MATRIPTASE 2 INHIBITORS AND USES THEREOF

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.

SUMMARY OF THE INVENTION

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

I

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0004] 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 EMBODIMENTS

1. General Description of Certain Embodiments of the Invention:

[0005] 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.

[0006] 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 invention 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 Ci _-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(0) ₂ -, -C(O)-, or -0-; 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 i-x 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(0)-NR-, -C(O)-, -S(0) ₂ -, -C(0)-0- , -O-C(O)-, -NR-S(0) ₂ -, -S(0) 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(0)H, -NH ₂ , -N0 ₂ , -COOH, -CONH ₂ , -NH-C(0)-0-Ci _-6 aliphatic, Ci- 6aliphatic, or -C(0)-Ci- ₆ aliphatic, wherein the Ci ^aliphatic is optionally substituted;

L ³ is bond, or an optionally substituted bivalent C i-x 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, -Ci-salkyl, -OCi-salkyl, -C(0)-Ci- ₈ alkyl, -C(0)-OCi- ₈ alkyl, 4-7

membered monocyclic carbocyclyl, -0-(4-7 membered monocyclic carbocyclyl), -C(0)-(4-7 membered monocyclic carbocyclyl), -C(0)-0-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(0)-phenyl, -C(0)-0-phenyl, 8-10 membered bicyclic aryl, -O-(8-l0 membered bicyclic aryl), -C(O)-(8-l0 membered bicyclic aryl), or -C(O)-O-(8-l0 membered bicyclic aryl), wherein each of the Ci _-8 alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.

2. Compounds and Definitions:

[0007] Compounds of the present invention 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, 75 ^th Ed. Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, ETniversity Science Books, Sausalito: 1999, and“March’s Advanced Organic Chemistry”, 5 ^th Ed., Ed. : Smith, M.B. and March, T, John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0008] 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.

[0009] 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:

[0010] The term“lower alkyl” refers to a Ci- ₄ straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and /er/-butyl.

[0011] The term“lower haloalkyl” refers to a Ci- ₄ straight or branched alkyl group that is substituted with one or more halogen atoms.

[0012] 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-di hydro-2//-pyrrol yl ), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)).

[0013] The term“unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

[0014] As used herein, the term“bivalent Ci _-8 (or Ci _-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.

[0015] 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.

[0016] 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. [0017] As used herein, the term“cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[0018] The term“halogen” means F, Cl, Br, or I.

[0019] 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.

[0020] 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 p 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, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,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.

[0021] 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-lO-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 pyrrol yl), NH (as in pyrrolidinyl), or ⁺ NR (as in N substituted pyrrolidinyl).

[0022] 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 indolyf 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.

[0023] 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.

[0024] 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.

[0025] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CEh)o^R°; -(CH ₂ )o- ₄ 0R°; -0(CH ₂ )o- ₄ R°, -0-(CH ₂ )o- ₄ C(0)OR°; -(CH ₂ ) _O ^CH(OR°) ₂ ; -(CH ₂ ) _O ^SR°; -(CH ₂ )o-4Ph, which may be substituted with R°; -(CH ₂ )o- ₄ 0(CH ₂ )o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH ₂ )o- ₄ 0(CH ₂ )o-i-pyridyl which may be substituted with R°; -N0 ₂ ; -CN; - Ns; -(CH ₂ ), N(R°) ₂ ; -(CH ₂ ) _O-4 N(R°)C(0)R ⁰ ; -N(R°)C(S)R°; -(CH ₂ ) _O -

₄ N(R°)C(0)NR° ₂ ; -N(R°)C(S)NR° ₂ ; -(CH ₂ ) _O-4 N(R ⁰ )C(0)OR°;

N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR° ₂ ; -N(R°)N(R°)C(0)OR°; -(CH ₂ ) _0-4 C(O)R°; - C(S)R°; -(CH ₂ > C(0)0R°; -(CH ₂ )O- ₄ C(0)SR°; -(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ; -(CH ₂ ) _0-4 OC(O)R ^o ; - OC(0)(CH ₂ ) _O-4 SR-, SC(S)SR°; -(CH ₂ ), SC(0)R°; -(CH ₂ ) _O-4 C(0)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -SC(S)SR°, -(CH ₂ ) _O-4 OC(0)NR° ₂ ; -C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH ₂ C(0)R°; - C(NOR°)R°; -(CH ₂ ), SSR°; -(CH ₂ > S(0) ₂ R°; -(CH ₂ > S(0) ₂ 0R°; -(CH ₂ ) _0-4 OS(O) ₂ R ^o ; - S(0) ₂ NR° ₂ ; -S(0)(NR°)R°; -S(0) ₂ N=C(NR° ₂ ) ₂ ; -(CH ₂ ), S(0)R°; -N(R°)S(0) ₂ NR° ₂ ; - N(R°)S(0) ₂ R°; -N(OR°)R°; -C(NH)NR° ₂ ; -P(0) ₂ R°; -P(0)R° ₂ ; -OP(0)R° ₂ ; -OP(0)(OR°) ₂ ; SiR° ₃ ; — (C i- ₄ straight or branched alkylene)0-N(R°) ₂ ; or -(Ci- ₄ straight or branched alkylene)C(0)0-N(R°) ₂ .

[0026] Each R° is independently hydrogen, Ci- ₆ aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, -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-l2-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 =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, - (CH ₂ ) _O-2 R·, -(haloR*), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR*, -(CH ₂ ) _0-2 CH(OR*) ₂ ; -0(haloR*), -CN, -N ₃ , -(CH ₂ ) _O-2 C(0)R·, -(CH ₂ ) _O-2 C(0)OH, -(CH ₂ ) _O-2 C(0)OR·, -(CH ₂ ) _O-2 SR*, -(CH ₂ ) _O-2 SH, -(CH ₂ ) _O - ₂ NH ₂ , -(CH ₂ ) _O-2 NHR*, -(CH ₂ ) _O-2 NR* ₂ , -N0 ₂ , -SiR* ₃ , -OSiR* ₃ , -C(0)SR* -(Ci^ straight or branched alkylene)C(0)OR*, or -SSR*.

[0027] Each R* is independently selected from C1 -4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, 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 =0, =S, =NNR%, =NNHC(0)R ^* , =NNHC(0)OR\ =NNHS(0) ₂ R ^* , =NR ^* , =NOR ^* , -0(C(R ^* ₂ )) _2-3 0-, or - S(C(R ^* ₂ )) _2-3 S-, or a divalent substituent bound to vicinal substitutable carbons of an“optionally substituted” group is -0(CR ^* ₂ ) _2-3 0-, wherein each independent occurrence of R ^* is selected from hydrogen, Ci- 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.

[0028] When R ^* is Ci- ₆ aliphatic, R ^* is optionally substituted with halogen, - R*, -(haloR*), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH ₂ , NHR*, -NR* ₂ , or - N0 ₂ , wherein each R* is independently selected from C1 -4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, 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.

[0029] An optional substituent on a substitutable nitrogen is independently -R ^÷ , -NR ^÷ ₂ , - C(0)R ^† , -C(0)OR ^† , -C(0)C(0)R ^† , -C(0)CH ₂ C(0)R ^† , -S(0) ₂ R ^† , -S(0) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , - C(NH)NR ^÷ ₂ , or -N(R ^÷ )S(0) ₂ R ^÷ ; wherein each R' is independently hydrogen, Ci- 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-l2-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 Ci- ₆ aliphatic, R' is optionally substituted with halogen, -R", -(haloR*), -OH, -OR*, -0(haloR*), - CN, -C(0)OH, -C(0)OR*, -NH ₂ , -NHR*, -NR* ₂ , or -N0 ₂ , wherein each R* is independently selected from Ci- ₄ aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, 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] 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 ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. 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, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, 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.

[0031] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (Ci^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. [0032] 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.

[0033] 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 IC50 and/or binding constant of less than about 100 mM, less than about 50 mM, less than about 20 mM, less than about 10 mM, or less than about 5 mM.

[0034] 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:

[0035] In one aspect, the present invention 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 Ci-x 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(0) ₂ -, -C(O)-, or -0-;

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 Ci _-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(0)-NR-, -C(O)-, -S(0) ₂ -, -C(0)-0- , -O-C(O)-, -NR-S(0) ₂ -, -S(0) 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(0)H, -NH ₂ , -N0 ₂ , -COOH, -CONH ₂ , -NH-C(0)-0-Ci _-6 aliphatic, Ci- 6aliphatic, or -C(0)-Ci _-6 aliphatic, wherein the Ci ^aliphatic is optionally substituted;

L ³ is a bond, or an optionally substituted bivalent Ci- 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, -Ci-salkyl, -OCi-salkyl, -C(0)-Ci- ₈ alkyl, -C(0)-0Ci- ₈ alkyl, 4-7

membered monocyclic carbocyclyl, -0-(4-7 membered monocyclic carbocyclyl), -C(0)-(4-7 membered monocyclic carbocyclyl), -C(0)-0-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(0)-phenyl, -C(0)-0-phenyl, 8-10 membered bicyclic aryl, -O-(8-l0 membered bicyclic aryl), -C(O)-(8-l0 membered bicyclic aryl), or -C(O)-O-(8-l0 membered bicyclic aryl), wherein each of the Ci-salkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.

[0036] As defined generally above, each X is independently C or N.

[0037] In some embodiments, X is C. In some embodiments, X is N.

[0038] In some embodiments, each X is independtly C or N such that is selected from the following

[0039] In some embodiments, each X is independently selected from those depicted in Table A, below. [0040] As defined generally above, L ¹ is a bond, or an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(0) ₂ -, -C(O)-, or -0-.

[0041] In some embodiments, L ¹ is a bond.

[0042] In some embodiments, L ¹ is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(0) ₂ -, -C(O)-, or -0-. In some embodiments, L ¹ is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is optionally replaced by -S(0) ₂ -, -C(O)-, or -0-. In some embodiments, L ¹ is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 2 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(0) ₂ -, -C(O)-, or -0-. In some embodiments, L ¹ is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(0) ₂ -, -C(O)-, or -0-.

[0043] In some embodiments, L ¹ is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is replaced by -S(0) ₂ -. In some embodiments, L ¹ is an optionally substituted Ci _-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 Ci- ₈ bivalent hydrocarbon chain, wherein 1 methylene unit of the hydrocarbon chain is replaced by -0-.

[0044] 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(0) ₂ CH ₂ -. In some embodiments, L ¹ is -S(0) ₂ (CH ₂ ) ₂ -. In some embodiments, L ¹ is -S(0) ₂ -. In some embodiments, L ¹ is -CH ₂ S(0) ₂ -. In some embodiments, L ¹ is -(CH ₂ ) ₂ -S(0) ₂ -.

[0045] In some embodiments, L ¹ is selected from those depicted in Table A, below.

[0046] 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.

[0047] 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.

[0048] In some embodiments, R ¹ is optionally substituted phenyl. In some embodiments, R ¹ is unsubstituted phenyl. In some embodiments, R , is _s . In some embodiments, R ¹ is . , . In some embodiments, R ^0CF "

. 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 is . In some embodiments, R is . In some embodiments, R is In some embodiments, R . In some

{= .halogen

embodiments, R ¹ is In some embodiments, R ¹ iss ⁵ K^ , wherein halogen — halogen

is F, Cl, or Br. In some embodiments, R is , wherein halogen is F, Cl, or Br. In so _{* i} L // OCH ₃

me embodiments, R ¹ is . In some embodiments, R ¹ is . In some embodiments, R ¹ is . In some embodiments, R i is I G ^¾ -L\ ^ / //— SCH _{3 .} In some

embodiments, R ¹ is In some embodiments,

[0049] 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.

[0050] In some embodiments, R ¹ is optionally substituted pyridyl. In some embodiments, R ¹

is unsubstituted pyridyl. In some embodiments, R ¹ is or

[0051] In some embodiments, R ¹ is [0052] 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 lO-membered bicyclic aromatic carbocyclic ring, optionally substituted by -CH ₂ -R ^U , -O-R ¹¹ , -N-R ¹¹ , -S-R ¹¹ , -

NR-C(0)-R ^u , -C(0)-NR-R ^u , -C(0)-R ^u , -S(0) ₂ -R ^u , -C(0)-0-R ^u , -0-C(0)-R ^u , -NR-S(0) ₂ -R ^u , or -S(0) ₂ -NR-R ^u , 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

[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 lO-membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0054] In some embodiments, [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 Ci _-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(0)-NR-, -C(O)-, -S(0) ₂ -, -C(0)-0-, -O-C(O)-, -NR-

S(0) ₂ -, -S(0) ₂ -NR-, or -Cy-.

[0057] In some embodiments, L ² is an optionally substituted Ci-x bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -NR-C(O)-, -C(0)-NR-, -C(O)-, -C(0)-0-, or -O-C(O)-. In some embodiments, a Ci- ₈ bivalent hydrocarbon chain is substituted by -OH.

[0058] In some embodiments, L ² is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -S(0) ₂ -, -NR-S(0) ₂ -, or -S(0) ₂ -NR-.

[0059] In some embodiments, L ² is an optionally substituted Ci _-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 Ci _-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(0)-NR-, -NR-S(0) ₂ -, or -S(0) ₂ -NR-.

[0061] In some embodiments, L ² is an optionally substituted Ci _-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(0) ₂ -.

[0062] In some embodiments, L ² is an optionally substituted Ci _-8 bivalent hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by -C(0)-0- or -O-C(O)-.

[0063] In some embodiments, L ² is -CH ₂ -, -NH-, -NH-CH3-, -CH3-NH-, -NH-C(O)-, -

[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 lO-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 lO-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(0)H, -NH ₂ , -N0 ₂ , -COOH, -CONH2, -NH-C(0)-0-Ci- ₆ aliphatic, Ci^aliphatic, or -C(0)-Ci- ₆ aliphatic, wherein the Ci- 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(0)H. In some embodiments, R ³ is - NH ₂ . In some embodiments, R ³ is -N0 ₂ . In some embodiments, R ³ is -COOH. In some embodiments, R ³ is -CONH ₂ . In some embodiments, R ³ is -NH-C(0)-0-Ci- ₆ aliphatic, wherein the Ci- ₆ aliphatic is optionally substituted. In some embodiments, R ³ is Ci _-6 aliphatic, wherein the Ci- ₆ aliphatic is optionally substituted. In some embodiments, R ³ is -C(0)-Ci- ₆ aliphatic, wherein the Ci- 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 -NO2. In some embodiments, R ³ is -COOH. In some embodiments, R ³ is - NH-C(0)-0-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 Ci _-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 Ci _-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 Ci _-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 Ci _-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 Ci _-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, -Ci-salkyl, -OCi-salkyl, -C(O)- Ci _-8 alkyl, -C(0)-OCi- ₈ alkyl, 4-7 membered monocyclic carbocyclyl, -0-(4-7 membered monocyclic carbocyclyl), -C(0)-(4-7 membered monocyclic carbocyclyl), -C(0)-0-(4-7 membered monocyclic carbocyclyl), phenyl, -O-phenyl, -C(0)-phenyl, -C(0)-0-phenyl, 8-10 membered bicyclic aryl, -O-(8-l0 membered bicyclic aryl), -C(O)-(8-l0 membered bicyclic aryl), or -C(O)-O-(8-l0 membered bicyclic aryl), wherein each of the C i-xalkyl, 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.

[00100] In some embodiments, R is optionally substituted -Ci-salkyl. In some embodiments, R is optionally substituted -OCi-salkyl. In some embodiments, R is optionally substituted -C(0)-Ci- xalkyl. In some embodiments, R is optionally substituted -C(0)-OCi- ₈ alkyl. In some embodiments, Ci-salkyl is Ci _-6 alkyl. In some embodiments, Ci-salkyl is isopropyl. In some embodiments, Ci- ₈ alkyl is tert-butyl. In some embodiments, C i-xalkyl is neopentyl. [00101] In some embodiments, R is optionally substituted 4-7 membered monocyclic carbocyclyl. In some embodiments, R is optionally substituted -0-(4-7 membered monocyclic carbocyclyl). In some embodiments, R is optionally substituted -C(0)-(4-7 membered monocyclic carbocyclyl). In some embodiments, R is optionally substituted -C(0)-0-(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.

[00102] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted -O-phenyl. In some embodiments, Ris optionally substituted -C(0)-phenyl. In some embodiments, R is optionally substituted -C(0)-0-phenyl.

[00103] In some embodiments, R is optionally substituted 8-10 membered bicyclic aryl. In some embodiments, R is optionally substituted -O-(8-l0 membered bicyclic aryl). In some embodiments, R is optionally substituted -C(O)-(8-l0 membered bicyclic aryl). In some embodiments, R is optionally substituted -C(O)-O-(8-l0 membered bicyclic aryl).

[00104] In some embodiments, R is selected from those depicted in Table A, below.

[00105] 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.

[00106] In some embodiments, a compound of formula I is selected from formulas Il-a to Il-f:

(II-a) (Il-b) (II-c)

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.

[00107] 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.

[00108] In some embodiments, a compound of formula I is selected from formulas III-a to III- 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. [00109] In some embodiments, a compound of formula I is 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.

[00110] 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.

[00111] Exemplary compounds of the invention are set forth in Table A, below.

Table A: Exemplary Compounds

Definition of % inhibition (I) range at 1 uM: [00112] In some embodiments, the present invention provides a compound set forth in Table A, above, or a pharmaceutically acceptable salt thereof.

[00113] In some embodiments, the present invention provides a compound described in the examples below, or a pharmaceutically acceptable salt thereof.

[00114] In some embodiments, a compound of the invention is not:

4. Uses, Formulation and Administration:

Pharmaceutically acceptable compositions

[00115] 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.

[00116] The term“patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00117] The term“pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that 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, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[00118] 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.

[00119] 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.

[00120] 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 l,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. [00121] 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 polyoxy ethylated 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.

[00122] 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 com 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.

[00123] 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.

[00124] 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.

[00125] 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. [00126] 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.

[00127] 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.

[00128] 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.

[00129] 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.

[00130] 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. [00131] 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

[00132] Compounds and compositions described herein are generally useful for the inhibition of Matriptase 2, or a mutant thereof.

[00133] 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.

[00134] 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.

[00135] 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.

[00136] 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.

[00137] 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.

[00138] 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.

[00139] 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.

[00140] 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.

[00141] 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.

[00142] 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.

[00143] 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.

[00144] 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).

[00145] 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.

[00146] 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).

[00147] 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.

[00148] 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.

[00149] 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.

[00150] 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.

[00151] 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 l,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.

[00152] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00153] 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 polylactide- polyglycolide. 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.

[00154] 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.

[00155] 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, pol yvi nyl pyrroli di none, 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.

[00156] 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. [00157] 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.

[00158] 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.

[00159] 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.

[00160] 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.

[00161] 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.”

[00162] 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.

[00163] 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.

EXEMPLIFICATION

General Synthetic Methods

[00164] 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:

[00165] 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.

[00166] 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.

[00167] 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.

[00168] The following abbreviations refer respectively to the definitions below:

[00169] ACN - Acetonitrile; br - Broad; °C - Degree Celsius ; CHCh - 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.HC1- l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; mg- Miligram; g - Gram; h - Hours; ¾- Proton; HC1- Hydrochloric acid; HPLC- High-Performance Liquid Chromatography; H ₂ - Hydrogen; HOBt- 1 -Hydroxy benzotriazole; K2CO3 - Potassium carbonate; LCMS - Liquid chromatography mass spectroscopy; LiOH.H ₂ 0 - 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; NH3 - Ammonia; NBS - N-Bromosuccinimide; NCS - A-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; m - Micron; and d- Delta; Zn - Zinc; mmol - millimoles. [00170] 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.

[00171] LCMS data has been recorded in +ve mode unless otherwise mentioned.

[00172] 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

PG = optional protecting group; X = Br or Cl; X,, X ₂ , R ₂ and R ₃ as defined in Formula (I)

Example 1: Synthesis of compound 1-1

[00173] N-(6-aminopyridin-3-yl)-6-carbamimidoyl-l-(4-(trifluoromethy l)benzyl)-lH- indole-2-carboxamide

[00174] Step-l : Ethyl 6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2-carboxylat e [00175] Ethyl 6-cyano-lH-indole-2-carboxylate (5.0 g, 23.34 mmol), dissolved in 150 mL of N,N-dimethylformamide, was added l-(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+l) ⁺ .

[00176] Step-2: 6-Cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2-carboxylic acid

[00177] Product of step-l of example-l(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+l) ⁺ .

[00178] Step-3 : tert-Butyl (5-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carboxamido)pyridin-2-yl)carbamate

[00179] Product of step-2 of example-l (350 mg, 1.01 mmol), dissolved in 5 mL of N,N- dimethylformamide, was added Butyl (5-aminopyridin-2-yl)carbamate (234mg, l . lmmol), EDCI.HC1 (292mg, l .52mmol), HOBt (l37mg, l .Olmmol) 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+l) ⁺ .

[00180] Step-4: Ethyl 2-((6-aminopyridin-3-yl)carbamoyl)-l-(4-(trifluoromethyl)ben zyl)-lH- indole-6-carbimidate

[00181] Product was step-3 of example-l (350 mg, 0.65 mmol) was dissolved in 50 mL of ethanolic-HCl (ethanol was saturated with HC1 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+l) ⁺ . [00182] Step-5: N-(6-aminopyridin-3-yl)-6-carbamimidoyl-l-(4-(trifluoromethy l)benzyl)-lH- indole-2-carboxamide

[00183] 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 l50mm, 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+l) ⁺ , ¹ H NMR (300MHz, DMSO-de): d 5.98 (s, 2H), 6.93 (d, 2H), 7.22 (d, lH),7.5 l(m, 4H), 7.81 (brs, 1H), 8.05 (m, 2H), 8.41 (s, 1H), 8.41 (s,lH), 9.11 (brs,2H), 9.25(brs,2H), 10.75 (brs, lH).

[00184] The following compounds listed in table-l, 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.

[00185] Table-1:

[00186] Table-2:

[00187] Table-3:

Example 2: Synthesis of compound 1-6.

[00188] N-(l-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-l-(4- (trifluoromethyl)benzyl)-lH indole-2-carboxamide

[00189] Step-l : tert-butyl 4-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carboxamido)-piperidine-l-carboxylate

[00190] The product of step-2 of example 1 and tert-butyl 4-aminopiperidine-l-carboxylate were treated together to afford the title compound following the procedure described in step-3 of example 1. LCMS: 527.2 (M+l) ⁺ .

[00191] Step-2: 6-cyano-N-(piperidin-4-yl)-l-(4-(trifluoromethyl)benzyl)-lH- indole-2- carboxamide

[00192] The product of step-l 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-l but reaction was done at 0 °C for 2 h. LCMS: 427.2 (M+l) ⁺ .

[00193] Step-3 : tert-butyl (3-(4-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carboxamido)-piperidin- 1 -yl)propyl)carbamate

[00194] 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-l of example -1. LCMS: 584.3 (M+l) ⁺ .

[00195] Step-4: Ethyl 2-((l-(3-aminopropyl)piperidin-4-yl)carbamoyl)-l-(4-

(trifluoromethyl)benzyl)-lH-indole-6-carbimidate

[00196] 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-l . LCMS: 530.3 (M+l) ⁺ .

[00197] Step-5: N-(l-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-l-(4-

(trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00198] The product of step-4 of example-2 (200 mg, 0.37 mmol) was treated with 30 mL of ethanol ic-NH-, to afford 95 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 501.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-7

[00199] 6-Carbamimidoyl-N-(l-(3-guanidinopropyl)piperidin-4-yl)-l-(4 - (trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00200] Step-l : N-(l-(3-aminopropyl)piperidin-4-yl)-6-cyano-l-(4-(trifluorom ethyl)benzyl)- lH-indole-2-carboxamide

[00201] 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+l) ⁺ .

[00202] Step-2 : 6-Cyano-N-(l -(3 -guani dinopropyl )piperidin-4-yl)- 1 -(4-

(trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00203] The product of step-l of example-3 ( 498 mg, 1.03 mmol) was dissolved in 15 mL of N,N-dimethylformamide and treated with lH-pyrazole-l-carboxamidine hydrochloride (329 mg, 2.25 mmol) andN,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+l) ⁺ .

[00204] Step-3: Ethyl 2-((l -(3 -guani dinopropyl )piperidin-4-yl)carbamoyl)-l -(4-

(trifluoromethyl)benzyl)-lH-indole-6-carbimidate

[00205] 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-l. LCMS: 572.3 (M+l) ⁺ .

[00206] Step-4: 6-Carbamimidoyl-N-(l -(3 -guani dinopropyl )piperidin-4-yl)-l -(4-

(trifluoromethyl)benzyl)-lH-indole-2-carboxamide [00207] The product of step-3 of example-3 (170 mg, 0.29 mmol) was treated with 30 mL of ethanol ic-NFL to afford 40 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 543.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-8

[00208] N-(l-(3-aminopropanoyl)piperidin-4-yl)-6-carbamimidoyl-l-(4- (trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00209] Step-l : tert-butyl (3-(4-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carboxamido)-piperidin-l-yl)-3-oxopropyl)carbamate

[00210] The product of step-2 of example-2 (553 mg, 1.3 mmol) and 3-((tert- butoxycarbonyl)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-l . LCMS: 598.3 (M+l) ⁺ .

[00211] Step-2: Ethyl 2-((l-(3-aminopropanoyl)piperidin-4-yl)carbamoyl)-l-(4-

(trifluoromethyl)benzyl)-lH-indole-6-carbimidate

[00212] The product of step-l 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-l . LCMS: 544.2 (M+l) ⁺ .

[00213] Step-3 : N-(l-(3-Aminopropanoyl)piperidin-4-yl)-6-carbamimidoyl-l-(4-

(trifluoromethyl)-benzyl)-lH-indole-2-carboxamide

[00214] The product of step-2 of example-4 (167 mg, 0.28 mmol) was treated with 30 mL of ethanolic-NLL to afford 80 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 515.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-9

[00215] 6-carbamimidoyl-N-((lr,4r)-4-(picolinamido)cyclohexyl)-l-(4- (trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00216] Step-l : tert-butyl ((lr,4r)-4-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole- 2- carb ox ami do) cy cl ohexyl )carb am ate

[00217] The product of step-2 of example-l (430 mg, 1.25 mmol) and tert-butyl ((lr,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-l. LCMS: 541.2 (M+l) ⁺ .

[00218] Step-2 : N-(( 1 r,4r)-4-aminocyclohexyl)-6-cyano- 1 -(4-(trifluorom ethyl )benzyl)- 1 H- indole-2-carboxamide

[00219] The product of step-l 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+l) ⁺ .

[00220] Step-3: 6 -cyano-N-((lr,4r)-4-(picolinamido)cyclohexyl)-l-(4-

(trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00221] 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-l. LCMS: 546.3 (M+l) ⁺ .

[00222] Step-4: Ethyl 2-(((lr,4r)-4-(picolinamido)cyclohexyl)carbamoyl)-l-(4-

(trifluoromethyl)benzyl)-lH-indole-6-carbimidate

[00223] 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-l. LCMS: 592.2 (M+l) ⁺ .

[00224] Step-5: 6-Carbamimidoyl-N-((lr,4r)-4-(picolinamido)cyclohexyl)-l-(4- (trifluoromethyl)benzyl)-lH-indole-2-carboxamide

[00225] The product of step-4 of example-5 (95mg, 0.16 mmol) was treated with 30 mL of ethanolic-NLL to afford 20 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 563.2 (M+l) ⁺ , ¾ NMR (300MHz, CD ₃ OD): d 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 1-20

[00226] 4-((2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl -lH-indol-l- yl)methyl)benzoic acid

[00227] Step-l : 6-Cyano-lH-indole-2-carboxylic acid

[00228] Ethyl 6-cyano-lH-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-l. LCMS : 187.1 (M+l) ⁺ .

[00229] Step-2: tert-Butyl ((lr,4r)-4-(6-cyano-lH-indole-2- carboxamido)cyclohexyl)carbamate

[00230] The product of step-l of example-6 (480 mg, 2.56 mmol) and tert-butyl((lr, 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-l. LCMS: 383.2 (M+l) ⁺ .

[00231] Step-3 : 4-((2-(((lr,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)car bamoyl)-6- cyano-lH-indol-l-yl)methyl)benzoic acid

[00232] 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-l of example-l. LCMS : 517.2 (M+l) ⁺ .

[00233] Step-4: 4-((2-(((lr,4r)-4-Aminocyclohexyl)carbamoyl)-6-(ethoxy(imino )methyl)-lH- indol-l-yl)methyl)benzoic acid

[00234] 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-l . LCMS : 463.2 (M+l) ⁺ .

[00235] Step-5: 4-((3-Amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carba mimidoyl- lH-indol- 1 -yl)methyl)benzoic acid

[00236] The product of step-4 of example-6 (80 mg, 0.17 mmol) was treated with 20 mL of ethanolic-ML to afford 14 mg of the title compound following the procedure described in step-5 of example-l . LCMS : 434.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-21

[00237] Methyl 4-((2-(((l r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-lH- indol-l-yl)methyl)- benzoate

[00238] Step-l : Methyl 4-((2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)car bamoyl)- 6-cyano- lH-indol- 1 -yl)m ethyl )benzoate

[00239] 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-l of example-l . LCMS : 531.2 (M+l) ⁺ .

[00240] Step-2: Methyl 4-((2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-

(ethoxy(imino)methyl)-lH-indol-l-yl)methyl)benzoate

[00241] The product of step-l 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-l . LCMS : 477.2 (M+l) ⁺ .

[00242] Step-3 : Methyl 4-((2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl -lH- indol-l-yl)methyl) benzoate

[00243] The product of step-2 of example-7 (150 mg, 0.28 mmol) was treated with 30 mL of ethanol ic-NFh to afford 42 mg of the title compound following the procedure described in step-5 of example-l . LCMS : 448.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-22.

[00244] Ethyl 4-((2-(((l r,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-lH-indol- l-yl)methyl)-benzoate

[00245] This compound was prepared by following the procedure described in step-l to step-3 of example-7 using ethyl 4-(bromomethyl)benzoate. LCMS : 462.2 (M+l) ⁺ , 'H NMR (300MHz, DMSO-de): d 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 1-23

[00246] Ethyl 4-((3-amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carba mimidoyl- lH-indol-l-yl)-methyl)benzoate

[00247] Step-l : tert-Butyl ((1 r,4r)-4-(6-cyano-3 -nitro- 1 H-indole-2- carboxamido)cyclohexyl)carbamate

[00248] 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 (40lmg, 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+l) ⁺ .

[00249] Step-2: Ethyl 4-((2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)car bamoyl)-6- cyano-3-nitro-lH-indol-l-yl)methyl)benzoate

[00250] The product of step-l 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-l of example-l . LCMS: 590.2 (M+l) ⁺ .

[00251] Step-3 : Ethyl 4-((3-amino-2-(((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-lH-indol- l-yl)methyl)benzoate

[00252] 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: ethyl acetate (6:4) and afforded the title compound (152 mg). LCMS: 560.3 (M+l) ⁺ .

[00253] Step-4: Ethyl 4-((3-amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-

(ethoxy(imino)methyl)-lH-indol-l-yl)methyl)benzoate

[00254] The product of step-3 of example-9 (150 mg, 0.27 mmol) was treated with 40 mL of ethanolic-HCl to afford 1 11 mg of the title compound following the procedure described in step-4 of example-l . LCMS : 506.3 (M+l) ⁺ .

[00255] Step-5: Ethyl 4-((3-amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6- carbamimidoyl- lH-indol- 1 -yl)methyl)benzoate

[00256] The product of step-4 of example-9 (108 mg, 0.21 mmol) was treated with 30 mL of ethanol ic-NFL to afford 29 mg of the title compound following the procedure described in step-5 of example-l . LCMS : 477.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-28

[00257] N-(l-(2-Aminoethyl)piperidin-4-yl)-6-carbamimidoyl-l-pheneth yl-lH-indole-2- carboxamide

[00258] Step-l : Ethyl 6-cyano-l-phenethyl-lH-indole-2-carboxylate

[00259] Ethyl 6-cyano-lH-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-l of example-l. LCMS : 319.1 (M+l) ⁺ .

[00260] Step-2: 6-Cyano-l-phenethyl-lH-indole-2-carboxylic acid

[00261] The product of step-l of example-lO (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-l. LCMS : 291.1 (M+l) ⁺ .

[00262] Step-3: tert-Butyl 4-(6-cyano-l-phenethyl-lH-indole-2-carboxamido)piperidine-l- carboxylate

[00263] The product of step-2 of example-lO (390 mg, 1.34 mmol) and tert-butyl 4- aminopiperidine-l-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-l. LCMS: 473.2 (M+l) ⁺ .

[00264] Step-4 : 6-Cyano- 1 -phen ethyl -N-(piperi din-4-yl)- lH-indole-2-carboxamide

[00265] The product of step-3 of example-lO (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+l) ⁺ .

[00266] Step-5: tert-Butyl (2-(4-(6-cyano-l-phenethyl-lH-indole-2-carboxamido)piperidin -l- yl)ethyl)carbamate

[00267] The product of step-4 of example-lO (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-l of example-l. LCMS: 516.3 (M+l) ⁺ .

[00268] Step-6: Ethyl 2-((l-(2-aminoethyl)piperidin-4-yl)carbamoyl)-l-phenethyl-lH -indole- 6-carbimidate

[00269] 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-l . LCMS : 462.3 (M+l) ⁺ .

[00270] Step-7: N-(l-(2-aminoethyl)piperidin-4-yl)-6-carbamimidoyl-l-pheneth yl-lH-indole- 2-carboxamide

[00271] The product of step-6 of example-lO (105 mg, 0.22 mmol) was treated with 50 mL of ethanolic-ML to afford 43 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 433.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-29

[00272] N-(l-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-l-phenet hyl-lH-indole-2- carboxamide

[00273] Step-l : tert-Butyl (3-(4-(6-cyano-l-phenethyl-lH-indole-2-carboxamido)piperidin -l- yl)propyl)carbamate

[00274] The product of step-4 of example-lO (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-l of example-l . LCMS: 530.3 (M+l) ⁺ .

[00275] Step-2: Ethyl 2-((l-(3-aminopropyl)piperidin-4-yl)carbamoyl)-l-phenethyl-l H- indole-6-carbimidate

[00276] The product of step-l of example-l 1 (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-l . LCMS : 476.3 (M+l) ⁺ .

[00277] Step-3 : N-(l-(3-Aminopropyl)piperidin-4-yl)-6-carbamimidoyl-l-phenet hyl-lH- indole-2-carboxamide

[00278] The product of step-2 of example-l 1 (250 mg, 0.55 mmol) was treated with 50 mL of ethanol ic-NFL to afford 135 mg of the title compound following the procedure described in step- 5 of example-l. LCMS: 447.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-33

[00279] 3-Amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(4-( trifluoromethyl)- phenethyl)-lH-indole-2-carboxamide

[00280] Step-l : tert-Butyl ((lr,4r)-4-(6-cyano-3-nitro-l-(4-(trifluoromethyl)phenethyl) -lH- indole-2-carboxamido)cyclohexyl)carbamate

[00281] The product of step-l of example-9 (580 mg, 1.35 mmol) and l-(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-l of example-l. LCMS : 600.2 (M+l) ⁺ .

