 mg, 0.29 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 40 mg of the title compound. LCMS: 543.3 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.72(m,6H),3.01(m,3H),3.18(m,3H),2.98(m,3H),3.96(brs,2H),5.95(s,2H),7.21(d,2H),7.35(s, 1H),7.52(d,1H),7.62(d,2H),7.88(m,1H),7.9(d,1H),8.21(s,1H),8.85(d,1H),9.05(brs,2H),9.24(brs,2H),9.89(brs,1H).

[0421] Example 4: Synthesis of Compound I-8

[0422] N-(1-(3-aminopropionyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0423]

[0424] Step-1: tert-Butyl (3-(4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)-piperidin-1-yl)-3-oxylidenepropyl)carbamate

[0425] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-2 (553 mg, 1.3 mmol) and 3-((tert-butoxycarbonyl)amino)propionic acid (245 mg, 1.3 mmol) were treated together to obtain 380 mg of the title compound. LCMS: 598.3 (M+1) + .

[0426] Step-2: Ethyl 2-((1-(3-aminopropionyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0427] According to the procedure described in Step-4 of Example-1, the product of Step-1 of Example-4 (304 mg, 0.51 mmol) was treated with 50 mL of ethanol-HCl to obtain 65 mg of the title compound. LCMS: 544.2 (M+1) + .

[0428] Step-3: N-(1-(3-aminopropionyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-benzyl)-1H-indole-2-carboxamide

[0429] According to the procedure described in step-5 of example-1, the product of step-2 of example-4 (167 mg, 0.28 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 80 mg of the title compound. LCMS: 515.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.35 (m, 2H), 1.75 (m, 2H), 2.72 (m, 4H), 2.95 (m, 4H), 3.78 (m, 1H), 5.95 (s, 2H), 7.23 (d, 2H), 7.35 (s, 1H), 7.58 (d, 1H), 7.66 (d, 2H), 7.85 (m, 2H), 8.41 (s, 1H), 8.75 (d, 1H), 9.18 (brs, 2H), 9.35 (brs, 2H); HPLC: 92.34% (retention time = 6.841 min).

[0430] Example 5: Synthesis of Compound I-9

[0431] 6-Carbamimidoyl-N-((1r,4r)-4-(methylpyridinylamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0432]

[0433] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0434] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-1 (430 mg, 1.25 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (268 mg, 1.25 mmol) were treated together to obtain 520 mg of the title compound. LCMS: 541.2 (M+1) + .

[0435] Step-2: N-((1r,4r)-4-aminocyclohexyl)-6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0436] The product of step-1 of example-5 (275 mg, 0.51 mmol) was treated with 20 mL of ethanol-HCl according to the procedure described in step-2 of example-6 to obtain 115 mg of the title compound. LCMS: 441.2 (M+1) + .

[0437] Step-3: 6-cyano-N-((1r,4r)-4-(methylpyridinylamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0438] According to the procedure described in step-3 of example-1, the product of step-2 of example-5 (572 mg, 1.3 mmol) and picolinic acid (160 mg, 1.3 mmol) were treated together to obtain 420 mg of the title compound. LCMS: 546.3 (M+1) + .

[0439] Step-4: Ethyl 2-(((1r,4r)-4-(methylpyridinylamido)cyclohexyl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidate

[0440] The product of Step-3 of Example-5 (275 mg, 0.51 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in Step-4 of Example-1 to obtain 95 mg of the title compound. LCMS: 592.2 (M+1) +.

[0441] Step-5: 6-Carbamimidoyl-N-((1r,4r)-4-(methylpyridinylamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0442] According to the procedure described in Step-5 of Example-1, the product of Step-4 of Example-5 (95 mg, 0.16 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 20 mg of the title compound. LCMS: 563.2 (M+1) + , 1 H NMR (300 MHz, CD3OD): δ 1.48 (m, 4H), 1.93 (m, 4H), 3.82 (m, 2H), 5.93 (s, 2H), 7.18 (d, 3H), 7.52 (m, 4H), 7.91 (m, 2H), 8.22 (m, 2H), 8.61 (m, 1H); HPLC: 97.78% (retention time = 8.714 min).

[0443] Example 6: Synthesis of Compound I-20

[0444] 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoic acid

[0445]

[0446] Step-1: 6-Cyano-1H-indole-2-carboxylic acid

[0447] Following the procedure described in step-2 of Example-1, ethyl 6-cyano-1H-indole-2-carboxylate (710 mg, 3.31 mmol) and lithium hydroxide (486 mg, 11.58 mmol) were treated together to obtain 480 mg of the title compound. LCMS: 187.1 (M+1) + .

[0448] Step-2: tert-Butyl ((1r,4r)-4-(6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0449] According to the procedure described in Step-3 of Example-1, the product of Step-1 of Example-6 (480 mg, 2.56 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (547 mg, 2.56 mmol) were treated together to obtain 325 mg of the title compound. LCMS: 383.2 (M+1) + .

[0450] Step-3: 4-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoic acid

[0451] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-6 (325 mg, 0.84 mmol) and 4-(bromomethyl)benzoic acid (179 mg, 0.84 mmol) were treated together to obtain 198 mg of the title compound. LCMS: 517.2 (M+1) + .

[0452] Step-4: 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoic acid

[0453] The product of Step-3 of Example-6 (198 mg, 0.38 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in Step-4 of Example-1 to obtain 82 mg of the title compound. LCMS: 463.2 (M+1) +.

[0454] Step-5: 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoic acid

[0455] According to the procedure described in step-5 of example-1, the product of step-4 of example-6 (80 mg, 0.17 mmol) was treated with 20 mL of ethanol-NH 3 to obtain 14 mg of the title compound. LCMS: 434.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.32 (m, 4H), 1.83 (m, 4H), 2.95 (m, 1H), 3.63 (m, 1H), 5.91 (s, 2H), 7.11 (d, 2H), 7.27 (s, 1H), 7.52 (d, 1H), 7.80 (m, 5H), 8.19 (s, 1H), 8.62 (d, 1H), 9.11 (brs, 2H), 9.25 (brs, 2H), 12.91 (brs, 1H); HPLC: 90.14% (retention time = 4.327 min).

[0456] Example 7: Synthesis of Compound I-21

[0457] 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)-benzoic acid methyl ester

[0458]

[0459] Step-1: Methyl 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0460] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-6 (300 mg, 0.78 mmol) and methyl 4-(bromomethyl)benzoate (177 mg, 0.78 mmol) were treated together to obtain 380 mg of the title compound. LCMS: 531.2 (M+1) + .

[0461] Step-2: Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoate

[0462] The product of step-1 of example-7 (350 mg, 0.65 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 153 mg of the title compound. LCMS: 477.2 (M+1) + .

[0463] Step-3: Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

[0464] According to the procedure described in step-5 of example-1, the product of step-2 of example-7 (150 mg, 0.28 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 42 mg of the title compound. LCMS: 448.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.32 (m, 4H), 1.82 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 3.81 (m, 3H), 5.96 (s, 2H), 7.13 (d, 2H), 7.32 (s, 1H), 7.55 (d, 1H), 7.82 (m, 5H), 8.19 (s, 1H), 8.65 (d, 1H), 9.24 (brs, 3H); HPLC: 96.693% (retention time = 5.524 min).

[0465] Example 8: Synthesis of compound 1-22.

[0466] 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)-benzoic acid ethyl ester

[0467]

[0468] This compound was prepared by following the procedures described in step-1 to step-3 of Example 7 using ethyl 4-(bromomethyl)benzoate. LCMS: 462.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.32 (m, 3H), 1.41 (m, 4H), 1.82 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 4.26 (m, 2H), 5.96 (s, 2H), 7.13 (d, 2H), 7.32 (s, 1H), 7.86 (m, 6H), 8.21 (s, 1H), 8.62 (d, 1H), 9.24 (brs, 3H); HPLC: 96.18% (retention time = 4.601 min).

[0469] Example 9: Synthesis of Compound I-23

[0470] Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)-methyl)benzoate

[0471]

[0472] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0473] The product of step 2 of Example 6 (535 mg, 1.39 mmol) was dissolved in 10 mL of acetic acid and cooled to 0 ° C. Copper (II) nitrate trihydrate (401 mg, 1.66) was added and stirred for 3 h. The reaction mixture was quenched with cold water and extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated to obtain a crude product, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (7: 3) to obtain 310 mg of the title compound. LCMS: 428.2 (M+1) + .

[0474] Step-2: Ethyl 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-3-nitro-1H-indol-1-yl)methyl)benzoate

[0475] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-9 (310 mg, 0.72 mmol) and ethyl 4-(bromomethyl)benzoate (174 mg, 0.72 mmol) were treated together to obtain 213 mg of the title compound. LCMS: 590.2 (M+1) + .

[0476] Step-3: Ethyl 4-((3-amino-2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0477] The product of step 2 of Example 9 (200 mg, 0.33 mmol) was dissolved in 10 mL of glacial acetic acid, and zinc (107 mg, 1.65 mmol) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 6 h. The contents were filtered through a celite pad, and the filtrate was concentrated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (6: 4) to obtain the title compound (152 mg). LCMS: 560.3 (M+1) + .

[0478] Step-4: Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoate

[0479] According to the procedure described in Step-4 of Example-1, the product of Step-3 of Example-9 (150 mg, 0.27 mmol) was treated with 40 mL of ethanol-HCl to obtain 111 mg of the title compound. LCMS: 506.3 (M+1) + .

[0480] Step-5: Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

[0481] According to the procedure described in step-5 of example-1, the product of step-4 of example-9 (108 mg, 0.21 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 29 mg of the title compound. LCMS: 477.2 (M+1) + , 1H NMR (300MHz, DMSO-d6): δ1.32(m,3H),1.41(m,5H),1.85(m,4H),3.0(m,1H),3.62(m,2H),4.26(m,2H),3.6 2(m,2H),7.12(d,2H),7.42(m,1H),7.76(m,5H),7.88(d,1H),8.42(m,2H),8.85(brs,2H),9.19(brs,2H).

[0482] Example 10: Synthesis of Compound I-28

[0483] N-(1-(2-aminoethyl)piperidin-4-yl)-6-carbamimidoyl-1-phenylethyl-1H-indole-2-carboxamide

[0484]

[0485] Step-1: Ethyl 6-cyano-1-phenethyl-1H-indole-2-carboxylate

[0486] According to the procedure described in step-1 of Example-1, ethyl 6-cyano-1H-indole-2-carboxylate (2500 mg, 11.67 mmol) and (2-bromoethyl)benzene (2160 mg, 11.67 mmol) were treated together to obtain 3100 mg of the title compound. LCMS: 319.1 (M+1) + .

[0487] Step-2: 6-Cyano-1-phenethyl-1H-indole-2-carboxylic acid

[0488] The product of Step-1 of Example-10 (3000 mg, 9.42 mmol) and lithium hydroxide (792 mg, 32.97 mmol) were treated together according to the procedure described in Step-2 of Example-1 to obtain 2100 mg of the title compound. LCMS: 291.1 (M+1) + .

[0489] Step-3: tert-Butyl 4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidine-1-carboxylate

[0490] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-10 (390 mg, 1.34 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (205 mg, 1.5 mmol) were treated together to obtain 378 mg of the title compound. LCMS: 473.2 (M+1) + .

[0491] Step-4: 6-Cyano-1-phenethyl-N-(piperidin-4-yl)-1H-indole-2-carboxamide

[0492] According to the procedure described in Step-2 of Example-2, the product of Step-3 of Example-10 (350 mg, 0.73 mmol) was treated with 20 mL of ethanol-HCl to obtain 212 mg of the title compound. LCMS: 373.2 (M+1) + .

[0493] Step-5: tert-Butyl (2-(4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidin-1-yl)ethyl)carbamate

[0494] According to the procedure described in Step-1 of Example-1, the product of Step-4 of Example-10 (200 mg, 0.53 mmol) and tert-butyl (2-bromomethyl)carbamate (118 mg, 0.53 mmol) were treated together to obtain 226 mg of the title compound. LCMS: 516.3 (M+1) + .

[0495] Step-6: Ethyl 2-((1-(2-aminoethyl)piperidin-4-yl)carbamoyl)-1-phenethyl-1H-indole-6-carboximidate

[0496] The product of step-5 of example-10 (220 mg, 0.42 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 105 mg of the title compound. LCMS: 462.3 (M+1) + .

[0497] Step-7: N-(1-(2-aminoethyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0498] According to the procedure described in step-5 of example-1, the product of step-6 of example-10 (105 mg, 0.22 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 43 mg of the title compound. LCMS: 433.3 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 1.62 (m, 2H), 1.19 (m, 2H), 2.12 (m, 3H), 3.00 (m, 4H), 3.33 (m, 4H), 3.62 (m, 2H), 4.12 (m, 1H), 4.81 (m, 2H), 7.35 (m, 3H), 7.51 (d, 1H), 7.85 (d, 1H), 8.05 (m, 2H), 8.70 (m, 1H), 9.07 (brs, 2H), 9.24 (brs, 2H), 9.91 (brs, 1H); HPLC: 94.7% (retention time = 4.194 min).

[0499] Example 11: Synthesis of Compound I-29

[0500] N-(1-(3-aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-phenylethyl-1H-indole-2-carboxamide

[0501]

[0502] Step-1: tert-Butyl (3-(4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidin-1-yl)propyl)carbamate

[0503] According to the procedure described in Step-1 of Example-1, the product of Step-4 of Example-10 (380 mg, 1.01 mmol) and tert-butyl (3-bromopropyl)carbamate (239 mg, 1.01 mmol) were treated together to obtain 350 mg of the title compound. LCMS: 530.3 (M+1) + .

[0504] Step-2: Ethyl 2-((1-(3-aminopropyl)piperidin-4-yl)carbamoyl)-1-phenethyl-1H-indole-6-carboximidate

[0505] The product of step-1 of Example-11 (350 mg, 0.66 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 253 mg of the title compound. LCMS: 476.3 (M+1) + .

[0506] Step-3: N-(1-(3-aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0507] According to the procedure described in Step-5 of Example-1, the product of Step-2 of Example-11 (250 mg, 0.55 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 135 mg of the title compound. LCMS: 447.3 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.62(m,2H),1.19(m,4H),2.85(m,4H),3.05(m,6H),4.05(m,1H),4.73(m,2H),7.1 5(m,5H),7.51(d,1H),7.85(m,3H),8.15(d,1H),8.70(d,1H),9.07(brs,2H),9.24(brs,2H),9.69(brs,1H).

[0508] Example 12: Synthesis of Compound I-33

[0509] 3-amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-2-carboxamide

[0510]

[0511] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1-(4-(trifluoromethyl)phenethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0512] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-9 (580 mg, 1.35 mmol) and 1-(2-bromoethyl)-4-(trifluoromethyl)benzene (340 mg, 1.35 mmol) were treated together to obtain 550 mg of the title compound. LCMS: 600.2 (M+1) + .

[0513] Step-2: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(4-(trifluoromethyl)phenethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0514] The product of step-1 of example-12 (455 mg, 0.75 mmol) and zinc (246 mg, 3.79 mmol) were treated together according to the procedure described in step-3 of example-9 to obtain 345 mg of the title compound. LCMS: 570.3 (M+1) + .

[0515] Step-3: Ethyl-3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-6-carboximidate

[0516] The product of step-2 of example-12 (345 mg, 0.60 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 180 mg of the title compound. LCMS: 516.2 (M+1) + .

[0517] Step-4: 3-amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-2-carboxamide

[0518] According to the procedure described in Step-5 of Example-1, the product of Step-3 of Example-12 (180 mg, 0.34 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 65 mg of the title compound. LCMS: 487.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.38 (m, 4H), 1.92 (m, 4H), 2.93 (m, 3H), 3.05 (m, 1H), 3.75 (m, 3H), 3.72 (m, 1H), 4.65 (m, 2H), 7.35 (m, 3H), 7.59 (d, 2H), 7.82 (m, 3H), 8.52 (d, 1H), 8.89 (brs, 2H), 9.19 (brs, 2H); HPLC: 95.67% (retention time = 4.682 min).

[0519] Example 13: Synthesis of Compound I-36

[0520] N-((1r,4r)-4-aminocyclohexyl)-1-((3-(3-aminopropionamido)phenyl)sulfonyl)-6-carbamimidino-1H-indole-2-carboxamide

[0521]

[0522] Step-1: Ethyl 6-cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxylate

[0523] According to the procedure described in step-1 of Example-1, ethyl 6-cyano-1H-indole-2-carboxylate (780 mg, 3.64 mmol) and 3-nitrobenzene-1-sulfonyl chloride (2011 mg, 9.1 mmol) were treated together to obtain 660 mg of the title compound. LCMS: 401.1 (M+1) + .

[0524] Step-2: 6-Cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxylic acid

[0525] The product of step-1 of Example-13 (550 mg, 1.37 mmol) and lithium hydroxide (201 mg, 4.79 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 425 mg of the title compound. LCMS: 372.1 (M+1) + .

[0526] Step-3: tert-Butyl ((1r,4r)-4-(6-cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0527] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-13 (400 mg, 1.07 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (230 mg, 1.07 mmol) were treated together to obtain 368 mg of the title compound. LCMS: 568.2 (M+1) + .

[0528] Step-4: tert-Butyl ((1r,4r)-4-(1-((3-aminophenyl)sulfonyl)-6-cyano-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0529] The product of step-3 of Example-13 (360 mg, 0.63 mmol) was treated with zinc (205 mg, 3.16 mmol) according to the procedure described in step-3 of Example 9 to obtain 210 mg of the title compound. LCMS: 538.2 (M+1) + .

[0530] Step-5: tert-Butyl ((1r,4r)-4-(1-((3-(3-(tert-butylcarbamate)-propionamido)phenyl)sulfonyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0531] According to the procedure described in Step-3 of Example-1, the product of Step-4 of Example-13 (200 mg, 0.37 mmol) and 3-((tert-butoxycarbonyl)amino)propionic acid (70 mg, 0.37 mmol) were treated together to obtain 185 mg of the title compound. LCMS: 709.3 (M+1) + .

[0532] Step-6: Ethyl-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-((3-(3-aminopropionamido)phenyl)-sulfonyl)-1H-indole-6-carboximidate

[0533] According to the procedure described in Step-4 of Example-1, the product of Step-5 of Example-1 (185 mg, 0.26 mmol) was treated with 50 mL of ethanol-HCl to obtain 88 mg of the title compound. LCMS: 555.2 (M+1) + .

[0534] Step-7: N-((1r,4r)-4-aminocyclohexyl)-1-((3-(3-aminopropionamido)phenyl)sulfonyl)-6-carbamimidino-1H-indole-2-carboxamide

[0535] According to the procedure described in Step-5 of Example-1, the product of Step-6 of Example-13 (85 mg, 0.15 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 18 mg of the title compound. LCMS: 526.2 (M+1) + .

[0536] General synthetic scheme 2:

[0537]

[0538] Example 14: Synthesis of Compound I-40

[0539] 6-Carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0540]

[0541] Step-1: Ethyl 6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxylate

[0542] According to the procedure described in step-1 of Example-1, ethyl 6-cyano-1H-indole-2-carboxylate (3.5 g, 16.33 mmol) and ((2-bromomethyl)sulfonyl)benzene (4.68 mg, 16.33 mmol) were treated together to obtain 5.2 g of the title compound. LCMS: 383.1 (M+1) + .

[0543] Step-2: 6-Cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxylic acid

[0544] The product of step-1 of Example-14 (5.1 g, 13.33 mmol) and lithium hydroxide (1.12 g, 46.65 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 4.1 g of the title compound. LCMS: 355.1 (M+1) + .

[0545] Step-3: 6-Cyano-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0546] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-14 (578 mg, 1.63 mmol) and 3-(trifluoromethyl)aniline (262 mg, 1.63 mmol) were treated together to obtain 645 mg of the title compound. LCMS: 498.1 (M+1) + .

[0547] Step-4: 6-(N'-Hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)-phenyl)-1H-indole-2-carboxamide

[0548] The product of step 3 of Example 14 (550 mg, 1.10 mmol) was dissolved in 10 mL of ethanol, and an aqueous hydroxylamine solution (1.3 mL) was added, and the resulting mixture was refluxed at 80° C. for 4 h. The solvent was evaporated under vacuum to give the title compound (425 mg), which was used in the next step without further purification. LCMS: 531.1 (M+1) + .

[0549] Step-5: 6-(N'-acetoxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0550] The product of step 4 of Example 14 (570 mg, 1.07 mmol) was dissolved in 5 mL of acetic acid, and acetic anhydride (0.87 mg, 8.56 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum to give the title compound (560 mg), which was used in the next step without further purification. LCMS: 573.1 (M+1) + .

[0551] Step-6: 6-Carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0552] The product of step 5 of Example 14 (450 mg, 0.78 mmol) was dissolved in 5 mL of acetic acid, and zinc (408 mg, 6.24 mmol) was added portionwise, and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under vacuum to obtain a crude product, which was purified by reverse phase preparative HPLC to obtain the title compound (275 mg). LCMS: 573.1 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 4.00 (m, 2H), 4.92 (m, 2H), 7.45 (s, 1H), 7.49 (m, 2H), 7.59 (m, 3H), 7.63 (m, 1H), 7.90 (m, 3H), 7.96 (m, 2H), 8.21 (s, 1H), 9.09 (brs, 2H), 9.32 (brs, 2H), 10.76 (s, 1H); HPLC: 97.32% (retention time = 3.595 min).

[0553] The following compounds listed in Table-4 were prepared according to Scheme-2 by following a similar procedure as described above for Example-14 using appropriate reagents with suitable modifications known to one skilled in the art.

[0554] Table–4:

[0555]

[0556]

[0557]

[0558] Example 15: Synthesis of Compound I-55

[0559] N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0560]

[0561] Step-1: tert-Butyl-((1r,4r)-4-(6-cyano-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0562] The product of Step-1 of Example-9 (688 mg, 1.60 mmol) and ((2-bromoethyl)sulfonyl)benzene (395 mg, 1.60 mmol) were treated together according to the procedure described in Step-1 of Example-1 to obtain 780 mg of the title compound. LCMS: 596.2 (M+1) + .

[0563] Step-2: Ethyl-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidate

[0564] The product of step-1 of Example-15 (650 mg, 1.09 mmol) was treated with 60 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 380 mg of the title compound. LCMS: 542.2 (M+1) + .

[0565] Step-3: N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0566] According to the procedure described in Step-5 of Example-1, the product of Step-2 of Example-15 (250 mg, 0.46 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 135 mg of the title compound. LCMS: 513.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.21(m,2H),1.38(m,2H),1.85(m,4H),3.05(m,1H),3.55(m,1H),4.01(m,2H),4.5 5(m,2H),7.65(m,2H),7.81(m,6H),8.20(brs,1H),8.52(d,1H),9.12(d,1H),8.25(brs,2H),9.45(brs,2H).

[0567] Example 16: Synthesis of Compound I-56

[0568] 3-amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0569]

[0570] Step-1: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0571] The product of step-1 of example-15 (335 mg, 0.56 mmol) and zinc (182 mg, 2.80 mmol) were treated together according to the procedure described in step-3 of example-9 to obtain 180 mg of the title compound. LCMS: 566.2 (M+1) + .

[0572] Step-2: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidate

[0573] The product of step-1 of example-16 (175 mg, 0.30 mmol) was treated with 40 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 105 mg of the title compound. LCMS: 512.2 (M+1) + .

[0574] Step-3: tert-Butyl ((1r,4r)-4-(3-amino-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0575] According to the procedure described in Step-5 of Example-1, the product of Step-2 of Example-16 (105 mg, 0.20 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 43 mg of the title compound. LCMS: 483.2 (M+1) + , 1H NMR (300MHz, DMSO-d6): δ1.45(m,4H),1.91(m,4H),3.08(m,1H),3.52(m,1H),3.79(m,2H),4.67(m,2 H),7.37(d,1H),7.65(m,2H),7.73(m,2H),7.83(m,6H),7.91(d,1H),9.12(brs,2H),9.28(brs,2H).

[0576] Example 17: Synthesis of Compound I-17

[0577] Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)carbamate

[0578]

[0579] Step-1: tert-Butyl ((1r,4r)-4-(3-(ethylcarbamate)-6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0580] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-16 (630 mg, 1.11 mmol) and ethyl chloroformate (119 mg, 1.11 mmol) were treated together to obtain 553 mg of the title compound. LCMS: 638.3 (M+1) + .

[0581] Step-2: tert-Butyl ((1r,4r)-4-(3-(ethylcarbamate)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)-ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0582] According to the procedure described in Step-4 of Example-14, the product of Step-1 of Example-17 (540 mg, 0.84 mmol) was treated with aqueous hydroxylamine solution (2.7 mL) to obtain 329 mg of the title compound. LCMS: 671.3 (M+1) + .

