MATRIPTASE-2 Inhibitors and Uses Thereof

Description

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to compounds and methods useful for inhibition of Matriptase 2 ("Mat-2"), or a mutant thereof. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

[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 where the level of hepcidin is inappropriately high. The enzyme activity of matriptase-2 reduces hepcidin expression through the suppression of bone morphogenetic protein (BMP) / sons of mothers against decapentaplegic homologue protein (SMAD) signaling. Loss of or inhibition of matriptase-2 activity leads to an increase in hepcidin production by the liver.Cited documents

[0003] US 8,304,419 describes non-nucleoside reverse transcriptase inhibitors and processes for the preparation and use of the same. Asteian et al, ACS Medicinal Chemistry Letters, (2015), vol. 6, no. 9, pages 998-1003 describes indole biphenylcarboxylic acids as PPARγ antagonists. WO 2004 / 056768 describes use of 2,5-diamidoindole derivatives for the preparation of medicaments for treating urological disorders. WO 2018 / 112648 describes matriptase inhibitors and uses thereof for treating disorders associated with matriptase activity. SUMMARY OF THE INVENTION

[0004] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as Matriptase 2 inhibitors. A compound of Formula I is disclosed: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0005] 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 diseases, disorders, or conditions in which regulating iron metabolism by increasing hepcidin production by the liver may be therapeutically useful. Such diseases, disorders, or conditions include those described herein.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention:

[0006] Compounds of the present invention, and pharmaceutical compositions thereof, are useful as inhibitors of Matriptase 2, or a mutant thereof. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and pharmaceutical compositions thereof, may inhibit the activity of Matriptase 2, or a mutant thereof, and thus treat certain diseases, disorders, or conditions associated with relative or absolute hepcidin deficiency, or diseases, disorders, or conditions in which regulating iron metabolism by increasing hepcidin production by the liver may be therapeutically useful, such as those described herein.

[0007] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as Matripase 2 inhibitors. In one aspect, the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein each X is independently C or N; L 1< is a bond, or an optionally substituted bivalent C 1-8 saturated or unsaturated, straight 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-; 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, a 8-10 membered bicyclic aromatic carbocyclic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2< is an optionally substituted bivalent C 1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 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-, -O-C(O)-, -NR-S(O) 2 -, -S(O) 2 -NR-, or -Cy-; -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; R 2< is H, or an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocarboxylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and adamantly; R 3< is H, halogen, -CN, -C(O)H, -NH 2 , -NO 2 , -COOH, -CONH 2 , -NH-C(O)-O-C 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 bond, or an optionally substituted bivalent C 1-8 saturated or unsaturated, straight 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(N-R)-NHR, -NH-C(N-R)-NHR, -F, or -OH; and 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 each of the C 1-8 alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted. 2. Compounds and Definitions:

[0008] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0009] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that 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.

[0010] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may 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, a 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" refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: Exemplary bridged bicyclics include:

[0011] The term "lower alkyl" refers to a C 1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0012] The term "lower haloalkyl" refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0013] The term "heteroatom" means one or more of 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, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +< (as in N-substituted pyrrolidinyl)).

[0014] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.

[0015] As used herein, the term "bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain", refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0016] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0017] The term "alkenylene" refers to a bivalent 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 with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0018] As used herein, the term "cyclopropylenyl" refers to a bivalent cyclopropyl group of the following structure:

[0019] The term "halogen" means F, Cl, Br, or I.

[0020] The term "aryl" used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic or bicyclic ring systems 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" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0021] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl," or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. 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, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- 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 by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0022] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a 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).

[0023] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical," are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0024] 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 having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0025] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0026] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH 2 ) 0-4 R°; -(CH 2 ) 0-4 OR°; -O(CH 2 ) 0-4 R°, -O-(CH 2 ) 0-4 C(O)OR°; -(CH 2 ) 0-4 CH(OR°) 2 ; -(CH 2 ) 0-4 SR°; -(CH 2 ) 0-4 Ph, which may be substituted with R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R°; -NO 2 ; -CN; - N 3 ; -(CH 2 ) 0-4 N(R°) 2 ; -(CH 2 ) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH 2 ) 0-4 N(R°)C(O)NR° 2 ; -N(R°)C(S)NR° 2 ; -(CH 2 ) 0-4 N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR° 2 ; -N(R°)N(R°)C(O)OR°; -(CH 2 ) 0-4 C(O)R°; - C(S)R°; -(CH 2 ) 0-4 C(O)OR°; -(CH 2 ) 0-4 C(O)SR°; -(CH 2 ) 0-4 C(O)OSiR° 3 ; -(CH 2 ) 0-4 OC(O)R°; - OC(O)(CH 2 ) 0-4 SR-, SC(S)SR°; -(CH 2 ) 0-4 SC(O)R°; -(CH 2 ) 0-4 C(O)NR° 2 ; -C(S)NR° 2 ; -C(S)SR°; -SC(S)SR°, -(CH 2 ) 0-4 OC(O)NR° 2 ; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH 2 C(O)R°; - C(NOR°)R°; -(CH 2 ) 0-4 SSR°; -(CH 2 ) 0-4 S(O) 2 R°; -(CH 2 ) 0-4 S(O) 2 OR°; -(CH 2 ) 0-4 OS(O) 2 R°; - S(O) 2 NR° 2 ; -S(O)(NR°)R°; -S(O) 2 N=C(NR° 2 ) 2 ; -(CHz 2 ) 0-4 S(O)R°; -N(R°)S(O) 2 NR° 2 ; - N(R°)S(O) 2 R°; -N(OR°)R°; -C(NH)NR° 2 ; -P(O) 2 R°; -P(O)R° 2 ; -OP(O)R° 2 ; -OP(O)(OR°) 2 ; SiR° 3 ; -(C 1-4 straight or branched alkylene)O-N(R°) 2 ; or -(C 1-4 straight or branched alkylene)C(O)O-N(R°) 2 .

[0027] Each R° is independently hydrogen, C 1-6 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(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 definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by 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, - (CH 2 ) 0-2 R •< , -(haloR •< ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR •< , -(CH 2 ) 0-2 CH(OR •< ) 2 ; -O(haloR •< ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R •< , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR •< , -(CH 2 ) 0-2 SR •< , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR •< , -(CH 2 ) 0-2 NR •< 2 , -NO 2 , -SiR •< 3 , -OSiR •< 3 , -C(O)SR •< , -(C 1-4 straight or branched alkylene)C(O)OR •< , or -SSR •< .

[0028] Each R •< is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 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 where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR* 2 , =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O) 2 R*, =NR*, =NOR*, -O(C(R* 2 )) 2-3 O-, or - S(C(R* 2 )) 2-3 S-, or a divalent substituent bound to vicinal substitutable carbons of an "optionally substituted" group is -O(CR* 2 ) 2-3 O-, wherein each independent occurrence of R* is 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.

[0029] When R* is C 1-6 aliphatic, R* is optionally substituted with halogen, - R •< , -(haloR •< ), -OH, -OR •< , -O(haloR •< ), -CN, -C(O)OH, -C(O)OR •< , -NH 2 , -NHR •< , -NR •< 2 , or - NO 2 , wherein each R •< is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 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 where preceded by halo is substituted only with one or more halogens.

[0030] An optional substituent on a substitutable nitrogen is independently -R †< , -NR †< 2 , - C(O)R †< , -C(O)OR †< , -C(O)C(O)R †< , -C(O)CH 2 C(O)R †< , -S(O) 2 R †< , -S(O) 2 NR †< 2 , -C(S)NR †< 2 , - C(NH)NR †< 2 , or -N(R T< )S(O) 2 R †< ; wherein each R †< is 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 R †< , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R †< is C 1-6 aliphatic, R †< is optionally substituted with halogen, -R •< , -(haloR •< ), -OH, -OR •< , -O(haloR •< ), - CN, -C(O)OH, -C(O)OR •< , -NH 2 , -NHR •< , -NR •< 2 , or -NO 2 , wherein each R •< is independently selected from C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 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 where preceded by halo is substituted only with one or more halogens.

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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 salts, and the like.

[0032] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N +< (C 1-4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0033] 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, the 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 present compounds 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. Additionally, 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, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13< C- or 14< C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a compound of the invention comprises one or more deuterium atoms.

[0034] 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, an inhibitor has an IC 50 and / or 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.

[0035] The terms "measurable affinity" and "measurably inhibit," as used herein, means a measurable change in Matriptase 2, or a mutant thereof, activity between a sample comprising a compound of the present invention, or composition thereof, and Matriptase 2, or a mutant thereof, and an equivalent sample comprising Matriptase 2, or a mutant thereof, in the absence of said compound, or composition thereof.3. Description of Exemplary Embodiments:

[0036] In one aspect, the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein each X is independently C or N; L 1< is a bond, or an optionally substituted bivalent C 1-8 saturated or unsaturated, straight 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-; 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, a 8-10 membered bicyclic aromatic carbocyclic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2< is an optionally substituted bivalent C 1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 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-, -O-C(O)-, -NR-S(O) 2 -, -S(O) 2 -NR-, or -Cy-; -Cy- is an optionally substituted bivalent ring selected from phenyl, and a 4-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 2< is H, or an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocarboxylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and adamantly; R 3< is H, halogen, -CN, -C(O)H, -NH 2 , -NO 2 , -COOH, -CONH 2 , -NH-C(O)-O-C 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 bivalent C 1-8 saturated or unsaturated, straight 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(N-R)-NHR, -NH-C(N-R)-NHR, -F, or -OH; and 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 each of the C 1-8 alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.

[0037] As defined generally above, each X is independently C or N.

[0038] In some embodiments, X is C. In some embodiments, X is N.

[0039] In some embodiments, each X is independtly C or N such that is selected from the following

[0040] In some embodiments, each X is independently selected from those depicted in Table A, below.

[0041] As defined generally above, L 1< is a bond, or an optionally substituted C 1-8 bivalent 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-.

[0042] In some embodiments, L 1< is a bond.

[0043] In some embodiments, L 1< is an optionally substituted C 1-8 bivalent 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-. In some embodiments, L 1< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -S(O) 2 -, -C(O)-, or -O-. In some embodiments, L 1< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 2 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 bivalent hydrocarbon chain, wherein 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O) 2 -, -C(O)-, or -O-.

[0044] In some embodiments, L 1< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is replaced by -S(O) 2 -. In some embodiments, L 1< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is replaced by -C(O)-. In some embodiments, L 1< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is replaced by -O-.

[0045] In some embodiments, L 1< is -(CH 2 )-. In some embodiments, L 1< is -(CH 2 ) 2 -. In some embodiments, L 1< is -(CH 2 ) 3 -. In some embodiments, L 1< is -S(O) 2 CH 2 -. In some embodiments, L 1< is -S(O) 2 (CH 2 ) 2 -. In some embodiments, L 1< is -S(O) 2 -. In some embodiments, L 1< is -CH 2 S(O) 2 -. In some embodiments, L 1< is -(CH 2 ) 2 -S(O) 2 -.

[0046] In some embodiments, L 1< is selected from those depicted in Table A, below.

[0047] As defined generally 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, a 8-10 membered bicyclic aromatic carbocyclic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0048] In some embodiments, R 1< 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, a 8-10 membered bicyclic aromatic carbocyclic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] In some embodiments, R 1< is optionally substituted phenyl. In some embodiments, R 1< is unsubstituted phenyl. In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is . In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is wherein halogen is F, Cl, or Br. In some embodiments, R 1< is wherein halogen is F, Cl, or Br. In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is In some embodiments, R 1< is

[0050] 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. In some embodiments, R 1< is an optionally substituted 5-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1< is an optionally substituted 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0051] In some embodiments, R 1< is optionally substituted pyridyl. In some embodiments, R 1< is unsubstituted pyridyl. In some embodiments, R 1< is or

[0052] In some embodiments, R 1< is In some embodiments, R 1< is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 1< is an optionally substituted 8-membered bicyclic aromatic carbocyclic ring. In some embodiments, R 1< is an optionally substituted 9-membered bicyclic aromatic carbocyclic ring. In some embodiments, R 1< is an optionally substituted 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R 1< is a 10-membered bicyclic aromatic carbocyclic ring, optionally substituted by -CH 2 -R 11< , -O-R 11< , -N-R 11< , -S-R 11< , - NR-C(O)-R 11< , -C(O)-NR-R 11< , -C(O)-R 11< , -S(O) 2 -R 11< , -C(O)-O-R 11< , -O-C(O)-R 11< , -NR-S(O) 2 -R 11< , or -S(O) 2 -NR-R 11< , wherein R 11< is optionally substituted phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1< is In some embodiments, R 1< is

[0053] 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. In some embodiments, R 1< is an optionally substituted 8-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1< is an optionally substituted 9-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1< is an optionally substituted 10-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0054] In some embodiments, R 1< is

[0055] In some embodiments, R 1< is selected from those depicted in Table A, below.

[0056] As defined generally above, L 2< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 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-, -O-C(O)-, -NR-S(O) 2 -, -S(O) 2 -NR-, or -Cy-.

[0057] In some embodiments, L 2< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -C(O)-O-, or -O-C(O)-. In some embodiments, a C 1-8 bivalent hydrocarbon chain is substituted by -OH.

[0058] In some embodiments, L 2< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(O) 2 -, -NR-S(O) 2 -, or -S(O) 2 -NR-.

[0059] In some embodiments, L 2< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -Cy-.

[0060] In some embodiments, L 2< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 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-.

[0061] In some embodiments, L 2< is an optionally substituted C 1-8 bivalent 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 -.

[0062] In some embodiments, L 2< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -C(O)-O- or -O-C(O)-.

[0063] In some embodiments, L 2< is -CH 2 -, -NH-, -NH-CH 3 -, -CH 3 -NH-, -NH-C(O)-, - N(CH 3 )-C(O)-, -S(O) 2 -, -CH 2 -NH-C(O)-, -(CH 2 ) 2 -, -NH-CH(CH 3 )-, -NH-(CH 2 ) 2 -, -NH-(CH 2 ) 4 -NH-, or -NH-(CH 2 ) 3 -.

[0064] In some embodiments, L 2< is selected from those depicted in Table A, below.

[0065] As defined generally 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.

[0066] In some embodiments, -Cy- is optionally substituted phenylene. In some embodiments, -Cy- is unsubstituted phenylene.

[0067] In some embodiments, -Cy- is optionally substituted pyridylene. In some embodiments, -Cy- is unsubstituted pyridylene.

[0068] 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-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.

[0069] In some embodiments, -Cy- is an optionally substituted 4-6 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is an optionally substituted 4-membered monocyclic heterocyclic 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 heterocyclic 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 heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0070] In some embodiments, -Cy- is an optionally substituted bivalent ring which is oxadiazole. In some embodiments, -Cy- is an optionally substituted bivalent ring which is thiadizaole.

[0071] In some embodiments, -Cy- is selected from those depicted in Table A, below.

[0072] As defined generally above, R 2< is H, or an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocarboxylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and adamantyl.

[0073] In some embodiments, R 2< is H. In some embodiments, R 2< is an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocarboxylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and adamantyl.

[0074] In some embodiments, R 2< is an optionally substituted 4-7 membered monocyclic carbocyclic ring.

[0075] 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. In some embodiments, R 2< is an optionally substituted 4-membered monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 5-membered monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 6-membered monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 7-membered monocyclic heterocyclic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] In some embodiments, R 2< is an optionally substituted 7-10 membered bicyclic carbocyclic ring.

[0077] In some embodiments, R 2< is an optionally substituted 7-10 membered bicyclic heterocarboxylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 7-membered bicyclic heterocarboxylic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 8-membered bicyclic heterocarboxylic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 9-membered bicyclic heterocarboxylic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 10-membered bicyclic heterocarboxylic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, R 2< is optionally substituted phenyl.

[0079] 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. In some embodiments, R 2< 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, R 2< is an optionally substituted 6-membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0080] In some embodiments, R 2< is an optionally substituted 8-10 membered bicyclic aromatic ring.

[0081] 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. In some embodiments, R 2< is an optionally substituted 8-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 9-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2< is an optionally substituted 10-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments, R 2< is optionally substituted adamantyl.

[0083] In some embodiments, R 2< is selected from:

[0084] In some embodiments, R 2< is selected from those depicted in Table A, below.

[0085] As defined generally above, R 3< is H, -OH, halogen, -CN, -C(O)H, -NH 2 , -NO 2 , -COOH, -CONH 2 , -NH-C(O)-O-C 1-6 aliphatic, C 1-6 aliphatic, or -C(O)-C 1-6 aliphatic, wherein the C 1-6 aliphatic is optionally substituted.

[0086] 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 - NH 2 . In some embodiments, R 3< is -NO 2 . In some embodiments, R 3< is -COOH. In some embodiments, R 3< is -CONH 2 . In some embodiments, R 3< is -NH-C(O)-O-C 1-6 aliphatic, wherein the C 1-6 aliphatic is optionally substituted. In some embodiments, R 3< is C 1-6 aliphatic, wherein the C 1-6 aliphatic is optionally substituted. In some embodiments, R 3< is -C(O)-C 1-6 aliphatic, wherein the C 1-6 aliphatic is optionally substituted.

[0087] In some embodiments, R 3< is -OH. In some embodiments, R 3< is -NH 2 . In some embodiments, R 3< is -NO 2 . In some embodiments, R 3< is -COOH. In some embodiments, R 3< is - NH-C(O)-O-C 2 H 5 . In some embodiments, R 3< is -CH 2 -OCH 3 .

[0088] In some embodiments, R 3< is selected from those depicted in Table A, below.

[0089] As defined generally above, L 3< is a bond, or an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-.

[0090] In some embodiments, L 3< is a bond.

[0091] In some embodiments, L 3< is an optionally substituted C 1-8 bivalent 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 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -CO-. In some embodiments, L 3< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 2 methylene units of the hydrocarbon chain are optionally replaced by -CO-. In some embodiments, L 3< is an optionally substituted C 1-8 bivalent hydrocarbon chain, wherein 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-.

[0092] In some embodiments, L3 is -CH 2 -.

[0093] In some embodiments, L 3< is selected from those depicted in Table A, below.

[0094] As defined generally above, R 4< is -NHR, -C(N-R)-NHR, -NH-C(N-R)-NHR, -F, or - OH.

[0095] In some embodiments, R 4< is -NHR. In some embodiments, R 4< is -C(N-R)-NHR. In some embodiments, R 4< is -NH-C(N-R)-NHR. In some embodiments, R 4< is -F. In some embodiments, R 4< is -OH.

[0096] In some embodiments, R 4< is -NH 2 . In some embodiments, R 4< is selected from:

[0097] In some embodiments, R 4< is selected from those depicted in Table A, below.

[0098] As defined generally above, 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 each of the C 1-8 alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.

[0099] In some embodiments, R is H. In some embodiments, R is -OH.

[0100] In some embodiments, R is optionally substituted -C 1-8 alkyl. In some embodiments, R is optionally substituted -OC 1-8 alkyl. In some embodiments, R is optionally substituted -C(O)-C 1-8 alkyl. In some embodiments, R is optionally substituted -C(O)-OC 1-8 alkyl. In some embodiments, C 1-8 alkyl is C 1-6 alkyl. In some embodiments, C 1-8 alkyl is isopropyl. In some embodiments, C 1-8 alkyl is tert-butyl. In some embodiments, C 1-8 alkyl is neopentyl.

[0101] In some embodiments, R is optionally substituted 4-7 membered monocyclic carbocyclyl. In some embodiments, R is optionally substituted -O-(4-7 membered monocyclic carbocyclyl). In some embodiments, R is optionally substituted -C(O)-(4-7 membered monocyclic carbocyclyl). In some embodiments, R is optionally substituted -C(O)-O-(4-7 membered monocyclic carbocyclyl). In some embodiments, 4-7 membered monocyclic carbocyclyl is cyclopentyl. In some embodiments, 4-7 membered monocyclic carbocyclyl is cyclohexyl.

[0102] 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.

[0103] In some embodiments, R is optionally substituted 8-10 membered bicyclic aryl. In some embodiments, R is optionally substituted -O-(8-10 membered bicyclic aryl). In some embodiments, R is optionally substituted -C(O)-(8-10 membered bicyclic aryl). In some embodiments, R is optionally substituted -C(O)-O-(8-10 membered bicyclic aryl).

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

[0105] In some embodiments, a compound of formula I is of formula II: wherein each of L 1< , L 2< , L 3< , R 1< , R 2< , R 3< , R 4< , -Cy-, and R is as defined above and described in embodiments herein, both singly and in combination.

[0106] In some embodiments, a compound of formula I is selected from formulas II-a to II-f: or a pharmaceutically acceptable salt thereof, wherein each of L 1< , L 2< , L 3< , R 1< , R 2< , R 3< , R 4< , -Cy-, and R is as defined above and described in embodiments herein, both singly and in combination.

[0107] In some embodiments, a compound of formula I is of formula III: wherein each of L 1< , L 2< , L 3< , R 1< , R 2< , R 3< , R 4< , -Cy-, and R is as defined above and described in embodiments herein, both singly and in combination.

[0108] In some embodiments, a compound of formula I is selected from formulas III-a to IIIf: or a pharmaceutically acceptable salt thereof, wherein each of L 1< , L 2< , L 3< , R 1< , R 2< , R 3< , R 4< , -Cy-, and R is as defined above and described in embodiments herein, both singly and in combination.

[0109] The present invention embraces compounds of formula IV: wherein each of L 1< , L 2< , L 3< , R 1< , R 2< , R 3< , R 4< , -Cy-, and R is as defined above and described in embodiments herein, both singly and in combination. Compounds of formula IV according to the presently claimed invention are defined in the appended claims.

[0110] In some embodiments, a compound of formula I is selected from formulas IV-a to IV f: or a pharmaceutically acceptable salt thereof, wherein each of L 1< , L 2< , L 3< , R 1< , R 2< , R 3< , R 4< , -Cy-, and R is as defined above and described in embodiments herein, both singly and in combination.

[0111] Exemplary compounds of the invention are set forth in Table A, below.

[0112] In some embodiments, the present invention provides a compound set forth in Table A, above, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the present invention provides a compound described in the examples below, or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, a compound of the invention is not: 4. Uses, Formulation and Administration: Pharmaceutically acceptable compositions

[0115] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit Matriptase 2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit Matriptase 2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0116] The term "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0117] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a nontoxic 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 may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, 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 silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0118] A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[0119] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of Matriptase 2, or a mutant thereof.

[0120] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0121] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0122] Pharmaceutically acceptable compositions of this invention may be orally administered 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, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0123] Alternatively, pharmaceutically acceptable compositions of this invention may 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 therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0124] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0125] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0126] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0127] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0128] Pharmaceutically acceptable compositions of this 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, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0129] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0130] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0131] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body 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 particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0132] Compounds and compositions described herein are generally useful for the inhibition of Matriptase 2, or a mutant thereof.

[0133] The activity of a compound utilized in this invention as an inhibitor of Matriptase 2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of Matriptase 2, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to Matriptase 2, or a mutant thereof. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of Matriptase 2, or a mutant thereof, are set forth in the Examples below.

[0134] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress 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., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0135] As used herein, the terms "low hepcidin" disorders, diseases, and / or conditions 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 an increase in hepcidin may be therapeutically useful.

[0136] Provided compounds are inhibitors of Matriptase 2, or a mutant thereof, and are therefore useful for treating low hepcidin disorders, diseases, and / or conditions. Accordingly, in certain embodiments, the present invention provides a method for treating a low hepcidin disorder, disease, and / or condition, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.

[0137] Without wishing to be bound by any specific theory, inhibition of Matriptase-2 has been found to lead to increased hepcidin production by the liver. Accordingly, in some embodiments, the present invention provides a method for increasing hepcidin production by the liver in a patient, comprising the step of administering to the patient a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method for treating absolute and / or relative hepcidin deficiency in a patient, comprising the step of administering to the patient a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides a method for treating hepcidin underproduction in a patient, comprising the step of administering to the patient a compound of the present invention, or 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, comprising the step of administering to the patient a compound of the present invention, or pharmaceutically acceptable composition thereof in order to increase hepcidin production by the liver. In some embodiments, the present invention provides a method for treating ineffective erythropoiesis in a patient, comprising the step of administering to the patient a compound of the present invention, or pharmaceutically acceptable composition thereof.

[0138] In some embodiments, the present invention provides a method for treating one or more iron overload disorder, disease, and / or condition, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.

[0139] As used herein, the term "iron overload disorder, disease, and / or condition" refers to a condition, disease, or disorder associated with excessive iron levels or iron overload. Large amounts of free iron in the bloodstream can lead to cell damage, especially in the liver, heart and endocrine glands. The causes of excess iron may be genetic, for example the iron excess may be caused by a genetic condition such as hemochromatosis type 1 (classical hemochromatosis), hemochromatosis type 2A or 2B (juvenile hemochromatosis), hemochromatosis type 3, African iron overload, neonatal hemochromatosis, aceruloplasminemia, or congenital atransferrinemia. Examples of non-genetic causes of iron excess include dietary iron overload (including African iron overload), transfusional iron overload (due to a blood transfusion given to patients with thalassaemia or other congenital hematological disorders), hemodialysis, chronic liver disease (such as hepatitis C, cirrhosis, non-alcoholic steatohepatitis), porphyria cutanea tarda, post-portacaval shunting, dysmetabolic overload syndrome, iron tablet overdose (such as that caused by consumption by children of iron tablets intended for adults), or any other cause of acute or chronic iron overload.

[0140] In some embodiments, an iron overload disorder, disease, and / or condition is Hemochromatosis Type 1. In some embodiments, an iron overload disorder, disease, and / or condition is Hemochromatosis Type 2a. In some embodiments, an iron overload disorder, disease, and / or condition is Hemochromatosis Type 2b. In some embodiments, an iron overload disorder, disease, and / or condition is Hemochromatosis Type 3.

[0141] In some embodiments, an iron overload disorder, disease, and / or condition is hepcidin deficiency. In some embodiments, an iron overload disorder, disease, and / or condition is Transfusional iron overload. In some embodiments, an iron overload disorder, disease, and / or condition is African iron overload. In some embodiments, an iron overload disorder, disease, and / or condition is Iron overload cardiomyopathy.

[0142] In some embodiments, the present invention provides a method for treating one or more iron loading anemia, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, an Iron Loading Anemia is beta thalassemia, HbE / beta thalassemia, or other variants thereof, including but not limited to: thalassemia major, thalassemia intermedia, thalassemia minor, non-transfusion dependent thalassemia, and transfusion-dependent thalassemia. In some embodiments, an iron loading anemia is associated with, and / or caused by, alpha thalassemia. In some embodiments, an iron loading anemia is congenital dyserythropoietic anemia Type I and / or Type II. In some embodiments, an iron loading anemia is pyruvate kinase deficiency. In some embodiments, an iron loading anemia is myelodyplasia including but not limited to myelodysplastic syndrome (MDS), RARS and / or SF3B1 associated MDS.

[0143] In some embodiments, the present invention provides a method for treating one or more hematological disease, disorder, and / or condition, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, a hematological disease, disorder, and / or condition is sickle cell disease. In some embodiments, a hematological disease, disorder, and / or condition is sickle cell anemia. In some embodiments, a hematological disease, disorder, and / or condition is polycythemia vera. In some embodiments, a hematological disease, disorder, and / or condition is sideroblastic anemia. In some embodiments, a hematological disease, disorder, and / or condition is bone marrow transplantation.

[0144] In some embodiments, the present invention provides a method for treating one or more liver disease, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, a liver disease is Hepatitis B. In some embodiments, a liver disease is Hepatitis C or other forms of viral hepatitis. In some embodiments, a liver disease is alcoholic liver disease. In some embodiments, a liver disease is cirrhosis of the liver. In some embodiments, a liver disease is hepatocellular carcinoma. In some embodiments, a liver disease is non-alcoholic steatohepatitis (NASH).

[0145] In some embodiments, the present invention provides a method for treating one or more metabolic disease, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, a metabolic disease is metabolic syndrome. In some embodiments, a metabolic disease is insulin resistance. In some embodiments, a metabolic disease is Type II diabetes. In some embodiments, a metabolic disease is porphyria. In some embodiments, a metabolic disease is porphyria cutanea tarda. In some embodiments, a metabolic disease is Wilson's Disease. In some embodiments, a metabolic disease is acute iron overdose.

[0146] In some embodiments, the present invention provides a method for treating one or more neurodegenerative disorder, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, a 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).

[0147] In some embodiments, the present invention provides a method for treating one or more infectious disease, comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, an infectious disease is a siderophilic infection.

[0148] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a low hepcidin disease, disorder, and / or condition, or any amount and any route of administration effective for increasing hepcidin production by 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 particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0149] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0150] 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 compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0151] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0152] Injectable formulations can be sterilized, for example, by filtration through a bacterialretaining 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.

[0153] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0154] 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.

[0155] 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, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents 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 accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, 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 comprise buffering agents.

[0156] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0157] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0158] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0159] In some embodiments, the invention relates to a method of inhibiting matriptase 2 activity, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[0160] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0161] Depending upon the particular 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 this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0162] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two or more additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. In some embodiments, an additional therapeutic agent is an iron chelating compound, or a pharmaceutically acceptable salt thereof. In some embodiments, an iron chelating compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of deferasirox, deferiprone and deferoxamine.

[0163] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an iron chelating compound or a pharmaceutically acceptable salt thereof. In some embodiments, a patient is a patient with iron overload. In some embodiments, a patient is a patient with cardiac iron overload or iron overload related cardiomyopathy. In some embodiments, an iron chelating compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of deferasirox, deferiprone and deferoxamine.EXEMPLIFICATIONGeneral Synthetic Methods

[0164] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.General modes of preparation:

[0165] The general synthetic methods used in each General Procedure follow and include an illustration of a compound that was synthesized using the designated General Procedure. None of the specific conditions and reagents noted herein are to be construed as limiting the scope of the invention and are provided for illustrative purposes only.

[0166] Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.

[0167] Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over anhydrous sodium sulphate, filtration and distillation of the solvent under reduced pressure. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate / petroleum ether mixture of a suitable polarity as the mobile phase.

[0168] The following abbreviations refer respectively to the definitions below:

[0169] ACN - Acetonitrile; br - Broad; °C - Degree Celsius ; CHCl 3 - Chloroform; CD 3 OD - Deuterated Methanol; DMSO - d 6< - Deuterated dimethylsulfoxide; DCM - Dichloromethane; DIPEA - Diisopropylethylamine; DMF- N,N- Dimethylformamide; d - Doublet; dd - Doublet of doublet; EDC.HCl- 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; mg-Miligram; g - Gram; h - Hours; 1< H- Proton; HCl- Hydrochloric acid; HPLC- High-Performance Liquid Chromatography; H 2 - Hydrogen; HOBt- 1-Hydroxy benzotriazole; K 2 CO 3 - Potassium carbonate; LCMS - Liquid chromatography mass spectroscopy; LiOH.H 2 O - Lithium hydroxide monohydrate; M - Molar; MHz - Mega hertz (frequency); MeOH - Methanol; mL - MilliLiter; min - Minutes; mol - Moles; M +< - Molecular ion; M - Multiplet; N 2 - Nitrogen; NH 3 - 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; % - Percentage; µ - Micron; and δ- Delta; Zn - Zinc; mmol - millimoles.

[0170] Analysis for the compounds of the present invention unless mentioned, was conducted in the general methods well known to the person skilled in the art. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples, describing in detail the analysis of the compounds of the invention.

[0171] LCMS data has been recorded in +ve mode unless otherwise mentioned.