[00282] Step-2: tert-Butyl ((lr,4r)-4-(3-amino-6-cyano-l-(4-(trifluoromethyl)phenethyl) -lH- indole-2-carboxamido)cyclohexyl)carbamate

[00283] The product of step-l of example-l2 (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+l) ⁺ .

[00284] Step-3 : Ethyl-3-amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(4-

(trifluoromethyl)-phenethyl)-lH-indole-6-carbimidate

[00285] The product of step-2 of example-l2 (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-l. LCMS : 516.2 (M+l) ⁺ . [00286] Step-4: 3-Amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(4-

(trifluoromethyl)-phenethyl)-lH-indole-2-carboxamide

[00287] The product of step-3 of example-l2 (180 mg, 0.34 mmol) was treated with 50 mL of ethanol ic-NFL to afford 65 mg of the title compound following the procedure described in step-5 of example-l. LCMS : 487.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-36

[00288] N-((lr,4r)-4-Aminocyclohexyl)-l-((3-(3-aminopropanamido)phen yl)sulfonyl)-6- carbamimidoyl-lH-indole-2-carboxamide

[00289] Step-l : Ethyl 6-cyano-l-((3-nitrophenyl)sulfonyl)-lH-indole-2-carboxylate

[00290] Ethyl 6-cyano-lH-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-l of example-l. LCMS: 401.1 (M+l) ⁺ .

[00291] Step-2: 6-Cyano-l-((3-nitrophenyl)sulfonyl)-lH-indole-2-carboxylic acid

[00292] The product of step-l of example-l3 (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-l. LCMS: 372.1 (M+l) ⁺ .

[00293] Step-3: tert-Butyl ((lr,4r)-4-(6-cyano-l-((3-nitrophenyl)sulfonyl)-lH-indole-2- carboxamido)-cyclohexyl)carbamate

[00294] The product of step-2 of example-l3 (400 mg, 1.07 mmol) and tert-butyl ((lr,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-l. LCMS: 568.2 (M+l) ⁺ .

[00295] Step-4: tert-Butyl ((lr,4r)-4-(l-((3-aminophenyl)sulfonyl)-6-cyano-lH-indole-2- carboxamido)-cyclohexyl)carbamate [00296] The product of step-3 of example-l3 (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+l) ⁺ .

[00297] Step-5: tert-Butyl ((lr,4r)-4-(l-((3-(3-(tert-butyl carbamate)- propanamido)phenyl)sulfonyl)-6-cyano-lH-indole-2-carboxamido )cyclohexyl)carbamate

[00298] The product of step-4 of example-l3 (200 mg, 0.37 mmol) and 3-((tert- butoxycarbonyl)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-l . LCMS: 709.3 (M+l) ⁺ .

[00299] Step-6: Ethyl-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-((3-(3- aminopropanamido)phenyl)-sulfonyl)-lH-indole-6-carbimidate

[00300] The product of step-5 of example-l (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-l . LCMS: 555.2 (M+l) ⁺ .

[00301] Step-7: N-((lr,4r)-4-Aminocyclohexyl)-l-((3-(3- aminopropanamido)phenyl)sulfonyl)-6-carbamimidoyl-lH-indole- 2-carboxamide

[00302] The product of step-6 of example-l3 (85 mg, 0.15 mmol) was treated with 50 mL of ethanolic-NLb to afford 18 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 526.2 (M+l) ⁺ .

General synthetic scheme 2:

X = Br or Cl; PG = optional protecting group; = optional step only when PG is present.

Example 14: Synthesis of compound 1-40

[00303] 6-Carbamimidoyl-l-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluorom ethyl)phenyl)-lH- indole-2-carboxamide

[00304] Step-l : Ethyl 6-cyano-l-(2-(phenylsulfonyl)ethyl)-lH-indole-2-carboxylate

[00305] Ethyl 6 -cyano-lH-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-l of example- 1. LCMS : 383.1 (M+l) ⁺ .

[00306] Step-2: 6-Cyano-l-(2-(phenylsulfonyl)ethyl)-lH-indole-2-carboxylic acid

[00307] The product of step-l of example-l4 (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+l) ⁺ .

[00308] Step-3 : 6-Cyano-l-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluoromethyl)ph enyl)-lH- indole-2-carboxamide

[00309] The product of step-2 of example-l4 (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-l . LCMS : 498.1 (M+l) ⁺ .

[00310] Step-4: 6-(N'-hydroxycarbamimidoyl)-l-(2-(phenylsulfonyl)ethyl)-N-(3 -

(trifluoromethyl)-phenyl)-lH-indole-2-carboxamide

[00311] The product of step-3 of example-l4 (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+l) ⁺ .

[00312] Step-5: 6-(N'-acetoxycarbamimidoyl)-l-(2-(phenylsulfonyl)ethyl)-N-(3 -

(trifluoromethyl)phenyl)-lH-indole-2-carboxamide

[00313] The product of step-4 of example-l4 (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+l) ⁺ .

[00314] Step-6: 6-Carbamimidoyl-l-(2-(phenylsulfonyl)ethyl)-N-(3-(trifluorom ethyl)phenyl)- lH-indole-2-carboxamide

[00315] The product of step-5 of example-l4 (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+l) ⁺ , ¾ NMR (300MHz, DMSO- d ₆ ): d 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).

[00316] 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. [00317] Table-4:

[00318] N-((lr,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-3-nitro-l-(2- (phenylsulfonyl)ethyl)-lH-indole-2-carboxamide

[00319] Step-l : tert-Butyl-((lr,4r)-4-(6-cyano-3-nitro-l-(2-(phenylsulfonyl) ethyl)-lH-indole-

2-carboxamido)- cyclohexyl)carbamate

[00320] The product of step-l 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-l of example-l . LCMS : 596.2 (M+l) ⁺ .

[00321] Step-2: Ethyl-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-3-nitro-l-(2-

(phenylsulfonyl)ethyl)-lH-indole-6-carbimidate

[00322] The product of step-l 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-l . LCMS : 542.2 (M+l) ⁺ . [00323] Step-3 : N-((lr,4r)-4-Aminocyclohexyl)-6-carbamimidoyl-3-nitro-l-(2-

(phenylsulfonyl)ethyl)-lH-indole-2-carboxamide

[00324] The product of step-2 of example- 15 (250 mg, 0.46 mmol) was treated with 50 mL of ethanol ic-NFL to afford 135 mg of the title compound following the procedure described in step- 5 of example-l . LCMS: 513.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-56

[00325] 3-Amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(2- (phenylsulfonyl)ethyl)-lH-indole-2-carboxamide

[00326] Step-l : tert-Butyl ((lr,4r)-4-(3-amino-6-cyano-l-(2-(phenylsulfonyl)ethyl)-lH- indole-2-carboxamido)cyclohexyl)carbamate

[00327] The product of step-l of example-l5 (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+l) ⁺ .

[00328] Step-2: Ethyl 3-amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(2-

(phenylsulfonyl)ethyl)-lH-indole-6-carbimidate

[00329] The product of step-l of example-l6 (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-l . LCMS : 512.2 (M+l) ⁺ .

[00330] Step-3 : tert-Butyl ((lr,4r)-4-(3-amino-6-carbamimidoyl-l-(2-(phenylsulfonyl)eth yl)- lH-indole-2-carboxamido)cyclohexyl)carbamate

[00331] The product of step-2 of example-l6 (105 mg, 0.20 mmol) was treated with 30 mL of ethanolic-NLL to afford 43 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 483.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-17

[00332] Ethyl (2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'- hydroxycarbamimidoyl)-l-(2-(phenylsulfonyl)ethyl)-lH-indol-3 -yl)carbamate

[00333] Step-l : tert-Butyl ((lr,4r)-4-(3-(ethylcarbamate)-6-cyano-l-(2-(phenylsulfonyl) ethyl)- lH-indole-2-carboxamido)cyclohexyl)carbamate

[00334] The product of step-l of example-l6 (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-l of example- 1. LCMS : 638.3 (M+l) ⁺ .

[00335] Step-2: tert-Butyl ((lr,4r)-4-(3-(ethylcarbamate)-6-((Z)-N'-hydroxycarbamimidoy l)-l-

(2-(phenylsulfonyl)-ethyl)-lH-indole-2-carboxamido)cycloh exyl)carbamate

[00336] The product of step-l of example-l7 (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-l4. LCMS : 671.3 (M+l) ⁺ .

[00337] Step-3 : Ethyl (2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'- hydroxycarbamimidoyl)-l-(2-(phenylsulfonyl)ethyl)-lH-indol-3 -yl)carbamate

[00338] The product of step-2 of example-l7 (3 l5mg, 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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), 1 1.11 (brs, 1H), 12.80 (brs, 1H); HPLC: 90.09% (Retention Time= 4.488 min).

Example 18: Synthesis of compound 1-58 [00339] 3-Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-l-(2-(phenylsul fonyl)ethyl)-lH- indole-2-carboxamide

[00340] Step-l : 6-Cyano-N-(cyclohexylmethyl)-lH-indole-2-carboxamide

[00341] The product of step-l 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-l. LCMS : 282.2 (M+l) ⁺ .

[00342] Step-2: 6-Cyano-N-(cyclohexylmethyl)-3-nitro-lH-indole-2-carboxamide

[00343] The product of step-l of example-l8 (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-l of example-9. LCMS: 327.1 (M+l) ⁺ .

[00344] Step-3 : 6-Cyano-N-(cyclohexylmethyl)-3-nitro-l-(2-(phenylsulfonyl)et hyl)-lH- indole-2-carboxamide

[00345] 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-l of example-l. LCMS : 495.2 (M+l) ⁺ .

[00346] Step-4: 3-Amino-6-cyano-N-(cyclohexylmethyl)-l-(2-(phenylsulfonyl)et hyl)-lH- indole-2-carboxamide

[00347] The product of step-3 of example-l8 (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+l) ⁺ .

[00348] Step-5: Ethyl 3-amino-2-((cyclohexylmethyl)carbamoyl)-l-(2-(phenylsulfonyl )ethyl)- lH-indole-6-carbimidate

[00349] The product of step-4 of example-l8 (190 mg, 0.40 mmol) was treated with ethanolic- HC1 to afford 133 mg of the title compound following the procedure described in step-4 of example-l. LCMS : 511.2 (M+l) ⁺ . [00350] Step-6: 3 -Amino-6-carbamimidoyl-N-(cyclohexylmethyl)-l-(2-

(phenylsulfonyl)ethyl)-lH-indole-2-carboxamide

[00351] The product of step-5 of example-l8 (125 mg, 0.24 mmol) was treated with ethanolic- NFl·, to afford 38 mg of the title compound following the procedure described in step-5 of example- 1. LCMS: 482.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-59

[00352] 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-lH- indole-2- carboxamide

[00353] Step-l : Ethyl l-(4-carbamoylbenzyl)-6-cyano-lH-indole-2-carboxylate

[00354] Ethyl 6-cyano-lH-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-l of example 1. LCMS : 348.1 (M+l) ⁺ .

[00355] Step-2: l-(4-Carbamoylbenzyl)-6-cyano-lH-indole-2-carboxylic acid

[00356] The product of step-l 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+l) ⁺ .

[00357] Step-3 : l-(4-carbamoylbenzyl)-6-cyano-N-(4-fluorophenyl)-lH-indole-2 - carboxamide

[00358] 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+l) ⁺ .

[00359] Step-4: l-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-6-(N'-hydroxycarbam imidoyl)- lH-indole-2-carboxamide [00360] 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+l) ⁺ .

[00361] Step-5: 6-(N'-acetoxycarbamimidoyl)-l-(4-carbamoylbenzyl)-N-(4-fluor ophenyl)-lH- indole-2-carboxamide

[00362] 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+l) ⁺ .

[00363] Step-6: 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-lH- indole-2- carboxamide

[00364] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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).

[00365] 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.

[00366] Table -5:

[00367] Table-6:

Example 20: Synthesis of compound 1-103.

[00368] 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-methyl-N-(l-methylpy rrolidin-3-yl)- lH-indole-2-carboxamide

[00369] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-methyl-N-(l-methylpyrrolidin -3-yl)-lH- indole-2-carboxamide

[00370] The product of step-2 of example 19 (500 mg, 1.56 mmol) and N, l-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+l) ⁺ .

[00371] Step-2: l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-methyl-N -(l- methylpyrrolidin-3-yl)-lH-indole-2-carboxamide

[00372] The product of step-l 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+l) ⁺ .

[00373] Step-3 : 6-(N'-Acetoxycarbamimidoyl)-l-(4-carbamoylbenzyl)-N-methyl-N -(l- methylpyrrolidin-3-yl)-lH-indole-2-carboxamide

[00374] 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+l) ⁺ .

[00375] Step-4: 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(4-fluorophenyl)-lH- indole-2- carboxamide

[00376] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00377] l-(4-Carbamoylbenzyl)-N ² -(3-(pyrrolidin-l-yl)phenyl)-lH-indole-2,6- dicarboxamide

[00378] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-l-yl)phenyl)- lH-indole-2- carboxamide

[00379] The product of step-2 of example-l9 (500 mg, 1.56 mmol) and 3-(pyrrolidin-l- 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-l . LCMS: 464.2 (M+l) ⁺ .

[00380] Step-2 : 1 -(4-Carbamoylbenzyl)-N ² -(3 -(pyrrolidin- 1 -yl)phenyl)- lH-indole-2,6- dicarboxamide

[00381] To a solution of the product of step-l of example-2l (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 HC1. 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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).

[00382] General synthetic scheme-2A:

R,’ is an appropriate partial substituent of R4; R ₄ is as defined in formula (I)

Example 22: Synthesis of compound 1-118

[00383] Methyl ((l-(4-carbamoylbenzyl)-2-((4-(pyrrolidin-l-yl)phenyl)carbam oyl)-lH- indol-6-yl)(imino)methyl)carbamate

[00384] Step-l : Methyl ((l-(4-carbamoylbenzyl)-2-((4-(pyrrolidin-l-yl)phenyl)carbam oyl)- lH-indol-6-yl)(imino)methyl)carbamate

[00385] Compound 1-90 (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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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).

[00386] 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.

[00387] Table -7:

Example 23: Synthesis of compound 1-135

[00388] l-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbam imidoyl)-N-(3- (pyrrolidin-l-yl)phenyl)-lH-indole-2-carboxamide

[00389] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyrrolidin-l-yl)phenyl)- lH-indole-2- carboxamide

[00390] The product of step-2 of example-l9 (500 mg, 1.56 mmol) and 3-(pyrrolidin-l- 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-l . LCMS: 464.2 (M+l) ⁺ .

[00391] Step-2: l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrr olidin-l- yl)phenyl)-lH-indole-2-carboxamide

[00392] The product of step-l 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-l4. LCMS: 497.2 (M+l) ⁺ .

[00393] Step-3 : l-(4-Carbamoylbenzyl)-6-(N'-(2-(dimethylamino)acetoxy)carbam imidoyl)-N-

(3-(pyrrolidin-l-yl)phenyl)-lH-indole-2-carboxamide

[00394] The solution of N,N-dimethyl glycine (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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-136

[00395] l-(4-Carbamoylbenzyl)-N ² -(3-(pyridin-2-yl)phenyl)-lH-indole-2,6- dicarboxamide

[00396] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(3-(pyridin-2-yl)phenyl)-lH- indole-2- carboxamide

[00397] The product of step-2 of example-l9 (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-l . LCMS: 472.2 (M+l) ⁺ .

[00398] Step-2: l-(4-carbamoylbenzyl)-N ² -(3-(pyridin-2-yl)phenyl)-lH-indole-2,6- dicarboxamide

[00399] The product of step-l 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-2l . LCMS: 490.2 (M+l) ⁺ , ¾ NMK (300MHz, DMSO- de): d 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

[00400] l-(4-Carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrr olidin-l- yl)phenyl)-lH-indole-2-carboxamide

[00401] Step-l : l-(4-Carbamoylbenzyl)-6-(N'-methoxycarbamimidoyl)-N-(3-(pyrr olidin-l- yl)phenyl)-lH-indole-2-carboxamide

[00402] 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+l) ⁺ , ¾ NMR (300MHz,

DMSO-de): d 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

[00403] (R)-tert-butyl (l-(((amino(l-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-l-yl)phe nyl)- carbamoyl)-lH-indol-6-yl)methylene)amino)oxy)-3-methyl-l-oxo butan-2-yl)carbamate

[00404] Step-l : (R)-tert-butyl (l-(((amino(l-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-l- yl)phenyl)- carbamoyl)- lH-indol-6-yl)methylene)amino)oxy)-3-methyl-l -ox obutan-2- yl)carbamate

[00405] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-158 [00406] (S)-tert-butyl (l-(((amino(l-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-l- yl)phenyl)carbamoyl)-lH-indol-6-yl)methylene)amino)oxy)-l-ox opropan-2-yl)carbamate

[00407] Step-l : (S)-tert-butyl (l-(((amino(l-(4-carbamoylbenzyl)-2-((3-(pyrrolidin-l- yl)phenyl)- carbamoyl)- lH-indol-6-yl)methylene)amino)oxy)-l -ox opropan-2-yl)carbamate

[00408] 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 1-183

[00409] Ethyl ((l-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-l-yl)pyridin-2-yl) carbamoyl)- lH-indol-6-yl)(imino)methyl)carbamate

[00410] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(6-(pyrrolidin-l-yl)pyridin- 2-yl)-lH- indole-2-carboxamide

[00411] The product of step-2 of example-l9 (950 mg, 2.97 mmol) and 6-(pyrrolidin-l- 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-l. LCMS: 465.2 (M+l) ⁺ .

[00412] Step-2: l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(6-(pyrr olidin-l- yl)pyridin-2-yl)-lH-indole-2-carboxamide

[00413] The product of step-l 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-l4. LCMS: 498.2 (M+l) ⁺ .

[00414] Step-3 : 6-(N'-Acetoxycarbamimidoyl)-l-(4-carbamoylbenzyl)-N-(6-(pyrr olidin-l- yl)pyridin-2-yl)-lH-indole-2-carboxamide

[00415] 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-l4. LCMS: 540.2 (M+l) ⁺ .

[00416] Step-4: 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(6-(pyrrolidin-l-yl) pyridin-2-yl)- lH-indole-2-carboxamide

[00417] 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-l4. LCMS: 482.2 (M+l) ⁺ .

[00418] Step-5: Ethyl ((l-(4-carbamoylbenzyl)-2-((6-(pyrrolidin-l-yl)pyridin-2- yl)carbamoyl)-lH-indol-6-yl)(imino)methyl)carbamate

[00419] 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-l of example 22. LCMS: 554.2 (M+l) ⁺ , ¹ H NMR (300MHz, DMSO- de): d 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 1-199

[00420] 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-l -yl)-lH- indole-2-carboxamide

[00421] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(3-((2- methoxyethoxy)methoxy)adamantan-l-yl)-lH-indole-2-carboxamid e [00422] The product of step-2 of example-l9 (800 mg, 2.5 mmol) and 3-((2- methoxyethoxy)methoxy)adamantan-l -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+l) ⁺ .

[00423] Step-2: l-(4-Carbamoylbenzyl)-6-cyano-N-(3-hydroxyadamantan-l-yl)-lH -indole-2- carboxamide

[00424] The product of step-l 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+l) ⁺ .

[00425] Step-3 : l-(4-Carbamoylbenzyl)-6-cyano-N-(3-fluoroadamantan-l-yl)-lH- indole-2- carboxamide

[00426] 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+l) ⁺ .

[00427] Step-4: l-(4-carbamoylbenzyl)-N-(3-fluoroadamantan-l-yl)-6-(N'- hydroxycarbamimidoyl)-lH-indole-2-carboxamide

[00428] 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-l4. LCMS: 504.2 (M+l) ⁺ .

[00429] Step-5: 6-(N'-acetoxycarbamimidoyl)-l-(4-carbamoylbenzyl)-N-(3-fluor oadamantan- l-yl)-lH-indole-2-carboxamide

[00430] 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-l4. LCMS: 546.2 (M+l) ⁺ .

[00431] Step-6: 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-((lr,3r)-3-((2- methoxyethoxy)methoxy)-adamantan- 1 -yl)- lH-indole-2-carboxamide

[00432] 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-l4. LCMS: 488.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): 5 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.

[00433] 3-Amino-6-carbamimidoyl-l-(4-carbamoylbenzyl)-N-(cyclohexylm ethyl)-lH- indole-2-carboxamide

[00434] Step-l : l-(4-carbamoylbenzyl)-6-cyano-N-( cyclohexylmethyl)-lH-indole-2- carboxamide

[00435] The product of step-2 of example-l8 (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-l of example-l. LCMS: 413.1 (M+l) ⁺ .

[00436] Step-2: l-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'-hydroxycarb amimidoyl)- 3 -nitro- 1 H-indol e-2 -carb oxami de

[00437] The product of step-l 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-l4. LCMS: 493.2 (M+l) ⁺ .

[00438] Step-3 : 6-(N'-acetoxycarbamimidoyl)-l-(4-carbamoylbenzyl)-N-(cyclohe xylmethyl)- 3 -nitro- 1 H-indol e-2 -carb oxami de

[00439] 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-l4. LCMS: 535.2 (M+l) ⁺ .

[00440] Step-4: 3 -Amino-6-carbamimidoyl-l-(4-carbamoylbenzyl)-N-(cyclohexylme thyl)- lH-indole-2-carboxamide

[00441] 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-l4. LCMS: 447.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00442] 3-Amino-l-(4-carbamoylbenzyl)-N ² -(cyclohexylmethyl)-lH-indole-2,6- dicarboxamide

[00443] Step-l : l-(4-Carbamoylbenzyl)-N2-(cyclohexylmethyl)-3-nitro-lH-indol e-2,6- dicarboxamide

[00444] The product of step-l of example-8l (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-2l . LCMS: 478.2 (M+l) ⁺ .

[00445] Step-2: 3-amino-l-(4-carbamoylbenzyl)-N ² -(cyclohexylmethyl)-lH-indole-2,6- dicarboxamide

[00446] The product of step-l of example-8l (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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-212

[00447] 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-3 -hydroxy-lH- indole-2-carboxamide

[00448] Step-l : Ethyl 3-acetoxy-6-cyano-lH-indole-2-carboxylate

[00449] In a sealed tube ethyl 6-cyano-lH-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+l) ⁺ .

[00450] Step-2: Ethyl 3-acetoxy-l-(4-carbamoylbenzyl)-6-cyano-lH-indole-2-carboxyl ate

[00451] The product of step-l of example-2l2 (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-l of example-l . LCMS: 406.1 (M+l) ⁺ .

[00452]

[00453] Step-3 : Ethyl l-(4-carbamoylbenzyl)-6-cyano-3-hydroxy-lH-indole-2-carboxyl ate

[00454] 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+l) ⁺ .

[00455] Step-4: Ethyl l-(4-carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-lH-in dole- 2-carboxylate

[00456] The product of step-3 of example-32 (540 mg, 1.48 mmol), dissolved in 50 mL of tetrahydrofuran, was added l-(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: ethyl acetate (8:2) to afford 610 mg of the title compound. LCMS: 484.2 (M+l) ⁺ .

[00457] Step-5: l-(4-Carbamoylbenzyl)-6-cyano-3-((4-methoxybenzyl)oxy)-lH-in dole-2- carboxylic acid

[00458] 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-l. LCMS: 456.2 (M+l) ⁺ .

[00459] Step-6: l-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-cyano-3-((4- methoxybenzyl)oxy)-lH-indole-2-carboxamide

[00460] 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-l. LCMS: 551.3 (M+l) ⁺ .

[00461] Step-7: l-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'- hydroxycarbamimidoyl)-3-((4-methoxybenzyl)oxy)-lH-indole-2-c arboxamide

[00462] 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-l4. LCMS: 584.3 (M+l) ⁺ .

[00463] Step-8 : 6-(N'-acetoxycarbamimidoyl)- 1 -(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-

3-((4-methoxybenzyl)oxy)-lH-indole-2-carboxamide

[00464] 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-l4. LCMS: 626.3 (M+l) ⁺ .

[00465] Step-9: 6-Carbamimidoyl- 1 -(4-carbam oylbenzyl)-N-(cy cl ohexylmethyl)-3 -hydroxy- lH-indole-2-carboxamide

[00466] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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:

Example 33: Synthesis of compound 213

[00467] 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexyl methyl)-lH- indole-2-carboxamide

[00468] Step-l : Ethyl 3-chloro-6-cyano-lH-indole-2-carboxylate

[00469] Ethyl 6-cyano-lH-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: ethyl acetate (9: 1) to afford 820 mg of the title compound. LCMS: 249.1 (M+l) ⁺ .

[00470] Step-2: Ethyl 6-carbamimidoyl-l-(4-carbamoylbenzyl)-3-chloro-lH-indole-2- carboxylate

[00471] The product of step-l 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-l of example-l . LCMS: 399.1 (M+l) ⁺ .

[00472] Step-3 : 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-3-chloro-lH-indole-2-c arboxylic acid

[00473] 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-l . LCMS: 371.1 (M+l) ⁺ .

[00474] Step-4: l-(4-Carbam oylbenzyl)-3-chloro-6-cyano-N-(cycl ohexylmethyl)-lH-indole-2- carboxamide

[00475] 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-l . LCMS: 449.2 (M+l) ⁺ .

[00476] Step-5: Ethyl l-(4-carbamoylbenzyl)-3-chloro-2-((cyclohexylmethyl)carbamoy l)-lH- indole-6-carbimidate [00477] 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+l) ⁺ .

[00478] Step-6: 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-3-chloro-N-(cyclohexyl methyl)- lH-indole-2-carboxamide

[00479] The product of step-5 of example-33 (385 mg, 0.77 mmol) was treated with 50 mL of ethanolic-ML to afford 75 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 466.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 0.84 (m, 2H),L07 (m, 3H), 1.56 (m, 6H), 3.05 (m, 2H), 5.75 (s, 2H),7. l2 (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).

[00480] 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.

[00481] Table-8:

[00482] 6-Carbamimidoyl-N-(cyclohexylmethyl)-l-(4-(methylcarbamoyl)b enzyl)-lH- indole-2-carboxamide

[00483] Step-l : Methyl 4-((6-cyano-2-((cyclohexylmethyl)carbamoyl)-lH-indol-l- yl)methyl)benzoate

[00484] The product of step-l of example-l8 (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-l of example-l . LCMS: 430.2 (M+l) ⁺ .

[00485] Step-2: 4-((6-Cyano-2-((cyclohexylmethyl)carbamoyl)-lH-indol-l-yl)me thyl)benzoic acid

[00486] The product of step-l 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-l . LCMS: 417.2 (M+l) ⁺ .

[00487] Step-3 : 6-Cyano-N-(cyclohexylmethyl)-l-(4-(methylcarbamoyl)benzyl)-l H-indole-2- carboxamide [00488] 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-l . LCMS: 429.2 (M+l) ⁺ .

[00489] Step-4: Ethyl 2-((cyclohexylmethyl)carbamoyl)-l-(4-(methylcarbamoyl)benzyl )-lH- indole-6-carbimidate

[00490] 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-l . LCMS: 475.3 (M+l) ⁺ .

[00491] Step-5: 6-Carbamimidoyl-N-(cyclohexylmethyl)-l-(4-(methylcarbamoyl)b enzyl)-lH- indole-2-carboxamide

[00492] The product of step-4 of example-34 (265 mg, 0.55 mmol) was treated with 30 mL of ethanolic-NLL to afford 80 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 446.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00493] 6-Carbamimidoyl-N-(cyclohexylmethyl)-l-(4-(dimethylcarbamoyl )benzyl)-lH- indole-2-carboxamide

[00494] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-217

[00495] 6-Carbamimidoyl-N-(cyclohexylmethyl)-l-(4-(cyclopropylcarbam oyl)benzyl)- lH-indole-2-carboxamide

[00496] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 0.49 (m, 2H), 0.64 (m, 2H), 0.84 (m, 2H), 1.11 (m, 3H), 1.61 (m, 6H), 2.75 (m,lH), 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 1-218

[00497] 6-Carbamimidoyl-l-(4-(dimethylcarbamoyl)benzyl)-N-(4-methylc yclohexyl)-lH- indole-2-carboxamide

[00498] Step-l : 6-Cyano-N-(4-methylcyclohexyl)-lH-indole-2-carboxamide

[00499] The product of step-l 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+l) ⁺ .

[00500] Step-2: Methyl 4-((6-cyano-2-((4-m ethyl cy cl ohexyl)carbamoyl)-lH-indol-l- yl)methyl)benzoate

[00501] The product of step-l 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-l of example-l. LCMS: 430.2 (M+l) ⁺ .

[00502] Step-3 : 4-((6-Cyano-2-((4-methylcyclohexyl)carbamoyl)-lH-indol-l- yl)methyl)benzoic acid

[00503] 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-l. LCMS: 416.2 (M+l) ⁺ .

[00504] Step-4: 6-Cyano-l -(4-(dimethylcarbamoyl)benzyl)-N-(4-methyl cyclohexyl)- 1H- indole-2-carboxamide

[00505] 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-l. LCMS: 443.2 (M+l) ⁺ .

[00506] Step-5: Ethyl l-(4-(dimethylcarbamoyl)benzyl)-2-((4-methylcyclohexyl)carba moyl)- lH-indole-6-carbimidate

[00507] 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-l. LCMS: 489.3 (M+l) ⁺ .

[00508] Step-6: 6-Carbamimidoyl-l-(4-(dimethylcarbamoyl)benzyl)-N-(4-methyl cyclohexyl)- lH-indole-2-carboxamide

[00509] The product of step-5 of example 37 (160 mg, 0.32 mmol) was treated with 30 mL of ethanolic-NLL to afford 35 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 460.3 (M+l) ⁺ , ¹ HNMR (300MHz, DMSO-de): d 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 1-219

[00510] 6-Carbamimidoyl-l-(4-(cyclopropylcarbamoyl)benzyl)-N-(4-meth ylcyclohexyl)- lH-indole-2-carboxamide

[00511] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00512] 6-Carbamimidoyl-l-(4-(methylcarbamoyl)benzyl)-N-(4-methylcyc lohexyl)-lH- indole-2-carboxamide

[00513] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-221

[00514] 6-Carbamimidoyl-l-(4-(ethylcarbamoyl)benzyl)-N-(4-methylcycl ohexyl)-lH- indole-2-carboxamide

[00515] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00516] 6-Carbamimidoyl-N-(cyclohexylmethyl)-l-(4-((2- hydroxyethyl)carbamoyl)benzyl)-lH-indole-2-carboxamide

[00517] 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+l) ⁺ , ¹ H NMR (300MHz, DMSO-de): d 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 1-223

[00518] 6-Carbamimidoyl-l-(4-((2-hydroxyethyl)carbamoyl)benzyl)-N-(4 - methylcyclohexyl)-lH-indole-2-carboxamide

[00519] 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+l) ⁺ , ¹ H NMR (300MHz, DMSO-de): d 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 1-224

[00520] l-(4-((2-Aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(4- methylcyclohexyl)-lH-indole-2-carboxamide

[00521] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-225

[00522] l-(4-((2-Aminoethyl)carbamoyl)benzyl)-6-carbamimidoyl-N-(cyc lohexylmethyl)- lH-indole-2-carboxamide

[00523] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-232

[00524] 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N -methyl-lH- indole-2-carboxamide

[00525] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(cyclohexylmethyl)-N-methyl- lH-indole-

2-carboxamide

[00526] 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+l) ⁺ .

[00527] Step-2: l-(4-Carbamoylbenzyl)-N-(cyclohexylmethyl)-6-(N'- hydroxycarbamimidoyl)-N-methyl-lH-indole-2-carboxamide

[00528] The product of step-l 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+l) ⁺ .

[00529] Step-3 : 6-(N'-Acetoxycarbamimidoyl)-l-(4-carbamoylbenzyl)-N-(cyclohe xylmethyl)- N-methyl-lH-indole-2-carboxamide

[00530] 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+l) ⁺ .

[00531] Step-4: 6-Carbamimidoyl-l-(4-carbamoylbenzyl)-N-(cyclohexylmethyl)-N -methyl- lH-indole-2-carboxamide

[00532] 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+l) ⁺ , ¾NMR (300MHz, DMSO-de): d 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, lH),9.05 (brs, 2H), 9.24 (brs, 2H); HPLC: 96.43% (Retention Time= 3.663 min).

Example 46: Synthesis of compound 1-226

[00533] 6-Carbamimidoyl-l-(4-carbamoyl-phenethyl)-N-(cyclohexylmethy l)-lH-indole- 2-carboxamide

The synthesis of compound in Example 1-226 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+l)+ ¾ NMR (300MHz, DMSO-de): d 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 1-227

[00534] 6-Carbamimidoyl-l-(2-Fluoro-4-carbamoyl-benzyl)-N-(cyclohexy lmethyl)-lH- indole-2-carboxamide

The synthesis of compound in Example 1-227 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 (MTl)+ 'H NMR (300MHz, DMSO-de): d 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 1-228

[00535] 6-Carbamimidoyl-l-(2-Chloro-4-carbamoyl-benzyl)-N-(cyclohexy lmethyl)-lH- indole-2-carboxamide

The synthesis of compound in Example 1-228 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 corresponding 2 chloro derivative. LCMS: 466.2 (M+l)+ ¾ NMR (300MHz, DMSO-de): d 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 1-229

[00536] 6-Carbamimidoyl-l-(3-Chloro-4-carbamoyl-benzyl)-N-(cyclohexy lmethyl)-lH- indole-2-carboxamide

The synthesis of compound in Example 1-229 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 corresponding 3 chloro derivative. LCMS: 466.2 (M+l)+ ¾ NMR (300MHz, DMSO-de): d d 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 1-230

[00537] 6-Carbamimidoyl-l-(3-carbamoylbenzyl)-N-(4-difluorocyclohexy l)-lH-indole-2- carboxamide

The synthesis of compound in Example 1-230 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 corresponding 3 carbamoyl derivative LCMS: 454.2 (M+l)+ 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 1-241

[00538] 6-Carbamimidoyl-N-((lr,4r)-4-guanidinocyclohexyl)-l-(4-pheno xybenzyl)-lH- indole-2-carboxamide

[00539] Step-l : Ethyl 6-cyano-l-(4-phenoxybenzyl)-lH-indole-2-carboxylate

[00540] Ethyl 6-cyano-lH-indole-2-carboxylate (3.2 g, 14.95 mmol) and l-(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-l of example-l . LCMS: 397.2 (M+l) ⁺ .

[00541] Step-2 : 6-Cyano- 1 -((4'-ethoxy-[ 1 , 1 '-biphenyl] -3 -yl)methyl)- lH-indole-2-carboxylic acid

[00542] The product of step-l of example-5 ! (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-l. LCMS: 367.2 (M+l) ⁺ .

[00543] Step-3: tert-Butyl ((lr,4r)-4-(6-cyano-l-(4-phenoxybenzyl)-lH-indole-2- carb ox ami do) cy cl ohexyl )carb am ate

[00544] The product of step-2 of example-51 (650 mg, 1.77 mmol) and tert-butyl ((lr,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-l. LCMS: 565.3 (M+l) ⁺ .

[00545] Step-4: N-((lr,4r)-4-Aminocyclohexyl)-6-cyano-l-(4-phenoxybenzyl)-lH -indole-2- carboxamide

[00546] 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+l) ⁺ .