[0583] Step-3: Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)carbamate

[0584] The product of step-2 of Example-17 (315 mg, 0.46 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in step-2 of Example-2 to obtain 180 mg of the title compound. LCMS: 571.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.45 (m, 7H), 1.91 (m, 4H), 3.08 (m, 1H), 3.52 (m, 1H), 3.89 (m, 2H), 4.67 (m, 2H), 7.37 (d, 1H), 7.56 (m, 3H), 7.73 (m, 2H), 7.83 (m, 5H), 8.05 (d, 1H), 8.93 (brs, 1H), 11.11 (brs, 1H), 12.80 (brs, 1H); HPLC: 90.09% (retention time = 4.488 min).

[0585] Example 18: Synthesis of Compound I-58

[0586] 3-Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0587]

[0588] Step-1: 6-Cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0589] According to the procedure described in Step-3 of Example-1, the product of Step-1 of Example-6 (1.0 g, 5.34 mmol) and cyclohexylmethylamine (603 mg, 5.34 mmol) were treated together to obtain 1.25 g of the title compound. LCMS: 282.2 (M+1) + .

[0590] Step-2: 6-cyano-N-(cyclohexylmethyl)-3-nitro-1H-indole-2-carboxamide

[0591] The product of step-1 of Example-18 (610 mg, 2.16 mmol) and copper (II) nitrate trihydrate (622 mg, 2.59 mmol) were treated together according to the procedure described in step-1 of Example-9 to obtain 352 mg of the title compound. LCMS: 327.1 (M+1) + .

[0592] Step-3: 6-Cyano-N-(cyclohexylmethyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0593] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-18 (345 mg, 1.05 mmol) and ((2-bromoethyl)sulfonyl)benzene (389 mg, 1.57 mmol) were treated together to obtain 356 mg of the title compound. LCMS: 495.2 (M+1) + .

[0594] Step-4: 3-Amino-6-cyano-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0595] The product of step-3 of Example-18 (350 mg, 0.70 mmol) and zinc (229 mg, 3.5 mmol) were treated together according to the procedure described in step-3 of Example-9 to obtain 195 mg of the title compound. LCMS: 465.2 (M+1) + .

[0596] Step-5: Ethyl 3-amino-2-((cyclohexylmethyl)carbamoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidate

[0597] The product of step-4 of Example-18 (190 mg, 0.40 mmol) was treated with ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 133 mg of the title compound. LCMS: 511.2 (M+1) + .

[0598] Step-6: 3-amino-6-carbamimidoyl-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0599] The product of step-5 of Example-18 (125 mg, 0.24 mmol) was treated with ethanol-NH 3 according to the procedure described in step-5 of Example-1 to obtain 38 mg of the title compound. LCMS: 482.2 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 0.92 (m, 2H), 1.11 (m, 3H), 1.52 (m, 1H), 1.66 (m, 4H), 3.08 (m, 2H), 3.77 (m, 2H), 4.67 (m, 2H), 5.03 (brs, 2H), 7.37 (d, 1H), 7.60 (m, 2H), 7.73 (m, 2H), 7.83 (m, 2H), 7.91 (d, 2H), 8.10 (m, 1H), 8.92 (brs, 2H), 9.25 (brs, 2H); HPLC: 93.49% (retention time = 6.417 min).

[0600] Example 19: Synthesis of Compound I-59

[0601] 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0602]

[0603] Step-1: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0604] Following the procedure described in step-1 of Example 1, ethyl 6-cyano-1H-indole-2-carboxylate (4.0 g, 18.67 mmol) and 4-(bromomethyl)benzamide (4.8 g, 22.4 mmol) were treated together to obtain 5.26 g of the title compound. LCMS: 348.1 (M+1) + .

[0605] Step-2: 1-(4-Carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid

[0606] According to the procedure described in step-2 of example 1, the product of step-1 of example 19 (1.2 g, 3.44 mmol) and lithium hydroxide (505 mg, 12.04 mmol) were treated together to obtain 882 mg of the title compound. LCMS: 320.1 (M+1) + .

[0607] Step-3: 1-(4-Carbamoylbenzyl)-6-cyano-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0608] According to the procedure described in step-3 of example 1, the product of step-2 of example 19 (500 mg, 1.56 mmol) and 4-fluoroaniline (174 mg, 1.56 mmol) were treated together to obtain 385 mg of the title compound. LCMS: 413.1 (M+1) + .

[0609] Step-4: 1-(4-Carbamoylbenzyl)-N-(4-fluorophenyl)-6-(N'-hydroxycarbamimidoyl)-1H-indole-2-carboxamide

[0610] According to the procedure described in step-4 of example 40, the product of step-3 of example 19 (360 mg, 0.87 mmol) and aqueous hydroxylamine solution (1.8 mL) were treated together to obtain 310 mg of the title compound. LCMS: 446.2 (M+1) + .

[0611] Step-5: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0612] According to the procedure described in step-5 of example 14, the product of step-4 of example 19 (285 mg, 0.64 mmol) and acetic anhydride (261 mg, 2.56 mmol) were treated together to obtain 240 mg of the title compound. LCMS: 488.2 (M+1) + .

[0613] Step-6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0614] The product of step-5 of Example 19 (230 mg, 0.47 mmol) and zinc (125 mg, 1.89 mmol) were treated together according to the procedure described in step-6 of Example 14 to obtain 128 mg of the title compound. LCMS: 430.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ5.94(s,2H),7.10(d,2H),7.18(m,2H),7.34(brs,1H),7.52(brs,1H),7.57(d,1H),7.74(m,4H), 7.89 (brs, 1H), 7.98 (d, 1H), 8.21 (brs, 1H), 9.01 (brs, 2H), 9.27 (s, 2H), 10.65 (brs, 1H); HPLC: 98.09% (retention time = 3.018min).

[0615] The following compounds listed in Table-5 and Table-6 were prepared according to Scheme-2 by following a similar procedure as described above for Example-19 using appropriate reagents with suitable modifications known to those skilled in the art.

[0616] Table–5:

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634] Table–6:

[0635]

[0636]

[0637]

[0638] Example 20: Synthesis of compound I-103.

[0639] 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0640]

[0641] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0642] According to the procedure described in step-3 of example 1, the product of step-2 of example 19 (500 mg, 1.56 mmol) and N,1-dimethylpyrrolidin-3-amine (178 mg, 1.56 mmol) were treated together to obtain 385 mg of the title compound. LCMS: 413.1 (M+1) + .

[0643] Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0644] According to the procedure described in step-4 of example 14, the product of step-1 of example 20 (360 mg, 0.87 mmol) and aqueous hydroxylamine solution (1.7 mL) were treated together to obtain 310 mg of the title compound. LCMS: 448.2 (M+1) + .

[0645] Step-3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0646] According to the procedure described in step-5 of example 14, the product of step-2 of example 20 (280 mg, 0.62 mmol) and acetic anhydride (260 mg, 2.54 mmol) were treated together to obtain 240 mg of the title compound. LCMS: 491.2 (M+1) + .

[0647] Step-4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0648] According to the procedure described in step-6 of example 14, the product of step-3 of example 20 (230 mg, 0.46 mmol) and zinc (125 mg, 1.89 mmol) were treated together to obtain 108 mg of the title compound. LCMS: 433.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.94 (m, 2H), 2.40 (m, 2H), 2.60 (m, 2H), 2.94 (s, 3H), 3.05 (s, 3H), 5.76 (m, 2H), 7.00 (d, 1H), 7.20 (d, 2H), 7.26 (brs, 1H), 7.58 (d, 1H), 7.83 (d, 2H), 7.92 (d, 1H), 8.17 (m, 1H); HPLC: 94.31% (retention time = 4.429 min).

[0649] Example 21: Synthesis of Compound I-117

[0650] 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyrrolidin-1-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0651]

[0652] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0653] The product of Step-2 of Example-19 (500 mg, 1.56 mmol) and 3-(pyrrolidin-1-yl)aniline (254 mg, 1.56 mmol) were treated according to the procedure described in Step-3 of Example-1 to obtain 520 mg of the title compound. LCMS: 464.2 (M+1)+.

[0654] Step-2: 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyrrolidin-1-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0655] To a solution of the product of step-1 of Example-21 (250 mg, 0.53 mmol) in a mixture of 5 mL of methanol and water (1: 1) was added solid sodium hydroxide (65 mg, 1.6 mmol). The reaction was stirred at 50 ° C. After completion of the reaction, the reaction mixture was concentrated to remove methanol and acidified with 2N HCl. The aqueous mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse phase preparative HPLC to obtain 120 mg of the title compound. LCMS: 482.2 (M+1) +, 1 H NMR (300 MHz, DMSO-d6): δ 1.93 (m, 4H), 3.20 (m, 4H), 5.94 (s, 2H), 6.30 (d, 2H), 6.99 (m, 6H), 7.22 (d, 2H), 7.42 (s, 1H), 7.69 (m, 4H), 7.87 (brs, 1H), 7.97 (brs, 1H), 8.11 (s, 1H), 10.26 (brs, 1H); HPLC: 98.46% (retention time = 6.85 min).

[0656] General Synthesis Scheme-2A:

[0657]

[0658] R4' is a suitable partial substituent of R4; R4 is as defined in formula (I)

[0659] Example 22: Synthesis of Compound I-118

[0660] Methyl ((1-(4-carbamoylbenzyl)-2-((4-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0661]

[0662] Step-1: Methyl ((1-(4-carbamoylbenzyl)-2-((4-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0663] Compound I-90 (300 mg, 0.64 mmol) and potassium carbonate (355 mg, 2.57 mmol) were dissolved in 10 mL of DMF, and methyl chloroformate (95 mg, 0.96 mmol) was added dropwise at 0 ° C. and the mixture was stirred at room temperature for 8 h. After the reaction was completed, the mixture was quenched with ice-cold water and extracted with ethyl acetate, followed by extraction with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse phase HPLC to obtain the title compound (120 mg, yield: 70%-80%). LCMS: 539.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.92(m,4H),3.18(m,4H),3.61(s,3H),5.96(s,2H),6.49(d,2H),7.07(d,2H),7.30(brs,1H),7.39(s,1H), 7.50 (d, 2H), 7.73 (d, 2H), 7.80 (s, 2H), 7.87 (brs, 1H), 8.24 (s, 1H), 9.20 (brs, 2H), 10.22 (brs, 1H); HPLC: 97.37% (retention time = 3.765min).

[0664] The following compounds listed in Table-7 were prepared according to Scheme-2 followed by Scheme-2A by following similar procedures as described above for Example-22 using appropriate reagents with suitable modifications known to those skilled in the art.

[0665] Table–7:

[0666]

[0667]

[0668]

[0669] Example 23: Synthesis of Compound I-135

[0670] 1-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0671]

[0672] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0673] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-19 (500 mg, 1.56 mmol) and 3-(pyrrolidin-1-yl)aniline (254 mg, 1.56 mmol) were treated together to obtain 520 mg of the title compound. LCMS: 464.2 (M+1) + .

[0674] Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0675] According to the procedure described in Step-4 of Example-14, the product of Step-1 of Example-23 (500 mg, 0.24 mmol) and aqueous hydroxylamine solution (0.063 mL) were treated together to obtain 350 mg of the title compound. LCMS: 497.2 (M+1) + .

[0676] Step-3: 1-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0677] At 0 ° C, to a solution of N, N-dimethylglycine (45 mg, 0.44 mmol) and triethylamine (66 mg, 0.66 mmol) in 10 mL of tetrahydrofuran, isobutyl chloroformate (60 mg, 0.44 mmol) was added and stirred for 2 hours, followed by the addition of the product of step 2 of Example 23 (220 mg, 0.44 mmol) and stirring at room temperature for 8 hours. After the reaction was completed, the solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse phase HPLC to obtain the title compound (85 mg, yield: 20%-30%). LCMS: 582.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.95 (m, 4H), 2.54 (s, 6H), 3.18 (m, 6H), 5.84 (brs, 2H), 5.92 (s, 2H), 6.29 (d, 2H), 7.02 (m, 2H), 7.09 (m, 3H), 7.29 (brs, 1H), 7.40 (s, 1H), 7.52 (d, 1H), 7.68 (m, 3H), 7.84 (m, 2H), 9.61 (brs, 1H), 10.19 (brs, 1H); HPLC: 93.11% (retention time = 3.869 min).

[0678] Example 24: Synthesis Example I-136

[0679] 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyridin-2-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0680]

[0681] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyridin-2-yl)phenyl)-1H-indole-2-carboxamide

[0682] The product of step-2 of Example-19 (1.2 g, 3.76 mmol) and 3-(pyridin-2-yl)aniline (640 mg, 3.76 mmol) were treated together according to the procedure described in step-3 of Example-1 to obtain 1230 mg of the title compound. LCMS: 472.2 (M+1) + .

[0683] Step-2: 1-(4-Carbamoylbenzyl)-N 2 -(3-(Pyridin-2-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0684] The product of step-1 of Example-24 (150 mg, 0.31 mmol) and sodium hydroxide (38 mg, 0.93 mmol) were treated together according to the procedure described in step-2 of Example-21 to obtain 300 mg of the title compound. LCMS: 490.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 5.98 (s, 2H), 7.10 (d, 2H), 7.30 (brs, 1H), 7.35 (brs, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 7.54 (s, 1H), 7.70 (m, 8H), 7.96 (m, 3H), 8.13 (s, 1H), 8.54 (s, 1H), 8.69 (d, 1H), 10.63 (brs, 1H); HPLC: 99.42% (retention time = 6.151 min).

[0685] Example 25: Synthesis of Compound I-149

[0686] 1-(4-Carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0687]

[0688] Step-1: 1-(4-Carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0689] To a solution of the product of step 2 of Example 23 (300 mg, 0.6 mmol) in 10 mL of dioxane was added dropwise a 0.7 N aqueous solution of sodium hydroxide (25 mg, 0.6 mmol) at 0°C and stirred for 10 minutes, followed by dropwise addition of dimethyl sulfate (1860 mg, 10 mmol) at the same temperature, and the reaction mixture was stirred at 0°C for 4 hours. The solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse phase preparative HPLC to obtain 35 mg of the title compound. LCMS: 511.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.95(m,4H),3.16(m,7H),5.95(s,2H),6.29(d,1H),7.80(br,2H), 7.00(s,1H),7.06(m,2H),7.20(m,3H),7.29(s,1H),7.75(d,3H),7.84(m,2H),10.22(s,1H).

[0690] Example 26: Synthesis of Compound I-157

[0691] (R)-tert-Butyl(1-(((Amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-3-methyl-1-oxybutan-2-yl)carbamate

[0692]

[0693] Step-1: (R)-tert-butyl(1-(((amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)-carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-3-methyl-1-oxobutan-2-yl)carbamate

[0694] According to the procedure described in Step-3 of Example-23, the product of Step-2 of Example-23 (230 mg, 0.46 mmol) and (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (100 mg, 0.46 mmol) were treated together to obtain 60 mg of the title compound. LCMS: 696.3 (M+1) + , 1H NMR (300MHz, DMSO-d6): δ0.90(m,6H),1.41(s,9H),1.95(m,4H),3.18(m,4H),4.04 (m,1H),5.95(s,2H),6.28(d,1H),6.84(brs,1H),6.97(s,1H),7.06(d,1H),7.11( m,2H),7.28(brs,1H),7.34(d,1H),7.43(s,1H),7.51(d,1H),7.72(d,2H),7.81(d , 1H), 7.85 (brs, 1H), 9.26 (brs, 2H), 10.21 (s, 1H); HPLC: 90.92% (retention time = 4.537min).

[0695] Example 27: Synthesis of Compound I-158

[0696] (S)-tert-Butyl(1-(((amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-1-oxypropan-2-yl)carbamate

[0697]

[0698] Step-1: (S)-tert-Butyl(1-(((amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-1-oxypropan-2-yl)carbamate

[0699] The product of step-2 of Example-23 (0.2 mg, 0.4 mmol) and (S)-Boc alanine were treated together according to the procedure described in step-3 of Example-23 to obtain 45 mg of the title compound.

[0700] Example 28: Synthesis of Compound I-183

[0701] Ethyl ((1-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0702]

[0703] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0704] The product of step-2 of Example-19 (950 mg, 2.97 mmol) and 6-(pyrrolidin-1-yl)pyridin-2-amine (485 mg, 2.97 mmol) were treated together according to the procedure described in step-3 of Example-1 to obtain 685 mg of the title compound. LCMS: 465.2 (M+1) + .

[0705] Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0706] According to the procedure described in Step-4 of Example-14, the product of Step-1 of Example-28 (685 mg, 1.47 mmol) was treated with aqueous hydroxylamine solution (0.4 mL) to obtain 520 mg of the title compound. LCMS: 498.2 (M+1) + .

[0707] Step-3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0708] The product of step-2 of Example-28 (520 mg, 1.04 mmol) and acetic anhydride (213 mg, 2.08 mmol) were treated together according to the procedure described in step-5 of example-14 to obtain 465 mg of the title compound. LCMS: 540.2 (M+1) + .

[0709] Step-4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0710] The product of step-3 of Example-28 (460 mg, 0.85 mmol) and zinc (112 mg, 1.7 mmol) were treated together according to the procedure described in step-6 of Example-14 to obtain 60 mg of the title compound. LCMS: 482.2 (M+1) + .

[0711] Step-5: Ethyl ((1-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0712] According to the procedure described in step-1 of example 22, the product of step-4 of example-28 (350 mg, 0.72 mmol) and ethyl chloroformate (78 mg, 0.72 mmol) were treated together to obtain 70 mg of the title compound. LCMS: 554.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.19 (m, 3H), 1.92 (m, 4H), 3.38 (m, 4H), 4.04 (m, 2H), 4.12 (m, 1H), 5.95 (s, 2H), 6.18 (d, 1H), 7.05 (d, 2H), 7.22 (d, 1H), 7.29 (brs, 1H), 7.46 (m, 1H), 7.59 (m, 1H), 7.72 (d, 2H), 7.80 (s, 1H), 7.85 (s, 1H), 8.24 (s, 1H), 9.01 (brs, 2H), 10.4 (brs, 1H); HPLC: 97.47% (retention time = 5.938 min).

[0713] Example 29: Synthesis of Compound I-199

[0714] 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0715]

[0716] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-((2-methoxyethoxy)methoxy)adamantan-1-yl)-1H-indole-2-carboxamide

[0717] The product of step-2 of Example-19 (800 mg, 2.5 mmol) and 3-((2-methoxyethoxy)methoxy)adamantan-1-amine (640 mg, 2.5 mmol) were treated together according to the procedure described in step-3 of Example-1 to obtain 635 mg of the title compound. LCMS: 557.3 (M+1) + .

[0718] Step-2: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-hydroxyadamantan-1-yl)-1H-indole-2-carboxamide

[0719] The product of step-1 of Example-29 (650 mg, 1.07 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-2 of Example-2 to obtain 320 mg of the title compound. LCMS: 469.2 (M+1)+ .

[0720] Step-3: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0721] The product of step-2 of Example-29 (320 mg, 0.68 mmol) was dissolved in 10 mL of dichloromethane and cooled to -78 ° C. Diethylaminosulfur trifluoride (165 mg, 1.02 mmol) was added, and the reaction mixture was stirred at -30 ° C for 1 h. The mixture was quenched with ice-cold water and extracted with dichloromethane, dried over sodium sulfate, and the solvent was evaporated under vacuum to obtain 180 mg of the title compound, which was subjected to the next step without further purification. LCMS: 471.2 (M+1) + .

[0722] Step-4: 1-(4-Carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-6-(N'-hydroxycarbamimidoyl)-1H-indole-2-carboxamide

[0723] According to the procedure described in Step-4 of Example-14, the product of Step-3 of Example-29 (180 mg, 0.38 mmol) was treated with aqueous hydroxylamine solution (0.1 mL) to obtain 150 mg of the title compound. LCMS: 504.2 (M+1) + .

[0724] Step-5: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0725] The product of step-4 of example-29 (150 mg, 0.29 mmol) and acetic anhydride (60 mg, 0.6 mmol) were treated together according to the procedure described in step-5 of example-14 to obtain 120 mg of the title compound. LCMS: 546.2 (M+1) + .

[0726] Step-6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-((1r,3r)-3-((2-methoxyethoxy)methoxy)-adamantan-1-yl)-1H-indole-2-carboxamide

[0727] The product of step-5 of example-29 (120 mg, 0.21 mmol) and zinc (30 mg, 0.45 mmol) were treated together according to the procedure described in step-6 of example-14 to obtain 25 mg of the title compound. LCMS: 488.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.51(s,2H),1.80(m,4H),1.94(s,4H),2.17(m,2H),2.29(m,2H),5.84(s,2H),7.15(m,3H), 7.33(brs,1H),7.52(d,1H),7.75(d,2H),7.87(m,2H),8.19(brs,1H),8.27(brs,1H),8.93(brs,2H),9.22(brs,2H).

[0728] Example 30: Synthesis of compound 1-210.

[0729] 3-Amino-6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0730]

[0731] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0732] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-18 (780 mg, 2.76 mmol) and 4-(bromomethyl)benzamide (592 mg, 2.76 mmol) were treated together to obtain 645 mg of the title compound. LCMS: 413.1 (M+1) + .

[0733] Step-2: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-3-nitro-1H-indole-2-carboxamide

[0734] According to the procedure described in Step-4 of Example-14, the product of Step-1 of Example-30 (645 mg, 1.56 mmol) was treated with aqueous hydroxylamine solution (0.5 mL) to obtain 470 mg of the title compound. LCMS: 493.2 (M+1) + .

[0735] Step-3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-nitro-1H-indole-2-carboxamide

[0736] The product of step-2 of example-30 (470 mg, 0.95 mmol) and acetic anhydride (194 mg, 1.9 mmol) were treated together according to the procedure described in step-5 of example-14 to obtain 385 mg of the title compound. LCMS: 535.2 (M+1) + .

[0737] Step-4: 3-amino-6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0738] The product of step-3 of Example-30 (385 mg, 0.71 mmol) and zinc (187 mg, 2.87 mmol) were treated together according to the procedure described in step-6 of Example-14 to obtain 55 mg of the title compound. LCMS: 447.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ0.83(m,2H),1.06(m,3H),1.45(m,2H),1.55(m,6H),3.07(m,2H),5.08(brs,2H),5 .68(s,2H),6.98(d,2H),7.30(brs,1H),7.39(d,1H),7.69(d,2H),7.86(brs,1H),7.92(d,1H),8.06(m,2H).

[0739] Example 31: Synthesis of Compound I-211

[0740] 3-amino-1-(4-carbamoylbenzyl)-N 2 -(Cyclohexylmethyl)-1H-indole-2,6-dicarboxamide

[0741]

[0742] Step-1: 1-(4-Carbamoylbenzyl)-N2-(cyclohexylmethyl)-3-nitro-1H-indole-2,6-dicarboxamide

[0743] According to the procedure described in step-2 of example-21, the product of step-1 of example-81 (340 mg, 0.82 mmol) and sodium hydroxide (65 mg, 1.64 mmol) were treated together to obtain 165 mg of the title compound. LCMS: 478.2 (M+1)+ .

[0744] Step-2: 3-amino-1-(4-carbamoylbenzyl)-N 2 -(Cyclohexylmethyl)-1H-indole-2,6-dicarboxamide

[0745] According to the procedure described in Step-3 of Example-9, the product of Step-1 of Example-81 (165 mg, 0.34 mmol) and zinc (45 mg, 0.69 mmol) were treated together to obtain 300 mg of the title compound. LCMS: 448.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.76 (m, 2H), 1.06 (m, 3H), 1.38 (m, 1H), 1.48 (m, 5H), 3.03 (m, 2H), 5.08 (brs, 2H), 5.73 (s, 2H), 7.00 (d, 1H), 7.12 (brs, 1H), 7.25 (brs, 1H), 7.41 (d, 1H), 7.78 (d, 1H), 7.98 (d, 1H), 8.04 (m, 2H), 8.95 (brs, 2H), 9.19 (brs, 2H); HPLC: 96.22% (retention time = 6.176 min).

[0746] Example 32: Synthesis of Compound I-212

[0747] 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-hydroxy-1H-indole-2-carboxamide

[0748]

[0749] Step-1: Ethyl 3-acetoxy-6-cyano-1H-indole-2-carboxylate

[0750] In a sealed tube, ethyl 6-cyano-1H-indole-2-carboxylate (1.46 g, 6.82 mmol), (diacetoxyiodo)benzene (2.85 g, 8.86 mmol), palladium II acetate (75 mg, 0.34 mmol) were dissolved in 150 mL of acetic acid, and the mixture was slowly heated to 100 ° C for 3 h. The reaction mixture was diluted with ethyl acetate and filtered through a celite pad, and the filtrate was washed with water and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (7: 3) to obtain 645 mg of the title compound. LCMS: 273.1 (M+1) + .