[0172] It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.General synthetic Scheme 1

[0173] Examples cited below which do not fall within the scope of the claims are intended as reference examples only.Example 1: Synthesis of compound I-1 N-(6-aminopyridin-3-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0174] Step-1: Ethyl 6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylate

[0175] Ethyl 6-cyano-1H-indole-2-carboxylate (5.0 g, 23.34 mmol), dissolved in 150 mL of N,N-dimethylformamide, was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (6.14 g, 25.67 mmol) and potassium carbonate (3.55 g, 25.67 mmol) and stirred at room temperature for 8 h. After reaction completion, mixture was quenched with ice-cold water and precipitated product was filtered off. Thus obtained solid was further washed with water and dried under vacuum to give crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with 30-40% ethylacetate / hexane to afford the title compound (7.4 g). LCMS: 373.1 (M+1) +< .Step-2: 6-Cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxylic acid

[0176] Product of step-1 of example-1(7.0 g, 18.8 mmol) was dissolved in 100 mL mixture of tetrahydrofuran / methanol / water (1:1:1) and added lithium hydroxide (1.57 g, 65.8 mmol) at room temperature. Resulting mixture was stirred at room temperature for 4 h. Mixture was acidified with saturated aqueous solution of citric acid and extracted with ethyl acetate followed by washed with brine and dried over anhydrous sodium sulphate and then solvent was evaporated under vacuum to get the title compound (5.2 g). LCMS: 345.1 (M+1) +< .Step-3: tert-Butyl (5-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)pyridin-2-yl)carbamate

[0177] Product of step-2 of example-1 (350 mg, 1.01 mmol), dissolved in 5 mL of N,N-dimethylformamide, was added Butyl (5-aminopyridin-2-yl)carbamate (234mg, 1.1mmol), EDCI.HCl (292mg, 1.52mmol), HOBt (137mg, 1.01mmol) and DIEA (526mg, 4.066mmol) to the reaction mixture and resulted solution was stirred at RT for overnight. Reaction mixture was quenched with water, extracted with ethyl acetate followed by washed with brine and water and dried over sodium sulphate. Solvent was evaporated under vacuum to give crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with 20% ethylacetate / hexane and afforded the title compound (380 mg). LCMS: 536.2 (M+1) +< .Step-4: Ethyl 2-((6-aminopyridin-3-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carbimidate

[0178] Product was step-3 of example-1 (350 mg, 0.65 mmol) was dissolved in 50 mL of ethanolic-HCl (ethanol was saturated with HCl gas at -20 °C) and kept in a glass sealed tube for 12 h at RT. After reaction completion, solvent was evaporated under vacuum to afford the title compound (205 mg). LCMS: 482.2 (M+1) +< .Step-5: N-(6-aminopyridin-3-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0179] Product of step-4 of example-1 (200 mg, 0.41 mmol) was dissolved in 50 mL of ethanolic-ammonia (ethanol was saturated with ammonia gas at -70 °C) and kept for overnight in a steel bomb at RT. After reaction completion, solvent was evaporated under vacuum to give crude product which was purified by preparative High-performance liquid chromatography instrument with a Agilent XDB C18 reverse phase column (21.2x 150mm, 5micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 100% acetonitrile (0.1% TFA) which afforded the title compound (110 mg). LCMS: 452.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 5.98 (s, 2H), 6.93 (d, 2H), 7.22 (d, 1H),7.51(m, 4H), 7.81 (brs, 1H), 8.05 (m, 2H), 8.41 (s, 1H), 8.41 (s,1H), 9.11 (brs,2H), 9.25(brs,2H), 10.75 (brs,1H).

[0180] The following compounds listed in table-1, table-2 and table-3 were prepared according to Scheme-1 by following similar procedure as described above for example-1 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-1: Cpd. ID.R 1 R 2 R 3 LLCMS (M+1) +< 1< H NMRI-1H -CF 3 CH 2 452.2δ 5.98 (s, 2H), 6.93 (d, 2H), 7.22 (d, 1H), 7.51(m, 4H), 7.81 (brs, 1H), 8.05 (m, 2H), 8.41 (s, 1H), 8.41 (s, 1H), 9.11 (brs, 2H), 9.25 (brs, 2H), 10.75 (brs,1H).I-2H -CF 3 CH 2 492.2δ 5.98 (s, 2H), 7.21 (d, 2H), 7.32 (d, 1H), 7.47 (m, 1H), 7.62 (m, 4H), 7.95 (d, 1H), 8.11 (d, 1H), 8.21 (s, 1H), 8.35 (brs, 1H),8.51 (brs, 2H), 9.15 (brs, 2H), 9.24 (brs, 2H), 10.71(s,1H).I-3-CH 3 -CF 3 CH 2 458.2δ 3.12 (s, 3H), 4.92 (s, 2H), 5.68 (s, 2H), 7.18 (d, 4H), 7.42 (m, 4H), 7.62 (m, 2H), 7.91 (m, 2H), 8.12 (brs, 1H), 8.87 (brs, 2H), 9.21 (brs, 2H).I-4H -CF 3 CH 2 458.2δ 1.32 (m, 4H), 1.75 (m, 4H),2.92 (m, 1H), 3.65 (m, 1H), 5.98 (s, 2H), 7.21 (d, 2H), 7.32 (brs, 1H), 7.55 (d, 1H), 7.62 (d, 2H), 7.82 (m, 3H), 8.21 (s, 1H), 8.62 (d, 1H), 9.08 (brs, 2H), 9.24 (brs, 2H); HPLC: 97.17% (Retention Time= 6.79 min).I-5H -CF 3 CH 2 444.2δ 1.68 (m, 2H), 1.83 (m, 2H),2.92 (m, 2H), 3.32 (m, 2H), 3.92 (m, 1H),5.98 (s, 2H), 7.25 (d, 2H), 7.38 (s, 1H), 7.55 (m, 3H), 7.92 (d, 1H),8.41 (s, 1H), 8.85 (m, 2H), 9.18 (brs, 2H), 9.35 (brs, 2H); HPLC: 92.63% (Retention Time= 7.63 min).I-10H -CF 3 CH 2 457.2δ 0.87 (m, 2H), 1.09 (d, 3H),1.56 (m, 6H), 3.03 (m, 2H), 5.97 (s, 2H), 7.17 (d, 2H), 7.29 (s, 1H), 7.58 (d, 2H), 7.93 (d, 1H), 8.22 (s, 1H), 8.73 (m, 1H), 9.00 (brs, 2H), 9.24 (brs, 2H); HPLC: 95.02% (Retention Time= 3.82 min).I-11H -OCF 3 CH 2 474.2δ 1. 4H),2.96 (m, 1H), 3.62 (m, 1H), 5.97 (s, 2H), 7.17 (d, 2H), 7.29 (d, 3H), 7.53 (m, 1H), 7.81 (m, 4H), 8.22 (s, 1H), 8.58 (d, 1H), 9.00 (brs, 2H), 9.24 (brs, 2H); HPLC: 90.18% (Retention Time= 6.7 min).I-12H -OCF 3 CH 2 473.2δ 0.87 (m, 2H), 1.09 (d, 3H),1.56 (m, 6H), 3.05 (m, 2H), 5.89 (s, 2H), 7.12 (d, 2H), 7.25 (d, 3H), 7.53 (m, 1H), 7.90 (d, 1H), 8.22 (s, 1H), 8.73 (m, 1H), 8.99 (brs, 2H), 9.24 (brs, 2H); HPLC: 98.78% (Retention Time= 4.05 min).I-13H -SCH 3 CH 2 436.2δ 1.32 (m, 4H), 1.75 (m, 4H), 2.41 (s,3H),2.96 (m, 1H), 3.62 (m, 1H), 5.82 (s, 2H), 7.05 (d, 2H), 7.12 (d, 3H), 7.22 (s, 1H), 7.52 (m, 1H), 7.83 (d, 1H), 7.93 (m, 3H), 8.22 (s,1H), 9.22 (brs, 2H), 9.24 (brs, 2H); HPLC: 88.69% (Retention Time= 7.36 min).I-14H -C(CH 3 ) 2 CH 2 415.2δ 1.13 (d, 6H), 1.51 (m, 1H), 1.81(m, 1H), 2.12 (m, 2H), 2.28 (m, 2H),2.45 (m, 1H), 3.91 (m, 1H), 5.65 (m, 2H), 5.83 (s, 2H), 7.02 (d, 2H), 7.13 (d, 2H), 7.23 (s, 1H), 7.52 (d, 1H), 7.88 (d, 1H), 8.24 (s, 1H), 8.63 (m, 1H), 9.00 (brs, 2H), 9.26 (brs, 2H).I-15H -C(CH 3 ) 2 CH 2 453.2δ 1.13 (d, 6H), 1.51 (m, 2H), 1.81(m, 3H), 2.12 (m, 3H), 2.81 (m, 1H), 3.91 (m, 1H), 5.83 (s, 2H), 7.02 (d, 2H), 7.13 (d, 2H),7.54 (d, 1H), 7.88 (d, 1H), 8.24 (s, 1H), 8.63 (m, 1H), 9.00 (brs, 2H), 9.26 (brs, 2H); HPLC: 87.34% (Retention Time= 7.27 min).I-16H -C(CH 3 ) 2 CH 2 431.3δ 0.87 (m, 2H), 1.11 (d, 6H), 1.12(m, 3H), 1.60 (m, 6H), 2.78 (m, 1H), 3.05 (m, 2H), 5.83 (s, 2H), 6.97 (d, 2H), 7.10 (d, 2H), 7.19 (m, 1H), 7.52 (d, 1H), 7.88 (d, 1H), 8.22 (s, 1H), 8.70 (m, 1H), 8.86 (brs, 2H), 9.24 (brs, 2H); HPLC: 92.57% (Retention Time= 4.15 min).I-17H -C(CH 3 ) 3 CH 2 446.3δ 1.40(s, 9H), 1.42 (m, 4H), 1.81(m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 5.83 (s, 2H), 6.97 (d, 2H), 7.20 (m, 3H), 7.53 (d, 1H), 7.83 (m, 3H), 8.21 (s, 1H), 8.58 (d, 1H), 9.20 (brs, 2H), 9.22 (brs, 2H); HPLC: 95.69% (Retention Time= 6.89 min).I-24H -H(CH 2 ) 2 426.2δ 3.04 (m, 2H), 4.03 (m, 2H), 4.5 (d, 2H), 4.8 (m, 2H), 7.21 (m, 5H), 7.35 (m, 4H), 7.50 (m, 1H), 7.85 (d, 1H), 8.15 (m, 4H), 9.05 (brs, 2H), 9.25 (brs, 2H); HPLC: 95.36% (Retention Time= 5.59 min).I-25H -H(CH 2 ) 2 426.2δ 3.04 (m, 2H), 4.91 (m, 2H), 7.21 (m, 6H), 7.45 (s, 1H), 7.55 (m, 1H), 7.82 (m, 6H), 8.15 (s, 1H), 8.90 (brs, 2H), 9.30 (brs, 2H), 10.30 (s, 1H); HPLC: 95.18% (Retention Time= 4.96 min).I-26H -H(CH 2 ) 2 426.2δ 3.11 (m, 2H), 4.84 (m, 2H), 7.14 (m, 5H), 7.42 (m, 3H), 7.54 (d, 1H), 7.63 (d, 1H), 7.91 (m, 2H), 8.01 (brs, 1H), 8.16 (s, 1H), 8.26 (s,1H), 9.09 (brs, 2H), 9.31 (brs, 2H),10.50 (s, 1H); HPLC: 94.08% (Retention Time= 5.069 min).I-27H -H(CH 2 ) 2 404.2CD3ODδ 1.51 (m, 5H), 2.05 (m, 4H), 3.19(m, 3H), 3.81 (m, 2H), 7.01 (m, 2H), 7.03 (s, 1H), 7.12 (m, 4H), 7.43 (m, 1H), 7.79 (d, 1H), 7.89 (s, 1H); HPLC: 98.05% (Retention Time= 6.313 min).I-30H -F(CH 2 ) 2 422.2δ 1.42 (m, 4H), 1.81(m, 4H), 2.95 (m, 3H), 3.71 (m, 1H),4.81 (m, 2H), 7.05 (m, 2H), 7.15 (m, 3H), 7.48 (d, 1H), 7.83 (m, 3H), 8.13 (s, 1H), 8.45 (d, 1H), 9.08 (brs, 2H), 9.28 (brs, 2H); HPLC: 96.43% (Retention Time= 4.461 min).I-31H -Br(CH 2 ) 2 482.2δ 1.38 (m, 4H), 1.92 (m, 4H), 3.12 (m, 3H),3.7 (m, 1H), 4.75 (m, 2H), 7.15 (m, 3H), 7.39 (m, 3H), 7.82 (m, 3H), 8.18 (s, 1H), 8.45 (d, 1H), 9.08 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.72% (Retention Time= 5.029 min).I-32H -OCH 3 (CH 2 ) 2 434.3δ 1.38 (m, 4H), 1.92 (m, 4H), 2.98 (m, 3H),3.71 (m, 3H), 4.75 (m, 2H), 6.81 (d, 2H), 7.39 (m, 3H), 7.48 (d, 1H), 7.82 (d, 1H), 7.91 (m, 3H), 8.11 (s,1H),8.46 (d, 1H),9.08 (brs, 2H), 9.27 (brs, 2H); HPLC: 91.07% (Retention Time= 5.432 min).I-34H -H(CH 2 ) 3 418.2δ 1.28 (m, 4H), 1.85 (m, 4H), 2.01 (m, 2H),2.52 (m, 3H), 3.54 (m, 1H),4.65 (m, 2H), 7.12 (m, 3H), 7.22 (m, 2H), 7.44 (d, 1H), 7.79 (d, 1H), 8.09 (brs, 1H),8.51 (d,1H); HPLC: 99.07% (Retention Time= 6.417 min).I-35H (CH 2 ) 2 508.3δ 1.18 (m, 7H), 1.82 (m, 4H),2.52 (m, 3H), 3.14 (m, 2H),3.71 (m, 1H), 4.65 (m, 2H), 6.91 (m, 3H), 7.81 (m, 3H), 7.49 (m, 3H), 7.81 (m, 4H), 8.18 (brs, 1H), 8.49 (d, 1H),9.19 (brs, 3H); HPLC: 98.51% (Retention Time= 5.998 min).I-38-H -H- SO 2 CH 2 454.2CD3ODδ 1.51(m, 4H), 2.15 (m, 4H) 3.13 (m, 1H),3.85 (m, 1H), 5.25 9s, 2H), 7.11 (s, 1H), 7.12 (m, 3H), 7.25 (m, 2H), 7.48 (m, 2H), 7.75 (d, 1H).I-39H H- CH 2 SO 2 454.2δ 1.33(m, 4H), 1.82 (m, 4H) 2.96 (m, 1H),3.71 (m, 1H), 7.11 (s, 1H),6.33 (s, 2H), 7.28 (s, 1H), 7.42 (m, 4H), 7.65 (m, 1H), 7.85 (m, 3H), 8.08 (s, 1H), 8.52 (d, 1H),9.15 (m, 3H); HPLC: 93.09% (Retention Time= 4.23 min). Table-2: Cpd. ID.R 2 R 3 'LLCMS (M+1) + 1< H NMRI-18 CH 2 391.2δ 1.35 (m, 4H), 1.83 (m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 5.95 (s, 2H), 7.15 (d, 2H), 7.48 (s, 1H), 7.66 (d, 1H), 7.80 (m, 2H), 7.92 (d, 1H), 8.15 (s, 1H), 8.58 (d, 2H), 8.65 (d, 1H), 9.12 (brs, 2H), 9.22 (brs, 2H).I-19 CH 2 391.2δ 1.35 (m, 4H), 1.83 (m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 5.95 (s, 2H), 7.15 (d, 2H), 7.38 (s, 1H), 7.53 (d, 1H), 7.75 (m, 2H),7.92 (d, 1H), 8.15 (s, 1H), 8.58 (d, 2H), 8.65 (d, 1H), 9.12 (brs, 2H), 9.22 (brs, 2H); HPLC: 93.22% (Retention Time= 5.738 min).I-37 -SO 2 -490.2δ 1.42 (m, 4H), 1.98 (m, 4H), 3.03 (m, 1H), 3.71 (m, 1H), 7.11 (s, 1H), 7.63 (m, 3H), 7.83 (m, 3H), 8.08 (d, 1H), 8.12 (m, 3H), 8.49 (s, 1H), 8.79 (m, 2H), 9.19 (brs, 2H), 9.42 (brs, 2H); HPLC: 98.49% (Retention Time= 4.824 min).I-243 CH 2 500.2δ 1.32 (m, 4H), 1.82 (m, 2H), 1.95 (m, 2H), 2.95 (m, 1H), 3.71 (m, 1H), 5.82 (s, 2H), 6.88 (d, 2H), 6.98 (m, 2H), 7.12 (m, 5H), 7.55 (d, 1H), 7.88 (d, 1H), 7.98 (m, 2H), 8.28 (s, 1H), 8.64 (d, 1H), 9.21 (brs, 2H), 9.32 (brs, 2H); HPLC: 93.848% (Retention Time= 7.131 min).I-244 CH 2 553.3δ 1.48 (m, 6H), 1.88 (m, 6H), 2.15 (m, 2H), 4.51 (s, 1H), 5.79 (s, 2H), 6.84 (d, 2H), 6.97 (m, 2H), 7.15 (m, 5H), 7.53 (d, 1H), 7.82 (d, 1H), 8.09 (s, 1H), 8.31 (s, 1H), 8.96 (brs, 2H), 9.28 (brs, 2H); HPLC: 98.0% (Retention Time= 8.857 min).I-245 CH 2 537.3δ 1.45 (m, 2H), 1.68 (m, 8H), 1.92 (m, 5H), 5.79 (s, 2H), 6.84 (d, 2H), 6.97 (m, 2H), 7.08 (brs, 1H), 7.15 (m, 2H), 7.24 (d, 1H), 7.42 (s, 1H), 7.58 (d, 1H), 7.85 (d, 1H), 8.31 (m, 2H), 9.08 (brs, 2H), 9.33 (brs, 2H); HPLC: 98.92% (Retention Time= 10.588 min).I-246 CH 2 501.2δ 1.32 (m, 4H), 1.95 (m, 4H), 3.15 (m, 1H), 3.71 (m, 1H), 5.82 (s, 2H), 7.02 (d, 1H), 7.15 (m, 2H), 7.25 (m, 4H), 7.58 (m, 2H), 7.88 (m, 2H), 8.05 (m, 1H), 8.35 (s, 1H), 8.64 (d, 1H), 9.14 (brs, 2H), 9.32 (brs, 2H); HPLC: 97.62% (Retention Time= 4.705 min).I-247 CH 2 516.2δ 1.41 (m, 4H), 1.83 (m, 4H), 2.96 (m, 1H), 3.71 (m, 1H), 5.85 (s, 2H), 6.91 (m, 3H), 7.15 (m, 3H), 7.35 (d, 2H), 7.55 (d, 1H),7.81 (m, 4H), 8.25 (s, 1H), 8.61 (d, 1H), 9.12 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.19% (Retention Time= 7.746 min).I-248 CH 2 516.2δ 1.31 (m, 4H), 1.83 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 5.85 (s, 2H), 7.12 (d, 1H), 7.15 (m, 3H), 7.45 (d, 1H), 7.55 (m, 3H), 7.81 (m, 3H), 8.25 (s, 1H), 8.61 (s, 1H), 9.05 (brs, 2H), 9.25 (brs, 2H); HPLC: 92.54% (Retention Time= 7.347 min).I-249 CH 2 497.3δ 1.31 (m, 4H), 1.83 (m, 4H), 2.96 (m, 1H), 3.72 (m, 1H), 5.82 (s, 2H), 6.95 (m, 4H), 7.15 (m, 4H), 7.45 (s, 1H), 7.55 (d, 1H), 7.85 (m, 3H), 8.25 (s, 1H), 8.61 (d, 1H), 8.61 (d, 1H), 9.15 (brs, 2H), 9.28 (brs, 2H).I-255 CH 2 482.2δ 1.31 (m, 4H), 1.83 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 5.83 (s, 2H), 6.65 (s, 1H), 6.85 (m, 2H), 6.93 (m, 2H), 7.12 (m, 1H), 7.25 (m, 2H), 7.45 (m, 2H), 7.55 (m, 1H), 8.85 (m, 3H), 8.21 (s, 1H), 8.65 (d, 1H), 9.18 (brs, 2H), 9.25 (brs, 2H). Table-3: Cpd. ID.R 2 LCMS (M+1) +< 1< H NMRI-74 452.2δ 5.96 (s, 2H), 7.12 (d, 2H), 7.31 (brs, 1H), 7.50 (m, 4H), 7.74 (d, 2H), 7.86 (brs, 1H),7.97 (d, 1H), 8.04 (s, 1H), 8.20 (brs, 2H), 8.91 (brs, 2H), 9.24 (brs, 2H), 10.61 (s, 1H), 13.01 (brs, 1H); HPLC: 89.45% (Retention Time= 4.718 min).I-85 456.2δ 3.64 (m, 2H), 5.00 (m, 1H), 5.86 (s, 2H), 7.07 (d, 2H), 7.21 (m, 1H), 7.30 (m, 5H), 7.43 (brs, 1H), 7.53 (d, 1H), 7.70 (d, 2H), 7.89 (m, 2H), 8.15 (s, 1H), 9.17 (d, 1H); HPLC: 94.87% (Retention Time= 5.506 min).I-86 456.2δ 3.66 (m, 2H), 5.02 (m, 1H), 5.87 (s, 2H), 7.07 (d, 2H),7.23 (m, 1H), 7.30 (m, 5H), 7.44 (brs, 1H), 7.54 (d, 1H), 7.71 (d, 2H), 7.89 (brs, 1H), 7.94 (d, 1H), 8.16 (s, 1H), 8.95 (brs, 2H), 9.07 (d, 1H), 9.23 (brs, 2H); HPLC: 92.65% (Retention Time= 5.291 min).I-125 484.2δ 0.99 (s, 3H), 1.11 (s, 3H), 4.65 (s, 1H), 4.91 (d, 1H), 7.04 (d, 2H), 7.22 (m, 5H), 7.38 (s, 1H), 7.41 (d, 2H), 7.54 (d, 1H), 7.68 (d, 2H), 7.88 (brs, 1H), 7.93 (d, 1H), 8.18 (s, 1H), 8.73 (d, 1H), 8.90 (brs, 2H), 9.23 (brs, 2H), 10.41 (brs, 1H); HPLC: 93.29% (Retention Time= 5.627 min).I-128 497.2δ 1.87 (m, 1H), 2.02 (m, 1H), 3.04 (d, 1H), 3.23 (m, 2H), 3.38 (m, 2H), 5.95 (s, 2H), 6.27 (d, 1H), 6.27 (d, 1H), 6.94 (m, 2H), 7.08 (m, 3H), 7.32 (brs, 1H), 7.50 (s, 1H), 7.56 (d, 2H), 7.74 (d, 2H), 7.88 (brs, 1H), 8.19 (s, 1H), 8.93 (brs, 2H), 9.25 (brs, 2H), 10.35 (brs, 1H); HPLC: 90.58% (Retention Time= 5.801 min).I-137 478.2δ 5.97 (s, 2H), 7.10 (d, 2H), 7.34 (brs, 1H), 7.59 (m, 2H), 7.72 (m, 2H), 7.75 (m, 6H), 7.88 (s, 1H), 8.01 (d, 1H), 8.20 (s, 1H), 8.51 (s, 1H), 8.96 (brs, 2H), 9.26 (brs, 2H), 10.89 (brs, 1H); HPLC: 94.83% (Retention Time= 4.861 min). Example 2: Synthesis of compound 1-6.N-(1-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H indole-2-carboxamide

[0181] Step-1: tert-butyl 4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)-piperidine-1-carboxylate

[0182] The product of step-2 of example 1 and tert-butyl 4-aminopiperidine-1-carboxylate were treated together to afford the title compound following the procedure described in step-3 of example 1. LCMS: 527.2 (M+1) +< .Step-2: 6-cyano-N-(piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0183] The product of step-1 of example-2 (884 mg, 1.68 mmol) was treated with 30 mL of ethanolic-HCl to afford 665 mg of the title compound following the procedure described in step-4 of example-1 but reaction was done at 0 °C for 2 h. LCMS: 427.2 (M+1) +< .Step-3: tert-butyl (3-(4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)-piperidin-1-yl)propyl)carbamate

[0184] 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) to afford 525 mg of the title compound following the procedure described in step-1 of example -1. LCMS: 584.3 (M+1) +< .Step-4: Ethyl 2-((1-(3-aminopropyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carbimidate

[0185] The product of step-3 of example-2 (450 mg, 0.77 mmol) was treated with 50 mL of ethanolic-HCl to afford 215 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 530.3 (M+1) +< .Step-5: N-(1-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0186] The product of step-4 of example-2 (200 mg, 0.37 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 95 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 501.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 3: Synthesis of compoune I-7 6-Carbamimidoyl-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0187] Step-1: N-(1-(3-aminopropyl)piperidin-4-yl)-6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0188] The product of step-3 of example-2 (550 mg, 1.28 mmol) was treated with 20 mL of ethanolic-HCl to afford 520 mg of the title compound following the procedure described in step-2 of example-2. LCMS: 484.2 (M+1) +< .Step-2: 6-Cyano-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0189] 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-carboxamidine hydrochloride (329 mg, 2.25 mmol) and N,N-diisopropylethylamine (452 mg, 3.50 mmol) and resulted mixture was stirred for 24 h at room temperature. The solvent was evaporated under vacuum to give 250 mg of the title compound which was used as such without further purification. LCMS: 526.2 (M+1) +< .Step-3: Ethyl 2-((1-(3-guanidinopropyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carbimidate

[0190] The product of step-2 of example-3 (250 mg, 0.47 mmol) was treated with 50 mL of ethanolic-HCl to afford 180 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 572.3 (M+1) +< .Step-4: 6-Carbamimidoyl-N-(1-(3-guanidinopropyl)piperidin-4-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0191] The product of step-3 of example-3 (170 mg, 0.29 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 40 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 543.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.72 (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).Example 4: Synthesis of compound I-8 N-(1-(3-aminopropanoyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0192] Step-1: tert-butyl (3-(4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido)-piperidin-1-yl)-3-oxopropyl)carbamate

[0193] The product of step-2 of example-2 (553 mg, 1.3 mmol) and 3-((tertbutoxycarbonyl)amino)propanoic acid (245 mg, 1.3 mmol) were treated together to afford 380 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 598.3 (M+1) +< .Step-2: Ethyl 2-((1-(3-aminopropanoyl)piperidin-4-yl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carbimidate

[0194] The product of step-1 of example-4 (304 mg, 0.51 mmol) was treated with 50 mL of ethanolic-HCl to afford 65 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 544.2 (M+1) +< .Step-3: N-(1-(3-Aminopropanoyl)piperidin-4-yl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-benzyl)-1H-indole-2-carboxamide

[0195] The product of step-2 of example-4 (167 mg, 0.28 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 80 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 515.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 5: Synthesis of compound I-96-carbamimidoyl-N-((1r,4r)-4-(picolinamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0196] Step-1: tert-butyl ((1r,4r)-4-(6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamido) cyclohexyl)carbamate

[0197] 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 afford 520 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 541.2 (M+1) +< .Step-2: N-((1r,4r)-4-aminocyclohexyl)-6-cyano-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0198] The product of step-1 of example-5 (275 mg, 0.51 mmol) was treated with 20 mL of ethanolic-HCl to afford 115 mg of the title compound following the procedure described in step-2 of example-6. LCMS: 441.2 (M+1) +< .Step-3: 6-cyano-N-((1r,4r)-4-(picolinamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0199] 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 afford 420 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 546.3 (M+1) +< .Step-4: Ethyl 2-(((1r,4r)-4-(picolinamido)cyclohexyl)carbamoyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-6-carbimidate

[0200] The product of step-3 of example-5 (275 mg, 0.51 mmol) was treated with 50 mL of ethanolic-HCl to afford 95 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 592.2 (M+1) +< .Step-5: 6-Carbamimidoyl-N-((1r,4r)-4-(picolinamido)cyclohexyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide

[0201] The product of step-4 of example-5 (95mg, 0.16 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 20 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 563.2 (M+1) +< , 1< H NMR (300MHz, CD 3 OD): 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).Example 6: Synthesis of compound I-20 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-+yl)methyl)benzoic acid

[0202] Step-1: 6-Cyano-1H-indole-2-carboxylic acid

[0203] Ethyl 6-cyano-1H-indole-2-carboxylate (710 mg, 3.31 mmol) and lithium hydroxide (486 mg, 11.58 mmol) were treated together to afford 480 mg of the title compound following the procedure described in step-2 of example-1. LCMS : 187.1 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0204] 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 afford 325 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 383.2 (M+1) +< .Step-3: 4-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoic acid

[0205] The product of step-2 of example-6 (325mg, 0.84 mmol) and 4-(bromomethyl)benzoic acid (179 mg, 0.84 mmol) were treated together to afford 198 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 517.2 (M+1) +< .Step-4: 4-((2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoic acid

[0206] The product of step-3 of example-6 (198 mg, 0.38 mmol) was treated with 30 mL of ethanolic-HCl to afford 82 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 463.2 (M+1) +< .Step-5: 4-((3-Amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoic acid

[0207] The product of step-4 of example-6 (80 mg, 0.17 mmol) was treated with 20 mL of ethanolic-NH 3 to afford 14 mg of the title compound following the procedure described in step-5 of example-1. LCMS : 434.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 7: Synthesis of compound I-21 Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)- benzoate

[0208] Step-1: Methyl 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0209] 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 afford 380 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 531.2 (M+1) +< .Step-2: Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoate

[0210] The product of step-1 of example-7 (350 mg, 0.65 mmol) was treated with 50 mL of ethanolic-HCl to afford 153 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 477.2 (M+1) +< .Step-3: Methyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl) benzoate

[0211] The product of step-2 of example-7 (150 mg, 0.28 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 42 mg of the title compound following the procedure described in step-5 of example-1. LCMS : 448.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 8: Synthesis of compound I-22. Ethyl 4-((2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)-benzoate

[0212]

[0213] This compound was prepared by following the procedure described in step-1 to step-3 of example-7 using ethyl 4-(bromomethyl)benzoate. LCMS : 462.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 9: Synthesis of compound I-23Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)-methyl)benzoate

[0214] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0215] The product of step-2 of example-6 (535mg, 1.39 mmol) was dissolved in 10 mL of acetic acid and cooled it to 0 °C. Copper(II) nitrate trihydrate (401mg, 1.66) was added and stirred for 3 h. Reaction mixture was quenched with cold-water and extracted with ethyl acetate, followed by washed with brine and dried over sodium sulphate. Solvent was evaporated to give crude product which was purified with column chromatography using silica-gel as an adsorbent and elution with hexane:ethyl acetate (7:3) afforded 310 mg of the title compound. LCMS: 428.2 (M+1) +< .Step-2: Ethyl 4-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-3-nitro-1H-indol-1-yl)methyl)benzoate

[0216] 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 afford 213 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 590.2 (M+1) +< .Step-3: Ethyl 4-((3-amino-2-(((1r,4r)-4-((tertbutoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0217] The product of step-2 of example-9 (200 mg, 0.33mmol) was dissolved in 10 mL of glacial acetic acid and added zinc (107 mg, 1.65 mmol) in portions at room temperature. Reaction mixture was stirred at RT for 6 h. Contents were filtered through celite pad and filtrate was concentrated under vacuum to afford crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with hexane:ethylacetate (6:4) and afforded the title compound (152 mg). LCMS: 560.3 (M+1) +< .Step-4: Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzoate

[0218] The product of step-3 of example-9 (150 mg, 0.27 mmol) was treated with 40 mL of ethanolic-HCl to afford 111 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 506.3 (M+1) +< .Step-5: Ethyl 4-((3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzoate

[0219] The product of step-4 of example-9 (108 mg, 0.21 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 29 mg of the title compound following the procedure described in step-5 of example-1. LCMS : 477.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.32 (m, 3H), 1.41 (m, 5H), 1.85 (m, 4H), 3.0 (m, 1H), 3.62 (m, 2H), 4.26 (m, 2H),3.62 (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).Example 10: Synthesis of compound I-28 N-(1-(2-Aminoethyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0220] Step-1: Ethyl 6-cyano-1-phenethyl-1H-indole-2-carboxylate

[0221] 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 afford 3100 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 319.1 (M+1) +< .Step-2: 6-Cyano-1-phenethyl-1H-indole-2-carboxylic acid

[0222] The product of step-1 of example-10 (3000 mg, 9.42 mmol) and lithium hydroxide (792 mg, 32.97 mmol) were treated together to afford 2100 mg of the title compound following the procedure described in step-2 of example-1. LCMS : 291.1 (M+1) +< .Step-3: tert-Butyl 4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidine-1-carboxylate

[0223] 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 afford 378 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 473.2 (M+1) +< .Step-4: 6-Cyano-1-phenethyl-N-(piperidin-4-yl)-1H-indole-2-carboxamide

[0224] The product of step-3 of example-10 (350 mg, 0.73 mmol) was treated with 20 mL of ethanolic-HCl to afford 212 mg of the title compound following the procedure described in step-2 of example-2. LCMS: 373.2 (M+1) +< .Step-5: tert-Butyl (2-(4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidin-1-yl)ethyl)carbamate

[0225] The product of step-4 of example-10 (200 mg, 0.53 mmol) and tert-butyl (2-bromoethyl)carbamate (118 mg, 0.53 mmol) were treated together to afford 226 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 516.3 (M+1) +< .Step-6: Ethyl 2-((1-(2-aminoethyl)piperidin-4-yl)carbamoyl)-1-phenethyl-1H-indole-6-carbimidate

[0226] The product of step-5 of example-10 (220 mg, 0.42 mmol) was treated with 50 mL of ethanolic-HCl to afford 105 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 462.3 (M+1) +< .Step-7: N-(1-(2-aminoethyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0227] The product of step-6 of example-10 (105 mg, 0.22 mmol) was treated with 50 mL of ethanolic-NH 3 to afford 43 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 433.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 11: Synthesis of compound I-29 N-(1-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0228] Step-1: tert-Butyl (3-(4-(6-cyano-1-phenethyl-1H-indole-2-carboxamido)piperidin-1-yl)propyl)carbamate

[0229] 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 afford 350 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 530.3 (M+1) +< .Step-2: Ethyl 2-((1-(3-aminopropyl)piperidin-4-yl)carbamoyl)-1-phenethyl-1H-indole-6-carbimidate