[00547] Step-5: 6-Cyano-N-((lr,4r)-4-guanidinocyclohexyl)-l-(4-phenoxybenzyl )-lH-indole- 2-carboxamide

[00548] The product of step-4 of example-51 (640 mg, 1.37 mmol), dissolved in 10 mL ofN,N- dimethylformamide, was treated with lH-pyrazole-l-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+l) ⁺ .

[00549] Step-6: Ethyl 2-(((lr,4r)-4-guanidinocyclohexyl)carbamoyl)-l-(4-phenoxyben zyl)- lH-indole-6-carbimidate

[00550] 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-l. LCMS: 553.3 (M+l) ⁺ .

[00551] Step-7: 6-Carbamimidoyl-N-((lr,4r)-4-guanidinocyclohexyl)-l-(4-pheno xybenzyl)- lH-indole-2-carboxamide

[00552] The product of step-6 of example-51 (150 mg, 0.28 mmol) was treated with 30 mL of ethanolic-ML to afford 80 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 524.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 [00553] N-((lr,4r)-4-(3-Aminopropanamido)cyclohexyl)-6-carbamimidoyl -l-(4- phenoxybenzyl)-lH-indole-2-carboxamide

[00554] Step-l : tert-Butyl (3-(((lr,4r)-4-(6-cyano-l-(4-phenoxybenzyl)-lH-indole-2- carboxamido)-cyclohexyl)-amino)-3-oxopropyl)carbamate

[00555] 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-l . LCMS: 636.3 (M+l) ⁺ .

[00556] Step-2: Ethyl 2-(((lr,4r)-4-(3-aminopropanamido)cyclohexyl)carbamoyl)-l-(4 - phenoxybenzyl)-lH-indole-6-carbimidate

[00557] The product of step-l 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+l) ⁺ .

[00558] Step-3 : N-((lr,4r)-4-(3-Aminopropanamido)cyclohexyl)-6-carbamimidoyl -l-(4- phenoxybenzyl)-lH-indole-2-carboxamide

[00559] The product of step-2 of example 52 (195 mg, 0.33 mmol) was treated with 30 mL of ethanolic-NLL to afford 62 mg of the title compound following the procedure described in step-5 of example 1. LCMS: 553.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00560] 3-amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(4-p henoxybenzyl)- lH-indole-2-carboxamide

[00561] Step-l : tert-Butyl ((lr,4r)-4-(6-cyano-3-nitro-l-(4-phenoxybenzyl)-lH-indole-2- carboxamido)-cyclohexyl)carbamate

[00562] The product of step-l of example-9 (980 mg, 2.29 mmol) and l-(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-l of example-l. LCMS: 610.3 (M+l) ⁺ .

[00563] Step-2: tert-Butyl ((lr,4r)-4-(3-amino-6-cyano-l-(4-phenoxybenzyl)-lH-indole-2- carboxamido)-cyclohexyl)carbamate

[00564] The product of step-l 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+l) ⁺ .

[00565] Step-3: Ethyl 3-amino-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(4- phenoxybenzyl)-lH-indole-6-carbimidate

[00566] 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-l. LCMS: 526.3 (M+l) ⁺ .

[00567] Step-4: 3-Amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(4- phenoxybenzyl)-lH-indole-2-carboxamide

[00568] The product of step-3 of example-53 (155 mg, 0.29 mmol) was treated with 30 mL of ethanolic-NLL to afford 15 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 497.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 1.31 (m, 4H), 1.83 (m, 4H), 2.95 (m, 1H), 3.7l(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.l8(brs, 1H), 9.10 (brs, 2H), 9.21 (brs, 2H).

Example 54: Synthesis of compound 1-253

[00569] ((lr,4r)-4-(3-Amino-6-carbamimidoyl-l-(4-phenoxybenzyl)-lH-i ndole-2- carboxamido)-cyclohexyl) carbamic acid

[00570] Step-l : ((lr,4r)-4-(3-Amino-6-cyano-l-(4-phenoxybenzyl)-lH-indole-2- carb ox ami do)-cy cl ohexy l)carb ami c aci d

[00571] 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+l) ⁺ .

[00572] Step-2 : (( 1 r,4r)-4-(3 - Amino-6-(ethoxy(imino)methyl)- 1 -(4-phenoxyb enzyl)- 1 H- indole-2-carboxamido)-cyclohexyl)carbamic acid

[00573] The product of step-l 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-l . LCMS: 570.3 (M+l) ⁺ .

[00574] Step-3 : ((lr,4r)-4-(3-Amino-6-carbamimidoyl-l-(4-phenoxybenzyl)-lH-i ndole-2- carb ox ami do)-cy cl ohexy l)carb ami c aci d

[00575] The product of step-2 of example-53 (65 mg, 0.11 mmol) was treated with 20 mL of ethanol ic-NFL to afford 10 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 541.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 1.21 (m, 2H), 1.36 (m, 2H), 1.79 (m, 4H), 2.95 (m, 1H), 3.7l(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), 8.3 l(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 1-254

[00576] Ethyl (2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'- hydroxycarbamimidoyl)-l-(4-phenoxybenzyl)-lH-indol-3-yl)carb amate

[00577] Step-l : tert-Butyl ((lr,4r)-4-(3-ethylcarbamate-6-cyano-l-(4-phenoxybenzyl)-lH- indole-2-carboxamido)cyclohexyl)carbamate

[00578] 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-l of example-l . LCMS: 652.3 (M+l) ⁺ .

[00579] Step-2: tert-Butyl ((lr,4r)-4-(3-ethylcarbamate-6-((Z)-N'-hydroxycarbamimidoyl) -l- (4-phenoxybenzyl)-lH-indole-2-carboxamido)cyclohexyl)carbama te

[00580] The product of step-l 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-l4. LCMS: 613.3 (M+l) ⁺ .

[00581] Step-3 : Ethyl (2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-((Z)-N'- hydroxycarbamimidoyl)- 1 -(4-phenoxybenzyl)- lH-indol-3 -yl)carbamate

[00582] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00583] l-(3-Aminobenzyl)-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimid oyl-lH-indole- 2-carboxamide

[00584] Step-l : tert-Butyl ((lr,4r)-4-(6-cyano-l-(3-nitrobenzyl)-lH-indole-2-carboxamid o)- cyclohexyl)carbamate

[00585] The product of step-2 of example-6 (1200 mg, 3.13 mmol) and l-(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-l of example- 1. LCMS: 518.2 (M+l) ⁺ .

[00586] Step-2: tert-Butyl ((lr,4r)-4-(l-(3-aminobenzyl)-6-cyano-lH-indole-2- carboxamido)cyclohexyl)-carbamate

[00587] The product of step-l 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+l) ⁺ .

[00588] Step-3: Ethyl l-(3-aminobenzyl)-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l H- indole-6-carbimidate

[00589] 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-l. LCMS: 434.2 (M+l) ⁺ .

[00590] Step-4: l-(3-Aminobenzyl)-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimid oyl-lH- indole-2-carboxamide

[00591] The product of step-3 of example-56 (235 mg, 0.54 mmol) was treated with 30 mL of ethanolic-NLL to afford 35 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 405.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00592] N-((lr,4r)-4-aminocyclohexyl)-l-(3-(3-aminopropanamido)benzy l)-6- carbamimidoyl-lH-indole-2-carboxamide

[00593] 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-l . LCMS: 476.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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, lH),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 1-258

[00594] N-((lr,4r)-4-Aminocyclohexyl)-l-(3-(azetidine-3-carboxamido) benzyl)-6- carbamimidoyl-lH-indole-2-carboxamide

[00595] 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-l . LCMS: 488.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-259

[00596] 3-(3-((2-(((lr,4r)-4-Amiocyclohexyl)carbamoyl)-6-carbamimido yl-lH-indol-l- yl)methyl)benzamido)propanoic acid

[00597] Step-l : methyl 3-((2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)car bamoyl)- 6-cyano- lH-indol- 1 -yl)m ethyl )benzoate

[00598] 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-l of example-l. LCMS: 531.2 (M+l) ⁺ .

[00599] Step-2: 3-((2-(((lr,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)car bamoyl)-6- cyano-lH-indol-l-yl)methyl)benzoic acid

[00600] The product of step-l 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-l. LCMS: 517.2 (M+l) ⁺ .

[00601] Step-3: Methyl 3-(3-((2-(((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamoyl)-6-cyano-lH-indol- l- yl)methyl)benzamido)propanoate

[00602] 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-l. LCMS: 602.3 (M+l) ⁺ .

[00603] Step-4: 3-(3-((2-(((lr,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl) carbamoyl)-6- cyano-lH-indol-l-yl)methyl)benzamido)propanoic acid

[00604] 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-l. LCMS: 588.3 (M+l) ⁺ .

[00605] Step-5 : 3-(3-((2-(((lr,4r)-4-Aminocyclohexyl)carbamoyl)-6-(ethoxy(im ino)methyl)- lH-indol-l-yl)methyl)benzamido)propanoic acid

[00606] 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-l . LCMS: 534.3 (M+l) ⁺ .

[00607] Step-6: 3-(3-((2-(((lr,4r)-4-Aminocyclohexyl)carbamoyl)-6-carbamimid oyl-lH- indol-l-yl)methyl)benzamido)propanoic acid

[00608] The product of step-5 of example-59 (70 mg, 0.13 mmol) was treated with 20 mL of ethanol ic-NFL to afford 23 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 505.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00609] l-(3-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4- difluorocyclohexyl)-lH-indole-2-carboxamide

[00610] Step-l : Ethyl 6-cyano-l-(3-nitrobenzyl)-lH-indole-2-carboxylate

[00611] Ethyl 6-cyano-lH-indole-2-carboxylate (1.45 g, 6.77 mmol) and l-(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-l of example-l . LCMS: 350.1 (M+l) ⁺ .

[00612] Step-2: 6-Cyano-l-(3-nitrobenzyl)-lH-indole-2-carboxylic acid

[00613] The product of step-l 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-l . LCMS: 322.1 (M+l) ⁺ .

[00614] Step-3 : 6-Cyano-N-(4,4-difluorocyclohexyl)-l-(3-nitrobenzyl)-lH-indo le-2- carboxamide

[00615] 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-l. LCMS: 439.2 (M+l) ⁺ .

[00616] Step-4: l-(3-Aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-lH-indo le-2- carboxamide

[00617] 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+l) ⁺ .

[00618] Step-5: tert-Butyl (3-((3-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-lH-in dol-

1-yl)-methyl)phenyl)amino)-3-oxopropyl)carbamate

[00619] 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-l. LCMS: 580.3 (M+l) ⁺ .

[00620] Step-6: Ethyl 2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(3-((2- aminoethyl)carbamoyl)-benzyl)-lH-indole-6-carbimidate

[00621] 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-l. LCMS: 526.3 (M+l) ⁺ .

[00622] Step-7: l-(3-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4- difluorocyclohexyl)-lH-indole-2-carboxamide

[00623] The product of step-6 of example-60 (115 mg, 0.21 mmol) was treated with 30 mL of ethanolic-NLL to afford 34 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 497.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00624] l-(4-Aminobenzyl)-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimid oyl-lH-indole-

2-carboxamide

[00625] Step-l : tert-Butyl ((lr,4r)-4-(6-cyano-l-(4-nitrobenzyl)-lH-indole-2-carboxamid o)- cyclohexyl)carbamate

[00626] The product of step-2 of example-6 (1.2 g, 3.13 mmol) and l-(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-l of example- 1. LCMS: 518.2 (M+l) ⁺ .

[00627] Step-2: tert-Butyl ((lr,4r)-4-(l-(3-aminobenzyl)-6-cyano-lH-indole-2- carboxamido)cyclohexyl)-carbamate

[00628] The product of step-l of example-6l (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+l) ⁺ .

[00629] Step-3 : Ethyl l-(4-aminobenzyl)-2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l H- indole-6-carbimidate

[00630] 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-l . LCMS: 434.2 (M+l) ⁺ .

[00631] Step-4: l-(4-Aminobenzyl)-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimid oyl-lH- indole-2-carboxamide

[00632] The product of step-3 of example-6l (150 mg, 0.34 mmol) was treated with 30 mL of ethanolic-NLL to afford 22 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 405.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00633] N-((lr,4r)-4-Aminocyclohexyl)-l-(4-(3-aminopropanamido)benzy l)-6- carbamimidoyl-lH-indole-2-carboxamide

[00634] Step-l : tert-Butyl (( 1 r,4r)-4-(l -(4-(3 -((tert- butoxycarbonyl)amino)propanamido)benzyl)-6-cyano-lH-indole-2 - carboxamido)cyclohexyl)carbamate

[00635] The product of step-2 of example-6l (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-l . LCMS: 659.3 (M+l) ⁺ .

[00636] Step-2: Ethyl 2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(4-(3- aminopropanamido)benzyl)-lH-indole-6-carbimidate

[00637] The product of step-l 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-l . LCMS: 505.3 (M+l) ⁺ .

[00638] Step-3 : N-((lr,4r)-4-Aminocyclohexyl)-l-(4-(3-aminopropanamido)benzy l)-6- carbamimidoyl-lH-indole-2-carboxamide

[00639] The product of step-2 of example-62 (170 mg, 0.33 mmol) was treated with 30 mL of ethanolic-NLL to afford 28 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 476.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00640] l-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4- difluorocyclohexyl)-lH-indole-2-carboxamide

[00641] Step-l : Ethyl 6-cyano-l-(4-nitrobenzyl)-lH-indole-2-carboxylate

[00642] The product of step-2 of example-6 (1.35 g, 3.52 mmol) and l-(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-l of example-l. LCMS: 350.1 (M+l) ⁺ .

[00643] Step-2: 6-Cyano-l-(4-nitrobenzyl)-lH-indole-2-carboxylic acid

[00644] The product of step-l 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-l. LCMS: 322.1 (M+l) ⁺ .

[00645] Step-3 : 6-Cyano-N-(4,4-difluorocyclohexyl)-l-(4-nitrobenzyl)-lH-indo le-2- carboxamide

[00646] 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-l. LCMS: 439.2 (M+l) ⁺ .

[00647] Step-4: l-(4-Aminobenzyl)-6-cyano-N-(4,4-difluorocyclohexyl)-lH-indo le-2- carboxamide

[00648] 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+l) ⁺ .

[00649] Step-5: tert-Butyl (3-((4-((6-cyano-2-((4,4-difluorocyclohexyl)carbamoyl)-lH-in dol- l-yl)-methyl)phenyl)amino)-3-oxopropyl)carbamate

[00650] 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-l. LCMS: 580.3 (M+l) ⁺ . [00651] Step-6: Ethyl l-(4-(3-aminopropanamido)benzyl)-2-((4,4- difluorocyclohexyl)carbamoyl)-lH-indole-6-carbimidate

[00652] 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+l) ⁺ .

[00653] Step-7 : 1 -(4-(3 -Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4- difluorocyclohexyl)-lH-indole-2-carboxamide

[00654] The product of step-6 of example 63 (125 mg, 0.23 mmol) was treated with 30 mL of ethanolic-NEb to afford 22 mg of the title compound following the procedure described in step-5 of example-l . LCMS: 497.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-264

[00655] l-(4-(3-Aminopropanamido)benzyl)-6-carbamimidoyl-N-(cyclohex -3-en-l-yl)- lH-indole-2-carboxamide

[00656] Step-l : 6-Cyano-N-(cyclohex-3-en-l-yl)-l-(4-nitrobenzyl)-lH-indole-2 -carboxamide

[00657] 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-l . LCMS: 401.2 (M+l) ⁺ .

[00658] Step-2 : 1 -(4- Aminobenzyl)-6-cyano-N-(cyclohex-3 -en- 1 -yl)- 1 H-indole-2- carboxamide

[00659] The product of step-l 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+l) ⁺ .

[00660] Step-3: tert-Butyl (3-((4-((6-cyano-2-(cyclohex-3-en-l-ylcarbamoyl)-lH-indol-l- yl)methyl)phenyl) amino)-3-oxopropyl)carbamate

[00661] 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-l. LCMS: 542.3 (M+l) ⁺ .

[00662] Step-4: Ethyl l-(4-(3-aminopropanamido)benzyl)-2-(cyclohex-3-en-l-ylcarbam oyl)- lH-indole-6-carbimidate

[00663] 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-l. LCMS: 488.3 (M+l) ⁺ .

[00664] Step-5 : 1 -(4-(3 -Aminopropanamido)benzyl)-6-carbamimidoyl-N-(4,4- difluorocyclohexyl)-lH-indole-2-carboxamide

[00665] The product of step-4 of example-64 (85 mg, 0.17 mmol) was treated with 20 mL of ethanolic-NLL to afford 14 mg of the title compound following the procedure described in step-5 of example-l. LCMS: 459.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

[00666] l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(3-(pyrr olidin-l- yl)phenyl)-lH-indole-2-carboxamide

[00667] The crude product of step-2 of example-23 was purified by preparative High- performance liquid chromatography instrument with a Agilent XDB Cl 8 reverse phase column (21.2x l50mm, 5micron). The mobile phases were 30% acetonitrile in water (0.1% TF A) to 100% acetonitrile (0.1% TFA) which afforded the title compound (25 mg). LCMS: 497.2 (M+l) ⁺ , ' H NMR (300MHz, DMSO-de): d 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 1-268

[00668] l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrr olidin-l- yl)phenyl)-lH-indole-2-carboxamide

[00669] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-l-yl)phenyl)- lH-indole-2- carboxamide

[00670] The product of step-2 of example 19 (500 mg, 1.56 mmol) and 4-(pyrrolidin-l- 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+l) ⁺ .

[00671] Step-2: l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrr olidin-l- yl)phenyl)-lH-indole-2-carboxamide

[00672] The product of step-l 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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 1-269

[00673] l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrr olidin-l- yl)pyridin-2-yl)-lH-indole-2-carboxamide

[00674] Step-l : l-(4-Carbamoylbenzyl)-6-cyano-N-(4-(pyrrolidin-l-yl)pyridin- 2-yl)-lH- indole-2-carboxamide

[00675] The product of step-2 of example 19 (500 mg, 1.56 mmol) and 4-(pyrrolidin-l- 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+l) ⁺ .

[00676] Step-2: l-(4-Carbamoylbenzyl)-6-(N'-hydroxycarbamimidoyl)-N-(4-(pyrr olidin-l- yl)pyridin-2-yl)-lH-indole-2-carboxamide

[00677] The product of step-l 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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

R _] = H; X = Cl/Br; Pg = optional Protecting group; R ₂ , R ₃ , m and n are as defined in formula (I)

[00678] The first general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-4. Ethyl 6-cyano-lH-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 HC1 and the interemediate imidate were quenched with ammonia to form compound of formula (I).

Example 68: Synthesis of compound 1-270

[00679] 2-(4-Fluoropiperidine-l-carbonyl)-l-isopentyl-lH-indole-6-ca rboximidamide

[00680] Step-l : Ethyl 6-cyano-l-isopentyl-lH-indole-2-carboxylate

[00681] Ethyl 6-cyano-lH-indole-2-carboxylate (10.0 g, 46.71 mmol), dissolved in 250 mL of N,N-dimethylformamide (DMF), was added l-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+l) ⁺ .

[00682] Step-2: 6-Cyano-l-isopentyl-lH-indole-2-carboxylic acid

[00683] Product of step-l 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+l) ⁺ .

[00684] Ste-3 : 2-(4-Fluoropiperidine-l-carbonyl)-l-isopentyl-lH-indole-6-ca rbonitrile

[00685] 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), hydroxybenzotri azole (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+l) ⁺ .

[00686] Step-4: Ethyl 2-(4-fluoropiperidine-l-carbonyl)-l-isopentyl-lH-indole-6-ca rbimidate

[00687] Product was step-3 of example-68 (450 mg, 1.31 mmol) was dissolved in 50 mL of ethanolic-HCl (ethanol was saturated with HC1 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+l) ⁺ .

[00688] Step-5: 2-(4-Fluoropiperidine-l-carbonyl)-l-isopentyl-lH-indole-6-ca rboximidamide

[00689] Product of step-4 of example-68 (220 mg, 0.56 mmol) was dissolved in 50 mL of ethanolic-NFL (ethanol was saturated with NFF 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 l50mm, 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+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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).

[00690] The following compounds listed in table-9 were prepared according to scheme-l by following similar procedure as described above for example-68 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00691] Table-9

General synthetic scheme 5

R _] = H, Pg = optional protecting group;---·*- = optional step when Pg is present; R ₂ . R ₃ , m and n are as defined in formula (I)

[00692] 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 0 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 1-323 [00693] 3-((6-Carbamimidoyl-2-(3-fluoropyrrolidine-l-carbonyl)-lH-in dol-l- yl)methyl)benzamide

[00694] Step-l : Ethyl l-(3-carbamoylbenzyl)-6-cyano-lH-indole-2-carboxylate

[00695] Ethyl 6-cyano-lH-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-l of example-68. LCMS: 348.1 (M+l) ⁺ .

[00696] Step-2: l-(3-carbamoylbenzyl)-6-cyano-lH-indole-2-carboxylic acid

[00697] Product of step-l 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+l) ⁺ .

[00698] Ste-3 : 3 -((6-Cyano-2-(3 -fluoropyrrolidine- 1 -carbonyl)- 1 H-indol- 1 - yl)methyl)benzamide

[00699] 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+l) ⁺ .

[00700] Step-4: 3-((2-(3-fluoropyrrolidine-l-carbonyl)-6-(N'-hydroxycarbamim idoyl)-lH- indol-l-yl)methyl)benzamide

[00701] 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+l) ⁺ .

[00702] Step-5 : 3 -((6-(N'- Acetoxycarbamimidoyl)-2-(3 -fluoropyrrolidine- 1 -carbonyl)- 1 H- indol-l-yl)methyl)benzamide

[00703] 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+l) ⁺ .

[00704] Step-6 : 3 -((6-Carbamimidoyl-2-(3 -fluoropyrrolidine- 1 -carbonyl)- lH-indol- 1 - yl)methyl)benzamide

[00705] 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+l) ⁺ , ¾ NMR (300MHz, DMSO-d ₆ ): d 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).

[00706] The following compounds listed in table-lO 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.

[00707] Table-10

General synthetic scheme - 6

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

[00708] 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 (K2CO3) 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 HC1 to get compound imidates, which was then treated with ethanolic ammonia to afford compound of formula (I).

Example 70: Synthesis of compound 1-345

[00709] 3-Amino-2-(4-(2-aminoethyl)piperidine-l-carbonyl)-l-isopenty l-lH-indole-6- carboximidamide

[00710] Step-l : tert-Butyl (2-(l-(6-cyano-lH-indole-2-carbonyl)piperidin-4- yl)ethyl)carbamate

[00711] 6-Cyano-lH-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+l) ⁺ .

[00712] Step-2: tert-Butyl (2-(l-(6-cyano-3-nitro-lH-indole-2-carbonyl)piperidin-4- yl)ethyl)carbamate

[00713] The product of step-l 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 (40lmg, 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+l) ⁺ . [00714] Step-3: tert-Butyl (2-(l-(6-cyano-l-isopentyl-3-nitro-lH-indole-2-carbonyl)pipe ridin- 4-yl)ethyl)-carbamate

[00715] The product of step-2 of example-70 (600 mg, 1.36 mmol) and l-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-l of example 1. LCMS: 512.3 (M+l) ⁺ .

[00716] Step-4: tert-Butyl (2-(l-(3-amino-6-cyano-l-isopentyl-lH-indole-2- carbonyl)piperidin-4-yl)ethyl)-carbamate

[00717] 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: ethyl acetate (6:4) and afforded the title compound (190 mg). LCMS: 482.3 (M+l) ⁺ .

[00718] Step-5: Ethyl 3-amino-2-(4-(2-aminoethyl)piperidine-l-carbonyl)-l-isopenty l-lH- indole-6-carbimidate

[00719] 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+l) ⁺ .

[00720] Step-6: 2-(4-Fluoropiperidine-l-carbonyl)-l-isopentyl-lH-indole-6-ca rboximidamide

[00721] The product of step-5 of example-70 (130 mg, 0.3 mmol) was treated with 50 mL of ethanolic-NLL to afford the title compound (35 mg) following the procedure described in step-5 of example 1. LCMS: 399.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 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).

[00722] The following compounds listed in table-l l 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.

[00723] Table-11

General synthetic scheme 7

Pg = optional Protecting group; L, R ₂ , R ₃ , m and n are as defined in formula (I)

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 HC1 or TFA to afford the compound of formula (I).

Example 71: Synthesis of compound 1-349

[00724] 3-Amino-2-(4-(2-aminoethyl)piperidine-l-carbonyl)-l-(2-(phen ylsulfonyl)ethyl)- lH-indole-6-carboximidamide

[00725] Step-l : tert-Butyl (2-(l-(6-cyano-lH-indole-2-carbonyl)piperidin-4- yl)ethyl)carbamate

[00726] 6-Cyano-lH-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+l) ⁺ .

[00727] Step-2: tert-Butyl (2-(l-(6-cyano-3-nitro-lH-indole-2-carbonyl)piperidin-4- yl)ethyl)carbamate

[00728] The product of step-l of example-7l (1.7 g, 4.29 mmol) and copper(II) nitrate trihydrate (401 mg, 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+l) ⁺ .

[00729] Step-3 : tert-Butyl (2-(l-(6-cyano-3-nitro-l-(2-(phenylsulfonyl)ethyl)-lH-indole -2- carbonyl)piperidin-4-yl)ethyl)carbamate

[00730] The product of step-2 of example-7l (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-l of example 1. LCMS: 610.2 (M+l) ⁺ .

[00731] Step-4: tert-Butyl-(2-(l-(6-(N'-hydroxycarbamimidoyl)-3-nitro-l-(2-

(phenylsulfonyl)ethyl)-lH-indole-2-carbonyl)piperidin-4-y l)ethyl)carbamate

[00732] The product of step-3 of example-7l (540 mg, 0.88 mmol) was treated with aq NLLOH 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+l) ⁺ .

[00733] Step-5: tert-Butyl-(2-(l-(6-(N'-acetoxycarbamimidoyl)-3-nitro-l-(2-

(phenylsulfonyl)ethyl)-lH-indole-2-carbonyl)piperidin-4-y l)ethyl)carbamate

[00734] The product of step-4 of example-7! (410 mg, 0.63 mmol) was treated with acetic anhydride (Ac ₂ 0) (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+l) ⁺ .

[00735] Step-6: tert-Butyl (2-(l-(3-amino-6-carbamimidoyl-l-(2-(phenylsulfonyl)ethyl)-l H- indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[00736] The product of step-5 of example-7l (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+l) ⁺ .

[00737] Step-7 : 3 - Amino-2-(4-(2-aminoethyl)piperidine- 1 -carbonyl)- 1 -(2-

(phenylsulfonyl)ethyl)-lH-indole-6-carboximidamide

[00738] The product of step-6 of example-7l (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-l except reaction was done at 0 °C for 2 h. LCMS: 497.2 (M+l) ⁺ , ¾NMR (300MHz, DMSO-de): d 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).

[00739] The following compounds listed in table-l2 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.

[00740] Table-12

General synthetic scheme - 8

X = Br; Pg = optional Protecting group; L, R ₂ , R ₃ , m and n are as defined in formula (I)

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 (K2CO3) and a suitable solvent (DMF) gives compound N-alkylated derivatives. Hydrolysis of C(2) ethyl ester in presence of LiOH/H ₂ 0 followed by coupling with cyclic yieled corresponding amides which were treatred with ethanolic HC1. This intermediate imidates on further treatment with ethanolic ammonia yielded compounds of formula (I).

Example 72: Synthesis of compound 1-353

[00741] l-([l,l'-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidin e-l-carbonyl)-lH- indole-6-carboximidamide

[00742] Step-l : Ethyl 3-chloro-6-cyano-lH-indole-2-carboxylate

[00743] Ethyl 6-cyano-lH-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: ethyl acetate (9: 1) to afford 820 mg of the title compound. LCMS: 249.1 (M+l) ⁺ .

[00744] Step-2: Ethyl l-([l,r-biphenyl]-4-ylmethyl)-3-chloro-6-cyano-lH-indole-2- carboxylate

[00745] The product of step-2 of example-72 (800 mg, 3.22 mmol) was treated with 4- (brom om ethyl)- l, l'-biphenyl (792 mg, 3.22 mmol) to afford the title compound (910 mg) following the procedure described in step-l of example-68. LCMS: 415.1 (M+l)+.

[00746] Step-3 : l-([l, r-Biphenyl]-4-ylmethyl)-3-chloro-6-cyano-lH-indole-2-carboxy lic acid

[00747] The product of step-3 of example-72 (900 mg, 2.17 mmol) was treated with lithium hydroxide (417 mg, 17.4 mmol) to afford the title compound (640 mg) following the procedure described in step-2 of example-68. LCMS: 387.1 (M+l) ⁺ .

[00748] Step-4: l-([l, r-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-l -carbonyl)- lH-indole-6-carbonitrile

[00749] The product of step-3 of example-72 (640 mg, 1.65 mmol) and 4-fluoropiperidine (170 mg, 1.65 mmol) were treated together to afford the title compound (430 mg) following the procedure described in step-3 of example-68. LCMS: 472.1 (M+l) ⁺ .

[00750] Step-5: Ethyl l-([l, r-biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-l- carbonyl)-lH-indole-6-carbimidate

[00751] The product of step-4 of example-72 (430 mg, 0.91 mmol) was treated with 50 mL of ethanolic-HCl to afford the title compound (225 mg) following the procedure described in step-4 of example-68. LCMS: 518.2 (M+l) ⁺ .

[00752] Step-6: l-([l, r-Biphenyl]-4-ylmethyl)-3-chloro-2-(4-fluoropiperidine-l -carbonyl)- lH-indole-6-carboximidamide

[00753] The product of step-5 of example-72 (220 mg, 0.42 mmol) was treated with 50 mL of ethanolic-NLL to afford the title compound (65 mg) following the procedure described in step-5 of example-68. LCMS: 489.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 1.52 (m, 2H), 1.66 (m, 2H), 2.96 (m, 1H), 3.13 (m, 1H), 3.46 (m, 1H), 3.79 (m, 2H), 5.33 (m, 1H), 5.72 (m, 1H), 7.21 (m, 2H), 7.35 (m, 1H), 7.42 (m, 2H), 7.58 (m, 3H), 7.66 (m, 1H), 7.82 (m, 1H), 8.46 (d, 1H), 9.07 (brs, 2H), 9.36 (brs, 2H); HPLC: 97.53% (Retention Time= 4.135 min).

[00754] The following compounds listed in table-l3 were prepared according to scheme-8 by following similar procedure as described above for example-72 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00755] Table-13

General synthetic scheme -9

Pg = Protecting group; L, R ₂ and m are as defined in formula (I)

Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-9. N-functionalized 6-cyano indole 2 carboxylic acids previously described were coupled with ester containing cyclic amines to yield corresponding cyclic amides. Hydrolysis of the ester functionality appended to the cyclic amines followed by further coupling with various amines yielded diamide derivatives. Treatement of diamides with ethanolic HC1 followed by ethanolic ammonia yieled compounds of formula (I).

Example 73: Synthesis of compound 1-356

[00756] N-(3-Aminopropyl)-l-(6-carbamimidoyl-l-(4-(trifluoromethyl)b enzyl)-lH- indole-2-carbonyl)-piperidine-4-carboxamide

[00757] Step-l : Ethyl 6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2-carboxylat e

[00758] Ethyl 6-cyano-lH-indole-2-carboxylate (10.0 g, 46.71 mmol) and l-(bromomethyl)-4- (trifluoromethyl)benzene (7.0 g, 46.71 mmol) were treated together to afford the title compound (6.2 g) following the procedure described in step-l of example-68. LCMS: 285.1 (M+l) ⁺ . [00759] Step-2: 6-Cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2-carboxylic acid

[00760] The product of step-l of example-73 (5.8 g, 19.64 mmol) was treated with LiOH (1.89 g, 78.6 mmol) to afford the title compound (3.65 g) following the procedure described in step-2 of example 68. LCMS: 257.1 (M+l) ⁺ .

[00761] Step-3: Ethyl l-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carbonyl)piperidine-4-carboxylate

[00762] The product of step-2 of example-73 (1.55 g, 6.05 mmol) and ethyl piperidine-4- carboxylate (950 mg, 6.05 mmol) were treated together to afford the title compound (1.75 g) following the procedure described in step-3 of example-68. LCMS: 484.2 (M+l) ⁺ .

[00763] Step-4: l-(6-Cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2-carbony l)piperidine-4- carboxylic acid

[00764] The product of step-3 of example-73 (1.7 g, 3.51 mmol) was treated with LiOH (338 mg, 14.0 mmol) in H ₂ 0 to afford the title compound (1.04 g) following the procedure described in step-2 of example 68. LCMS: 456.2 (M+l) ⁺ .

[00765] Step-5: tert-Butyl (3-(l-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carbonyl)piperidine-4-carboxamido)propyl)carbamate

[00766] The product of step-4 of example-73 (800 mg, 1.75 mmol) and /er/-butyl (3- aminopropyl)carbamate (305 mg, 1.75 mmol) were treated together to afford 580 mg of the title compound following the procedure described in step-3 of example-68. LCMS: 612.3 (M+l) ⁺ .

[00767] Step-6: Ethyl 2-(4-((3-aminopropyl)carbamoyl)piperidine-l-carbonyl)-l-(4-

(trifluoromethyl)-benzyl)-lH-indole-6-carbimidate

[00768] The product of step-5 of example-73 (550 mg, 0.9 mmol) was treated with 50 mL of ethanolic-HCl to afford the title compound (340 mg) following the procedure described in step-4 of example-68. LCMS: 558.3 (M+l) ⁺ .

[00769] Step-7: N-(3-Aminopropyl)-l-(6-carbamimidoyl-l-(4-(trifluoromethyl)b enzyl)-lH- indole-2-carbonyl)piperidine-4-carboxamide

[00770] The product of step-6 of example-73 (340 mg, 0.61 mmol) was treated with 50 mL of ethanolic-ML to afford the title compound (90 mg) following the procedure described in step-5 of example 68. LCMS: 529.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 1.51 (m, 4H), 2.49 (m, 2H), 2.71 (m, 4H), 3.15 (m, 3H), 3.82 (m, 1H), 4.38 (m, 1H), 5.65 (s, 2H), 6.83 (s, 1H), 7.23 (m, 2H), 7.52 (d, 1H), 7.78 (m, 4H), 7.94 (m, 1H), 9.13 (brs, 2H), 9.23 (brs, 2H); HPLC: 79.68% (Retention Time= 6.572 min).

[00771] The following compounds listed in Table-l4 were prepared according to scheme-9 by following similar procedure as described above for example 73 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00772] Table-14

General synthetic scheme 10

[00773] Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme 10. Amino analogs obtained from scheme 9 upon treating with lH-pyrazole-l-carboxamidine hydrochloride in presence of a suitable base (DIPEA) in a suitable solvent (DMF) affords compound of formula (I).