[0751] Step-2: Ethyl 3-acetoxy-1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0752] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-212 (645 mg, 2.37 mmol) and 4-(bromomethyl)benzamide (507 mg, 2.37 mmol) were treated together to obtain 745 mg of the title compound. LCMS: 406.1 (M+1) + .

[0753] Step-3: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-3-hydroxy-1H-indole-2-carboxylate

[0754] The product of step-2 of Example-32 (745 mg, 1.83 mmol) was dissolved in 150 mL of toluene and treated with silica gel (165 mg, 2.75 mmol), 4-methylbenzenesulfonic acid (380 mg, 2.2 mmol) and water (72 mg, 4.02 mmol). The mixture was heated to 80 ° C for 6 h. The reaction mixture was quenched with cold water and extracted with ethyl acetate, then washed with water and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (6: 4) to obtain 540 mg of the title compound. LCMS: 364.1 (M+1) + .

[0755] Step-4: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxylate

[0756] To the product of step-3 of Example-32 (540 mg, 1.48 mmol) dissolved in 50 mL of tetrahydrofuran was added 1-(bromomethyl)-4-methoxybenzene (298 mg, 1.48 mmol) and sodium hydride (60 mg, 1.48 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 6 h. The mixture was quenched with cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (8: 2) to obtain 610 mg of the title compound. LCMS: 484.2 (M+1) + .

[0757] Step-5: 1-(4-Carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxylic acid

[0758] The product of step-4 of Example-32 (610 mg, 1.26 mmol) and lithium hydroxide (60 mg, 2.52 mmol) were treated together according to the procedure described in step-2 of example-1 to obtain 385 mg of the title compound. LCMS: 456.2 (M+1) + .

[0759] Step-6: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0760] According to the procedure described in Step-3 of Example-1, the product of Step-5 of Example-32 (385 mg, 0.84 mmol) and cyclohexylmethylamine (95 mg, 0.84 mmol) were treated together to obtain 310 mg of the title compound. LCMS: 551.3 (M+1) + .

[0761] Step-7: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0762] According to the procedure described in Step-4 of Example-14, the product of Step-6 of Example-32 (310 mg, 0.56 mmol) was treated with aqueous hydroxylamine solution (0.2 mL) to obtain 165 mg of the title compound. LCMS: 584.3 (M+1) + .

[0763] Step-8: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0764] The product of step-7 of example-32 (165 mg, 0.28 mmol) and acetic anhydride (58 mg, 0.56 mmol) were treated together according to the procedure described in step-5 of example-14 to obtain 145 mg of the title compound. LCMS: 626.3 (M+1) + .

[0765] Step-9: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-hydroxy-1H-indole-2-carboxamide

[0766] The product of step 8 of Example 32 (145 mg, 0.23 mmol) dissolved in 20 mL of methanol was treated with 10% palladium on carbon (24 mg, 0.23 mmol) at room temperature under nitrogen for 4 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase preparative column chromatography to obtain 20 mg of the title compound. LCMS: 448.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.95 (m, 2H), 1.06 (m, 3H), 1.38 (m, 1H), 1.48 (m, 5H), 3.18 (m, 2H), 5.92 (s, 2H), 7.01 (d, 2H), 7.32 (brs, 1H), 7.43 (d, 1H), 7.72 (d, 2H), 7.88 (d, 1H), 7.88 (brs, 1H), 7.98 (m, 2H), 8.09 (s, 1H), 8.89 (brs, 2H), 9.22 (brs, 2H); HPLC: 95.18% (retention time = 3.216 min).

[0767] General synthetic scheme 3:

[0768]

[0769] Example 33: Synthesis of Compound 213

[0770] 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0771]

[0772] Step-1: Ethyl 3-chloro-6-cyano-1H-indole-2-carboxylate

[0773] Ethyl 6-cyano-1H-indole-2-carboxylate (1.25 g, 5.84 mmol) was dissolved in 125 mL of dimethylformamide and N-chlorosuccinimide (932 mg, 7.0 mmol) was added portionwise at 0 ° C. and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched into cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated under vacuum and the resulting crude residue was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (9: 1) to obtain 820 mg of the title compound. LCMS: 249.1 (M+1) + .

[0774] Step-2: Ethyl 6-carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-1H-indole-2-carboxylate

[0775] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-33 (820 mg, 3.29 mmol) and 4-(bromomethyl)benzamide (704 mg, 3.29 mmol) were treated together to obtain 1150 mg of the title compound. LCMS: 399.1 (M+1) + .

[0776] Step-3: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-1H-indole-2-carboxylic acid

[0777] The product of step-2 of Example-33 (1150 mg, 2.88 mmol) and lithium hydroxide (138 mg, 5.76 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 735 mg of the title compound. LCMS: 371.1 (M+1) + .

[0778] Step-4: 1-(4-Carbamoylbenzyl)-3-chloro-6-cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0779] According to the procedure described in Step-3 of Example-1, the product of Step-3 of Example-33 (735 mg, 1.98 mmol) and cyclohexylmethylamine (223 mg, 1.98 mmol) were treated together to obtain 630 mg of the title compound. LCMS: 449.2 (M+1) + .

[0780] Step-5: Ethyl 1-(4-carbamoylbenzyl)-3-chloro-2-((cyclohexylmethyl)carbamoyl)-1H-indole-6-carboximidate

[0781] The product of step-4 of Example-33 (630 mg, 1.4 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 385 mg of the title compound. LCMS: 495.2 (M+1) + .

[0782] Step-6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0783] According to the procedure described in Step-5 of Example-1, the product of Step-5 of Example-33 (385 mg, 0.77 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 75 mg of the title compound. LCMS: 466.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.84 (m, 2H), 1.07 (m, 3H), 1.56 (m, 6H), 3.05 (m, 2H), 5.75 (s, 2H), 7.12 (d, 2H), 7.36 (brs, 1H), 7.63 (d, 1H), 7.77 (m, 3H), 7.93 (brs, 1H), 8.26 (brs, 1H), 8.78 (m, 1H), 9.02 (brs, 2H), 9.29 (brs, 2H); HPLC: 98.64% (retention time = 3.759 min).

[0784] The following compounds listed in Table-8 were prepared according to Scheme-3 by following a similar procedure as described above for Example-33 using appropriate reagents with suitable modifications known to one skilled in the art.

[0785] Table–8:

[0786]

[0787]

[0788]

[0789] Example 34: Synthesis of Compound I-215

[0790] 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0791]

[0792] Step-1: Methyl 4-((6-cyano-2-((cyclohexylmethyl)carbamoyl)-1H-indol-1-yl)methyl)benzoate

[0793] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-18 (950 mg, 3.36 mmol) and methyl 4-(bromomethyl)benzoate (771 mg, 3.36 mmol) were treated together to obtain 1.16 g of the title compound. LCMS: 430.2 (M+1) + .

[0794] Step-2: 4-((6-Cyano-2-((cyclohexylmethyl)carbamoyl)-1H-indol-1-yl)methyl)benzoic acid

[0795] The product of step-1 of Example-34 (1.16 g, 2.7 mmol) and lithium hydroxide (130 mg, 5.41 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 835 mg of the title compound. LCMS: 417.2 (M+1) + .

[0796] Step-3: 6-Cyano-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0797] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-34 (830 mg, 1.99 mmol) and methylamine (62 mg, 1.99 mmol) were treated together to obtain 445 mg of the title compound. LCMS: 429.2 (M+1) + .

[0798] Step-4: Ethyl 2-((cyclohexylmethyl)carbamoyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-6-carboximidate

[0799] The product of step-3 of Example-34 (445 mg, 1.03 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 265 mg of the title compound. LCMS: 475.3 (M+1) + .

[0800] Step-5: 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0801] The product of step-4 of Example-34 (265 mg, 0.55 mmol) was treated with 30 mL of ethanol-NH 3 according to the procedure described in step-5 of example-1 to obtain 80 mg of the title compound. LCMS: 446.2 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 0.84 (m, 2H), 1.09 (m, 3H), 1.58 (m, 6H), 2.73 (d, 3H), 3.03 (m, 2H), 5.91 (s, 2H), 7.06 (d, 2H), 7.24 (brs, 1H), 7.53 (d, 1H), 7.69 (d, 2H), 7.90 (d, 1H), 8.18 (brs, 1H), 8.33 (m, 1H), 8.72 (m, 1H), 8.90 (brs, 2H), 9.22 (brs, 2H); HPLC: 91.68% (retention time = 3.622 min).

[0802] Example 35: Synthesis of Compound I-216

[0803] 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0804]

[0805] This compound was prepared by reacting the product of step-2 of Example-34 with dimethylamine according to a similar procedure as described in step-3 to step-5 of Example-34. LCMS: 460.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.84 (m, 2H), 1.11 (m, 3H), 1.61 (m, 6H), 2.85 (s, 3H), 2.93 (s, 3H), 3.05 (m, 2H), 5.90 (s, 2H), 7.06 (d, 2H), 7.25 (m, 3H), 7.55 (d, 1H), 8.19 (s, 1H), 8.72 (m, 1H), 8.87 (brs, 1H), 9.23 (brs, 2H); HPLC: 91.37% (retention time = 3.758 min).

[0806] Example 36: Synthesis of Compound I-217

[0807] 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(cyclopropylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0808]

[0809] This compound was prepared by reacting the product of step-2 of Example-34 with cyclopropylamine according to a similar procedure as described in step-3 to step-5 of Example-34. LCMS: 472.3 (M+1) + ,1 H NMR (300 MHz, DMSO-d6): δ 0.49 (m, 2H), 0.64 (m, 2H), 0.84 (m, 2H), 1.11 (m, 3H), 1.61 (m, 6H), 2.75 (m, 1H), 3.03 (m, 2H), 5.90 (s, 2H), 7.05 (d, 2H), 7.24 (s, 1H), 7.53 (d, 1H), 7.68 (d, 1H), 7.90 (d, 1H), 8.17 (brs, 1H), 8.34 (m, 1H), 8.71 (m, 1H), 8.88 (brs, 2H), 9.22 (brs, 2H); HPLC: 95.16% (retention time = 3.363 min).

[0810] Example 37: Synthesis of Compound I-218

[0811] 6-Carbamimidoyl-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0812]

[0813] Step-1: 6-Cyano-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0814] According to the procedure described in step-3 of example 1, the product of step-1 of example-6 (850 mg, 4.54 mmol) and 4-methylcyclohexylamine (513 mg, 4.54 mmol) were treated together to obtain 530 mg of the title compound. LCMS: 282.2 (M+1) + .

[0815] Step-2: Methyl 4-((6-cyano-2-((4-methylcyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)benzoate

[0816] The product of step-1 of Example-37 (530 mg, 1.87 mmol) and methyl 4-(bromomethyl)benzoate (430 mg, 1.87 mmol) were treated together according to the procedure described in step-1 of Example-1 to obtain 565 mg of the title compound. LCMS: 430.2 (M+1) + .

[0817] Step-3: 4-((6-cyano-2-((4-methylcyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)benzoic acid

[0818] The product of step-2 of Example 37 (550 mg, 1.27 mmol) and lithium hydroxide (60 mg, 2.54 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 410 mg of the title compound. LCMS: 416.2 (M+1) + .

[0819] Step-4: 6-Cyano-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0820] According to the procedure described in Step-3 of Example-1, the product of Step-3 of Example 37 (410 mg, 0.98 mmol) and dimethylamine (45 mg, 0.98 mmol) were treated together to obtain 270 mg of the title compound. LCMS: 443.2 (M+1) + .

[0821] Step-5: Ethyl 1-(4-(dimethylcarbamoyl)benzyl)-2-((4-methylcyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0822] According to the procedure described in Step-4 of Example-1, the product of Step-4 of Example 37 (270 mg, 0.6 mmol) was treated with 50 mL of ethanol-HCl to obtain 160 mg of the title compound. LCMS: 489.3 (M+1) + .

[0823] Step-6: 6-Carbamimidoyl-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0824] According to the procedure described in Step-5 of Example-1, the product of Step-5 of Example 37 (160 mg, 0.32 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 35 mg of the title compound. LCMS: 460.3 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 0.85 (d, 3H), 1.34 (m, 6H), 1.60 (m, 4H), 2.84 (s, 3H), 2.93 (s, 3H), 3.85 (m, 1H), 5.87 (d, 2H), 7.08 (m, 2H), 7.24 (m, 1H), 7.53 (m, 1H), 7.88 (m, 1H), 8.21 (d, 1H), 8.43 (d, 1H), 8.99 (brs, 2H), 9.24 (brs, 2H); HPLC: 93.97% (retention time = 6.536 min).

[0825] Example 38: Synthesis of Compound I-219

[0826] 6-Carbamimidoyl-1-(4-(cyclopropylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0827]

[0828] This compound was prepared by reacting the product of step-3 of Example-37 with cyclopropylamine according to a similar procedure as described in step-4 to step-6 of Example-37. LCMS: 472.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.50 (m, 2H), 0.63 (m, 2H), 0.88 (m, 3H), 1.34 (m, 3H), 1.49 (m, 3H), 1.62 (m, 3H), 2.78 (m, 1H), 3.81 (m, 1H), 5.87 (s, 2H), 7.15 (d, 2H), 7.23 (d, 1H), 7.51 (d, 1H), 7.67 (d, 2H), 7.84 (m, 1H), 8.14 (m, 1H), 8.33 (d, 1H), 8.42 (d, 1H); HPLC: 88.81% (retention time = 6.469 min).

[0829] Example 39: Synthesis of Compound I-220

[0830] 6-Carbamimidoyl-1-(4-(methylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0831]

[0832] This compound was prepared by reacting the product of step-3 of Example-37 with methylamine according to a similar procedure as described in step-4 to step-6 of Example-37. LCMS: 446.3 (M+1)+ , 1 H NMR (300 MHz, DMSO-d6): δ 0.86 (d, 3H), 1.32 (m, 3H), 1.46 (m, 3H), 1.62 (m, 3H), 2.73 (d, 3H), 3.3.78 (m, 1H), 5.88 (d, 2H), 7.12 (d, 2H), 7.25 (d, 1H), 7.53 (d, 1H), 7.70 (d, 2H), 7.88 (m, 1H), 8.16 (m, 1H), 8.34 (m, 1H), 8.44 (d, 1H), 8.91 (brs, 2H), 9.22 (brs, 2H); HPLC: 89.03% (retention time = 6.274 min).

[0833] Example 40: Synthesis of Compound I-221

[0834] 6-Carbamimidoyl-1-(4-(ethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0835]

[0836] This compound was prepared by reacting the product of step-3 of Example-37 with ethylamine according to a similar procedure as described in step-4 to step-6 of Example-37. LCMS: 460.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.90 (d, 3H), 1.05 (m, 3H), 1.34 (m, 6H), 1.61 (m, 3H), 3.23 (m, 2H), 3.85 (m, 1H), 5.87 (s, 2H), 7.12 (d, 2H), 7.26 (s, 1H), 7.53 (d, 1H), 7.70 (d, 2H), 7.89 (m, 1H), 8.17 (s, 1H), 8.37 (m, 1H), 8.44 (d, 1H), 8.92 (brs, 2H); HPLC: 97.38% (retention time = 3.915 min).

[0837] Example 41: Synthesis of Compound I-222

[0838] 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-((2-hydroxyethyl)carbamoyl)benzyl)-1H-indole-2-carboxamide

[0839]

[0840] This compound was prepared by reacting the product of step-2 of Example-34 with 2-((2-methoxyethoxy)methoxy)ethanamine according to a similar procedure as described in step-3 to step-5 of Example-34. LCMS: 476.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.82 (m, 2H), 1.09 (m, 3H), 1.61 (m, 6H), 3.03 (m, 2H), 3.25 (m, 2H), 3.43 (m, 2H), 5.91 (s, 2H), 7.06 (d, 2H), 7.24 (s, 1H), 7.53 (d, 1H), 7.72 (d, 2H), 7.90 (d, 1H), 8.17 (brs, 1H), 8.36 (m, 1H), 8.72 (m, 1H), 8.86 (brs, 2H), 9.22 (brs, 2H); HPLC: 91.88% (retention time = 6.012 min).

[0841] Example 42: Synthesis of Compound I-223

[0842] 6-Carbamimidoyl-1-(4-((2-hydroxyethyl)carbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0843]

[0844] This compound was prepared by reacting the product of step-3 of Example-37 with 2-((2-methoxyethoxy)methoxy)ethanamine according to a similar procedure as described in step-4 to step-6 of Example-39. LCMS: 476.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.90 (m, 3H), 1.37 (m, 2H), 1.46 (m, 4H), 1.63 (m, 3H), 3.25 (m, 2H), 3.44 (m, 2H), 3.91 (m, 1H), 5.90 (s, 2H), 7.14 (d, 2H), 7.27 (d, 1H), 7.74 (d, 2H), 7.89 (d, 1H), 8.24 (brs, 1H), 8.39 (m, 1H), 8.47 (d, 1H), 8.98 (brs, 2H), 9.30 (brs, 2H); HPLC: 96.87% (retention time = 6.14 min).

[0845] Example 43: Synthesis of Compound I-224

[0846] 1-(4-((2-aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0847]

[0848] This compound was prepared by reacting the product of step-3 of Example-37 with tert-butyl (2-aminoethyl)carbamate according to a similar procedure as described in step-4 to step-6 of Example-37. LCMS: 475.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.91 (m, 3H), 1.34 (m, 2H), 1.47 (m, 4H), 1.63 (m, 3H), 2.93 (m, 2H), 3.35 (m, 2H), 3.88 (m, 1H), 5.89 (s, 2H), 7.16 (d, 2H), 7.28 (d, 1H), 7.54 (d, 2H), 7.74 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.45 (m, 1H), 8.54 (m, 1H), 8.97 (s, 2H), 9.23 (brs, 2H); HPLC: 92.46% (retention time = 5.517 min).

[0849] Example 44: Synthesis of Compound I-225

[0850] 1-(4-((2-aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0851]

[0852] This compound was prepared by reacting the product of step-2 of Example-34 with tert-butyl (2-aminoethyl)carbamate according to a similar procedure as described in step-3 to step-5 of Example-34. LCMS: 475.3 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 0.83 (m, 2H), 1.07 (m, 4H), 1.47 (m, 1H), 1.60 (m, 4H), 2.94 (m, 2H), 3.05 (m, 2H), 3.34 (m, 2H), 5.92 (s, 2H), 7.11 (d, 2H), 7.27 (s, 1H), 7.54 (d, 2H), 7.73 (m, 3H), 7.90 (m, 1H), 8.16 (s, 1H), 8.56 (m, 1H), 8.74 (m, 1H), 9.03 (brs, 2H), 9.23 (brs, 2H); HPLC: 95.19% (retention time = 5.421 min).

[0853] Example 45: Synthesis of Compound I-232

[0854] 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0855]

[0856] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0857] According to the procedure described in step-3 of example 1, the product of step-2 of example 19 (500 mg, 1.56 mmol) and 1-cyclohexyl-N-methylmethanamine (198 mg, 1.56 mmol) were treated together to obtain 395 mg of the title compound. LCMS: 429.2 (M+1) + .

[0858] Step-2: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-1H-indole-2-carboxamide

[0859] According to the procedure described in step-4 of example 14, the product of step-1 of example 50 (380 mg, 0.88 mmol) and aqueous hydroxylamine solution (1.7 mL) were treated together to obtain 300 mg of the title compound. LCMS: 462.2 (M+1) + .

[0860] Step-3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0861] According to the procedure described in step-5 of example 14, the product of step-2 of example 50 (250 mg, 0.54 mmol) and acetic anhydride (260 mg, 2.54 mmol) were treated together to obtain 180 mg of the title compound. LCMS: 504.2 (M+1) + .

[0862] Step-4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0863] According to the procedure described in step-6 of example 14, the product of step-3 of example 50 (160 mg, 0.31 mmol) and zinc (80 mg, 1.24 mmol) were treated together to obtain 65 mg of the title compound. LCMS: 446.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.76 (m, 2H), 1.08 (m, 3H), 1.38 (m, 1H), 1.48 (m, 6H), 2.90 (s, 3H), 3.23 (d, 2H), 5.65 (d, 2H), 6.99 (s, 1H), 7.04 (d, 1H), 7.35 (brs, 1H), 7.56 (d, 1H), 7.79 (d, 2H), 7.86 (d, 1H), 7.92 (brs, 1H), 8.23 ​​(d, 1H), 9.05 (brs, 2H), 9.24 (brs, 2H); HPLC: 96.43% (retention time = 3.663 min).

[0864] Example 46: Synthesis of Compound I-226

[0865] 6-Carbamimidoyl-1-(4-carbamoyl-phenethyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0866]

[0867] The synthesis of the compound in Example I-226 was completed according to a procedure similar to that of Example 45 (using steps 1 to 4 in which N-methylcyclohexylmethylamine was replaced with cyclohexylmethylamine) and Step 1 of Example 19. LCMS: 446.2 (M+1) + 1H NMR (300 MHz, DMSO-d6): δ 0.85 (m, 2H), 1.17 (m, 4H), 1.51 (m, 1H), 1.63 (m, 4H), 2.03 (m, 3H), 3.06 (m, 2H), 3.15 (m, 1H), 6.33 (m, 1H), 7.09 (s, 1H), 7.27 (d, 1H), 7.41 (m, 2H), 7.56 (brs, 1H), 7.78 (m, 3H); HPLC: 84.28% (retention time = 6.495 min).

[0868] Example 47: Synthesis of Compound I-227

[0869] 6-Carbamimidoyl-1-(2-fluoro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0870]

[0871] The synthesis of the compound in Example I-227 was completed according to a procedure similar to that of Example 45 (using steps 1 to 4 in which N-methylcyclohexylmethylamine was replaced with cyclohexylmethylamine) and Step 1 of Example 19. LCMS: 450.2 (M+1) + 1 H NMR (300 MHz, DMSO-d6): δ 0.82 (m, 2H), 1.08 (m, 3H), 1.47 (m, 1H), 1.60 (m, 5H), 3.01 (m, 2H), 5.96 (s, 2H), 6.46 (m, 1H), 7.28 (s, 1H), 7.48 (m, 3H), 7.67 (d, 1H), 7.89 (d, 1H), 7.99 (brs, 1H), 8.16 (s, 1H), 8.72 (m, 1H); HPLC: 98.05% (retention time = 3.057 min).

[0872] Example 48: Synthesis of Compound I-228

[0873] 6-Carbamimidoyl-1-(2-chloro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0874]

[0875] The synthesis of the compound in Example I-228 was completed by a similar procedure to Example 45 (using steps 1 to 4 in which N-methylcyclohexylmethylamine was replaced with cyclohexylmethylamine) and Example 19 step 1 (using the corresponding 2-chloro derivative). LCMS: 466.2 (M+1) + 1H NMR (300 MHz, DMSO-d6): δ 0.76 (m, 2H), 1.05 (m, 3H), 1.40 (m, 1H), 1.52 (m, 5H), 2.98 (m, 2H), 5.97 (s, 2H), 6.08 (d, 1H), 6.37 (s, 1H), 7.48 (brs, 1H), 7.58 (m, 2H), 7.95 (m, 2H), 8.03 (brs, 1H), 8.14 (brs, 1H), 8.77 (m, 1H), 9.11 (brs, 2H), 9.24 (brs, 2H); HPLC: 97.51% (retention time = 6.278 min).

[0876] Example 49: Synthesis of Compound I-229

[0877] 6-Carbamimidoyl-1-(3-chloro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0878]

[0879] The synthesis of the compound in Example I-229 was completed by a similar procedure to Example 45 (using steps 1 to 4 in which N-methylcyclohexylmethylamine was replaced with cyclohexylmethylamine) and Example 19 step 1 (using the corresponding 3-chloro derivative). LCMS: 466.2 (M+1) + 1 H NMR (300 MHz, DMSO-d6): δδ 0.88 (m, 2H), 1.10 (m, 3H), 1.52 (m, 1H), 1.61 (m, 5H), 3.07 (m, 2H), 5.88 (s, 2H), 7.06 (d, 1H), 7.16 (s, 1H), 7.27 (m, 2H), 7.53 (m, 2H), 7.78 (brs, 1H), 7.86 (d, 1H), 8.15 (brs, 1H), 8.77 (m, 1H); HPLC: 94.47% (retention time = 2.907 min).