[0230] The product of step-1 of example-11 (350 mg, 0.66 mmol) was treated with 50 mL of ethanolic-HCl to afford 253 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 476.3 (M+1) +< .Step-3: N-(1-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-1-phenethyl-1H-indole-2-carboxamide

[0231] The product of step-2 of example-11 (250 mg, 0.55 mmol) was treated with 50 mL of ethanolic-NH 3 to afford 135 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 447.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.62 (m, 2H), 1.19 (m, 4H), 2.85 (m, 4H), 3.05 (m, 6H), 4.05 (m, 1H), 4.73 (m, 2H), 7.15 (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).Example 12: Synthesis of compound I-33 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-2-carboxamide

[0232] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1-(4-(trifluoromethyl)phenethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0233] 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 afford 550 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 600.2 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(4-(trifluoromethyl)phenethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0234] The product of step-1 of example-12 (455 mg, 0.75 mmol) and zinc (246 mg, 3.79 mmol) were treated together to afford 345 mg of the title compound following the procedure described in step-3 of example-9. LCMS : 570.3 (M+1) +< .Step-3: Ethyl-3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-6-carbimidate

[0235] The product of step-2 of example-12 (345 mg, 0.60 mmol) was treated with 50 mL of ethanolic-HCl to afford 180 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 516.2 (M+1) +< .Step-4: 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-(trifluoromethyl)-phenethyl)-1H-indole-2-carboxamide

[0236] The product of step-3 of example-12 (180 mg, 0.34 mmol) was treated with 50 mL of ethanolic-NH 3 to afford 65 mg of the title compound following the procedure described in step-5 of example-1. LCMS : 487.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 13: Synthesis of compound I-36 N-((1r,4r)-4-Aminocyclohexyl)-1-((3-(3-aminopropanamido)phenyl)sulfonyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0237] Step-1: Ethyl 6-cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxylate

[0238] 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 afford 660 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 401.1 (M+1) +< .Step-2: 6-Cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxylic acid

[0239] The product of step-1 of example-13 (550 mg, 1.37 mmol) and lithium hydroxide (201 mg, 4.79 mmol) were treated together to afford 425 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 372.1 (M+1) +< .Step-3: tert-Butyl ((1r,4r)-4-(6-cyano-1-((3-nitrophenyl)sulfonyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0240] 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 afford 368 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 568.2 (M+1) +< .Step-4: tert-Butyl ((1r,4r)-4-(1-((3-aminophenyl)sulfonyl)-6-cyano-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0241] The product of step-3 of example-13 (360 mg, 0.63 mmol) was treated with zinc (205 mg, 3.16 mmol) to afford 210 mg of the title compound following the procedure described in step-3 of example 9. LCMS: 538.2 (M+1) +< .Step-5: tert-Butyl ((1r,4r)-4-(1-((3-(3-(tert-butyl carbamate)-propanamido)phenyl)sulfonyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0242] The product of step-4 of example-13 (200 mg, 0.37 mmol) and 3-((tertbutoxycarbonyl)amino)propanoic acid (70 mg, 0.37 mmol) were treated together to afford 185 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 709.3 (M+1) +< .Step-6: Ethyl-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-((3-(3-aminopropanamido)phenyl)-sulfonyl)-1H-indole-6-carbimidate

[0243] The product of step-5 of example-1 (185 mg, 0.26 mmol) was treated with 50 mL of ethanolic-HCl to afford 88 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 555.2 (M+1) +< .Step-7: N-((1r,4r)-4-Aminocyclohexyl)-1-((3-(3-aminopropanamido)phenyl)sulfonyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0244] The product of step-6 of example-13 (85 mg, 0.15 mmol) was treated with 50 mL of ethanolic-NH 3 to afford 18 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 526.2 (M+1) +< .General synthetic scheme 2:

[0245] Example 14: Synthesis of compound I-406-Carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0246] Step-1: Ethyl 6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxylate

[0247] Ethyl 6-cyano-1H-indole-2-carboxylate (3.5 g, 16.33 mmol) and ((2-bromoethyl)sulfonyl)benzene (4.68 mg, 16.33 mmol) were treated together to afford 5.2 g of the title compound following the procedure described in step-1 of example-1. LCMS : 383.1 (M+1) +< .Step-2: 6-Cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxylic acid

[0248] 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 to afford 4.1 g of the title compound following the procedure described in step-2 of example-1. LCMS : 355.1 (M+1) +< .Step-3: 6-Cyano-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0249] 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 afford 645 mg of the title compound following the procedure described in step-3 of example-1. LCMS : 498.1 (M+1) +< .Step-4: 6-(N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)-phenyl)-1H-indole-2-carboxamide

[0250] The product of step-3 of example-14 (550 mg, 1.10 mmol) was dissolved in 10 mL of ethanol and added aqueous hydroxylamine solution (1.3 mL) and resulting mixture was refluxed for 4 h at 80 °C. Solvent was evaporated under vacuum to afford the title compound (425 mg) which was used for the next step without further purification. LCMS : 531.1 (M+1) +< .Step-5: 6-(N'-acetoxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0251] The product of step-4 of example-14 (570 mg, 1.07 mmol) was dissolved in 5 mL of acetic acid and added acetic anhydride (0.87 mg, 8.56 mmol) and resulting mixture was stirred at RT for 2 h. Solvent was evaporated under vacuum to afford the title compound (560 mg) which was used for the next step without further purification. LCMS : 573.1 (M+1) +< .Step-6: 6-Carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide

[0252] The product of step-5 of example-14 (450 mg, 0.78 mmol) was dissolved in 5 mL of acetic acid and added zinc (408 mg, 6.24 mmol) in portions and resulting mixture was stirred at RT for 6h. Reaction mixture was filtered through celite pad and resulting filtrate was concentrated under vacuum to give crude product which was purified with reversed-phase preparative HPLC and afforded the title compound (275 mg). LCMS : 573.1 (M+1) +< , 1< H NMR (300MHz, DMSOd 6 ): 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).

[0253] The following compounds listed in table-4 were prepared according to Scheme-2 by following similar procedure as described above for example-14 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-4: Cpd. ID.R 2 LCMS (M+1) +< 1< H NMRI-41 465.1δ 3.98 (m, 2H), 4.92 (m, 2H), 6.97 (m, 1H), 7.42 (m, 2H), 7.51 (m, 2H), 7.59 (m, 2H), 7.69 (m, 2H), 7.90 (m, 3H), 8.00 (s, 1H), 9.25 (brs, 2H), 9.33 (brs, 2H), 10.76 (s, 1H); HPLC: 93.52% (Retention Time= 6.336 min).I-42 465.1δ 3.97 (m, 2H), 4.91 (m, 2H), 7.21 (m, 2H), 7.38 (s, 1H), 7.51 (d, 2H), 7.60 (m, 2H), 7.72 (m, 2H), 7.88 (m, 3H), 7.97 (s, 1H), 9.21 (brs, 2H), 9.32 (brs, 2H), 10.6 (s, 1H); HPLC: 94.07% (Retention Time= 7.022 min).I-43 515.1δ 4.08 (m, 2H), 5.02 (m, 2H), 7.53 (s, 1H), 7.60 (d, 1H), 7.69 (m, 2H), 7.83 (m, 3H), 7.99 (m, 6H), 9.23 (brs, 2H), 9.40 (brs, 2H), 10.88 (brs, 1H); HPLC: 95.35% (Retention Time= 6.922 min).I-44 516.2δ 1.91 (m, 4H), 3.20 (m, 4H), 3.95 (m, 2H), 4.89 (m, 2H), 6.53 (m, 2H), 7.30 (s, 1H), 7.49 (d, 3H), 7.57 (m, 2H), 7.73 (m, 1H), 7.84 (m, 4H), 8.98 (brs, 2H), 9.28 (brs, 2H), 10.18 (brs, 1H); HPLC: 98.7% (Retention Time= 6.79 min).I-45 468.2δ 1.41 (m, 4H), 1.85 (m, 5H), 2.90 (m, 1H), 3.54 (m, 1H), 3.85 (m, 2H), 4.87 (m, 2H), 7.18 (s, 1H), 7.47 (d, 1H), 7.59 (m, 2H), 7.71 (m, 1H), 7.81 (m, 3H), 7.95 (m, 2H), 8.54 (d, 1H), 9.23 (d, 3H); HPLC: 98.89% (Retention Time= 4.35 min).I-46 467.2δ 0.88 (m, 3H), 1.50 (m, 4H), 1.65 (m, 5H), 3.90 (m, 3H), 4.87 (m, 2H), 7.14 (d, 1H), 7.47 (d, 1H), 7.61 (m, 2H), 7.74 (m, 2H), 7.81 (m, 3H), 8.35 (m, 1H), 9.06 (brs, 2H), 9.27 (brs, 2H); HPLC: 96.87% (Retention Time= 3.598 min).I-47 451.2δ 1.54 (m, 2H), 1.81 (m, 2H), 2.22 (m, 2H), 3.92 (m, 3H), 4.88 (m, 2H), 5.67 (m, 2H), 7.16 (s, 1H), 7.47 (d, 1H), 7.59 (m, 2H), 7.71 (m, 1H), 7.81 (m, 3H), 8.52 (m, 1H), 8.92 (d, 1H), 8.92 (brs, 2H), 9.27 (brs, 2H); HPLC: 96.25% (Retention Time= 3.256 min).I-48 489.2δ 1.61 (m, 2H), 1.84 (m, 3H), 2.04 (m, 4H), 3.91 (m, 3H), 4.89 (m, 2H), 7.16 (s, 1H), 7.47 (d, 1H), 7.61 (m, 2H), 7.72 (m, 1H), 7.81 (m, 3H), 8.54 (m, 1H), 9.00 (brs, 2H), 9.27 (brs, 2H); HPLC: 95.67% (Retention Time= 6.084 min).I-49 467.2δ 0.89 (m, 2H), 1.15 (m, 3H), 1.63 (m, 6H), 3.05 (m, 2H), 3.92 (m, 2H), 4.87 (m, 2H), 7.13 (s, 1H), 7.47 (d, 1H), 7.58 (m, 2H), 7.71 (m, 1H), 7.80 (m, 4H), 8.68 (m, 1H), 9.14 (brs, 2H), 9.29 (brs, 2H); HPLC: 98.85% (Retention Time= 7.193 min).I-50 468.2δ 1.34 (m, 2H), 1.84 (m, 3H), 2.86 (m, 2H), 3.16 (m, 2H), 3.30 (m, 2H), 3.95 (m, 2H), 4.93 (m, 2H), 7.16 (s, 1H), 7.51 (d, 1H), 7.63 (m, 2H), 7.73 (m, 1H), 7.81 (m, 3H), 8.49 (brs, 1H), 8.69 (brs, 1H), 8.84 (m, 1H), 9.27 (brs, 3H); HPLC: 90.13% (Retention Time= 4.522 min).I-51 468.2δ 1.20 (m, 1H), 1.60 (m, 1H), 1.78 (m, 2H), 1.96 (m, 1H), 2.66 (m, 2H), 3.15 (m, 2H), 3.93 (m, 2H), 4.91 (m, 2H), 7.14 (s, 1H), 7.47 (d, 1H), 7.56 (m, 2H), 7.69 (m, 1H), 7.79 (m, 3H), 7.83 (s, 1H), 8.45 (m, 1H), 8.79 (m, 1H), 8.84 (m, 1H), 9.22 (brs, 2H), 9.29 (brs, 2H); HPLC: 98.74% (Retention Time= 4.635 min).I-52 468.2δ 1.40 (m, 1H), 1.60 (m, 4H), 3.11 (m, 2H), 3.44 (m, 4H), 3.75 (m, 1H), 3.94 (m, 2H), 4.33 (brs, 1H), 4.90 (m, 2H), 7.16 (s, 1H), 7.49 (d, 1H), 7.63 (m, 2H), 7.73 (m, 2H), 7.83 (m, 3H), 8.70 (m, 1H), 9.02 (brs, 2H), 9.30 (brs, 2H); HPLC: 76.34% (Retention Time= 5.455 min).I-53 468.2δ 1.38 (m, 1H), 1.58 (m, 4H), 2.49 (m, 1H), 3.08 (m, 2H), 3.90 (m, 4H), 4.87 (m, 4H), 7.11 (s, 1H), 7.45 (d, 1H), 7.57 (m, 2H), 7.69 (m, 2H), 7.83 (m, 3H), 8.66 (m, 1H); HPLC: 95.96% (Retention Time= 5.498 min).I-54 503.2δ 1.91 (m, 2H), 1.70 (m, 5H), 2.01 (m, 2H),3.14 (m, 2H), 3.93 (m, 2H), 4.90 (m, 2H), 7.14 (s, 1H), 7.48 (d, 1H), 7.60 (m, 2H), 7.71 (m, 1H), 7.81 (m, 3H), 8.78 (brs, 1H), 9.03 (brs, 2H), 9.28 (brs, 2H), 10.18 (brs, 1H); HPLC: 98% (Retention Time= 6.214 min). Example 15: Synthesis of compound I-55N-((1r,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0254] Step-1: tert-Butyl-((1r,4r)-4-(6-cyano-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)- cyclohexyl)carbamate

[0255] 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 to afford 780 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 596.2 (M+1) +< .Step-2: Ethyl-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carbimidate

[0256] The product of step-1 of example-15 (650 mg, 1.09 mmol) was treated with 60 mL of ethanolic-HCl to afford 380 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 542.2 (M+1) +< .Step-3: N-((1r,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0257] The product of step-2 of example-15 (250 mg, 0.46 mmol) was treated with 50 mL of ethanolic-NH 3 to afford 135 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 513.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.21 (m, 2H), 1.38 (m, 2H), 1.85 (m, 4H), 3.05 (m, 1H), 3.55 (m, 1H), 4.01 (m, 2H), 4.55 (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).Example 16: Synthesis of compound I-56 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0258] Step-1: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0259] The product of step-1 of example-15 (335 mg, 0.56 mmol) and zinc (182 mg, 2.80 mmol) were treated together to afford 180 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 566.2 (M+1) +< .Step-2: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carbimidate

[0260] The product of step-1 of example-16 (175 mg, 0.30 mmol) was treated with 40 mL of ethanolic-HCl to afford 105 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 512.2 (M+1) +< .Step-3: tert-Butyl ((1r,4r)-4-(3-amino-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0261] The product of step-2 of example-16 (105 mg, 0.20 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 43 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 483.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.45 (m, 4H), 1.91 (m, 4H), 3.08 (m, 1H), 3.52 (m, 1H), 3.79 (m, 2H), 4.67 (m, 2H), 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).Example 17: Synthesis of compound I-17Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)carbamate

[0262] Step-1: tert-Butyl ((1r,4r)-4-(3-(ethylcarbamate)-6-cyano-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0263] 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 afford 553 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 638.3 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(3-(ethylcarbamate)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)-ethyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0264] The product of step-1 of example-17 (540 mg, 0.84 mmol) and aqueous hydroxylamine (2.7 mL) were treated together to afford 329 mg of the title compound following the procedure described in step-4 of example-14. LCMS : 671.3 (M+1) +< .Step-3: Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'hydroxycarbamimidoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indol-3-yl)carbamate

[0265] The product of step-2 of example-17 (315mg, 0.46 mmol) was treated with 30 mL of ethanolic-HCl to afford 180 mg of the title compound following the procedure described in step-2 of example-2. LCMS: 571.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 18: Synthesis of compound I-58 3-Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0266] Step-1: 6-Cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0267] The product of step-1 of example-6 (1.0 g, 5.34 mmol) and cyclohexylmethanamine (603 mg, 5.34 mmol) were treated together to afford 1.25 g of the title compound following the procedure described in step-3 of example-1. LCMS : 282.2 (M+1) +< .Step-2: 6-Cyano-N-(cyclohexylmethyl)-3-nitro-1H-indole-2-carboxamide

[0268] 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 to afford 352 mg of the title compound following the procedure described in step-1 of example-9. LCMS: 327.1 (M+1) +< .Step-3: 6-Cyano-N-(cyclohexylmethyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0269] 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 afford 356 mg of the title compound following the procedure described in step-1 of example-1. LCMS : 495.2 (M+1) +< .Step-4: 3-Amino-6-cyano-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0270] The product of step-3 of example-18 (350 mg, 0.70 mmol) and zinc (229 mg, 3.5 mmol) were treated together to afford 195 mg of the title compound following the procedure described in step-3 of example-9. LCMS : 465.2 (M+1) +< .Step-5: Ethyl 3-amino-2-((cyclohexylmethyl)carbamoyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carbimidate

[0271] The product of step-4 of example-18 (190 mg, 0.40 mmol) was treated with ethanolic-HCl to afford 133 mg of the title compound following the procedure described in step-4 of example-1. LCMS : 511.2 (M+1) +< .Step-6: 3-Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carboxamide

[0272] The product of step-5 of example-18 (125 mg, 0.24 mmol) was treated with ethanolic-NH 3 to afford 38 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 482.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 19: Synthesis of compound I-596-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0273] Step-1: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0274] 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 afford 5.26 g of the title compound following the procedure described in step-1 of example 1. LCMS : 348.1 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid

[0275] 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 afford 882 mg of the title compound following the procedure described in step-2 of example 1. LCMS : 320.1 (M+1) +< .Step-3: 1-(4-carbamoylbenzyl)-6-cyano-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0276] 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 afford 385 mg of the title compound following the procedure described in step-3 of example 1. LCMS : 413.1 (M+1) +< .Step-4: 1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-6-(N'-hydroxycarbamimidoyl)-1H-indole-2-carboxamide

[0277] The product of step-3 of example 19 (360 mg, 0.87 mmol) and aqueous hydroxylamine (1.8 mL) were treated together to afford 310 mg of the title compound following the procedure described in step-4 of example 40. LCMS : 446.2 (M+1) +< .Step-5: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0278] 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 afford 240 mg of the title compound following the procedure described in step-5 of example 14. LCMS : 488.2 (M+1) +< .Step-6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0279] The product of step-5 of example 19 (230 mg, 0.47 mmol) and zinc (125 mg, 1.89 mmol) were treated together to afford 128 mg of the title compound following the procedure described in step-6 of example 14. LCMS : 430.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 5.94 (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= 3.018 min).