Example 74: Synthesis of compound 1-359

[00774] l-(6-Carbamimidoyl-l-(4-(trifluoromethyl)benzyl)-lH-indole-2 -carbonyl)-N-(3- guanidinopropyl)-piperidine-4-carboxamide

[00775] Step-l : l-(6-Carbamimidoyl-l-(4-(trifluoromethyl)benzyl)-lH-indole-2 -carbonyl)-N- (3-guanidinopropyl)piperidine-4-carboxamide

[00776] The product of step-7 of example-73 (90 mg, 0.17 mmol), dissolved in 10 mL of DMF, was treated with lH-pyrazole-l-carboxamidine hydrochloride (50 mg, 0.34 mmol) and DIPEA (88 mg, 0.68 mmol) and stirred at room temperature for 24 h. The solvent was evaporated under vacuum to give crude compound which was purified by reversed-phase preparative high performance column chromatography to afford 20 mg of the title compound. LCMS: 571.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 1.49 (m, 3H), 1.71 (m, 2H), 2.31 ( m, 2H), 3.12 (m, 6H), 3.85 (m, 1H), 4.45 (m, 1H), 5.65 (s, 2H), 6.95 (s, 1H), 7.22 (d, 2H), 7.50 (m, 2H), 7.63 (d, 2H), 7.83 (m, 2H), 8.22 (s, 1H), 8.89 (brs, 2H), 9.25 (brs, 2H).

[00777] The following compounds listed in table-l5 were prepared according to scheme 10 followed by scheme-7 by following similar procedure as described above for example 74 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00778] Table-15

General synthetic scheme - 11

Pg = Protecting group; R ₂ is -N0 ₂ substituted; R _j , R ₃ and m are as defined in formula (I)

Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme- 11. Nitro derivative upon reduction with Zn in presence of acetic acid Yielded amines which were coupling with the carboxylic acid under standard coupling conditions yields compound N-l functionlized amides. Deprotection of the protecting group with ethanolic HC1 also resulted in conversion of the nitrile to immediate which on treatment with ammonia yielded analogs of formula (I).

Example 75: Synthesis of compound 1-363

[00779] 3-Amino-N-(3-((2-(4-(2-aminoethyl)piperidine-l-carbonyl)-6-c arbamimidoyl-lH- indol-l-yl)methyl)phenyl)propenamide

[00780] Step-l : Ethyl 6-cyano-l-(3-nitrobenzyl)-lH-indole-2-carboxylate

[00781] Ethyl 6-cyano-lH-indole-2-carboxylate (10.0 g, 46.71 mmol) and l-(bromomethyl)-3- nitrobenzene (10.04 g, 46.71 mmol) were treated together to afford 6.8 g of the title compound following the procedure described in step-l of example-68. LCMS: 350.1 (M+l) ⁺ .

[00782] Step-2: 6-Cyano-l-(3-nitrobenzyl)-lH-indole-2-carboxylic acid

[00783] The product of step-l of example-75 (1.6 g, 4.58 mmol) was treated with lithium hydroxide (440 mg, 18.33 mmol to afford 930 mg of the title compound following the procedure described in step-2 of example-68. LCMS: 322.1 (M+l) ⁺ .

[00784] Step-3 : Ethyl l-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carbonyl)piperidine-4-carboxylate

[00785] The product of step-2 of example-75 (900 mg, 2.8 mmol) and tert-butyl (2-(piperidin- 4-yl)ethyl)-carbamate (638 mg, 2.8 mmol) were treated together to afford 740 mg of the title compound following the procedure described in step-3 of example-68. LCMS: 532.2 (M+l) ⁺ .

[00786]

[00787] Step-4: tert-Butyl (2-(l-(l-(3-aminobenzyl)-6-cyano-lH-indole-2-carbonyl)piperi din- 4-yl)ethyl)carbamate

[00788] The product of step-3 of example-75 (730 mg, 1.37 mmol) was treated with zinc (350 mg, 5.48 mmol) to afford 400 mg of the title compound following the procedure described in step- 4 of example 70. LCMS: 502.3 (M+l) ⁺ .

[00789] Step-5: tert-Butyl (2-(l-(l-(3-(3-((tert-butoxycarbonyl)amino)propanamido)benzy l)- 6-cyano-lH-indole-2-carbonyl)piperidin-4-yl)ethyl)carbamate

[00790] The product of step-4 of example-75 (400 mg, 0.59 mmol) and 3-((tert- butoxycarbonyl)-amino)propanoic acid (112 mg, 0.59 mmol) were treated together to afford 320 mg of the title compound following the procedure described in step-3 of example 68. LCMS : 673.3 (M+l) ⁺ .

[00791] Step-6: Ethyl 2-(4-(2-aminoethyl)piperidine-l -carbonyl)- 1 -(3 -(3- aminopropanamido)benzyl)-lH-indole-6-carbimidate

[00792] The product of step-5 of example-75 (320 mg, 0.47 mmol) was treated with 50 mL of ethanolic-HCl to afford 1 10 mg of the title compound following the procedure described in step-4 of example 68. LCMS: 519.3 (M+l) ⁺ .

[00793] Step-7: 3-Amino-N-(3-((2-(4-(2-aminoethyl)piperidine-l-carbonyl)-6- carbamimidoyl- lH-indol- 1 -yl)methyl)phenyl)propanamide

[00794] The product of step-6 of example-75 (110 mg, 0.21 mmol) was treated with 50 mL of ethanolic-NEb to afford 22 mg of the title compound following the procedure described in step-5 of example 68. LCMS: 490.3 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 0.51 (m, 1H), 0.81 (m, 1H), 1.32 (m, 2H), 1.49 ( m, 2H), 1.61 (m, 1H), 2.65 (m, 4H), 2.81 (m, 1H), 3.05 (m, 2H), 3.71 (m, 2H), 4.41 (m, 1H), 5.52 (d, 2H), 6.52 (s, 1H), 6.75 (m, 2H), 7.21 (m, 1H), 7.31 (s, 1H), 7.52 (m, 2H), 7.81 (m, 6H), 8.35 (s, 1H), 9.12 (brs, 2H), 9.27 (brs, 2H), 10.10 (brs, 2H).

[00795] The following compounds listed in table- 16 were prepared according to scheme- 11 by following similar procedure as described above for example 75 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00796] Table-16

General synthetic scheme - 12

[00797] Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-l2. Appropriately functionalized 6-cyano indole 2 carboxylic acids were coupled functionalized cyclic amines using EDC/HOBt to yield C(2) amides which on treatment with aq. hydroxylamine followed by deprotection of acid labile protecting groups with ethanolic HC1 yieled analogs of general formula (I).

Example 76: Synthesis of compound 1-379

[00798] 2-(4-(2-Aminoethyl)piperidine-l-carbonyl)-N'-hydroxy-l-(4- (trifluoromethyl)benzyl)-lH-indole-6-carboximidamide

[00799] Ste-l : tert-Butyl (2-(l-(6-cyano-l-(4-(trifluoromethyl)benzyl)-lH-indole-2- carbonyl)piperidin-4-yl)ethyl)carbamate

[00800] The product of step-2 of example-73 (753 mg, 2.19 mmol) and tert-butyl (2-(piperidin- 4-yl)ethyl)carbamate (500 mg, 2.19 mmol) were treated together to afford 575 mg of the title compound following the procedure described in step-3 of example 68. LCMS: 555.3 (M+l) ⁺ .

[00801] Step-2: tert-Butyl-(2-(l-(6-(N'-hydroxycarbamimidoyl)-l-(4-

(trifluoromethyl)benzyl)-lH-indole-2-carbonyl)piperidin-4 -yl)ethyl)carbamate

[00802] The product of step-l of example-76 (500 mg, 0.9 mmol) was treated with aq NLhOH solution (0.3 mL) to afford 425 mg of the title compound following the procedure described in step-4 of example 69. LCMS: 588.3 (M+l) ⁺ .

[00803] Step-3 : 2-(4-(2- Aminoethyl)piperidine-l-carbonyl)-N' -hydroxy- 1 -(4-

(trifluoromethyl)benzyl)-lH-indole-6-carboximidamide

[00804] The product of step-2 of example-76 (420 mg, 0.71 mmol) was treated with 30 mL of ethanolic-HCl to afford 180 mg of the title compound following the procedure described in step-7 of example 71. LCMS: 488.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 0.66 (m, 1H), 0.95 (m, 1H), 1.31 (m, 5H), 2.61 (m, 5H), 4.21 (m, 1H), 5.61 (s, 2H), 6.91 (s, 1H), 7.32 (d, 2H), 7.41 (d, 1H), 7.60 (m, 4H), 7.85 (d, 1H), 8.20 (s, 1H), 9.00 (brs, 2H), 11.10 (brs, 1H).

[00805] The following compounds listed in table-l7 were prepared according to scheme-l2 by following similar procedure as described above for example 76 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00806] Table-17

General synthetic scheme - 13

R _[ = H; R ₃ , m and n are as defined in formula (1); R ¹ and R" are appropriate substitutions as given in the examples below

[00807] Yet another general approach for the synthesis of compounds of general formula (I) is depicted in general synthetic scheme-l3. Following procedures described in the scheme above compounds of Formula (I) were synthesized.

Example 77: Synthesis of compound 1-385

[00808] 4-((6-Carbamimidoyl-2-(3,3-difluoropyrrolidine-l-carbonyl)-l H-indol-l- yl)methyl)-N -ethylbenzamide

[00809] Step-l : 2-(3,3-Difluoropyrrolidine-l-carbonyl)-lH-indole-6-carbonitr ile

[00810] 6-Cyano-lH-indole-2-carboxylic acid (1.5 g, 8.06 mmol) and 3,3-difluoropyrrolidine (862 mg, 8.06 mmol) were treated together to afford 1.27 g of the title compound following the procedure described in step-3 of example 68. LCMS: 276.1 (M+l) ⁺ .

[00811] Step-2: Methyl 4-((6-cyano-2-(3,3-difluoropyrrolidine-l-carbonyl)-lH-indol- l- yl)methyl)-benzoate

[00812] The product of step-l of example-77 (1.2 g, 4.34 mmol) was treated with methyl 4- (bromomethyl)benzoate (990 mg, 4.34 mmol) to afford 1.28 g of the title compound following the procedure described in step-l of example 68. LCMS: 424.1 (M+l) ⁺ .

[00813] Step-3 : 4-((6-Cyano-2-(3 ,3 -difluoropyrrolidine- 1 -carbonyl)- lH-indol- 1 - yl)methyl)benzoic acid

[00814] The product of step-2 of example-77 (1.2 g, 2.83 mmol) was treated with LiOH (544 mg, 22.7 mmol) to afford 810 mg of the title compound following the procedure described in step- 2 of example 68. LCMS: 410.1 (M+l) ⁺ .

[00815] Step-4 : 4-((6-Cyano-2-(3 ,3 -difluoropyrrolidine- 1 -carbonyl)- 1 H-indol- 1 -yl)methyl)-N- ethylbenzamide

[00816] The product of step-3 of example-77 (800 mg, 1.95 mmol) and tert-butyl (3- aminopropyl)carbamate (340 mg, 1.95 mmol) were treated together to afford 530 mg of the title compound following the procedure described in step-3 of example 68. LCMS: 437.2 (M+l) ⁺ .

[00817] Step-5: 4-((2-(3, 3 -Difluoropyrrolidine- l-carbonyl)-6-(N'-hydroxycarbamimidoyl)- lH-indol- 1 -yl)methyl)-N-ethylbenzamide

[00818] The product of step-4 of example-77 (500 mg, 1.14 mmol) was treated with aq. NLLOH solution (0.4 mL) to afford 375 mg of the title compound following the procedure described in step-4 of example 69. LCMS: 470.2 (M+l) ⁺ .

[00819] Step-6: 4-((6-(N'-Acetoxycarbamimidoyl)-2-(3,3-difluoropyrrolidine-l -carbonyl)-lH- indol-l-yl)methyl)-N-ethylbenzamide

[00820] The product of step-5 of example-77 (250 mg, 0.53 mmol) was treated with Ac ₂ 0 (435 mg, 4.26 mmol) to afford 180 mg of the title compound following the procedure described in step- 5 of example 69 LCMS: 512.2 (M+l) ⁺ .

[00821] Step-7: 4-((6-Carbamimidoyl-2-(3,3-difluoropyrrolidine-l-carbonyl)-l H-indol-l- yl)methyl)-N-ethylbenzamide

[00822] The product of step-6 of example-77 (150 mg, 0.29 mmol) was treated with Zn (150 mg, 2.34 mmol) to afford 35 mg of the title compound following the procedure described in step- 6 of example 69. LCMS: 454.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 1.06 (m, 3H), 2.29 (m, 2H), 3.22 (m, 2H), 3.68 (m, 2H), 3.89 (m, 2H), 5.67 (d, 2H), 7.10 (m, 3H), 7.54 (d, 2H), 7.73 (m, 2H), 7.86 (d, 1H), 8.40 (m, 1H), 8.95 (brs, 2H), 9.25 (brs, 2H); HPLC: 96.93% (Retention Time= 3.264 min).

[00823] The following compounds listed in table- 18 were prepared according to scheme- 13 by following similar procedure as described above for example-77 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00824] Table-18

Example 78: Synthesis of compound 1-394

[00825] l-([l,l'-Biphenyl]-4-ylmethyl)-2-(l,2,3,4-tetrahydroisoquino line-2-carbonyl)-lH- indole-6-carboxamide

[00826] Step-l : Ethyl l-([l,l'-biphenyl]-4-ylmethyl)-6-cyano-lH-indole-2-carboxyla te

[00827] Ethyl 6-cyano-lH-indole-2-carboxylate (800 mg, 3.73 mmol) and 4-(bromomethyl)- l, l'-biphenyl (917 mg, 3.73 mmol) were treated together to afford 985 mg of the title compound following the procedure described in step-l of example 68. LCMS: 381.1 (M+l) ⁺ .

[00828] Step-2: l-([l, l'-Biphenyl]-4-ylmethyl)-6-cyano-lH-indole-2-carboxylic acid

[00829] The product of step-l of example-78 (980 mg, 2.57 mmol) was treated with LiOH (495 mg, 20.63 mmol) to afford 630 mg of the title compound following the procedure described in step-2 of example 68. LCMS: 353.1 (M+l) ⁺ .

[00830] Ste-3 : l-([l, r-Biphenyl]-4-ylmethyl)-2-(l,2,3,4-tetrahydroisoquinoline-2- carbonyl)- lH-indole-6-carbonitrile

[00831] The product of step-2 of example-78 (600 mg, 1.7 mmol) and 1, 2,3,4- tetrahydroisoquinoline (226 mg, 1.7 mmol) were treated together to afford 410 mg of the title compound following the procedure described in step-3 of example 68. LCMS: 468.2 (M+l) ⁺ .

[00832] Step-4: l-([l, r-Biphenyl]-4-ylmethyl)-2-(l,2,3,4-tetrahydroisoquinoline-2- carbonyl)- lH-indole-6-carboxamide

[00833] To a solution of the product of step-3 of example-78 (350 mg, 0.75 mmol) in 5 mL of the mixture of MeOH and LEO (1 : 1) was added solid NaOH (240 mg, 6.0 mmol). The reaction was stirred at 50 °C. LTpon reaction completion, the reaction mixture was concentrated to remove methanol and acidified with 2N HC1. The aq 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 80 mg of the title compound. LCMS: 486.2 (M+l) ⁺ , ¾ NMR (300MHz, DMSO-de): d 2.61 (m, 2H), 3.6 (m, 2H), 4.74 (m, 2H), 4.71 (s, 2H), 5.81 (s, 2H), 6.90 (s, 1H), 7.07 (m, 3H), 7.16 (m, 3H), 7.34 (m, 5H), 7.52 (m, 2H), 7.69 (s, 2H), 7.98 (brs, 2H), 8.26 (brs, 2H); HPLC: 89.33% (Retention Time= 5.639 min). General synthetic scheme -14

Example 79: Synthesis of compound 1-395:

[00834] Carbamimidoyl-N-(4-carbamimidoylbenzyl)-l-(naphthalen-l-ylme thyl)-lH- indole-2-carboxamide)

[00835] Step-l : Ethyl 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylate.

[00836] To a solution of ethyl 6-cyano-lH-indole-2-carboxylate (2.0 g, 8.433 mmol) in DMF (20 ml) was added potassium carbonate (3.90 g, 28.32 mmol), solution of 1- (bromomethyl)naphthalene (3.1 g, 14.15 mmol) dissolved in THF (10 mL) and stirred at room temperature for 3 h. After reaction completion, THF was distilled off, added ice-cold water and precipitated product was filtered off. Thus, obtained solid was dried under vacuum to give title compound (2.2 g, crude) which was proceeded to next step without purification. LCMS: 353.1 (M- 1) ⁺ -

[00837] Step-2: 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylic acid.

[00838] Product of step-l of example-79 (1.0 g, 2.8 mmol) was dissolved in mixture of tetrahydrofuran/ethanol/water (10 mL: 5mL: 3mL) and added lithium hydroxide monohydrate (l55mg, 2.67 mmol) at room temperature. Resulting mixture was stirred at room temperature for 12 h. Reaction mixture was distilled off and acidified with 2N HC1, precipitated product was filtered off. Thus obtained solid was dried under vacuum to give titled compound (850 mg, crude) which was proceeded to next step. LCMS: 325.2 (M-l) ⁺ .

[00839] Step-3 : 6-cyano-N-(4-cyanobenzyl)-l-(naphthalen-l-ylmethyl)-lH-indol e-2- carboxamide

[00840] Product of step-2 of example 395 (350 mg, 1.01 mmol) was dissolved in 5 mL of N,N- dimethylformamide and added 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (194 mg, 1.01 mmol), hydroxybenzotri azole (109 mg, 1.01 mmol) and 4-(aminomethyl)benzonitrile (136 mg, 0.81 mmol) and N,N-diisopropylethylamine (0.352 ml, 2.02 mmol) at 0°C under nitrogen atmosphere and resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-cold water and precipitated product was filtered off and dried under vacuum. The crude solid obtained was purified by combiflash on silica-gel and eluted with 0.5% methanol in dichloromethane afforded the title compound (235mg). LCMS: 441.3 (M+l) ⁺ .

[00841] Step-4: Ethyl 2-((4-(ethoxy(imino)m ethyl )benzyl)carbamoyl)-l-(naphthalen-l- ylmethyl)-lH-indole-6-carbimidate.

[00842] Product of step-3 of example 79 (170 mg, 0.39 mmol) was dissolved in 10 mL of ethanolic-HCl and 5 mL of dioxane.HCl kept in a glass sealed tube at 0°C and stirred for 12 h at room temperature. Reaction was not completed. Again added 10 mL 4M soln of HC1 in dioxane and stirred for 2 days at RT. After reaction completion, solvent was evaporated under vacuum to afford the title compound (not isolated) and as such crude product proceeded to next step. LCMS: 533.7 (M+l) ⁺ .

[00843] Step-5 : Carbamimidoyl-N-(4-carbamimidoylbenzyl)- 1 -(naphthalen- 1 -ylmethyl)- 1H- indole-2-carboxamide (TFA salt)

[00844] Product of step-4 of example 79 was dissolved in 50 mL of methanolic-ammonia kept in sealed tube, stirred for 12 h at RT. After reaction completion, solvent was evaporated under vacuum to give crude product which was purified by preparative HPLC instrument with a Kinetex EVO C18 reverse phase column (21.2x l50mm, 5micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 60% acetonitrile (0.1% TFA) which afforded the title compound (100 mg) as a TFA Salt. [00845] LCMS: 475.2 [M+l] ⁺ ; ¹ HNMR (400 MHz, CD ₃ OD): d 4.52 (s, 2H), 6.20 (dd, 1H), 6.45 (s, 2H), 7.19 (dd, 1H), 7.27 - 7.34 (m, 2H), 7.37 (d, 1H), 7.50- 7.65 (m, 5H), 7.77 (d, 1H), 7.90- 8.02 (m, 3H), 8.16-8.22 (m, 1H). HPLC: 99.45% (Retention Time=4.88 min).

Example 80: Synthesis of compound 1-396:

[00846] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen- l-ylsulfonyl)-lH- indole-2-carboxamide

[00847] Step-l : 6-cyano-lH-indole-2-carboxylic acid

[00848] Ethyl 6-cyano-lH-indole-2-carboxylate (700 mg, 3.28 mmol) was treated with lithium hydroxide monohydrate (207 mg, 4.92 mmol) to afford 600 mg of title compound following the procedure described in step-2 of example 79. LCMS: 184.9(M-1) ⁺ .

[00849]

[00850] Step-2: tert-butyl ((lr,4r)-4-(6-cyano-lH-indole-2- carboxamido)cyclohexyl)carbamate

[00851] The product of step-l of example 80 (600 mg, 3.22 mmol) and tert-butyl ((lr,4r)-4- aminocyclohexyl)carbamate (700 mg, 3.22 mmol) were treated together to afford l . lg of the title compound following the procedure described in step-3 of example 79. LCMS: 283.0 (M-l00) ⁺ .

[00852] Step-3 : tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-l-ylsulfonyl)-lH-indole-2- carb ox ami do)cy cl ohexyl) carb am ate

[00853] To a solution of product of step 2 of example 80 (500 mg, 1.305 mmol) in THF (15 ml) was added potassium tert-butoxide (250m g, 2.21 mmol) and l8-crown-6 (35mg, 0.130 mmol) at 0°C followed by the addition of THF solution (5 mL) of naphthalene- l-sulfonyl chloride (442mg, 1.958 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 12 h. After reaction completion, added ice water and extracted with ethyl acetate (2 X 50 mL). Separated the organic layers and concentrated under vacuum. The crude residue obtained was purified by combiflash on silica gel eluted with 0.5 % methanol in dichloromethane to give title compound (200 mg). LCMS: 517.4 (M-56) ⁺ . [00854] Step-4: Ethyl2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(naphthalen- l-ylsulfonyl)- lH-indole-6-carbimidate

[00855] The product of step-3 of example 80 (220 mg, 0.384 mmol) was treated with 10 mL of ethanolic-HCl and 4M soln of HC1 in dioxane at room temperature for 3days to afford 250 mg of the title compound following the procedure described in step-4 of example 79. LCMS: 518.8 (M) ⁺ . As such crude product proceeded to next step

[00856] Step-5 : N-(( 1 r,4r)-4-aminocyclohexyl)-6-carbamimidoyl- 1 -(naphthalen- 1 -yl sulfonyl)- lH-indole-2-carboxamide (TFA salt)

[00857] The product of step-4 of example 80 (250 mg (crude), 0.482 mmol) was treated with 10 mL of ethanolic-ML at room temperature as described in the step-5 of example 1 to give the crude product which was purified by preparative HPLC instrument with a LUNA C18 reverse phase column (21.2x l50mm, 5micron). The mobile phases were 30% acetonitrile in water (0.02% TFA) to 60% acetonitrile (0.02% TFA) which afforded the title compound (50 mg) as a TFA Salt.

[00858] LCMS: 490.3 (M+l) ⁺ ; ¹ HNMR (300MHz, CD ₃ OD):5 1.52-1.38 (m, 4H), 2.08-2.05 (m, 4H), 3.08-3.06 (m, 1H), 3.78-3.62 (m, 1H), 7.11 (s, 1H), 7.70-7.54 (m, 4H), 7.90-7.87 (m, 1H), 8.04-8.00 (m, 2H), 8.24-8.21 (d, 1H), 8.49-8.40 (m, 2H); HPLC: 99.5% (Retention Time= 4.55 min).

[00859] The following compound listed in table-l9 prepared according to Scheme-l4 by following similar procedure as described above for example 80 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00860] Table-19: Compounds synthesized using general scheme-14

General synthetic scheme -15

Example 81: Synthesis of compound 1-398:

[00861] 6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-2-ylmethyl)-N-(pip eridin-4- ylmethyl)-lH-indole-2-carboxamide

[00862] Step-l : Ethyl 6-cyano-l-(naphthalen-2-ylmethyl)-lH-indole-2-carboxylate.

[00863] To a solution of ethyl 6-cyano-lH-indole-2-carboxylate (380mg, 1.77 mmol) in DMF (10 ml) was added potassium carbonate (6l2mg, 4.43 mmol) and 2-(bromomethyl)naphthalene (392 mg, 1.77 mmol) at room temperature and stirred for overnight (12 h) at room temperature. After reaction completion, added water and extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated to give crude product (720 mg) which was further purified by combiflash on silica gel (40g column)eluted with 30% ethyl acetate in hexane to give title compound (560 mg). LCMS: 355.2 (M+l) ⁺ .

[00864] Step-2: 6-cyano-l-(naphthalen-2-ylmethyl)-lH-indole-2-carboxylic acid

[00865] Product of step-l of example 81 (560 mg, 1.58 mmol) was dissolved in mixture of tetrahydrofuran/ethanol (7 mL: 2mL) and added aqueous solution of lithium hydroxide monohydrate (66 mg, 1.58 mmol) at room temperature. Resulting mixture was stirred at room temperature for 2 h. Reaction mixture was distilled off and acidified with dilute HC1 to pH 4, precipitated product was filtered off. Thus obtained solid was dried under vacuum to give titled compound (460 mg, crude) which was proceeded to next step.

[00866] Step-3 : tert-butyl-4-((6-cyano-l-(naphthalen-2-ylmethyl)-lH-indole-2 - carboxamido)methyl)piperidine- 1 -carboxylate

[00867] To a stirred solution of product of step-2 of example 81 (330 mg, 1.01 mmol) in DMF added HATU (403 mg, 1.06 mmol) and N, N-diisopropylethylamine (253 mg, 2.02 mmol) at 0°C. After stirred at RT for 10 min, added tert-butyl 4-(amino methyl) piperidine- 1 -carboxylate (216 mg, 1.01 mmol) and stirred for 3h at room temperature. After reaction completion, added water and extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated to give crude product (470 mg) which was further purified by combiflash on silica gel (24 g column)eluted with 5% methanol in dichloromethane to give title compound (370 mg). LCMS: 523.6 9 (M+l) ⁺ .

[00868] Step-4: tert-butyl-4-((6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-2-y lmethyl)-lH- indole-2-carboxamido) m ethyl )piperidine-l -carboxylate

[00869] The product of step-3 of example 81 (90 mg, 0.172 mmol) was dissolved in 5 mL of ethanol and added 50% aqueous hydroxylamine solution (1.3 mL) and resulting mixture was refluxed for 2 h at 90°C. Solvent was evaporated under vacuum to get crude, water was added and precipitated solid was filtered off and dried under vacuum to afford the title compound (60 mg). LCMS: 556.6(M+l) ⁺ .

[00870] Step-5: 6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-2-ylmethyl)-N-(pip eridin-4- ylmethyl)-lH-indole-2-carboxamide (TFA salt)

[00871] To a stirred solution of product of step-4 of example 81 (60 mg, 0.108 mmol) in dichloromethane was added TFA (0.2 mL) at room temperature and stirred for 3h. Evaporated off reaction mixture under reduced pressure at room temperature to give crude product which was purified by preparative HPLC instrument with a Kinetex C18 reverse phase column (19 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.3% TFA) to 40% acetonitrile (0.3% TFA) which afforded the title compound (90 mg) as a TFA Salt. LCMS: 456.2(M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.28-1.09 (m, 2H),l .54-l .48(d, 2H), 1.59-1.55 (m, 1H), 2.51- 2.44 (m, 2H),3.0l-2.98(d, 2H),3. l6-3. l4(d, 2H),6.03 (s, 2H),7. l4-7. l2(d, lH),7.20 (s, lH),7.33 (s, 1H), 7.43-7.42 (m, 3H), 7.69-7.66 (m, 1H), 7.82-7.75 (m, 2H), 7.93-7.9l(dd,lH), 8.03 (s, 1H); HPLC: 99.8% (Retention Time= 5.11 min)

[00872] The following compound listed in table-20 prepared according to general scheme-l5 by following similar procedure as described above for example 81 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00873] Table-20: Compounds synthesized using general scheme-15

Example 82: Synthesis of compound 1-402:

[00874] tert-butyl ((lr,4r)-4-(6-carbamimidoyl-l-(naphthalen-2-ylmethyl)-lH-ind ole-2- carboxamido) cyclohexyl) carbamate

[00875] Step-l : tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-2-ylmethyl)-lH-indole-2- carb ox ami do)cy cl ohexyl) carb am ate

[00876] Product of step-2 of example 81 (310 mg, 0.950 mmol) and tert-butyl ((lr,4r)-4- aminocyclohexyl)carbamate (220 mg, 1.1 mmol) were treated together for lh at room temperature to afford 370 mg of the title compound following the procedure described in step-3 of example 81. LCMS: 567.15 (M-56) ⁺ .

[00877] Step-2: tert-butyl ((lr,4r)-4-(6-(-N'-hydroxycarbamimidoyl)-l-(naphthalen-2- ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate

[00878] Product of step-l of example 82 (370 mg, 0.708 mmol) was treated with 50% aqueous hydroxylamine solution (10 mL) to afford the 300 mg of the title compound following the procedure described in step-4 of example 81. LCMS: 555.85 (M+l) ⁺ .

[00879] Step-3 : tert-butyl ((lr,4r)-4-(6-(-N'-acetoxycarbamimidoyl)-l-(naphthalen-2- ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate

[00880] To a stirred solution of product of step-2 of example 82 (300 mg, 0.540 mmol) in acetic acid (l2mL) was added acetic anhydride (0.6 mL) at room temperature and resulting reaction mixture was stirred for 4h. Evaporated off the reaction mixture under reduced pressure at room temperature. The crude obtained was basified with aqueous sodium bicarbonate. The precipitated solid was filtered off and dried under vacuum to give the title compound (270 mg, crude). LCMS: 597.91 (M+l) ⁺ .

[00881] Step-4: tert-butyl ((lr,4r)-4-(6-carbamimidoyl-l-(naphthalen-2-ylmethyl)-lH-ind ole- 2-carboxamido)cyclohexyl) carbamate

[00882] To a solution of product of step-3 of example 82 (220 mg, 0.360 mmol) in a mixture of Methanol :THF (1 : 1) (20 mL) was added 10% Palladium on Carbon (25 mg) and resulted mixture was stirred at room temperature for 5h under the hydrogen atmosphere (balloon filled with hydrogen gas). After reaction completion, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure. The crude obtained was purified by preparative HPLC instrument using LUNA Cl 8 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 15% acetonitrile: Methanol (1 : 1) in water to 80% acetonitrile: Methanol (1 : 1) in water which afforded the title compound (140 mg) as a TFA Salt. LCMS: 540.25 (M+l) ⁺ ; ¹ HNMR (400 MHz, DMSO-de): d 1.20-125 (m, 4H), 1.32 (s, 9H), 1.75-178 (m, 4H), 3.14-3.20 (m, 1H), 3.62-3.70 (m, 1H), 6.00 (s, 2H), 6.75 (d, 1H), 7.20 (s, 1H), 7.29 (d, 1H), 7.45-7.47 (m, 2H), 7.52-7.57 (m, 2H), 7.74-7.77 (m, 1H), 7.80-7.85 (m, 3H), 8.22 (s, 1H), 8. 55 (d, 1H). HPLC: 99.13% (Retention Time= 6.83 min)

[00883] The following compound listed in table-2l prepared according to general scheme-l5 by following similar procedure as described above for example 82 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00884] Table-21: Compounds synthesized using general scheme-15

[00885]

Example 83: Synthesis of compound 1-406:

[00886] 6-carbamimidoyl-l-(naphthalen-2-ylmethyl)-N-(piperidin-4-ylm ethyl)-lH- indole-2-carboxamide

[00887] Step-l : Tert-butyl -4-((6-(N'-acetoxycarbamimidoyl)-l-(naphthalen-2-ylmethyl)-l H- indole-2-carboxamido) methyl)piperidine-l-carboxylate

[00888] Product of step-4 of example 81 (240 mg, 0.432mmol) and acetic anhydride (0.5mL) were treated together to afford 200 mg of the title compound following the procedure described in step-3 of example 82. LCMS: 598.4 (M+l) ⁺ .

[00889] Step-2: tert-butyl 4-((6-carbamimidoyl-l-(naphthalen-2-ylmethyl)-lH-indole-2- carboxamido)methyl)piperidine- 1 -carboxylate [00890] Product of step-l of example 83 (200 mg, 0.335 mmol) was treated with 10% Palladium on carbon (40 mg) in presence of hydrogen atmosphere for 6 h afforded 200 mg of the title compound following the procedure described in step-4 of example 82. LCMS: 540.9 (M+l) ⁺ .

[00891] Step-3 :6-carbamimidoyl-l-(naphthalen-2-ylmethyl)-N-(piperidin-4-yl methyl)-lH- indole-2-carboxamide

[00892] Product of step-2 of example 83 (200 mg, 0.335 mmol) was dissolved in ethanol (5 mL) and was added ethanolic HC1 (5 mL) at 0°C and then stirred at room temperature for 5 h. After reaction completion, reaction mixture was concentrated under reduced pressure to give crude product (218 mg), further triturated with pentane and dried under vacuum to afford the title compound (130 mg) as HC1 salt. LCMS: 440.4 (M+l) ⁺ , ¹ HNMR (400MHz, CD ₃ OD): 51.17 (m, 2H), 1.52-1.48 (m, 3H), 2.49-2.48(t, 2H),3.0l-2.98(d, 2H),3. l7-3. l5(d, 2H),6.05 (s, 2H),7. l5- 7. l2(d, lH),7.2l (s, lH),7.34 (s, 1H), 7.46-7.43 (m, 2H), 7.58-7.55 (m, 1H), 7.70-7.68 (m, 1H), 7.81-7.76 (m, 2H), 7.94-7.92(d, 1H), 8.17 (s, 1H); HPLC: 95.22% (Retention Time= 5.08 min).

[00893] The following compounds listed in table-22 prepared according to general scheme-l5 by following similar procedure as described above for example 406 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00894] Table-22: Compounds synthesized using general scheme-15

General synthetic scheme -15A

( from scheme-15)

PG = optional protecting group; X = Br or Cl;

Example 84: Synthesis of compound 1-411:

[00895] Tert-butyl ((lr,4r)-4-(6-(N-ethylcarbamimidoyl)-l-(naphthalen-2-ylmethy l)-lH- indole-2-carboxamido) cyclohexyl)carbamate

[00896] To a suspension of Example-82 (70 mg, 0.130 mmol) in ethanol (7 mL) was added 10% THF solution of ethanolamine (5mL) and resultant mixture was stirred at room temperature for 16 h. After reaction completion, excess of solvent was removed under reduced pressure. The crude obtained was purified by preparative HPLC instrument using LUNA Cl 8 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 30% acetonitrile in water (0.02% TFA) to 60% acetonitrile in water (0.02% TFA) which afforded the title compound (15 mg) as a TFA Salt.

[00897] LCMS: 568.9 (M+l) ⁺ ; ¹ HNMR(300 MHz, CD ₃ OD): d 1.22- 1.28 (m, 4H), 1.34 (t, 3H), 1.42 (s, 9H), 1.78-1.86 (m, 4H), 3.23-3.26 (m, 1H), 3.48 (q, 2H), 3.68-3.73 (m, 1H), 6.00 (s, 2H), 7.14 (d, 1H), 7.19-7.23 (m, 1H), 7.39-7.45 (m, 4H), 7.65-7.68 (m, 1H), 7.73- 7.80 (m, 2H), 7.87 (d, 1H), 8.00 (s, 1H); HPLC: 98.33% (Retention Time= 6.11 min)

[00898] The following compound listed in table-23 prepared according to general scheme-l5A by following similar procedure as described above for example 84 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00899] Table-23: Compounds synthesized using general scheme-15A

Example 85: Synthesis of compound 1-413:

[00900] N-((lr,4r)-4-aminocyclohexyl)-6-(N-ethylcarbamimidoyl)-l-(na phthalen-2- ylmethyl)-lH-indole-2-carboxamide

[00901] Example 84 (10 mg, 0.02 mmol) was treated with TFA (0.1 mL) afforded 5 mg of title compound as TFA salt following the procedure described in step-5 of example 81. LCMS: 468.04 (M+l) ⁺ ; ¹ HNMR(400 MHz, CD ₃ OD): d 1.27- 1.35 (m, 5H), 1.43-1.46 (m, 2H), 1.86-1.89 (m, 2H), 1.98-2.01 (m, 2H), 2.97-3.10 (m, 1H) 3.45-3.47 (m, 2H), 3.71-3.75 (m, 1H), 6.00 (s, 2H), 7.16-7.21 (m, 2H), 7.41-7.45 (m, 4H), 7.63-7.67 (m, 1H), 7.73-7.76 (m, 2H), 7.87 (d, 1H), 8. 01 (s, 1H); HPLC: 96.36% (Retention Time= 4.56 min).