[0880] Example 50: Synthesis of Compound I-230

[0881] 6-Carbamimidoyl-1-(3-carbamoylbenzyl)-N-(4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0882]

[0883] The synthesis of the compound in Example 1-230 was accomplished according to procedures similar to those of Example 45 (using Steps 1 to 4 in which N-methylcyclohexylmethylamine was replaced with 4, difluorocyclohexylamine) and Step 1 of Example 19 (using the corresponding 3-carbamoyl derivative). LCMS: 454.2 (M+1) + 1.56 (m, 2H), 1.80 (m, 3H), 1.95 (m, 3H), 3.59 (m, 1H), 5.90 (s, 2H), 7.08 (s, 1H), 7.19 (m, 2H), 7.26 (s, 1H), 7.30 (m, 2H), 7.55 (d, 1H), 7.65 (s, 1H), 7.70 (d, 1H), 7.89 (m, 1H), 8.30 (brs, 1H), 8.66 (d, 1H), 8.99 (brs, 2H), 9.33 (brs, 2H); HPLC: 95.37% (retention time = 3.356 min).

[0884] Example 51: Synthesis of Compound I-241

[0885] 6-Carbamimidoyl-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0886]

[0887] Step-1: Ethyl 6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxylate

[0888] Following the procedure described in step-1 of Example-1, ethyl 6-cyano-1H-indole-2-carboxylate (3.2 g, 14.95 mmol) and 1-(bromomethyl)-4-phenoxybenzene (3.93 g, 14.95 mmol) were treated together to obtain 4.65 g of the title compound. LCMS: 397.2 (M+1) + .

[0889] Step-2: 6-Cyano-1-((4'-ethoxy-[1,1'-biphenyl]-3-yl)methyl)-1H-indole-2-carboxylic acid

[0890] The product of step-1 of Example-51 (4.5 g, 11.33 mmol) and lithium hydroxide (544 mg, 22.67 mmol) were treated together according to the procedure described in step-2 of example-1 to obtain 3.28 g of the title compound. LCMS: 367.2 (M+1) + .

[0891] Step-3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0892] The product of step-2 of Example-51 (650 mg, 1.77 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (378 mg, 1.77 mmol) were treated together according to the procedure described in step-3 of Example-1 to obtain 485 mg of the title compound. LCMS: 565.3 (M+1) + .

[0893] Step-4: N-((1r,4r)-4-aminocyclohexyl)-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0894] According to the procedure described in Step-2 of Example-2, the product of Step-3 of Example-51 (840 mg, 1.48 mmol) was treated with 50 mL of ethanol-HCl to obtain 645 mg of the title compound. LCMS: 465.2 (M+1) + .

[0895] Step-5: 6-cyano-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0896] According to the procedure described in Step-2 of Example-3, the product of Step-4 of Example-51 (640 mg, 1.37 mmol) dissolved in 10 mL of N,N-dimethylformamide was treated with 1H-pyrazole-1-carboximidamide hydrochloride (405 mg, 2.76 mmol) and N,N-diisopropylethylamine (535 mg, 4.11 mmol) to obtain 320 mg of the title compound. LCMS: 507.3 (M+1) + .

[0897] Step-6: Ethyl 2-(((1r,4r)-4-guanidinocyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carboximidate

[0898] The product of step-5 of Example-51 (320 mg, 0.63 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 175 mg of the title compound. LCMS: 553.3 (M+1) + .

[0899] Step-7: 6-Carbamimidoyl-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0900] According to the procedure described in Step-5 of Example-1, the product of Step-6 of Example-51 (150 mg, 0.28 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 80 mg of the title compound. LCMS: 524.3 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.32(m,4H),1.82(m,4H),2.45(m,2H),3.71(m,2H),5.82(s,2H),6.88(m,4H),7.12(m,3H ),7.22(brs,1H),7.33(m,2H),7.53(m,2H),7.88(d,1H),8.31(s,1H),8.65(d,1H),9.12(brs,2H),9.32(brs,2H).

[0901] Example 52: Synthesis of Compound I-242

[0902] N-((1r,4r)-4-(3-aminopropionamido)cyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0903]

[0904] Step-1: tert-Butyl (3-(((1r,4r)-4-(6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)-amino)-3-oxyidenepropyl)carbamate

[0905] According to the procedure described in Step-3 of Example-1, the product of Step-4 of Example 51 (730 mg, 1.56 mmol) and 3-((tert-butoxycarbonyl)amino)propionic acid (296 mg, 1.56 mmol) were treated together to obtain 425 mg of the title compound. LCMS: 636.3 (M+1) + .

[0906] Step-2: Ethyl 2-(((1r,4r)-4-(3-aminopropionamido)cyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carboximidate

[0907] According to the procedure described in step-4 of example 1, the product of step-1 of example 52 (425 mg, 0.66 mmol) was treated with 50 mL of ethanol-HCl to obtain 195 mg of the title compound. LCMS: 582.3 (M+1) + .

[0908] Step-3: N-((1r,4r)-4-(3-aminopropionamido)cyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0909] According to the procedure described in step-5 of example 1, the product of step-2 of example 52 (195 mg, 0.33 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 62 mg of the title compound. LCMS: 553.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.32 (m, 4H), 1.82 (m, 4H), 2.45 (m, 2H), 2.95 (m, 2H), 3.71 (m, 2H), 5.82 (s, 2H), 6.88 (m, 3H), 7.12 (m, 3H), 7.22 (m, 2H), 7.33 (m, 2H), 7.53 (d, 1H), 7.81 (m, 3H), 8.21 (d, 1H), 8.28 (d, 1H), 9.12 (brs, 2H), 9.32 (brs, 2H); HPLC: 93.49% (retention time = 7.133 min).

[0910] Example 53: Synthesis of Compound I-252

[0911] 3-amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0912]

[0913] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0914] According to the procedure described in Step-1 of Example-1, the product of Step-1 of Example-9 (980 mg, 2.29 mmol) and 1-(bromomethyl)-4-phenoxybenzene (605 mg, 2.29 mmol) were treated together to obtain 760 mg of the title compound. LCMS: 610.3 (M+1) + .

[0915] Step-2: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0916] The product of step-1 of example-53 (750 mg, 1.22 mmol) and zinc (160 mg, 2.45 mmol) were treated together according to the procedure described in step-3 of example-9 to obtain 430 mg of the title compound. LCMS: 580.3 (M+1) + .

[0917] Step-3: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carboximidate

[0918] The product of step-2 of Example-53 (430 mg, 0.74 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 155 mg of the title compound. LCMS: 526.3 (M+1) + .

[0919] Step-4: 3-amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0920] According to the procedure described in Step-5 of Example-1, the product of Step-3 of Example-53 (155 mg, 0.29 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 15 mg of the title compound. LCMS: 497.3 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.31(m,4H),1.83(m,4H),2.95(m,1H),3.71(m,1H),5.63(s,2H),6.85(d,4H),7.12(m,1H ),7.21(d,2H),7.36(m,3H),7.81(m,3H),7.94(d,1H),8.13(d,1H),8.18(brs,1H),9.10(brs,2H),9.21(brs,2H).

[0921] Example 54: Synthesis of Compound I-253

[0922] ((1r,4r)-4-(3-amino-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0923]

[0924] Step-1: ((1r,4r)-4-(3-amino-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0925] The product of step-2 of Example 53 (510 mg, 0.87 mmol) and sodium hydroxide (52 mg, 1.3 mmol) were treated together according to the procedure described in step-2 of Example-1 without using lithium hydroxide as a base to obtain 180 mg of the title compound. LCMS: 524.2 (M+1) + .

[0926] Step-2: ((1r,4r)-4-(3-amino-6-(ethoxy(imino)methyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0927] The product of step-1 of example-53 (180 mg, 0.51 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 65 mg of the title compound. LCMS: 570.3 (M+1) + .

[0928] Step-3: ((1r,4r)-4-(3-amino-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0929] According to the procedure described in Step-5 of Example-1, the product of Step-2 of Example-53 (65 mg, 0.11 mmol) was treated with 20 mL of ethanol-NH 3 to obtain 10 mg of the title compound. LCMS: 541.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.21 (m, 2H), 1.36 (m, 2H), 1.79 (m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 5.63 (s, 2H), 6.85 (d, 4H), 7.12 (m, 3H), 7.32 (m, 3H), 7.52 (m, 1H), 7.71 (d, 1H), 7.82 (m, 2H), 8.19 (d, 1H), 8.31 (brs, 1H), 9.10 (brs, 2H), 9.21 (brs, 2H), 9.65 (brs, 1H); HPLC: 87.13% (retention time = 6.683 min).

[0930] Example 55: Synthesis of Compound I-254

[0931] Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indol-3-yl)carbamate

[0932]

[0933] Step-1: tert-Butyl ((1r,4r)-4-(3-ethylcarbamate-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0934] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example 53 (650 mg, 1.12 mmol) and ethyl chloroformate (121 mg, 1.12 mmol) were treated together to obtain 370 mg of the title compound. LCMS: 652.3 (M+1) + .

[0935] Step-2: tert-Butyl ((1r,4r)-4-(3-ethylcarbamate-6-((Z)-N'-hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0936] According to the procedure described in Step-4 of Example-14, the product of Step-1 of Example-55 (370 mg, 0.56 mmol) was treated with aqueous hydroxylamine solution (0.2 mL) to obtain 230 mg of the title compound. LCMS: 613.3 (M+1) + .

[0937] Step-3: Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indol-3-yl)carbamate

[0938] The product of step-2 of Example-55 (230 mg, 0.37 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in step-2 of Example-2 to obtain 65 mg of the title compound. LCMS: 585.3 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 1.21 (m, 7H), 1.81 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 4.09 (m, 2H), 5.83 (s, 2H), 6.89 (m, 4H), 7.11 (m, 3H), 7.32 (m, 3H), 7.62 (d, 1H), 7.81 (m, 3H), 8.08 (d, 1H), 8.18 (brs, 1H), 8.88 (brs, 1H), 11.10 (brs, 1H), 12.6 (brs, 1H); HPLC: 97.32% (retention time = 4.97 min).

[0939] Example 56: Synthesis of Compound I-256

[0940] 1-(3-aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0941]

[0942] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0943] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-6 (1200 mg, 3.13 mmol) and 1-(bromomethyl)-3-nitrobenzene (676 mg, 3.13 mmol) were treated together to obtain 850 mg of the title compound. LCMS: 518.2 (M+1) + .

[0944] Step-2: ((1r,4r)-4-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)-carbamic acid tert-butyl ester

[0945] The product of step-1 of example-56 (850 mg, 1.64 mmol) and zinc (213 mg, 3.28 mmol) were treated together according to the procedure described in step-3 of example-9 to obtain 410 mg of the title compound. LCMS: 488.3 (M+1) + .

[0946] Step-3: Ethyl 1-(3-aminobenzyl)-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0947] The product of step-2 of example-56 (410 mg, 0.84 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-1 to obtain 235 mg of the title compound. LCMS: 434.2 (M+1) + .

[0948] Step-4: 1-(3-aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0949] The product of step-3 of Example-56 (235 mg, 0.54 mmol) was treated with 30 mL of ethanol-NH 3 according to the procedure described in step-5 of example-1 to obtain 35 mg of the title compound. LCMS: 405.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.42 (m, 4H), 1.81 (m, 4H), 2.95 (m, 1H), 3.45 (m, 1H), 5.83 (s, 2H), 6.41 (m, 3H), 6.97 (m, 1H), 7.22 (s, 1H), 7.52 (d, 1H), 7.82 (m, 4H), 8.15 (brs, 1H), 8.61 (d, 1H), 9.05 (brs, 2H), 9.25 (brs, 2H); HPLC: 94.55% (retention time = 4.255 min).

[0950] Example 57: Synthesis of Compound I-257

[0951] N-((1r,4r)-4-aminocyclohexyl)-1-(3-(3-aminopropionamido)benzyl)-6-carbamimidino-1H-indole-2-carboxamide

[0952]

[0953] This compound was prepared by treating the product of step-2 of Example-56 with 3-((tert-butoxycarbonyl)amino)propionic acid according to a similar procedure as described in step-3 to step-5 of Example-1. LCMS: 476.3 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 1.32 (m, 4H), 1.83 (m, 4H), 2.63 (m, 2H), 3.11 (m, 3H), 3.71 (m, 1H), 5.84 (s, 2H), 7.14 (m, 1H), 7.27 (s, 1H), 7.32 (brs, 1H), 7.48 (m, 2H), 7.84 (m, 4H), 7.93 (m, 2H), 8.18 (s, 1H), 8.58 (d, 1H), 9.22 (d, 3H), 10.18 (brs, 1H); HPLC: 97.1% (retention time = 4.042 min).

[0954] Example 58: Synthesis of Compound I-258

[0955] N-((1r,4r)-4-aminocyclohexyl)-1-(3-(azetidine-3-carboxamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0956]

[0957] This compound was prepared by treating the product of step-2 of Example-56 with 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid according to a similar procedure as described in step-3 to step-5 of Example-1. LCMS: 488.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.42 (m, 4H), 1.81 (m, 4H), 2.95 (m, 2H), 3.55 (m, 3H), 4.05 (m, 2H), 5.83 (s, 2H), 6.71 (d, 1H), 7.22 (m, 2H), 7.51 (m, 2H), 7.82 (m, 4H), 8.15 (brs, 1H), 8.61 (d, 1H), 8.71 (brs, 1H), 9.05 (brs, 2H), 9.25 (brs, 2H), 10.21 (s, 1H); HPLC: 94.31% (retention time = 4.177 min).

[0958] Example 59: Synthesis of Compound I-259

[0959] 3-(3-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0960]

[0961] Step-1: Methyl 3-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0962] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example 6 (1.2 g, 3.13 mmol) and methyl 3-(bromomethyl)benzoate (717 mg, 3.13 mmol) were treated together to obtain 930 mg of the title compound. LCMS: 531.2 (M+1) + .

[0963] Step-2: 3-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoic acid

[0964] The product of step-1 of Example-59 (930 mg, 1.75 mmol) and lithium hydroxide (85 mg, 3.5 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 630 mg of the title compound. LCMS: 517.2 (M+1) + .

[0965] Step-3: Methyl 3-(3-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzamido)propanoate

[0966] The product of step-2 of Example-59 (630 mg, 1.21 mmol) and methyl 3-aminopropionate (125 mg, 1.21 mmol) were treated together according to the procedure described in step-3 of example-1 to obtain 340 mg of the title compound. LCMS: 602.3 (M+1) + .

[0967] Step-4: 3-(3-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0968] According to the procedure described in Step-2 of Example-1, the product of Step-3 of Example-59 (340 mg, 0.56 mmol) and lithium hydroxide (55 mg, 2.26 mmol) were treated together to obtain 210 mg of the title compound. LCMS: 588.3 (M+1) + .

[0969] Step-5: 3-(3-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0970] The product of step-4 of Example-59 (200 mg, 0.34 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 75 mg of the title compound. LCMS: 534.3 (M+1) + .

[0971] Step-6: 3-(3-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0972] The product of step-5 of Example-59 (70 mg, 0.13 mmol) was treated with 20 mL of ethanol-NH 3 according to the procedure described in step-5 of Example-1 to obtain 23 mg of the title compound. LCMS: 505.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.32 (m, 4H), 1.83 (m, 4H), 2.33 (m, 3H), 2.95 (m, 1H), 3.45 (m, 2H), 5.84 (s, 2H), 6.82 (s, 1H), 7.17 (d, 1H), 7.28 (s, 1H), 7.36 (m, 2H), 7.52 (m, 3H), 7.81 (m, 2H), 8.21 (s, 1H), 8.45 (m, 1H), 8.65 (d, 1H), 9.02 (brs, 2H), 9.25 (brs, 2H), 13.24 (brs, 1H); HPLC: 96.04% (retention time = 4.45 min).

[0973] Example 60: Synthesis of Compound I-260

[0974] 1-(3-(3-aminopropionamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0975]

[0976] Step-1: Ethyl 6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylate

[0977] Following the procedure described in step-1 of Example-1, ethyl 6-cyano-1H-indole-2-carboxylate (1.45 g, 6.77 mmol) and 1-(bromomethyl)-3-nitrobenzene (1.46 g, 6.77 mmol) were treated together to obtain 1.05 g of the title compound. LCMS: 350.1 (M+1) + .

[0978] Step-2: 6-Cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylic acid

[0979] According to the procedure described in Step-2 of Example-1, the product of Step-1 of Example-60 (1.05 g, 3.0 mmol) and lithium hydroxide (145 mg, 6.0 mmol) were treated together to obtain 680 mg of the title compound. LCMS: 322.1 (M+1) + .

[0980] Step-3: 6-cyano-N-(4,4-difluorocyclohexyl)-1-(3-nitrobenzyl)-1H-indole-2-carboxamide

[0981] According to the procedure described in step-3 of example-1, the product of step-2 of example-60 (680 mg, 2.11 mmol) and 4,4-difluorocyclohexylamine (285 mg, 2.11 mmol) were treated together to obtain 570 mg of the title compound. LCMS: 439.2 (M+1) + .

[0982] Step-4: 1-(3-aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0983] According to the procedure described in Step-3 of Example-9, the product of Step-3 of Example-60 (570 mg, 1.29 mmol) and zinc (170 mg, 2.62 mmol) were treated together to obtain 410 mg of the title compound. LCMS: 409.2 (M+1) + .

[0984] Step-5: tert-Butyl (3-((3-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indol-1-yl)-methyl)phenyl)amino)-3-oxylidenepropyl)carbamate

[0985] According to the procedure described in Step-3 of Example-1, the product of Step-4 of Example-60 (410 mg, 1.0 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (190 mg, 1.0 mmol) were treated together to obtain 365 mg of the title compound. LCMS: 580.3 (M+1) + .

[0986] Step-6: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(3-((2-aminoethyl)carbamoyl)-benzyl)-1H-indole-6-carboximidate

[0987] According to the procedure described in Step-4 of Example-1, the product of Step-5 of Example-60 (350 mg, 0.6 mmol) was treated with 50 mL of ethanol-HCl to obtain 115 mg of the title compound. LCMS: 526.3 (M+1) + .

[0988] Step-7: 1-(3-(3-aminopropionamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0989] According to the procedure described in step-5 of example-1, the product of step-6 of example-60 (115 mg, 0.21 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 34 mg of the title compound. LCMS: 497.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.61 (m, 2H), 1.83 (m, 3H), 2.03 (m, 3H), 2.63 (m, 2H), 3.04 (m, 2H), 3.95 (m, 1H), 5.83 (s, 2H), 6.71 (d, 1H), 7.17 (m, 1H), 7.28 (s, 1H), 7.36 (brs, 1H), 7.47 (d, 1H), 7.54 (m, 1H), 7.74 (brs, 3H), 7.90 (d, 1H), 8.18 (s, 1H), 8.59 (d, 1H), 9.02 (brs, 2H), 9.25 (brs, 2H); HPLC: 89.25% (retention time = 5.796 min).

[0990] Example 61: Synthesis of Compound I-261

[0991] 1-(4-aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0992]

[0993] Step 1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0994] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-6 (1.2 g, 3.13 mmol) and 1-(bromomethyl)-4-nitrobenzene (676 mg, 3.13 mmol) were treated together to obtain 970 mg of the title compound. LCMS: 518.2 (M+1) + .

[0995] Step-2: ((1r,4r)-4-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)-carbamic acid tert-butyl ester

[0996] The product of step-1 of Example-61 (970 mg, 1.87 mmol) and zinc (244 mg, 3.74 mmol) were treated together according to the procedure described in step-3 of Example-9 to obtain 530 mg of the title compound. LCMS: 488.3 (M+1) + .

[0997] Step-3: Ethyl 1-(4-aminobenzyl)-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[0998] The product of step-2 of Example-61 (340 mg, 0.69 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 150 mg of the title compound. LCMS: 434.2 (M+1) + .

[0999] Step-4: 1-(4-aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[1000] According to the procedure described in step-5 of example-1, the product of step-3 of example-61 (150 mg, 0.34 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 22 mg of the title compound. LCMS: 405.2 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 1.41 (m, 4H), 1.75 (m, 4H), 2.96 (m, 1H), 3.62 (m, 1H), 5.67 (s, 2H), 6.67 (brs, 2H), 6.97 (d, 2H), 7.13 (s, 1H), 7.52 (d, 1H), 7.85 (d, 1H), 7.95 (m, 3H), 8.25 (s, 1H), 9.00 (brs, 2H), 9.24 (brs, 2H); HPLC: 91.55% (retention time = 5.551 min).

[1001] Example 62: Synthesis of Compound I-262

[1002] N-((1r,4r)-4-aminocyclohexyl)-1-(4-(3-aminopropionamido)benzyl)-6-carbamimidino-1H-indole-2-carboxamide

[1003]

[1004] Step-1: tert-Butyl ((1r,4r)-4-(1-(4-(3-((tert-butoxycarbonyl)amino)propionamido)benzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1005] The product of step-2 of Example-61 (640 mg, 1.31 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (248 mg, 1.31 mmol) were treated together according to the procedure described in step-3 of Example-1 to obtain 430 mg of the title compound. LCMS: 659.3 (M+1) + .

[1006] Step-2: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-(3-aminopropionamido)benzyl)-1H-indole-6-carboximidate

[1007] The product of step-1 of Example-62 (430 mg, 0.65 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 170 mg of the title compound. LCMS: 505.3 (M+1) + .

[1008] Step-3: N-((1r,4r)-4-aminocyclohexyl)-1-(4-(3-aminopropionamido)benzyl)-6-carbamimidino-1H-indole-2-carboxamide

[1009] According to the procedure described in step-5 of example-1, the product of step-2 of example-62 (170 mg, 0.33 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 28 mg of the title compound. LCMS: 476.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.48 (m, 4H), 1.83 (m, 4H), 2.15 (m, 2H), 3.10 (m, 2H), 3.70 (m, 1H), 5.88 (s, 2H), 7.08 (d, 2H), 7.22 (s, 1H), 7.45 (d, 2H), 7.53 (d, 2H), 7.73 (brs, 3H), 7.88 (m, 3H), 8.18 (s, 1H), 8.61 (d, 1H), 9.09 (brs, 2H), 9.23 (brs, 2H), 10.13 (s, 1H); HPLC: 85.85% (retention time = 4.127 min).

[1010] Example 63: Synthesis of Compound I-263

[1011] 1-(4-(3-aminopropionamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[1012]

[1013] Step-1: Ethyl 6-cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxylate

[1014] According to the procedure described in Step-1 of Example-1, the product of Step-2 of Example-6 (1.35 g, 3.52 mmol) and 1-(bromomethyl)-4-nitrobenzene (761 mg, 3.52 mmol) were treated together to obtain 955 mg of the title compound. LCMS: 350.1 (M+1) + .

[1015] Step-2: 6-Cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxylic acid

[1016] The product of step-1 of Example-63 (950 mg, 2.71 mmol) and lithium hydroxide (130 mg, 5.42 mmol) were treated together according to the procedure described in step-2 of Example-1 to obtain 710 mg of the title compound. LCMS: 322.1 (M+1) + .

[1017] Step-3: 6-cyano-N-(4,4-difluorocyclohexyl)-1-(4-nitrobenzyl)-1H-indole-2-carboxamide

[1018] The product of step-2 of Example-63 (650 mg, 2.01 mmol) and 4,4-difluorocyclohexylamine (272 mg, 2.01 mmol) were treated together according to the procedure described in step-3 of example-1 to obtain 512 mg of the title compound. LCMS: 439.2 (M+1) + .

[1019] Step-4: 1-(4-aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[1020] The product of step-3 of Example-63 (510 mg, 1.16 mmol) and zinc (151 mg, 2.32 mmol) were treated together according to the procedure described in step-3 of Example-9 to obtain 365 mg of the title compound. LCMS: 409.2 (M+1) + .

[1021] Step-5: tert-Butyl (3-((4-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indol-1-yl)-methyl)phenyl)amino)-3-oxyidenepropyl)carbamate

[1022] According to the procedure described in Step-3 of Example-1, the product of Step-4 of Example-63 (365 mg, 0.89 mmol) and 3-((tert-butoxycarbonyl)amino)propionic acid (120 mg, 0.89 mmol) were treated together to obtain 280 mg of the title compound. LCMS: 580.3 (M+1) + .

[1023] Step-6: Ethyl 1-(4-(3-aminopropionamido)benzyl)-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indole-6-carboximidate

[1024] The product of step-5 of Example-63 (280 mg, 0.48 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example 1 to obtain 125 mg of the title compound. LCMS: 526.3 (M+1) + .

[1025] Step-7: 1-(4-(3-aminopropionamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[1026] According to the procedure described in step-5 of example-1, the product of step-6 of example 63 (125 mg, 0.23 mmol) was treated with 30 mL of ethanol-NH 3 to obtain 22 mg of the title compound. LCMS: 497.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.21 (m, 2H), 1.83 (m, 3H), 2.03 (m, 3H), 2.63 (m, 2H), 3.04 (m, 2H), 3.95 (m, 1H), 5.88 (s, 2H), 7.08 (d, 2H), 7.22 (s, 1H), 7.45 (d, 2H), 7.53 (d, 2H), 7.73 (brs, 3H), 7.88 (d, 1H), 8.61 (d, 1H), 9.04 (brs, 2H), 9.25 (brs, 2H), 10.13 (s, 1H); HPLC: 92.28% (retention time = 5.091 min).