[0280] The following compounds listed in table-5 and table-6 were prepared according to Scheme-2 by following similar procedure as described above for example-19 using appropriate reagents with suitable modifications known to the one skilled in the art. Table -5: Cpd. ID.R 2 LCMS (M+1) +< 1< H NMRI-60 480.2δ 6.02 (s, 2H), 7.25 (d, 2H), 7.48 (d, 1H), 7.59 (m, 2H), 7.67 (brs, 1H), 7.71 (d, 2H), 7.99 (m, 2H), 8.20 (brs, 2H), 9.17 (m, 4H), 9.29 (brs, 2H), 10.91 (brs, 1H); HPLC: 95.48% (Retention Time= 5.739 min).I-61 480.2δ 6.02 (s, 2H), 7.25 (d, 2H), 7.61 (d, 1H), 7.68 (s, 1H), 7.71 (m, 5H), 7.96 (d, 2H), 8.02 (d, 1H), 8.22 (brs, 1H), 9.20 (m, 3H), 9.30 (brs, 2H), 10.93 (brs, 1H); HPLC: 90.47% (Retention Time= 5.632 min).I-62 430.2δ 6.02 (s, 2H), 6.96 (m, 1H), 7.28 (d, 2H), 7.41 (m, 1H), 7.57 (m, 3H), 7.70 (m, 3H), 7.98 (d, 1H), 8.22 (brs, 1H); HPLC: 97.26% (Retention Time= 5.232 min).I-63 458.2δ 1.44 (m, 3H), 5.10 (m, 1H), 5.87 (s, 2H), 7.03 (d, 2H), 7.10 (m, 2H), 7.31 (m, 4H), 7.55 (d, 1H), 7.73 (d, 2H), 7.93 (m, 2H), 8.19 (s, 1H), 8.95 (brs, 2H), 9.16 (d, 1H), 9.24 (brs, 2H); HPLC: 91.78% (Retention Time= 3.935 min).I-64 452.2δ 1.92 (m, 2H), 2.68 (m, 2H), 2.86 (m, 2H), 5.94 (s, 2H), 7.11 (m, 5H), 7.34 (brs, 1H), 7.48 (s, 1H), 7.57 (d, 1H), 7.76 (d, 2H), 7.90 (brs, 1H), 7.96 (d, 1H), 8.24 (brs, 1H), 8.99 (brs, 2H), 9.28 (brs, 2H), 10.27 (brs, 1H); HPLC: 89.92% (Retention Time= 6.261 min).I-65 504.2δ 5.94 (s, 2H), 6.97 (m, 3H), 7.09 (m, 3H), 7.32 (brs, 1H), 7.35 (m, 3H), 7.50 (s, 1H), 7.55 (d, 1H), 7.74 (d, 4H), 7.89 (brs, 1H), 7.94 (d, 1H), 8.20 (brs, 1H), 10.61 (brs, 1H); HPLC: 92.49% (Retention Time= 3.238 min).I-66 488.2δ 5.96 (s, 2H), 7.12 (d, 2H), 7.34 (m, 2H), 7.45 (m, 3H), 7.57 (m, 2H), 7.67 (m, 5H), 7.75 (d, 2H), 7.82 (d, 3H), 7.84 (brs, 1H), 7.99 (d, 1H), 8.22 (brs, 1H), 8.91 (brs, 2H), 9.26 (brs, 2H), 10.61 (brs, 1H); HPLC: 91.77% (Retention Time= 6.153 min).I-67 442.2δ 3.74 (s, 3H), 5.90 (s, 2H), 6.68 (m, 1H), 7.10 (d, 2H), 7.23 (m, 2H), 7.33 (m, 2H), 7.41 (brs, 1H), 7.47 (s, 1H), 7.69 (s, 1H), 7.75 (d, 2H), 7.81 (d, 1H), 8.20 (brs, 1H),9.12 (brs, 2H), 9.27 (brs, 2H), 10.42 (brs, 1H); HPLC: 92.58% (Retention Time= 5.984 min).I-68 456.2δ 2.45 (s, 3H), 5.93 (s, 2H), 6.93 (d, 1H), 7.08 (d, 2H), 7.23 (m, 2H), 7.45 (m, 2H), 7.66 (brs, 1H), 7.72 (d, 2H), 7.88 (m, 1H), 8.19 (d, 1H), 9.01 (brs, 2H), 9.25 (brs, 2H), 10.56 (brs, 1H); HPLC: 93.76% (Retention Time= 6.256 min).I-69 472.2δ 3.73 (s, 6H), 5.95 (s, 2H), 6.91 (d, 1H), 7.13 (d, 2H), 7.29 (m, 2H), 7.39 (m, 1H), 7.46 (m, 1H), 7.55 (d, 2H), 7.88 (m, 1H), 7.92 (d, 1H), 8.17 (brs, 1H),9.28 (brs, 2H),10.42 (brs, 1H); HPLC: 89.19% (Retention Time= 11.717 min).I-70 440.2δ 1.44 (d, 3H), 5.1 (m, 1H), 5.88 (s, 2H), 7.04 (d, 2H), 7.23 (m, 1H), 7.30 (m, 4H), 7.35 (brs, 1H), 7.38 (s, 2H), 7.54 (d, 1H), 7.72 (d, 1H), 7.90 (m, 2H), 8.18 (brs, 1H), 8.95 (brs, 2H), 9.21 (d, 1H), 9.26 (brs, 2H); HPLC: 91.23% (Retention Time= 2.78 min).I-71 442.2δ 2.07 (s, 3H), 5.94 (s, 2H), 6.99 (s, 2H), 7.11 (d, 2H), 7.33 (s, 1H), 7.38 (s, 1H), 7.49 (s, 1H), 7.56 (d, 1H), 7.74 (d, 1H), 7.89 (s, 1H), 7.96 (d, 1H), 8.20 (s, 1H), 9.00 (brs, 2H),9.26 (brs, 2H), 9.41 (s, 1H), 10.4(s, 1H); HPLC: 93.04% (Retention Time= 4.949 min).I-72 440.2δ 1.44 (d, 3H), 5.11 (m, 1H), 5.87 (s, 2H), 7.04 (d, 2H), 7.21 (m, 1H), 7.30 (m, 4H), 7.32 (brs, 1H), 7.38 (s, 2H), 7.54 (d, 1H), 7.72 (d, 1H), 7.90 (m, 2H), 8.18 (brs, 1H), 8.93 (brs, 2H), 9.14 (d, 1H), 9.23 (brs, 2H); HPLC: 95.71% (Retention Time= 6.119 min).I-73 463.2δ 5.96 (s, 2H), 7.10 (d, 2H), 7.37 (brs, 1H), 7.56 (d, 1H), 7.60 (d, 1H), 7.70 (m, 2H),7.80 (m, 3H),7.94 (brs, 1H), 8.03 (d, 1H), 8.08 (d, 1H), 8.29 (brs, 1H), 8.44 (d, 1H), 8.95 (brs, 2H), 9.28 (brs, 2H), 9.39 (brs, 1H); HPLC: 87.91% (Retention Time= 4.704 min).I-75 458.2δ 1.42 (d, 3H), 5.1 (m, 1H), 5.87 (s, 2H), 7.03 (m, 4H), 7.30 (m, 4H), 7.54 (d, 1H), 7.72 (d, 2H), 7.90 (m, 2H), 8.18 (brs, 1H), 8.93 (brs, 2H), 9.14 (d, 1H), 9.23 (brs, 2H); HPLC: 94.97% (Retention Time= 6.236 min).I-76 444.2δ 4.45 (d, 2H), 5.94 (s, 2H), 7.01 (m, 4H), 7.31 (m, 2H), 7.37 (s, 1H), 7.54 (d, 1H), 7.74 (d, 2H), 7.87 (brs, 1H), 7.93 (d, 1H), 8.19 (s, 1H), 8.89 (brs, 2H), 9.23 (brs, 2H), 9.33 (m, 1H); HPLC: 96.13% (Retention Time= 2.712 min).I-77 426.2δ 4.45 (d, 2H), 5.97 (s, 2H), 7.06 (d, 2H), 7.23 (d, 2H), 7.30 (m, 5H), 7.56 (d, 1H), 7.76 (d, 2H), 7.94 (m, 2H), 8.22 (brs, 1H), 8.92 (brs, 2H), 9.25 (brs, 2H), 9.34 (m, 1H); HPLC: 90.23% (Retention Time= 6.194 min).I-78 509.2δ 1.84 (m, 4H), 3.41 (m, 4H), 5.95 (s, 2H), 7.10 (d, 2H), 7.31 (brs, 1H), 7.52 (m, 4H), 7.75 (m, 4H), 7.87 (brs, 1H), 7.99 (d, 1H), 8.21 (brs, 1H),8.93 (brs, 2H), 9.26 (brs, 2H); HPLC: 96.67% (Retention Time= 5.828 min).I-79 454.2δ 1.19 (m, 6H), 2.86 (m, 1H), 5.96 (s, 2H), 6.99 (m, 1H), 7.10 (d, 1H), 7.31 (m, 2H), 7.44 (m, 1H), 7.57 (m, 3H),7.65 (m, 1H), 7.77 (d, 1H), 7.93 (m, 2H), 8.19 (d, 1H), 8.95 (d, 2H), 9.26 (d, 2H), 10.51 (brs, 1H); HPLC: 93.09% (Retention Time= 3.885 min).I-80 462.2δ 4.45 (d, 2H), 5.94 (s, 2H), 6.94 (d, 2H), 7.04 (m, 2H), 7.31 (brs, 2H), 7.39 (s, 1H), 7.54 (m, 1H), 7.73 (d, 2H), 7.86 (brs, 1H), 7.94 (d, 1H), 8.18 (s, 1H), 8.89 (brs, 2H), 9.23 (brs, 2H), 9.38 (m, 1H); HPLC: 99.33% (Retention Time= 3.464 min).I-81 462.2δ 2.78 (m, 2H), 3.48 (m, 2H), 5.93 (s, 2H), 7.06 (d, 2H), 7.16 (m, 3H), 7.23 (m, 3H), 7.28 (brs, 1H), 7.54 (d, 1H), 7.76 (d, 2H), 7.91 (m, 2H), 8.16 (s, 1H), 8.86 (m, 1H), 8.92 (brs, 2H), 9.23 (brs, 2H); HPLC: 97.89% (Retention Time= 5.911 min).I-82 468.2δ 0.68 (d, 3H), 0.92 (d, 3H), 4.58 (m, 1H), 2.48 (m, 1H), 5.82 (d, 2H), 7.03 (m, 3H), 7.23 (m, 8H), 7.53 (d, 1H), 7.67 (d, 2H), 7.87 (brs, 1H), 7.92 (d, 1H), 8.18 (s, 1H), 8.95 (brs, 2H), 9.09 (d, 1H), 9.23 (brs, 2H); HPLC: 89.62% (Retention Time= 2.908 min).I-83 468.2δ 4.52 (d, 2H), 5.95 (s, 2H), 7.04 (d, 2H), 7.33 (brs, 1H), 7.38 (s, 1H), 7.46 (m, 5H), 7.73 (d, 2H), 7.89 (brs, 1H), 7.94 (d, 1H), 8.19 (brs, 1H), 8.94 (brs, 2H), 9.24 (brs, 2H), 9.40 (m, 1H); HPLC: 99.08% (Retention Time= 2.884 min).I-84 446.1δ 5.94 (s, 2H), 7.10 (d, 2H), 7.35 (brs, 1H), 7.41 (m, 2H), 7.54 (s, 1H), 7.57 (m, 1H), 7.75 (m, 4H), 7.89 (brs, 1H), 7.99 (d, 1H), 8.21 (s, 1H), 8.96 (brs, 2H), 9.27 (brs, 2H), 10.71 (s, 1H); HPLC: 96.173% (Retention Time= 3.279 min).I-87 448.1δ 5.92 (s, 2H), 7.08 (d, 2H), 7.33 (brs, 1H), 7.44 (m, 4H), 7.73 (d, 2H), 7.84 (m, 2H), 7.98 (d, 1H), 8.20 (s, 1H),8.98 (brs, 2H), 9.25 (brs, 2H), 10.78 (brs, 1H); HPLC: 96.26% (Retention Time= 3.586 min).I-88 469.1δ 5.97 (s, 2H), 7.12 (d, 2H), 7.31 (brs, 1H), 7.58 (m, 2H), 7.74 (m, 3H), 7.87 (brs, 1H), 7.99 (m, 2H), 8.21 (s, 1H), 8.64 (d, 1H), 9.00 (brs, 2H), 9.27 (brs, 2H), 9.30 (s, 1H) 10.83 (brs, 1H); HPLC: 87.07% (Retention Time= 5.59 min).I-89 466.1δ 5.92 (s, 2H), 7.07 (d, 2H), 7.32 (brs, 1H), 7.53 (m, 2H), 7.65 (m, 2H), 7.73 (d, 2H), 7.88 (brs, 1H), 7.99 (d, 1H), 8.20 (s, 1H), 8.97 (brs, 2H), 9.26 (brs, 2H), 10.88 (brs, 1H); HPLC: 97.15% (Retention Time= 3.249 min).I-90 481.2δ 1.92 (m, 4H), 3.35 (m, 4H), 5.96 (s, 2H), 6.48 (d, 2H), 7.10 (d, 2H), 7.31 (brs, 1H), 7.42 (m, 4H), 7.75 (d, 2H), 7.87 (brs, 1H), 7.95 (d, 1H), 8.18 (s, 1H), 8.90 (brs, 2H), 9.29 (brs, 2H), 10.40 (s, 1H); HPLC: 92.5% (Retention Time= 3.176 min).I-91 452.2δ 1.92 (m, 2H), 2.68 (m, 2H), 2.87 (m, 2H), 5.94 (s, 2H), 7.11 (d, 4H), 7.33 (brs, 1H), 7.46 (s, 1H), 7.56 (d, 1H), 7.76 (d, 2H), 7.91 (m, 2H), 8.23 (s, 1H), 10.27 (brs, 1H); HPLC: 90.02% (Retention Time= 6.249 min).I-92 495.2δ 2.24 (m, 2H), 4.01 (m, 2H), 4.32 (m, 2H), 5.96 (s, 2H), 7.11 (d, 2H), 7.34 (brs, 1H), 7.59 (m, 4H), 7.75 (d, 2H), 7.80 (d, 2H), 7.83 (brs, 1H), 8.00 (d, 1H),8.24 (s, 2H), 9.00 (brs, 2H), 9.29 (brs, 2H), 10.80 (s, 1H); HPLC: 96.38% (Retention Time= 5.454 min).I-93 513.2δ 2.99 (s, 3H), 3.14 (s, 3H), 4.83 (s, 2H), 6.03 (s, 2H), 6.76 (m, 1H), 7.20 (d, 2H), 7.26 (d, 2H), 7.40 (m, 2H), 7.46 (s, 1H), 7.53 (brs, 1H), 7.58 (d, 1H), 7.77 (d,2H), 7.96 (d, 1H), 8.09 (s, 1H); HPLC: 95.16% (Retention Time= 5.498 min).I-94 476.2δ 1.42 (m, 3H), 5.08 (m, 1H), 5.85 (s, 2H), 7.03 (d, 2H), 7.14 (brs, 1H), 7.31 (m, 4H), 7.55 (d, 1H), 7.72 (d, 2H), 7.90 (m, 2H), 8.19 (s, 1H), 8.98 (brs, 2H), 9.16 (d, 1H), 9.24 (brs, 2H); HPLC: 98.37% (Retention Time= 3.123 min).I-95 458.2δ 1.44 (d, 3H), 5.10 (m, 1H), 5.88 (s, 2H), 7.03 (d, 2H), 7.14 (m, 2H), 7.31 (m, 2H),7.41 (s, 2H), 7.55 (d, 1H), 7.72 (d, 2H), 7.90 (brs, 1H), 7.93 (d, 1H), 8.20 (brs, 1H), 8.97 (brs, 2H), 9.19 (d, 1H), 9.26 (brs, 2H); HPLC: 96.55% (Retention Time= 3.073 min).I-96 454.2δ 0.87 (m, 3H), 1.80 (m, 2H), 4.89 (m, 1H), 5.85 (s, 2H), 7.07 (d, 2H), 7.21 (m, 1H), 7.31 (m, 6H), 7.53 (d, 1H), 7.70 (d, 2H), 7.87 (brs, 1H), 8.17 (s, 1H), 9.11 (d, 1H); HPLC: 97.36% (Retention Time= 6.276 min).I-97 517.2δ 2.41 (m, 2H), 3.44 (s, 4H), 5.93 (s, 2H), 6.58 (d, 2H), 7.09 (d, 2H), 7.43 (brs, 1H),7.53 (m, 3H), 7.71 (d, 2H), 7.93 (d, 1H), 8.11 (s, 1H), 8.86 (s, 2H), 9.28 (brs, 2H), 10.37 (s, 1H); HPLC: 97.56% (Retention Time= 6.406 min).I-98 474.2δ 1.44 (m, 3H), 5.04 (m, 1H), 5.87 (s, 2H), 7.03 (d, 2H), 7.32 (m, 6H), 7.55 (d, 1H), 7.73 (d, 2H), 7.93 (m, 1H), 8.19 (s, 1H), 8.92 (brs, 2H), 9.16 (d, 1H), 9.24 (brs, 2H); HPLC: 90.81% (Retention Time= 3.207 min).I-99 513.2δ 2.66 (s, 3H), 2.83 (s, 3H), 4.76 (s, 2H), 5.94 (s, 2H), 6.88 (d, 2H), 7.09 (d, 2H), 7.31 (brs, 1H),7.55 (m, 3H), 7.73 (d, 2H), 7.87 (brs, 1H), 7.97 (d, 1H), 8.20 (s, 1H), 8.92 (brs, 2H), 9.24 (brs, 2H), 10.46 (s, 1H); HPLC: 97.01% (Retention Time= 2.729 min).I-100 495.2δ 1.90 (m, 4H),3.12 (m, 4H), 4.37 (m, 2H), 5.97 (s, 2H), 6.39 (m, 2H), 7.03 (m, 3H), 7.35 (m, 2H), 7.55 (d, 1H), 7.73 (d, 2H), 7.90 (m, 2H), 8.17 (s, 1H), 8.91 (brs, 2H), 9.23 (m, 3H).I-101 481.2δ 1.92 (m, 4H), 3.19 (m, 4H), 5.94 (s, 2H), 6.29 (d, 2H), 6.95 (s, 1H), 7.01 (d, 1H), 7.07 (m, 2H), 7.32 (brs, 1H), 7.48 (s, 1H), 7.55 (d, 1H), 7.75 (d, 2H), 7.87 (brs, 1H), 7.95 (d, 1H), 8.17 (s, 1H), 8.87 (brs, 2H), 9.23 (s, 2H), 10.34 (brs, 1H).I-102 495.2δ 1.52 (m, 2H), 1.63 (m, 4H), 3.12 (m, 4H), 5.94 (s, 2H), 6.97 (brs, 1H), 7.12 (d, 2H), 7.32 (s, 1H), 7.46 (s, 1H), 7.55 (d, 3H), 7.73 (d, 2H), 7.87 (brs, 1H), 7.97 (d, 1H), 8.19 (s, 1H), 8.97 (brs, 2H), 9.24 (brs, 2H), 10.41 (brs, 1H); HPLC: 99.18% (Retention Time= 5.13 min).I-104 499.2δ 1.85 (m, 4H), 3.25 (m, 4H), 5.94 (s, 2H), 6.71(m, 1H), 7.10 (d, 2H), 7.28 (m, 2H), 7.45 (brs, 1H), 7.51 (m, 2H), 7.73 (d, 2H), 7.87 (brs, 1H), 7.94 (d, 1H), 8.17 (s, 1H), 9.00 (brs, 2H), 9.23 (s, 2H), 10.45 (brs, 1H); HPLC: 97.83% (Retention Time= 6.589 min).I-105 499.2δ 2.24 (m, 2H), 3.44 (m, 4H), 5.38 (m, 1H), 5.94 (s, 2H), 6.56 (d, 2H), 7.10 (d, 2H), 7.32 (brs, 1H), 7.51 (s, 1H), 7.54 (d, 3H), 7.73 (d, 2H), 7.87 (brs, 1H), 7.94 (d, 1H), 8.17 (s, 1H), 8.85 (brs, 2H), 9.23 (s, 2H), 10.30 (brs, 1H); HPLC: 97.53% (Retention Time= 5.88 min).I-106 527.2δ 2.13 (m, 2H), 3.66 (m, 4H), 5.31 (m, 1H), 5.95 (s, 2H), 7.10 (d, 2H), 7.33 (brs, 1H), 7.57 (m, 4H), 7.74 (d, 2H), 7.79 (m, 2H), 7.88 (brs, 1H), 7.99 (d, 1H), 8.96 (d, 2H), 9.26 (brs, 2H), 10.76 (brs, 1H); HPLC: 99.76% (Retention Time= 3.192 min).I-107 527.2δ 1.42 (d, 3H), 5.10 (m, 1H), 5.86 (s, 2H), 7.01 (m, 2H), 7.13 (s, 1H), 7.26 (m, 2H), 7.33 (brs, 1H), 7.54 (m, 3H), 7.72 (d, 2H), 7.89 (brs, 1H), 7.93 (d, 1H), 8.18 (brs, 1H), 9.00 (brs, 2H), 9.25 (m, 2H); HPLC: 96.45% (Retention Time= 3.809 min).I-108 499.2δ 1.95 (m, 4H), 3.18 (m, 4H), 5.92 (s, 2H), 6.06 (d, 1H), 6.73 (s, 1H), 6.93 (m, 1H), 7.08 (d, 2H), 7.29 (brs, 1H), 7.49 (s, 1H), 7.55 (d, 1H), 7.73 (d, 2H), 7.85 (brs, 1H), 7.95 (d, 1H), 8.17 (s, 1H), 8.90 (brs, 2H), 9.23 (brs, 2H), 10.46 (brs, 1H); HPLC: 94.68% (Retention Time= 6.566 min).I-109 499.2δ 1.60 (s, 6H), 5.78 (s, 2H), 7.03 (d, 2H), 7.22 (m, 4H), 7.39 (brs, 1H), 7.55 (d, 1H), 7.71 (m, 4H), 7.92 (d, 1H), 8.20 (brs, 1H), 8.87 (d, 2H), 9.23 (s, 2H); HPLC: 98.01% (Retention Time= 6.207 min).I-110 495.2δ 1.57 (m, 2H), 1.71 (m, 4H), 3.12 (m, 4H), 5.94 (s, 2H), 6.97 (brs, 1H), 7.10 (d, 2H), 7.32 (m, 3H), 7.53 (s, 1H), 7.59 (m, 1H), 7.74 (d, 2H), 7.88 (brs, 1H), 7.97 (d, 1H), 8.19 (s, 1H), 9.07 (brs, 2H), 9.26 (brs, 2H), 10.60 (brs, 1H); HPLC: 98.38% (Retention Time= 5.321 min).I-111 508.1δ 5.93 (s, 2H), 7.10 (d, 2H), 7.32 (brs, 1H), 7.58 (m, 1H), 7.69 (m, 2H), 7.71 (m, 2H), 7.87 (brs, 2H), 8.01 (d, 1H), 8.12 (m, 1H), 8.20 (s, 1H), 9.00 (brs, 2H), 9.25 (brs, 2H), 10.73 (brs, 1H); HPLC: 93.19% (Retention Time= 6.496 min).I-112 495.2CD 3 ODδ 2.08 (m, 4H), 3.38 (m, 4H), 4.43 (s, 2H), 5.99 (s, 2H), 6.71 (d, 1H), 7.04 (m, 3H), 7.22 (s, 1H), 7.55 (d, 1H), 7.75 (d, 2H), 7.75 (d, 2H), 7.90 (d, 1H), 8.09 (s, 1H).I-113 492.1δ 1.42 (d, 3H),5.10 (m, 1H), 5.84 (s, 2H), 7.03 (d, 2H), 7.29 (m, 3H), 7.36 (s, 1H), 7.52 (m, 2H), 7.70 (d, 2H), 7.89 (m, 2H), 8.15 (s, 1H), 9.16 (d, 1H); HPLC: 93.96% (Retention Time= 6.382 min).I-114 495.2δ 1.67 (m, 4H), 2.40 (m, 4H), 3.52 (s, 2H), 5.94 (s, 2H), 7.14 (d, 2H), 7.25 (d, 2H), 7.32 (brs, 1H), 7.49 (s, 1H), 7.55 (d, 1H), 7.65 (d, 2H), 7.73 (d, 2H), 7.88 (brs, 1H), 7.95 (d, 1H), 8.20 (brs, 1H), 10.56 (brs, 1H); HPLC: 97.89% (Retention Time= 4.784 min).I-115 448.1δ 5.96 (s, 2H), 7.12 (m, 1H), 7.18 (d, 2H), 7.34 (m, 2H), 7.53 (m, 3H), 7.76 (d, 1H), 7.91 (brs, 1H), 8.19 (brs, 1H); HPLC: 96.34% (Retention Time= 5.636 min).I-116 499.2δ 2.24 (m, 2H), 3.44 (m, 4H), 5.40 (m, 1H), 5.97 (s, 2H), 6.57 (d, 2H), 7.14 (d, 2H), 7.35 (brs, 1H), 7.54 (s, 1H), 7.56 (d, 3H), 7.76 (d, 2H), 7.90 (brs, 1H), 7.97 (d, 1H), 8.20 (d, 1H), 8.85 (brs, 2H), 9.26 (m, 2H), 10.34 (brs, 1H); HPLC: 98.26% (Retention Time= 6.179 min).I-121 482.2δ 0.31 (m, 2H), 0.56 (m, 2H), 1.22 (m, 1H), 3.78 (d, 2H), 5.95 (s, 2H), 6.68 (d, 1H), 7.11 (d, 2H), 7.23 (m, 1H), 7.33 (m, 2H), 7.39 (brs, 1H), 7.51 (s, 1H), 7.58 (d, 1H), 7.75 (d, 2H), 7.89 (d, 1H), 8.21 (s, 2H), 9.07 (brs, 2H),9.26 (brs, 2H), 10.54 (brs, 1H); HPLC: 98.8% (Retention Time= 6.16 min).I-122 499.2δ 2.24 (m, 2H), 3.44 (m, 4H), 5.40 (m, 1H), 5.95 (s, 2H), 6.35 (d, 1H), 7.00 (s, 2H), 7.08 (m, 4H), 7.31 (s, 2H), 7.49 (s, 1H), 7.58 (d, 1H), 7.74 (d, 2H), 7.79 (brs, 1H), 7.94 (d, 1H), 8.19 (s, 1H), 9.26 (m, 2H), 10.41 (brs, 1H); HPLC: 94.11% (Retention Time= 6.127 min).I-123 511.2δ 2.05 (m, 2H), 3.25 (s, 3H),3.39 (m, 4H), 4.09 (m, 1H), 5.95 (s, 2H), 6.30 (d, 1H), 6.98 (s, 1H), 7.04 (m, 4H), 7.32 (s, 1H), 7.48 (s, 1H), 7.56 (d, 1H), 7.75 (d, 2H), 7.89 (brs, 1H), 7.93 (d, 2H), 8.19 (s, 1H),10.41 (brs, 1H); HPLC: 94.36% (Retention Time= 6.304 min).I-124 495.2δ 1.14 (m, 3H), 1.71 (m, 1H), 1.98 (m, 2H), 2.55 (m, 2H), 3.83 (m, 2H), 5.97 (s, 2H), 7.13 (d, 4H), 7.32 (s, 2H), 7.53 (s, 1H), 7.59 (d, 1H), 7.75 (d, 2H), 7.90 (brs, 1H), 7.96 (d, 1H), 8.30 (s, 1H), 9.06 (brs, 2H), 9.36 (brs, 2H), 10.51 (brs, 1H); HPLC: 96.59% (Retention Time= 3.283 min).I-126 508.1δ 5.94 (s, 2H), 7.09 (d, 2H), 7.30 (m, 2H), 7.57 (d, 2H), 7.64 (d, 1H), 7.75 (d, 2H), 7.84 (s, 1H), 8.89 (s, 1H), 8.01 (d, 1H), 8.21 (s, 1H), 8.95 (s, 2H), 9.27 (brs, 2H), 10.85 (brs, 1H); HPLC: 95.08% (Retention Time= 6.285 min).I-127 499.2δ 2.18 (m, 2H), 3.44 (m, 4H), 5.36 (m, 1H), 5.95 (s, 2H), 6.55 (d, 2H), 7.13 (d, 2H), 7.31 (brs, 1H), 7.53 (s, 1H), 7.55 (d, 3H), 7.74 (d, 2H), 7.87 (brs, 1H), 7.92 (d, 1H), 8.17 (s, 1H), 9.61 (brs, 3H), 10.34 (brs, 1H); HPLC: 94% (Retention Time= 6.168 min).I-129 497.2δ 3.08 (m, 4H), 3.75 (m, 4H), 5.95 (s, 2H), 6.72 (d, 1H), 7.10 (d, 2H), 7.19 (m, 2H), 7.34 (s, 2H), 7.50 (s, 1H), 7.57 (m, 1H), 7.75 (d, 2H), 7.89 (brs, 1H), 7.98 (d, 1H), 8.19 (s, 1H), 8.97 (brs, 2H), 9.26 (brs, 2H), 10.33 (brs, 1H); HPLC: 92.81% (Retention Time= 5.608 min).I-130 526.1δ 5.94 (s, 2H), 7.09 (d, 2H), 7.34 (brs, 1H), 7.58 (m, 2H), 7.75 (d, 2H), 7.82 (m, 3H), 8.01 (d, 1H), 8.21 (s, 1H), 8.98 (brs, 2H), 9.27 (brs, 2H), 10.85 (brs, 1H); HPLC: 99.28% (Retention Time= 3.935 min).I-131 457.2δ 5.98 (s, 2H), 7.11 (d, 2H), 7.59 (brs, 1H), 7.59 (m, 3H), 7.76 (d, 2H), 7.78 (brs, 1H), 7.98 (d, 1H), 8.01 (d, 1H), 8.15 (d, 1H), 8.22 (s, 1H), 8.75(m, 1H), 8.92 (brs, 2H), 9.27 (brs, 2H), 11.01 (brs, 1H); HPLC: 99.38% (Retention Time= 3.527 min).I-132 478.2δ 5.97 (s, 2H), 7.11 (m, 2H), 7.32 (brs, 1H), 7.46 (m, 1H), 7.60 (m, 3H), 7.67 (m, 1H), 7.77 (m, 3H), 7.88 (brs, 1H), 8.01 (d, 1H), 8.20 (brs, 1H), 8.36 (m, 1H), 8.44 (d, 1H), 8.91 (brs, 2H), 9.26 (brs, 2H), 10.75 (brs, 1H); HPLC: 97.82% (Retention Time= 5.634 min).I-133 513.2δ 2.68 (m, 4H), 3.50 (m, 4H), 5.95 (s, 2H),6.72 (d, 1H), 7.10 (d, 2H), 7.19 (m, 2H), 7.30 (m, 2H), 7.50 (s, 1H), 7.57 (m, 1H), 7.75 (d, 2H), 7.89 (brs, 1H), 7.98 (d, 1H), 8.19 (s, 1H), 8.91 (brs, 2H), 9.25 (brs, 2H), 10.41 (brs, 1H); HPLC: 98.29% (Retention Time= 3.667 min).I-134 489.2δ 5.98 (s, 2H), 7.12 (d, 2H), 7.32 (brs, 1H), 7.38 (m, 1H), 7.48 (m, 1H), 7.58 (m, 2H), 7.78 (m, 2H), 7.80 (m, 3H), 7.84 (brs, 1H), 7.92 (m, 1H), 8.02 (d, 1H), 8.20 (s, 1H), 8.68 (d, 1H), 8.95 (brs, 2H), 9.27 (brs, 2H), 10.71 (brs, 1H); HPLC: 98.07% (Retention Time= 5.528 min).I-138 436.2δ 4.22 (s, 1H), 5.95 (s, 2H), 7.11 (d, 2H), 7.22 (d, 1H), 7.33 (brs, 1H), 7.39 (m, 1H), 7.55 (s, 1H), 7.59 (m, 1H), 7.77 (m, 3H), 7.88 (m, 3H), 7.99 (d, 1H), 8.21 (s, 1H), 8.91 (brs, 1H), 9.25 (brs, 2H), 10.66 (brs, 1H); HPLC: 92.38% (Retention Time= 6.114 min).I-139 468.2δ 4.54 (d, 2H), 5.25 (m, 1H), 5.38 (m, 1H), 5.95 (s, 2H), 6.01 (m, 1H), 6.71 (m, 1H), 7.12 (d, 2H), 7.22 (m, 1H), 7.32 (m, 2H), 7.43 (s, 1H), 7.52 (s, 1H), 7.58 (d, 1H), 7.75 (d, 2H), 7.89 (brs, 1H), 7.97 (d, 1H), 8.22 (brs, 1H), 9.19 (brs, 2H), 9.28 (brs, 2H), 10.56 (brs, 1H); HPLC: 97.72% (Retention Time= 3.082 min).I-140 499.2δ 2.25 (m, 2H), 3.44 (m, 4H), 5.41 (m, 1H), 5.98 (s, 2H), 6.36 (d, 1H), 7.00 (s, 1H), 7.14 (m, 3H), 7.35 (brs, 1H), 7.53 (s, 1H), 7.59 (d, 1H), 7.77 (d, 2H), 7.90 (brs, 1H), 7.99 (d, 1H), 8.22 (s, 1H), 8.97 (brs, 2H), 9.28 (brs, 2H),10.41 (brs, 1H).I-141 499.2δ 2.29 (m, 2H), 3.44 (m, 4H), 5.41 (m, 1H),5.97 (s, 2H), 6.36 (d, 1H), 7.00 (s, 1H), 7.14 (m, 4H), 7.19 (brs, 1H), 7.50 (s, 1H), 7.58 (d, 1H), 7.77 (d, 2H), 7.90 (brs, 1H), 7.95 (d, 1H), 8.21 (s, 1H), 10.41 (brs, 1H).I-144 495.2δ 5.98 (s, 2H), 7.12 (d, 1H), 7.32 (brs, 1H), 7.48 (m, 1H), 7.60 (m, 2H), 7.69 (m, 2H), 7.75 (d, 1H), 7.77 (d, 2H), 7.81 (d, 1H), 7.86 (m, 1H), 7.94 (d, 1H), 8.00 (d, 1H), 8.20 (brs, 1H), 8.45 (s, 1H), 8.89 (brs, 2H), 9.26 (brs, 2H), 10.78 (brs, 1H); HPLC: 98.19% (Retention Time= 3.551 min).I-145 508.1δ 5.97 (s, 2H), 7.14 (d, 2H), 7.22 (m, 1H), 7.36 (brs, 1H), 7.54 (m, 4H), 7.78 (d, 2H), 7.92 (brs, 1H), 8.02 (d, 1H), 8.25 (s, 1H), 8.94 (brs, 2H), 9.30 (s, 2H), 10.64 (brs, 1H); HPLC: 94.52% (Retention Time= 6.199 min).I-146 466.2δ 3.60 (m, 1H), 4.78 (d, 2H), 5.96 (s, 2H), 6.78 (m, 1H), 7.12 (d, 2H), 7.26 (m, 1H), 7.30 (brs, 1H), 7.37 (d, 1H), 7.53 (s, 1H), 7.58 (d, 1H), 7.75 (d, 2H), 7.88 (brs, 1H), 8.01 (d, 1H), 8.22 (s, 1H), 8.93 (brs, H) 9.27 (brs, 2H), 10.61 (brs, 1H); HPLC: 93.72% (Retention Time= 5.91 min).I-150 490.2δ 3.21(s, 3H), 5.97 (s, 2H), 7.12 (d, 2H), 7.32 (brs, 1H), 7.62 (m, 5H), 7.67 (d, 2H), 7.88 (br, 1H), 8.05 (m, 2H), 8.20 (s, 1H), 8.39 (s, 1H), 8.95 (brs, 2H), 9.27 (brs, 2H), 10.95 (s, 1H); HPLC: 97.34% (Retention Time= 5.398 min).I-151 488.2δ 5.95 (s, 2H), 7.15 (d, 2H), 7.32 (brs, 1H), 7.43(m, 4H), 7.51 (m, 2H), 7.62 (d, 1H), 7.72 (d, 2H), 7.87 (d, 1H), 8.05 (s, 1H), 8.19 (s, 1H), 10.60 (s, 1H); HPLC: 98.19% (Retention Time= 3.928 min).I-152 499.2δ 1.93 (m, 4H), 3.17 (m, 4H), 5.94 (s, 2H), 6.37 (m, 1H), 6.58 (m, 1H), 7.08 (m, 3H), 7.33 (brs, 1H), 7.53 (s, 1H), 7.56 (d, 2H), 7.78 (brs, 1H), 7.96 (d, 1H), 8.21 (s, 1H), 8.95 (brs, 2H) 9.26 (brs, 2H), 10.30 (brs, 1H); HPLC: 94.93% (Retention Time= 3.196 min).I-153 505.2δ 5.95 (s, 2H), 6.30 (m, 1H), 6.50 (m, 1H), 7.24 (m, 3H), 7.32 (brs, 1H), 7.52 (m, 2H), 7.59 (d, 2H), 7.65 (d, 1H), 7.76 (m, 3H), 7.87 (d, 2H), 8.01 (d,1H), 8.20 (s, 1H), 8.96 (brs, 2H), 9.26 (brs,2H), 10.80 (brs, 1H); HPLC: 96.58% (Retention Time= 5.543 min).I-154 477.2δ 5.96 (s, 2H), 6.28 (m, 2H), 7.14 (m, 2H), 7.21 (m, 2H), 7.27 (m, 2H), 7.41 (m, 1H), 7.56 (m, 2H), 7.59 (m, 2H), 7.75 (d, 2H), 7.87 (brs, 1H), 7.93 (d, 1H), 8.20 (s, 1H), 8.88 (brs, 2H), 9.26 (brs, 1H), 10.85 (s, 1H); HPLC: 96.49% (Retention Time= 3.164 min).I-155 499.2δ 1.88 (m, 4H), 3.30(m, 4H), 5.94 (s, 2H), 6.90 (m, 2H), 7.14 (m, 4H), 7.27 (s, 2H), 7.32 (brs, 1H), 7.44 (s, 1H), 7.59 (d, 2H), 7.88 (brs, 1H), 7.96 (d, 1H), 8.20 (s, 1H), 9.01 (brs, 2H) 9.26 (brs, 2H), 10.49 (brs, 1H); HPLC: 90.72% (Retention Time= 6.585 min).I-156 495.2δ 2.06 (m, 2H), 3.83 (s, 2H), 5.94 (s, 2H), 7.11 (d, 2H), 7.36 (m, 3H), 7.57 (s, 3H), 7.74 (d, 2H), 7.88 (brs, 1H), 7.94 (d, 1H), 8.07 (brs, 1H), 8.08 (s, 1H), 8.20 (s, 1H), 8.92 (brs, 2H) 9.26 (brs, 2H), 10.61 (brs, 1H); HPLC: 90.51% (Retention Time= 5.523 min).I-163 479.2δ 5.97 (s, 2H), 7.11 (d, 2H), 7.32 (brs, 1H), 7.44 (m, 2H), 7.58 (m, 2H), 7.67 (s, 1H), 7.77 (m, 2H), 7.88 (brs, 1H), 8.16 (d, 1H), 8.20 (d, 1H), 8.47(d, 2H), 8.92 (brs, 2H), 9.26 (brs, 2H), 10.79 (brs, 1H); HPLC: 90.61% (Retention Time= 3.114 min).I-165 546.2δ 5.97 (s, 2H), 7.11 (d, 2H), 7.32 (brs, 1H), 7.50 (m, 1H), 7.58 (m, 3H), 7.74 (m, 3H), 7.77 (brs, 1H), 8.01 (d, 1H), 8.21 (d, 2H), 8.23 (s, 1H), 8.94 (brs, 2H), 9.17 (s, 1H), 9.26 (brs, 2H), 10.81 (brs, 1H); HPLC: 99.46% (Retention Time= 3.901 min).I-166 546.2δ 5.97 (s, 2H), 7.04 (s, 1H), 7.05 (d, 2H) 7.30 (brs, 1H), 7.53 (m, 4H), 7.73 (d, 2H), 7.82 (d, 1H), 7.85 (brs, 1H), 8.01 (d, 1H), 8.18 (s, 1H), 8.31 (s, 1H), 8.69 (s, 1H), 8.91 (brs, 2H), 9.24 (brs, 2H); HPLC: 96.62% (Retention Time= 2.574 min).I-167 546.2δ 2.58 (s, 3H), 5.96 (s, 2H), 7.11 (d, 2H), 7.32 (brs, 1H), 7.52 (m, 1H), 7.58 (m, 2H), 7.73 (m, 3H), 7.87 (brs, 1H), 7.99 (d, 2H), 8.21 (s, 1H), 8.32 (s, 1H), 9.00 (brs, 2H), 9.26 (brs, 2H), 10.98 (brs, 1H).I-168 427.2δ 4.54 (d, 2H), 5.92 (s, 2H), 7.02 (d, 2H),7.41 (m, 3H), 7.58 (d, 2H), 7.75 (d, 2H), 7.94 (m, 2H), 8.23 (s, 1H), 8.57 (m, 2H),9.13 (brs, 2H), 9.27 (brs, 2H), 9.49 (brs, 1H); HPLC: 91.94% (Retention Time= 4.304 min).I-169 431.2δ 5.95 (s, 2H), 7.11 (d, 2H), 7.32 (brs, 1H), 7.58 (d, 1H), 7.70 (s, 1H), 7.78 (m, 3H), 7.89 (brs, 1H), 7.98 (d, 1H),8.09 (m, 1H), 8.20 (brs, 1H),8.42 (d, 1H), 8.96 (brs, 2H), 9.27 (brs, 2H), 11.22 (brs, 1H); HPLC: 95.21% (Retention Time= 5.883 min).I-170 413.2δ 5.95 (s, 2H), 7.11 (d, 2H), 7.34 (brs, 1H),7.48 (m, 1H), 7.58 (m, 2H), 7.75 (d, 2H), 7.89 (brs, 1H), 8.01 (d, 1H), 8.22 (m, 2H), 8.38(d, 1H), 8.95 (s, 3H), 9.27 (brs, 2H), 10.87 (brs, 1H); HPLC: 87.15% (Retention Time= 6.782 min).I-171 427.2(CD 3 OD) δ 2.31 (s, 3H), 6.03 (s, 2H), 7.18 (d, 2H), 7.48 (s, 1H), 7.57 (m, 1H), 7.63 (m, 1H), 7.76 (d, 2H), 7.96 (m, 2H), 8.04 (s, 1H), 8.18 (s, 1H); HPLC: 95.12% (Retention Time= 5.551 min).I-172 431.2δ 5.95 (s, 2H), 7.11 (d, 2H), 7.32 (brs, 1H), 7.60 (d, 2H), 7.75 (d, 2H), 7.89 (brs, 1H), 8.00 (d, 1H), 8.14 (m, 1H), 8.21 (s, 1H), 8.35 (m, 1H), 8.75 (s, 1H), 9.03 (brs, 2H), 9.28 (brs, 2H), 11.0 (brs, 1H); HPLC: 94.12% (Retention Time= 2.683 min).I-173 431.2δ 5.95 (s, 2H), 7.11 (d, 2H),7.21 (m, 1H), 7.32 (brs, 1H), 7.58 (m, 2H), 7.75 (d, 2H), 7.90 (brs, 1H), 8.00 (d, 1H), 8.22 (s, 1H), 8.28 (m, 1H), 8.55 (s, 1H), 9.06 (brs, 2H), 9.28 (brs, 2H), 10.87 (brs, 1H); HPLC: 90.57% (Retention Time= 5.733 min).I-174 447.1δ 5.93 (s, 2H), 7.08 (d, 2H), 7.32 (brs, 1H), 7.49 (m, 1H), 7.58 (m, 2H), 7.73 (m, 2H), 7.87 (brs, 1H), 7.99 (m, 1H), 8.18 (m, 2H), 8.74 (m, 1H), 8.94 (brs, 2H), 9.25 (brs, 2H), 10.88 (brs, 1H); HPLC: 95.74% (Retention Time= 5.917 min).I-175 427.1δ 2.53 (s, 3H), 5.95 (s, 2H), 7.09 (d, 2H), 7.32 (brs, 1H), 7.58 (m, 2H), 7.75 (d, 2H), 7.88 (brs, 1H), 8.00 (d, 1H), 8.13 (s, 1H), 8.21 (s, 1H), 8.27 (s, 1H), 8.79 (s, 1H), 9.02 (brs, 2H), 9.27 (brs, 2H), 10.87 (brs, 1H); HPLC: 92.07% (Retention Time= 4.846 min).I-176 427.1δ 2.3 (m, 3H), 5.90 (s, 2H), 7.00 (s, 1H), 7.10 (d, 2H), 7.21 (brs, 1H), 7.55 (d, 1H), 7.69 (s, 1H), 7.75 (d, 2H), 7.87 (m, 3H), 8.18 (s, 1H), 8.25 (d, 1H); HPLC: 95.5% (Retention Time= 5.413 min).I-177 482.2δ 2.0 (m, 4H), 3.47 (m, 4H), 5.94 (s, 2H), 6.99 (m, 1H), 7.08 (d, 2H), 7.31 (brs, 1H), 7.53 (s, 1H), 7.59 (d, 1H), 7.74 (d, 2H), 7.86 (brs, 1H), 7.98 (d, 1H), 8.03 (m, 1H), 8.20 (s, 1H), 8.97 (brs, 2H), 9.25 (brs, 2H), 10.68 (brs, 1H); HPLC: 97.67% (Retention Time= 4.906 min).I-178 482.2δ 2.0 (m, 4H), 3.44 (m, 4H), 5.93 (s, 2H), 7.05 (m, 3H), 7.34 (m, 2H), 7.58 (d, 1H), 7.67 (brs, 1H), 7.76 (d, 1H), 7.88 (brs, 1H), 7.91 (d, 1H), 8.02 (d, 1H), 8.21 (s, 1H), 9.02 (brs, 2H), 9.27 (brs, 2H), 11.21 (brs, 1H); HPLC: 96.07% (Retention Time= 5.001 min).I-179 482.2δ 1.93 (m, 4H), 3.26 (m, 4H), 5.96 (s, 2H), 6.30 (m, 1H), 7.10 (d, 2H), 7.26 (brs, 1H), 7.31 (brs, 1H), 7.54 (m, 1H), 7.61 (s, 1H), 7.74 (d, 2H), 7.90 (m, 3H), 8.11 (s, 1H), 10.41 (brs, 1H); HPLC: 97.64% (Retention Time= 5.087 min).I-180 482.2δ 1.96 (m, 4H), 3.42 (m, 4H), 5.97 (s, 2H), 6.25 (d, 2H), 7.12 (d, 2H), 7.26 (d, 1H), 7.50 (brs, 1H), 7.52 (m, 1H), 7.58 (d, 1H), 7.66 (s, 1H), 7.90 (brs, 1H), 7.98 (d, 1H), 8.21 (s, 1H), 8.96 (brs, 2H), 9.28 (brs, 2H), 10.41 (brs, 1H); HPLC: 93.47% (Retention Time= 5.776 min).I-181 479.2δ 5.97 (s, 2H), 6.61 (m, 1H) 7.11 (d, 2H), 7.32 (brs, 1H), 7.58 (d, 2H), 7.65 (m, 2H), 7.67 (m, 2H), 7.57 (s, 1H), 7.77 (brs, 1H), 7.98 (m, 2H), 8.22 (s, 1H), 8.57 (d, 1H), 8.97 (brs, 2H), 9.27 (brs, 2H), 11.11 (brs, 1H); HPLC: 97.49% (Retention Time= 6.088 min).I-182 496.2δ 1.16 (d, 3H), 1.66 (m, 1H), 2.01 (m, 4H), 3.33 (m, 1H), 4.12 (m, 1H), 5.94 (s, 2H), 6.22 (d, 1H), 7.10 (d, 2H), 7.19 (d, 1H), 7.32 (brs, 1H), 7.48 (m, 1H), 7.58 (m, 1H), 7.75 (d, 2H), 7.88 (brs, 1H), 7.96 (d, 1H), 8.19 (brs, 1H), 8.88 (brs, 2H), 9.25 (brs, 2H), 10.4 (brs, 1H).I-184 533.3δ 1.35 (m, 4H), 1.85 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 5.81 (s, 2H), 7.15 (d, 2H), 7.32 (brs, 1H), 7.35 (brs, 1H), 7.55 (d, 1H), 7.75 (d, 2H), 7.85 (m, 3H), 8.21 (brs, 1H), 8.65 (d, 1H), 9.08 (brs, 2H), 9.30 (brs, 2H); HPLC: 89.53% (Retention Time= 4.231 min).I-185 432.3δ 0.81 (m, 3H), 1.33 (m, 2H), 1.49 (m, 2H), 1.65 (m, 3H), 1.85 (m, 2H), 3.74 (m, 1H), 5.81 (s, 2H), 6.86 (s, 1H), 7.15 (d, 1H), 7.29 (brs, 1H), 7.61 (d, 1H), 7.83 (m, 3H), 7.95 (brs, 1H), 8.33 (s, 1H), 8.94 (brs, 2H), 9.30 (brs, 2H); HPLC: 91.33% (Retention Time= 5.751 min).I-186 432.3δ 0.91 (m, 3H), 1.37 (m, 2H), 1.45 (m, 4H), 1.52 (m, 3H), 3.85 (m, 1H), 5.88 (s, 2H), 7.12 (d, 2H), 7.27 (s 1H), 7.34 (brs, 1H), 7.54 (d, 1H), 7.75 (d, 2H), 7.90 (m, 2H), 8.19 (s, 1H), 8.45 (d, 1H), 8.98 (brs, 2H), 9.24 (brs, 2H);I-187 432.3δ 0.86 (m, 3H), 1.34 (m, 2H), 1.43 (m, 4H), 1.53 (m, 3H), 3.85 (m, 1H), 5.88 (s, 2H),7.10 (d, 2H), 7.25 (m, 1H), 7.33 (brs, 1H), 7.74 (d, 1H), 7.89 (m, 3H), 8.17 (s, 1H), 8.44 (d, 1H), 8.94 (brs, 2H), 9.22 (brs, 2H).I-188 487.3δ 1.37 (m, 2H), 1.46 (m, 2H), 1.82 (m, 4H), 1.99 (m, 2H), 2.10 (m, 2H), 3.08 (m, 3H), 3.42 (m, 2H), 3.71 (m, 1H), 5.90 (s, 2H), 7.10 (m, 2H), 7.26 (s, 1H), 7.35 (brs, 1H), 7.54 (d, 1H), 7.74 (d, 2H), 7.90 (d, 2H), 8.19 (s, 1H), 8.65 (d, 1H), 9.01(brs, 2H), 9.24 (brs, 2H), 9.67 (brs, 1H); HPLC: 91.75% (Retention Time= 4.459 min).I-189 416.3δ 1.52 (m, 1H), 1.81 (m, 1H), 2.09 (m, 2H), 2.21 (m, 2H), 3.92 (m, 1H), 5.64 (s, 1H), 5.91 (s, 1H), 6.95 (s, 1H), 7.10 (m, 2H), 7.27 (d, 1H), 7.34 (brs, 1H), 7.54 (d, 1H), 7.74 (d, 2H), 7.90 (d, 1H), 8.18 (s, 1H), 8.62 (d, 1H), 8.99 (brs, 2H), 9.24 (brs, 2H); HPLC: 97.03% (Retention Time= 3.364 min).I-190 454.2δ 1.57 (m, 2H), 1.81 (m, 3H), 1.97 (m, 3H), 3.93 (m, 1H), 5.90 (s, 2H), 7.10 (m, 2H), 7.28 (s, 1H), 7.34 (brs, 1H), 7.54 (d, 1H), 7.74 (d, 2H), 7.90 (d, 2H), 8.19 (s, 1H), 8.65 (d, 1H), 9.01(brs, 2H), 9.24 (brs, 2H); HPLC: 97.47% (Retention Time= 3.318 min).I-191 432.2δ 0.83 (m, 2H), 1.10 (m, 3H), 1.49 (m, 1H), 1.58 (m, 5H), 3.04 (m, 2H), 5.93 (s, 2H), 7.06 (m, 2H), 7.25 (s, 1H), 7.34 (brs, 1H), 7.55 (d, 1H), 7.75 (d, 2H), 7.91 (m, 2H), 8.21 (s, 1H), 8.74 (m, 1H), 9.05 (brs, 2H), 9.25 (brs, 2H); HPLC: 91.99% (Retention Time= 3.073 min).I-192 434.2δ 1.07 (m, 2H), 1.39 (m, 2H), 1.66 (m, 1H), 3.07 (m, 2H), 3.14 (m, 2H), 3.76 (m, 2H), 5.91 (s, 2H), 7.03 (m, 2H), 7.24 (s, 1H), 7.33 (brs, 1H), 7.54 (d, 1H), 7.74 (d, 2H), 7.90 (m, 2H), 8.21 (s, 1H), 8.75 (m, 1H), 9.05 (brs, 2H), 9.24 (brs, 2H); HPLC: 93.25% (Retention Time= 4.987 min).I-193 446.2δ 0.82 (m, 2H), 1.05 (m, 5H), 1.38 (m, 1H), 1.51 (m, 6H), 3.75 (m, 1H), 5.89 (s, 2H), 7.04 (m, 2H), 7.17 (brs, 1H), 7.22 (s, 1H), 7.30 (m, 1H), 7.54 (d, 1H), 7.74 (d, 1H), 7.89 (d, 2H), 8.21 (s, 1H), 8.46 (d, 1H), 9.15 (brs, 2H), 9.24 (brs, 2H); HPLC: 94.99% (Retention Time= 2.943 min).I-194 446.2δ 0.82 (m, 2H), 1.05 (m, 6H), 1.57 (m, 6H), 3.75 (m, 1H), 5.89 (s, 2H), 7.06 (d, 2H), 7.22 (s, 1H), 7.30 (brs, 1H), 7.53 (m, 1H), 7.73 (d, 2H), 7.87 (m, 2H), 8.20 (s, 1H), 8.43 (d, 1H), 8.93 (brs, 2H), 9.22 (brs, 2H); HPLC: 90.54% (Retention Time= 2.949 min).I-195 446.2δ 0.84 (m, 2H), 1.07 (m, 4H), 1.34 (m, 2H), 1.62 (m, 5H), 3.17 (m, 2H), 5.93 (s, 2H), 7.09 (d, 2H), 7.22 (s, 1H), 7.32 (brs, 1H), 7.53 (d, 1H), 7.74 (d, 2H), 7.86 (d, 2H), 8.15 (s, 1H), 8.71 (m, 1H); HPLC: 93.96% (Retention Time= 6.625 min).I-196 447.2δ 1.25 (m, 6H), 1.98 (m, 1H), 2.15 (m, 1H), 2.94 (m, 1H), 3.20 (s, 1H), 3.52 (m, 3H), 4.48 (m, 1H), 5.91 (s, 2H), 7.07 (m, 2H), 7.34 (m, 2H), 7.56 (d, 1H), 7.76 (d, 2H), 7.91 (m, 2H), 8.19 (d, 1H), 8.93 (m, 2H), 9.25 (brs, 2H), 9.88 (m, 1H); HPLC: 93.87% (Retention Time= 4.423 min).I-197 486.2δ 1.45 (m, 6H), 1.85 (m, 6H), 2.15 (s, 2H), 4.55 (brs, 1H), 5.84 (s, 2H), 7.15 (m, 3H), 7.35 (brs, 1H), 7.51 (m, 1H), 7.74 (d, 2H), 7.85 (m, 2H), 8.13 (m, 1H), 8.92 (brs, 2H), 9.22 (brs, 2H); HPLC: 90.86% (Retention Time= 2.668 min).I-198 486.2δ 1.45 (m, 6H), 1.84 (m, 6H), 2.14 (s, 2H), 5.86 (s, 2H), 7.18 (m, 3H), 7.51 (d, 1H), 7.83 (m, 3H), 8.11 (brs, 1H), 8.16 (brs, 1H), 8.90 (brs, 2H), 9.21 (brs, 2H); HPLC: 93.37% (Retention Time= 2.707 min).I-200 470.2δ 1.64 (s, 6H), 2.03 (m, 9H), 5.85 (s, 2H), 7.17 (m, 3H), 7.35 (brs, 1H), 7.52 (d, 1H), 7.75 (d, 2H), 7.86 (m, 2H), 8.05 (brs, 1H), 8.19 (brs, 1H), 9.00 (brs, 2H), 9.23 (brs, 2H); HPLC: 95.67% (Retention Time= 3.979 min).I-201 452.2δ 2.85 (m, 2H), 3.16 (m, 2H),4.65 (m, 1H), 5.92 (s, 2H), 6.98 (s, 1H), 7.11 (m, 3H), 7.20 (m, 2H), 7.29 (s, 1H), 7.35 (brs, 1H), 7.52 (d, 1H), 7.75 (d, 2H), 7.88 (m, 2H), 8.18 (brs, 1H), 8.94 (m, 3H), 9.23 (brs, 2H); HPLC: 91.77% (Retention Time= 3.566 min).I-202 452.2δ 2.85 (m, 2H), 2.81 (m, 2H),5.5 (m, 1H), 5.98 (d, 2H), 6.83 (d, 2H), 7.06 (m, 2H), 7.18 (m, 2H), 7.31 (s, 1H), 7.37 (brs, 1H), 7.54 (d, 1H), 7.79 (d, 2H), 7.90 (m, 2H), 8.23 (brs, 1H), 8.94 (brs, 1H), 9.10 (m, 1H), 9.30 (brs, 2H); HPLC: 96.98% (Retention Time= 5.987 min).I-203 468.2δ 2.73 (m, 1H), 3.10 (m, 2H), 4.38 (m, 1H), 5.16 (m, 1H), 5.99 (d, 2H), 6.64 (d, 1H), 7.03 (m, 1H), 7.09 (d, 2H), 7.16 (d, 2H), 7.33 (s, 1H), 7.54 (d, 1H), 7.78 (d, 1H), 7.91 (m, 2H), 8.23 (brs, 1H), 8.89 (brs, 2H), 9.03 (d, 1H), 9.23 (brs, 2H); HPLC: 98.7% (Retention Time= 5.507 min).I-204 468.2δ 2.88 (m, 1H), 3.08 (m, 2H), 4.53 (m, 1H), 5.20 (d, 1H), 5.38 (m, 1H), 5.99 (d, 2H), 6.93 (d, 1H), 7.10 (m, 5H), 7.37 (brs, 1H), 7.55 (d, 1H), 7.80 (d, 1H), 7.92 (d, 2H), 8.21 (brs, 1H), 8.53 (d, 1H), 8.89 (brs, 2H), 9.25 (brs, 2H); HPLC: 95.44% (Retention Time= 5.292 min).I-205 405.2δ 1.93 (m, 1H), 2.14 (m, 1H), 3.07 (m, 1H), 3.22 (m, 1H), 3.27 (m, 2H), 4.44 (m, 1H), 5.90 (m, 2H), 7.08 (d, 2H), 7.33 (m, 2H), 7.54 (d, 1H), 7.74 (d, 2H), 7.90 (m, 2H), 8.81 (brs, 1H), 8.84 (m, 1H), 9.03 (brs, 2H), 9.24 (brs, 2H); HPLC: 84.25% (Retention Time= 4.151 min).I-206 433.2δ 1.68 (m, 2H), 1.95 (m, 2H), 2.75 (d, 3H), 3.04 (m, 2H), 3.35 (m, 2H), 3.85 (m, 1H), 5.90 (m, 2H), 7.08 (d, 2H), 7.3 (s, 1H), 7.37 (m, 1H), 7.54 (d, 1H), 7.74 (d, 2H), 7.90 (m, 2H), 8.19 (m, 1H), 8.79 (d, 1H), 9.00 (brs, 2H), 9.24 (brs, 2H); HPLC: 90.61% (Retention Time= 4.181 min).I-207 394.2δ 0.99 (d, 3H), 3.14 (m, 2H), 3.75 (m, 1H), 5.92 (s, 2H), 7.08 (d, 2H), 7.31 (m, 2H), 7.52 (d, 1H), 7.73 (d, 2H), 7.90 (m, 2H), 8.15 (s, 1H), 8.71 (m, 1H), 8.94 (brs, 2H), 9.22 (brs, 2H), 9.24 (brs, 2H); HPLC: 94.0% (Retention Time= 4.667 min).I-208 408.2δ 1.05 (m, 6H), 3.20 (m, 2H), 4.55 (brs, 1H), 5.91 (s, 2H), 7.08 (d, 2H), 7.32 (m, 2H), 7.44 (d, 1H), 7.73 (d, 2H), 7.81 (d, 1H), 7.89 (m, 1H), 7.97 (brs, 1H), 8.51 (m, 1H), 9.03 (brs, 2H), 9.24 (brs, 2H); HPLC: 91.342% (Retention Time= 4.396 min).I-209 408.2δ 0.80 (m, 3H), 1.35 (m, 1H), 1.64 (m, 1H), 3.34 (m, 1H), 3.39 (m, 1H), 3.82 (m, 1H), 5.93 (s, 2H), 7.15 (d, 2H), 7.31 (brs, 2H), 7.75 (d, 2H), 7.89 (d, 2H), 8.27 (s, 1H), 8.40 (d, 1H), 9.02 (brs, 2H), 9.33 (brs, 2H).I-265 469.1δ 5.96 (s, 2H), 7.12 (d, 2H), 7.33 (brs, 1H), 7.58 (m, 2H), 7.75 (m, 3H), 7.88 (brs, 1H), 8.00 (m, 2H), 8.21 (s, 1H), 8.64 (s, 1H), 8.90 (brs, 2H), 9.26 (m, 2H), 10.92 (s, 1H); HPLC: 86.89% (Retention Time= 2.924 min).I-266 433.1δ 2.30 (s, 3H), 6.00 (s, 2H), 6.83 (brs, 1H), 7.06 (d, 2H), 7.33 (s, 1H), 7.56 (d, 1H), 7.74 (m, 3H), 7.88 (brs, 1H), 7.98 (d, 1H), 8.18 (brs, 1H), 8.93 (brs, 2H), 9.26 (m, 2H); HPLC: 93.75% (Retention Time= 5.786 min). Table-6: Cpd. ID.R 2 R 3 'LCMS (M+1) +< 1< H NMRI-226 446.2δ 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).I-227 450.2δ 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).I-228 466.2δ 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).I-229 466.2δ 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).I-230 454.2δ 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).I-231 433.2δ 0.83 (m, 2H), 1.08 (m, 4H), 1.47 (m, 1H), 1.59 (m, 4H), 3.04 (m, 2H), 5.88 (s, 2H), 6.98 (d, 2H), 7.21 (s, 1H), 7.54 (d, 1H), 7.65 (d, 2H), 7.87 (d, 1H), 8.02 (brs, 2H), 8.20 (s, 1H), 8.71 (m, 1H), 8.99 (brs, 2H), 9.25 (brs, 2H).I-233 440.2δ 1.27 (m, 4H), 1.79 (m, 4H), 2.93 (m, 1H), 3.64 (m, 1H), 6.00 (s, 1H), 7.23 (m, 2H), 7.44 (m, 2H), 7.52 (m, 2H), 7.73 (m, 7H), 8.27 (s, 1H), 8.61 (d, 1H), 9.03 (brs, 2H), 9.25 (brs, 2H); HPLC: 98.31% (Retention Time= 5.043 min).I-234 466.2δ 1.31 (m, 4H), 1.86 (m, 4H), 2.96 (m, 1H), 3.65 (m, 1H), 5.65 (s, 1H), 7.28 (d, 2H), 7.41 (m, 2H), 7.57 (m, 4H), 7.65 (d, 1H), 7.78 (d, 1H), 7.94 (m, 3H), 8.44 (s, 1H), 8.80 (d, 1H), 9.39 (brs, 2H); HPLC: 95.23% (Retention Time= 6.883 min).I-235 487.2δ 1.62 (m, 2H), 1.86 (m, 3H), 2.06 (m, 3H), 3.98 (m, 1H), 5.94 (s, 2H), 7.20 (d, 2H), 7.31 (s, 1H), 7.37 (m, 1H), 7.47 (m, 2H), 7.58 (m, 5H), 7.94 (d, 1H), 8.28 (s, 1H), 8.68 (d, 1H), 8.94 (brs, 2H), 9.29 (brs, 2H); HPLC: 92.73% (Retention Time= 3.851 min).I-238 494.3δ 1.42 (m, 3H), 1.45 (m, 4H), 1.81(m, 4H), 2.52 (m, 2H), 2.95 (m, 1H), 3.71 (m, 1H), 7.33 (d, 1H), 7.22 (s, 1H), 7.33 (m, 4H), 7.42 (m, 3H), 7.58 (d, 2H), 7.89 (m, 4H), 8.35 (brs, 1H), 8.71 (d, 1H), 9.13 (brs, 2H), 9.32 (brs, 2H); HPLC: 96.01% (Retention Time= 5.108 min).I-239 510.3δ 1.42 (m, 7H), 1.82 (m, 4H), 2.95 (m, 1H), 3.71 (m, 1H), 4.01 (m, 2H), 6.95 (m, 4H), 7.21 (s, 1H), 7.33 (m, 1H), 7.42 (m, 5H), 7.52 (d, 1H), 7.89 (m, 4H), 8.35 (d, 1H), 9.13 (brs, 2H), 9.32 (brs, 2H); HPLC: 91.03% (Retention Time= 5.008 min).I-240 482.2δ 1.32 (m, 4H), 1.82 (m, 4H), 2.96 (m, 1H), 3.71 (m, 1H), 5.82 (s, 2H), 6.88 (m, 4H), 7.12 (m, 3H), 7.22 (brs, 1H), 7.33 (m, 2H), 7.53 (d, 1H), 7.83 (m, 3H), 8.24 (s, 1H), 8.58 (d, 1H), 8.88 (brs, 2H), 9.28 (brs, 2H); HPLC: 98.51% (Retention Time= 5.74 min). Example 20: Synthesis of compound I-103. 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)- 1H-indole-2-carboxamide