[00902] The following compound listed in table-24 prepared according to general scheme-l5A by following similar procedure as described above for example 85 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00903] Table-24: Compounds synthesized using Scheme-15A

General synthetic scheme -15B

Example 86: Synthesis of compound 1-415:

[00904] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen- l-yl)-lH-indole- 2-carboxamide

[00905] Step-l : Ethyl 6-cyano-l-(naphthalen-l-yl)-lH-indole-2-carboxylate

[00906] To a stirred solution of ethyl 6-cyano-lH-indole-2-carboxylate (2.0g, 9.34mmol) in dichloromethane (50 mL) was added naphthalen-l-ylboronic acid (3.1 g, 18.69 mmol), copper (II) acetate (3.25 g, 18.69 mmol) and N,N-diisopropylethylamine (3.6 g, 28.038 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature under atmosphere of oxygen gas (oxygen bladder) for l6h. After reaction completion, water was added, separated the layers, organic layer concentrated under reduced pressure. The crude obtained above was purified by combiflash on silica gel eluted with 10% ethyl acetate in hexane to give the title product (200 mg). LCMS: 340.9 (M) ⁺

[00907] Step-2: 6-cyano-l-(naphthalen-l-yl)-lH-indole-2-carboxylic acid

[00908] Product of step-l of example 86 (200 mg, 0.588 mmol) was treated with lithium hydroxide monohydrate (38 mg, 0.882 mmol) in THF: Ethanol: water (3:3: 1) afforded the 150 mg of title compound following the procedure described in step-2 of example 81. Here the reaction mixture stirred for l2h at room temperature. LCMS: 3 l l .2(M-l) ⁺

[00909] Step-3 : tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-l-yl)-lH-indole-2- carboxamido)cyclohexyl)carbamate

[00910] Product of step-2 of example 86 (50 mg, 0.160 mmol) and tert-butyl ((lr,4r)-4- aminocyclohexyl)carbamate (42 mg, 0.192 mmol) were treated together afforded the 66 mg of title compound following the procedure described in step-3 of example 81. LCMS: 453.4 (M-56) ⁺

[00911] Step-4: tert-butyl ((lr,4r)-4-(6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l-yl)- lH- indole-2-carboxamido) cyclohexyl)carbamate

[00912] To a stirred solution of product of step-3 of example 86 (100 mg, 0.196 mmol) and N,N-diisopropylethylamine (152 mg, 1.176 mmol) in ethanol was added hydroxylamine hydrochloride at room temperature . The resulting reaction mixture was stirred at 80°C for 5h. After reaction completion distilled off excess solvent, added water, precipitated solid was filtered off and dried under vacuum to give the title compound as crude (100 mg). LCMS: 542.2 [M+l] ⁺ .

[00913] Also confirmed the formation of amide derivative of title compound as minor product as below which was inseparable by TLC in this step. LCMS: 527.3 [M+l] ⁺ .

[00914] (tert-butyl ((lr,4r)-4-(6-carbamoyl-l-(naphthalen-l-yl)-lH-indole-2- carboxamido)cyclohexyl)carbamate)

[00915] This crude mixture of compounds proceeded to next step without purification.

[00916] Step-5 Tert-butyl ((lr,4r)-4-(6-(N'-acetoxycarbamimidoyl)-l-(naphthalen-l-yl)- lH- indole-2-carboxamido) cyclohexyl)carbamate

[00917] To a stirred solution of product of step-4 of example 86 (100 mg, 0.184 mmol) in acetic acid (lmL) was added acetic anhydride (0.2 mL) at room temperature and resulting reaction mixture was stirred for 2h. Evaporated off the reaction mixture under reduced pressure at room temperature, added ice-cold water. The precipitated solid was filtered off and dried under vacuum. The crude solid obtained was further purified by combiflash on silica gel, eluted with 0.5% methanol in dichloromethane.

[00918] The nonpolar compound isolated was confirmed as title compound (50 mg). LCMS: 584.2(M+1) ⁺ .

[00919] The polar compound isolated was confirmed as amide derivative which was formed in a step-4 of example 86 (30 mg) as below. LCMS: 527.2 (M+l) ⁺ .

[00920] tert-butyl ((lr,4r)-4-(6-carbamoyl-l-(naphthalen-l-yl)-lH-indole-2- carboxamido)cyclohexyl)carbamate) (Polar)

[00921] Step-6: tert-butyl ((lr,4r)-4-(6-carbamimidoyl-l-(naphthalen-l-yl)-lH-indole-2- carb ox ami do)cy cl ohexyl) carb am ate

[00922] The nonpolar product of step-5 of example 86 (50 mg) was treated with 10% palladium on carbon (15 mg) under hydrogen atmosphere afforded the 40 mg of title compound following the procedure described in step-4 of example 82. Here reaction mixture stirred for 2h at room temperature. LCMS: 526.4 (M+l) ⁺ .

[00923] Following compound listed in table-25 prepared according to general scheme-l5B by following similar procedure as described above for the product of step-6 of example 86 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00924] Table-25: Compounds synthesized using general Scheme-15B

[00925] Step-7: N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen- l-yl)-lH- indole-2-carboxamide

[00926] Product of step-6 of example 86 (40 mg, 0.069 mmol) was treated with TFA (0.1 mL) afforded the 30 mg of title compound as TFA salt following the procedure described in step-5 of example 81. LCMS: 426.3(M+l) ⁺ ; ¹ HNMR (300MHz, CD ₃ OD): d 1.41-1.30 (m, 4H), 1.99-1.75 (m, 4H), 3.02-3.00 (m, 1H), 3.53-3.47 (m, 1H), 7.05-7.02(d, 1H), 7.41-7.36 (m, 3H), 7.72-7.51 (m, 4H), 8.11-7.99 (m, 3H); HPLC: 95.53% (Retention Time= 4.60 min)

[00927] Following compound listed in table-25 A prepared according to general scheme-l5B by following similar procedure as described above for the product of step-7 of example 86 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00928] Table-25A: Compounds synthesized using general Scheme-15B

Example 87: Synthesis of compound 1-417:

[00929] N2-((lr,4r)-4-aminocyclohexyl)-l-(naphthalen-l-yl)-lH-indole -2,6- dicarboxamide

[00930] The polar product isolated in step-5 of example 86 (30 mg, 0.057 mmol) was treated with TFA (0.1 mL) afforded the 15 mg of title compound as TFA salt following the procedure described in step-5 of example 81. LCMS: 427.2(M+l) ⁺ ; ¹ HNMR(300MHz, CD ₃ OD): d 1.38-1.28 (m, 4H), 1.97-1.78 (m, 4H), 3.07-2.99 (m, 1H), 3.53-3.51 (m, 1H), 7.05-7.03(d, 1H), 7.39-7.32 (m, 2H), 7.71-7.46 (m, 5H), 7.85-7.82(d, 1H), 8.08-8.00 (m, 2H); HPLC: 99.63% (Retention Time= 5.04 min)

General synthetic scheme -15C

Example 88: Synthesis of compound 1-418:

[00931] 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-N-(piperidin-4-yl) -lH-indole-2- carboxamide

[00932] Step-l :6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH-in dole-2- carboxylic acid

[00933] The product of step-2 of example 81 (2.7 g, 8.273 mmol) was dissolved in 50 mL of ethanol and added 50% aqueous hydroxylamine solution (20 mL) and resulting mixture was refluxed for 2 h at 80°C. Solvent was evaporated under vacuum to get crude, water was added and precipitated solid was filtered off. The solid obtained was triturated with cold water followed by n-pentane and dried under vacuum to give the title compound (2.45 g). LCMS : 360.2 (M+l) ⁺ .

[00934] Step-2 : 6-(N'-acetoxycarbamimidoyl)- 1 -(naphthalen- 1 -ylmethyl)- lH-indole-2- carboxylic acid [00935] To a stirred solution of product of step-l of example 88 (2.40g, 6.678 mmol) in acetic acid (20 mL) was added acetic anhydride (4.09 g, 40.07mmol) at 0°C. Resulting reaction mixture was stirred at room temperature for 3h. Evaporated off the reaction mixture under reduced pressure at room temperature. The residue obtained was triturated with diethyl ether, dried under vacuum to give the title compound (2.65g, crude). LCMS: 402.2 (M+l) ⁺ .

[00936] Step-3 : 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylic acid

[00937] To a stirred suspension of product of step-2 of example 88 (2.65g, 6.601 mmol)in methanol was added acetic acid (3.0 mL), 10% palladium on carbon (wet) (300 mg) at room temperature and was stirred for 3h under hydrogen atmosphere (Balloon filled with hydrogen gas) . After reaction completion, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure. The crude obtained was triturated with 50 ml of mixture of diethyl ether: pentane (1 :4) and solid obtained was dried under vacuum afforded the title compound (2.40 g). LCMS: 343.7 (M-l) ⁺ .

[00938] Step-4: 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-(naphthalen-l-ylm ethyl)-lH- indole-2-carboxylic acid

[00939] To a stirred suspension of product of step-3 of example 88 (2.40g, 6.98 mmol) in methanol was added di-tert-butyl dicarbonate (2.28 g, 10.48 mmol) and N,N- diisopropylethylamine (2.44 mL, 13.97 mmol) at 0°C and resulting reaction mixture was stirred at room temperature for 20 h. After reaction completion, reaction mixture was evaporated off under reduced pressure. The residue obtained above was redissolved in water and extracted with equal volume of ethyl acetate and aqueous layer were acidified with citric acid solution and precipitated solid was filtered off and dried to give title compound (2.40 g). LCMS: 444.4 (M+l) ⁺ .

[00940] Step-5 :tert-butyl 4-(6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-(naphthalen-l- ylmethyl)-lH-indole-2-carboxamido) piperidine- 1 -carboxyl ate.

[00941] To a stirred solution of product of step-4 of example 88 (200 mg, 0.441 mmol) in DMF added HATU (251 mg, 0.662 mmol) and N,N-diisopropylethylamine (142 mg, 2.02 mmol) at 0°C. After stirred at room temperature for 10 min, added tert-butyl 4-aminopiperidine-l-carboxylate (105 mg, 0.529 mmol) and stirred for 16 h at room temperature. After reaction completion, added ice cold water, precipitated solid was filtered off and dried to give title compound (340 mg), LCMS: 626.4 (M+l) ⁺ .

[00942] Following compounds listed in table-26 prepared according to general scheme-l5C by following similar procedure as described above for the product of step-5 of example 88 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00943] Table-26: Compounds synthesized using general scheme-15C

[00944] Step-6 : 6-carbamimidoyl- 1 -(naphthalen- 1 -ylmethyl)-N-(piperidin-4-yl)- lH-indole-2- carboxamide

[00945] To a stirred solution of product of step-5 of example 88 (340 mg, 0.523 mmol) in dichloromethane was added TFA (0.2 mL) at 0°C and stirred at room temperature for 4h. Evaporated off of reaction mixture under reduced pressure to give the crude compound (490 mg). The crude obtained was purified by preparative HPLC instrument using X-B ridge Cl 8 reverse phase column (19 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.02% TFA) to 50% acetonitrile in water (0.02% TFA) which afforded the title compound (100 mg) as a TFA Salt.

[00946] LCMS: 426.2(M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.99-1.69 (m, 4H), 3.36-3.00 (m, 4H),3.95 (m, lH),6.26-6.25(d, lH),6.43 (s, 2H),7.20-7. l7(t,lH),7.32 (s, 1H), 7.62-7.55 (m, 3H),7.75-7.73(d, 1H), 7.58-7.50 (m, 3H),8.20-8. l8(d, 1H); HPLC: 99.36% (Retention Time= 4.84 min)

[00947] Following compounds listed in table-27 prepared according to general scheme-l5C by following similar procedure as described above for the example 88 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00948] Table-27: Compounds synthesized using general scheme-15C

Example 89: Synthesis of compound 1-455:

[00949] l-(naphthalen-l-ylmethyl)-N2-(piperidin-4-yl)-lH-indole-2, 6-dicarboxamide

[00950] The above title compound (50 mg) was isolated as TFA salt in the preparative HPLC purification in a step-6 of example 88. LCMS: 428.0 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 52.00- 1.69 (m, 4H), 3.36-2.96 (m, 4H), 3.93 (m, 1H), 6.242-6.224(d, 1H), 6.38 (s, 2H), 7. l8-7. l4(t, lH), 7.25 (s, 1H), 7.61-7.51 (m, 2H), 7.71-7.67 (m, 2H), 7.79-7.71 (m, 1H), 7.89-7.87 (m, 1H), 8.00 (s, 1H), 8.19—8.17(d, 1H); HPLC: 98.45% (Retention Time= 5.25 min)

[00951] Following compounds listed in table-27A were isolated in final preparative HPLC purification of following similar procedure as described above for the example 89 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00952] Table-27A:

General synthetic scheme -15D

Example 90: Synthesis of compound 1-458:

[00953] 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylic acid

[00954] Step-l : 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylic acid

[00955] A 0°C cooled solution of product of step-l of example 79 (250m g, 0.766 mmol) in THF (3 mL) maintained under inert atmosphere was added to pre dissolved solution of LiHMDS (solid) (896 mg, 5.367 mmol) in THF (lmL) at 0°C under inert atmosphere .The resulting solution was stirred for overnight (16 h) at room temperature. After reaction completion, reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The precipitated product was filtered off and dried to give title compound (180 mg). LCMS: 344.0 (M+l) ⁺ .

[00956] Step-2: 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-(naphthalen-l-ylm ethyl)-lH- indole-2-carboxylic acid

[00957] To a stirred solution of product of step-l of example 90 (980mg, 2.85 mmol) in THF (20 mL) was added 2M aqueous solution of sodium hydroxide (250 mg, 4.28 mmol) followed by addition of di-tert-butyl dicarbonate (932.5mg, 4.28 mmol) at room temperature and resulting reaction mixture was refluxed at 50 °C for 3h. After reaction completion, evaporated off the reaction mixture under reduced pressure. The residue obtained was diluted with water and adjusted the pH= 6-7 using citric acid solution. The precipitated solid was filtered off and dried to give title compound (1.1 g). LCMS: 443.0 (M+l) ⁺ .

[00958] Step-2a: 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylic acid

[00959] To a stirred solution of product of step-2 of example 90s (85 mg, 0.191 mmol) in dichloromethane (8 mL) was added predissolved solution of TFA (0.4 mL) in 2 mL of dichloromethane at 0°C and stirred reaction mixture for 4h at room temperature. Evaporated off reaction mixture under reduced pressure and the crude obtained was purified by preparative HPLC instrument using X-Bridge C18 reverse phase column (19 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 50% acetonitrile in water (0.02% TFA) which afforded the title compound (46 mg) as a TFA Salt. LCMS: 342.0(M-l) ⁺ ; ¹ HNMR (600MHz, CD ₃ OD): 56.16-6. l5(d, 1H), 6.50 (s, 2H),7. l8 (t,lH), 7.57-7.53 (m, 3H), 7.64 (t, lH), 7.74-7.72(d, 1H), 7.92-7.89 (m, 2H), 7.99-7.97(d, 1H), 8.24-8.23(d, 1H); HPLC: 97.95% (Retention Time= 5.38 min)

[00960] Following compound listed in table-28 prepared according to general scheme-l5D by following similar procedure as described above for the example 90 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00961] Table-28: Compounds synthesized using Scheme-15D

Example 91: Synthesis of compound 1-460:

[00962] 6-carbamimidoyl-N-((l-methylpiperidin-4-yl)methyl)-l-(naphth alen-l- ylmethyl)-lH-indole-2-carboxamide

[00963] Step-l : tert-butyl (imino(2-(((l-methylpiperidin-4-yl)methyl)carbamoyl)-l-

(naphthalen- 1 -ylmethyl)- lH-indol-6-yl)methyl)carbamate

[00964] Product of step-2 of example 90 (100 mg, 0.230 mmol) and (l-methylpiperidin-4-yl) methanamine (38 mg, 0.290 mmol) were treated together afforded the title compound (110 mg) as crude following the procedure described in step-3 of example 79. LCMS: 554.85 (M+l) ⁺ .

[00965] Step-2: 6-carbamimidoyl-N-((l-methylpiperidin-4-yl) methyl)- l-(naphthalen-l - ylmethyl)-lH-indole-2-carboxamide

[00966] To a stirred solution of product of step-l of example 91 (110 mg, 0.200 mmol) in dichloromethane was added TFA (0.456 mL, 5.96 mmol) at 0°C under nitrogen atmosphere and stirred at room temperature for 3h. After completion of reaction, reaction mixture was evaporated off under reduced pressure. The crude obtained was triturated with diethyl ether and dried. The crude obtained was purified by preparative HPLC instrument using Kinetex EVO C18 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (50 mg) as a TFA Salt.

[00967] LCMS: 453.9(M+l) ⁺ ; ¹ HNMR(400 MHz, CD ₃ OD) : d 1.24 - 1.30 (m, 2H), 1.67 (d, 2H), 2.64 (m, 5H), 2.89-2.99 (m, 1H),3.15 (dd, 2H), 3.29-3.30 (m, 2H), 6.18 (dt, 1H), 6.44 (s, 2H),7. l9 (dd, lH),7.28 (d, 1H), 7.56-7.59 (m, 2H), 7.60-7.66 (m, 1H), 7.75 (d, 1H), 7.76-7.96 (m, 2H), 7.99-8.06 (s, 1H), 8.18-8.26 (m, 1H); HPLC: 99.69% (Retention Time= 5.11 min)

[00968] Following compound listed in table-29 prepared according to general scheme-l5D by following similar procedure as described above for the example 91 using appropriate reagents with suitable modifications known to the one skilled in the art.

[00969] Table-29: Compounds synthesized using Scheme-15D

General synthetic scheme -15D-1

[00970]

Method G:

( from Scheme-15D)

Ethanolic HCI

OR Method H:

Ethanolic/Dioxane. HCI

PG = optional protecting group;

Example 92: Synthesis of compound 1-485:

[00971] (lr,4r)-4-aminocyclohexyl 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indole-2-carboxylate

[00972] Step-l :(lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 6-(N-(tert- butoxycarbonyl)carbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH-i ndole-2-carboxylate

[00973] To a solution of product of step-2 of example 90 (70 mg, 0.150 mmol) in dichloromethane was added 4-dimethylaminopyridine (4 mg, 0.030 mmol) followed by addition of N, N’-dicyclohexylcarbodiimide (40 mg, 0.180 mmol) and tert-butyl ((lr, 4r)-4- hy dr oxy cyclohexyl) carbamate (40 mg, 0.180 mmol) at room temperature and resulting reaction mixture was stirred for 2h. Reaction mixture was diluted with dichloromethane, washed with water and dried over sodium sulphate. The organic layer was concentrated under reduced pressure afforded the title compound (200 mg). LCMS: 641.2 (M+l) ⁺ .

[00974] Step-2. (lr, 4r)-4-aminocy cl ohexyl 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indole-2-carboxylate

[00975] Product of step-l of example 92 (200 mg, 0.300 mmol) was treated with TFA (0.5 mL) afforded the crude product following the procedure described in step-5 of example 81.

[00976] The crude obtained was purified by preparative HPLC instrument using X-Bridge Cl 8 reverse phase column (19 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (50 mg) as a TFA Salt.

[00977] LCMS: 440.85 (M+l) ⁺ ; ¹ HNMR(400 MHz, CD ₃ OD): d 1.37-1.46 (m, 4H), 1.99 - 2.03 (m, 4H), 3.54-3.58 (m, 1H), 4.78-4.82 (m, 1H), 6.16 (d, 1H), 6.41 (s, 2H), 7.20 (t, 1H), 7.59-7.61 (m, 3H), 7.68 (t, 1H), 7.78 (d, 1H), 7.95-8.02 (m, 3H), 8.27 (d, 1H); HPLC: 98.35% (Retention Time= 5.24 min)

[00978] General synthetic scheme -15D-2

Example 93: Synthesis of compound 1-486:

[00979] Methyl 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylate

[00980] Step -1 : Methyl 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylate

[00981] To a stirred solution of product of step-2 of example 90 (200 mg, 0.400 mmol) in methanol (5mL) was added thionyl chloride (0.160 mL, 2.2 mmol) dropwise at 0°C. The resulting reaction mixture was stirred at 65°C for 2h. After reaction completion, reaction mixture was concentrated under reduced pressure. The residue obtained was basified with aqueous sodium carbonate solution up to pH 9-10 and extracted with mixture of methanol: dichloromethane (10:90) three times. Combined organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude solid obtained was triturated with diethyl ether and dried. The crude obtained was purified by preparative HPLC instrument using X-Bridge C18 reverse phase column (19 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (65 mg) as a TFA Salt.

[00982] LCMS: 358.0 (M+l) ⁺ ; ¹ HNMR (400MHz, CD ₃ OD): 53.82 (s, 3H), 6.17-6. l5(d, 1H), 6.51 (s, 2H), 7.22-7.19 (m, 1H), 7.78-7.57 (m, 5H), 8.02-7.94 (m, 3H), 8.28-8.26(d, 1H); HPLC: 95.95% (Retention Time= 5.21 min)

Example 94: Synthesis of compound 1-487

[00983] 2-(hydroxymethyl)-l-(naphthalen-l-ylmethyl)-lH-indole-6-carb oximidamide

[00984] Step-l : 2-(hydroxymethyl)-l-(naphthalen-l-ylmethyl)-lH-indole-6-carb oximidamide

[00985] To a stirred solution of lithium aluminium hydride (104 mg, 2.6 mmol) in THF (7.5 mL) was added the predissovled solution of product of step-l of example 93 (250mg, 0.600 mmol) in THF at 0°C under inert atmosphere. The resulting reaction mixture was stirred at room temperature for 4h. After reaction completion reaction mixture was quenched with ethyl acetate (2mL), water (3 mL) and 15% Aq. NaOH (lmL) at 0°C, stirred for 10 min. The resulting suspension was filtered through celite bed, washed with ethyl acetate and filtrate was concentrated under reduced pressure to dryness. The crude obtained was purified by preparative HPLC instrument using X-Bridge C18 reverse phase column (19 x l50mm, 5micron). The mobile phases were 20% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (50 mg) as a TFA Salt.

[00986] LCMS: 330.15 (M+l) ⁺ ; ¹ HNMR (400MHz, CD ₃ OD): 54.72 (s, 2H), 6.16 (s, 2H), 6.28- 6.24(d, 1H), 6.81 (s, 1H), 7.28-7.20 (m, 1H), 7.90-7.55 (m, 6H), 7.98-7.94(d, 1H), 8.30-8.25(d, 1H); HPLC: 98.69% (Retention Time= 5.33 min)

General synthetic scheme -15D-3

Example 95: Synthesis of compound 1-488:

[00987] 6-carbamimidoyl-l-(naphthalen-2-yl)-lH-indole-2-carboxylic acid

[00988] Step-l : ethyl 6-cyano-l-(naphthalen-2-yl)-lH-indole-2-carboxylate

[00989] To a predegassed (10 min.) solution of ethyl 6-cyano-lH-indole-2-carboxylate (2.0g, 9.34mmol) in DMSO (25 mL) was added naphthalen-2-ylboronic acid (3.99 g, 0.023 mmol), trimethylamine (3.77 g, 0.037 mmol) followed by degassing for 5 min and then addition of copper (II) acetate (6.76 g, 0.373 mmol) at room temperature in a sealed tube. The sealed tube closed under nitrogen atmosphere and stirred at room temperature for 2 days. After reaction completion, reaction mixture was diluted with ethyl acetate and filtered through celite bed. The filtrate collected was washed with water, brine and dried over sodium sulphate and concentrated to yield the crude product (2.54 g). The crude obtained was purified by combiflash on silica gel (64 g column) eluted with 10 % ethyl acetate in hexane afforded the title compound (1.45 g). LCMS: 340.75 (M+l) ⁺

[00990] Step-2: 6-cyano-l-(naphthalen-2-yl)-lH-indole-2-carboxylic acid

[00991] Product of step-l of example 95 (l .45g, 4.2 mmol) was treated with lithium hydroxide monohydrate (179 mg, 4.2 mmol) in THF: Ethanol: water afforded the 590 mg of title compound as crude following the procedure described in step-2 of example 81. LCMS: 3 l l .4(M-l) ⁺ .

[00992] Step-3 : 6-carbamimidoyl-l-(naphthalen-2-yl)-lH-indole-2-carboxylic acid

[00993] Product of step-2 of example 95 (200 mg, 0.640 mmol) was treated with solid LiHMDS (750 mg, 4.48 mmol) afforded the 210 mg of title compound following the procedure described in step-l of example 90. LCMS: 328.2(M-l) ⁺ .

[00994] Step-4:6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-(naphthale n-2-yl)-lH-indole-2- carboxylic acid

[00995] Product of step-3 of example 95 (210 mg, 0.636 mmol) and Di-tert-butyl dicarbonate (207 mg, 0.954 mmol)were treated together afforded the 200 mg of title compound following the procedure described in step-2 of example 90. LCMS: 428.4(M-l) ⁺ .

[00996] Step-4a: 6-carbamimidoyl-l-(naphthalen-2-yl)-lH-indole-2-carboxylic acid

[00997] Product of step-4 of example 95 (70 mg, 0.163 mmol) was treated with TFA (0.2 ml) in dichloromethane afforded the initial crude product following the procedure described in step- 2a of example 90. The crude obtained was purified by preparative HPLC instrument using X- Bridge C18 reverse phase column (19 x l50mm, 5micron). The mobile phases were 20% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (25 mg) as a TFA Salt.

[00998] LCMS: 330.15 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 57.49-7.46 (dd,lH), 7.64-7.57 (m, 5H), 8.08-7.97 (m, 5H); HPLC: 99.59 % (Retention Time= 4.68 min)

[00999] Following compound listed in table-30 prepared according to general scheme- 15D-3 by following similar procedure as described above for the example 95 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001000] Table-30: Compounds synthesized using Scheme-15D-3.

Example 96: Synthesis of compound 1-490:

[001001] 6-carbamimidoyl-l-(naphthalen-2-yl)-N-(piperidin-4-ylmethyl) -lH-indole-2- carboxamide

[001002] Step-l :tert-butyl-4-((6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-( naphthalen-2- yl)-lH-indole-2-carboxamido) methyl)piperidine-l-carboxylate

[001003] Product of step-4 of example 95 (55 mg, 0.128 mmol) and tert-butyl 4- (aminomethyl)piperidine-l-carboxylate (28 mg, 0.129 mmol) were treated together afforded 88 mg of title compound following the procedure described in step-5 of example 25. LCMS: 626.4 (M+l) ⁺ .

[001004] Step-2: 6-carbamimidoyl-l-(naphthalen-2-yl)-N-(piperidin-4-ylmethyl) -lH- indole-2-carboxamide

[001005] Product of step-l of example 96 (88 mg, 0.140 mmol) was treated with TFA (0.5 mL) in dichloromethane afforded the initial crude product following the procedure described in step-2a of example 90. The crude obtained was purified by preparative HPLC instrument using Kinetex EVO C18 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 30% acetonitrile in water (0.05% TFA) to 70% acetonitrile in water (0.05% TFA) which afforded the title compound (43 mg) as a TFA Salt.

[001006] LCMS: 426.2 [M+l] ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.25 (m, 2H), 1.75 (m, 3H), 2.75 (m, 2H), 3.32-3.15 (m, 4H), 7.28 (s, 1H), 7.55(dd,lH), 7.60 (m, 3H), 7.75 (s, 1H), 8.13-7.96 (m, 5H); HPLC: 98.11% (Retention Time=4.94 min).

[001007] Following compound listed in table-31 prepared according to general scheme-l5D- 3 by following similar procedure as described above for the example 96 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001008] Table-31: Compounds synthesized using Scheme-15D-3

General synthetic scheme -15E

Example 97: Synthesis of compound 1-492

[001009] tert-butyl4-((6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-(na phthalen-l- ylmethyl)-lH-indole-2-carboxamido)methyl)piperidine-l-carbox ylate

[001010] Step-l : 6-cyano-lH-indole-2-carboxylic acid

[001011] Ethyl 6-cyano-lH-indole-2-carboxylate (3.5 g, 0.016 mmol) was treated with lithium hydroxide monohydrate (0.86 mg, 0.167 mmol) afforded the title compound (2.95 g) following the procedure described in step-2 of example 79. LCMS: 185.0 [M-l] ⁺ .

[001012] Step-2: 6-(N'-hydroxycarbamimidoyl)-lH-indole-2-carboxylic acid

[001013] The product of step-l of example 97 (2.95g, 15.84 mmol) was treated with 50% aqueous hydroxylamine solution (10 mL) afforded the 4.0 g of title compound following the procedure described in step-l of example 418. LCMS : 219.9 (M+l) ⁺ .

[001014] Step-3: 6-(N'-acetoxycarbamimidoyl)-lH-indole-2-carboxylic acid

[001015] The product of step-2 of example 97 (4.0g, 18.26 mmol) was treated with acetic anhydride (5.58 g, 54.79 mmol) to afford the 7.0 g of title compound following the procedure described in step-2 of example 10. LCMS : 262.0 (M+l) ⁺ .

[001016] Step-4: 6-carbamimidoyl-lH-indole-2-carboxylic acid.

[001017] The product of step-3 of example 97 (3.5g, 13.39 mmol) was treated with 10% palladium on carbon (400 mg) in an atmosphere of hydrogen gas to afford the title compound (4.0 g) following the procedure described in step-3 of example 88. LCMS : 203.9 (M+l) ⁺ .

[001018] Step-5: 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-lH-indole-2-carboxy lic acid.

[001019] The product of step-4 of example 97 (4.0 g, 0.0l9mmol) was treated with di-tert- butyl dicarbonate (4.29 g, 0.019 mmol) to afford the title compound (1.7 g) following the procedure described in step-4 of example 88. LCMS : 304.0 (M+l) ⁺ .

[001020] Step-6: tert-butyl 4-((6-(N-(tert-butoxycarbonyl)carbamimidoyl)-lH-indole-2- carboxamido)methyl)piperidine- 1 -carboxylate

[001021] The product of step-5 of example 97 (250 mg, 0.825 mmol) and tert-butyl 4-(amino methyl)piperidine-l -carboxylate (211 mg, 0.990 mmol) were treated together afforded the 250 mg of title compound following the procedure described in step-5 of example 88. LCMS : 500.6 (M+l) ⁺ .

[001022] Step-7: tert-butyl 4-((6-(N-(tert-butoxycarbonyl)carbamimidoyl)-lH-indole-2- carboxamido)methyl)piperidine- 1 -carboxylate

[001023] To a solution of product of step-6 of example 97 (100 mg, 0.200 mmol) in DMF (3 ml) was added potassium carbonate (82.96 mg, 0.601 mmol) and l-(bromom ethyl) naphthalene (53. lmg, 0.240 mmol) at room temperature and stirred at 60 °C for 5h. After reaction completion, added ice cold water, precipitated solid was filtered off and dried. The crude product obtained above was purified by preparative TLC (mobile Phase: 2% methanol in dichloromethane) afforded the title compound (25 mg) as impure which was further purified by preparative HPLC instrument using Gemini -NX C18 reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 40% acetonitrile in water (0.02% ammonia) to 90% acetonitrile in water (0.02% ammonia) which afforded the title compound (10 mg).

[001024] LCMS: 640.5 [M+l] ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): d 0.87-0.85 (m, 2H), 1.39- 1.29 (m, 3H), 1.41 (s, 9H), 1.45 (s, 9H), 2.59-2.49 (m, 2H), 3.20-3.06 (m, 2H), 3.86-3.83 (m, 2H), 6.19-6.17 (d, 1H), 6.39 (s, 2H), 7.18-7.14 (t, 2H), 7.55-7.53 (m, 3H), 7.65-7.63 (m, 1H), 7.81-7.79 (d, 1H), 7.9l-7.89(d, 1H), 8.04 (s, 1H), 8.22-8.20(d, 1H); HPLC: 98.23% (Retention Time= 6.64 min).

[001025] Following compound listed in table-32 prepared according to general scheme-l5E by following similar procedure as described above for the example 97 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001026] Table-32: Compounds synthesized using Scheme-15E

Example 98: Synthesis of compound 1-496:

[001027] 6-carbamimidoyl-N-(piperidin-4-ylmethyl)-lH-indole-2-carboxa mide

[001028] Step -1 : 6-carbamimidoyl-N-(piperidin-4-ylmethyl)-lH-indole-2-carboxa mide

[001029] To a solution of product of step-6 of example 97 (60 mg, 0.120 mmol) in 1,4 dioxane (2mL) was added HC1 in 1,4 dioxane (4 mL) at 0°C and then stirred at room temperature for 3h. After reaction completion, reaction mixture was concentrated under reduced pressure to give crude product (60 mg). The crude product obtained above was further purified by preparative HPLC instrument using Gemini -NX C18 reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 0.5% acetonitrile in water (0.1% TFA) to 25% acetonitrile in water (0.1 % TFA) which afforded the title compound (10 mg) as a TFA salt.

[001030] LCMS: 300.0 [M+l] ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): d 1.54-1.28 (m, 2H), 2.03- 1.96 (m, 3H), 3.01-2.95 (m, 2H), 3.43-3.32 (m, 4H), 7.19 (s, 1H), 7.47-7.44 (d, 1H), 7.84-7.82 (d, 1H), 7.97 (s, 1H), 8.78-8.75 (m, 1H); HPLC: 98.94% (Retention Time= 4.21 min).

Example 99: Synthesis of compound 1-497:

[001031] 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-N-(piperidin-4-ylm ethyl)-lH- indole-2-carboxamide.

[001032] Step-l : 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-N-(piperidin-4-ylm ethyl)- lH-indole-2-carboxamide.

[001033] Product of step-7 of example 97 (45 mg, 0.076 mmol) was treated with HC1 in 1,4 dioxane afforded the crude product following the procedure described in example 20. The crude product obtained above was further purified by preparative HPLC instrument using Kinetex EVO C18 reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (19 mg) as a TFA salt.

[001034] LCMS: 440.2 [M+l] ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): d 1.19-1.16 (m, 2H), 1.65- 1.58 (m, 3H), 2.71-2.65 (m, 2H), 3.17-3.14 (m, 4H), 6.18-6.16 (d, 1H), 6.44 (s, 2H), 7.27-7.16 (m, 1H), 7.27 (s, 1H), 7.59-7.568 (m, 1H), 7.66-7.62 (m, 1H), 7.76-7.74(d, 1H), 7.96-7.91 (m, 2H), 8.02 (s, 1H), 8.22-8.2l(d, 1H), 8.85-8.79 (m, 1H); HPLC: 98.97% (Retention Time= 4.68 min).