[1027] Example 64 Synthesis of Compound I-264

[1028] 1-(4-(3-aminopropionamido)benzyl)-6-carbamimidoyl-N-(cyclohex-3-en-1-yl)-1H-indole-2-carboxamide

[1029]

[1030] Step-1: 6-Cyano-N-(cyclohex-3-en-1-yl)-1-(4-nitrobenzyl)-1H-indole-2-carboxamide

[1031] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-63 (500 mg, 1.55 mmol) and cyclohex-3-enamine (150 mg, 1.55 mmol) were treated together to obtain 360 mg of the title compound. LCMS: 401.2 (M+1) + .

[1032] Step-2: 1-(4-aminobenzyl)-6-cyano-N-(cyclohex-3-en-1-yl)-1H-indole-2-carboxamide

[1033] According to the procedure described in Step-3 of Example-9, the product of Step-1 of Example-64 (360 mg, 0.89 mmol) and zinc (116 mg, 1.8 mmol) were treated together to obtain 265 mg of the title compound. LCMS: 371.2 (M+1) + .

[1034] Step-3: tert-Butyl (3-((4-((6-cyano-2-(cyclohex-3-en-1-ylcarbamoyl)-1H-indol-1-yl)methyl)phenyl)amino)-3-oxylidenepropyl)carbamate

[1035] According to the procedure described in Step-3 of Example-1, the product of Step-2 of Example-64 (260 mg, 0.7 mmol) and 3-((tert-butoxycarbonyl)amino)propionic acid (132 mg, 0.7 mmol) were treated together to obtain 200 mg of the title compound. LCMS: 542.3 (M+1) + .

[1036] Step-4: Ethyl 1-(4-(3-aminopropionamido)benzyl)-2-(cyclohex-3-en-1-ylcarbamoyl)-1H-indole-6-carboximidate

[1037] The product of step-3 of Example-64 (200 mg, 0.36 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in step-4 of Example-1 to obtain 85 mg of the title compound. LCMS: 488.3 (M+1) + .

[1038] Step-5: 1-(4-(3-aminopropionamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[1039] According to the procedure described in step-5 of example-1, the product of step-4 of example-64 (85 mg, 0.17 mmol) was treated with 20 mL of ethanol-NH 3 to obtain 14 mg of the title compound. LCMS: 459.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.51 (m, 1H), 1.81 (m, 1H), 2.01 (m, 3H), 2.25 (m, 1H), 2.63 (m, 2H), 3.02 (m, 2H), 3.91 (m, 1H), 5.65 (brs, 2H), 5.79 (s, 2H), 7.09 (d, 1H), 7.23 (s, 1H), 7.45 (d, 2H), 7.52 (m, 1H), 7.71 (m, 3H), 7.88 (d, 1H), 8.60 (d, 1H), 8.96 (brs, 2H), 9.24 (brs, 2H), 10.12 (s, 1H); HPLC: 81.94% (retention time = 5.292 min).

[1040] Example 65: Synthesis of Compound I-267

[1041] 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[1042]

[1043] The crude product of step 2 of Example 23 was purified by preparative high performance liquid chromatography using an Agilent XDB C18 reverse phase column (21.2 x 150 mm, 5 microns). The mobile phase was 30% acetonitrile to 100% acetonitrile (0.1% TFA) in water (0.1% TFA), providing the title compound (25 mg). LCMS: 497.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.94 (m, 4H), 3.19 (m, 4H), 5.93 (s, 2H), 6.28 (d, 2H), 6.96 (s, 1H), 7.01 (d, 1H), 7.07 (m, 3H), 7.31 (brs, 1H), 7.44 (m, 2H), 7.73 (m, 2H), 7.87 (brs, 1H), 7.91 (d, 2H), 8.03 (s, 1H), 10.34 (brs, 1H); HPLC: 94.73% (retention time = 3.839 min).

[1044] Example 66: Synthesis of Compound I-268

[1045] 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[1046]

[1047] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[1048] According to the procedure described in step-3 of example 1, the product of step-2 of example 19 (500 mg, 1.56 mmol) and 4-(pyrrolidin-1-yl)aniline (252 mg, 1.56 mmol) were treated together to obtain 375 mg of the title compound. LCMS: 464.2 (M+1) + .

[1049] Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[1050] According to the procedure described in step-4 of example 14, the product of step-1 of example 66 (370 mg, 0.79 mmol) and aqueous hydroxylamine solution (1.3 mL) were treated together to obtain 180 mg of the title compound. LCMS: 497.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.92 (m, 4H), 3.21 (m, 4H), 5.93 (s, 2H), 6.49 (d, 2H), 7.11 (d, 2H), 7.31 (brs, 1H), 7.43 (m, 4H), 7.73 (d, 2H), 7.87 (m, 2H), 8.01 (s, 1H), 10.24 (brs, 1H); HPLC: 99.76% (retention time = 3.663 min).

[1051] Example 67: Synthesis of Compound I-269

[1052] 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[1053]

[1054] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[1055] The product of step-2 of Example 19 (500 mg, 1.56 mmol) and 4-(pyrrolidin-1-yl)pyridin-2-amine (254 mg, 1.56 mmol) were treated together according to the procedure described in step-3 of Example 1 to obtain 285 mg of the title compound. LCMS: 465.2 (M+1) + .

[1056] Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[1057] According to the procedure described in step-4 of example 14, the product of step-1 of example 67 (250 mg, 0.53 mmol) was treated with aqueous hydroxylamine solution (1.2 mL) to obtain 110 mg of the title compound. LCMS: 498.2 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 2.02 (m, 4H), 3.42 (m, 4H), 5.93 (s, 2H), 6.69 (m, 2H), 7.08 (d, 2H), 7.34 (brs, 1H), 7.53 (d, 1H), 7.70 (s, 1H), 7.78 (d, 2H), 7.88 (m, 1H), 7.92 (m, 2H), 11.85 (brs, 1H); HPLC: 98.17% (retention time = 2.79 min).

[1058] General synthetic scheme 4

[1059]

[1060] R1=H;X=Cl / Br;Pg=optional protecting group;R2, R3, m and n are as defined in formula (I)

[1061] The first general method for synthesizing compounds of formula (I) is depicted in general synthetic scheme 4. 6-Cyano-1H-indole-2-carboxylic acid ethyl ester is treated with various alkylating agents in the presence of a suitable base (K2CO3) and a suitable solvent (DMF) to produce alkylated derivatives. The C(2) ethyl ester is hydrolyzed with aqueous LiOH and subsequently coupled with an amine using EDCI and HOBt to produce an amide. The cyano group in the resulting amide derivative is converted to the amine analog by treatment with ethanolic HCl, and the intermediate imide ester is quenched with ammonia to form compounds of formula (I).

[1062] Example 68: Synthesis of Compound I-270

[1063] 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[1064]

[1065] Step-1: Ethyl 6-cyano-1-isopentyl-1H-indole-2-carboxylate

[1066] 1-Bromo-3-methylbutane (7.0 g, 46.71 mmol) and potassium carbonate (K2CO3) (7.73 g, 56.0 mmol) were added to 6-cyano-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 46.71 mmol) dissolved in 250 mL of N, N-dimethylformamide (DMF) and stirred at room temperature for 8 h. After completion of the reaction, the mixture was quenched with ice-cold water and the precipitated product was filtered out. Therefore, the solid obtained was further washed with water and dried under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with 10-20% ethyl acetate / hexane to obtain the title compound (6.2 g). LCMS: 285.1 (M+1) + .

[1067] Step-2: 6-Cyano-1-isopentyl-1H-indole-2-carboxylic acid

[1068] The product of step-1 of Example-68 (5.8 g, 19.64 mmol) was dissolved in a mixture of 100 mL of tetrahydrofuran / methanol / water (1:1:1), and lithium hydroxide (LiOH) (1.9 g, 78.6 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4-6 h. The mixture was acidified with a saturated aqueous solution of citric acid and extracted with ethyl acetate, then washed with brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under vacuum to obtain the title compound (3.65 g). LCMS: 257.1 (M+1) + .

[1069] Step-3: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carbonitrile

[1070] The product (650 mg, 2.53 mmol) of step 2 of embodiment 68 was dissolved in 10 mL of N, N-dimethylformamide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (392 mg, 2.53 mmol), hydroxybenzotriazole (HOBt) (341 mg, 2.53 mmol) and N, N-diisopropylethylamine (DIPEA) (327 mg, 2.53 mmol) were added and stirred at room temperature for 15 min. 4-fluoropiperidine (260 mg, 2.53 mmol) dissolved in 5 mL of DMF was added to the reaction mixture, and the resulting solution was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with ethyl acetate, then washed with brine and water, and dried over sodium sulfate. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with 10% ethyl acetate / hexane, and the title compound (510 mg) was obtained. LCMS: 342.2 (M+1) + .

[1071] Step-4: Ethyl 2-(4-fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidate

[1072] The product of step 3 of Example 68 (450 mg, 1.31 mmol) was dissolved in 50 mL of ethanol-HCl (ethanol was saturated with HCl gas at -20°C) and kept in a glass sealed tube at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under vacuum to obtain the title compound (235 mg). LCMS: 388.2 (M+1) + .

[1073] Step-5: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboxamidine

[1074] The product of step-4 of Example-68 (220 mg, 0.56 mmol) was dissolved in 50 mL of ethanol-NH 3 (ethanol was saturated with NH 3 gas at -70°C) and kept overnight in a steel bomb at room temperature. After the reaction was completed, the solvent was evaporated under vacuum to obtain a crude product, which was purified by preparative high performance liquid chromatography with an Agilent XDB C18 reverse phase column (21.2x150 mm, 5 microns). The mobile phase was 30% acetonitrile to 100% acetonitrile (0.1% TFA) in water (0.1% TFA), providing the title compound (110 mg). LCMS: 359.2 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 0.90 (m, 6H), 1.49 (m, 1H), 1.61 (m, 2H), 1.71 (m, 2H), 1.81 (m, 2H), 3.72 (m, 4H), 4.33 (m, 2H), 4.90 (m, 1H), 6.84 (s, 1H), 7.51 (d, 1H), 7.81 (d, 1H), 8.11 (s, 1H), 9.06 (brs, 2H), 9.28 (brs, 2H); HPLC: 96.96% (retention time = 3.613 min).

[1075] The following compounds listed in Table-9 were prepared according to Scheme-1 by following a similar procedure as described above for Example-68 using appropriate reagents with suitable modifications known to one skilled in the art.

[1076]

[1077] Table–9

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089] General synthetic scheme 5

[1090]

[1091] R1=H;Pg=optional protecting group = an optional step when Pg is present; R2, R3, m and n are as defined in formula (I)

[1092] Other general methods for synthesizing compounds of formula (I) are described in General Synthesis Scheme-5. C(2) amide-derived 6-cyanoindole-2-carboxylic acid derivatives are treated with hydroxylamine to form amidoxime derivatives, which are acylated with Ac2O and reduced with Zn / AcOH to install the amidine functionality. Acid-labile protection groups are deprotected with appropriate reagents (TFA / DCM or EtOH.HCl) to provide compounds of formula (I).

[1093] Example 69: Synthesis of Compound I-323

[1094] 3-((6-Carbamimidoyl-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[1095]

[1096] Step-1: Ethyl 1-(3-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[1097] Following the procedure described in step-1 of Example-68, ethyl 6-cyano-1H-indole-2-carboxylate (3.57 g, 16.71 mmol) and 3-(bromomethyl)benzamide (3.56 g, 16.71 mmol) were treated together to obtain the title compound. LCMS: 348.1 (M+1) + .

[1098] Step-2: 1-(3-Carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid

[1099] The product of step-1 of Example-69 (1.2 g, 3.45 mmol) was treated with lithium hydroxide (331 mg, 13.82 mmol) according to the procedure described in step-2 of Example 1 to obtain the title compound (770 mg). LCMS: 320.1 (M+1) + .

[1100] Step-3: 3-((6-Cyano-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[1101] The product of step-2 of Example-69 (700 mg, 2.19 mmol) was treated with 3-fluoropyrrolidine (195 mg, 2.19 mmol) according to the procedure described in step-3 of Example 1 to obtain the title compound (525 mg). LCMS: 391.1 (M+1) + .

[1102] Step-4: 3-((2-(3-Fluoropyrrolidine-1-carbonyl)-6-(N'-hydroxycarbamimidoyl)-1H-indol-1-yl)methyl)benzamide

[1103] The product of step 3 of Example 69 (500 mg, 1.28 mmol) was dissolved in 20 mL of ethanol, and an aqueous hydroxylamine solution (0.3 mL) was added, and the resulting mixture was refluxed at 80° C. for 4-6 h. The solvent was evaporated under vacuum to give the title compound (425 mg), which was used in the next step without further purification. LCMS: 424.2 (M+1) + .

[1104] Step-5: 3-((6-(N'-acetoxycarbamimidoyl)-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[1105] The product of step 4 of Example 69 (400 mg, 0.94 mmol) was dissolved in 10 mL of acetic acid, and acetic anhydride (767 mg, 7.52 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum to give the title compound (260 mg), which was used in the next step without further purification. LCMS: 466.2 (M+1) + .

[1106] Step-6: 3-((6-Carbamimidoyl-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[1107] The product of step 5 of Example 69 (250 mg, 0.53 mmol) was dissolved in 5 mL of acetic acid, and Zn (275 mg, 4.3 mmol) was added portionwise, and the resulting mixture was stirred at room temperature for 6-8 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under vacuum to obtain a crude product, which was purified by reverse phase preparative HPLC to obtain the title compound (75 mg). LCMS: 408.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 2.05 (m, 3H), 3.43 (m, 2H), 3.57 (m, 2H), 5.67 (s, 2H), 7.10 (m, 2H), 7.26 (m, 3H), 7.55 (m, 2H), 7.72 (m, 1H), 7.85 (m, 1H), 7.88 (m, 1H), 8.24 (d, 1H), 9.04 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.03% (retention time = 5.033 min).

[1108] The following compounds listed in Table-10 were prepared according to Scheme-5 by following a similar procedure as described above for Example-69 using appropriate reagents with suitable modifications known to one skilled in the art.

[1109]

[1110] Table 10

[1111]

[1112]

[1113]

[1114]

[1115]

[1116] General Synthesis Scheme-6

[1117]

[1118] X = Cl / Br; Pg = optional protecting group; L, R2, R3, m and n are as defined in formula (I)

[1119] In general synthetic scheme-6, another general method for synthesizing compounds of general formula (I) is described. Under standard coupling conditions, 6-cyanoindole 2-carboxylic acid is coupled with a suitable amine to generate a coupled compound, which is then dissolved in acetic acid and treated with copper (II) nitrate trihydrate to obtain 3-nitroindole derivatives. In the presence of a suitable base (K2CO3) and a suitable solvent (DMF), these 3-nitroindole derivatives are further treated with alkyl halides to produce N-alkylated analogs, which are reduced with Zn / glacial AcOH to obtain 3-amino derivatives. The corresponding 3-amino analogs are then treated with ethanolic HCl to obtain compound imide esters, which are then treated with ethanolamine to obtain compounds of formula (I).

[1120] Example 70: Synthesis of Compound I-345

[1121] 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboxamidine

[1122]

[1123] Step-1: tert-Butyl (2-(1-(6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1124] Following the procedure described in step-3 of Example-68, 6-cyano-1H-indole-2-carboxylic acid (1.85 g, 9.94 mmol) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (2.26 g, 9.94 mmol) were treated together to obtain the title compound (1.77 g). LCMS: 397.2 (M+1) + .

[1125] Step-2: tert-Butyl (2-(1-(6-cyano-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1126] The product of step-1 of Example-70 (1.7 g, 4.29 mmol) was dissolved in 30 mL of acetic acid and cooled to 0 ° C. Copper (II) nitrate trihydrate (401 mg, 5.16) was added and stirred for 3 h. The reaction mixture was quenched with cold water and extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated to obtain a crude product, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (7: 3) to obtain 610 mg of the title compound. LCMS: 442.2 (M+1) + .

[1127] Step-3: (2-(1-(6-Cyano-1-isopentyl-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)-carbamic acid tert-butyl ester

[1128] According to the procedure described in Step-1 of Example 1, the product of Step-2 of Example-70 (600 mg, 1.36 mmol) and 1-bromo-3-methylbutane (204 mg, 1.36 mmol) were treated together to obtain the title compound (1.52 g). LCMS: 512.3 (M+1) + .

[1129] Step-4: (2-(1-(3-amino-6-cyano-1-isopentyl-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)-carbamic acid tert-butyl ester

[1130] The product of step 3 of Example 70 (510 mg, 0.99 mmol) was dissolved in 10 mL of glacial acetic acid (AcOH), and Zn (383 mg, 5.98 mmol) was added portionwise at room temperature. The reaction mixture was stirred at room temperature for 6 h. The contents were filtered through a pad of celite, and the filtrate was concentrated under vacuum to obtain a crude compound, which was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (6:4) to obtain the title compound (190 mg). LCMS: 482.3 (M+1) + .

[1131] Step-5: Ethyl 3-amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidate

[1132] The product of step-4 of Example-70 (190 mg, 0.39 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example 1 to obtain the title compound (135 mg). LCMS: 428.3 (M+1) + .

[1133] Step-6: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboxamidine

[1134] According to the procedure described in step-5 of example 1, the product of step-5 of example-70 (130 mg, 0.3 mmol) was treated with 50 mL of ethanol-NH 3 to obtain the title compound (35 mg). LCMS: 399.3 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 0.81 (m, 6H), 0.98 (m, 1H), 1.48 (m, 6H), 1.65 (m, 3H), 2.81 (m, 3H), 3.11 (m, 1H), 4.01 (m, 1H), 4.21 (m, 3H), 7.38 (m, 1H), 7.71 (m, 3H), 7.82 (m, 1H), 7.93 (m, 1H), 9.00 (brs, 2H), 9.21 (brs, 2H); HPLC: 97.75% (retention time = 4.399 min).

[1135] The following compounds listed in Table-11 were prepared according to Scheme-6 by following a similar procedure as described above for Example 70 using appropriate reagents with suitable modifications known to those skilled in the art.

[1136]

[1137] Table 11

[1138]

[1139]

[1140] General synthetic scheme 7

[1141]

[1142] Pg = optional protecting group; L, R2, R3, m and n are as defined in formula (I)

[1143] Another general method for synthesizing compounds of formula (I) is described in general synthetic scheme 7. The 3-nitroindole derivatives described in scheme 6 are treated with aqueous hydroxylamine to produce amide oximes, which are acylated in the presence of acetic acid and acetic anhydride and subsequently reduced with Zn / AcOH to give amidine derivatives. The amidine analogs are then deprotected with HCl or TFA under acidic conditions to give compounds of formula (I).

[1144] Example 71: Synthesis of Compound I-349

[1145] 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboxamidine

[1146]

[1147] Step-1: tert-Butyl (2-(1-(6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1148] Following the procedure described in step-3 of Example-68, 6-cyano-1H-indole-2-carboxylic acid (1.85 g, 9.94 mmol) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (2.26 g, 9.94 mmol) were treated together to obtain the title compound (1.77 g). LCMS: 397.2 (M+1) + .

[1149] Step-2: tert-Butyl (2-(1-(6-cyano-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1150] According to the procedure described in step-2 of example-70, the product of step-1 of example-71 (1.7 g, 4.29 mmol) and copper (II) nitrate trihydrate (401 g, 5.16) were treated together to obtain the title compound (610 mg). LCMS: 442.2 (M+1)+ .

[1151] Step-3: tert-Butyl (2-(1-(6-cyano-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1152] According to the procedure described in Step-1 of Example 1, the product of Step-2 of Example-71 (600 mg, 1.36 mmol) and ((2-bromomethyl)sulfonyl)benzene (337 mg, 1.36 mmol) were treated together to obtain the title compound (540 mg). LCMS: 610.2 (M+1) + .

[1153] Step-4: tert-Butyl-(2-(1-(6-(N'-hydroxycarbamimidoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1154] The product of step-3 of Example-71 (540 mg, 0.88 mmol) was treated with NH2OH aqueous solution (0.3 mL) according to the procedure described in step-4 of Example-69 to obtain the title compound (410 mg). LCMS: 643.2 (M+1) + .

[1155] Step-5: tert-Butyl-(2-(1-(6-(N'-acetoxycarbamimidoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1156] The product of step-4 of example-71 (410 mg, 0.63 mmol) was treated with acetic anhydride (Ac2O) (521 mg, 5.1 mmol) according to the procedure described in step-5 of example-69 to obtain the title compound (325 mg). LCMS: 685.3 (M+1) + .

[1157] Step-6: tert-Butyl (2-(1-(3-amino-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1158] The product of step-5 of Example-71 (325 mg, 0.47 mmol) was treated with zinc (365 mg, 5.7 mmol) according to the procedure described in step-6 of Example 69 to obtain the title compound (185 mg). LCMS: 597.3 (M+1) + .

[1159] Step-7: 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidamide

[1160] The product of step-6 of Example-71 (185 mg, 0.31 mmol) was treated with 20 mL of ethanol-HCl according to the procedure described in step-4 of Example-1, except that the reaction was carried out at 0° C. for 2 h to obtain 65 mg of the title compound. LCMS: 497.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ0.98(m,2H),1.40(m,3H),1.61(m,3H),2.81(m,3H),2.99(m,2H),3.65(m,2H),3.95 (m,2H),4.45(brs,2H),4.80(brs,2H),7.32(m,1H),7.61(m,6H),7.82(m,3H),9.01(brs,2H),9.24(brs,2H).

[1161] The following compounds listed in Table-12 were prepared according to Scheme-7 by following a similar procedure as described above for Example-71 using appropriate reagents with suitable modifications known to one skilled in the art.

[1162]

[1163] Table 12

[1164]

[1165]

[1166] General Synthesis Scheme-8

[1167]

[1168] X = Br; Pg = optional protecting group; L, R2, R3, m and n are as defined in formula (I)

[1169] Yet another general method for synthesizing compounds of formula (I) is depicted in General Synthesis Scheme-8. 6-Cyno-indole 2-ethylcarboxylate is reacted with N-chlorosuccinimide in the presence of a suitable solvent (DMF) to produce 3-chloro-6-cyano-indole-2-carboxylate, which is treated with an appropriate alkylating agent in the presence of a suitable base (K2CO3) and a suitable solvent (DMF) to yield an N-alkylated derivative of the compound. The C(2) ethyl ester is hydrolyzed in the presence of LiOH / H2O and subsequently cyclocoupled to form the corresponding amide, which is then treated with ethanolic HCl. The intermediate imidoester is further treated with ethanolamine to produce the compound of formula (I).

[1170] Example 72: Synthesis of Compound I-353

[1171] 1-([1,1'-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidamide

[1172]

[1173] Step-1: Ethyl 3-chloro-6-cyano-1H-indole-2-carboxylate

[1174] Ethyl 6-cyano-1H-indole-2-carboxylate (1.25 g, 5.84 mmol) was dissolved in 125 mL of dimethylformamide and N-chlorosuccinimide (932 mg, 7.0 mmol) was added portionwise at 0 ° C. and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched into cold water, extracted with ethyl acetate, then washed with brine and dried over sodium sulfate. The solvent was evaporated under vacuum and the resulting crude residue was purified by column chromatography using silica gel as an adsorbent and eluted with hexane: ethyl acetate (9: 1) to obtain 820 mg of the title compound. LCMS: 249.1 (M+1) + .

[1175] Step-2: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-6-cyano-1H-indole-2-carboxylate

[1176] According to the procedure described in Step-1 of Example-68, the product of Step-2 of Example-72 (800 mg, 3.22 mmol) was treated with 4-(bromomethyl)-1,1'-biphenyl (792 mg, 3.22 mmol) to obtain the title compound (910 mg). LCMS: 415.1 (M+1)+.

[1177] Step-3: 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-6-cyano-1H-indole-2-carboxylic acid

[1178] The product of step-3 of Example-72 (900 mg, 2.17 mmol) was treated with lithium hydroxide (417 mg, 17.4 mmol) according to the procedure described in step-2 of Example-68 to obtain the title compound (640 mg). LCMS: 387.1 (M+1) + .

[1179] Step-4: 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carbonitrile

[1180] The product of step-3 of Example-72 (640 mg, 1.65 mmol) and 4-fluoropiperidine (170 mg, 1.65 mmol) were treated together according to the procedure described in step-3 of Example-68 to obtain the title compound (430 mg). LCMS: 472.1 (M+1) + .

[1181] Step-5: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidate

[1182] The product of step-4 of example-72 (430 mg, 0.91 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-68 to obtain the title compound (225 mg). LCMS: 518.2 (M+1) + .