[0281] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0282] 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 afford 385 mg of the title compound following the procedure described in step-3 of example 1. LCMS : 413.1 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0283] The product of step-1 of example 20 (360 mg, 0.87 mmol) and aqueous hydroxylamine (1.7 mL) were treated together to afford 310 mg of the title compound following the procedure described in step-4 of example 14. LCMS : 448.2 (M+1) +< .Step-3: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide

[0284] 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 afford 240 mg of the title compound following the procedure described in step-5 of example 14. LCMS : 491.2 (M+1) +< .Step-4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-1H-indole-2-carboxamide

[0285] The product of step-3 of example 20 (230 mg, 0.46 mmol) and zinc (125 mg, 1.89 mmol) were treated together to afford 108 mg of the title compound following the procedure described in step-6 of example 14. LCMS : 433.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 21: Synthesis of compound 1-117 1-(4-Carbamoylbenzyl)-N 2< -(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0286] Step-1:1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0287] 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 afford 520 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 464.2 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-N 2< -(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0288] To a solution of the product of step-1 of example-21 (250 mg, 0.53 mmol) in 5 mL of the mixture of methanol and water (1:1) was added solid sodium hydroxide (65 mg, 1.6 mmol). The reaction was stirred at 50 °C. Upon reaction completion, 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 sulphate. Solvent was evaporated under vacuum to give crude product which was purified by reverse-phase preparative HPLC and afforded 120 mg of the title compound. LCMS : 482.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).General synthetic scheme-2A:

[0289] Example 22: Synthesis of compound I-118 Methyl ((1-(4-carbamoylbenzyl)-2-((4-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0290] Step-1: Methyl ((1-(4-carbamoylbenzyl)-2-((4-(pyrrolidin-1-yl)phenyl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0291] Compound I-90 (300 mg, 0.64 mmol) and potassium carbonate (355 mg, 2.57 mmol) were dissolved in 10 mL of DMF and added methyl carbonochloridate (95 mg, 0.96 mmol) drop wise at 0 °C and stirred the mixture at RT for 8h. After reaction completion, mixture was quenched with ice-cold water and extracted with ethyl acetate followed with brine and dried over anhydrous sodium sulphate. Solvent was evaporated under vacuum to give crude product which was purified with reverse-phase HPLC and afforded the title compound (120 mg, Yield: 70%-80%). LCMS : 539.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.92 (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= 3.765 min).

[0292] The following compounds listed in table-7 were prepared according to Scheme-2 followed by Scheme-2A by following similar procedure as described above for example-22 using appropriate reagents with suitable modifications known to the one skilled in the art. Table -7: Cpd. ID.R 2 R 4 'LCMS (M+1) +< 1< H NMRI-119 553.2δ 1.19 (m, 3H), 1.92 (m, 4H), 3.18 (m, 4H), 4.04 (m, 2H), 5.96 (s, 2H), 6.49 (d, 2H), 7.07 (d, 2H), 7.30 (brs, 1H), 7.39 (s, 1H), 7.49 (d, 2H), 7.73 (d, 2H), 7.80 (s, 2H), 7.86 (brs, 1H), 8.23 (s, 1H), 9.2 (br, 2H), 10.21 (brs, 1H); HPLC: 96.94% (Retention Time= 5.974 min).I-120 553.2δ 1.19 (m, 3H), 1.94 (m, 4H), 3.20 (m, 4H), 4.03 (m, 2H), 5.96 (s, 2H), 6.28 (d, 1H), 6.97 (s, 1H), 7.01 (m, 4H), 7.30 (brs, 1H), 7.44 (m, 1H), 7.73 (d, 2H), 7.81 (s, 2H), 7.86 (brs, 1H), 8.24 (s, 1H), 9.1(brs, 2H), 10.34 (brs, 1H); HPLC: 95.99% (Retention Time= 6.717 min).I-142 567.2δ 1.23 (d, 6H), 1.94 (m, 4H), 3.17 (m, 4H), 4.82 (m, 1H), 5.98 (s, 2H), 6.29 (d, 1H), 6.98 (s, 1H), 7.08 (m, 4H), 7.30 (brs, 1H), 7.46 (s, 1H), 7.74 (d, 2H), 7.84 (s, 2H), 7.86 (brs, 1H), 8.24 (s, 1H), 9.2 (brs, 2H), 10.28 (s, 1H); HPLC: 93.15% (Retention Time= 6.804 min).I-143 615.3δ 1.96 (m, 4H), 3.21 (m, 4H), 5.13 (s, 2H), 5.98 (s, 2H), 6.33 (d, 1H), 7.00 (s, 1H), 7.04 (m, 4H), 7.34 (m, 5H), 7.47 (s, 1H), 7.75 (d, 2H), 7.84 (m, 2H), 8.29 (s, 1H), 9.2 (brs, 3H), 10.31 (s, 1H); HPLC: 97.16% (Retention Time= 3.771 min).I-147 581.3δ 0.90 (d, 6H), 1.91 (m, 5H), 3.20 (m, 4H), 3.80 (d, 2H), 5.96 (s, 2H), 6.28 (d, 1H), 7.01 (m, 2H), 7.07 (m, 2H), 7.29 (brs, 1H), 7.44 (s, 1H), 7.73 (d, 2H), 7.81 (s, 2H), 7.86 (brs, 1H), 8.24 (s, 1H), 9.2 (br, 2H), 10.30 (s, 1H); HPLC: 97.86% (Retention Time= 4.472 min).I-148 601.3δ 1.93 (m, 4H), 3.20 (m, 4H), 5.95 (s, 2H), 6.29 (d, 1H), 6.97 (s, 1H), 7.07 (m, 5H), 7.17 (m, 4H), 7.30 (s, 1H), 7.37 (m, 2H), 7.46 (s, 1H), 7.74 (d, 2H), 8.87 (m, 3H), 8.28 (s, 2H), 9.29 (brs, 1H); HPLC: 95.06% (Retention Time= 4.331 min).I-159 609.3δ 0.87 (m, 3H), 1.34 (m, 6H), 1.55 (m, 2H), 1.93 (m, 4H), 3.20 (m, 4H), 4.00 (m, 2H), 5.83 (s, 2H), 6.28 (d, 1H), 6.97 (brs, 1H), 7.01 (d, 1H), 7.06 (m, 2H), 7.29 (brs, 1H), 7.45 (s, 1H), 7.73 (d, 2H), 7.81 (s, 2H), 7.86 (s, 1H), 8.24 (s, 1H), 9.03 (brs, 2H), 10.30 (s, 1H); HPLC: 96.75% (Retention Time= 4.221 min).I-160 581.3δ 0.90 (m, 3H), 1.34 (m, 2H), 1.55 (m, 2H), 1.93 (m, 4H), 3.18 (m, 4H), 4.13 (m, 2H), 5.96 (s, 2H), 6.28 (d, 1H), 6.97 (brs, 1H), 7.01 (d, 1H), 7.06 (m, 3H), 7.30 (brs, 1H), 7.44 (s, 1H), 7.73 (d, 2H), 7.86 (m, 3H), 8.28 (s, 1H), 9.03 (br, 2H), 10.30 (s, 1H); HPLC: 98.32% (Retention Time= 6.936 min).I-161 595.3δ 0.87 (m, 3H), 1.30 (m, 4H), 1.55 (m, 2H), 1.93 (m, 4H), 3.20 (m, 4H), 4.01 (m, 2H), 5.96 (s, 2H), 6.28 (d, 1H), 6.97 (brs, 1H), 7.01 (d, 1H), 7.06 (m, 3H), 7.29 (brs, 1H), 7.44 (s, 1H), 7.73 (d, 2H), 7.81 (s, 2H), 7.86 (s, 1H), 8.24 (s, 1H), 9.03 (brs, 2H), 10.30 (s, 1H); HPLC: 98.51% (Retention Time= 3.81 min).I-162 567.3δ 0.90 (m, 3H), 1.61 (m, 2H), 2.32 (m, 4H), 3.21 (m, 4H), 3.95 (m, 2H), 5.96 (s, 2H), 6.28 (d, 1H), 6.97 (s, 1H), 7.01 (d, 1H), 7.09 (m, 3H), 7.44 (s, 1H), 7.73 (d, 2H), 7.81 (s, 2H), 7.86 (m, 1H), 8.24 (s, 1H), 10.23 (s, 1H); HPLC: 91.46% (Retention Time= 3.984 min).I-164 607.3δ 1.21 (m, 6H),1.51 (m, 1H), 1.69 (m, 2H), 1.85 (m, 2H), 1.95 (m, 4H), 3.20 (m, 4H), 4.55 (m, 1H), 5.96 (s, 2H), 6.28 (d, 1H), 6.97 (s, 1H), 7.01 (m, 4H), 7.29 (s, 1H), 7.44 (s, 1H), 7.73 (d, 2H), 7.81 (m, 3H), 8.23 (s, 1H), 9.20 (brs, 2H), 10.23 (s,1H); HPLC: 92.67% (Retention Time= 7.061 min). Example 23: Synthesis of compound I-135 1-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0293] Step-1:1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0294] 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 afford 520 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 464.2 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0295] The product of step-1 of example-23 (500 mg, 0.24 mmol) and aqueous hydroxylamine (0.063 mL) were treated together to afford 350 mg of the title compound following the procedure described in step-4 of example-14. LCMS: 497.2 (M+1) +< .Step-3: 1-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0296] The solution of N,N-dimethylglycine (45 mg, 0.44 mmol), triethylamine (66 mg, 0.66 mmol) in 10 mL of tetrahydrofuran, at 0 °C isobutyl chloroformate (60 mg, 0.44 mmol) was added and stirred for 2h, followed by the addition of product of step-2 of example-23 (220 mg, 0.44 mmol) and stirred at RT for 8h. After reaction completion, the solvent was evaporated under vacuum to give crude product which was purified with reverse-phase HPLC and afforded the title compound (85 mg, Yield: 20%-30%). LCMS: 582.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 24: Synthesis of example I-136 1-(4-Carbamoylbenzyl)-N 2< -(3-(pyridin-2-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0297] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyridin-2-yl)phenyl)-1H-indole-2-carboxamide

[0298] 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 to afford 1230 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 472.2 (M+1) +< .Step-2: 1-(4-carbamoylbenzyl)-N 2< -(3-(pyridin-2-yl)phenyl)-1H-indole-2,6-dicarboxamide

[0299] The product of step-1 of example-24 (150 mg, 0.31 mmol) and sodium hydroxide (38 mg, 0.93 mmol) were treated together to afford 300 mg of the title compound following the procedure described in step-2 of example-21. LCMS: 490.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 25: Synthesis of compound 1-149 1-(4-Carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0300] Step-1: 1-(4-Carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0301] To the solution of the product of step-2 of example-23 (300 mg, 0.6 mmol) in 10 mL of dioxane was added 0.7 N sodium hydroxide (25 mg, 0.6 mmol) aqueous solution drop wise at 0 °C and stirred for 10 minutes followed by dimethyl sulfate (1860 mg, 10 mmol) was added drop wise at the same temperature and reaction mixture was stirred for 4 h at 0 °C. Solvent was evaporated under vacuum to give crude product which was purified by reverse-phase preparative HPLC and afforded 35 mg of the title compound. LCMS: 511.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.95 (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).Example 26: Synthesis of compound 1-157 (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

[0302] 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

[0303] 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 afford 60 mg of the title compound following the procedure described in step-3 of example-23. LCMS: 696.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 0.90 (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= 4.537 min).Example 27: Synthesis of compound I-158 (S)-tert-butyl (1-(((amino(1-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-1- yl)phenyl)carbamoyl)-1H-indol-6-yl)methylene)amino)oxy)-1-oxopropan-2-yl)carbamate

[0304] 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-oxopropan-2-yl)carbamate

[0305] The product of step-2 of example-23 (0.2 mg, 0.4 mmol) and (S)- Boc alanine were treated together to afford 45 mg of the title compound following the procedure described in step-3 of example-23.Example 28: Synthesis of compound I-183 Ethyl ((1-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0306] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0307] 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 to afford 685 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 465.2 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0308] The product of step-1 of example-28 (685 mg, 1.47 mmol) and aqueous hydroxylamine (0.4 mL) were treated together to afford 520 mg of the title compound following the procedure described in step-4 of example-14. LCMS: 498.2 (M+1) +< .Step-3: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0309] The product of step-2 of example-28 (520 mg, 1.04 mmol) and acetic anhydride (213 mg, 2.08 mmol) were treated together to afford 465 mg of the title compound following the procedure described in step-5 of example-14. LCMS: 540.2 (M+1) +< .Step-4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0310] The product of step-3 of example-28 (460 mg, 0.85 mmol) and zinc (112 mg, 1.7 mmol) were treated together to afford 60 mg of the title compound following the procedure described in step-6 of example-14. LCMS: 482.2 (M+1) +< .Step-5: Ethyl ((1-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-1-yl)pyridin-2-yl)carbamoyl)-1H-indol-6-yl)(imino)methyl)carbamate

[0311] The product of step-4 of example-28 (350 mg, 0.72 mmol) and ethyl carbonochloridate (78 mg, 0.72 mmol) were treated together to afford 70 mg of the title compound following the procedure described in step-1 of example 22. LCMS: 554.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 29: Synthesis of compound I-199 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0312] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-((2-methoxyethoxy)methoxy)adamantan-1-yl)-1H-indole-2-carboxamide

[0313] 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 to afford 635 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 557.3 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-hydroxyadamantan-1-yl)-1H-indole-2-carboxamide

[0314] The product of step-1 of example-29 (650 mg, 1.07 mmol) was treated with 50 mL of ethanolic-HCl to afford 320 mg of the title compound following the procedure described in step-2 of example-2. LCMS: 469.2 (M+1) +< .Step-3: 1-(4-Carbamoylbenzyl)-6-cyano-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0315] 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 reaction mixture was stirred for 1 h at -30 °C. Mixture was quenched with ice-cold water and extracted with dichloromethane, dried over sodium sulphate and solvent was evaporated under vacuum to afford 180 mg of the title compound, which was subjected to next step without further purification. LCMS: 471.2 (M+1) +< .Step-4: 1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-6-(N'-hydroxycarbamimidoyl)-1H-indole-2-carboxamide

[0316] The product of step-3 of example-29 (180 mg, 0.38 mmol) and aqueous hydroxylamine (0.1 mL) were treated together to afford 150 mg of the title compound following the procedure described in step-4 of example-14. LCMS: 504.2 (M+1) +< .Step-5: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-1-yl)-1H-indole-2-carboxamide

[0317] The product of step-4 of example-29 (150 mg, 0.29 mmol) and acetic anhydride (60 mg, 0.6 mmol) were treated together to afford 120 mg of the title compound following the procedure described in step-5 of example-14. LCMS: 546.2 (M+1) +< .Step-6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-((1r,3r)-3-((2-methoxyethoxy)methoxy)-adamantan-1-yl)-1H-indole-2-carboxamide