[001035] Following compounds listed in table-33 prepared according to general scheme-l5E by following similar procedure as described above for the example 99 using appropriate reagents with suitable modifications known to the one skilled in the art

[001036] Table-33: Compounds synthesized using Scheme-15E

General synthetic scheme -16

Example 100: Synthesis of compound 1-511:

[001037] 3-amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(nap hthalen-l- ylmethyl)-lH-indole-2-carboxamide

[001038] Step-l : 6-cyano-3-nitro-lH-indole-2-carboxylic acid

[001039] To a -5°C precooled acetic anhydride (4.5 tnL) was added Cone nitric acid (0.5 mL) slowly. After being stirred the reaction mixture at same temperature (-5°C), product of step- 1 of example 97 (0.860g, 4.62 mmol) was added and maintain the temperature -5°C for 30 min. The reaction mixture gradually brought to room temperature and further stirred for overnight (-16 h). After reaction completion, reaction mixture was poured into water, precipitated solid was filtered off and washed with cold water and dried to afford 700 mg of title compound. LCMS: 230.2 [M-l] ⁺

[001040] Step-2: tert-butyl ((lr,4r)-4-(6-cyano-3-nitro-lH-indole-2- carboxamido)cyclohexyl)carbamate

[001041] Product of step-l of example 100 (650 mg, 2.81 mmol) and tert-butyl ((lr,4r)-4- aminocyclohexyl)carbamate (662 mg, 3.09 mmol) were treated to give 365 mg crude product following the procedure described in step-3 of example 81. Crude compound was further purified by combiflash on silica gel (24g column), eluted with 5% methanol in dichloromethane afforded the title compound (300 mg).LCMS: 426.0 (M-l) ⁺ .

[001042] Step-3 : tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-l-ylmethyl)-3-nitro-lH- indole-2-carboxamido)cyclohexyl) carbamate

[001043] To a solution of product of step-2 of example 100 (300 mg, 0.702 mmol) in DMF (5 ml) was added potassium carbonate (242 mg, 1.756 mmol) and l-(bromom ethyl) naphthalene (204 mg, 0.910 mmol) at room temperature and stirred at for overnight (l6h). After reaction completion, added ice cold water, precipitated solid was filtered off and dried afforded the title compound (320 mg). LCMS: 512.15 (M-56) ⁺ .

[001044] Step-4: tert-butyl ((lr,4r)-4-(6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l- ylmethyl)-3-nitro-lH-indole-2-carboxamido)cyclohexyl)carbama te.

[001045] The product of step-3 of example 100 (320 mg, 0.560 mmol) was treated with 50% aqueous hydroxyl amine solution (8 mL) afforded the title compound (270 mg) following the procedure described in step-4 of example 86. LCMS: 601.4 (M+l) ⁺ .

[001046] Step-5: tert-butyl ((lr,4r)-4-(6-(N'-acetoxycarbamimidoyl)-l-(naphthalen-l- ylmethyl)-3-nitro-lH-indole-2-carboxamido)cyclohexyl)carbama te

[001047] Product of step-4 of example 100 (270 mg, 0.450 mmol) and acetic anhydride

(0.5mL) were treated together to afford 220 mg of the title compound following the procedure described in step-3 of example 82. LCMS: 643.5 (M+l) ⁺ .

[001048] Step-6: tert-butyl ((lr,4r)-4-(3-amino-6-carbamimidoyl-l-(naphthalen-l- ylmethyl)-lH-indole-2-carboxamido) cyclohexyl)carbamate

[001049] Product of step-5 of example 100 (220 mg, 0.340 mmol) was treated with 10% Palladium on carbon (44 mg) in presence of hydrogen atmosphere for overnight afforded 190 mg of the title compound following the procedure described in step-4 of example 82. LCMS: 556.0 (M+l) ⁺ .

[001050] Step-7: 3-amino-N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(nap hthalen-

1 -ylmethyl)- lH-indole-2-carboxamide

[001051] Product of step-6 of example 100 (100 mg, 0.200 mmol) was treated with 1,4 dioxane.HCl afforded the crude product following the procedure described in step-3 of example 83. The crude obtained was purified by preparative HPLC instrument using LUNA C18 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.05% HC1) to 50% acetonitrile in water (0.05% HC1) which afforded the title compound (36 mg) as a HC1 Salt.

[001052] LCMS: 455.2 [M+l] ⁺ ; ¹ HNMR (600MHz, CD3OD): d 1.17-1.15 (m, 2H), 1.35- 1.29 (m, 2H), 1.72-1.70 (m, 2H), 1.90-1.89 (m, 2H), 2.94 (m, 1H), 3.62 (m, 1H), 6.31 (s, 2H), 6.41 (m, 1H), 7.24 (m, 1H), 7.57 (m, 1H), 7.58 (m, 2H), 7.79 (m, 1H), 7.93 (m, 1H), 8.10 (m, 1H), 8.17 (m, 2H), HPLC: 94.45% (Retention Time= 5.76 min).

[001053] General synthetic scheme -16A

Example 101: Synthesis of compound 1-512:

[001054] 2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-l-( naphthalen-l- ylmethyl)-lH-indole-3-carboxylic acid

[001055] Step-l :Ethyl 6-cyano-3-formyl-lH-indole-2-carboxylate

[001056] To a 0°C cooled solution of N, N-Di m ethyl form am k/e (30 mL) was added phosphorus oxychloride (10.72 mL, 0.069 mmol) dropwise under nitrogen atmosphere maintaining the inside temperature below l0°C. The resultant reaction mixture was stirred at l0°C for lh followed by dropwise addition of solution of ethyl 6-cyano-lH-indole-2-carboxylate (5.0 g, 0.023 mmol) dissolved in 15 mL of N,N-Dimethylformamide. The reaction mixture was brought to room temperature gradually and stirred at 70°C for 6h. After reaction completion, the reaction mixture was quenched with ice-cold water and neutralised with 2N aq. sodium hydroxide solution (140 mL).The precipitated solid was filtered off and dried to give crude product (5.6 g) which was further purified by combiflash on silica-gel (40 g column) and eluted with neat dichloromethane afforded the title compound (3.9 g). LCMS: 243 (M+l) ⁺ .

[001057] Step-2: Ethyl 6-cyano-3 -formyl- l-(naphthalen-l -ylmethyl)-l H-indole-2- carboxylate

[001058] Product of step-lof example 101 (1.35 g, 5.578 mmol) and l-(bromom ethyl) naphthalene (1.60 g, 7.25 mmol) were treated together afforded the crude product following the procedure described in step-3 of example 100. The crude was further purified by combiflash on silica-gel (40 g column) and eluted with neat dichloromethane afforded the title compound (1.95 g). LCMS: 383.1 (M+l) ⁺ .

[001059] Step-3 : 6-cyano-3-formyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbo xylic acid

[001060] Product of step-2 of example 101 (1.75 g, 4.58 mmol) was treated with lithium hydroxide monohydrate (183 mg, 4.58 mmol) in THF: Ethanol: water afforded the 1.57 g of title compound as crude following the procedure described in step-2 of example 1. Here reaction mixture was stirred for 4h. LCMS: 353.2(M+l) ⁺ .

[001061] Step-4 :tert-butyl ((lr,4r)-4-(6-cyano-3-formyl-l-(naphthalen-l-ylmethyl)-lH- indole-2-carboxamido) cyclohexyl)carbamate

[001062] Product of step-3 of example 101 (1.57 g, 4.43 mmol) and tert-butyl ((lr,4r)-4- aminocyclohexyl) carbamate (0.95 g, 4.43 mmol) were treated to give crude product following the procedure described in step-3 of example 79 which was further purified by combiflash on silica gel (24g column), eluted with 1.5% methanol in dichloromethane afforded the title compound (1.47 g). LCMS: 451.5 (M-l00) ⁺ .

[001063] Step-5 :2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbam oyl)-6- cyano-l-(naphthalen-l-ylmethyl)-lH-indole-3 -carboxylic acid

[001064] To a stirred solution of product of step-4 of example 101 (500 mg, 0.909 mmol) in tert-butanol (40 mL) was added 2 -Methyl-2 -butene (12 niL) at room temperature and cooled to 10 °C. Sodium chlorite (740 mg, 8.18 mmol) and sodium dihydrogen phosphate (740 mg, 6 135 mmol) were dissolved in water (7.5 mL) and added dropwise to above preparation at 0°C. Resulting reaction mixture was stirred at room temperature for overnight. TLC monitoring shown the presence of starting material. To above reaction mixture was added THF (40 mL) and acetonitrile (40 mL), cooled to 10°C and 1.5 equivalent of hydrogen peroxide was added followed by addition of aqueous solution (150 mL) of sodium chlorite and sodium dihydrogen phosphate. The resulting reaction mixture was stirred overnight (~16 h) at room temperature .After reaction completion, the reaction mixture was concentrated under reduced pressure. The residue obtained was diluted with water and acidified to pH 5.0 with citric acid maintaining the temperature l 0°C. The precipitated solid was filtered off and dried to afford title compound (510 mg). LCMS: 565.0 (M+l) ⁺ .

[001065] Step-6: 2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamo yl)-6-(N'- hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH-indole-3- carboxylic acid

[001066] The product of step-5of example 101 (150 mg, 0.215 mmol) was treated with hydroxylamine hydrochloride (46 mg, 0.662 mmol) afforded the title compound (158 mg) following the procedure described in step-4 of example 86. LCMS: 599.9 (M+l) ⁺ .

[001067] Step-7: 6-(N'-acetoxycarbamimidoyl)-2-(((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamoyl)-l-(naphthalen-l-y lmethyl)-lH-indole-3- carboxylic acid

[001068] The product of step-6 of example 101 (158 mg, 0.215 mmol) and acetic anhydride (0.3 mL) were treated together to afford 148 mg of the title compound following the procedure described in step-3 of example 82. Here reaction mixture was stirred for 8h. LCMS: 64l .8 (M+l) ⁺ .

[001069] Step-8: 2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamo yl)-6- carbamimidoyl- 1 -(naphthalen- 1 -ylmethyl)- lH-indole-3 -carboxylic acid

[001070] The product of step-7 of example 101 (148 mg, 0.230 mmol) was treated with 10% Palladium on carbon (35mg) in presence of hydrogen atmosphere for 4h afforded 92 mg of the title compound following the procedure described in step-4 of example 82. LCMS: 582.8.0(M-l) ⁺ .

[001071] Step-9: 2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-l-

(naphthalen- 1 -ylmethyl)- lH-indole-3 -carboxylic acid

[001072] The product of step-8 of example 101 (60 mg, 0.102 mmol) was treated with TFA (0.35 mL) in dichloromethane following the procedure described in step-6 of example 10. Here reaction mixture was stirred for 5h. The crude obtained was purified by preparative HPLC instrument using X-Bridge Cl8 reverse phase column (19 x l50mm, 5 micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 50% acetonitrile in water (0.1% TFA) which afforded the title compound (32 mg) as a TFA Salt.

[001073] LCMS: 482.3(M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.16-1.10 (m, 2H), 1.37-1.31 (m, 2H), 1.70-1.67(d, 2H), 1.92-1.90(d, 2H), 2.94 (m, 1H), 3.61 (m, 1H), 6.16 (s, 2H), 6.63- 6.6l(d, 1H), 7.32-7.28 (m, 1H), 7.64-7.57 (m, 3H), 7.84-7.8l(d, 1H), 7.96-7.94(d, 1H), 8.06 (s, 1H), 8.18—8. l6(d, 1H), 8.49-8.47(d, 1H); HPLC: 99.46 % (Retention Time= 4.56 min)

General synthetic scheme -16B

Example 102: Synthesis of compound 1-513:

[001074] N2-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen -l-ylmethyl)- lH-indole-2, 3-dicarboxamide

[001075] Step-l : tert-butyl ((lr,4r)-4-(3-carbamoyl-6-cyano-l-(naphthalen-l-ylmethyl)-lH - indole-2-carboxamido) cyclohexyl)carbamate

[001076] The product of step-5of example 101 (200 mg, 0.353 mmol) and ammonium chloride (95mg, 1.766 mmol) were treated to afford the title compound (188 mg) following the procedure described in step-3 of example 79. In this reaction after completion of reaction, ice cold water was added, and precipitated solid was filtered off and dried. LCMS: 566.2 (M+l) ⁺ .

[001077] Step-2: tert-butyl ((lr,4r)-4-(3-carbamoyl-6-(N'-hydroxycarbamimidoyl)-l-

(naphthalen- 1 -ylmethyl)- lH-indole-2-carboxamido)cyclohexyl)carbamate

[001078] The product of step-l of Example 102 (194 mg, 0.343 mmol) was treated with hydroxylamine hydrochloride (82 mg, 1.2 mmol) afforded the title compound (187 mg) following the procedure described in step-4 of example 86. LCMS: 599.4 (M+l) ⁺ .

[001079] Step-3: tert-butyl ((lr,4r)-4-(6-(N'-acetoxycarbamimidoyl)-3-carbamoyl-l-

(naphthalen- 1 -ylmethyl)- lH-indole-2-carboxamido)cyclohexyl)carbamate

[001080] The product of step-2 of Example 102 (187 mg, 0.312 mmol) and acetic anhydride (0.32 mL) were treated together to afford 200 mg of the title compound following the procedure described in step-3 of example 82. Here reaction mixture was stirred for 12 h. LCMS: 642 (M+l) ⁺ .

[001081] Step-4: tert-butyl ((lr,4r)-4-(6-carbamimidoyl-3-carbamoyl-l-(naphthalen-l- ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate

[001082] The product of step-3 of Example 102 (200 mg, 0.312 mmol) was treated with 10% Palladium on carbon (50 mg) in presence of hydrogen atmosphere for 4h afforded 167 mg of the title compound following the procedure described in step-4 of example 82. LCMS: 583.5(M+l) ⁺ .

[001083] Step-5: N2-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen -l- ylmethyl)-lH-indole-2, 3 -dicarboxamide

[001084] The product of step-4 of Example 102 (67 mg, 0.1 15 mmol) was treated with TFA (0.35 mL) in dichloromethane and the reaction mixture was stirred for 5h. The crude obtained was purified by preparative HPLC instrument using X-Bridge Cl 8 reverse phase column (19 x l50mm, 5 micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 50% acetonitrile in water (0.1% TFA) which afforded the title compound (39 mg) as a TFA Salt.

[001085] LCMS: 48l .4(M-l) ⁺ ; ¹ HNMR(600MHz, CD ₃ OD): 51.22-1.15 (m, 2H), 1.35-1.31

(m, 2H), 1.75-1.73(d, 2H), 1.92-1.90(d, 2H), 2.95 (m, 1H), 3.61 (m, 1H), 6.25 (s, 2H), 6.48-

6.47(d, 1H), 7.24-7.23(t, lH), 7.57-7.53 (m, 1H), 7.63-7.61 (m, 1H), 7.69-7.67 (m, 1H), 7.79- 7.77(d, 1H), 7.9l(d, 1H), 8.05 (s, 1H), 8. l6-8. l5(d, 1H), 8.26-8.24(d, 1H); HPLC: 97.58% (Retention Time= 4.63 min)

General synthetic scheme -16C

Example 103: Synthesis of compound 1-514:

[001086] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-cyano-l-(nap hthalen-l- ylmethyl)-lH-indole-2-carboxamide

[001087] Step-l :tert-butyl ((lr,4r)-4-(6-(N-(tert-butoxycarbonyl)carbamimidoyl)-3- carbamoyl- 1 -(naphthalen- 1 -ylmethyl)- lH-indole-2-carboxamido)cyclohexyl)carbamate

[001088] To a stirred solution of product of step-4 of Example 103 (80 mg, 0.137 mmol) in THF (5 mL) was added 1N aq. solution of sodium hydroxide (5.5 mg, 0l37mmol) at l0°C and stirred for 15 min. followed by addition of di-tert-butyl dicarbonate (30 mg, 0.206 mmol). The resulting reaction mixture was stirred for overnight (-16 h) at room temperature. After reaction completion, evaporated off the reaction mixture under reduced pressure. The residue obtained was diluted with water. The precipitated solid was filtered off and dried to give title compound (80 mg). LCMS: 683.05(M+l) ⁺ .

[001089] Step-2 : tert-butyl ((lr,4r)-4-(6-(N-(tert-butoxycarbonyl)carbamimidoyl)-3-cyano -

1 -(naphthalen- 1 -ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate

[001090] To a stirred solution of product of step-l of example 103 (80 mg, 0.137 mmol) and triethylamine (177 mg, 1.759 mmol) in dry dichloromethane (5.0 mL) was added trifluoroacetic anhydride (295 mg, 1.407 mmol) at l0°C and resulting reaction mixture was stirred at room temperature for overnight (-16 h). After reaction completion, reaction mixture was diluted with dichloromethane washed with aq. sodium bicarbonate solution. The organic layer separated, dried over sodium sulphate and concentrated under reduced pressure afforded the title compound (71 mg). LCMS: 665.4(M+l) ⁺ .

[001091] Step-3 : N-(( 1 r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3 -cyano- 1 -(naphthalen- 1 -ylmethyl)- lH-indole-2-carboxamide

[001092] The product of step-2 of example 103 (71 mg, 0.106 mmol) was treated with TFA (0.20 mL) in dichloromethane. The crude obtained was purified by preparative HPLC using X- Bridge Cl 8 reverse phase column (19 x l50mm, 5 micron). The mobile phases were 20% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (20 mg) as a TFA Salt.

[001093] LCMS: 465.2 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.41-1.26 (m, 4H), 1.81- l.78(d, 2H), l.99-l.96(d, 2H), 2.99 (m, 1H), 3.68 (m, 1H), 6.33 (s, 2H), 6.6l-6.60(d, 1H), 7.32- 7.28(t,lH), 7.64-7.57 (m, 2H), 7.85-7.78 (m, 2H), 7.96-7.94(d, 1H), 8.06-8.04 (m, 1H), 8.14- 8. l2(d, 1H), 8.243-8.240(d, 1H); HPLC: 99.50% (Retention Time= 4.94 min)

General synthetic scheme -16D

Example 104: Synthesis of compound 1-515

[001094] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-formyl-l-(na phthalen-l- ylmethyl)-lH-indole-2-carboxamide

[001095] Step-l : Ethyl 2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-3-formyl-l-(naphtha len-

1 -ylmethyl)- lH-indole-6-carbimidate

[001096] Product of step-4 of example 101 (150 mg, 0.272mmol) was treated with ethanolic HC1 (5 mL) and 1,4 dioxane HC1 (10 mL) for 4 days afforded the 235 mg of title compound as crude following the procedure described in step-4 of example 79. LCMS: 497.2 (M+l) ⁺ .

[001097] Step-2: N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-formyl-l-(na phthalen- 1 -ylmethyl)- lH-indole-2-carboxamide

[001098] Product of step-l of example 104 (135 mg, 0.272mmol) was treated with methanolic ammonia (20 ml) afforded the 27 mg crude product following the procedure described in step-5 of example 1. The crude obtained was purified by preparative HPLC instrument using Zorbax XDB Cl 8 reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 25% acetonitrile in water (0.1% TFA) which afforded the title compound (3 mg) as a TFA Salt. LCMS: 468.3 (M+l) ⁺ ; ¹ HNMR(600MHz, CD ₃ OD): 51.16-1.10 (m, 2H), 1.35-1.31 (m, 2H), 1.68-1.66 (d, 2H), 1.90-1.88 (d, 2H), 2.90 (m, 1H), 3.63 (m, 1H), 6.25 (s, 2H), 6.62-6.6l(d, 1H), 7.29-7.26(t,lH), 7.62-7.55 (m, 2H), 7.77-7.75(d, 1H), 7.82- 7.8l(d, 1H), 7.93-7.92(d, 1H), 8. l3-8. l l(d, 1H), 8.16 (s, 1H), 8.59-8.57(d, 1H), 10.14 (s, 1H); HPLC: 98.86% (Retention Time=5.08 min).

Example 105: Synthesis of compound 1-516:

[001099] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-(hydroxymeth yl)-l- (naphthalen-l-ylmethyl)-lH-indole-2-carboxamide

[001100] Step-l : tert-butyl((lr,4r)-4-(6-cyano-3-(hydroxymethyl)-l-(naphthale n-l- ylmethyl)-lH-indole-2-carboxamido) cyclohexyl)carbamate

[001101] To a stirred solution of product of step-4 of example 101 (250 mg, 0.454 mmol) in methanol (30 mL) was added sodium borohydride (86 mg, 2.292 mmol) at 0°C and resulting reaction mixture was stirred at room temperature for overnight (~l6h). After reaction completion, reaction mixture was concentrated under reduced vacuum. The residue obtained was diluted with water; precipitated solid was filtered off and dried completely afforded 250 mg of title compound. LCMS: 535.75 (M-l7) ⁺ .

[001102] Step-2: tert-butyl ((lr,4r)-4-(6-carbamimidoyl-3 -(hydroxymethyl)- l-(naphthalen-

1 -ylmethyl)- lH-indole-2-carboxamido)cyclohexyl)carbamate

[001103] T he product of step-l of example 105 (230 mg, 0.416 mmol) was treated consequently in three steps with hydroxyl amine hydrochloride, acetic anhydride followed by hydrogenation with 10% palladium carbon following the procedure described in step-4, step-5 and step-6 of example 100 afforded the 171 mg of title compound. LCMS: 570.3 (M+l) ⁺ .

[001104] Step-3 :N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-(hydroxymet hyl)-l- (naphthalen- 1 -ylmethyl)- lH-indole-2-carboxamide

[001105] The product of step-2 of example 105 (70 mg, 0.123 mmol) was treated with 4 M solution of HC1 in 1,4 dioxane afforded the crude product following the procedure described in step-3 of example 83. The crude obtained was purified by preparative HPLC instrument using Gemini -NX Cl 8 reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 5% acetonitrile in water (0.02 % TFA) to 30% acetonitrile in water (0.02 % TFA) which afforded the title compound (12 mg) as a TFA Salt.

[001106] LCMS: 470.2 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.44-1.23 (m, 4H), 1.98-1.85 (m, 4H), 3.01 (m, 1H), 3.68 (m, 1H), 4.98 (s, 2H), 6.34 (s, 2H), 6.40-6.38(d, 1H), 7.25-7.2 l(t, lH), 7.65-7.55 (m, 3H), 7.79-7.77(d, 1H), 7.94-7.92(d, 1H), 8.03 (s, 1H), 8. l0-8.07(d, 1H), 8.20- 8.18(d, 1H); HPLC: 89.62% (Retention Time= 8.17 min).

Example 106: Synthesis of compound 1-517:

[001107] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-3-(methoxymeth yl)-l- (naphthalen-l-ylmethyl)-lH-indole-2-carboxamide

[001108] While isolation of step-3 of example 105 by preparative HPLC method methanol was added for solubilising purpose which leaded the title compound as side product isolated by preparative HPLC method using Zorbax XDB reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 15% acetonitrile in water (0.1% TFA) to 40% acetonitrile in water (0.1% TFA) which afforded the title compound (1.7 mg) as a TFA Salt.

[001109] LCMS: 484.4 (M+l) ⁺ ; ¹ HNMR(400MHz, CD3OD): 51.30-1.24 (m, 2H), 1.43-1.39 (m, 2H), l .87-l .84(d, 2H), 2.00-l .97(d, 2H), 3.04 (m, 1H), 3.46 (s, 3H), 3.67 (m, 1H), 4.85 (s, 2H), 6.33 (s, 2H), 6.4l-6.39(d, 1H), 7.26-7.25(t, lH), 7.64-7.57 (m, 3H), 7.79-7.77(d,lH), 7.94- 7.92(d, 1H), 8.08-8.05 (m, 2H), 8. l9-8. l7(d, 1H); HPLC: 97.15% (Retention Time= 5.01 min).

General synthetic scheme -17:

PG = optional protecting group; X = Br or Cl;

Example 107: Synthesis of compound 1-518

[001110] tert-butyl ((lr,4r)-4-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-ind ole- 3-carboxamido) cyclohexyl) carbamate

[001111] Step-l : 6-cyano-lH-indole-3 -carboxylic acid

[001112] The title compound mentioned above was prepared from lH-indole-6-carbonitrile in two steps as described in literature procedure of Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, 1, p. 81 86.

[001113] Step-2: tert-butyl ((lr,4r)-4-(6-cyano-lH-indole-3- carboxamido)cyclohexyl)carbamate

[001114] The product of step-l of example 107 (750mg, 4.02mmol) and tert-butyl ((lr,4r)- 4-amino cyclohexyl) carbamate (879 mg, 4.1 mmol) were treated together to afford 740 mg of the title compound following the procedure described in step-3 of example 79. LCMS: 383.0 (M+l) ⁺ .

[001115] Step-3: tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-3- carb ox ami do)cy cl ohexyl) carb am ate [001116] The product of step-2 of example 107 (350 mg, 0.915 mmol) was treated with 1- (bromomethyl) naphthalene (222mg, 1.006 mmol) afforded the title compound (520 mg) following the procedure described in step-l of example 79. In this reaction, reaction mixture was stirred for 5h at room temperature. LCMS: 523.5 (M+l) ⁺ .

[001117] Step-4: tert-butyl ((lr,4r)-4-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indole-3-carboxamido)cyclohexyl) carbamate

[001118] The product of step-3 of example 107 (550 mg, 1.05 mmol) was treated consequently in three steps with hydroxyl amine (50% in water), acetic anhydride followed by hydrogenation with 10% palladium carbon following the procedure described in step-l, step-2 and step-3 of example 88 gave the 560 mg of crude compound which was further purified (150 mg) by preparative TLC (mobile phase: 8% methanol in dichloromethane) afforded 55 mg of title compound.

[001119] LCMS: 540.0 (M+l) ⁺ ; ¹ HNMR(CDCl ₃ , 400MHz): 50.81-0.71 (m, 4H), 1.33-1.15 (m, 9H), 1.89-1.88 (m, 4H), 3.23 (m, 1H), 3.76 (m, 1H), 5.76 (s, 2H), 6.99-6.97(dd, lH), 7.34- 7.30 (t, lH), 7.50-7.41 (m, 3H), 7.64 (s, 1H), 7.85-7.76 (m, 3H), 7.930 (s, 1H), 8.24-8.22(dd,lH); HPLC: 94.43% (Retention Time= 9.18 min).

Example 108: Synthesis of compound 1-519:

[001120] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen- l-ylmethyl)- lH-indole-3-carboxamide

[001121] Step-l :N-((lr, 4r)-4-aminocyclohexyl)-6-carbamimidoyl-l -(naphthalen-l- ylmethyl)-lH-indole-3-carboxamide

[001122] The product of step-4 of example 108 (100 mg, 0.185 mmol) was treated with TFA (0.5 mL) in dichloromethane following the procedure described in step-6 of example 88. The crude obtained was purified by preparative HPLC instrument using Gemini -NX C18 reverse phase column (2l .2 x l50mm, 5 micron). The mobile phases were 30% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (45 mg) as a TFA Salt.

[001123] LCMS: 440.2 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.53-1.27 (m, 4H), 2.07-2.04 (m, 4H), 3.06 (m, lH),3.84 (m, 1H), 6.0 (s, 2H), 7. l5-7. l3(dd,lH), 7.46-7.42 (t, lH), 7.55-7.46 (m, 2H), 7.66-7.63(dd, lH), 7.98-7.91 (m, 4H), 8.177-8.174 (s, 1H), 8.43-8.4l(dd,lH); HPLC: 95.01% (Retention Time= 4.97 min).

[001124] Following compound listed in table-34 prepared according to general scheme-l7 by following similar procedure as described above for the examples 108 using appropriate reagents with suitable modifications known to the one skilled in the art

[001125] Table-34: Compounds synthesized using General Scheme -17

General synthetic scheme -17A:

Example 109: Synthesis of compound 1-521:

[001126] l-(naphthalen-l-ylmethyl)-lH-indole-6-carboximidamide

[001127] Step-l : l-(naphthalen-l-ylmethyl)-lH-indole-6-carbonitrile

[001128] lH-indole-6-carbonitrile was treated with (300 mg, 2.1 mmol) was treated with 1- (bromomethyl) naphthalene (560 mg, 2.5 mmol) and gave the crude product following the procedure described in step-l of example 81. The reaction mixture was stirred for overnight at room temperature. The crude product obtained was further purified by combiflash on silica gel (40 g) and eluted with dichloromethane afforded the 530 mg of title compound. LCMS: 283.05(M+l)

+

[001129] Step-2 : 1 -(naphthalen- 1 -ylmethyl)- lH-indole-6-carboximidamide

[001130] Product of step-l of example 109 (200 mg, 0.7mmol) was treated with solid LiHMDS (0.827 mg, 4.9 mmol) afforded crude product (220 mg) following the procedure described in step-l of example 90. The crude obtained was purified by preparative HPLC instrument using Zorbax XDB C18 reverse phase column (21.2 x l50mm, 5 micron). The mobile phases were 20% acetonitrile in water (0.1% TFA) to 60% acetonitrile in water (0.1% TFA) which afforded the title compound (90 mg) as a TFA Salt. LCMS: 300.2 (M+l) ⁺ ; ¹ HNMR (400 MHz, CD ₃ OD): d 6.00 (s, 2H), 6.69-6.70 (m, 1H), 6.89-6.91 (m, 1H), 7.36-7.39 (m, 1H), 7.47- 7.57 (m, 4H), 7.83-7.88 (m, 2H), 7.94 - 8.03 (m, 1H), 8.06 (s, 1H), 8.06 - 8.08 (m, 1H); HPLC: 99.14% (Retention Time=6.49 min).

General synthetic scheme -18:

Example 110: Synthesis of compound 1-522:

[001131] 2-(N-((lr,4r)-4-aminocyclohexyl)sulfamoyl)-l-(naphthalen-l-y lmethyl)-lH- indole-6-carboximidamide

[001132] Step-l : l-(phenylsulfonyl)-lH-indole-6-carbonitrile

[001133] The title compound mentioned above was prepared from lH-indole-6-carbonitrile as described in Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9480 9497.

[001134] Step-2: 6-cyano-l-(phenylsulfonyl)-lH-indole-2-sulfonyl chloride

[001135] Stage-l : Product of step-l of example 110 (l .Og, 3.546) dissolved in THF (15 mL), cooled to -70°C under nitrogen atmosphere and was added n-butyl lithium (1.7 M in n-hexane) (2.29 mL, 3.90 mmol) dropwise maintaining the same temperature. The resulting reaction mixture was stirred at -70°C for 35 min followed by purging of sulphur dioxide gas for 15 min. The reaction mixture was gradually warmed to room temperature over 2 h. After reaction completion, the reaction mixture was diluted with hexane (2 X 50 mL) and stirred for 15 min and hexane layer was decanted off and dried to give the lithium salt (1.7 g).

[001136] Stage-2: To a stirred solution of product of stage-l (lithium salt) in dichloromethane was added N-chlorosuccinimide (700 mg, 5.319 mmol) at 0°C and resulting reaction mixture was stirred at room temperature for l2h. After reaction completion, the reaction mixture was filtered through celite bed and washed with dichloromethane. Collected filtrate was concentrated under reduced pressure, residue obtained was diluted with 20 % dichloromethane in hexane, precipitated solid filtered and washed with dichloromethane. The solid was discarded and collected filtrates were concentrated to give title compound as crude (1.25 g). LCMS: 360.6 (M-19, sulphonic acid) ⁺ .

[001137] Step-3 : tert-butyl ((lr,4r)-4-((6-cyano-lH-indole)-2- sulfonamido)cyclohexyl)carbamate.

[001138] Stage-l : To a 0°C cooled stirred solution of product of step-2 of example 1 10 (250 mg, l . lmmol) in dichloromethane (15 mL) was added triethylamine (0.81 mL, 5.8 mmol), stirred for 5 min followed by addition of tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate (0.976 g, 2.5 mmol). The resultant reaction mixture was stirred at room temperature for l6h. After reaction completion, the reaction mixture was concentrated under reduced pressure. The crude obtained (1.8 g) was proceeded to next stage.

[001139] Stage-2: To a solution of crude obtained in stage-l above in ethanol (6 mL) was added 10% sodium hydroxide solution (6 mL) and stirred at 80°C for lh. After reaction completion distilled off ethanol completely and crude obtained was diluted with water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude residue obtained above was purified by combiflash on silica gel eluted with 55% ethyl acetate in hexane afforded the title compound (150 mg). LCMS: 557.75 (M+l) ⁺ .

[001140] Step-4 : tert-butyl (( 1 r,4r)-4-((6-cyano- 1 -(naphthalen- 1 -ylmethyl)- 1 H-indole)-2- sulfonamido) cyclohexyl) carbamate (polar compound)

[001141] Product of step-3 of example 110 (600 mg, 1.4 mmol) treated with 1- (bromomethyl)naphthalene (3 l7mg, 1.4 mmol) afforded the crude product following the procedure described in step-7 of example 97. Here reaction was stirred at room temperature for 16 h. The crude obtained above was purified by combiflash on silica gel eluted with 20% ethyl acetate in hexane afforded the title compound (230 mg) from polar fractions. LCMS: 559.3 (M+l) ⁺

[001142] The non-polar compound isolated (400 mg) was confirmed as di alkylated product tert-butyl ((lr,4r)-4-((6-cyano-N, l-bis(naphthalen-l-ylmethyl)-lH-indole)-2- sulfonamido)cyclohexyl) carbamate. LCMS: 643.5(M-56) ⁺

[001143] Step-5: tert-butyl ((lr,4r)-4-((6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indole)-2-sulfonamido) cyclohexyl)carbamate

[001144] The polar product of step-4 of example 110 (200 mg, 0.3 mmol) was treated in consequent three steps with hydroxyl amine (50% in water), acetic anhydride followed by hydrogenation with 10% palladium carbon (here hydrogenation carried out in ethanol at room temperature for 2h) following the procedure described in step-l, step-2 and step-3 of example 88 afforded the 120 mg of title compound. LCMS: 576.85 (M+l) ⁺

[001145] Step-6:2-(N-((lr,4r)-4-aminocyclohexyl)sulfamoyl)-l-(naphtha len-l-ylmethyl)- lH-indole-6-carboximidamide

[001146] Product of step-5 of example 110 (120 mg, 0.2 mmol) was treated with TFA (0.3 mL). The crude obtained was purified by preparative HPLC instrument using Zorbax XDB Cl 8 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 50% acetonitrile in water (0.1% TFA) which afforded the title compound (45 mg) as a TFA Salt. LCMS: 474.5 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): 51.25-1.20 (m, 4H), 1.76- 1.72 (m, 2H), 1.88-1.84 (m, 2H), 2.95-2.88 (m, 1H), 3.10-3.05 (m, 1H), 6.26-6.25(d, 1H), 6.34 (s, 2H), 7.23-7. l9(t, lH), 7.43 (s, 1H), 7.60-7.58 (m, 2H), 7.69-7.65(t, lH), 7.79-7.76 (m, 2H), 8.01-7.93 (m, 2H), 8.24-8.22(d, 1H); HPLC: 98.96% (Retention Time= 5.46 min).