[1183] Step-6: 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidamide

[1184] According to the procedure described in Step-5 of Example-68, the product of Step-5 of Example-72 (220 mg, 0.42 mmol) was treated with 50 mL of ethanol-NH 3 to obtain the title compound (65 mg). LCMS: 489.2 (M+1) + , 1H NMR (300 MHz, DMSO-d6): δ 1.52 (m, 2H), 1.66 (m, 2H), 2.96 (m, 1H), 3.13 (m, 1H), 3.46 (m, 1H), 3.79 (m, 2H), 5.33 (m, 1H), 5.72 (m, 1H), 7.21 (m, 2H), 7.35 (m, 1H), 7.42 (m, 2H), 7.58 (m, 3H), 7.66 (m, 1H), 7.82 (m, 1H), 8.46 (d, 1H), 9.07 (brs, 2H), 9.36 (brs, 2H); HPLC: 97.53% (retention time = 4.135 min).

[1185] The following compounds listed in Table-13 were prepared according to Scheme-8 by following a similar procedure as described above for Example-72 using appropriate reagents with suitable modifications known to one skilled in the art.

[1186]

[1187] Table–13

[1188]

[1189] General Synthesis Scheme-9

[1190]

[1191] Pg = protecting group; L, R2 and m are as defined in formula (I)

[1192] Yet another general method for synthesizing compounds of formula (I) is depicted in General Synthesis Scheme-9. The aforementioned N-functionalized 6-cyanoindole dicarboxylic acid is coupled with an ester-containing cyclic amine to produce the corresponding cyclic amide. Hydrolysis of the ester functionality attached to the cyclic amine, followed by further coupling with various amines, produces diamide derivatives. Treatment of the diamide with ethanolic HCl followed by ethanolic ammonia produces compounds of formula (I).

[1193] Example 73: Synthesis of Compound I-356

[1194] N-(3-Aminopropyl)-1-(6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)-piperidine-4-carboxamide

[1195]

[1196] Step-1: Ethyl 6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylate

[1197] Following the procedure described in step 1 of Example 68, ethyl 6-cyano-1H-indole-2-carboxylate (10.0 g, 46.71 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (7.0 g, 46.71 mmol) were treated together to obtain the title compound (6.2 g). LCMS: 285.1 (M+1)+.

[1198] Step-2: 6-Cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylic acid

[1199] The product of step-1 of Example-73 (5.8 g, 19.64 mmol) was treated with LiOH (1.89 g, 78.6 mmol) according to the procedure described in step-2 of Example 68 to obtain the title compound (3.65 g). LCMS: 257.1 (M+1) + .

[1200] Step-3: Ethyl 1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylate

[1201] The product of step-2 of Example-73 (1.55 g, 6.05 mmol) and ethyl piperidine-4-carboxylate (950 mg, 6.05 mmol) were treated together according to the procedure described in step-3 of Example-68 to obtain the title compound (1.75 g). LCMS: 484.2 (M+1) + .

[1202] Step-4: 1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid

[1203] The product of step-3 of Example-73 (1.7 g, 3.51 mmol) was treated with LiOH (338 mg, 14.0 mmol) in H2O according to the procedure described in step-2 of Example 68 to obtain the title compound (1.04 g). LCMS: 456.2 (M+1) + .

[1204] Step-5: tert-Butyl (3-(1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxamido)propyl)carbamate

[1205] The product of step-4 of Example-73 (800 mg, 1.75 mmol) and tert-butyl (3-aminopropyl)carbamate (305 mg, 1.75 mmol) were treated together according to the procedure described in step-3 of Example-68 to obtain 580 mg of the title compound. LCMS: 612.3 (M+1) + .

[1206] Step-6: Ethyl 2-(4-((3-aminopropyl)carbamoyl)piperidine-1-carbonyl)-1-(4-(trifluoromethyl)-benzyl)-1H-indole-6-carboximidate

[1207] The product of step-5 of example-73 (550 mg, 0.9 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of example-68 to obtain the title compound (340 mg). LCMS: 558.3 ​​(M+1) + .

[1208] Step-7: N-(3-aminopropyl)-1-(6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxamide

[1209] The product of step-6 of Example-73 (340 mg, 0.61 mmol) was treated with 50 mL of ethanol-NH 3 according to the procedure described in step-5 of Example 68 to obtain the title compound (90 mg). LCMS: 529.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 1.51 (m, 4H), 2.49 (m, 2H), 2.71 (m, 4H), 3.15 (m, 3H), 3.82 (m, 1H), 4.38 (m, 1H), 5.65 (s, 2H), 6.83 (s, 1H), 7.23 (m, 2H), 7.52 (d, 1H), 7.78 (m, 4H), 7.94 (m, 1H), 9.13 (brs, 2H), 9.23 (brs, 2H); HPLC: 79.68% (retention time = 6.572 min).

[1210] The following compounds listed in Table-14 were prepared according to Scheme-9 by following a similar procedure as described above for Example 73 using appropriate reagents with suitable modifications known to those skilled in the art.

[1211]

[1212] Table 14

[1213]

[1214] General Synthesis Scheme 10

[1215]

[1216] Yet another general method for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme 10. The amino analogue obtained from scheme 9 is treated with 1H-pyrazole-1-carboximidamide hydrochloride in a suitable solvent (DMF) in the presence of a suitable base (DIPEA) to afford compounds of formula (I).

[1217] Example 74: Synthesis of Compound I-359

[1218] 1-(6-Carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)-N-(3-guanidinopropyl)-piperidine-4-carboxamide

[1219]

[1220] Step-1: 1-(6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)-N-(3-guanidinopropyl)piperidine-4-carboxamide

[1221] The product of step 7 of Example 73 (90 mg, 0.17 mmol) dissolved in 10 mL of DMF was treated with 1H-pyrazole-1-carboximidamide hydrochloride (50 mg, 0.34 mmol) and DIPEA (88 mg, 0.68 mmol) and stirred at room temperature for 24 h. The solvent was evaporated under vacuum to obtain a crude compound, which was purified by reverse phase preparative high performance column chromatography to obtain 20 mg of the title compound. LCMS: 571.3 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ1.49(m,3H),1.71(m,2H),2.31(m,2H),3.12(m,6H),3.85(m,1H),4.45(m,1H),5.65(s,2 H),6.95(s,1H),7.22(d,2H),7.50(m,2H),7.63(d,2H),7.83(m,2H),8.22(s,1H),8.89(brs,2H),9.25(brs,2H).

[1222] The following compounds listed in Table-15 were prepared according to Scheme-10 followed by Scheme-7 by following similar procedures as described above for Example 74 using appropriate reagents with suitable modifications known to those skilled in the art.

[1223]

[1224] Table 15

[1225]

[1226]

[1227] General Synthesis Scheme-11

[1228]

[1229] Pg = protecting group; R2 is substituted with -NO2; R1, R3 and m are as defined in formula (I)

[1230] Yet another general method for synthesizing compounds of formula (I) is depicted in General Synthesis Scheme-11. Nitro derivatives are reduced with Zn in the presence of acetic acid to yield amines, which are coupled with carboxylic acids under standard coupling conditions to yield functionalized amides of compound N-1. Deprotection of the protecting group with ethanolic HCl also results in conversion of the nitrile to an imidoester, which, upon treatment with ammonia, yields analogs of formula (I).

[1231] Example 75: Synthesis of Compound I-363

[1232] 3-Amino-N-(3-((2-(4-(2-aminoethyl)piperidine-1-carbonyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)phenyl)acrylamide

[1233]

[1234] Step-1: Ethyl 6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylate

[1235] According to the procedure described in step-1 of Example-68, ethyl 6-cyano-1H-indole-2-carboxylate (10.0 g, 46.71 mmol) and 1-(bromomethyl)-3-nitrobenzene (10.04 g, 46.71 mmol) were treated together to obtain 6.8 g of the title compound. LCMS: 350.1 (M+1) + .

[1236] Step-2: 6-Cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylic acid

[1237] The product of step-1 of Example-75 (1.6 g, 4.58 mmol) was treated with lithium hydroxide (440 mg, 18.33 mmol) according to the procedure described in step-2 of Example-68 to obtain 930 mg of the title compound. LCMS: 322.1 (M+1) + .

[1238] Step-3: Ethyl 1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylate

[1239] The product of step-2 of Example-75 (900 mg, 2.8 mmol) and (2-(piperidin-4-yl)ethyl)-carbamic acid tert-butyl ester (638 mg, 2.8 mmol) were treated together according to the procedure described in step-3 of Example-68 to obtain 740 mg of the title compound. LCMS: 532.2 (M+1) + .

[1240] Step-4: tert-Butyl (2-(1-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1241] The product of step-3 of Example-75 (730 mg, 1.37 mmol) was treated with zinc (350 mg, 5.48 mmol) according to the procedure described in step-4 of Example 70 to obtain 400 mg of the title compound. LCMS: 502.3 (M+1) + .

[1242] Step-5: tert-Butyl (2-(1-(1-(3-(3-((tert-butoxycarbonyl)amino)propionamido)benzyl)-6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1243] According to the procedure described in step-3 of example 68, the product of step-4 of example-75 (400 mg, 0.59 mmol) and 3-((tert-butoxycarbonyl)-amino)propionic acid (112 mg, 0.59 mmol) were treated together to obtain 320 mg of the title compound. LCMS: 673.3 (M+1) + .

[1244] Step-6: Ethyl 2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(3-(3-aminopropionamido)benzyl)-1H-indole-6-carboximidate

[1245] The product of step-5 of Example-75 (320 mg, 0.47 mmol) was treated with 50 mL of ethanol-HCl according to the procedure described in step-4 of Example 68 to obtain 110 mg of the title compound. LCMS: 519.3 (M+1) + .

[1246] Step-7: 3-amino-N-(3-((2-(4-(2-aminoethyl)piperidine-1-carbonyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)phenyl)propanamide

[1247] According to the procedure described in step-5 of example 68, the product of step-6 of example-75 (110 mg, 0.21 mmol) was treated with 50 mL of ethanol-NH 3 to obtain 22 mg of the title compound. LCMS: 490.3 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ0.51(m,1H),0.81(m,1H),1.32(m,2H),1.49(m,2H) ,1.61(m,1H),2.65(m,4H),2.81(m,1H),3.05(m,2H),3.71(m,2H),4.41(m,1H ),5.52(d,2H),6.52(s,1H),6.75(m,2H),7.21(m,1H),7.31(s,1H),7.52(m,2 H),7.81(m,6H),8.35(s,1H),9.12(brs,2H),9.27(brs,2H),10.10(brs,2H).

[1248] The following compounds listed in Table-16 were prepared according to Scheme-11 by following a similar procedure as described above for Example 75 using appropriate reagents with suitable modifications known to one skilled in the art.

[1249]

[1250] Table 16

[1251]

[1252]

[1253]

[1254]

[1255]

[1256] General Synthesis Scheme–12

[1257]

[1258] Yet another general method for synthesizing compounds of general formula (I) is depicted in General Synthesis Scheme-12. Appropriately functionalized 6-cyanoindole-2-carboxylic acids are coupled with functionalized cyclic amines using EDC / HOBt to generate C(2) amides, which are treated with aqueous hydroxylamine followed by deprotection of acid-labile protecting groups with ethanolic HCl to generate analogs of general formula (I).

[1259] Example 76: Synthesis of Compound I-379

[1260] 2-(4-(2-aminoethyl)piperidine-1-carbonyl)-N'-hydroxy-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidamide

[1261]

[1262] Step-1: tert-Butyl (2-(1-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1263] The product of step-2 of Example-73 (753 mg, 2.19 mmol) and tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (500 mg, 2.19 mmol) were treated together according to the procedure described in step-3 of Example 68 to obtain 575 mg of the title compound. LCMS: 555.3 (M+1) + .

[1264] Step-2: tert-Butyl-(2-(1-(6-(N'-hydroxycarbamimidoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[1265] The product of step-1 of Example-76 (500 mg, 0.9 mmol) was treated with aqueous NH2OH solution (0.3 mL) according to the procedure described in step-4 of Example 69 to obtain 425 mg of the title compound. LCMS: 588.3 (M+1) + .

[1266] Step-3: 2-(4-(2-aminoethyl)piperidine-1-carbonyl)-N'-hydroxy-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carboximidamide

[1267] The product of step-2 of Example-76 (420 mg, 0.71 mmol) was treated with 30 mL of ethanol-HCl according to the procedure described in step-7 of Example 71 to obtain 180 mg of the title compound. LCMS: 488.2 (M+1) + , 1 H NMR (300MHz, DMSO-d6): δ0.66(m,1H),0.95(m,1H),1.31(m,5H),2.61(m,5H),4.21(m,1H),5.61(s,2H),6.9 1(s,1H),7.32(d,2H),7.41(d,1H),7.60(m,4H),7.85(d,1H),8.20(s,1H),9.00(brs,2H),11.10(brs,1H).

[1268] The following compounds listed in Table-17 were prepared according to Scheme-12 by following a similar procedure as described above for Example 76 using appropriate reagents with suitable modifications known to those skilled in the art.

[1269]

[1270] Table 17

[1271]

[1272]

[1273] General Synthesis Scheme-13

[1274]

[1275] R1=H; R3, m and n are as defined in formula (I); R' and R" are appropriate substituents as given in the following examples

[1276] Yet another general method for the synthesis of compounds of general formula (I) is depicted in General Synthesis Scheme-13. Following the procedures described in the above schemes, compounds of formula (I) were synthesized.

[1277] Example 77: Synthesis of Compound I-385

[1278] 4-((6-Carbamimidoyl-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[1279]

[1280] Step-1: 2-(3,3-Difluoropyrrolidine-1-carbonyl)-1H-indole-6-carbonitrile

[1281] According to the procedure described in step-3 of Example 68, 6-cyano-1H-indole-2-carboxylic acid (1.5 g, 8.06 mmol) and 3,3-difluoropyrrolidine (862 mg, 8.06 mmol) were treated together to obtain 1.27 g of the title compound. LCMS: 276.1 (M+1) + .

[1282] Step-2: 4-((6-Cyano-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-benzoic acid methyl ester

[1283] The product of step-1 of Example-77 (1.2 g, 4.34 mmol) was treated with methyl 4-(bromomethyl)benzoate (990 mg, 4.34 mmol) according to the procedure described in step-1 of Example 68 to obtain 1.28 g of the title compound. LCMS: 424.1 (M+1) + .

[1284] Step-3: 4-((6-Cyano-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzoic acid

[1285] The product of step-2 of Example-77 (1.2 g, 2.83 mmol) was treated with LiOH (544 mg, 22.7 mmol) according to the procedure described in step-2 of Example 68 to obtain 810 mg of the title compound. LCMS: 410.1 (M+1) + .

[1286] Step-4: 4-((6-cyano-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[1287] The product of step-3 of Example-77 (800 mg, 1.95 mmol) and tert-butyl (3-aminopropyl)carbamate (340 mg, 1.95 mmol) were treated together according to the procedure described in step-3 of Example 68 to obtain 530 mg of the title compound. LCMS: 437.2 (M+1) + .

[1288] Step-5: 4-((2-(3,3-difluoropyrrolidine-1-carbonyl)-6-(N'-hydroxycarbamimidoyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[1289] The product of step-4 of Example-77 (500 mg, 1.14 mmol) was treated with aqueous NH2OH solution (0.4 mL) according to the procedure described in step-4 of Example 69 to obtain 375 mg of the title compound. LCMS: 470.2 (M+1) + .

[1290] Step-6: 4-((6-(N'-acetoxycarbamimidoyl)-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[1291] The product of step-5 of Example-77 (250 mg, 0.53 mmol) was treated with Ac2O (435 mg, 4.26 mmol) according to the procedure described in step-5 of Example 69 to afford 180 mg of the title compound. LCMS: 512.2 (M+1) + .

[1292] Step-7: 4-((6-Carbamimidoyl-2-(3,3-difluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)-N-ethylbenzamide

[1293] The product of step-6 of Example-77 (150 mg, 0.29 mmol) was treated with Zn (150 mg, 2.34 mmol) according to the procedure described in step-6 of Example 69 to obtain 35 mg of the title compound. LCMS: 454.2 (M+1) + , 1 HNMR (300 MHz, DMSO-d6): δ1.06 (m, 3H), 2.29 (m, 2H), 3.22 (m, 2H), 3.68 (m, 2H), 3.89 (m, 2H), 5.67 (d, 2H), 7.10 (m, 3H), 7.54 (d, 2H), 7.73 (m, 2H), 7.86 (d, 1H), 8.40 (m, 1H), 8.95 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.93% (retention time = 3.264 min).

[1294] The following compounds listed in Table-18 were prepared according to Scheme-13 by following a similar procedure as described above for Example-77 using appropriate reagents with suitable modifications known to one skilled in the art.

[1295]

[1296] Table-18

[1297]

[1298]

[1299]

[1300] Example 78: Synthesis of Compound I-394

[1301] 1-([1,1'-Biphenyl]-4-ylmethyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-6-carboxamide

[1302]

[1303] Step-1: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-6-cyano-1H-indole-2-carboxylate

[1304] According to the procedure described in step-1 of Example 68, ethyl 6-cyano-1H-indole-2-carboxylate (800 mg, 3.73 mmol) and 4-(bromomethyl)-1,1'-biphenyl (917 mg, 3.73 mmol) were treated together to obtain 985 mg of the title compound. LCMS: 381.1 (M+1) + .

[1305] Step-2: 1-([1,1'-Biphenyl]-4-ylmethyl)-6-cyano-1H-indole-2-carboxylic acid

[1306] The product of step-1 of Example-78 (980 mg, 2.57 mmol) was treated with LiOH (495 mg, 20.63 mmol) according to the procedure described in step-2 of Example 68 to obtain 630 mg of the title compound. LCMS: 353.1 (M+1) + .

[1307] Step-3: 1-([1,1'-biphenyl]-4-ylmethyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-6-carbonitrile

[1308] According to the procedure described in step-3 of example 68, the product of step-2 of example-78 (600 mg, 1.7 mmol) and 1,2,3,4-tetrahydroisoquinoline (226 mg, 1.7 mmol) were treated together to obtain 410 mg of the title compound. LCMS: 468.2 (M+1) + .

[1309] Step-4: 1-([1,1'-biphenyl]-4-ylmethyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-6-carboxamide

[1310] To a solution of the product of step-3 of Example-78 (350 mg, 0.75 mmol) in 5 mL of a mixture of MeOH and H2O (1: 1) was added solid NaOH (240 mg, 6.0 mmol). The reaction was stirred at 50°C. After completion of the reaction, the reaction mixture was concentrated to remove methanol and acidified with 2N HCl. The aqueous mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to obtain a crude product, which was purified by reverse phase preparative HPLC to obtain 80 mg of the title compound. LCMS: 486.2 (M+1) + , 1 H NMR (300 MHz, DMSO-d6): δ 2.61 (m, 2H), 3.6 (m, 2H), 4.74 (m, 2H), 4.71 (s, 2H), 5.81 (s, 2H), 6.90 (s, 1H), 7.07 (m, 3H), 7.16 (m, 3H), 7.34 (m, 5H), 7.52 (m, 2H), 7.69 (s, 2H), 7.98 (brs, 2H), 8.26 (brs, 2H); HPLC: 89.33% (retention time = 5.639 min).

[1311] General Synthesis Scheme–14

[1312]

[1313] Example 79: Synthesis of Compound I-395:

[1314] N-(4-carbamimidoylbenzyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide)

[1315]

[1316] Step-1: Ethyl 6-cyano-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylate.

[1317] To a solution of ethyl 6-cyano-1H-indole-2-carboxylate (2.0 g, 8.433 mmol) in DMF (20 ml) was added potassium carbonate (3.90 g, 28.32 mmol), a solution of 1-(bromomethyl)naphthalene (3.1 g, 14.15 mmol) dissolved in THF (10 mL), and stirred at room temperature for 3 h. After the reaction was complete, THF was distilled off, ice-cold water was added, and the precipitated product was filtered out. Therefore, the solid obtained was dried under vacuum to obtain the title compound (2.2 g, crude product), which was continued for the next step without purification. LCMS: 353.1 (M-1) +.

[1318] Step-2: 6-Cyano-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid.

[1319] The product of step-1 of Example-79 (1.0 g, 2.8 mmol) was dissolved in a mixture of tetrahydrofuran / ethanol / water (10 mL: 5 mL: 3 mL), and lithium hydroxide monohydrate (155 mg, 2.67 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was distilled off and acidified with 2N HCl, and the precipitated product was filtered out. Therefore, the obtained solid was dried under vacuum to obtain the title compound (850 mg, crude product), which was used in the next step. LCMS: 325.2 (M-1) + .

[1320] Step-3: 6-Cyano-N-(4-cyanobenzyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

[1321] The product of step-2 of Example 395 (350 mg, 1.01 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (194 mg, 1.01 mmol), hydroxybenzotriazole (109 mg, 1.01 mmol) and 4-(aminomethyl)benzonitrile (136 mg, 0.81 mmol) and N,N-diisopropylethylamine (0.352 ml, 2.02 mmol) were added at 0 ° C. under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-cold water, and the precipitated product was filtered off and dried under vacuum. The crude solid obtained was purified by combiflash on silica gel and eluted with 0.5% methanol in dichloromethane to give the title compound (235 mg). LCMS: 441.3 (M+1) + .

[1322] Step-4: Ethyl 2-((4-(ethoxy(imino)methyl)benzyl)carbamoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-6-carboximidate.

[1323] The product of step-3 of Example 79 (170 mg, 0.39 mmol) was dissolved in 10 mL of ethanol-HCl and 5 mL of dioxane. HCl was kept in a glass sealed tube at 0 ° C and stirred at room temperature for 12 h. The reaction was not completed. 10 mL of a 4 M solution of HCl in dioxane was added again and stirred at room temperature for 2 days. After the reaction was completed, the solvent was evaporated under vacuum to obtain the title compound (not separated), and the crude product was used in the next step as is. LCMS: 533.7 (M+1) + .

[1324] Step-5: Carbamimidoyl-N-(4-carbamimidoylbenzyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide (TFA salt)

[1325] The product of step-4 of Example 79 was dissolved in 50 mL of methanol-ammonia maintained in a sealed tube and stirred at room temperature for 12 h. After completion of the reaction, the solvent was evaporated under vacuum to give a crude product, which was purified using a preparative HPLC instrument with a Kinetex EVO C18 reverse phase column (21.2 x 150 mm, 5 microns). The mobile phase was 30% acetonitrile to 60% acetonitrile (0.1% TFA) in water (0.1% TFA) to provide the title compound (100 mg) as a TFA salt.

[1326] LCMS:475.2[M+1] + ; 1 H NMR (400 MHz, CD3OD): δ 4.52 (s, 2H), 6.20 (dd, 1H), 6.45 (s, 2H), 7.19 (dd, 1H), 7.27–7.34 (m, 2H), 7.37 (d, 1H), 7.50–7.65 (m, 5H), 7.77 (d, 1H), 7.90–8.02 (m, 3H), 8.16–8.22 (m, 1H). HPLC: 99.45% (retention time = 4.88 min).

[1327] Example 80: Synthesis of Compound I-396:

[1328] N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(naphthalen-1-ylsulfonyl)-1H-indole-2-carboxamide

[1329]

[1330] Step-1: 6-Cyano-1H-indole-2-carboxylic acid

[1331] According to the procedure described in step-2 of Example 79, ethyl 6-cyano-1H-indole-2-carboxylate (700 mg, 3.28 mmol) was treated with lithium hydroxide monohydrate (207 mg, 4.92 mmol) to obtain 600 mg of the title compound. LCMS: 184.9 (M-1) + .

[1332] Step-2: tert-Butyl ((1r,4r)-4-(6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1333] According to the procedure described in step-3 of Example 79, the product of step-1 of Example 80 (600 mg, 3.22 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (700 mg, 3.22 mmol) were treated together to obtain 1.1 g of the title compound. LCMS: 283.0 (M-100) + .

[1334] Step-3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(naphthalen-1-ylsulfonyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1335] To a solution of the product of step 2 of Example 80 (500 mg, 1.305 mmol) in THF (15 ml) was added potassium tert-butoxide (250 mg, 2.21 mmol) and 18-crown-6 (35 mg, 0.130 mmol) at 0°C, followed by a THF solution (5 mL) of naphthalene-1-sulfonyl chloride (442 mg, 1.958 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, ice water was added and extracted with ethyl acetate (2X50 mL). The organic layer was separated and concentrated under vacuum. The crude residue obtained was purified by combiflash on silica gel eluting with 0.5% methanol in dichloromethane to give the title compound (200 mg). LCMS: 517.4 (M-56) + .