[0318] The product of step-5 of example-29 (120 mg, 0.21 mmol) and zinc (30 mg, 0.45 mmol) were treated together to afford 25 mg of the title compound following the procedure described in step-6 of example-14. LCMS: 488.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.51 (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).Example 30: Synthesis of compound 1-210. 3-Amino-6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0319] Step-1: 1-(4-carbamoylbenzyl)-6-cyano-N-( cyclohexylmethyl)-1H-indole-2-carboxamide

[0320] 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 afford 645 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 413.1 (M+1) +< .Step-2: 1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-3-nitro-1H-indole-2-carboxamide

[0321] The product of step-1 of example-30 (645 mg, 1.56 mmol) and aqueous hydroxylamine (0.5 mL) were treated together to afford 470 mg of the title compound following the procedure described in step-4 of example-14. LCMS: 493.2 (M+1) +< .Step-3: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-nitro-1H-indole-2-carboxamide

[0322] The product of step-2 of example-30 (470 mg, 0.95 mmol) and acetic anhydride (194 mg, 1.9 mmol) were treated together to afford 385 mg of the title compound following the procedure described in step-5 of example-14. LCMS: 535.2 (M+1) +< .Step-4: 3-Amino-6-carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0323] The product of step-3 of example-30 (385 mg, 0.71 mmol) and zinc (187 mg, 2.87 mmol) were treated together to afford 55 mg of the title compound following the procedure described in step-6 of example-14. LCMS: 447.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 0.83 (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).Example 31: Synthesis of compound 1-211 3-Amino-1-(4-carbamoylbenzyl)-N 2< -(cyclohexylmethyl)-1H-indole-2,6-dicarboxamide

[0324] Step-1: 1-(4-Carbamoylbenzyl)-N2-(cyclohexylmethyl)-3-nitro-1H-indole-2,6-dicarboxamide

[0325] 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 afford 165 mg of the title compound following the procedure described in step-2 of example-21. LCMS: 478.2 (M+1) +< .Step-2: 3-amino-1-(4-carbamoylbenzyl)-N 2< -(cyclohexylmethyl)-1H-indole-2,6-dicarboxamide

[0326] The product of step-1 of example-81 (165 mg, 0.34 mmol) and zinc (45 mg, 0.69 mmol) were treated together to afford 300 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 448.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 32: Synthesis of compound I-212 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-hydroxy-1H-indole-2-carboxamide

[0327] Step-1: Ethyl 3-acetoxy-6-cyano-1H-indole-2-carboxylate

[0328] 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 mixture was slowly heated to 100 °C for 3h. The reaction mixture was diluted with ethyl acetate and filtered it through celite pad and filtrate was washed with water and dried over sodium sulphate. Solvent was evaporated under vacuum to give crude compound which was purified with column chromatography using silica-gel as an adsorbent and eluted with hexane:ethyl acetate (7:3) to afford 645 mg of the title compound. LCMS: 273.1 (M+1) +< .Step-2: Ethyl 3-acetoxy-1-(4-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0329] 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 afford 745 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 406.1 (M+1) +< .Step-3: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-3-hydroxy-1H-indole-2-carboxylate

[0330] 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). Mixture was heated to 80 °C for 6 h. The reaction mixture quenched with cold-water and extracted with ethyl acetate, followed by washed with water and dried over sodium sulphate. Solvent was evaporated under vacuum to give crude compound which was purified with column chromatography using silica-gel as an adsorbent and eluted with hexane:ethyl acetate (6:4) to afford 540 mg of the title compound. LCMS: 364.1 (M+1) +< .Step-4: Ethyl 1-(4-carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxylate

[0331] 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. Reaction mixture was stirred at room temperature for 6 h. Mixture was quenched with cold water, extracted with ethyl acetate followed by washed with brine and dried over sodium sulphate. Solvent was evaporated under vacuum to give crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with hexane:ethylacetate (8:2) to afford 610 mg of the title compound. LCMS: 484.2 (M+1) +< .Step-5: 1-(4-Carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxylic acid

[0332] The product of step-4 of example-32 (610 mg, 1.26 mmol) and lithium hydroxide (60 mg, 2.52 mmol) were treated together to afford 385 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 456.2 (M+1) +< .Step-6: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-cyano-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0333] The product of step-5 of example-32 (385 mg, 0.84 mmol) and cyclohexylmethanamine (95 mg, 0.84 mmol) were treated together to afford 310 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 551.3 (M+1) +< .Step-7: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0334] The product of step-6 of example-32 (310 mg, 0.56 mmol) and aqueous hydroxylamine (0.2 mL) were treated together to afford 165 mg of the title compound following the procedure described in step-4 of example-14. LCMS: 584.3 (M+1) +< .Step-8: 6-(N'-acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-((4-methoxybenzyl)oxy)-1H-indole-2-carboxamide

[0335] The product of step-7 of example-32 (165 mg, 0.28 mmol) and acetic anhydride (58 mg, 0.56 mmol) were treated together to afford 145 mg of the title compound following the procedure described in step-5 of example-14. LCMS: 626.3 (M+1) +< .Step-9: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3-hydroxy-1H-indole-2-carboxamide

[0336] 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) under nitrogen at room temperature for 4 h. Mixture was filtered through celite pad and filtrate was concentrated to give crude product which was purified with reversed-phase preparative column chromatography and afforded 20 mg of the title compound. LCMS: 448.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).General synthetic scheme 3:

[0337] Example 33: Synthesis of compound 213 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0338] Step-1: Ethyl 3-chloro-6-cyano-1H-indole-2-carboxylate

[0339] Ethyl 6-cyano-1H-indole-2-carboxylate (1.25 g, 5.84 mmol) was dissolved in 125 mL of dimethylformamide and added N-chlorosuccinimide (932 mg, 7.0 mmol) at 0 °C in portions and stirred the mixture for 12 h at room temperature. Reaction mixture was quenched to cold water, extracted with ethylacetate, followed by washed with brine and dried over sodium sulphate. Solvent was evaporated under vacuum and resulted crude residue was purified by column chromatography using silica-gel as an adsorbent and eluted with hexane:ethylacetate (9:1) to afford 820 mg of the title compound. LCMS: 249.1 (M+1) +< .Step-2: Ethyl 6-carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-1H-indole-2-carboxylate

[0340] 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 afford 1150 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 399.1 (M+1) +< .Step-3: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-1H-indole-2-carboxylic acid

[0341] The product of step-2 of example-33 (1150 mg, 2.88 mmol) and lithium hydroxide (138 mg, 5.76 mmol) were treated together to afford 735 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 371.1 (M+1) +< .Step-4:1-(4-Carbamoylbenzyl)-3-chloro-6-cyano-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0342] The product of step-3 of example-33 (735 mg, 1.98 mmol) and cyclohexylmethanamine (223 mg, 1.98 mmol) were treated together to afford 630 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 449.2 (M+1) +< .Step-5: Ethyl 1-(4-carbamoylbenzyl)-3-chloro-2-((cyclohexylmethyl)carbamoyl)-1H-indole-6-carbimidate

[0343] The product of step-4 of example-33 (630 mg, 1.4 mmol) was treated with 50 mL of ethanolic-HCl to afford 385 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 495.2 (M+1) +< .Step-6: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0344] The product of step-5 of example-33 (385 mg, 0.77 mmol) was treated with 50 mL of ethanolic-NH 3 to afford 75 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 466.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).

[0345] The following compounds listed in table-8 were prepared according to Scheme-3 by following similar procedure as described above for example-33 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-8: Cpd. ID.R 2 R 5 R 3 LCMS (M+1) +< 1< H NMRI-214 Cl 466.2δ 0.85 (d, 3H), 1.26 (m, 6H), 1.65 (m, 2H), 1.75 (m, 1H), 3.52 (m, 1H), 5.75 (s, 2H), 7.21 (m, 2H), 7.37 (brs, 1H), 7.64 (m, 1H), 7.77 (m, 3H), 7.94 (brs, 1H), 8.26 (d, 1H), 8.65 (m, 1H), 9.03 (brs, 2H), 9.30 (brs, 2H); HPLC: 90.92% (Retention Time= 6.563 min).1-236 Cl 500.2δ 0.87 (m, 2H), 1.07 (m, 4H), 1.47 (m, 1H), 1.60 (m, 4H), 3.09 (m, 2H), 5.70 (s, 2H),7.19 (d, 2H), 7.34 (m, 1H), 7.42 (m, 2H), 7.56 (m, 4H), 7.64 (d, 1H), 7.82 (d, 1H), 8.82 (m, 1H), 9.05 (brs, 2H), 9.32 (brs, 2H); HPLC: 95.15% (Retention Time= 7.397 min).I-237 Cl 499.2δ 0.83 (m, 3H), 1.25 (m, 2H), 1.40 (m, 5H), 1.62 (m, 2H), 3.98 (m, 1H), 5.67 (s, 2H), 7.27 (d, 2H), 7.35 (m, 1H), 7.44 (m, 2H), 7.56 (m, 4H), 7.60 (d, 1H), 7.82 (m, 1H), 8.34 (d, 1H), 8.6 (m, 1H), 9.05 (brs, 2H), 9.32 (brs, 2H); HPLC: 87.94% (Retention Time= 4.346 min).I-250 Br 560.2δ 1.31 (m, 4H), 1.83 (m, 4H),2.96 (m, 1H), 3.52 (m, 1H), 5.61 (s, 2H), 6.91 (d, 3H), 7.12 (m, 1H), 7.21 (d, 2H), 7.36 (m, 2H), 7.65 (d, 1H), 7.75 (m, 2H), 8.35 (brs, 2H), 8.37 (brs, 1H), 8.71 (d, 1H), 9.18 (brs, 2H), 9.35 (brs, 2H); HPLC: 98.88% (Retention Time= 4.847 min).I-251 Cl 516.2δ 1.31 (m, 4H), 1.83 (m, 4H), 2.96 (m, 1H), 3.52 (m, 1H), 5.63 (s, 2H), 6.91 (d, 4H), 7.12 (m, 1H), 7.21 (d, 2H), 7.36 (m, 2H), 7.65 (d, 1H), 7.81 (m, 4H), 8.41 (brs, 1H), 8.85 (d, 1H), 9.18 (brs, 2H), 9.35 (brs, 2H); HPLC: 97.1% (Retention Time= 5.37 min). Example 34: Synthesis of compound I-215 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0346] Step-1: Methyl 4-((6-cyano-2-((cyclohexylmethyl)carbamoyl)-1H-indol-1-yl)methyl)benzoate

[0347] 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 afford 1.16 g of the title compound following the procedure described in step-1 of example-1. LCMS: 430.2 (M+1) +< .Step-2: 4-((6-Cyano-2-((cyclohexylmethyl)carbamoyl)-1H-indol-1-yl)methyl)benzoic acid

[0348] 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 to afford 835 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 417.2 (M+1) +< .Step-3: 6-Cyano-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0349] The product of step-2 of example-34 (830 mg, 1.99 mmol) and methanamine (62 mg, 1.99 mmol) were treated together to afford 445 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 429.2 (M+1) +< .Step-4: Ethyl 2-((cyclohexylmethyl)carbamoyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-6-carbimidate

[0350] The product of step-3 of example-34 (445 mg, 1.03 mmol) was treated with 50 mL of ethanolic-HCl to afford 265 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 475.3 (M+1) +< .Step-5: 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(methylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0351] The product of step-4 of example-34 (265 mg, 0.55 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 80 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 446.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 35: Synthesis of compound 1-216 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxamide

[0352]

[0353] This compound was prepared by reacting the product of step-2 of example-34 with dimethylamine by following a similar procedure described in step-3 to step-5 of example-34. LCMS: 460.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 36: Synthesis of compound I-217 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-(cyclopropylcarbamoyl)benzyl)- 1H-indole-2-carboxamide

[0354]

[0355] This compound was prepared by reacting the product of step-2 of example-34 with cyclopropylamine by following a similar procedure described in step-3 to step-5 of example-34. LCMS: 472.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 37: Synthesis of compound I-218 6-Carbamimidoyl-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0356] Step-1: 6-Cyano-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0357] The product of step-1 of example-6 (850 mg, 4.54 mmol) and 4-methylcyclohexanamine (513 mg, 4.54 mmol) were treated together to afford 530 mg of the title compound following the procedure described in step-3 of example 1. LCMS: 282.2 (M+1) +< .Step-2: Methyl 4-((6-cyano-2-((4-methylcyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)benzoate

[0358] 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 to afford 565 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 430.2 (M+1) +< .Step-3: 4-((6-Cyano-2-((4-methylcyclohexyl)carbamoyl)-1H-indol-1-yl)methyl)benzoic acid

[0359] The product of step-2 of example 37 (550 mg, 1.27 mmol) and lithium hydroxide (60 mg, 2.54 mmol) were treated together to afford 410 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 416.2 (M+1) +< .Step-4: 6-Cyano-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0360] The product of step-3 of example 37 (410 mg, 0.98 mmol) and dimethylamine (45 mg, 0.98 mmol) were treated together to afford 270 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 443.2 (M+1) +< .Step-5: Ethyl 1-(4-(dimethylcarbamoyl)benzyl)-2-((4-methylcyclohexyl)carbamoyl)-1H-indole-6-carbimidate

[0361] The product of step-4 of example 37 (270 mg, 0.6 mmol) was treated with 50 mL of ethanolic-HCl to afford 160 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 489.3 (M+1) +< .Step-6: 6-Carbamimidoyl-1-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0362] The product of step-5 of example 37 (160 mg, 0.32 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 35 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 460.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 38: Synthesis of compound I-219 6-Carbamimidoyl-1-(4-(cyclopropylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0363]

[0364] This compound was prepared by reacting the product of step-3 of example-37 with cyclopropylamine by following a similar procedure described in step-4 to step-6 of example-37. LCMS: 472.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 39: Synthesis of compound I- 220 6-Carbamimidoyl-1-(4-(methylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0365]

[0366] This compound was prepared by reacting the product of step-3 of example-37 with methylamine by following a similar procedure described in step-4 to step-6 of example-37. LCMS: 446.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 40: Synthesis of compound I-221 6-Carbamimidoyl-1-(4-(ethylcarbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0367]

[0368] This compound was prepared by reacting the product of step-3 of example-37 with ethylamine by following a similar procedure described in step-4 to step-6 of example-37. LCMS: 460.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 41: Synthesis of compound I- 222 6-Carbamimidoyl-N-(cyclohexylmethyl)-1-(4-((2- hydroxyethyl)carbamoyl)benzyl)-1H-indole-2-carboxamide

[0369]

[0370] This compound was prepared by reacting the product of step-2 of example-34 with 2-((2-methoxyethoxy)methoxy)ethanamine by following a similar procedure described in step-3 to step-5 of example-34. LCMS: 476.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 42: Synthesis of compound I-223 6-Carbamimidoyl-1-(4-((2-hydroxyethyl)carbamoyl)benzyl)-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0371]

[0372] This compound was prepared by reacting the product of step-3 of example-37 with 2-((2-methoxyethoxy)methoxy)ethanamine by following a similar procedure described in step-4 to step-6 of example-39. LCMS: 476.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 43: Synthesis of compound I-224 1-(4-((2-Aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(4-methylcyclohexyl)-1H-indole-2-carboxamide

[0373]

[0374] This compound was prepared by reacting the product of step-3 of example-37 with tert-butyl (2-aminoethyl)carbamate by following a similar procedure described in step-4 to step-6 of example-37. LCMS: 475.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 44: Synthesis of compound I-225 1-(4-((2-Aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0375]

[0376] This compound was prepared by reacting the product of step-2 of example-34 with tert-butyl (2-aminoethyl)carbamate by following a similar procedure described in step-3 to step-5 of example-34. LCMS: 475.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 45: Synthesis of compound I-232 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0377] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0378] 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 afford 395 mg of the title compound following the procedure described in step-3 of example 1. LCMS : 429.2 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-1H-indole-2-carboxamide

[0379] The product of step-1 of example 50 (380 mg, 0.88 mmol) and aqueous hydroxylamine (1.7 mL) were treated together to afford 300 mg of the title compound following the procedure described in step-4 of example 14. LCMS : 462.2 (M+1) +< .Step-3: 6-(N'-Acetoxycarbamimidoyl)-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0380] 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 afford 180 mg of the title compound following the procedure described in step-5 of example 14. LCMS : 504.2 (M+1) +< .Step-4: 6-Carbamimidoyl-1-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N-methyl-1H-indole-2-carboxamide

[0381] The product of step-3 of example 50 (160 mg, 0.31 mmol) and zinc (80 mg, 1.24 mmol) were treated together to afford 65 mg of the title compound following the procedure described in step-6 of example 14. LCMS : 446.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 46: Synthesis of compound 1-226 6-Carbamimidoyl-1-(4-carbamoyl-phenethyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0382] The synthesis of compound in Example I-226 was accomplished following similar procedures to example 45 using Steps 1 to Step 4 where N- methyl cyclohexylmethyl amine was replaced with cylohexyl methyl amine and Example 19 step 1. LCMS: 446.2 (M+1)+ 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 47: Synthesis of compound I-227 6-Carbamimidoyl-1-(2-Fluoro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0383]

[0384] The synthesis of compound in Example I-227 was accomplished following similar procedures to example 45 using Steps 1 to Step 4 where N- methyl cyclohexylmethyl amine was replaced with cylohexyl methyl amine and Example 19 step 1. LCMS: 450.2 (M+1)+ 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 48: Synthesis of compound I-228 6-Carbamimidoyl-1-(2-Chloro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0385] The synthesis of compound in Example I-228 was accomplished following similar procedures to example 45 using Steps 1 to Step 4 where N- methyl cyclohexylmethyl amine was replaced with cylohexyl methyl amine and Example 19 step 1 using the corrosponding 2 chloro derivative. LCMS: 466.2 (M+1)+ 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 49: Synthesis of compound I-229 6-Carbamimidoyl-1-(3-Chloro-4-carbamoyl-benzyl)-N-(cyclohexylmethyl)-1H- indole-2-carboxamide

[0386] The synthesis of compound in Example I-229 was accomplished following similar procedures to example 45 using Steps 1 to Step 4 where N- methyl cyclohexylmethyl amine was replaced with cylohexyl methyl amine and Example 19 step 1 using the corrosponding 3 chloro derivative. LCMS: 466.2 (M+1)+ 1< H NMR (300MHz, DMSO-d 6 ): δ δ 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).Example 50: Syntheis of compound I-230 6-Carbamimidoyl-1-(3-carbamoylbenzyl)-N-(4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0387] The synthesis of compound in Example I-230 was accomplished following similar procedures to example 45 using Steps 1 to Step 4 where N- methyl cyclohexylmethyl amine was replaced with 4,difluorocyclohexyl amine and Example 19 step 1 using the corrosponding 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).Example 51: Synthesis of compound I-241 6-Carbamimidoyl-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0388] Step-1: Ethyl 6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxylate

[0389] 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 afford 4.65 g of the title compound following the procedure described in step-1 of example-1. LCMS: 397.2 (M+1) +< .Step-2: 6-Cyano-1-((4'-ethoxy-[1,1'-biphenyl]-3-yl)methyl)-1H-indole-2-carboxylic acid

[0390] 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 to afford 3.28 g of the title compound following the procedure described in step-2 of example-1. LCMS: 367.2 (M+1) +< .Step-3: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido) cyclohexyl)carbamate

[0391] 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 to afford 485 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 565.3 (M+1) +< .Step-4: N-((1r,4r)-4-Aminocyclohexyl)-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0392] The product of step-3 of example-51 (840 mg, 1.48 mmol) was treated with 50 mL of ethanolic-HCl to afford 645 mg of the title compound following the procedure described in step-2 of example-2. LCMS: 465.2 (M+1) +< .Step-5: 6-Cyano-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0393] The product of step-4 of example-51 (640 mg, 1.37 mmol), dissolved in 10 mL ofN,N-dimethylformamide, was treated with 1H-pyrazole-1-carboxamidine hydrochloride (405 mg, 2.76 mmol) and N,N-diisopropylethylamine (535 mg, 4.11 mmol) to afford 320 mg of the title compound following the procedure described in step-2 of example-3. LCMS: 507.3 (M+1) +< .Step-6: Ethyl 2-(((1r,4r)-4-guanidinocyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carbimidate

[0394] The product of step-5 of example-51 (320 mg, 0.63 mmol) was treated with 50 mL of ethanolic-HCl to afford 175 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 553.3 (M+1) +< .Step-7: 6-Carbamimidoyl-N-((1r,4r)-4-guanidinocyclohexyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0395] The product of step-6 of example-51 (150 mg, 0.28 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 80 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 524.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.32 (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).Example 52: Synthesis of compound 1-242 N-((1r,4r)-4-(3-Aminopropanamido)cyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0396] Step-1: tert-Butyl (3-(((1r,4r)-4-(6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)-amino)-3-oxopropyl)carbamate

[0397] The product of step-4 example 51 (730 mg, 1.56 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (296 mg, 1.56 mmol) were treated together to afford 425 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 636.3 (M+1) +< .Step-2: Ethyl 2-(((1r,4r)-4-(3-aminopropanamido)cyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carbimidate

[0398] The product of step-1 of example 52 (425 mg, 0.66 mmol) was treated with 50 mL of ethanolic-HCl to afford 195 mg of the title compound following the procedure described in step-4 of example 1. LCMS: 582.3 (M+1) +< .Step-3: N-((1r,4r)-4-(3-Aminopropanamido)cyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0399] The product of step-2 of example 52 (195 mg, 0.33 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 62 mg of the title compound following the procedure described in step-5 of example 1. LCMS: 553.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 53: Synthesis of compound 1-252 3-amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0400] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-3-nitro-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0401] 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 afford 760 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 610.3 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(3-amino-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0402] The product of step-1 of example-53 (750 mg, 1.22 mmol) and zinc (160 mg, 2.45 mmol) were treated together to afford 430 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 580.3 (M+1) +< .Step-3: Ethyl 3-amino-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-phenoxybenzyl)-1H-indole-6-carbimidate

[0403] The product of step-2 of example-53 (430 mg, 0.74 mmol) was treated with 50 mL of ethanolic-HCl to afford 155 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 526.3 (M+1) +< .Step-4: 3-Amino-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamide

[0404] The product of step-3 of example-53 (155 mg, 0.29 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 15 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 497.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 1.31 (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).Example 54: Synthesis of compound 1-253 ((1r,4r)-4-(3-Amino-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2- carboxamido)-cyclohexyl) carbamic acid

[0405] Step-1: ((1r,4r)-4-(3-Amino-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0406] The product of step-2 of example 53 (510 mg, 0.87 mmol) and sodium hydroxide (52 mg, 1.3 mmol) were treated together to afford 180 mg of the title compound following the procedure described in step-2 of example-1 without using lithium hydroxide as base. LCMS: 524.2 (M+1) +< .Step-2: ((1r,4r)-4-(3-Amino-6-(ethoxy(imino)methyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0407] The product of step-1 of example-53 (180 mg, 0.51 mmol) was treated with 30 mL of ethanolic-HCl to afford 65 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 570.3 (M+1) +< .Step-3: ((1r,4r)-4-(3-Amino-6-carbamimidoyl-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamic acid

[0408] The product of step-2 of example-53 (65 mg, 0.11 mmol) was treated with 20 mL of ethanolic-NH 3 to afford 10 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 541.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 55: Synthesis of compound I-254 Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'- hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indol-3-yl)carbamate

[0409] Step-1: tert-Butyl ((1r,4r)-4-(3-ethylcarbamate-6-cyano-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0410] The product of step-2 of example 53 (650 mg, 1.12 mmol) and ethyl carbonochloridate (121 mg, 1.12 mmol) were treated together to afford 370 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 652.3 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(3-ethylcarbamate-6-((Z)-N'-hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0411] The product of step-1 of example-55 (370 mg, 0.56 mmol) and aqueous hydroxylamine (0.2 mL) were treated together to afford 230 mg of the title compound following the procedure described in step-4 of example-14. LCMS: 613.3 (M+1) +< .Step-3: Ethyl (2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'-hydroxycarbamimidoyl)-1-(4-phenoxybenzyl)-1H-indol-3-yl)carbamate

[0412] The product of step-2 of example-55 (230 mg, 0.37 mmol) was treated with 30 mL of ethanolic-HCl to afford 65 mg of the title compound following the procedure described in step-2 of example-2. LCMS: 585.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 56: Synthesis of compound 1-256 1-(3-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0413] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0414] 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 afford 850 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 518.2 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)-carbamate

[0415] The product of step-1 of example-56 (850 mg, 1.64 mmol) and zinc (213 mg, 3.28 mmol) were treated together to afford 410 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 488.3 (M+1) +< .Step-3: Ethyl 1-(3-aminobenzyl)-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1H-indole-6-carbimidate

[0416] The product of step-2 of example-56 (410 mg, 0.84 mmol) was treated with 50 mL of ethanolic-HCl to afford 235 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 434.2 (M+1) +< .Step-4: 1-(3-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0417] The product of step-3 of example-56 (235 mg, 0.54 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 35 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 405.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 57: Synthesis of compound 1-257 N-((1r,4r)-4-aminocyclohexyl)-1-(3-(3-aminopropanamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0418]

[0419] This compound was prepared by treating the product of step-2 of example-56 with 3-((tert-butoxycarbonyl)amino)propanoic acid by following a similar procedure as described in step-3 to step-5 of example-1. LCMS: 476.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 58: Synthesis of compound I-258 N-((1r,4r)-4-Aminocyclohexyl)-1-(3-(azetidine-3-carboxamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0420]

[0421] This compound was prepared by treating the product of step-2 of example-56 with 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid by following a similar procedure as described in step-3 to step-5 of example-1. LCMS: 488.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 59: Synthesis of compound I-259 3-(3-((2-(((1r,4r)-4-Amiocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0422] Step-1: methyl 3-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoate

[0423] 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 afford 930 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 531.2 (M+1) +< .Step-2: 3-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzoic acid

[0424] The product of step-1 of example-59 (930 mg, 1.75 mmol) and lithium hydroxide (85 mg, 3.5 mmol) were treated together to afford 630 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 517.2 (M+1) +< .Step-3: Methyl 3-(3-((2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzamido)propanoate

[0425] The product of step-2 of example-59 (630 mg, 1.21 mmol) and methyl 3-aminopropanoate (125 mg, 1.21 mmol) were treated together to afford 340 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 602.3 (M+1) +< .Step-4: 3-(3-((2-(((1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0426] 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 afford 210 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 588.3 (M+1) +< .Step-5: 3-(3-((2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-(ethoxy(imino)methyl)-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0427] The product of step-4 of example-59 (200 mg, 0.34 mmol) was treated with 50 mL of ethanolic-HCl to afford 75 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 534.3 (M+1) +< .Step-6: 3-(3-((2-(((1r,4r)-4-Aminocyclohexyl)carbamoyl)-6-carbamimidoyl-1H-indol-1-yl)methyl)benzamido)propanoic acid

[0428] The product of step-5 of example-59 (70 mg, 0.13 mmol) was treated with 20 mL of ethanolic-NH 3 to afford 23 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 505.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 60: Synthesis of compound 1-260 1-(3-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0429] Step-1: Ethyl 6-cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylate

[0430] 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 afford 1.05 g of the title compound following the procedure described in step-1 of example-1. LCMS: 350.1 (M+1) +< .Step-2: 6-Cyano-1-(3-nitrobenzyl)-1H-indole-2-carboxylic acid

[0431] 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 afford 680 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 322.1 (M+1) +< .Step-3: 6-Cyano-N-(4,4-difluorocyclohexyl)-1-(3-nitrobenzyl)-1H-indole-2-carboxamide

[0432] The product of step-2 of example-60 (680 mg, 2.11 mmol) and 4,4-difluorocyclohexanamine (285 mg, 2.11 mmol) were treated together to afford 570 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 439.2 (M+1) +< .Step-4: 1-(3-Aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0433] The product of step-3 of example-60 (570 mg, 1.29 mmol) and zinc (170 mg, 2.62 mmol) were treated together to afford 410 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 409.2 (M+1) +< .Step-5: tert-Butyl (3-((3-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indol-1-yl)-methyl)phenyl)amino)-3-oxopropyl)carbamate

[0434] 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 afford 365 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 580.3 (M+1) +< .Step-6: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(3-((2-aminoethyl)carbamoyl)-benzyl)-1H-indole-6-carbimidate

[0435] The product of step-5 of example-60 (350 mg, 0.6 mmol) was treated with 50 mL of ethanolic-HCl to afford 115 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 526.3 (M+1) +< .Step-7: 1-(3-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0436] The product of step-6 of example-60 (115 mg, 0.21 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 34 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 497.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 61: Synthesis of compound 1-261 1-(4-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0437] Step-1: tert-Butyl ((1r,4r)-4-(6-cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxamido)-cyclohexyl)carbamate

[0438] 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 afford 970 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 518.2 (M+1) +< .Step-2: tert-Butyl ((1r,4r)-4-(1-(3-aminobenzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)-carbamate

[0439] The product of step-1 of example-61 (970 mg, 1.87 mmol) and zinc (244 mg, 3.74 mmol) were treated together to afford 530 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 488.3 (M+1) +< .Step-3: Ethyl 1-(4-aminobenzyl)-2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1H-indole-6-carbimidate

[0440] The product of step-2 of example-61 (340 mg, 0.69 mmol) was treated with 50 mL of ethanolic-HCl to afford 150 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 434.2 (M+1) +< .Step-4: 1-(4-Aminobenzyl)-N-((1r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0441] The product of step-3 of example-61 (150 mg, 0.34 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 22 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 405.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 62: Synthesis of compound 1-262 N-((1r,4r)-4-Aminocyclohexyl)-1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0442] Step-1: tert-Butyl ((1r,4r)-4-(1-(4-(3-((tert-butoxycarbonyl)amino)propanamido)benzyl)-6-cyano-1H-indole-2-carboxamido)cyclohexyl)carbamate

[0443] 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 to afford 430 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 659.3 (M+1) +< .Step-2: Ethyl 2-(((1r,4r)-4-aminocyclohexyl)carbamoyl)-1-(4-(3-aminopropanamido)benzyl)-1H-indole-6-carbimidate

[0444] The product of step-1 of example-62 (430 mg, 0.65 mmol) was treated with 50 mL of ethanolic-HCl to afford 170 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 505.3 (M+1) +< .Step-3: N-((1r,4r)-4-Aminocyclohexyl)-1-(4-(3-aminopropanamido)benzyl)-6-carbamimidoyl-1H-indole-2-carboxamide

[0445] The product of step-2 of example-62 (170 mg, 0.33 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 28 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 476.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 63: Synthesis of compound 1-263 1-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0446] Step-1: Ethyl 6-cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxylate

[0447] 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 afford 955 mg of the title compound following the procedure described in step-1 of example-1. LCMS: 350.1 (M+1) +< .Step-2: 6-Cyano-1-(4-nitrobenzyl)-1H-indole-2-carboxylic acid

[0448] The product of step-1 of example-63 (950 mg, 2.71 mmol) and lithium hydroxide (130 mg, 5.42 mmol) were treated together to afford 710 mg of the title compound following the procedure described in step-2 of example-1. LCMS: 322.1 (M+1) +< .Step-3: 6-Cyano-N-(4,4-difluorocyclohexyl)-1-(4-nitrobenzyl)-1H-indole-2-carboxamide

[0449] The product of step-2 of example-63 (650 mg, 2.01 mmol) and 4,4-difluorocyclohexanamine (272 mg, 2.01 mmol) were treated together to afford 512 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 439.2 (M+1) +< .Step-4: 1-(4-Aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0450] The product of step-3 of example-63 (510 mg, 1.16 mmol) and zinc (151 mg, 2.32 mmol) were treated together to afford 365 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 409.2 (M+1) +< .Step-5: tert-Butyl (3-((4-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indol-1-yl)-methyl)phenyl)amino)-3-oxopropyl)carbamate

[0451] The product of step-4 of example-63 (365 mg, 0.89 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (120 mg, 0.89 mmol) were treated together to afford 280 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 580.3 (M+1) +< .Step-6: Ethyl 1-(4-(3-aminopropanamido)benzyl)-2-((4,4-difluorocyclohexyl)carbamoyl)-1H-indole-6-carbimidate

[0452] The product of step-5 of example-63 (280 mg, 0.48 mmol) was treated with 50 mL of ethanolic-HCl to afford 125 mg of the title compound following the procedure described in step-4 of example 1. LCMS: 526.3 (M+1) +< .Step-7: 1-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0453] The product of step-6 of example 63 (125 mg, 0.23 mmol) was treated with 30 mL of ethanolic-NH 3 to afford 22 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 497.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 64 Synthesis of compound I-264 1-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(cyclohex-3-en-1-yl)-1H-indole-2-carboxamide

[0454] Step-1: 6-Cyano-N-(cyclohex-3-en-1-yl)-1-(4-nitrobenzyl)-1H-indole-2-carboxamide

[0455] 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 afford 360 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 401.2 (M+1) +< .Step-2: 1-(4-Aminobenzyl)-6-cyano-N-(cyclohex-3-en-1-yl)-1H-indole-2-carboxamide

[0456] The product of step-1 of example-64 (360 mg, 0.89 mmol) and zinc (116 mg, 1.8 mmol) were treated together to afford 265 mg of the title compound following the procedure described in step-3 of example-9. LCMS: 371.2 (M+1) +< .Step-3: tert-Butyl (3-((4-((6-cyano-2-(cyclohex-3-en-1-ylcarbamoyl)-1H-indol-1-yl)methyl)phenyl) amino)-3-oxopropyl)carbamate