[001147] Following compound listed in table-35 prepared according to general scheme-l8 starting from the non-polar product of step-4 of example 110 by following similar procedure as described above for the examples 110 using appropriate reagents with suitable modifications known to the one skilled in the art

[001148] Table 35: Compounds synthesized using General Scheme -18

General synthetic scheme -19:

Example 111: Synthesis of compound 1-524:

[001149] tert-butyl ((lr,4r)-4-(5-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indol-2-yl)- 1 ,3,4-oxadiazol-2-yl) c clohexyl)car hamate

[001150] Step-l : 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbohydrazide

[001151] To a solution of product of step-l of example 79 (700mg, 1.977 mmol) in ethanol (10 mL) was added hydrazine hydrate monohydrate (2 mL) and stirred at 90°C for overnight (-16 h). Evaporated off the reaction mixture under reduced pressure, diluted with ice cold water, precipitated solid was filtered off and dried to afford the title compound (600 mg) as crude. LCMS: 341.1 (M+l) ⁺

[001152] Step-2: tert-butyl ((lr,4r)-4-(2-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2 - carbonyl)hydrazine- 1 -carbonyl)cyclohexyl)carbamate

[001153] To a solution of product of step-l of example-l l l (600 mg, 1.764 mmol) and (lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-l -carboxylic acid (471 mg, 1.941 mmol) in DMF was added TBTU (850 mg, 2.646 mmol) and N, N-Diisopropylethylamine (456 mg, 3.528 mmol) and stirred at room temperature for overnight (~l6h). After reaction completion, ice-cold water was added and the precipitated solid was filtered off to give title compound (1.0 g) as crude. LCMS: 466.3 (M-l00) ⁺

[001154] Step-3 : tert-butyl ((lr,4r)-4-(5-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2- yl)-l,3,4-oxadiazole-2-carbonyl)cyclohexyl)carbamate

[001155] To a solution of product of step-2 of example-l 11 (1 0g, 1.769 mmol) in acetonitrile was added N, N-Diisopropylethylamine (456 mg, 3.538 mmol) and 4-Toluenesulfonyl chloride (1.0 g, 5.309 mmol) and stirred for 4h at room temperature. Evaporated reaction mixture under reduced pressure and crude obtained was purified by combiflash on silica gel, eluted with 0.2% methanol in dichloromethane afforded the title compound (750 mg).

[001156] Step-4: tert-butyl ((lr,4r)-4-(5-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indol-2-yl)-l,3,4-oxadiazole-2-carbonyl)cyclohexyl)carbamate

[001157] The product of step-3 of example-l 11 (1 0g, 1.769 mmol) was treated consequently in three steps with hydroxyl amine hydrochloride, acetic anhydride followed by hydrogenation with 10% palladium carbon (here hydrogenation carried out in ethanol and acetic acid at room temperature for 3h) following the procedure described in step-4, step-5 and step-6 of example 100 afforded the 180 mg of title compound. LCMS: 565.4 (M+l) ⁺ ; ¹ HNMR(300MHz, CD ₃ OD): d 1.29-1.17 (m, 4H), 1.43 (s, 9H), 1.91 (s, 3H), 1.98-1.93 (m, 5H), 2.79-2.75 (m, 1H), 6.22-6. l9(d, 1H), 6.57 (s, 2H), 7. l9-7. l4(t,lH), 7.76-7.57 (m, 5H), 7.95-7.93(d, 1H), 8.04-8.01 (m, 2H), 8.29- 8.26(d, 1H); HPLC: 91.35% (Retention Time= 7.02 min).

Example 112: Synthesis of compound 1-525

[001158] 2-(5-((lr,4r)-4-aminocyclohexyl)-l,3,4-oxadiazol-2-yl)-l-(na phthalen-l- ylmethyl)-lH-indole-6-carboximidamide

[001159] The product of step-4 of example-l l l (l .Og, 1.769 mmol) was treated with TFA (0.3 mL) following the procedure described in step-6 of example 88. The crude product obtained was triturated with diethyl ether afforded the title compound (l40mg) as a TFA salt. LCMS: 465.2 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): d 1.45-1.42 (m, 4H), 2.07-2.04 (m, 4H), 3.00-2.80 (m, 2H), 6.35-6.25(d, 1H), 6.58 (s, 2H), 7.20-7. l5(t,lH), 7.76-7.61 (m, 5H), 7.95-7.93(d, 1H), 8.04-8.02 (m, 2H), 8.30-8.28(d, lH);HPLC: 95.29% (Retention Time= 5.23min).

General synthetic scheme -19A:

Example 113: Synthesis of compound 1-526

[001160] 2-(5-((lr,4r)-4-aminocyclohexyl)-l,3,4-thiadiazol-2-yl)-l-(n aphthalen-l- ylmethyl)-lH-indole-6-carboximidamide

[001161] Step-l : tert-butyl ((lr,4r)-4-(5-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2- yl)-l,3,4-thiadiazole-2-carbonyl)cyclohexyl)carbamate

[001162] To a solution of product of step-2 of example-l 11 (450 mg, 0.796 mmol) was added Lawesson's reagent (643 mg, 1.592 mmol) and irradiated in microwave at l20°C for 1.5 h. After reaction completion, ice cold water was added, extracted with ethyl acetate (2 X 20 mL). The organic layers separated, dried over sodium sulphate and concentrated under reduced pressure. The crude obtained was purified by combiflash on silica gel, eluted with 30% ethyl acetate in hexane afforded the title compound (30 mg). LCMS: 492.4 (M-l00) ⁺

[001163] Step-2: tert-butyl ((lr,4r)-4-(5-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indol-2-yl)-l,3,4-thiadiazole-2-carbonyl)cyclohexyl)carbamat e

[001164] The product of step-l of example-l 13 (3 l0mg, 0.550 mmol) was treated consequently in three steps with hydroxyl amine hydrochloride, acetic anhydride followed by hydrogenation with 10% palladium carbon (here hydrogenation carried out in methanol for 3h) following the procedure described in step-4, step-5 and step-6 of example 100 afforded the 170 mg of title compound. LCMS: 609.5 (M+l) ⁺

[001165] Step-3 : 2-(5-((lr,4r)-4-aminocyclohexyl)-l,3,4-thiadiazol-2-yl)-l-(n aphthalen-l- ylmethyl)-lH-indole-6-carboximidamide

[001166] The product of step-2 of example-l 13 (l70mg, 0.293 mmol) was treated with TFA (0.3 mL) following the procedure described in step-6 of example 88. The crude obtained was purified by preparative HPLC instrument using Zorbax ECLIPSR XDB C 18 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 10% acetonitrile: methanol (1 : 1) in water (0.1% TFA) to 50% acetonitrile: methanol (1 : 1) in water (0.1% TFA) which afforded the title compound (15 mg) as a TFA Salt. [001167] LCMS: 481.3 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): d 1.72-1.53 (m, 4H), 2.27- 2.13 (m, 4H), 3.18-3.14 (m, 2H), 6.24-6.22(d, 1H), 6.66 (s, 2H), 7.l9-7. l5(t,lH), 7.48 (s, 1H), 7.75-7.60 (m, 4H), 8.01-7.92 (m, 3H), 8.26-8.24(d, 1H); HPLC: 96.46% (Retention Time= 4.43 min).

Example 114: Synthesis of compound 1-527

[001168] 2-(5-((lr,4r)-4-aminocyclohexyl)-l,3,4-thiadiazol-2-yl)-l-(n aphthalen-l- ylmethyl)-lH-indole-6-carboxamide

[001169] The title compound mentioned above was isolated (20 mg) as TFA salt in preparative HPLC purification of product of step-3 of example- 113

[001170] LCMS: 482.3 (M+l) ⁺ ; ¹ HNMR(400MHz, CD ₃ OD): d 1.70-1.50 (m, 4H), 2.25- 2.10 (m, 4H), 3.15-3.07 (m, 2H), 6.2l-6.l8(d, 1H), 6.59 (s, 2H), 7.l6-7. lO(t,lH), 7.35 (s, 1H), 7.74-7.54 (m, 4H), 7.91-7.81 (m, 2H), 8.01 (s, 1H), 8.24-8.2l(d, 1H); HPLC: 98.70% (Retention Time= 5.99 min).

General synthetic scheme -19B:

Example 115: Synthesis of compound 1-528

[001171] 2-(5-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-l-(naphth alen-l- ylmethyl)-lH-indole-6-carboximidamide

[001172] Step-l : 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxamide

[001173] Product of step-2 of example 1 (400 mg, 1.2 mmol) was treated with ammonium chloride (135 mg, 2.4 mmol) following the procedure described in step-6 of example 398 afforded the title compound (400 mg) as crude. LCMS: 324.4 (M+l) ⁺ .

[001174] Step-2: 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbothioamide

[001175] To a solution of product of step-l of example-H5 (350 mg, 1.0 mmol) in THF (5 mL) was added Lawesson's reagent (810 mg, 2.0 mmol) and irradiated in microwave at l50°C for lh. Evaporated the reaction mixture and crude obtained was purified by combiflash on silica gel eluted with 30% ethyl acetate in hexane afforded the title compound (180 mg). LCMS: 342.1 (M+l) ⁺ .

[001176] Step-3 : 2-(5-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-l-(naphth alen-l- ylmethyl)-lH-indole-6-carbonitrile

[001177] To a solution of product of step-2 of example-l 15 (50 mg, 0.114 mmol) in ethanol (2 mL) was added tert-butyl (3-bromo-4-oxocyclohexyl)carbamate (50 mg,0. l80 mmol) and resulting reaction mixture was refluxed for 6h. Evaporated off reaction mixture under reduce pressure afforded the title compound (110 mg) as crude. LCMS: 435.15 (M+l) ⁺ .

[001178] Step-4: tert-butyl (2-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl)-4, 5,6,7- tetrahydrobenzo[d]thiazol-5-yl)carbamate

[001179] To a stirred solution of product of step-3 of example 115 (340 mg, 0.78 mmol) and N,N-diisopropylethylamine (0.150 ml, 0.780 mmol) in THF (lOmL) was added di-tert-butyl dicarbonate (0.20 mL, 0.780 mmol). The resulting reaction mixture was stirred for 3h at room temperature. After reaction completion, water was added and extracted with ethyl acetate. Organic layer separated, dried over sodium sulphate and concentrated under reduced pressure. The crude obtained above was purified by combiflash on silica gel eluted with 20% ethyl acetate in hexane afforded the title compound (80 mg). LCMS: 535.2 (M+l) ⁺ .

[001180] Step-5: tert-butyl (2-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl) -

4,5,6,7-tetrahydrobenzo[d] thiazol-5-yl) carbamate

[001181] The product of step-4 of example 115 (80 mg, 0.150 mmol) was treated consequently in three steps with hydroxyl amine hydrochloride, acetic anhydride followed by hydrogenation with 10% palladium carbon (here hydrogenation carried out in methanol for 4h) following the procedure described in step-4, step-5 and step-6 of example 100 afforded the 50 mg of title compound as crude. LCMS: 552.25 (M+l) ⁺

[001182] Step-6:-2-(5-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-l -(naphthalen-l- ylmethyl)-lH-indole-6-carboximidamide

[001183] The product of step-5 of example 115 (50 mg, 0.01 mmol) was treated with TFA (0.2 mL) following the procedure described in step-6 of example 88. The crude obtained was purified by preparative HPLC instrument using Kinetex Cl 8 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 10% acetonitrile: methanol (1 : 1) in water (0.1% TFA) to 55% acetonitrile: methanol (1 : 1) in water (0.1% TFA) which afforded the title compound (5 mg) as a TFA Salt.

[001184] LCMS: 452.3 (M+l) ⁺ ; ¹ HNMR (400 MHz, CD ₃ OD): d 1.55- 1.16 (m, 2H), 1.86- 2.0 (m, 1H), 2.05-2.10 (m, 1H), 2.70-2.90 (m, 2H), 3.22-3.28 (m, 1H), 3.45-3.48 (m, 1H),

3.63-3.65 (m, 1H), 6.25 (d, 1H), 6.66 (s, 2H), 7.16 (t, 1H), 7.34 (s, 1H), 7.58-7.60 (m, 2H),

7.63-7.72 (m, 2H), 7.92-7.96 (m, 3H), 8.26 (d, 1H); HPLC: 96.82% (Retention Time= 5.15 min).

General synthetic scheme -20:

Example 116: Synthesis of compound 1-529

[001185] (lr,4r)-4-amino-N-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl) -lH-indol-2- yl) cyclohexane-l-carboxamide

[001186] Step-l : tert-butyl (6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl) carbamate.

[001187] To a solution of product of step-2 of example 79 (1.0 g, 3.067 mmol) in toluene (5 mL) and tert-butanol (1.0 mL) was added Diphenylphosphoryl azide (338 mg, 1 226mmol) followed by addition of N,N-diisopropylethylamine (0.352 mL, 2.02 mmol) at room temperature .The resulting reaction mixture was stirred at 80°C for overnight . After reaction completion evaporated off the reaction mixture, added ice cold water, extracted with ethyl acetate (2 X 20 mL) and separated organic layer was concentrated. The crude obtained was purified by combiflash on silica gel eluted with 20% ethyl acetate in hexane afforded the 70 mg of title compound. LCMS: 398.2 (M+l) ⁺

[001188] Step-2: 2-amino-l-(naphthalen-l-ylmethyl)-lH-indole-6-carbonitrile

[001189] The product of step-l of example 116 (655mg, 1.649 mmol) was treated with TFA

(1.0 mL) afforded the title compound (500 mg) as a TFA salt following the procedure described in step-6 of example 88. LCMS: 298. l(M+l) ⁺

[001190] Step-3 : tert-butyl ((lr,4r)-4-((6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2- yl)carbamoyl)cyclohexyl) carbamate

[001191] The product of step-2 of example 116 (250mg, 0.608 mmol) and (lr,4r)-4-((tert- butoxycarbonyl) amino) cyclohexane- 1 -carboxylic acid (178 mg, 0.729 mmol) treated together afforded the title product following the procedure described in step-3 of example 81, which was purified by combiflash on silica gel eluted with 1% methanol in dichlorom ethane to give title compound (180 mg). LCMS: 523.3(M+l) ⁺

[001192] Step-4: tert-butyl ((lr,4r)-4-((6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- indol-2-yl)carbamoyl)cyclohexyl) carbamate

[001193] The product of step-3 of example 116 (180 mg, 0.344 mmol) was treated consequently in three steps with hydroxyl amine hydrochloride, acetic anhydride followed by hydrogenation with 10% palladium carbon (here hydrogenation carried out in methanol for 2h) following the procedure described in step-4, step-5 and step-6 of example 100 afforded the 60 mg of title compound as crude. LCMS: 540.4 (M+l) ⁺

[001194] Step-5 : ( 1 r,4r)-4-amino-N-(6-carbamimidoyl- 1 -(naphthalen- 1 -ylmethyl)- 1H- indol-2-yl)cyclohexane-l -carboxamide

[001195] The product of step-4 of example 116 (60 mg, 0.1 11 mmol) was treated with TFA (0.2 mL) afforded the crude product following the procedure described in step-6 of example 88. The crude obtained was purified by preparative HPLC instrument using LUNA C18 reverse phase column (20 x 250mm, 5micron). The mobile phases were 10% acetonitrile in water (0.1% TFA) to 50% acetonitrile in water (0.1% TFA) which afforded the title compound (30 mg) as a TFA salt.

[001196] LCMS: 440.3 (M+l) ⁺ ; ¹ HNMR (300MHz, CD ₃ OD): d 1.48-1.24 (m, 4H), 1.97- 1.71 (m, 4H), 2.29-2.25 (m, 1H), 2.99-2.98 (m, 1H), 6.02 (s, 2H), 6.30-6.28(d, 1H), 6.82 (s, 1H), 7.25-7.20(t, lH), 7.68-7.52 (m, 3H), 7.95-7.77 (m, 4H), 8.20-8. l8(d, 1H); HPLC: 98.03% (Retention Time= 5.15 min.)

General synthetic scheme -21:

Example 117: Synthesis of compound 1-530:

[001197] tert-butyl ((lr,4r)-4-(6-(aminomethyl)-l-(naphthalen-l-ylmethyl)-lH-ind ole- 2-carboxamido)cyclohexyl) carbamate

[001198] Step-l : tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxamido) cyclohexyl) carbamate

[001199] Product of step-2 of example 81 (100 mg, 0.300 mmol) and tert-butyl ((lr,4r)-4- aminocyclohexyl) carbamate (78 mg, 0.300 mmol) were treated together afforded the title compound (150 mg) following the procedure described in step-3 of example 79. (In this step the solid precipitated out was filtered and dried to get the title compound). LCMS: 521.75 (M-l) ⁺ .

[001200] Step-2: tert-butyl ((lr,4r)-4-(6-(aminom ethyl)- l-(naphthalen-l-ylmethyl)-lH- indole-2-carboxamido) cyclohexyl) carbamate

[001201] To stirred solution of product of step-l of example 117 (130 mg, 0.200 mmol) in methanol was added Raney Ni (50 mg) and methanolic ammonia (5 mL). The resultant suspension was stirred at room temperature for overnight under the hydrogen atmosphere (balloon filled with hydrogen gas). After reaction completion, the reaction mixture was filtered through celite bed, washed with 10% methanol in dichlorom ethane and filtrate was concentrated under reduced pressure. The crude obtained was purified by preparative HPLC instrument using XBridge Cl 8 reverse phase column (20.0 x 150 mm, 5 micron). The mobile phases were 30% acetonitrile in water (10 mM ammonium bicarbonate) to 70% acetonitrile in water (10 mM ammonium bicarbonate) which afforded the title compound (12 mg).

[001202] LCMS: 528.4 (M+l) ⁺ ; ¹ HNMR (DMSO-de, 400MHz): 51.26-1.11 (m, 4H), 1.33 (s, 9H), 1.74-1.67 (m, 4H), 3.20-3.15 (m, 1H), 3.58-3.51 (m, 1H), 3.72 (s, 2H), 6. l2-6. l0(d, 1H), 6.34 (s, 2H), 6.70-6.68(d, 1H), 7.33-7.10 (m, 4H), 7.67-7.58 (m, 3H), 7.77-7.74(d, 1H), 7.98- 7.96(d, 1H), 8.31-8.24 (m, 2H); HPLC: 95.15% (Retention Time= 6.08 min)

Example 118: Synthesis of compound 1-531

[001203] N-((lr,4r)-4-aminocyclohexyl)-6-(aminomethyl)-l-(naphthalen- l-ylmethyl)- lH-indole-2-carboxamide

[001204] Product of step-2 of example 117 (80 mg, 0.150 mmol) was treated with TFA (0.2 mL) afforded the crude product (130 mg) following the procedure described in step-6 of example 88. The crude obtained was purified by preparative HPLC instrument using Zorbax C18 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 5% acetonitrile: methanol (1 : 1) in water (0.05% TFA) to 60% acetonitrile: methanol (1 : 1) in water (0.05% TFA) which afforded the title compound (45 mg) as a TFA salt. LCMS: 428.3 (M+l) ⁺ ; ¹ HNMR(DMSO-D ₂ 0, 400MHz): 51.30-1.29 (m, 4H), 1.91-1.65 (m, 4H), 3.01-2.90 (m, 1H), 3.58-3.50 (m, 1H), 3.99 (s, 2H), 6.07- 6.05 (d, 1H), 6.26 (s, 2H), 7.19-7.10 (m, 2H),7.22 (s, 1H), 7.43 (s, 1H), 7.65-7.50 (m, 2H),7.78- 7.75 (m, 2H), 7.95-7.90(d, 1H), 8.25-8.20(d, 1H); HPLC: 99.51% (Retention Time=5.59 min).

[001205] The following compound listed in table-36 prepared according to general scheme- 21 by following similar procedure as described above for example 118 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001206] Table-36: Compounds synthesized using General Scheme -21

General synthetic scheme -21A:

[001207] The following compound listed in table-37 prepared according to general scheme- 21 A starting from product of step-2 of example 95 by following similar procedure as described above for example 118 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001208] Table-37: Compounds synthesized using General Scheme -21 A

General synthetic scheme -21B:

MethodD:

H ₂ N-R ₂ -PG,HATU,

DIPEA, DMF PG - optional protecting group; X - Br or Cl;

Example 119: Synthesis of compound 1-538:

[001209] 6-(aminomethyl)-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylic acid

[001210] Step-l : 6-(aminomethyl)-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbox ylic acid [001211] Product of step-2 of example 398 (1.0 g, 3.06 mmol) was treated with Raney Ni (200 mg) in methanolic ammonia (50 mL) under hydrogen atmosphere at room temperature afforded the title compound (l . lOg) following the procedure described in step-2 of example 117. LCMS: 331.1 (M+l) ⁺ ; ¾ NMR (400 MHz, CD ₃ OD): d 4.12 (s, 2H), 6.15 (d, 1H), 6.46 (s, 2H), 7.17 (t, 1H), 7.25 (d, 1H), 7.43 (s, 1H), 7.52 (s, 1H), 7.58 (t, 1H), 7.66 (t, 1H), 7.73 (d, 1H), 7.86- 7.92 (dd,lH), 8.25 (d,lH); HPLC: 99.61% (Retention Time=5.89 min).

Example 120: Synthesis of compound 1-539:

[001212] 6-(((tert-butoxycarbonyl) amino)methyl)-l-(naphthalen-l-ylmethyl)-lH- indole-2-carboxylic acid

[001213] Step-l : 6-(((tert-butoxycarbonyl) amino)m ethyl)- l-(naphthalen-l -ylmethyl)-lH- indole-2-carboxylic acid

[001214] Product of step-l of example 119 (600mg, l .8l6mmol) was treated with di-tert- butyl dicarbonate (594 mg, 2.72 mmol) afforded the crude product (506 mg) following the procedure described in step-2 of example 90. The crude obtained above was purified by preparative TLC (Mobile phase: 3% methanol in dichloromethane, run twice) afforded the title compound (14 mg). LCMS: 429.2 (M+l) ⁺ ; ¾ NMR (400 MHz, CD ₃ OD): 51.27- 1.30 (d, 9H), 4.24 (s, 2H), 6.20 (d, 1H), 6.43 (s, 2H), 7.04-7.12 (m, 1H), 7.14-7.22 (m, 2H), 7.64 (m, 2H), 7.41 (s, 1H), 7.70 (dd, 2H), 7.91 (d, 1H), 8.25 (d, 1H); HPLC: 97.76% (Retention Time=6.68 min).

[001215] The following compound listed in table-38 prepared according to general scheme- 21B starting from example 120 by following similar procedure as described above for example 117 and 118 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001216] Table-38: Compounds synthesized using General Scheme -21B

General synthetic scheme -21C:

Example 121: Synthesis of compound 1-542:

[001217] N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen- l-ylmethyl)- lH-benzo[d]imidazole-2-carboxamide

[001218] Step-l : 2-(trichloromethyl)-lH-benzo[d]imidazole-6-carbonitrile

[001219] The title compound mentioned above was prepared as described in Bioorganic and

Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 586 - 590

[001220] Step-2: tert-butyl ((lr,4r)-4-(6-cyano-lH-benzo[d]imidazole-2- carboxamido)cyclohexyl)carbamate

[001221] Product of step-lof example 121 in 30 mL of THF: Water (2: 1) was added sodium bicarbonate (1.6 g, 19.2 mmol), stirred for 10 min at room temperature and was added tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate (411 mg, 1.92 mmol). The resultant reaction mixture was stirred at room temperature for 4h. Evaporated off the reaction mixture under reduced pressure, water was added and extracted with dichloromethane. Separated the organic layers, dried over sodium sulphate and concentrated under reduced pressure afforded the title compound (540 mg). LCMS: 382.30 (M-l) ⁺ .

[001222] Step-3: tert-butyl ((lr,4r)-4-(6-cyano-l-(naphthalen-l-ylmethyl)-lH- benzo[d]imidazole-2-carboxamido) cyclohexyl) carbamate (Polar) & tert-butyl ((lr,4r)-4-(5- cyano-l-(naphthalen-l-ylmethyl)-lH-benzo[d]imidazole-2-carbo xamido) cyclohexyl) carbamate (non-polar)

[001223] Product of step-2 of example 121 (540mg, 1.40 mmol) and l-(bromomethyl) naphthalene (467mg, 2.11 mmol) were treated together afforded the crude product (340 mg) following the procedure described in step-l of example 22. The crude product was a mixture of both title polar and non-polar compounds which were separated by combiflash on silica gel (40 g column) eluted with 50% ethyl acetate in hexane afforded the title compound (l50mg) from polar fractions. LCMS: 523.85(M+l) ⁺ .

[001224] The non-polar compound isolated (120 mg) was confirmed as regioisomer. LCMS: 523.9 (M+l) ⁺ .

[001225] Step-4: tert-butyl ((lr,4r)-4-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH- benzo[d]imidazole-2-carboxamido) cyclohexyl) carbamate

[001226] The polar product of step-3 of example 121 (l50mg, 0.464 mmol) was treated in consequent three steps with hydroxyl amine (50% in water), acetic anhydride followed by hydrogenation with 10% palladium carbon (here hydrogenation carried out in ethanol at room temperature for 5h) following the procedure described in step-l, step-2 and step-3 of example 88 afforded the 60 mg of title compound. LCMS: 541.75 (M+l) ⁺ . [001227] Step-5: N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-(naphthalen- l- ylmethyl)-lH-benzo[d]imidazole-2-carboxamide

[001228] fhe product of step-4 of example 121 (60 mg, 0.110 mmol) was treated with TFA (0.3 mL) afforded the crude product (130 mg) following the procedure described in step-5 of example 81.

[001229] The crude obtained was purified by preparative HPLC instrument using Kinetex EVO Cl 8 reverse phase column (21.2 x l50mm, 5micron). The mobile phases were 15% acetonitrile in water (0.1% TFA) to 40% acetonitrile in water (0.1% TFA) which afforded the title compound (30 mg) as a TFA Salt.

[001230] LCMS: 441.1 (M+l) ⁺ ; ¹ H NMR(CD ₃ OD, 300 MHz) : d 1.58-1.48 (m, 4H), 2.07- 1.99 (m, 4H), 3.10 (m, 1H), 3.81 (m, 1H), 6.46-6.44(d, 1H), 6.56 (s, 2H), 7.28-7.23(t,lH), 7.65- 7.58 (m, 2H), 7.8l-7.62(t,2H), 7.95-7.92 (m, 1H), 8.08-8.00 (m, 2H), 8.23-8.20(d, 1H); HPLC: 99.13% (Retention Time=4.63 min).

General synthetic scheme -22:

[001231] The following compound listed in table-39 was prepared according to general scheme-22 starting from non-polar compound isolated (120 mg) in step-3 of example 121 by following similar procedure as described above for example 121 using appropriate reagents with suitable modifications known to the one skilled in the art.

[001232] Table-39: Compounds synthesized using General Scheme -22

Table -40: Compounds synthesized using general scheme -15. Table -41: Compounds synthesized using general scheme-15.

Table -44: Compounds synthesized using general scheme -15C.

Table -45: Compounds synthesized using general scheme -15D.

Table -46: Compounds synthesized using general scheme -15D.

Table -48: Compounds synthesized using general scheme -15D-1.

Table -49: Compounds synthesized using general scheme -15D-2.

Table -50: Compounds synthesized using general scheme -15E.

Table -52: Compounds synthesized using general scheme -21.

Table -53: Compounds synthesized using general scheme -23.

General synthetic scheme -24

Example 122: Synthesis of compound 1-719

Step-1: Synthesis of Ethyl 6-(N-(isobutoxycarbonyl)carbamimidoyl)-l-(naphthalen-l- ylmethyl) -lH-indole-2-carboxylate

[001233] Following the experimental protocol of Scheme 2A, ethyl 6-(N- (isobutoxycarbonyl) carbamimidoyl)- 1 -(naphthalen- 1 -ylmethyl)- lH-indole-2-carboxylate compound was synthesized. LCMS: 472.2 (M+l) ⁺ ; ¹ HNMR (DMSO-de _, 400 MHz): d 0.85 (d, 6H), 1.14 (t, 3H), 1.87 (m, 1H), 3.75 (d, 2H), 4.19 (q, 2H), 6.03 (d, 1H), 6.41 (brs, 2H), 7.23 (t, 1H), 7.54 (s, 1H), 7.63 (t, 1H), 7.70 (t, 1H), 7.80 (d, 1H), 7.87 (m, 2H), 8.00 (d, 1H), 8.19 (s, 1H), 8.23 (d, 1H), 8.90 (brs, 1H), 9.20 (brs, 1H); HPLC: 96.72 % (Retention Time=7.23 min).

Table -54: Compounds synthesized using step 1 of general scheme -24

Step-2: Potassium 6-(N-((hexyloxy)carbonyl)carbamimidoyl)-l-(naphthalen-l-ylme thyl)- lH-indole-2-carboxylate: (1-720)

[001234] To a stirred solution of Step-l compound (100 mg, 0.20 mmol) in 2 ml of THF was added Potassium trimethylsilanolate (24 mg, 0.19 mmol) at 0°C in one portion under N ₂ and the reaction mixture was stirred at room temperature for about l6h. The reaction mixture was diluted with diethyl ether and the solids obtained were filtered, washed with ether and dried under nitrogen atmosphere further dried using Lyophilization to give 50 mg of title compound as Potassium salt. LCMS: 472.2 (M+l) ⁺ ; ¾ NMR (400MHz, DMSO-de): d 0.84 (t, 6H), 1.29-1.20 (m, 6H), 1.52 (m, 1H), 3.90 (t, 2H), 6.06 (d, 1H), 6.66 (brs, 2H), 6.84 (s, 1H), 7.19 (t, 1H), 7.71-7.60 (m, 5H), 7.91 (s, 1H), 7.96 (d, 1H), 8.32 (d, 1H), 8.80 (brs, 1H), 9.20 (brs, 1H); HPLC: 97.12% (Retention Time=7.086 min).

Table -55: Compounds synthesized using step 2 of general scheme -24

General synthetic scheme -25

Step-1: Synthesis of Ethyl 6-cyano-l-(4-(hydroxymethyl)naphthalen-2-yl)-lH-indole-2- carboxylate

[001235] In a sealed tube was added (3 -bromonaphthalen-l-yl)m ethanol (410 mg, 1.74 mmol), K3P04 (0.4 g, 3.48 mmol,), ethyl 6-cyano-lH-indole-2-carboxylate (377 mg, 1.74 mmol,) and trans-N,N'-Dimethyl cyclohexane- 1, 2-diamine (247 mg , 1.74 mmol), in toluene in presence of argon gas, Copper iodide (165 mg, 0.87 mmol) was added, closed and stirred at 90°C for 16 h. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate twice. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuum to get a crude compound. It was purified by using combi-flash with 50 % EA/Hex, the obtained fractions were concentrated to get 200 mg of ethyl 6-cyano-l-(4-(hydroxymethyl)naphthalen-2-yl)-lH- indole-2-carboxylate.

Table -56: Compounds synthesized using general scheme -25

General synthetic scheme -26

( from Scheme-15C)

Example 123: Synthesis of compound 1-675

Step-1: Synthesis of Ethyl (Z)-6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)- lH-indole-2-carboxylate

[001236] Following the experimental protocol of Step 1 in Scheme 15D-2, ethyl (Z)-6-(N'- hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylate was synthesized LCMS: 388.2 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 400 MHz): d 1.07-1.11 (m, 3H), 4.08-4.14 (m, 2H), 6.05-6.07 (d, 1H), 6.31 (s, 2H), 7.05-7.09 (m, 1H), 7.38-7.69 (m, 7H), 7.81-7.83 (d, 1H), 8.14-8.16 (d, 1H); HPLC: 99.91% (Retention Time= 5.54 min).

Table -58: Compounds synthesized using general scheme-26

General synthetic scheme -27

Example 124: Synthesis of compound 1-598

Synthesis of 6-cyano-lH-indole-2-carboxylic acid

[001237] To a solution of ethyl 6-cyano-lH-indole-2-carboxylate (15 g, 0.07 mol) in EtOH (150 ml), and THF (150 ml), LiOH.H ₂ 0 (8.9 g, 0.21 mol) dissolved in water (100 ml) was added and resulting mixture was stirred at rt for 4 h. Excess of solvent was removed under reduce pressure and residue was suspended in 100 ml of ice water. Aqueous layer was further acidified with 1N HC1 and resultant solid was filtered and dried to afford title compound (13 g, 99 %).

Synthesis of (E)-6-(N'-hydroxycarbamimidoyl)-lH-indole-2-carboxylic acid

[001238] To solution of 6-cyano-lH-indole-2-carboxylic acid (13 g, 0.07 mol) in EtOH (200 ml) and THF (200 ml), DIPEA (226 ml, 1.26 mol) and hydroxyl amine hydrochloride (NH2OH.HCI) was added at 0 ^° C. After addition completed reaction mass was heated at 75 ^° C for overnight. After cooling to ambient temperature reaction mass was concentrated to dryness under reduce pressure and residue was resuspended in 200 ml ice water. Resultant solid was filtered and dried under vacuum to afford desire compound (14 g, 91 %).

Synthesis of (E)-6-(N'-acetoxycarbamimidoyl)-lH-indole-2-carboxylic acid

[001239] To a solution of (E)-6-(N'-hydroxycarbamimidoyl)-lH-indole-2-carboxylic acid (16 g, 0.07 mol) in acetic acid (200 ml) & acetonitrile (400 ml), acetic anhydride (10 ml) was added at 0 ^° C. Reaction mass was stirred at rt for 2 h and after completion of reaction, excess of solvent was removed under vacuum. Residue were resuspended in water and filtered to afford title compound (12 g, 63 %).

Synthesis of 6-carbamimidoyl-lH-indole-2-carboxylic acid

[001240] (E)-6-(N'-acetoxycarbamimidoyl)-lH-indole-2-carboxylic acid (12 g,0.04 mol) was dissolved in acetic acid (200 ml) and EtOH (100 ml) mixture. Pd/C (1.2 g) was added and reaction mixture was stirred at rt for 6 h under hydrogen atmosphere. Reaction mass was filtered through celite bed and wash with 2 % TFA in MeOH. Combine filtrate was collected and concentrated to afford title compound (9.0 g, 98 %).

Synthesis of Ethyl 6-carbamimidoyl-lH-indole-2-carboxylate [001241] To a solution of 6-carbamimidoyl-lH-indole-2-carboxylic acid (6 g, 0.029 mol), in EtOH (100 ml), SOCh (7.2 ml) was added at 0 ^° C. After addition completed reaction mass was refluxed for overnight. Excess of solvent was removed under reduce pressure. Residue were resuspended in 200 ml of ice water and resultant solid was filtered, dried to afford title compound (5.5 g, 88 %).

Synthesis of Ethyl 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-lH-indole-2-carboxy late

[001242] To a solution of ethyl 6-carbamimidoyl-lH-indole-2-carboxylate (16 g, 0.073 mol), in THF (100 ml) and water (50 ml), DIPEA (8.5 ml) and Boc ₂ 0 was added at 0 ^° C. Resulting mixture was stirred at rt for 3 h. Excess of solvent was removed under reduce pressure and residue were resuspended in water (200 ml). Aqueous layer was extracted with EtOAc (2 *200ml) and combined organic layer was dried overNa ₂ S0 ₄ and concentrated to afford crude compound. Crude was further resuspended in 10 % EtOAc in Hexane (lOOml), stirred, filtered and dried to afford sufficient pure title compound (5.3 g, 68 %).