[1336] Step-4: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(naphthalen-1-ylsulfonyl)-1H-indole-6-carboximidate

[1337] According to the procedure described in step-4 of example 79, the product of step-3 of example 80 (220 mg, 0.384 mmol) was treated with 10 mL of ethanol-HCl and 4 M solution of HCl in dioxane at room temperature for 3 days to obtain 250 mg of the title compound. LCMS: 518.8 (M)+ The crude product was used as is in the next step

[1338] Step-5: N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(naphthalen-1-ylsulfonyl)-1H-indole-2-carboxamide (TFA salt)

[1339] As described in Step-5 of Example 1, the product of Step-4 of Example 80 (250 mg (crude), 0.482 mmol) was treated with 10 mL of ethanol-NH at room temperature to give a crude product, which was purified by preparative HPLC with a LUNA C18 reverse phase column (21.2 x 150 mm, 5 microns). The mobile phase was 30% acetonitrile to 60% acetonitrile (0.02% TFA) in water (0.02% TFA), providing the title compound (50 mg) as a TFA salt.

[1340] LCMS: 490.3 (M+1) + ; 1 HNMR (300 MHz, CD3OD): δ1.52–1.38 (m, 4H), 2.08–2.05 (m, 4H), 3.08–3.06 (m, 1H), 3.78–3.62 (m, 1H), 7.11 (s, 1H), 7.70–7.54 (m, 4H), 7.90–7.87 (m, 1H), 8.04–8.00 (m, 2H), 8.24–8.21 (d, 1H), 8.49–8.40 (m, 2H); HPLC: 99.5% (retention time = 4.55 min).

[1341] The following compounds listed in Table-19 were prepared according to Scheme-14 by following a similar procedure as described above for Example 80 using appropriate reagents with suitable modifications known to those skilled in the art.

[1342] Table-19: Compounds synthesized using general scheme-14

[1343]

[1344] General Synthesis Scheme-15

[1345]

[1346] Example 81: Synthesis of Compound I-398:

[1347] 6-(N'-Hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

[1348]

[1349] Step-1: Ethyl 6-cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxylate.

[1350] To a solution of ethyl 6-cyano-1H-indole-2-carboxylate (380 mg, 1.77 mmol) in DMF (10 ml) was added potassium carbonate (612 mg, 4.43 mmol) and 2-(bromomethyl)naphthalene (392 mg, 1.77 mmol) at room temperature, and the mixture was stirred at room temperature overnight (12 h). After the reaction was complete, water was added and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give a crude product (720 mg), which was further purified by combiflash on silica gel (40 g column) eluted with 30% ethyl acetate in hexane to give the title compound (560 mg). LCMS: 355.2 (M+1) + .

[1351] Step-2: 6-Cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxylic acid

[1352] The product (560 mg, 1.58 mmol) of step-1 of Example 81 was dissolved in a mixture of tetrahydrofuran / ethanol (7 mL: 2 mL), and an aqueous solution of lithium hydroxide monohydrate (66 mg, 1.58 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was distilled off and acidified to pH 4 with dilute HCl, and the precipitated product was filtered out. Therefore, the solid obtained was dried under vacuum to obtain the title compound (460 mg, crude product), which was continued for the next step.

[1353] Step-3: tert-Butyl-4-((6-cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1354] To a stirred solution of the product of step-2 of Example 81 (330 mg, 1.01 mmol) in DMF at 0°C were added HATU (403 mg, 1.06 mmol) and N,N-diisopropylethylamine (253 mg, 2.02 mmol). After stirring at room temperature for 10 min, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (216 mg, 1.01 mmol) was added and stirred at room temperature for 3 h. After the reaction was complete, water was added and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give a crude product (470 mg), which was further purified by combiflash on silica gel (24 g column) eluting with 5% methanol in dichloromethane to give the title compound (370 mg). LCMS: 523.6 9 (M+1) + .

[1355] Step-4: tert-Butyl-4-((6-(N'-hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1356] The product of step 3 of Example 81 (90 mg, 0.172 mmol) was dissolved in 5 mL of ethanol, and a 50% aqueous solution of hydroxylamine (1.3 mL) was added, and the resulting mixture was refluxed at 90° C. for 2 h. The solvent was evaporated under vacuum to obtain a crude product, water was added, and the precipitated solid was filtered and dried under vacuum to obtain the title compound (60 mg). LCMS: 556.6 (M+1) + .

[1357] Step-5: 6-(N'-Hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide (TFA salt)

[1358] To a stirred solution of the product of step-4 of Example 81 (60 mg, 0.108 mmol) in dichloromethane was added TFA (0.2 mL) at room temperature and stirred for 3 h. The reaction mixture was evaporated under reduced pressure at room temperature to give a crude product, which was purified by preparative HPLC with a Kinetex C18 reverse phase column (19x150 mm, 5 microns). The mobile phase was 10% acetonitrile to 40% acetonitrile (0.3% TFA) in water (0.3% TFA), providing the title compound (90 mg) as a TFA salt. LCMS: 456.2 (M+1) + ; 1HNMR (400 MHz, CD3OD): δ1.28–1.09 (m, 2H), 1.54–1.48 (d, 2H), 1.59–1.55 (m, 1H), 2.51–2.44 (m, 2H), 3.01–2.98 (d, 2H), 3.16–3.14 (d, 2H), 6.03 (s, 2H), 7.14–7.12 (d, 1H), 7.20 (s, 1H), 7.33 (s, 1H), 7.43–7.42 (m, 3H), 7.69–7.66 (m, 1H), 7.82–7.75 (m, 2H), 7.93–7.91 (dd, 1H), 8.03 (s, 1H); HPLC: 99.8% (retention time = 5.11 min)

[1359] The following compounds listed in Table-20 were prepared according to general scheme-15 by following a similar procedure as described above for Example 81 using appropriate reagents with suitable modifications known to one skilled in the art.

[1360] Table-20: Compounds synthesized using General Scheme-15

[1361]

[1362]

[1363] Example 82: Synthesis of Compound I-402:

[1364] tert-Butyl ((1r,4r)-4-(6-carbamimidoyl-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1365]

[1366] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1367] According to the procedure described in step-3 of Example 81, the product of step-2 of Example 81 (310 mg, 0.950 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (220 mg, 1.1 mmol) were treated together at room temperature for 1 h to obtain 370 mg of the title compound. LCMS: 567.15 (M-56) + .

[1368] Step-2: tert-Butyl ((1r,4r)-4-(6-(-N'-hydroxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1369] The product of step-1 of Example 82 (370 mg, 0.708 mmol) was treated with 50% aqueous hydroxylamine solution (10 mL) according to the procedure described in step-4 of Example 81 to obtain 300 mg of the title compound. LCMS: 555.85 (M+1) + .

[1370] Step-3: tert-Butyl ((1r,4r)-4-(6-(-N'-acetoxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1371] To a stirred solution of the product of step-2 of Example 82 (300 mg, 0.540 mmol) in acetic acid (12 mL) was added acetic anhydride (0.6 mL) at room temperature, and the resulting reaction mixture was stirred for 4 h. The reaction mixture was evaporated under reduced pressure at room temperature. The crude product obtained was basified with aqueous sodium bicarbonate solution. The precipitated solid was filtered and dried under vacuum to give the title compound (270 mg, crude product). LCMS: 597.91 (M+1) + .

[1372] Step-4: tert-Butyl ((1r,4r)-4-(6-carbamimidoyl-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1373] To a solution of the product (220 mg, 0.360 mmol) of step-3 of Example 82 in a mixture of methanol:THF (1: 1) (20 mL) was added 10% palladium on carbon (25 mg), and the resulting mixture was stirred at room temperature for 5 h under a hydrogen atmosphere (a balloon filled with hydrogen). After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by a preparative HPLC instrument using a LUNA C18 reverse phase column (21.2 × 150 mm, 5 microns). The mobile phase was 15% acetonitrile in water:methanol (1: 1) to 80% acetonitrile in water:methanol (1: 1), providing the title compound (140 mg) as a TFA salt. LCMS: 540.25 (M+1) + ; 1HNMR (400 MHz, DMSO–d6): δ 1.20–125 (m, 4H), 1.32 (s, 9H), 1.75–178 (m, 4H), 3.14–3.20 (m, 1H), 3.62–3.70 (m, 1H), 6.00 (s, 2H), 6.75 (d, 1H), 7.20 (s, 1H), 7.29 (d, 1H), 7.45–7.47 (m, 2H), 7.52–7.57 (m, 2H), 7.74–7.77 (m, 1H), 7.80–7.85 (m, 3H), 8.22 (s, 1H), 8.55 (d, 1H). HPLC: 99.13% (retention time = 6.83 min)

[1374] The following compounds listed in Table-21 were prepared according to general scheme-15 by following a similar procedure as described above for Example 82 using appropriate reagents with suitable modifications known to one skilled in the art.

[1375] Table-21: Compounds synthesized using general scheme-15

[1376]

[1377]

[1378] Example 83: Synthesis of Compound I-406:

[1379] 6-Carbamimidoyl-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

[1380]

[1381] Step-1: tert-Butyl-4-((6-(N'-acetoxycarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1382] According to the procedure described in step-3 of example 82, the product of step-4 of example 81 (240 mg, 0.432 mmol) and acetic anhydride (0.5 mL) were treated together to obtain 200 mg of the title compound. LCMS: 598.4 (M+1) + .

[1383] Step-2: tert-Butyl 4-((6-carbamimidoyl-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1384] According to the procedure described in step-4 of Example 82, the product of step-1 of Example 83 (200 mg, 0.335 mmol) was treated with 10% palladium on carbon (40 mg) under a hydrogen atmosphere for 6 h to obtain 200 mg of the title compound. LCMS: 540.9 (M+1) + .

[1385] Step-3: 6-Carbamimidoyl-1-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

[1386] The product of step-2 of Example 83 (200 mg, 0.335 mmol) was dissolved in ethanol (5 mL), and ethanolic HCl (5 mL) was added at 0° C., and then stirred at room temperature for 5 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a crude product (218 mg), which was further triturated with pentane and dried under vacuum to give the title compound (130 mg) as an HCl salt. LCMS: 440.4 (M+1) + , 1 HNMR (400 MHz, CD3OD): δ1.17 (m, 2H), 1.52–1.48 (m, 3H), 2.49–2.48 (t, 2H), 3.01–2.98 (d, 2H), 3.17–3.15 (d, 2H), 6.05 (s, 2H), 7.15–7.12 (d, 1H), 7.21 (s, 1H), 7.34 (s, 1H), 7.46–7.43 (m, 2H), 7.58–7.55 (m, 1H), 7.70–7.68 (m, 1H), 7.81–7.76 (m, 2H), 7.94–7.92 (d, 1H), 8.17 (s, 1H); HPLC: 95.22% (retention time = 5.08 min).

[1387] The following compounds listed in Table-22 were prepared according to general scheme-15 by following similar procedures as described above for Example 406 using appropriate reagents with suitable modifications known to one skilled in the art.

[1388] Table-22: Compounds synthesized using general scheme-15

[1389]

[1390]

[1391] General Synthesis Scheme-15A

[1392]

[1393] Example 84: Synthesis of Compound I-411:

[1394] tert-Butyl ((1r,4r)-4-(6-(N-ethylcarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1395]

[1396] To a suspension of embodiment-82 (70 mg, 0.130 mmol) in ethanol (7 mL) was added 10% ethanolamine in THF solution (5 mL), and the resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, excess solvent was removed under reduced pressure. The crude product obtained was purified using a preparative HPLC instrument using a LUNA C18 reversed-phase column (21.2 × 150 mm, 5 microns). Mobile phase was 30% acetonitrile in water (0.02% TFA) to 60% acetonitrile in water (0.02% TFA), providing title compound (15 mg) as a TFA salt.

[1397] LCMS: 568.9 (M+1) + ; 1 HNMR (300 MHz, CD3OD): δ 1.22–1.28 (m, 4H), 1.34 (t, 3H), 1.42 (s, 9H), 1.78–1.86 (m, 4H), 3.23–3.26 (m, 1H), 3.48 (q, 2H), 3.68–3.73 (m, 1H), 6.00 (s, 2H), 7.14 (d, 1H), 7.19–7.23 (m, 1H), 7.39–7.45 (m, 4H), 7.65–7.68 (m, 1H), 7.73–7.80 (m, 2H), 7.87 (d, 1H), 8.00 (s, 1H); HPLC: 98.33% (retention time = 6.11 min)

[1398] The following compounds listed in Table-23 were prepared according to general scheme-15A by following similar procedures as described above for Example 84 using appropriate reagents with suitable modifications known to one skilled in the art.

[1399] Table-23: Compounds synthesized using General Scheme-15A

[1400]

[1401] Example 85: Synthesis of Compound I-413:

[1402] N-((1r,4r)-4-aminocyclohexyl)-6-(N-ethylcarbamimidoyl)-1-(naphthalen-2-ylmethyl)-1H-indole-2-carboxamide

[1403]

[1404] Example 84 (10 mg, 0.02 mmol) was treated with TFA (0.1 mL) according to the procedure described in step-5 of Example 81 to obtain 5 mg of the title compound as TFA salt. LCMS: 468.04 (M+1) + ; 1 HNMR (400 MHz, CD3OD): δ1.27–1.35 (m, 5H), 1.43–1.46 (m, 2H), 1.86–1.89 (m, 2H), 1.98–2.01 (m, 2H), 2.97–3.10 (m, 1H) 3.45–3.47 (m, 2H), 3.71–3.75 (m, 1H), 6.00 (s, 2H), 7.16–7.21 (m, 2H), 7.41–7.45 (m, 4H), 7.63–7.67 (m, 1H), 7.73–7.76 (m, 2H), 7.87 (d, 1H), 8.01 (s, 1H); HPLC: 96.36% (retention time = 4.56 min).

[1405] The following compounds listed in Table-24 were prepared according to general scheme-15A by following similar procedures as described above for Example 85 using appropriate reagents with suitable modifications known to one skilled in the art.

[1406] Table-24: Compounds synthesized using Scheme-15A

[1407]

[1408]

[1409] General Synthesis Scheme-15B

[1410]

[1411] Example 86: Synthesis of Compound I-415:

[1412] N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamide

[1413]

[1414] Step-1: Ethyl 6-cyano-1-(naphthalen-1-yl)-1H-indole-2-carboxylate

[1415] To a stirred solution of ethyl 6-cyano-1H-indole-2-carboxylate (2.0 g, 9.34 mmol) in dichloromethane (50 mL) was added naphthalene-1-ylboronic acid (3.1 g, 18.69 mmol), copper (II) acetate (3.25 g, 18.69 mmol) and N,N-diisopropylethylamine (3.6 g, 28.038 mmol) at room temperature. The resulting reaction mixture was stirred for 16 h at room temperature under an oxygen atmosphere (oxygen balloon). After the reaction was complete, water was added, the layers were separated, and the organic layer was concentrated under reduced pressure. The crude product obtained above was purified by combiflash on silica gel eluting with 10% ethyl acetate in hexane to give the title product (200 mg). LCMS: 340.9 (M) +

[1416] Step-2: 6-Cyano-1-(naphthalen-1-yl)-1H-indole-2-carboxylic acid

[1417] According to the procedure described in step-2 of Example 81, the product of step-1 of Example 86 (200 mg, 0.588 mmol) was treated with lithium hydroxide monohydrate (38 mg, 0.882 mmol) in THF:ethanol:water (3:3:1) to obtain 150 mg of the title compound. Here, the reaction mixture was stirred at room temperature for 12 hours. LCMS: 311.2 (M-1) +

[1418] Step-3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1419] According to the procedure described in step-3 of Example 81, the product of step-2 of Example 86 (50 mg, 0.160 mmol) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (42 mg, 0.192 mmol) were treated together to obtain 66 mg of the title compound. LCMS: 453.4 (M-56) +

[1420] Step-4: tert-Butyl ((1r,4r)-4-(6-(N'-hydroxycarbamimidoyl)-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1421] To a stirred solution of the product of step-3 of Example 86 (100 mg, 0.196 mmol) and N,N-diisopropylethylamine (152 mg, 1.176 mmol) in ethanol was added hydroxylamine hydrochloride at room temperature. The resulting reaction mixture was stirred at 80°C for 5 h. After the reaction was complete, the excess solvent was distilled off, water was added, and the precipitated solid was filtered and dried under vacuum to obtain the title compound as a crude product (100 mg). LCMS: 542.2 [M+1] + .

[1422] The formation of an amide derivative of the title compound was also confirmed as a minor product, which was inseparable by TLC in this step. LCMS: 527.3 [M+1] + .

[1423]

[1424] (tert-Butyl ((1r,4r)-4-(6-carbamoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate)

[1425] The crude mixture of compounds was carried forward to the next step without purification.

[1426] Step-5: tert-Butyl ((1r,4r)-4-(6-(N'-acetoxycarbamimidoyl)-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1427] To a stirred solution of the product of step-4 of Example 86 (100 mg, 0.184 mmol) in acetic acid (1 mL) was added acetic anhydride (0.2 mL) at room temperature, and the resulting reaction mixture was stirred for 2 h. The reaction mixture was evaporated under reduced pressure at room temperature, and ice-cold water was added. The precipitated solid was filtered off and dried under vacuum. The crude solid obtained was further purified by combiflash on silica gel eluting with 0.5% methanol in dichloromethane.

[1428] The isolated non-polar compound was confirmed to be the title compound (50 mg). LCMS: 584.2 (M+1) + .

[1429] The isolated polar compound was confirmed to be an amide derivative, which was formed in Step-4 of Example 86 below (30 mg). LCMS: 527.2 (M+1) + .

[1430]

[1431] tert-Butyl ((1r,4r)-4-(6-carbamoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate) (polar)

[1432] Step-6: tert-Butyl ((1r,4r)-4-(6-carbamimidoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[1433] According to the procedure described in step 4 of Example 82, the non-polar product (50 mg) from step 5 of Example 86 was treated with 10% palladium on carbon (15 mg) under a hydrogen atmosphere to obtain 40 mg of the title compound. The reaction mixture was stirred at room temperature for 2 hours. LCMS: 526.4 (M+1) + .

[1434] The following compounds listed in Table-25 were prepared according to general scheme-15B by following similar procedures as described above for the product of step-6 of Example 86 using appropriate reagents with suitable modifications known to those skilled in the art.

[1435] Table-25: Compounds synthesized using General Scheme-15B

[1436]

[1437] Step-7: N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(naphthalen-1-yl)-1H-indole-2-carboxamide

[1438] The product of step-6 of Example 86 (40 mg, 0.069 mmol) was treated with TFA (0.1 mL) according to the procedure described in step-5 of Example 81 to obtain 30 mg of the title compound as a TFA salt. LCMS: 426.3 (M+1) + ; 1 HNMR (300 MHz, CD3OD): δ 1.41–1.30 (m, 4H), 1.99–1.75 (m, 4H), 3.02–3.00 (m, 1H), 3.53–3.47 (m, 1H), 7.05–7.02 (d, 1H), 7.41–7.36 (m, 3H), 7.72–7.51 (m, 4H), 8.11–7.99 (m, 3H); HPLC: 95.53% (retention time = 4.60 min)

[1439] The following compounds listed in Table-25A were prepared according to general scheme-15B by following similar procedures as described above for the product of step-7 of Example 86 using appropriate reagents with suitable modifications known to those skilled in the art.

[1440] Table-25A: Compounds synthesized using General Scheme-15B

[1441]

[1442] Example 87: Synthesis of Compound I-417:

[1443] N2-((1r,4r)-4-aminocyclohexyl)-1-(naphthalen-1-yl)-1H-indole-2,6-dicarboxamide

[1444]

[1445] The polar product (30 mg, 0.057 mmol) isolated in step-5 of Example 86 was treated with TFA (0.1 mL) according to the procedure described in step-5 of Example 81 to obtain 15 mg of the title compound as a TFA salt. LCMS: 427.2 (M+1) + ; 1 HNMR (300 MHz, CD3OD): δ 1.38–1.28 (m, 4H), 1.97–1.78 (m, 4H), 3.07–2.99 (m, 1H), 3.53–3.51 (m, 1H), 7.05–7.03 (d, 1H), 7.39–7.32 (m, 2H), 7.71–7.46 (m, 5H), 7.85–7.82 (d, 1H), 8.08–8.00 (m, 2H); HPLC: 99.63% (retention time = 5.04 min)

[1446] General Synthesis Scheme – 15C

[1447]

[1448] Example 88: Synthesis of Compound I-418:

[1449] 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-N-(piperidin-4-yl)-1H-indole-2-carboxamide

[1450]

[1451] Step-1: 6-(N'-Hydroxycarbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1452] The product of step-2 of Example 81 (2.7 g, 8.273 mmol) was dissolved in 50 mL of ethanol, and 50% aqueous hydroxylamine solution (20 mL) was added, and the resulting mixture was refluxed at 80 ° C for 2 h. The solvent was evaporated under vacuum to obtain a crude product, water was added and the precipitated solid was filtered out. The obtained solid was triturated with cold water, then triturated with n-pentane, and dried under vacuum to obtain the title compound (2.45 g). LCMS: 360.2 (M+1) + .

[1453] Step-2: 6-(N'-acetoxycarbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1454] To a stirred solution of the product of step-1 of Example 88 (2.40 g, 6.678 mmol) in acetic acid (20 mL) was added acetic anhydride (4.09 g, 40.07 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated under reduced pressure at room temperature. The obtained residue was triturated with diethyl ether and dried under vacuum to give the title compound (2.65 g, crude). LCMS: 402.2 (M+1) + .

[1455] Step-3: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1456] To a stirred suspension of the product of step-2 of Example 88 (2.65 g, 6.601 mmol) in methanol was added acetic acid (3.0 mL), 10% palladium on carbon (wet) (300 mg) at room temperature and stirred for 3 h under a hydrogen atmosphere (a balloon filled with hydrogen). After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the filtrate was concentrated under reduced pressure. The crude product obtained was triturated with 50 ml of a mixture of diethyl ether: pentane (1:4), and the solid obtained was dried under vacuum to give the title compound (2.40 g). LCMS: 343.7 (M-1). + .

[1457] Step-4: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1458] To a stirred suspension of the product of step-3 of Example 88 (2.40 g, 6.98 mmol) in methanol were added di-tert-butyl dicarbonate (2.28 g, 10.48 mmol) and N,N-diisopropylethylamine (2.44 mL, 13.97 mmol) at 0°C, and the resulting reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue obtained above was redissolved in water and extracted with an equal volume of ethyl acetate, and the aqueous layer was acidified with citric acid solution, and the precipitated solid was filtered out and dried to obtain the title compound (2.40 g). LCMS: 444.4 (M+1) + .

[1459] Step-5: tert-Butyl 4-(6-(N-(tert-butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamido)piperidine-1-carboxylate.

[1460] To a stirred solution of the product of step 4 of Example 88 (200 mg, 0.441 mmol) in DMF at 0°C were added HATU (251 mg, 0.662 mmol) and N,N-diisopropylethylamine (142 mg, 2.02 mmol). After stirring at room temperature for 10 min, tert-butyl 4-aminopiperidine-1-carboxylate (105 mg, 0.529 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, ice-cold water was added, and the precipitated solid was filtered and dried to give the title compound (340 mg). LCMS: 626.4 (M+1). + .

[1461] The following compounds listed in Table-26 were prepared according to general scheme-15C by following a similar procedure as described above for the product of step-5 of Example 88 using appropriate reagents with suitable modifications known to those skilled in the art.

[1462] Table-26: Compounds synthesized using General Scheme-15C

[1463]

[1464]

[1465]

[1466] Step-6: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-N-(piperidin-4-yl)-1H-indole-2-carboxamide

[1467] To a stirred solution of the product of step-5 of Example 88 (340 mg, 0.523 mmol) in dichloromethane was added TFA (0.2 mL) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure to give a crude compound (490 mg). The crude product obtained was purified using a preparative HPLC instrument using an X-Bridge C18 reverse phase column (19×150 mm, 5 microns). The mobile phase was 10% acetonitrile in water (0.02% TFA) to 50% acetonitrile in water (0.02% TFA), providing the title compound (100 mg) as a TFA salt.

[1468] LCMS: 426.2 (M+1) + ; 1 HNMR (400 MHz, CD3OD): δ1.99–1.69 (m, 4H), 3.36–3.00 (m, 4H), 3.95 (m, 1H), 6.26–6.25 (d, 1H), 6.43 (s, 2H), 7.20–7.17 (t, 1H), 7.32 (s, 1H), 7.62–7.55 (m, 3H), 7.75–7.73 (d, 1H), 7.58–7.50 (m, 3H), 8.20–8.18 (d, 1H); HPLC: 99.36% (retention time = 4.84 min)

[1469] The following compounds listed in Table-27 were prepared according to general scheme-15C by following similar procedures as described above for Example 88 using appropriate reagents with suitable modifications known to one skilled in the art.