[0457] The product of step-2 of example-64 (260 mg, 0.7 mmol) and 3-((tert-butoxycarbonyl)amino)propanoic acid (132 mg, 0.7 mmol) were treated together to afford 200 mg of the title compound following the procedure described in step-3 of example-1. LCMS: 542.3 (M+1) +< .Step-4: Ethyl 1-(4-(3-aminopropanamido)benzyl)-2-(cyclohex-3-en-1-ylcarbamoyl)-1H-indole-6-carbimidate

[0458] The product of step-3 of example-64 (200 mg, 0.36 mmol) was treated with 30 mL of ethanolic-HCl to afford 85 mg of the title compound following the procedure described in step-4 of example-1. LCMS: 488.3 (M+1) +< .Step-5: 1-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4-difluorocyclohexyl)-1H-indole-2-carboxamide

[0459] The product of step-4 of example-64 (85 mg, 0.17 mmol) was treated with 20 mL of ethanolic-NH 3 to afford 14 mg of the title compound following the procedure described in step-5 of example-1. LCMS: 459.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 65: Synthesis of compound 1-267 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0460]

[0461] The crude product of step-2 of example-23 was purified by preparative Highperformance liquid chromatography instrument with a Agilent XDB C18 reverse phase column (21.2x 150mm, 5micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 100% acetonitrile (0.1% TFA) which afforded the title compound (25 mg). LCMS: 497.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 66: Synthesis of compound I-268 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0462] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0463] 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 afford 375 mg of the title compound following the procedure described in step-3 of example 1. LCMS : 464.2 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-2-carboxamide

[0464] The product of step-1 of example 66 (370 mg, 0.79 mmol) and aqueous hydroxylamine (1.3 mL) were treated together to afford 180 mg of the title compound following the procedure described in step-4 of example 14. LCMS: 497.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).Example 67: Synthesis of compound I-269 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0465] Step-1: 1-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0466] 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 to afford 285 mg of the title compound following the procedure described in step-3 of example 1. LCMS : 465.2 (M+1) +< .Step-2: 1-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrrolidin-1-yl)pyridin-2-yl)-1H-indole-2-carboxamide

[0467] The product of step-1 of example 67 (250 mg, 0.53 mmol) and aqueous hydroxylamine (1.2 mL) were treated together to afford 110 mg of the title compound following the procedure described in step-4 of example 14. LCMS: 498.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).General synthetic scheme 4

[0468]

[0469] The first general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-4. Ethyl 6-cyano-1H-indole-2-carboxylate was treated with various alkylating agents in presence of a suitable base (K 2 CO 3 ) and suitable solvent (DMF) to yield alkylated derivatives. Hydrolysis of C (2) ethyl ester with aq. LiOH followed by coupling with amines using EDCI, HOBt yelided amides. The cyano group in the resultant amide derivatives were converted to the amine anlogs by treatment with ethanolic HCl and the interemediate imidate were quenched with ammonia to form compound of formula (I).Example 68: Synthesis of compound 1-270 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[0470] Step-1: Ethyl 6-cyano-1-isopentyl-1H-indole-2-carboxylate

[0471] Ethyl 6-cyano-1H-indole-2-carboxylate (10.0 g, 46.71 mmol), dissolved in 250 mL of N,N-dimethylformamide (DMF), was added 1-bromo-3-methylbutane (7.0 g, 46.71 mmol) and potassium carbonate (K 2 CO 3 ) (7.73 g, 56.0 mmol) and stirred at room temperature for 8 h. After reaction completion, mixture was quenched with ice-cold water and precipitated product was filtered off. Thus obtained solid was further washed with water and dried under vacuum to give crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with 10-20% ethylacetate / hexane to afford the title compound (6.2 g). LCMS: 285.1 (M+1) +< .Step-2: 6-Cyano-1-isopentyl-1H-indole-2-carboxylic acid

[0472] Product of step-1 of example-68 (5.8 g, 19.64 mmol) was dissolved in 100 mL mixture of tetrahydrofuran / methanol / water (1:1:1) and added lithium hydroxide (LiOH) (1.9 g, 78.6 mmol) at room temperature. Resulting mixture was stirred at room temperature for 4-6 h. Mixture was acidified with saturated aqueous solution of citric acid and extracted with ethyl acetate followed by washed with brine and dried over anhydrous sodium sulphate and then solvent was evaporated under vacuum to get the title compound (3.65 g). LCMS: 257.1 (M+1) +< .Ste-3: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carbonitrile

[0473] Product of step-2 of example-68 (650 mg, 2.53 mmol) was dissolved in 10 mL of N,N-dimethylformamide and added 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) and stirred for 15 min at RT. 4-Fluoropiperidine (260 mg, 2.53 mmol), dissolved in 5 mL of DMF, was added to the reaction mixture and resulted solution was stirred at RT for overnight. Reaction mixture was quenched with water, extracted with ethyl acetate followed by washed with brine and water and dried over sodium sulphate. Solvent was evaporated under vacuum to give crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with 10% ethylacetate / hexane and afforded the title compound (510 mg). LCMS: 342.2 (M+1) +< .Step-4: Ethyl 2-(4-fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carbimidate

[0474] Product was step-3 of example-68 (450 mg, 1.31 mmol) was dissolved in 50 mL of ethanolic-HCl (ethanol was saturated with HCl gas at -20 °C) and kept in a glass sealed tube for 12 h at RT. After reaction completion, solvent was evaporated under vacuum to afford the title compound (235 mg). LCMS: 388.2 (M+1) +< .Step-5: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[0475] Product of step-4 of example-68 (220 mg, 0.56 mmol) was dissolved in 50 mL of ethanolic-NH 3 (ethanol was saturated with NH 3 gas at -70 °C) and kept for overnight in a steel bomb at RT. After reaction completion, solvent was evaporated under vacuum to give crude product which was purified by preparative High-performance liquid chromatography instrument with a Agilent XDB C18 reverse phase column (21.2x 150mm, 5micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 100% acetonitrile (0.1% TFA) which afforded the title compound (110 mg). LCMS: 359.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).

[0476] The following compounds listed in table-9 were prepared according to scheme-1 by following similar procedure as described above for example-68 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-9 Cpd. ID. R 2 m R 3 Characteristic Data I-271 2-F 2 LCMS (M+1) +< : 377.2 1< H NMR: δ 0.84 (m, 6H), 1.49 (m, 1H), 1.61 (m, 2H), 2.09 (m, 4H), 3.72 (m, 4H), 4.30 (m, 2H), 6.90 (s, 1H), 7.51 (d, 1H), 7.81 (d, 1H), 8.09 (s, 1H), 8.93 (brs, 2H), 9.27 (brs, 2H); HPLC: 91.12% (Retention Time= 3.282 min).I-272 1-FLCMS (M+1) +< : 345.2 1< H NMR: δ 0.84 (m, 6H), 1.49 (m, 1H), 1.56 (m, 2H), 2.21 (m, 2H), 3.72 (m, 4H), 4.44 (m, 2H), 5.25 (m, 1H), 6.98 (d, 1H), 7.50 (d, 1H), 7.82 (d, 1H), 8.09 (d, 1H), 8.92 (brs, 2H), 9.27 (brs, 2H); HPLC: 96.63% (Retention Time= 2.94 min).I-273 1-F 2 LCMS (M+1) +< : 363.2 1< H NMR: δ 0.87 (m, 6H), 1.49 (m, 1H), 1.62 (m, 2H), 2.55 (m, 2H), 3.77 (m, 1H), 3.88 (m, 1H), 3.98 (m, 1H), 4.10 (m, 1H), 4.41 (m, 2H), 7.05 (s, 1H), 7.51 (d, 1H), 7.82 (d, 1H), 8.09 (s, 1H), 8.94 (brs, 2H), 9.28 (brs, 2H); HPLC: 93.83% (Retention Time= 6.136 min).I-274 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 371.2 1< H NMR: δ 1.49 (m, 4H), 1.91 (m, 6H), 2.72 (m, 2H), 3.00 (m, 1H), 3.71 (m, 4H), 4.52 (m, 2H), 7.25 (s, 1H), 7.51 (d, 1H), 7.81 (m, 4H), 8.21 (s, 1H), 8.63 (s, 1H), 925 (d, 3H); HPLC: 97.48% (Retention Time= 5.764 min).I-275 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 386.2 1< H NMR: δ 0.81 (m, 2H), 1.49 (m, 2H), 1.65 (m, 4H), 2.82 (m, 4H), 3.15 (m, 2H), 3.95 (m, 1H), 4.50 (m, 3H), 4.8 (m, 1H), 6.75 (s, 1H), 7.51 (m, 1H), 7.71 (brs, 2H), 7.81 (d, 2H), 8.91 (brs, 2H), 9.18 (brs, 2H).I-276 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 385.2 1< H NMR: δ 1.21 (m, 2H), 1.49 (m, 2H), 1.61 (m, 4H), 2.55 (m, 2H), 2.8 (m, 3H), 3.15 (m, 1H), 3. 95 (m, 1H), 4.45 (m, 3H), 6.73 (s, 1H), 6.87 (s, 1H), 7.51 (d, 1H), 7.32 (s, 1H), 7.70 (m, 2H), 8.15 (s, 1H), 9.15 (brs, 2H), 9.25 (brs, 2H); HPLC: 90.17% (Retention Time= 4.108 min).I-277 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 404.2 1< H NMR: δ 1.40 (m, 2H), 1.67 (m, 4H), 2.52 (m, 2H), 2.84 (m, 3H), 3.15 (m, 1H), 3. 95 (m, 1H), 4.68 (brs, 2H), 5.64 (s, 2H), 6.97 (s, 1H), 7.08 (d, 2H), 7.33 (m, 2H), 7.51 (d, 1H), 7.70 (m, 2H), 8.15 (s, 1H), 9.15 (brs, 2H), 9.25 (brs, 2H).I-278 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 472.2 1< H NMR: δ 0.45 (m, 1H), 0.73 (m, 1H), 1.33 (m, 3H), 1.49 (m, 1H), 1.71 (m, 1H), 2.71 (m, 4H), 3.68 (m, 3H), 4.44 (m, 1H), 5.52 (m, 2H), 6.88 (s, 1H), 7.25 (d, 2H), 7.59 (m, 1H), 7.65 (d, 2H), 7.73 (brs, 2H), 7.83 (d, 1H), 8.29 (s, 1H),9.15 (brs, 2H), 9.25 (brs, 2H).I-279 1-(S)-FLCMS (M+1) +< : 433.1 1< H NMR: δ 2.21 (m, 2H), 3.44 (m, 4H), 5.22 (m, 1H), 5.71 (s, 2H), 7.10 (s, 1H), 7.21 (m, 2H), 7.58 (m, 3H), 7.85 (d, 1H), 8.21 (s, 1H), 9.11 (brs, 2H), 9.23 (brs, 2H); HPLC: 98.0% (Retention Time= 8.305 min).I-280 2-(CH 2 ) 2 OHLCMS (M+1) +< : 473.2 1< H NMR: δ 0.33 (m, 1H), 0.78 (m, 1H), 1.21 (m, 4H), 1.35 (m, 1H), 1.49 (m, 3H), 2.80 (m, 1H), 3.65 (m, 1H), 4.33 (m, 2H), 5.62 (m, 2H), 6.84 (s, 2H), 7.22 (m, 2H), 7.53 (d, 1H), 7.64 (d, 2H), 7.83 (d, 1H), 8.28 (s, 1H), 8.96 (brs, 2H), 9.23 (brs, 2H).I-281 2(CH 2 ) 3 C(O)OCH 2 CH 3 LCMS (M+1) +< : 543.2 1< H NMR: δ 0.33 (m, 1H),0.81 (m, 1H), 1.12 (m, 2H), 1.25 (m, 3H), 1.31 (m, 4H), 1.61 (m, 1H), 2.22 (m, 2H), 2.62 (m, 1H), 2.91 (m, 1H), 3.71 (m, 1H), 4.11 (m, 2H), 4.35 (m, 1H), 5.23 (d, 2H), 6.85 (s, 1H), 7.25 (d, 2H), 7.55 (m, 3H), 7.83 (d, 1H), 8.35 (brs, 1H), 9.21 (brs, 3H); HPLC: 98.397% (Retention Time= 9.335 min).I-282 2-FLCMS (M+1) +< : 447.2 1< H NMR: δ 1.54 (m, 2H), 2.96 (m, 2H), 3.53 (m, 4H), 4.52 9m, 1H), 5.63 (s, 2H), 6.93 (s, 1H), 7.24 (d, 2H), 7.53 (s, 1H), 7.65 (d, 2H), 7.86 (d, 1H), 8.21 (s, 1H), 9.03 (brs, 2H), 9.25 (brs, 2H); HPLC: 83.54% (Retention Time= 3.351 min).I-283 2-F 2 LCMS (M+1) +< : 1< H NMR: δ 1.54 (m, 2H), 1.88 (m, 2H), 3.53 (m, 4H), 5.67 (s, 2H), 6.99 (s, 1H), 7.27 (d, 2H), 7.56 (d, 2H), 7.67 (d, 2H), 7.87 (d, 1H), 8.29 (s, 1H), 8.95 (brs, 2H), 9.25 (brs, 2H); HPLC: 93.59% (Retention Time= 3.359 min).I-284 1-FLCMS (M+1) +< : 433.2 1< H NMR: δ 3.62 (m, 3H), 3.83 (m,3H), 5.22 (m, 1H), 5.73 (s, 2H), 6.97 (s, 1H), 7.10 (d, 3H), 7.23 (m, 2H), 7.54 (d, 1H), 7.64 (m, 2H), 7.87 (m, 1H), 8.91 (brs, 2H), 9.24 (brs, 2H); HPLC: 88.08% (Retention Time= 6.732 min).I-285 1-F 2 LCMS (M+1) +< : 451.1 1< H NMR: δ 3.62 (m, 3H), 3.83 (m, 3H), 5.73 (s, 2H), 6.92 (s, 1H), 7.19 (d, 3H), 7.55 (d, 1H), 7.63 (m, 2H), 7.88 (d, 1H), 8.20 (d, 1H), 8.88 (brs, 2H), 9.24 (brs, 2H); HPLC: 85.91% (Retention Time= 6.459 min).I-286 2 LCMS (M+1) +< : 577.2 1< H NMR: δ 0.81 (m, 2H), 1.24 (m, 5H), 1.75 (m, 1H), 2.65 (m, 1H), 2.91 (m, 1H), 3.45 (m, 2H), 4.46 (m, 1H), 5.65 (s, 2H), 6.83 (s, 1H), 7.22 (m, 2H), 7.52 (m, 2H), 7.62 (d, 2H), 7.82 (d, 1H), 7.91 (m, 2H), 8.30 (s, 1H), 8.61 (d, 1H), 8.73 (m, 1H), 8.88 (brs, 2H), 9.18 (brs, 2H); HPLC: 94.95% (Retention Time= 8.471 min).I-287 2- (CH 2 ) 2 O(CH 2 ) 2 OHLCMS (M+1) +< : 517.2 1< H NMR: δ 3.46 (m, 3H), 3.51 (m, 3H), 3.72 (m, 2H), 5.65 (s, 2H), 7.02 (s, 1H), 7.21 (d, 2H), 7.55 (d, 1H), 7.61 (d, 2H), 7.86 (d, 1H), 8.19 (s, 1H), 9.10 (brs, 2H), 9.26 (brs, 2H), 10.33 (brs, 1H).I-288 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 488.2 1< H NMR: δ 0.52 (m, 4H), 0.81 (m, 2H), 1.48 (m, 2H), 1.61 (m, 2H), 2.65 (m, 2H), 3.71 (m, 2H), 4.49 (m, 1H), 5.61 (s, 2H), 6.82 (s, 1H), 7.16 (d, 2H), 7.24 (d, 2H), 7.55 (d, 1H), 7.63 (m, 3H), 7.82 (d, 2H), 8.28 1H), 9.10 (brs, 2H), 9.22 (brs, 2H); HPLC: 96.83% (Retention Time= 6.695 min).I-289 2-FLCMS (M+1) +< : 463.2 1< H NMR: δ 1.48 (m, 2H), 1.75 (m, 2H), 3.61 (m, 4H), 4.71 (m,1H), 5.60 (s, 2H), 6.92 (s, 1H), 7.19 (d, 2H), 7.32 (d, 2H), 7.56 (d, 1H), 7.86 (d, 1H), 8.32 (s, 1H), 8.96 (brs, 2H), 9.26 (brs, 2H); HPLC: 98.69% (Retention Time= 6.89 min).I-290 2-F 2 LCMS (M+1) +< : 481.2 1< H NMR: δ 1.48 (m, 2H), 1.85 (m, 2H), 3.61 (m, 4H), 4.71 (m,1H), 5.59 (s, 2H), 6.97 (s, 1H), 7.19 (d, 2H), 7.31 (d, 2H), 7.55 (d, 1H), 7.86 (d, 1H), 8.32 (s, 1H), 8.94 (brs, 2H), 9.25 (brs, 2H); HPLC: 98.03% (Retention Time= 3.908 min).I-291 2-CH 2 FLCMS (M+1) +< : 477.2 1< H NMR: δ 0.54 (m, 1H), 1.02 (m, 1H), 1.42 (m, 2H), 1.72 (m, 1H), 1.89 (m, 1H), 2.71 (m, 1H), 2.96 (m, 1H), 3.77 (m, 1H), 4.15 (m, 2H), 5.63 (s,2H), 5.59 (s, 2H), 6.90 (s, 1H), 7.21 (d, 2H), 7.34 (d, 2H), 7.58 (m, 1H), 7.88 (d, 1H), 8.34 (s, 1H), 9.00 (brs, 2H), 9.28 (brs, 2H); HPLC: 95.23% (Retention Time= 3.421 min).I-292 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 434.2 1< H NMR: δ 0.50 (m, 1H), 0.90 (m, 1H), 1.35 (m, 3H), 1.51 (m, 3H), 1.89 (m, 1H), 2.71 (m, 4H), 3.70 (s, 3H), 4.44 (m, 1H), 5.45 (s, 2H), 6.78 (s, 1H), 6.83 (d, 2H), 7.52 (d, 1H), 7.73 (m, 4H), 8.32 (s, 1H), 9.02 (brs, 2H), 9.23 (brs, 2H).I-293 1-FLCMS (M+1) +< : 407.2 1< H NMR: δ 1.10 (d, 6H), 2.44 (m, 2H), 2.80 (m, 2H), 3.33 (m, 3H), 3.68 (m, 1H), 5.53 (d, 2H), 6.98 (d, 2H), 7.04 (d, 1H), 7.10 (m, 2H), 7.53 (d, 1H), 7.83 (m, 1H), 8.25 (d, 1H), 8.87 (brs, 2H), 9.25 (brs, 2H); HPLC: 98.1% (Retention Time= 6.996 min).I-294 1-F 2 LCMS (M+1) +< : 425.2 1< H NMR: δ 1.11 (d, 6H), 2.35 (m, 1H), 2.80 (m, 1H), 3.49 (m, 1H), 3.66 (m, 1H), 3.79 (m, 2H), 5.55 (d, 2H), 6.96 (m, 2H), 7.08 (m, 3H), 7.54 (d, 1H), 7.84 (d, 1H), 7.29 (s, 1H), 9.04 (brs, 2H), 9.28 (brs, 2H); HPLC: 93.59% (Retention Time= 3.512 min).I-295 2-FLCMS (M+1) +< : 421.2 1< H NMR: δ 1.12 (d, 6H), 1.58 (m, 2H), 1.72 (m, 2H), 2.79 (m, 1H), 3.59 (m, 4H), 4.64 (m, 1H), 5.50 (d, 2H), 6.85 (s, 1H), 6.98 (d, 2H), 7.14 (d, 2H), 7.54 (d, 1H), 7.83 (d, 1H), 8.34 (s, 1H), 8.96 (brs, 2H), 9.26 (brs, 2H); HPLC: 98.0% (Retention Time= 3.663 min).I-296 2-F 2 LCMS (M+1) +< : 439.2 1< H NMR: δ 1.11 (d, 6H), 1.24 (m, 2H), 1.82 (m, 2H), 2.79 (m, 1H),3.35 (m, 2H), 3.65(m, 2H), 4.64 (m, 1H), 5.52 (s, 2H), 6.91 (s, 1H), 6.99 (d, 2H), 7.15 (d, 2H), 7.56 (d, 1H), 7.84 (d, 1H), 8.38 (s, 1H), 9.15 (brs, 2H), 9.29 (brs, 2H); HPLC: 98.25% (Retention Time= 4.072 min).I-297 2-CH 2 FLCMS (M+1) +< : 435.2 1< H NMR: δ 1.12 (d, 6H), 1.53 (m, 2H), 1.82 (m, 2H), 2.79 (m, 1H),3.39 (m, 2H), 3.65(m, 1H), 4.18 (m, 1H), 4.45 (m, 1H, 5.51 (s, 2H), 6.82 (s, 1H), 6.98 (d, 2H), 7.15 (d, 2H), 7.54 (d, 1H), 7.83 (d, 1H), 8.32 (s, 1H), 8.16 (brs, 2H), 9.25 (brs, 2H); HPLC: 97.1% (Retention Time= 3.598 min).I-298 1-FLCMS (M+1) +< : 421.2 1< H NMR: δ 1.17 (s, 9H), 1.59 (m, 2H), 1.89 (m, 2H), 2.65 (m, 2H), 3.33 (d, 1H), 5.60 (m, 2H), 6.95 (s, 1H), 7.07 (m,2H),7.30 ( m, 2H), 7.59 (m,1H) ,7.90 (d, 1H), 8.29 (d,1H); HPLC: 92.83% (Retention Time= 6.607 min).I-299 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 418.2 1< H NMR: δ 1.49 (m, 3H), 1.62 (m, 4H), 2.80 (m, 4H), 3.05 (m, 2H), 3.71 (m, 1H), 4.52 (m, 3H), 6.72 (s, 1H), 7.11 (m ,4H), 7.50 (d, 1H), 7.70 (m, 3H), 8.15 (s, 1H), 8.98 (brs, 2H), 9.26 (brs, 2H); HPLC: 90.67% (Retention Time= 6.348 min).I-300 1-(S)NH 2 LCMS (M+1) +< : 376.2 1< H NMR: δ 1.97 (m, 1H), 2.22 (m, 1H), 3.12 (m, 3H), 3.51 (m, 4H), 3.85 (m, 1H), 4.61 (m, 2H), 6.35 (d, 1H), 7.11 (d, 1H), 7.20 (m, 4H), 7.53 (d, 1H), 7.80 (d, 1H), 8.19 (m, 4H), 9.24 (brs, 3H); HPLC: 94.87% (Retention Time= 4.465 min).I-301 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 436.2 1< H NMR: δ 1.49 (m, 2H), 1.61 (m, 4H), 2.80 (m, 3H), 3.05 (m, 2H), 3.71 (m, 2H), 4.52 (m, 3H), 6.73 (s, 1H), 7.05 (m ,4H), 7.50 (d, 1H), 7.70 (m, 4H), 8.15 (s, 1H), 9.10 (brs, 2H), 9.32 (brs, 2H); HPLC: 96.98% (Retention Time= 4.552 min).I-302 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 448.3 1< H NMR: δ 1.05 (m, 3H), 1.49 (m, 3H), 1.60 (m, 4H), 2.80 (m ,2H), 2.95 (m, 2H), 3.71 (s, 3H), 4.50 (m, 3H), 6.73 (s, 1H), 6.80 (d, 2H), 7.13 (d, 2H), 7.50 (d, 1H), 7.80 (m, 4H), 8.15 (s, 1H), 9.15 (brs, 2H), 9.32 (brs, 2H).I-303 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 454.2 1< H NMR: δ 0.52 (m, 1H), 0.85 (m, 2H), 1.33 (m, 5H), 2.60 (m ,2H), 3.44 (m, 2H), 4.50 (m, 1H), 5.70 (m, 2H), 6.93 (s, 1H), 7.20 (d , 2H), 7.43 (m, 5H), 7.81 (m, 3H), 8.40 (s, 1H), 8.92 (brs, 2H), 9.22 (brs, 2H); HPLC: 86.08% (Retention Time= 5.488 min).I-304 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 480.3 1< H NMR: δ 0.50 (m, 1H), 0.85 (m, 1H), 1.33 (m, 4H), 1.71 (m, 1H), 2.65 (m ,3H), 2.82 (m, 1H), 3.72 (m, 1H), 4.50 (m, 1H), 5.60 (m, 2H), 6.85 (s, 1H), 7.18 (d, 2H), 7.35 (m, 1H), 7.45 (m, 2H), 7.55 (m, 7H), 7.85 (d, 1H), 8.35 (s, 1H), 9.04 (brs, 2H), 9.34 (brs, 2H).I-305 2-FLCMS (M+1) +< : 455.2 1< H NMR: δ 1.07 (m, 2H), 1.59 (brs, 2H), 1.89 (m, 2H), 3.65 (m, 2H), 4.80 (m, 1H), 5.60 (m, 2H), 6.95 (s, 1H), 7.07 (m, H), 7.40 (m, 1H), 7.59 (m, 2H), 7.90 (d, 1H), 7.75 (d, 5H), 8.29 (s, 1H), 9.04 (brs, 2H), 9.34 (brs, 2H).I-306 2-F 2 LCMS (M+1) +< : 473.2 1< H NMR: δ 1.44 (m, 2H), 1.91 (m, 2H), 3.40 (m, 2H), 3.68 (m, 2H), 5.61 (s, 2H), 6.96 (s, 1H), 7.17 (d, 2H), 7.35 (m, 1H), 7.42 (m, 2H), 7.55 (m, 5H), 7.86 (d, 1H), 9.01 (brs, 2H), 9.29 (brs, 2H); HPLC: 98.3% (Retention Time= 3.602 min).I-307 2-F 2 LCMS (M+1) +< : 473.2 1< H NMR: δ 1.41 (m, 2H), 2.11 (m, 2H), 3.62 (m, 4H), 5.60 (s, 2H), 6.93 (s, 1H), 7.18 (m, 2H), 7.35 (m, 1H), 7.44 (m, 2H), 7.56 (m, 5H), 7.86 (d, 1H), 9.01 (brs, 2H), 9.29 (brs, 2H); HPLC: 95.6% (Retention Time= 4.033 min).I-308 2-CH 2 FLCMS (M+1) +< : 469.2 1< H NMR: δ 0.5 (m, 1H), 1.0 (m, 1H), 1.38 (m, 1H), 1.65 (m, 2H), 2.72 (m, 1H), 2.95 (m, 1H), 3.78 (m, 1H), 3.98 (m, 2H), 4.51 (m, 1H), 5.62 (d, 2H), 6.89 (s, 1H), 7.19 (d, 2H), 7.38 (m, 1H), 7.40 (m, 2H), 7.59 (m, 5H), 7.88 (d, 1H), 8.38 (s, 1H), 8.91 (brs, 2H), 9.29 (brs, 2H); HPLC: 91.12% (Retention Time= 3.976 min).I-309 1-FLCMS (M+1) +< : 441.2 1< H NMR: δ 1.57 (m, 1H), 2.05 (m, 2H), 3.56 (m, 2H), 3.64 (m, 2H), 3.68 (m, 2H), 5.64 (m, 2H), 7.09 (d, 1H), 7.17 (m, 2H), 7.33 (m, 2H), 7.53 (m, 5H), 7.85 (m, 1H), 8.29 (d, 1H), 9.00 (brs, 2H), 9.28 (brs, 2H); HPLC: 95.82% (Retention Time= 3.8 min).I-310 1-F 2 LCMS (M+1) +< : 459.2 1< H NMR: δ 2.35 (m, 1H), 2.42 (m, 1H), 3.61 (m, 2H), 3.90 (m, 2H), 5.69 (d, 2H), 7.17 (m, 3H), 7.37 (m, 3H), 7.61 (m, 5H), 7.90 (d, 1H), 7.34 (s, 1H), 9.13 (brs, 2H), 9.32 (brs, 2H); HPLC: 96.98% (Retention Time= 3.436 min).I-311 2 LCMS (M+1) +< : 485.2 1< H NMR: δ 2.54 (m, 1H), 2.74 (m, 1H), 3.42 (m, 1H), 3.81 (m, 1H), 4.62 (m, 1H), 4.75 (m, 1H), 5.60 (s, 2H), 7.00 (m, 4H), 7.20 (m, 4H), 7.43 (m, 4H), 7.56 (m, 3H), 7.88 (m, 1H), 8.34 (s, 1H), 8.99 (brs, 2H), 9.28 (brs, 2H); HPLC: 87.73% (Retention Time= 4.384 min).I-312 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 496.3 1< H NMR: δ 0.88 (m, 2H), 1.45 (m, 2H), 1.51 (m, 4H), 2.81 (m, 2H), 3.62 (m, 2H), 4.45 (m, 1H), 5.60 (s, 2H), 6.82 (s, 1H), 6.95 (d, 3H), 7.10 (d, 3H), 7.33 (m, 2H), 7.53 (d, 2H), 7.77 (brs, 3H), 7.81 (d, 1H), 8.32 (s, 1H), 9.02 (brs, 2H), 9.25 (brs, 2H).I-313 1-FLCMS (M+1) +< : 457.2 1< H NMR: δ 2.28 (m, 3H), 3.48 (m, 4H), 5.60 (d, 2H), 6.87 (m, 4H), 7.10 (m, 4H), 7.33 (m, 2H), 7.53 (d, 2H), 7.83 (m, 1H), 8.28 (s, 1H), 8.96 (brs, 2H), 9.25 (brs, 2H); HPLC: 93.81% (Retention Time= 6.425 min).I-314 1-F 2 LCMS (M+1) +< : 475.2 1< H NMR: δ 2.28 (m, 1H), 2.41 (m, 1H), 3.58 (m, 2H), 3.68 (m, 1H), 3.81 (m, 2H), 5.60 (d, 2H), 6.89 (m, 4H), 7.10 (m, 4H), 7.34 (m, 2H), 7.56 (d, 2H), 7.84 (d, 1H), 8.39 (s, 1H), 9.06 (brs, 2H), 9.37 (brs, 2H); HPLC: 91.0% (Retention Time= 3.501 min).I-315 2-F 2 LCMS (M+1) +< : 489.2 1< H NMR: δ 1.49 (m, 2H), 2.08 (m, 2H), 3.36 (m, 2H), 3.91 (m, 2H), 5.53 (s, 2H), 6.88 (m, 5H), 7.10 (m, 3H), 7.34 (m, 2H), 7.54 (d, 2H), 7.80 (d, 1H), 8.25 (s, 1H); HPLC: 97.09% (Retention Time= 6.694 min).I-316 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 514.2 1< H NMR: δ 0.61 (m, 1H), 1.21 (m, 1H), 1.49 (m, 4H), 1.85 (m, 2H), 2.71 (m, 2H), 3.71 (m, 1H), 4.45 (m, 1H), 4.53 (m, 1H), 5.51 (s, 2H), 6.81 (s, 1H), 6.87 (m, 2H), 7.95 (m, 2H), 7.13 (m, 4H), 7.57 (d, 1H), 7.80 (d, 1H), 7.97 (brs, 2H), 8.40 (s, 1H), 9.32 (brs, 3H); HPLC: 95.49% (Retention Time= 5.995 min).I-317 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 515.2 1< H NMR: δ 1.49 (m, 4H), 1.71 (m, 2H), 2.81 (m, 4H), 3.72 (m, 2H), 4.50 (m, 1H), 5.51 (s, 2H), 6.85 (s, 1H), 6.97 (d, 1H), 7.11 (m, 2H), 7.22 (m, 2H), 7.52 (d, 1H), 7.70 (m, 3H), 7.81 (d, 1H), 8.60 (s, 1H), 8.95 (d, 2H), 9.25 (brs, 2H); HPLC: 99.15% (Retention Time= 4.707 min).I-318 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 530.2 1< H NMR: δ 0.61 (m, 1H), 1.21 (m, 1H), 1.51 (m, 4H), 1.85 (m, 2H), 2.71 (m, 2H), 2.82 (m, 1H), 3.85 (m, 1H), 4.53 (m, 1H), 5.61 (s, 2H), 6.85 (s, 1H), 6.97 (m, 4H), 7.11 (m, 2H), 7.33 (d, 2H), 7.52 (d, 1H), 7.80 (d, 1H), 7.97 (brs, 2H),8.43 (s, 1H), 9.32 (brs, 3H).I-319 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 564.2 1< H NMR: δ 1.49 (m, 4H), 1.71 (m, 1H), 2.61 (m, 4H), 3.68 (m, 3H), 4.44 (m, 1H), 4.52 (m, 1H), 6.82 (s, 1H), 7.21 (d, 2H), 7.19 (m, 4H), 7.42 (m, 1H), 7.53 (m, 2H), 7.73 (m, 3H), 8.32 (s, 1H), 9.11 (brs, 2H), 9.25 (brs, 2H); HPLC: 99.5% (Retention Time= 7.501 min).I-320 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 511.3 1< H NMR: δ 0.61 (m, 2H), 0.98 (m, 2H), 1.21 (m, 1H), 1.42 (m, 4H), 2.62 (m, 3H), 3.75 (m, 1H), 4.50 (m, 2H), 5.51 (s, 2H), 6.95 (s, 1H), 6.97 (m, 4H), 7.11 (m, 4H), 7.53 (d, 1H), 7.81 (m, 3H),8.33 (s, 1H), 9.22 (brs, 3H).I-321 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 496.3 1< H NMR: δ 0.51 (m, 1H), 0.91 (m, 1H), 1.37 (m, 6H), 2.71 (m, 4H), 4.45 (m, 1H), 6.85 (s, 1H), 6.95 (m, 4H), 7.20 (m, 1H), 7.35 (m, 3H), 7.58 (d, 1H), 7.88 (m, 3H), 8.32 (s, 1H),9.10 (brs, 2H), 9.35 (brs, 2H); HPLC: 98.12% (Retention Time= 6.806 min).I-322 2-(CH 2 ) 3 C(O)NH 2 LCMS (M+1) +< : 514.2 1< H NMR: δ 0.48 (m, 1H), 0.95 (m, 1H), 1.15 (m, 2H), 1.49 (m, 2H), 1.52 (m, 2H), 1.71 (m, 1H), 2.15 (m, 2H), 2.71 (m, 1H), 2.81 (m, 1H),3.71 (m, 1H), 4.50 (m, 1H), 5.65 (s, 2H), 6.85 (d, 2H), 7.55 (m, 3H), 7.86 (d, 1H), 8.15 (s, 1H); HPLC: 98.79% (Retention Time= 7.879 min). General synthetic scheme 5

[0477]

[0478] Another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-5. C (2) amide derived 6-cyano indole 2 carboxylic acid derivatives were treated with hydroxylamine to form amidoxime derivatives which were acylated with Ac 2 O and reduced with Zn / AcOH to install the amidine functionality. Deprotection of acidic labile protecting with a suitable reagent (TFA / DCM or EtOH.HCl) to afforded compound of formula (I).Example 69: Synthesis of compound I-323 3-((6-Carbamimidoyl-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0479] Step-1: Ethyl 1-(3-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylate

[0480] 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 afford the title compound following the procedure described in step-1 of example-68. LCMS: 348.1 (M+1) +< .Step-2: 1-(3-carbamoylbenzyl)-6-cyano-1H-indole-2-carboxylic acid

[0481] Product of step-1 of example-69 (1.2 g, 3.45 mmol) was treated with lithium hydroxide (331 mg, 13.82 mmol) to afford the title compound (770 mg) following the procedure described in step-2 of example 1. LCMS: 320.1 (M+1) +< .Ste-3: 3-((6-Cyano-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0482] Product of step-2 of example-69 (700 mg, 2.19 mmol) was treated with 3-fluoropyrrolidine (195 mg, 2.19 mmol) to afford the title compound (525 mg) following the procedure described in step-3 of example 1. LCMS: 391.1 (M+1) +< .Step-4: 3-((2-(3-fluoropyrrolidine-1-carbonyl)-6-(N'-hydroxycarbamimidoyl)-1H-indol-1-yl)methyl)benzamide

[0483] The product of step-3 of example-69 (500 mg, 1.28 mmol) was dissolved in 20 mL of ethanol and added aqueous hydroxylamine solution (0.3 mL) and resulting mixture was refluxed for 4-6 h at 80 °C. Solvent was evaporated under vacuum to afford the title compound (425 mg) which was used for the next step without further purification. LCMS: 424.2 (M+1) +< .Step-5: 3-((6-(N'-Acetoxycarbamimidoyl)-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0484] The product of step-4 of example-69 (400 mg, 0.94 mmol) was dissolved in 10 mL of acetic acid and added acetic anhydride (767 mg, 7.52 mmol) and resulting mixture was stirred at RT for 2 h. Solvent was evaporated under vacuum to afford the title compound (260 mg) which was used for the next step without further purification. LCMS: 466.2 (M+1) +< .Step-6: 3-((6-Carbamimidoyl-2-(3-fluoropyrrolidine-1-carbonyl)-1H-indol-1-yl)methyl)benzamide

[0485] The product of step-5 of example-69 (250 mg, 0.53 mmol) was dissolved in 5 mL of acetic acid and added Zn (275 mg, 4.3 mmol) in portions and resulting mixture was stirred at RT for 6-8 h. Reaction mixture was filtered through celite pad and resulting filtrate was concentrated under vacuum to give crude product which was purified with reversed-phase preparative HPLC and afforded the title compound (75 mg). LCMS: 408.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).