[1470] Table-27: Compounds synthesized using General Scheme-15C

[1471]

[1472]

[1473]

[1474]

[1475]

[1476] Example 89: Synthesis of Compound I-455:

[1477] 1-(Naphthalen-1-ylmethyl)-N2-(piperidin-4-yl)-1H-indole-2,6-dicarboxamide

[1478]

[1479] The above-mentioned title compound (50 mg) was isolated as a TFA salt in the preparative HPLC purification in step 6 of Example 88. LCMS: 428.0 (M+1) + ; 1 HNMR (400 MHz, CD3OD): δ 2.00–1.69 (m, 4H), 3.36–2.96 (m, 4H), 3.93 (m, 1H), 6.242–6.224 (d, 1H), 6.38 (s, 2H), 7.18–7.14 (t, 1H), 7.25 (s, 1H), 7.61–7.51 (m, 2H), 7.71–7.67 (m, 2H), 7.79–7.71 (m, 1H), 7.89–7.87 (m, 1H), 8.00 (s, 1H), 8.19–8.17 (d, 1H); HPLC: 98.45% (retention time = 5.25 min)

[1480] The following compounds listed in Table-27A were isolated in the final preparative HPLC purification following similar procedures as described above for Example 89 using appropriate reagents with appropriate modifications known to those skilled in the art.

[1481] Table-27A:

[1482]

[1483] General Synthesis Scheme-15D

[1484]

[1485] Example 90: Synthesis of Compound I-458:

[1486] 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1487]

[1488] Step-1: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1489] Under an inert atmosphere at 0 ° C, a 0 ° C cooled solution of the product of step-1 of Example 79 (250 mg, 0.766 mmol) in THF (3 mL) was added to a pre-dissolved solution of LiHMDS (solid) (896 mg, 5.367 mmol) in THF (1 mL) at 0 ° C. The resulting solution was stirred at room temperature overnight (16 h). After the reaction was completed, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. The precipitated product was filtered off and dried to obtain the title compound (180 mg). LCMS: 344.0 (M+1) + .

[1490] Step-2: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1491] To a stirred solution of the product of step-1 of Example 90 (980 mg, 2.85 mmol) in THF (20 mL) was added a 2M aqueous solution of sodium hydroxide (250 mg, 4.28 mmol) at room temperature, followed by di-tert-butyl dicarbonate (932.5 mg, 4.28 mmol), and the resulting reaction mixture was refluxed at 50 ° C for 3 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The obtained residue was diluted with water and adjusted to pH = 6-7 using citric acid solution. The precipitated solid was filtered off and dried to give the title compound (1.1 g). LCMS: 443.0 (M+1) + .

[1492] Step-2a: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid

[1493] At 0 ° C, to a stirred solution of the product of step-2 of Example 90 (85 mg, 0.191 mmol) in dichloromethane (8 mL) was added a pre-dissolved solution of TFA (0.4 mL) in 2 mL of dichloromethane, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure, and the obtained crude product was purified by a preparative HPLC instrument using an X-Bridge C18 reverse phase column (19x150 mm, 5 microns). The mobile phase was 10% acetonitrile in water (0.1% TFA) to 50% acetonitrile in water (0.02% TFA), providing the title compound (46 mg) as a TFA salt. LCMS: 342.0 (M-1) + ; 1HNMR (600 MHz, CD3OD): δ 6.16–6.15 (d, 1H), 6.50 (s, 2H), 7.18 (t, 1H), 7.57–7.53 (m, 3H), 7.64 (t, 1H), 7.74–7.72 (d, 1H), 7.92–7.89 (m, 2H), 7.99–7.97 (d, 1H), 8.24–8.23 (d, 1H); HPLC: 97.95% (retention time = 5.38 min)

[1494] The following compounds listed in Table-28 were prepared according to general scheme-15D by following similar procedures as described above for Example 90 using appropriate reagents with suitable modifications known to one skilled in the art.

[1495] Table-28: Compounds synthesized using Scheme-15D

[1496]

[1497] Example 91: Synthesis of Compound I-460:

[1498] 6-Carbamimidoyl-N-((1-methylpiperidin-4-yl)methyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

[1499]

[1500] Step-1: tert-Butyl (imino(2-(((1-methylpiperidin-4-yl)methyl)carbamoyl)-1-(naphthalen-1-ylmethyl)-1H-indol-6-yl)methyl)carbamate

[1501] According to the procedure described in step-3 of Example 79, the product of step-2 of Example 90 (100 mg, 0.230 mmol) and (1-methylpiperidin-4-yl)methanamine (38 mg, 0.290 mmol) were treated together to obtain the title compound (110 mg) as a crude product. LCMS: 554.85 (M+1) + .

[1502] Step-2: 6-Carbamimidoyl-N-((1-methylpiperidin-4-yl)methyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamide

[1503] To a stirred solution of the product of step-1 of Example 91 (110 mg, 0.200 mmol) in dichloromethane was added TFA (0.456 mL, 5.96 mmol) at 0 ° C under a nitrogen atmosphere and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The crude product obtained was ground with diethyl ether and dried. The crude product obtained was purified by a preparative HPLC instrument using a Kinetex EVO C18 reverse phase column (21.2×150 mm, 5 microns). The mobile phase was 30% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA), providing the title compound (50 mg) as a TFA salt.

[1504] LCMS: 453.9 (M+1) + ; 1 HNMR (400 MHz, CD3OD): δ 1.24-1.30 (m, 2H), 1.67 (d, 2H), 2.64 (m, 5H), 2.89–2.99 (m, 1H), 3.15 (dd, 2H), 3.29–3.30 (m, 2H), 6.18 (dt, 1H), 6.44 (s, 2H), 7.19 (dd, 1H), 7.28 (d, 1H), 7.56–7.59 (m, 2H), 7.60–7.66 (m, 1H), 7.75 (d, 1H), 7.76–7.96 (m, 2H), 7.99–8.06 (s, 1H), 8.18–8.26 (m, 1H); HPLC: 99.69% (retention time = 5.11 min)

[1505] The following compounds listed in Table-29 were prepared according to general scheme-15D by following similar procedures as described above for Example 91 using appropriate reagents with suitable modifications known to one skilled in the art.

[1506] Table-29: Compounds synthesized using Scheme-15D

[1507]

[1508]

[1509]

[1510]

[1511]

[1512]

[1513] General Synthesis Scheme-15D–1

[1514]

[1515] Example 92: Synthesis of Compound I-485:

[1516] 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (1r,4r)-4-aminocyclohexyl ester

[1517]

[1518] Step-1: (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylate

[1519] To a solution of the product of step 2 of Example 90 (70 mg, 0.150 mmol) in dichloromethane was added 4-dimethylaminopyridine (4 mg, 0.030 mmol) at room temperature, followed by N,N'-dicyclohexylcarbodiimide (40 mg, 0.180 mmol) and tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (40 mg, 0.180 mmol), and the resulting reaction mixture was stirred for 2 h. The reaction mixture was diluted with dichloromethane, washed with water, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (200 mg). LCMS: 641.2 (M+1) + .

[1520] Step-2: (1r,4r)-4-aminocyclohexyl 6-carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylate

[1521] The product of step-1 of Example 92 (200 mg, 0.300 mmol) was treated with TFA (0.5 mL) according to the procedure described in step-5 of Example 81 to obtain a crude product.

[1522] The crude product obtained is purified by the preparative HPLC instrument using an X-Bridge C18 reverse phase column (19 × 150 mm, 5 microns). Mobile phase is 10% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA), providing title compound (50 mg) as a TFA salt.

[1523] LCMS: 440.85 (M+1) + ; 1HNMR (400 MHz, CD3OD): δ 1.37–1.46 (m, 4H), 1.99–2.03 (m, 4H), 3.54–3.58 (m, 1H), 4.78–4.82 (m, 1H), 6.16 (d, 1H), 6.41 (s, 2H), 7.20 (t, 1H), 7.59–7.61 (m, 3H), 7.68 (t, 1H), 7.78 (d, 1H), 7.95–8.02 (m, 3H), 8.27 (d, 1H); HPLC: 98.35% (retention time = 5.24 min)

[1524] General synthetic scheme–15D–2

[1525]

[1526] Example 93: Synthesis of Compound I-486:

[1527] 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid methyl ester

[1528]

[1529] Step-1: 6-Carbamimidoyl-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid methyl ester

[1530] At 0 ° C, thionyl chloride (0.160 mL, 2.2 mmol) was added dropwise to a stirred solution of the product (200 mg, 0.400 mmol) of step 2 of Example 90 in methanol (5 mL). The resulting reaction mixture was stirred at 65 ° C for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The obtained residue was alkalized to pH 9-10 with an aqueous sodium carbonate solution and extracted three times with a mixture of methanol: dichloromethane (10: 90). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude solid was ground with diethyl ether and dried. The obtained crude product was purified by a preparative HPLC instrument using an X-Bridge C18 reverse phase column (19 × 150 mm, 5 microns). The mobile phase was 10% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA), providing the title compound (65 mg) as a TFA salt.

[1531] LCMS: 358.0 (M+1) + ; 1HNMR (400 MHz, CD3OD): δ 3.82 (s, 3H), 6.17–6.15 (d, 1H), 6.51 (s, 2H), 7.22–7.19 (m, 1H), 7.78–7.57 (m, 5H), 8.02–7.94 (m, 3H), 8.28–8.26 (d, 1H); HPLC: 95.95% (retention time = 5.21 min)

[1532] Example 94: Synthesis of Compound I-487

[1533] 2-(Hydroxymethyl)-1-(naphthalen-1-ylmethyl)-1H-indole-6-carboxamidine

[1534]

[1535] Step-1: 2-(Hydroxymethyl)-1-(naphthalen-1-ylmethyl)-1H-indole-6-carboximidamide

[1536] To a stirred solution of lithium aluminum hydride (104 mg, 2.6 mmol) in THF (7.5 mL) at 0°C under an inert atmosphere was added a pre-dissolved solution of the product of step-1 of Example 93 (250 mg, 0.600 mmol) in THF. The resulting reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was quenched with ethyl acetate (2 mL), water (3 mL) and 15% aqueous NaOH solution (1 mL) at 0°C and stirred for 10 min. The resulting suspension was filtered through a bed of celite, washed with ethyl acetate, and the filtrate was concentrated to dryness under reduced pressure. The crude product obtained was purified by a preparative HPLC instrument using an X-Bridge C18 reverse phase column (19×150 mm, 5 microns). The mobile phase was 20% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA), providing the title compound (50 mg) as a TFA salt.

[1537] LCMS: 330.15 (M+1) + ; 1 HNMR (400 MHz, CD3OD): δ 4.72 (s, 2H), 6.16 (s, 2H), 6.28–6.24 (d, 1H), 6.81 (s, 1H), 7.28–7.20 (m, 1H), 7.90–7.55 (m, 6H), 7.98–7.94 (d, 1H), 8.30–8.25 (d, 1H); HPLC: 98.69% (retention time = 5.33 min)

[1538] General synthetic scheme–15D–3

[1539]

[1540] Example 95: Synthesis of Compound I-488:

[1541] 6-Carbamimidoyl-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

[1542]

[1543] Step-1: Ethyl 6-cyano-1-(naphthalen-2-yl)-1H-indole-2-carboxylate

[1544] At room temperature in a sealed tube, to a pre-degassed (10 min) solution of ethyl 6-cyano-1H-indole-2-carboxylate (2.0 g, 9.34 mmol) in DMSO (25 mL) was added naphthalene-2-ylboronic acid (3.99 g, 0.023 mmol), trimethylamine (3.77 g, 0.037 mmol), followed by degassing for 5 min, and then adding copper (II) acetate (6.76 g, 0.373 mmol). The sealed tube was closed under a nitrogen atmosphere and stirred at room temperature for 2 days. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through a celite bed. The collected filtrate was washed with water, brine, dried over sodium sulfate and concentrated to obtain a crude product (2.54 g). The obtained crude product was purified by combiflash on silica gel (64 g column) eluting with 10% ethyl acetate in hexane to obtain the title compound (1.45 g). LCMS: 340.75 (M+1) +

[1545] Step-2: 6-Cyano-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

[1546] According to the procedure described in step-2 of Example 81, the product of step-1 of Example 95 (1.45 g, 4.2 mmol) was treated with lithium hydroxide monohydrate (179 mg, 4.2 mmol) in THF:ethanol:water to obtain 590 mg of the title compound as a crude product. LCMS: 311.4 (M-1) + .

[1547] Step-3: 6-Carbamimidoyl-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

[1548] According to the procedure described in step-1 of Example 90, the product of step-2 of Example 95 (200 mg, 0.640 mmol) was treated with solid LiHMDS (750 mg, 4.48 mmol) to obtain 210 mg of the title compound. LCMS: 328.2 (M-1) + .

[1549] Step-4: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

[1550] According to the procedure described in step-2 of Example 90, the product of step-3 of Example 95 (210 mg, 0.636 mmol) and di-tert-butyl dicarbonate (207 mg, 0.954 mmol) were treated together to obtain 200 mg of the title compound. LCMS: 428.4 (M-1) + .

[1551] Step-4a: 6-Carbamimidoyl-1-(naphthalen-2-yl)-1H-indole-2-carboxylic acid

[1552] Following the procedure described in step-2a of Example 90, the product of step-4 of Example 95 (70 mg, 0.163 mmol) was treated with TFA (0.2 ml) in dichloromethane to obtain the initial crude product. The crude product obtained was purified by preparative HPLC using an X-Bridge C18 reverse phase column (19×150 mm, 5 microns). The mobile phase was 20% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) to provide the title compound (25 mg) as a TFA salt.

[1553] LCMS: 330.15 (M+1) + ; 1 HNMR (400 MHz, CD3OD): δ 7.49–7.46 (dd, 1H), 7.64–7.57 (m, 5H), 8.08–7.97 (m, 5H); HPLC: 99.59% (retention time = 4.68 min)

[1554] The following compounds listed in Table-30 were prepared according to general scheme-15D-3 by following similar procedures as described above for Example 95 using appropriate reagents with suitable modifications known to one skilled in the art.

[1555] Table-30: Compounds synthesized using Scheme-15D-3.

[1556]

[1557] Example 96: Synthesis of Compound I-490:

[1558] 6-Carbamimidoyl-1-(naphthalen-2-yl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

[1559]

[1560] Step-1: tert-Butyl-4-((6-(N-(tert-butoxycarbonyl)carbamimidoyl)-1-(naphthalen-2-yl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1561] According to the procedure described in step-5 of example 25, the product of step-4 of example 95 (55 mg, 0.128 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (28 mg, 0.129 mmol) were treated together to obtain 88 mg of the title compound. LCMS: 626.4 (M+1) + .

[1562] Step-2: 6-Carbamimidoyl-1-(naphthalen-2-yl)-N-(piperidin-4-ylmethyl)-1H-indole-2-carboxamide

[1563] The product of step-1 of Example 96 (88 mg, 0.140 mmol) was treated with TFA (0.5 mL) in dichloromethane according to the procedure described in step-2a of Example 90 to obtain a crude initial product. The crude product obtained was purified by preparative HPLC using a Kinetex EVO C18 reverse phase column (21.2×150 mm, 5 microns). The mobile phase was 30% acetonitrile in water (0.05% TFA) to 70% acetonitrile in water (0.05% TFA) to provide the title compound (43 mg) as a TFA salt.

[1564] LCMS:426.2[M+1] + ; 1 HNMR (400 MHz, CD3OD): δ1.25 (m, 2H), 1.75 (m, 3H), 2.75 (m, 2H), 3.32–3.15 (m, 4H), 7.28 (s, 1H), 7.55 (dd, 1H), 7.60 (m, 3H), 7.75 (s, 1H), 8.13–7.96 (m, 5H); HPLC: 98.11% (retention time = 4.94 min).

[1565] The following compounds listed in Table-31 were prepared according to general scheme-15D-3 by following similar procedures as described above for Example 96 using appropriate reagents with suitable modifications known to one skilled in the art.

[1566] Table-31: Compounds synthesized using Scheme-15D-3

[1567]

[1568] General Synthesis Scheme – 15E

[1569]

[1570] Example 97: Synthesis of Compound I-492

[1571] tert-Butyl 4-((6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1-(naphthalen-1-ylmethyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1572]

[1573] Step-1: 6-Cyano-1H-indole-2-carboxylic acid

[1574] According to the procedure described in step-2 of Example 79, ethyl 6-cyano-1H-indole-2-carboxylate (3.5 g, 0.016 mmol) was treated with lithium hydroxide monohydrate (0.86 mg, 0.167 mmol) to obtain the title compound (2.95 g). LCMS: 185.0 [M-1] + .

[1575] Step-2: 6-(N'-Hydroxycarbamimidoyl)-1H-indole-2-carboxylic acid

[1576] According to the procedure described in step-1 of Example 418, the product of step-1 of Example 97 (2.95 g, 15.84 mmol) was treated with 50% aqueous hydroxylamine solution (10 mL) to obtain 4.0 g of the title compound. LCMS: 219.9 (M+1) + .

[1577] Step-3: 6-(N'-acetoxycarbamimidoyl)-1H-indole-2-carboxylic acid

[1578] The product of step-2 of Example 97 (4.0 g, 18.26 mmol) was treated with acetic anhydride (5.58 g, 54.79 mmol) according to the procedure described in step-2 of Example 10 to obtain 7.0 g of the title compound. LCMS: 262.0 (M+1) + .

[1579] Step-4: 6-Carbamimidoyl-1H-indole-2-carboxylic acid.

[1580] According to the procedure described in step-3 of Example 88, the product of step-3 of Example 97 (3.5 g, 13.39 mmol) was treated with 10% palladium on carbon (400 mg) under hydrogen atmosphere to obtain the title compound (4.0 g). LCMS: 203.9 (M+1) + .

[1581] Step-5: 6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1H-indole-2-carboxylic acid.

[1582] The product of step-4 of Example 97 (4.0 g, 0.019 mmol) was treated with di-tert-butyl dicarbonate (4.29 g, 0.019 mmol) according to the procedure described in step-4 of Example 88 to obtain the title compound (1.7 g). LCMS: 304.0 (M+1) + .

[1583] Step-6: tert-Butyl 4-((6-(N-(tert-Butoxycarbonyl)carbamimidoyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1584] According to the procedure described in step-5 of example 88, the product of step-5 of example 97 (250 mg, 0.825 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (211 mg, 0.990 mmol) were treated together to obtain 250 mg of the title compound. LCMS: 500.6 (M+1) + .

[1585] Step-7: tert-Butyl 4-((6-(N-(tert-butoxycarbonyl)carbamimidoyl)-1H-indole-2-carboxamido)methyl)piperidine-1-carboxylate

[1586] To a solution of the product of step-6 of Example 97 (100 mg, 0.200 mmol) in DMF (3 ml) was added potassium carbonate (82.96 mg, 0.601 mmol) and 1-(bromomethyl)naphthalene (53.1 mg, 0.240 mmol) at room temperature and stirred at 60° C. for 5 h. After the reaction was complete, ice-cold water was added and the precipitated solid was filtered and dried. The crude product obtained above was purified by preparative TLC (mobile phase: 2% methanol in dichloromethane) to give the impure title compound (25 mg). The title compound was further purified by preparative HPLC using a Gemini-NX C18 reverse phase column (21.2 x 150 mm, 5 microns). The mobile phase was 40% acetonitrile in water (0.02% ammonia) to 90% acetonitrile in water (0.02% ammonia), providing the title compound (10 mg).

[1587] LCMS: 640.5[M+1] + ; 1HNMR (400MHz, CD3OD): δ0.87–0.85(m,2H),1.39–1.29(m,3H),1.41(s,9H),1.45(s, 9H),2.59–2.49(m,2H),3.20–3.06(m,2H),3.86–3.83(m,2H),6.19–6.17(d,1H),6.3 9(s,2H),7.18–7.14(t,2H),7.55–7.53(m,3H),7.65–7.63(m,1H),7.81–7.79(d,1H),7.91–7.89(d,1H),8.04(s,1H),8.22–8.20(d,1H); HPLC: 98.23% (retention time = 6.64 min).

[1588] ...

Claims

1. A compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond or an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -C(O)- or -O-; R 1 is an optionally substituted ring selected from phenyl, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L 2 is an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O)2-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR- or -Cy-, -Cy- is an optionally substituted divalent ring selected from phenyl, a 4-6 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 4-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 2 is an optionally substituted ring selected from the group consisting of a 4-7 membered monocyclic carbocycle, a 4-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic carbocycle, a 7-10 membered bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aromatic ring, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and adamantyl; R 3 H, -OH, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-OC 1-6 Aliphatic, C 1-6 Aliphatic or -C(O)-C 1-6 aliphatic, wherein the C 1-6 Aliphatic is optionally substituted; L 3 is a bond or an optionally substituted divalent C 1-8 a saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-; R 4 is –NHR, -C(NR)-NHR, or -NH-C(NR)-NHR; and Each R is independently H, -OH, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C(O)-C 1-8 Alkyl, -C(O)-OC 1-8 alkyl, 4-7 membered monocyclic carbocyclyl, -O-(4-7 membered monocyclic carbocyclyl), -C(O)-(4-7 membered monocyclic carbocyclyl), -C(O)-O-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(O)-phenyl, -C(O)-O-phenyl, 8-10 membered bicyclic aryl, -O-(8-10 membered bicyclic aryl), -C(O)-(8-10 membered bicyclic aryl) or -C(O)-O-(8-10 membered bicyclic aryl), wherein the C 1-8 Each of the alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl groups is optionally and independently substituted.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is optionally replaced by -C(O)- or -O-.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted phenyl or an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted C 1-8 A divalent hydrocarbon chain wherein one methylene unit of the hydrocarbon chain is optionally replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR-, or -Cy-.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -Cy- is optionally substituted phenylene, optionally substituted pyridinylene, or a 4-6 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic heteroaromatic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 -OH, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-OC 1-6 Aliphatic, C 1-6 Aliphatic or -C(O)-C 1-6 aliphatic, wherein the C 1-6 Aliphatics are optionally substituted.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 -OH, -NH2, -NO2, -COOH, -NH-C(O)-OC 1-6 Aliphatic, C 1-6 Aliphatic or -C(O)-C 1-6 aliphatic, wherein the C 1-6 Aliphatics are optionally substituted.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 3 is a bond or an optionally substituted C 1-8 A divalent hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is optionally replaced by -CO-.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 It is –NHR or -C(NR)NHR.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is an optionally substituted divalent C 1-8 A saturated or unsaturated, linear or branched hydrocarbon chain, wherein 1, 2 or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -C(O)- or -O-.

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted divalent C 1-8 A saturated or unsaturated, linear or branched hydrocarbon chain, wherein one, two or three methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR- or -Cy-.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is an optionally substituted divalent C 1-8 A hydrocarbon chain wherein one methylene unit of the hydrocarbon chain is replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, -OC(O)-, -NR-S(O)2-, -S(O)2-NR-, or -Cy-.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein -Cy- is an optionally substituted divalent 4-6 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally substituted ring selected from the group consisting of a 4-7 membered monocyclic carbocycle, a 4-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 3 is an optionally substituted divalent C 1-8 A saturated or unsaturated, linear or branched hydrocarbon chain, wherein one methylene unit of the hydrocarbon chain is optionally replaced by -CO-.

19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 3 is an optionally substituted C1 hydrocarbon chain, and R 4 Yes – NHR.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IV-a:

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IV-c:

22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula III-e:

23. A compound selected from: or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

25. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a low hepcidin condition, disease and / or disorder in a patient.

26. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for increasing hepcidin production in the liver of a patient.

27. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an iron overload disorder, disease and / or condition in a patient.

28. The use according to claim 27, wherein The iron overload disorder, disease and / or condition is selected from the group consisting of hemochromatosis types 1, 2a, 2b and 3, hepcidin deficiency, transfusional iron overload, African iron overload, and iron overload cardiomyopathy.

29. The use according to claim 28, wherein the iron overload disorder, disease and / or condition is hemochromatosis, Hfe hemochromatosis or juvenile hemochromatosis.

30. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating iron-overload anemia in a patient.

31. The use according to claim 30, wherein The iron-overloading anemia is selected from the group consisting of beta thalassemia, HbE / thalassemia, alpha thalassemia and congenital dyserythropoietic anemia.

32. The use according to claim 31, wherein the HbE / thalassemia is thalassemia major, thalassemia intermedia, thalassemia minor, non-transfusion-dependent thalassemia or transfusion-dependent thalassemia.

33. The use according to claim 31, wherein the congenital dyserythropoietic anemia is congenital dyserythropoietic anemia type I or congenital dyserythropoietic anemia type II.

34. An in vitro method for inhibiting matriptase 2 or a mutant thereof in a biological sample, comprising contacting the sample with a compound according to any one of claims 1 to 23.

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