[0486] The following compounds listed in table-10 were prepared according to scheme-5 by following similar procedure as described above for example-69 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-10 Cpd. ID. L R 2 m R 3 (binding site) Characteristic Data I-324-CH 2 - 1-F 2 LCMS (M+1) +< : 426.2 1< H NMR: δ 2.24 (m, 2H), 3.53 (m, 2H), 3.80 (m, 2H), 5.67 (s, 2H), 7.15 (m, 2H), 7.29 (m, 3H), 7.52 (m, 2H), 7.75 (m, 1H), 7.86 (m, 1H), 7.94 (m, 1H), 9.00 (brs, 2H), 9.26 (brs, 2H); HPLC: 95.0% (Retention Time= 5.282 min).I-325-CH 2 - 2-CH 2 FLCMS (M+1) +< : 436.2 1< H NMR: δ 1.28 (m, 2H), 1.52 (m, 2H), 2.63 (m, 2H), 3.53 (m, 2H), 4.12 9 (m, 1H), 4.80 (m, 2H), 5.61 (s, 2H), 6.87 (s, 1H), 7.29 (m, 1H), 7.38 (m, 2H), 7.55 (m, 2H), 7.75 (d, 1H), 7.85 (d, 1H), 7.95 (s, 1H), 8.31 (s, 1H), 8.97 (brs, 2H), 9.25 (brs, 2H); HPLC: 97.74% (Retention Time= 5.495 min).I-326-CH 2 - 2-FLCMS (M+1) +< : 422.2 1< H NMR: δ 1.84 (m, 4H), 1.89 (m, 4H), 4.8 (d, 1H), 5.85 (s, 2H), 6.95 (s, 1H), 7.17 (m, 2H), 7.40 (s, 1H), 7.59 (d, 1H), 7.81 (d, 2H), 7.90 (d, 1H), 7.95 (brs, 1H), 8.29 (s, 1H), 8.91 (brs, 2H), 9.28 (brs, 2H); HPLC: 85.43% (Retention Time= 5.317 min).I-327-CH 2 - 2-F 2 LCMS (M+1) +< : 440.2 1< H NMR: δ 1.07 (m, 2H), 1.59 (brs, 2H), 1.89 (brs, 2H), 3.65 (brs, 2H), 5.60 (s, 2H), 6.95 (s, 1H), 7.17 (m, 2H), 7.40 (s, 1H), 7.59 (d, 1H), 7.81 (d, 2H), 7.90 (d, 1H), 7.95 (brs, 1H), 8.29 (s, 1H), 8.91 (brs, 2H), 9.28 (brs, 2H); HPLC: 95.62% (Retention Time= 5.496 min).I-328-CH 2 - 2-F 2 LCMS (M+1) +< : 440.2 1< H NMR: δ 1.49 (m, 1H), 1.71 (m, 1H), 2.04 (m, 2H), 3.77 (m, 3H), 4.05(m, 1H), 5.58 (s, 2H), 6.92 (m, 1H), 7.10 (d, 2H), 7.33 (s, 1H), 7.53 (d, 1H), 7.75 (d, 2H), 7.85 (m, 2H), 8.13 (brs, 2H), 8.92 (brs, 2H), 9.25 (s, 2H); HPLC: 98.02% (Retention Time= 5.91 min).I-329-CH 2 - 2-CF 3 LCMS (M+1) +< : 472.2 1< H NMR: δ 0.59 (m, 2H), 1.08 (m, 2H), 1.55 (m, 1H), 1.85 (m, 1H), 2.71 (m, 1H),3.02 (m, 1H), 4.51 (m, 1H), 5.60 (d, 2H), 6.94 (s, 1H), 7.10 (d, 2H), 7.55 (d, 1H), 7.78 (d, 2H), 7.89 (d, 1H), 8.24 (s, 1H), 9.01 (brs, 2H), 9.25 (s, 2H); HPLC: 98.23% (Retention Time= 6.268 min).I-330-CH 2 - 1-(R)FLCMS (M+1) +< : 408.2 1< H NMR: δ 1.84 (m, 4H), 1.89 (m, 4H), 4.82 (d, 1H), 5.87 (m, 2H), 6.94 (s, 1H), 7.17 (m, 2H), 7.40 (s, 1H), 7.59 (d, 1H), 7.81 (d, 2H), 7.90 (d, 1H), 7.90 (brs, 1H), 8.22 (d, 1H); HPLC: 95.65% (Retention Time= 3.86 min).I-331-CH 2 - 1-F 2 LCMS (M+1) +< : 426.2 1< H NMR: δ 2.40 (m, 2H),3.40 (m,1H), 3.71 (m, 2H), 3.90 (m, 2H), 5.72 (m, 2H), 7.17 (m, 1H), 7.19 (brs, 1H), 7.39 (brs, 1H), 7.60 (d, 1H), 7.85 (m, 2H), 7.99 (s, 1H), 8.24 (brs, 1H), 9.14 (brs, 2H), 9.24 (brs, 2H); HPLC: 95.06% (Retention Time= 5.261 min).I-332-CH 2 - 2-CH 2 FLCMS (M+1) +< : 436.2 1< H NMR: δ 1.23 (m, 2H), 1.60 (m, 2H), 2.76 (m, 2H), 3.53 (m, 2H), 4.12 (m, 1H), 4.80 (m, 2H), 5.61 (s, 2H), 6.88 (s, 1H), 7.12 (d, 2H), 7.36 (s, 1H), 7.55 (d, 1H), 7.78 (d, 1H), 7.85 (d, 1H), 7.93 (s, 1H), 8.25 (s, 1H), 9.01 (brs, 2H), 9.24 (brs, 2H); HPLC: 98.3 1% (Retention Time= 5.28 min).I-333-CH 2 - 1 LCMS (M+1) +< : 475.2 1< H NMR: δ 1.82 (m, 2H), 2.35 (m, 2H), 3.62 (m, 6H), 3.82 (m, 2H), 5.62 (m, 3H), 7.17 (m, 1H), 7.07 (m, 2H), 7.36 (brs, 1H),7.53 (d, 1H), 7.75 (d, 2H), 7.86 (d, 1H), 7.90 (brs, 1H),8.19 (s, 1H), 8.99 (brs, 2H), 9.23 (brs, 2H).I-334-SO 2 - 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 472.2 1< H NMR: δ 1.52 (m, 5H), 1.81 (m, 1H), 2.81 (m, 3H), 3.21 (m, 1H), 3.47 (m, 2H), 4.52 (m, 1H), 7.71 (s, 1H), 7.46 (m, 2H), 7.72 (m, 1H), 7.78 (brs, 2H), 7.88 (m, 1H), 8.32 (m, 3H), 9.25 (brs, 2H), 9.45 (brs, 2H).1-335-SO 2 - 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 504.2 1< H NMR: δ 1.21 (m, 2H), 1.50 (m, 5H), 2.81 (m, 2H), 3.15 (m, 1H), 3.48 (m, 2H), 4.60 (m, 1H), 7.11 (s, 1H), 7.65 (m, 6H), 7.82 (d, 1H), 8.01 (d, 1H), 8.12 (m, 3H), 8.45 (s, 1H), 8.95 (s, 1H), 9.20 (brs, 2H), 9.42 (brs, 2H); HPLC: 90.02% (Retention Time= 5.696 min).I-336-SO 2 - 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 468.2 1l< H NMR: δ 1.21 (m, 2H), 1.45 (m, 5H), 2.81 (m, 2H), 3.15 (m, 2H), 3.65 (m, 1H), 4.51 (m, 1H), 5.21 (s, 2H), 6.78 (s, 1H), 7.08 (m, 1H), 7.16 (m, 5H), 7.53 (m, 1H), 7.65 (s, 4H), 7.80 (d, 1H), 9.05 (brs, 2H), 9.22 (brs, 2H); HPLC: 91.69% (Retention Time= 6.826 min).I-337-CH 2 - 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 482.2 1< H NMR: δ 1.49 (m, 6H), 1.51 (m, 6H), 2.81 (m, 3H), 3.15 (m, 2H), 3.91 (m, 2H), 4.11 (m, 1H), 4.45 (m,1H),4.71 (m, 2H), 6.78 (s, 1H), 7.49 (m, 1H), 7.62 (m, 6H), 7.87 (m, 2H), 7.95 (s, 1H), 9.05 (brs, 2H), 9.25 (brs, 2H); HPLC: 97.62% (Retention Time= 4.705 min).I-338-CH 2 - 2 LCMS (M+1) +< : 493.2 1< H NMR: δ 1.31 (m, 6H), 1.51 (m, 6H), 3.21 (m, 1H), 3.52 (m, 1H), 3.75 (m, 3H), 4.41 (m, 3H), 6.72 (m, 1H), 7.49 (d, 1H), 7.62 (m, 2H), 7.72 (m, 2H), 7.85 (m, 2H), 7.94 (s, 1H), 9.10 (brs, 2H), 9.25 (brs, 2H); HPLC: 99.41% (Retention Time= 6.109 min).I-339-CH 2 - 2 LCMS (M+1) +< : 493.2 1< H NMR: δ 0.98 (m, 2H), 1.15 (m, 5H), 1.51 (m, 5H), 2.71 (m, 1H), 3.15 (m, 1H), 3.81 (m, 3H), 3.89 (m, 3H), 4.31 (m, 1H), 4.61 (m, 2H), 6.75 (s, 1H), 7.51 (d, 1H), 7.65 (m, 2H), 7.55 (m, 2H), 7.82 (d, 2H), 7.94 (s, 1H), 9.11 (brs, 2H), 9.25 (brs, 2H); HPLC: 99.64% (Retention Time= 6.153 min).I-340-CH 2 - 2-CH 3 LCMS (M+1) +< : 453.2 1< H NMR: δ 0.92 (d, 3H), 1.22 (m, 2H), 1.68 (m, 3H), 2.71 (m, 1H), 3.15 (m, 1H), 3.90 (m, 4H), 4.35 (m, 1H), 4.65 (m, 2H), 6.76 (s, 1H), 7.51 (d, 1H), 7.65 (m, 2H), 7.76 (m, 2H), 7.87 (d, 2H), 7.97 (s, 1H), 9.16 (brs, 2H), 9.27 (brs, 2H); HPLC: 97.99% (Retention Time= 3.699 min).I-341-CH 2 - 1-FLCMS (M+1) +< : 443.2 1< H NMR: δ 2.15 (m, 2H), 2.44 (m, 2H), 3.67 (m, 4H), 4.71 (m, 2H), 5.33 (m, 1H), 7.02 (d, 1H), 7.52 (d, 1H), 7.64 (m, 2H), 7.76 (m, 1H), 7.81 (m, 4H), 7.96 (s, 1H), 9.04 (brs, 2H), 9.30 (brs, 2H); HPLC: 86.65% (Retention Time= 3.305 min).I-342-CH 2 - 1-F 2 LCMS (M+1) +< : 461.1 1< H NMR: δ 2.24 (m, 2H), 3.71 (m, 1H), 3.92 (m, 4H), 4.18 (m, 1H), 4.83 (m, 2H), 7.07 (d, 1H), 7.52 (d, 1H), 7.63 (m, 2H), 7.74 (m, 1H), 7.81 (m, 3H), 7.97 (brs, 1H), 9.08 (brs, 2H), 9.30 (brs, 2H); HPLC: 96.74% (Retention Time= 5.99 min).I-343-CH 2 - 2-FLCMS (M+1) +< : 457.2 1< H NMR: δ 1.79 (m, 4H), 3.67 (m, 4H), 3.91 (m, 2H), 4.72 (m, 2H), 4.91 (m, 1H), 6.84 (s, 1H), 7.51 (d, 1H), 7.65 (m, 2H), 7.74 (m, 2H), 7.81 (d, 1H), 7.97 (s, 1H), 9.18 (brs, 2H), 9.28 (brs, 2H); HPLC: 98.84% (Retention Time= 6.551 min).I-344-CH 2 - 2-F 2 LCMS (M+1) +< : 475.2 1< H NMR: δ 2.09 (m, 4H), 3.77 (m, 4H), 3.92 (m, 2H), 4.78 (m, 2H), 6.91 (s, 1H), 7.52 (d, 1H), 7.64 (m, 2H), 7.74 (m, 1H), 7.80 (d, 1H), 7.86 (d, 2H), 7.98 (s, 1H), 9.18 (brs, 2H), 9.29 (brs, 2H); HPLC: 97.1% (Retention Time= 3.105 min). General synthetic scheme - 6

[0487]

[0488] Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-6. 6-cyano indole 2-carboxylic acid on coupling with suitable amines under standard coupling conditions yields coupled compound which was then dissolved in acetic acid and treated with copper(II)nitrate trihydrate to get 3-nitro indole derivatives which on further treatment with alkyl halide in presence of a suitable base (K 2 CO 3 ) and a suitable solvent (DMF) yielded N-alkylated analogs which upon reducing with Zn / glacial AcOH affords 3-amino derivatives. The corresponding 3-amino analogs were then treated with ethanolic HCl to get compound imidates, which was then treated with ethanolic ammonia to afford compound of formula (I).Example 70: Synthesis of compound 1-345 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[0489] Step-1: tert-Butyl (2-(1-(6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0490] 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 afford the title compound (1.77 g) following the procedure described in step-3 of example-68. LCMS: 397.2 (M+1) +< .Step-2: tert-Butyl (2-(1-(6-cyano-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0491] The product of step-1 of example-70 (1.7 g, 4.29 mmol) was dissolved in 30 mL of acetic acid and cooled it to 0 °C. Copper(II) nitrate trihydrate (401mg, 5.16) was added and stirred for 3 h. Reaction mixture was quenched with cold-water and extracted with ethyl acetate, followed by washed with brine and dried over sodium sulphate. Solvent was evaporated to give crude product which was purified with column chromatography using silica-gel as an adsorbent and elution with hexane:ethyl acetate (7:3) afforded 610 mg of the title compound. LCMS: 442.2 (M+1) +< .Step-3: tert-Butyl (2-(1-(6-cyano-1-isopentyl-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)-carbamate

[0492] 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 afford the title compound (1.52 g) following the procedure described in step-1 of example 1. LCMS: 512.3 (M+1) +< .Step-4: tert-Butyl (2-(1-(3-amino-6-cyano-1-isopentyl-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)-carbamate

[0493] The product of step-3 of example-70 (510 mg, 0.99 mmol) was dissolved in 10 mL of glacial acetic acid (AcOH) and added Zn (383 mg, 5.98 mmol) in portions at room temperature. Reaction mixture was stirred at RT for 6 h. Contents were filtered through celite pad and filtrate was concentrated under vacuum to afford crude compound which was purified by column chromatography using silica-gel as an adsorbent and eluted with hexane:ethylacetate (6:4) and afforded the title compound (190 mg). LCMS: 482.3 (M+1) +< .Step-5: Ethyl 3-amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carbimidate

[0494] The product of step-4 of example-70 (190 mg, 0.39 mmol) was treated with 50 mL of ethanolic-HCl to afford the title compound (135 mg) following the procedure described in step-4 of example 1. LCMS: 428.3 (M+1) +< .Step-6: 2-(4-Fluoropiperidine-1-carbonyl)-1-isopentyl-1H-indole-6-carboximidamide

[0495] The product of step-5 of example-70 (130 mg, 0.3 mmol) was treated with 50 mL of ethanolic-NH 3 to afford the title compound (35 mg) following the procedure described in step-5 of example 1. LCMS: 399.3 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): 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).

[0496] The following compounds listed in table-11 were prepared according to Scheme-6 by following similar procedure as described above for example 70 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-11 Cpd. ID. R 2 m R 3 (binding site) Characteristic Data I-346 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 491.3 1< H NMR: δ 1.4 (m, 4H), 1.51 (m, 7H), 2.42 (m, 1H), 3.48 (m, 4H), 4.11 (m, 1H), 4.31 (m, 1H), 4.51 (m, 2H), 7.36 (d, 1H), 7.62 (m, 2H), 7.72 (m, 2H), 7.82 (m, 3H), 9.11 (brs, 2H), 9.21 (brs, 2H); HPLC: 92.85% (Retention Time= 4.452 min).I-347 2-(CH 2 ) 2 NHC(O)OHLCMS (M+1) +< : 555.3 1< H NMR: δ 1.31 (m, 3H), 1.48 (m, 4H), 2.76 (m, 2H), 3.25 (m, 2H), 4.44 (m, 2H), 5.48 (m, 2H), 6.85 (m, 3H), 7.12 (m, 3H), 7.31 (m, 2H), 7.35 (m, 2H), 7.52 (m, 1H), 8.35 (d, 1H), 9.98 (brs, 1H); HPLC: 94.04% (Retention Time= 4.695 min).I-348 2-(CH 2 ) 2 NH 2 LCMS (M+1) +< : 511.3 1< H NMR: δ 1.31 (m, 3H),1.48 (m, 4H), 2.76 (m, 4H), 3.48 (m, 2H), 5.48 (d, 2H), 6.88 (m, 4H), 7.12 (m, 2H), 7.36 (m, 3H), 7.75 (brs, 3H), 7.88 (d, 1H), 8.45 (s, 1H), 9.01 (brs, 2H), 9.24 (brs, 2H); HPLC: 97.94% (Retention Time= 4.774 min). General synthetic scheme 7

[0497]

[0498] Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-7. 3-Nitroindole derivative described in scheme 6 upon treating with aq. hydroxylamine yielded amidoximes which on acylation in presence of acetic acid and acetic anhydride followed by reduction with, Zn / AcOH yielded amidine derivatives. The amindine analogs were then deprotected under acidic condition with either HCl or TFA to afford the compound of formula (I).Example 71: Synthesis of compound 1-349 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidamide

[0499] Step-1: tert-Butyl (2-(1-(6-cyano-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0500] 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 afford the title compound (1.77 g) following the procedure described in step-3 of example-68. LCMS: 397.2 (M+1) +< .Step-2: tert-Butyl (2-(1-(6-cyano-3-nitro-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0501] The product of step-1 of example-71 (1.7 g, 4.29 mmol) and copper(II) nitrate trihydrate (401mg, 5.16) were treated together to afford the title compound (610 mg) following the procedure described in step-2 of example-70. LCMS: 442.2 (M+1) +< .Step-3: tert-Butyl (2-(1-(6-cyano-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0502] The product of step-2 of example-71 (600 mg, 1.36 mmol) and ((2-bromoethyl)sulfonyl)benzene (337 mg, 1.36 mmol) were treated together to afford the title compound (540 mg) following the procedure described in step-1 of example 1. LCMS: 610.2 (M+1) +< .Step-4: tert-Butyl-(2-(1-(6-(N'-hydroxycarbamimidoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0503] The product of step-3 of example-71 (540 mg, 0.88 mmol) was treated with aq NH 2 OH solution (0.3 mL) to afford the title compound (410 mg) following the procedure described in step-4 of example-69. LCMS: 643.2 (M+1) +< .Step-5: tert-Butyl-(2-(1-(6-(N'-acetoxycarbamimidoyl)-3-nitro-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0504] The product of step-4 of example-71 (410 mg, 0.63 mmol) was treated with acetic anhydride (Ac 2 O) (521 mg, 5.1 mmol) to afford the title compound (325 mg) following the procedure described in step-5 of example-69. LCMS: 685.3 (M+1) +< .Step-6: tert-Butyl (2-(1-(3-amino-6-carbamimidoyl-1-(2-(phenylsulfonyl)ethyl)-1H-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[0505] The product of step-5 of example-71 (325 mg, 0.47 mmol) was treated with zinc (365 mg, 5.7 mmol) to afford the title compound (185 mg) following the procedure described in step-6 of example 69. LCMS: 597.3 (M+1) +< .Step-7: 3-Amino-2-(4-(2-aminoethyl)piperidine-1-carbonyl)-1-(2-(phenylsulfonyl)ethyl)-1H-indole-6-carboximidamide

[0506] The product of step-6 of example-71 (185 mg, 0.31 mmol) was treated with 20 mL of ethanolic-HCl to afford 65 mg of the title compound following the procedure described in step-4 of example-1 except reaction was done at 0 °C for 2 h. LCMS: 497.2 (M+1) +< , 1< H NMR (300MHz, DMSO-d 6 ): δ 0.98 (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).

[0507] The following compounds listed in table-12 were prepared according to scheme-7 by following similar procedure as described above for example-71 using appropriate reagents with suitable modifications known to the one skilled in the art. Table-12 Cpd. ID. R 2 m R 3 Characteristic Data 1-350 2 LCMS (M+1) +< : 508.2 1< H NMR: δ 1.4 (m, 4H), 1.51 (m, 7H), 2.42 (m, 1H), 3.48 (m, 4H), 4.11 (m, 1H), 4.31 (m, 1H), 4.51 (m, 2H), 7.36 (d, 1H), 7.62 (m, 2H), 7.72 (m, 2H), 7.82 (m, 3H), 9.11 (brs, 2H), 9.21 (brs, 2H); HPLC: 97.8% (Retention Time= 5.857 min).I-351 2 LCMS (M+1) +< : 508.2 1< H NMR: δ 0.8 (m, 5H), 1.4 (m, 7H), 2.42 (m, 1H), 3.12 (m, 1H), 3.7 (m, 2H), 3.91 (m, 1H), 4.45 (m, 2H), 4.8 (m, 1H), 7.32 (d, 1H), 7.60 (m, 2H), 7.71 (m, 2H), 7.82 (m, 3H), 8.91 (brs, 2H), 9.18 (brs, 2H); HPLC: 95.06% (Retention Time= 5.819 min).1-352 2 LCMS (M+1) +< : 502.2 1< H NMR: δ 2.85 (m, 2H), 3.62 (m, 4H), 3.82 (m, 1H), 4.45 (m, 2H), 4.68 (s, 2H), 5.00 (m, 1H), 7.32 (d, 5H), 7.35 (m, 1H), 7.46 (m, 2H), 7.77 (m, 3H), 7.79 (s, 1H), 7.89 (d, 1H), 8.96 (brs, 2H), 9.18 (brs, 2H); HPLC: 97.02% (Retention Time= 5.524 min). General synthetic scheme - 8

[0508]

[0509] Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-8. 6-Cyno-indole 2 -ethyl carboxylate upon reacting with N-chlorosuccinimide in presence of suitable solvent (DMF) yielded 3-chloro-6-cyano-indole-2 carboxylate, which upon treating with appropriate alkylating agent in presence of a suitable base (K 2 CO 3 ) and a suitable solvent (DMF) gives compound N-alkylated derivatives. Hydrolysis of C(2) ethyl ester in presence of LiOH / H 2 O followed by coupling with cyclic yieled corresponding amides which were treatred with ethanolic HCl. This intermediate imidates on further treatment with ethanolic ammonia yielded compounds of formula (I).Example 72: Synthesis of compound I-353 1-([1,1'-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-1-carbonyl)-1H-indole-6-carboximidamide

[0510] Step-1: Ethyl 3-chloro-6-cyano-1H-indole-2-carboxylate

[0511] Ethyl 6-cyano-1H-indole-2-carboxylate (1.25 g, 5.84 mmol) was dissolved in 125 mL of dimethylformamide and added N-chlorosuccinimide (932 mg, 7.0 mmol) at 0 °C in portions and stirred the mixture for 12 h at room temperature. Reaction mixture was quenched to cold water, extracted with ethylacetate, followed by washed with brine and dried over sodium sulphate. Solvent was evaporated under vacuum and resulted crude residue was purified by column chromatography using silica-gel as an adsorbant and eluted with hexane:ethylacetate (9:1) to afford 820 mg of the title compound. LCMS: 249.1 (M+1) +< .Step-2: Ethyl 1-([1,1'-biphenyl]-4-ylmethyl)-3-chloro-6-cyano-1H-indole-2-carboxylate

[0512] The product of st...

Claims

1. A compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein L1 is a bond, or an optionally substituted bivalent C1-8 saturated or unsaturated, straight 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-; R1 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; L2 is an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 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-, -O-C(O)-, -NR-S(O)2-, -S(O)2-NR-, or -Cy-; -Cy- is an optionally substituted bivalent ring selected from phenylene, 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; R2 is an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 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; R3 is H, -OH, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-O-C1-6aliphatic, C1-6aliphatic, or -C(O)-C1-6aliphatic, wherein the C1-6aliphatic is optionally substituted; L3 is an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-; R4 is -NHR or -C(N-R)-NHR; and each R is independently H, -OH, -C1-8alkyl, -OC1-8alkyl, -C(O)-C1-8alkyl, -C(O)-OC1-8alkyl, 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 each of the C1-8alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.

2. A compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein L1 is an optionally substituted C1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -S(O)2-, -C(O)-, or -O-; R1 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; L2 is an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 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-, -O-C(O)-, - NR-S(O)2-, -S(O)2-NR-, or -Cy-, -Cy- is an optionally substituted bivalent ring selected from phenylene, 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; R2 is H, or an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 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; R3 is H, -OH, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-O-C1-6aliphatic, C1-6aliphatic, or -C(O)-C1-6aliphatic, wherein the C1-6aliphatic is optionally substituted; L3 is a bond, or an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally replaced by -CO-; R4 is -C(N-R)-NHR; and each R is independently H, -OH, -C1-8alkyl, -OC1-8alkyl, -C(O)-C1-8alkyl, -C(O)-OC1-8alkyl, 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 each of the C1-8alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein L3 is a bond.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 is an optionally substituted C1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -S(O)2-, -C(O)-, or -O-.

5. The compound of any one of claims 1-4, wherein the compound is of Formula (IV-e): or a pharmaceutically acceptable salt thereof.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted phenyl, or an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.

7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1 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.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L2 is an optionally substituted C1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -NR-C(O)-, -C(O)-NR-, -C(O)-, -S(O)2-, - C(O)-O-, -O-C(O)-, -NR-S(O)2-, -S(O)2-NR-, or -Cy-.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -Cy- is optionally substituted phenylene, optionally substituted pyridylene, or a 4-6 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein either (i) R2 is an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 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; or (ii) R2 is an optionally substituted ring selected from phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aromatic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein either (i) R3 is -OH, halogen, -CN, -C(O)H, -NH2, -NO2, -COOH, -CONH2, -NH-C(O)-O-C1-6aliphatic, C1-6aliphatic, or -C(O)-C1-6aliphatic, wherein the C1-6aliphatic is optionally substituted; or (ii) R3 is -OH, -NH2, -NO2, -COOH, -NH-C(O)-O-C1-6aliphatic, C1-6aliphatic, or -C(O)-C1-6 aliphatic, wherein the C1-6aliphatic is optionally substituted.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L3 is an optionally substituted C1-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -CO-.

13. A compound selected from: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

15. A compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, for use in a method for (i) treating a low hepcidin disorder, disease, and / or condition in a patient; (ii) increasing hepcidin production by the liver in a patient; (iii) treating an iron overload disorder, disease, and / or condition in a patient, preferably wherein the iron overload disorder, disease, and / or condition is selected from the group consisting of hemochromatosis Type 1, 2a, 2b and 3 (hemochromatosis, Hfe hemochromatosis (Type 1), juvenile hemochromatosis (types 2a and 2b)), hepcidin deficiency, transfusional iron overload, African iron overload, and iron overload cardiomyopathy; (iv) treating an iron loading anemia in a patient, preferably wherein the iron loading anemia is selected from the group consisting of beta thalassemia, HbE / thalassemia (thalassemia major, thalassemia intermedia, thalassemia minor, non-transfusion dependent thalassemia, transfusion-dependent thalassemia), alpha thalassemia, congenital dyserythropoietic anemias (Type I and Type II), pyruvate kinase deficiency, and myelodysplasia (such as myelodysplastic syndrome, and RARS SF3B1 associated MDS); (v) treating a hematological disease, disorder, and / or condition in a patient, preferably wherein the hematological disease, disorder, and / or condition is selected from the group consisting of sickle cell disease (such as sickle cell anemia), polycythemia vera, sideroblastic anemia, and bone marrow transplantation; (vi) treating a liver disease in a patient, preferably wherein the liver disease is selected from the group consisting of Hepatitis B, Hepatitis C, alcoholic liver disease, cirrhosis of the liver, epahtocellular carcinoma, and non-alcoholic steatohepatitis (NASH); (vii) treating a metabolic disease in a patient, preferably wherein the metabolic disease is selected from the group consisting of metabolic syndrome, insulin resistance, Type II diabetes, porphyria, porphyria cutanea tarda, Wilson's Disease, and acute iron overdose; (viii) treating a neurodegenerative disorder in a patient; (ix) treating an infectious disease in a patient, preferably wherein the infectious disease is a siderophilic infection; or (x) inhibiting matriptase 2, or a mutant thereof, in a biological sample, comprising contacting the sample with the compound of any one of claims 1-13.