Synthesis of Ethyl 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-((3-(pyrimidin-2- yloxy)naphthalen-l-yl)methyl)-lH-indole-2-carboxylate

[001243] Following the experimental protocol of Step 1 in Scheme 15, Ethyl 6-(N-(tert- butoxycarbonyl)carbamimidoyl)-l-((3-(pyrimidin-2-yloxy)napht halen-l-yl)methyl)-lH-indole- 2-carboxylate was synthesized

Synthesis of Ethyl 6-carbamimidoyl-l-((3-(pyrimidin-2-yloxy)naphthalen-l-yl)met hyl)-lH- indole-2-carboxylate

[001244] Following the experimental protocol of Step 7 in Scheme 15, Ethyl 6- carbamimidoyl-l-((3-(pyrimidin-2-yloxy)naphthalen-l-yl)methy l)-lH-indole-2-carboxylate. LCMS:466.2 (M+l) ^{+ 1} HNMR (CD ₃ OD, 400 MHz): 51.19-1.22 (m, 3H), 4.25-4.27 (m, 2H), 5.90 (s, 1H), 6.51 (s, 2H), 7.12-7.20 (m, 1H), 7.52-7.70 (m, 5H), 7.92-7.94 (m, 3H), 8.28-8.30 (d, 1H), 8.38-8.40 (d, 2H). HPLC: 97.80% (Retention Time= 4.68 min)

Table -59: Compounds synthesized using general scheme -27

Example 125: Synthesis of compound 1-695

Synthesis of 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-((3-hydroxynaphth alen-l- yl)methyl)-lH-indole-2-carboxylic acid

[001245] Following the experimental protocol of Step 2 in Scheme 15, 6-(N-(tert- butoxycarbonyl)carbamimidoyl)-l-((3-hydroxynaphthalen-l-yl)m ethyl)-lH-indole-2-carboxylic acid

Synthesis of 6-carbamimidoyl-l-((3-hydroxynaphthalen-l-yl)methyl)-lH-indo le-2- carboxylic acid

[001246] Following the experimental protocol of Step 7 in Scheme 15, 6-carbamimidoyl-l- ((3-hydroxynaphthalen-l-yl)methyl)-lH-indole-2-carboxylic acid. LCMS: 360.1 (M+l) ^{+ 1} HNMR (CD ₃ OD, 300 MHz): d 5.79-5.80 (s, 1H), 6.45 (s, 2H), 6.96-6.97 (d, 1H), 7.40-7.45 (m, 2H), 7.53- 7.55 (d, 2H), 7.67-7.70 (d, 1H), 7.90 (s, 1H), 7.97-8.00 (d, 1H), 8.09-8.11 (d, lH).HPLC: 96.73 % (Retention Time= 5.50 min)

Table -60: Compounds synthesized using general scheme -27 Synthetic Scheme -28

Example 126: Synthesis of compound 1-751

2-(5-methyl-l,3,4-oxadiazol-2-yl)-l-(naphthalen-l-ylmethyl)- lH-indole-6-carboximidamide

Step 1: 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbohydrazide

[001247] To a solution of Ethyl 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylate (0.5 g, 1.41 mmol) dissolved in ethanol (5 mL), hydrazine hydrate (5 mL) was added and reaction was heated at 90°C and stirred at same temperature for 16 h. Reaction mass was evaporated under vacuum and residue was quenched with ice cool water. Resultant solid was filtered and dried under vacuum to afford the title compound (0.35 g). LCMS: 341.05 (M+l) ⁺ . Step 2: N'-acetyl-6-cyano-l-(naphthalen-l-ylmethyl)-lH indole-2-carbohydrazide

[001248] To 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbohydrazide (0.35 g, 0.91 mmol) was added acetyl chloride (2 mL) and reaction was refluxed for 4 h. Acetyl chloride was removed under vacuum and basified with saturated sodium carbonate solution and extracted with ethyl acetate (2X50 mL). Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate, concentrated under vacuum to get crude product which was used for the next step without any further purification (0.35 g, crude).

Step 3: 2-(5-methyl-l,3,4-oxadiazol-2-yl)-l-(naphthalen-l-ylmethyl)- lH-indole-6- carbonitrile

[001249] T o N'-acetyl-6-cyano- 1 -(naphthalen- 1 -ylmethyl)- 1H indole-2-carbohydrazide

(0.35 g) was added phosphorous oxychloride (4 mL) and the reaction was refluxed for lh. Phosphorous oxychloride was removed under vacuum and neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (2X50 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, concentrated to get the crude product, which was purified through combiflash eluting with 20%ethyl acetate in hexane to afford the desired product (200 mg) LCMS: 365.05 (M+l) ⁺ .

Step 4: 2-(5-methyl-l,3,4-oxadiazol-2-yl)-l-(naphthalen-l-ylmethyl)- lH-indole-6- carboximidamide

[001250] Following experimental protocol of Scheme 15 Method E, above compound have been synthesized. LCMS: 382.0 (M+l) ⁺ , ¾ NMR (400 MHz, DMSO-^e) d 9.19 (s, 2H), 8.90-8.72 (bs, 2H), 8.33 (d, J= 8.0 Hz, 1H), 8.14 (s, 1H), 8.05-7.99 (m, 2H), 7.79 (d, J=8.40 Hz, 1H), 7.72- 7.11 (m, 1H), 7.65 (t, J=7.20 Hz, 2H), 7.59 (s, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.56 (s, 2H), 6.04 (d, J=6.80 Hz, 1H), 2.49 (s, 3H).

Synthetic Scheme -29

Example 127: Synthesis of compound 1-750

l-(naphthalen-l-ylmethyl)-2-(thiazol-2-yl)-lH-indole-6-carbo ximidamide

Step 1: 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxamide

[001251] To a stirred solution of 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylic acid(l .6 g,4.87 mmol) in N,N-Dimethylformamide (15.0 mL) was added 1- [Bis(dimethylamino) ethylene]-! H- \ ,2,3-triazolo[4,5-/>]pyridinium 3-oxid hexafluorophosphate (2.78 g, 7.3 lmmol) and N,N-Diisopropyl ethylamine (2.49 mL, 14.61 mmol). Then after 10 min, added Ammonium chloride (0.391 g, 7.31 mmol) and reaction mixture was stirred at ambient temperature for l6h. Reaction mass diluted with cold water (100.0 mL) stirred for 15 min, off- white solid was thrown out, which was filtered and dried to get the crude compound. The crude washed with n-Pentane (40 mL X 2), to get the title compound as an off-white solid, (1.47 g, 92.8%), LCMS: 326.05 (M+l) ⁺ .

Step 2: 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbothioamide

[001252] Product of Step 1 (0.5 g, 1.53 mmol), Lawesson’s reagent (0.62 g, 1.53 mmol) replaced in sealed tube, resulting mixture was stirred and heated at H0°C for 4h. After Reaction completion which was diluted with ethyl acetate (50.0 mL) and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to get the crude compound, which was purified by combi-flash eluting with 10 % ethyl acetate in hexane as an eluent to get the title compound as an off-white solid (0.256 g). LCMS: 340.1 (M-l) .

Step 3: l-(naphthalen-l-ylmethyl)-2-(thiazol-2-yl)-lH-indole-6-carbo nitrile

[001253] Product of Step 2 (0.2 g, 0.585 mmol) and 2-bromo-l, l-di ethoxy ethane (2.0 mL) together replaced in a sealed tube, which was heated at l00°C for 4h Reaction mixture cooled, diluted with ethyl acetate (50.0 mL) and washed with water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated to get the crude compound, which was purified by combi-flash eluting with 10 % ethyl acetate in hexane as an eluent to get the title compound as an off-white solid (90.0 mg, 42.13%), LCMS: 366.1 (M+l) ⁺ .

Step 4: l-(naphthalen-l-ylmethyl)-2-(thiazol-2-yl)-lH-indole-6-carbo ximidamide

[001254] Following experimental protocol of Scheme 15 Method E, l-(naphthalen-l- ylmethyl)-2-(thiazol-2-yl)-lH-indole-6-carboximidamide have been synthesized and purified by Preparative HPLC. The mobile phases (0.1% Formic acid in water to 100% acetonitrile, compound was lyophilized for 3 days to afford the title compound (5 mg). LCMS: 383.2 (M+l) ⁺ , ¹ HNMR (DMSOd6, 400MHz): d 6.13-6.11 (d,lH), 6.61 (S,2H),7.47-7. l8 (t, 1H), 7.59 (S, 1H), 7.67-7.62 (m, 2H),7.7l-7.68(m, 1H), 7.79-7.75(m, 3H), 7.99-7.97(m, 2H), 8.07(S, 1H), 8.31-8.29 (d, 1H), 8.42 (s, 1H), 8.6-9.4 (bs, 1H). HPLC: 99.97% (Retention Time= 5.39 min).

Synthetic Scheme -30

Example 128: Synthesis of compound 1-748

l-(naphthalen-l-ylmethyl)-2-(oxazol-2-yl)-lH-indole-6-carbox imidamide

Step 1: l-(naphthalen-l-ylmethyl)-2-(oxazol-2-yl)-lH-indole-6-carbon itrile

[001255] 6 -cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxamide (0.4 g, 1.23 mmol) and 2-bromo-l, l-diethoxyethane (4.0 mL) together replaced in a sealed tube and which was heated to 115 °C for 5h Reaction mixture cooled, diluted with ethyl acetate (60.0 mL) and washed with water (50.0 mL X 3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated to get the crude compound, which was purified by combi-flash eluting with 15 % ethyl acetate in hexane as an eluent to get the title compound as an off-white solid (0.19 g, 43.90%), LCMS: 350.1 (M+l) ⁺

Step 2: l-(naphthalen-l-ylmethyl)-2-(oxazol-2-yl)-lH-indole-6-carbox imidamide

[001256] Following experimental protocol of Scheme 15 Method E, l-(naphthalen-l- ylmethyl)-2-(oxazol-2-yl)-lH-indole-6-carboximidamide have been synthesized. LCMS: 367.1 (M+l)VHNMR ( DMSOd6, 400MHz): d 6.06-6.04 (d, 1H), 6.6l(S, 2H), 7.22-7.18 (t, 1H), 7.31 (S, 1H), 7.54 (S, 1H), 7.63-7.61 (m, 2H), 7.79-7.70 (m, 2H), 8.01-7.99 (d, 1H), 8.08(S, 1H), 8.24 (S, 1H), 8.34-8.32 (d, 1H), 8.79 (bS, 2H), 9.16 (bS, 2H), ( HPLC: 99.74%, Retention time: 5.33)

Synthetic scheme -31

Example 129: Synthesis of compound 1-726

l-(naphthalen-l-ylmethyl)-2-(2-oxooxazolidin-3-yl)-lH-indole -6-carboximidamide

Step 1: l-(naphthalen-l-ylmethyl)-2-(2-oxooxazolidin-3-yl)-lH-indole -6-carbonitrile

[001257] To as stirred solution of 2-amino- l-(naphthalen-l-ylmethyl)-lH-indole-6- carbonitrile (0.1 g, 0.33 mmol) in THF (5 mL), were added diisopropylethylamine (0.11 mL, 0.67 mmol), 2-chloroethyl chloroformate (0.038 mL, 0.37 mmol) at 0°C. The reaction was stirred for l6h at rt. To this potassium t-butoxide (0.18 g, 1.68 mmol) was added then the reaction was stirred for l6h at rt. Water was added to the reaction mixture, extracted with ethyl acetate (2X25 mL). The separated organic layer was washed with brine solution dried over anhydrous sodium sulphate, concentrated under vacuum to give the crude product which was purified through combiflash chromatography eluting with 30% EtOAc in Hexane to afford the desired product (40 mg) LCMS: 368.20 (M+l) ⁺ .

Step 2: l-(naphthalen-l-ylmethyl)-2-(2-oxooxazolidin-3-yl)-lH-indole -6-carboximidamide

[001258] Following experimental protocol of Scheme 15 Method E, l-(naphthalen-l- ylmethyl)-2-(2-oxooxazolidin-3-yl)-lH-indole-6-carboximidami de have been synthesized. ¾ NMR (400 MHz, DMSO-^e) d 9.12 (s, 2H), 8.70 (bs, 2H), 8.13 (d, J=8.80 Hz, 1H), 8.04-7.99 (m, 2H), 7.87 (d, J=8.40 Hz, 2H), 7.64-7.58 (m, 3H), 7.34-7.31 (m, 1H), 6.82 (s, 1H), 6.42(d, J=7.20 Hz, 1H), 5.98 (s, 2H), 4.23-4.19 (m, 2H), 3.69-3.65 (m, 2H) LCMS: 392.95 (M+l) ⁺ .

Synthetic Scheme -32

Example 130: Synthesis of compound I- 803

l-(naphthalen-l-ylmethyl)-2-(lH-tetrazol-5-yl)-lH-indole- 6-carboximidamide

Step 1: Ethyl 6-bromo-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylate:

[001259] To a solution of ethyl 6-bromo-lH-indole-2-carboxylate (0.5 g, 0.0096 mol) in DMF (10 ml) was added potassium carbonate (0.8 g, 0.00577 mol) and solution of 1- (bromomethyl) naphthalene (0.65 g, 0.0029 mol) dissolved in THF (3 mL). Then Reaction mass was stirred at room temperature for 3 h. After reaction completion, THF was distilled off, added ice-cold water and precipitated product was filtered and dried under vacuum to give title compound (0.7g, 87.5%) which was proceeded to next step without purification. LCMS: 409. l(M+l) ⁺ .

Step 2: 6-bromo-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylic acid.

[001260] To a stirred solution of Product of Step 1 (600 mg, 0.00147 mol) in tetrahydrofuran & ethanol (5 mL: lOmL) mixture, was added aqueous lithium hydroxide monohydrate (300 mg, 0.00737 mol) at room temperature. Resulting mixture was stirred at room temperature for 8 h. After reaction completion, THF and ethanol was distilled off, acidified with dilute HC1 to pH 4. Precipitated product was filtered off, dried under vacuum to give titled compound (600 mg, crude) which was proceeded to next step, LCMS: 379.9 (M-l).

Step 3: 6-bromo-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxamide.

[001261] To a stirred solution of product of Step 2 (100 mg, 0.00026 mol) in DMF added HATU (110 mg, 0.000286 mol) and N, N-diisopropylethylamine (84 mg, 0.00065 mol) at 0°C. After stirred at room temperature for 10 min., added NH ₄ Cl (21 mg, 0.00039 mol) and stirred for 16 h at room temperature. After reaction completion, added ice cold water, precipitated solid was filtered off and dried to give title compound (80 mg, 81.6%) LCMS: 378.95 (M-l) .

Step 4: 6-bromo-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbonitrile

[001262] To a solution of product of Step 3(1 g, 0.00263 mol) in DCM (10 mL) was added TEA (1.06 g, 0.0105 mol) and resulting was stirred at RT for 5 min. Then TFAA (1.1 g, 0.00526 mol) was added dropwise at 0°C and stirred at RT for 2 hr. After completion of reaction by TLC, quenched with aq.NaHCO, solution, and extracted with DCM. The separated organic layer was dried and concentrated, purified by combi-flash to give title compound ( (0.3 g , 31.5%) ; (1H- NMR-DMSO-d6 ); 8.2(d, 1H), 8.05(d, 2H), 7.9(d, 1H), 7.75(d, 1H), 7.65(m, 3H), 7.35(m, 2H), 6.25(d, 1H), 6.2(s, 2H).

Step 5: 6-bromo-l-(naphthalen-l-ylmethyl)-2-(lH-tetrazol-5-yl)-lH-in dole.

[001263] To a solution of product of Step 4(lg, 0.00276 mol) in DMF (10 mL), were added NaN ₃ (3.6 g, 0.0055 mol) & NH ₄ Cl( 1.44 g, 0.0269 mol) at RT and resulting suspension was heated to l20°C for 4 h. Then cooled to RT and poured into ice water to precipitate the product and solids were collected by filtration to give title compound (1 g, crude) LCMS: 404.1 (M+l) ⁺ . Step 6: l-(naphthalen-l-ylmethyl)-2-(lH-tetrazol-5-yl)-lH-indole-6-c arboximidamide.

[001264] Following experimental protocol of general Scheme 15 Method E, l-(naphthalen- l-ylmethyl)-2-(lH-tetrazol-5-yl)-lH-indole-6-carboximidamide have been synthesized. LCMS: 368.15 (M+l) ⁺ , lHNMR (CD30D, 300 MHz): d 6.21 (d, 1H), 6.632 (s, 2H), 7.124 (t, 1H), 7.469 (s, 1H), 7.56- 7.71 (m, 4H), 7.88-7.98 (m, 3H), 7.135 (d, 1H)

Synthetic Scheme -33

Example 131: Synthesis of compound 1-710

2-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-tetrazol-5-y l)-l-(naphthalen-l-ylmethyl)- lH-indole-6-carboximidamide

Step 1: 6-bromo-2-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-tetr azol-5-yl)-l-

(naphthalen-l-ylmethyl)-lH-indole.

[001265] To a solution of 6-bromo-l-(naphthalen-l-ylmethyl)-2-(lH-tetrazol-5-yl)-lH- indole (0.7 g, 0.00172 mol), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.5 g, 0.00207 mol) in DMF(5 ml), was added K ₂ CO ₃ (0.476 g, 0.00344) at RT and resulting suspension was heated to 70 °C for 3 h. After completion of reaction, cooled to RT and ice water was added then extracted with ethylacetate. The organic layer dried over Na ₂ S0 ₄ and concentrated to give the crude product. Crude purified by combi-flash to give title compound (0.3 g, 31%); LCMS: 564.2 (M+2) ⁺ .

Step 2 : 2-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-tetrazol-5-y l)-l-(naphthalen-l- ylmethyl)-lH-indole-6-carbonitrile.

[001266] To a solution of 6-bromo-2-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-tetr azol- 5-yl)-l-(naphthalen-l-ylmethyl)-lH-indole (0.3 g, 0.000534 mol) in DMF, was added Zn(CN) ₂ (0.156 g, 0.00133 mol) and resulting suspension was de-gassed with N ₂ for 5 min, then PdCl ₂ (dppf).DCM (23 mg , 0.05 mol) was added under N ₂ gas atmosphere. Reaction mixture heated to 150°C for overnight. After completion of reaction, cooled to RT and ice water was added and resulting solids were collected by filtration to give title compound (0.22 g, 81.4%) LCMS: 509.2 (M+l) ⁺ .

Step 3: 2-(l-(2-((tert-butyldimethylsilyl) oxy) ethyl)-lH-tetrazol-5-yl)-l-(naphthalen-l- ylmethyl)-lH-indole-6-carboximidamide

[001267] Following experimental protocol of Scheme 15 Method E, 2-(l-(2-((tert- butyldimethylsilyl) oxy) ethyl)-lH-tetrazol-5-yl)-l-(naphthalen-l-ylmethyl)-lH-indole -6- carboximidamide have been synthesized. LCMS: 526.1 (M+l) ⁺ , ¹ HNMR (DMSO-d ₆ , 400 MHz): d -0.32 (s, 6H), 0.53 l(s, 9H), 3.903 (t, 1H), 4.708 (t, 1H), 5.99-6.01 (d, 1H), 6.578 (s, 2H), 7.159 (t, 1H), 7.517 (s, 1H), 7.62-7.64 (m, 2H), 7.69-7.76 (m, 2H), 7.95-7.98 (m, 2H), 8.13 (s, 1H), 8.31- 8.33 (d, 1H), 8.493 (s, 2H).

2-(l-(2-hydroxyethyl)-lH-tetrazol-5-yl)-l-(naphthalen-l-ylme thyl)-lH-indole-6- carboximidamide

[001268] To a solution of 2-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-tetrazol-5-y l)-l- (naphthalen-l-ylmethyl)-lH-indole-6-carboximidamide (60 mg, 0.000114 mol) in DCM (5 ml), was added TFA (0.5 g) dropwise at 0°C and stirred at RT for overnight. After completion of reaction, evaporated the solvent and washed with ether, resulting solid was dried on high vacuum to give title compound (25 mg, 54%); LCMS : 412.2 (M+H) ⁺ ; ¾ NMR (400MHz, DMSO-de): d 9.3(bs, 3H), 8.35(d, 1H), 8. l(s, 1H), 8.0(d, 2H), 7.8(d, 1H), 7.7(d, 1H), 7.65(d, 1H), 7.55(s, 1H), 7.2(t, 1H), 6.6(s, 2H), 6. l(d, 1H), 5.0(bs, 1H), 4.7(t, 2H), 3.8(bs, 2H); HPLC; 99.9%.

Synthetic Scheme -34

Example 132: Synthesis of compound 1-603

tert-butyl (6-carbamimidoyl-l-((3-(phenylsulfonyl) naphthalen-l-yl) methyl)-lH-indol-2- yl)carbamate

Step 1: tert-butyl (6-cyano-l-((3-(phenylsulfonyl)naphthalen-l-yl)methyl)-lH-in dol-2- yl)carbamate

[001269] Following experimental protocol of Step 1 of general Scheme 20, tert-butyl (6- cyano-l-((3-(phenylsulfonyl)naphthalen-l-yl)methyl)-lH-indol -2-yl)carbamate have been synthesized. LCMS: 536.2 (M-l) .

[001270] Step 2: tert-butyl (6-carbamimidoyl-l-((3-(phenylsulfonyl) naphthalen-l-yl) methyl)-lH-indol-2-yl)carbamate

Following experimental protocol of general Scheme 15 Method E, tert-butyl (6-carbamimidoyl-l- ((3-(phenylsulfonyl) naphthalen-l-yl) methyl)- lH-indol-2-yl)carbamate have been synthesized. LCMS: 555.4 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 400 MHz): d 1.41 (s, 9H), 6.01 (s, 2H), 7.37 (t, 2H), 7.56-7.61 (m, 4H), 7.71-7.90 (m, 4H), 8.11-8.20 (d, 2H), 8.20-8.29 (d, 1H), 8.51 (s, 2H).

Synthetic Scheme -35

Example 133: Synthesis of compound 1-749

2-(5-methyl-l,3,4-oxadiazol-2-yl)-l-(naphthalen-l-ylmethyl)- lH-indole-6-carboximidamide

Step 1: 2-amino-l-(naphthalen-l-ylmethyl)-lH-indole-6-carbonitrile hydrochloride

[001271] tert-butyl (6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl)carbamate (0.15 g) in dichlorom ethane (5 mL) was added 4M Dioxane HC1 (5 mL) and the reaction was stirred for l6h at rt. Excess solvent was removed under vacuum afforded the crude product which was used for the next step without any further purification (150 mg, crude), LCMS: 298.2 (M-Cl)

Step 2: N-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl)methanesu lfonamide

[001272] 2 -amino- l-(naphthalen-l-ylmethyl)-lH-indole-6-carbonitrile hydrochloride (0.13 g, 0.38 mmol) in dichloromethane (3 mL), were added triethyl amine (0.16 mL, 1.55 mmol) and methane sulfonyl chloride (0.036 mL, 0.46 mmol) at 0°C and stirred for 1 h at the same temperature. Water was added to the reaction mixture, extracted with dichloromethane (2X50 mL). Combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate, concentrated to get the crude product which was purified through combiflash chromatography eluting with 20% EtOAc in hexane to afforded the desired product (95 mg) LCMS: 376.1 (M+l) ⁺ .

Step 3: 2-(methylsulfonamido)-l-(naphthalen-l-ylmethyl)-lH-indole-6- carboximidamide

[001273] Following experimental protocol of Scheme 15 Method E, 2-(methylsulfonamido)- l-(naphthalen-l-ylmethyl)-lH-indole-6-carboximidamide have been synthesized. LCMS: 392.95 (M+l) ⁺ , ¾ NMR (400 MHz, DMSO-^e) d 8.97 (bs, 1H), 8.56 (bs, 2H), 8.21 (d, J=6.40Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.40 Hz, 1H), 7.72-7.63 (m, 5H), 7.35 (t, J=7.60 Hz,IH), 7.18 (bs, 2H), 6.33 (d, J=6.80 Hz, 1H), 5.92 (s, 2H), 3.31 (s, 3H).

Example 134: Synthesis of compound 1-620

N-((lr,4r)-4-aminocyclohexyl)-6-guanidino-l-(naphthalen-l-yl methyl)-lH-indole-2- carboxamide

Step 1: N-((lr,4r)-4-aminocyclohexyl)-6-guanidino-l-(naphthalen-l-yl methyl)-lH-indole-2- carboxamide

[001274] tert-butyl ((lr,4r)-4-(6-((4,6-dimethoxypyrimidin-2-yl)amino)-l-(naphth alen-l- ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate (0.3 g, 0.461 mmol) was taken in sealed tube, added Acetic acid (3 mL) and 6N aqueous HC1 (5 ml), then stirred at lOO°C for 2 h. All the solvents were evaporated to dryness to get the crude product, which was purified by Prep HPLC (O.Olg). LCMS: 455.3 (M+l) ⁺ . ¹ HNMR (CD ₃ OD, 400 MHz): d 1.1-1.20 (m, 2H), 1.45-1.48 (m, 2H), 1.97-2.00 (d, 4H), 2.95-3.05 (m, 1H), 3.7-3.82 (m, 1H), 4.94 (s, 2H), 6.85-6.88 (d, 1H), 7.09-7.11 (d, 1H), 7.27-7.29 (t, 2H), 7.36 (s, 1H), 7.48-7.52 (m, 3H), 7.19-7.74 (d, 1H), 7.86-7.88 (d, 1H), 8.28-8.30 (d, 1H).

Synthetic Scheme -36

Example 135: Synthesis of compound 1-644

2-morpholino-l-(naphthalen-l-ylmethyl)-lH-indole-6-carboximi damide

Step 1: 2-bromo-l-(phenylsulfonyl)-lH-indole-6-carbonitrile [001275] l-(phenylsulfonyl)-lH-indole-6-carbonitrile (600 mg, 2.21 mmol) was dissolved in THF (10 mL) and cooled to -78°C temperature. Then sec-BuLi was dropwise added into the reaction mixture and gradually raised the temperature to -20°C and stirred for 1.5 h, then cyanogen bromide in THF (5ml) was dropwise added into the reaction mixture at -78°C. Reaction mixture gradually brought to room temperature and stirred for 16 hrs. After reaction completion, reaction mixture was quenched with added ice-cold water and 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. Crude product was purified by combi-flash to get compound (140 mg). LCMS: 361 (M+l) ⁺ .

Step 2: 2-bromo-lH-indole-6-carbonitrile

[001276] Product of Step 1 (140 mg, 0.387 mmol) was dissolved in THF (2 mL) and added TBAF (1.5 mL) at 0°C then stirred at room temperature for 4 h. After reaction completion, reaction mixture was diluted with ethyl acetate then washed with brine and water. Organic layer dried over sodium sulphate, evaporated under vacuum to give crude compound. (90 mg, crude) which was proceeded to next step. LCMS: 221.1 (M+l) ⁺ .

Step 3: 2-bromo-l-(naphthalen-l-ylmethyl)-lH-indole-6-carbonitrile

[001277] The product of Step 2 (80 mg, 0.36 mmol) in DMF, was treated with 1- (bromomethyl) naphthalene and potassium carbonate to afford 85 mg of the title compound. LCMS: 361.1 (M+l) ⁺ .

Step 4: 2-morpholino-l-(naphthalen-l-ylmethyl)-lH-indole-6-carbonitr ile

[001278] To a solution of Step 3 product (80 mg, 0.221 mmol), morpholine (38 mg, 0.442 mmol) and KOtBu (74 g, 0.66 mmol), were taken in toluene (10 mL) and degassed for lOmins. Now palladium acetate (1.5 mg, 0.006 mmol) and BINAP (8.5 mg, 0.13 mmol) were added and heated at l20°C for 16 h. After reaction completion, reaction mass was diluted with ethyl acetate and washed with brine, dried over sodium sulphate. Solvent was evaporated under vacuum to give crude compound. Crude product was purified by combi-flash to get compound (25 mg). LCMS: 368.1 (M+l) ⁺ .

Step 5: 2-morpholino-l-(naphthalen-l-ylmethyl)-lH-indole-6-carboximi damide

[001279] Following experimental protocol of general Scheme 15 Method E, above compound have been synthesized. LCMS: 385.1 (M+l) ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ): d 2.98 (m, 4H), 3.62 (m, 4H), 5.85 (s, 2H), 6.27 (s, 1H), 6.57 (d, 1H), 7.32-7.37 (m, 2H), 7.52 (m, 1H), 7.62-7.70 (m, 4H), 7.84 (d, 1H), 8.01 (d, 1H), 8.30 (d, 1H), 8.47 (s, 1H), 8.83 (bs, 1H); HPLC: 99.3% (Retention Time= 5.27 min).

Synthetic Scheme -37

Example 136: Synthesis of compound 1-801

6-carbamimidoyl-l-((6-(3-(methylamino)propoxy)naphthalen-l-y l)methyl)-lH-indole-2- carboxylic acid

Step 1: methyl 6-carbamimidoyl-l-((6-hydroxynaphthalen-l-yl)methyl)-lH-indo le-2- carboxylate

[001280] Following experimental protocol of Step 1 in Scheme 15D-2, above compound have been prepared. LCMS: 374.0 (M+l) ⁺

Step 2: methyl 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-((6-hydroxynaphth alen-l- yl)methyl)-lH-indole-2-carboxylate

[001281] Following experimental protocol of Step 2 in Scheme 15D, above compound have been prepared. LCMS: 474.2 (M+l) ⁺

Step 3: 6-carbamimidoyl-l-((6-hydroxynaphthalen-l-yl)methyl)-lH-indo le-2-carboxylic acid

[001282] To a stirred solution of methyl 6-(N-(tert-butoxycarbonyl)carbamimidoyl)-l-((6- hydroxynaphthalen-l-yl)methyl)-lH-indole-2-carboxylate (120 mg, 0.25 mmol) and tert-butyl (3- bromopropyl)(methyl)carbamate (95.8 mg, 0.38 mmol) in THF:DMF (2mL:2mL) was added K ₂ CO ₃ (105 mg, 0.76 mmol) at room temperature and stirred the reaction mixture at 80°C for 5 hours. Once the reaction was completed, reaction mixture poured into ice cold water, solid obtained was filtered and dried to afford the title compound (120 mg). LCMS: 645.1 (M+l) ⁺ .

Step 4: l-((6-(3-((tert-butoxycarbonyl)(methyl)amino)propoxy)naphtha len-l-yl)methyl)-6- (N-(tert-butoxycarbonyl)carbamimidoyl)-lH-indole-2-carboxyli c acid

[001283] Following experimental protocol of Step 2 in Scheme 15, above compound have been prepared. LCMS: 631.1 (M+l) ⁺ .

Step 5: 6-carbamimidoyl-l-((6-(3-(methylamino)propoxy)naphthalen-l-y l)methyl)-lH- indole-2-carboxylic acid

[001284] Following experimental protocol of method F, above compound have been prepared. LCMS: 431.1 (M+l) ⁺ , 1HNMR (CD30D, 400 MHz): d 2.28-2.24 (m, 2H), 2.76 (s, 3H), 3.27-3.26 (t, 2H), 4.27-4.24 (t, 2H), 6.04-6.02 (d, 1H), 6.47 (s, 2H), 7.33-7.14 (m, 3H), 7.65-7.52 (m, 3H), 7.89 (s, 1H), 7.98-7.96 (d, 1H), 8.18-8.16 (m, 1H).

Table -61: Compounds synthesized using synthetic scheme -37

Example 137: Synthesis of compound 1-804

N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((6-(3-(dime thylamino)propoxy) naphthalen-l-yl)methyl)-lH-indole-2-carboxamide

Step 1 : N-((l r,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((6-(3-(dimethyla mino)propoxy) naphthalen-l-yl)methyl)-lH-indole-2-carboxamide

[001285] Following experimental procedure of Scheme 15 D, above compound have been prepared. LCMS: 541.3 (M+l)+, 1HNMR (CD30D, 400 MHz): d 1.50-1.41 (m, 4H), 2.00-1.90 (m, 4H), 2.35-2.30 (m, 2H), 2.97 (s, 6H), 3.10-3.07 (m, 1H), 3.44-3.40 (t, 1H), 3.70-3.60 (m, 1H), 4.26-4.14 (t, 2H), 6.10-6.09 (d, 1H), 6.39 (s, 2H), 7.20-7.14 (m, 1H), 7.33-7.29 (m, 3H), 7.66-7.54 (m, 2H), 7.95-7.92 (d, 2H), 8.15-8.13 (d, 1H).

Synthetic Scheme -38

Example 138: Synthesis of compound 1-577

6-carbamimidoyl-3-fluoro-l-(naphthalen-l-ylmethyl)-lH-indole -2-carboxylic acid

Step 1: ethyl 6-cyano-3-fluoro-lH-indole-2-carboxylate

[001286] To a mixture of N-fluoro-2,4,6-trimethylpyridinium triflate (658 mg, 2.28 mmol) and ethyl 6-cyano-lH-indole-2-carboxylate (150 mg, 0.70 mmol) was added 1, 1,2,2- tetrachloroethane (3 mL) and heated to 100 °C for 16 h. After completion of reaction, mixture was allowed to cool to rt. Then diluted with EtOAc and washed with water. The organic layer was dried and evaporated to get the crude, which was azeotrope with toluene to remove residual l,l,2,2-tetrachloroethane, then purified by combi flash using 20 % Ethyl acetate in Hexane as an eluent. LCMS: 231.05 (M-l) .

Step 2-3: 6-cyano-3-fluoro-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbo xylic acid

[001287] Following experimental protocol of Step 1 and Step 2 of Scheme 15, above compound have been prepared. LCMS: 343. l(M-l) .

Step 4: 6-carbamimidoyl-3-fluoro-l-(naphthalen-l-ylmethyl)-lH-indole -2-carboxylic acid

[001288] Following experimental protocol of Scheme 15C, above compound have been prepared. LCMS: 360.15 (M-l) ; ¹ HNMR (CD ₃ OD, 300 MHz): d 6.21 (d, 1H), 6.44 (s, 1H), 6.510 (s, 1H), 7.22 (m, 1H), 7.556-7.595 (m, 2H), 7.649-7.652 (m, 1H), 7.744 (d, 1H), 7.916-7.916 (d, 2H), 7.938-7.945 (d, 1H), 7.991-8.016 (m, 1H).

Synthetic Scheme -39

Example 139: Synthesis of compound 1-569

6-carbamimidoyl-4-fluoro-l-((3-(pyrimidin-2-yloxy)naphthalen -l-yl)methyl)-lH-indole-2- carboxylic acid

Step 1: ethyl 6-cyano-4-fluoro-lH-indole-2-carboxylate

[001289] To a stirred solution of ethyl 6-bromo-4-fluoro-lH-indole-2-carboxylate (240 mg, 0.83 mmol) in DMF (10 mL) under argon was added CuCN (300 mg, 3.35 mmol) and heated to 155 °C for l6h. After completion of reaction, Reaction mixture was poured in water, solid obtain was filtered, dried which was dissolved in THF and filter through celite bed. Filtrate was concentrated to get the crude. Crude was purified by combi flash using DCM as an eluent. (190 mg) LCMS: 231.15 (M-l) .

Step 2: 6-cyano-4-fluoro-l-((3-(pyrimidin-2-yloxy)naphthalen-l-yl)me thyl)-lH-indole-2- carboxylic acid

[001290] Following experimental protocol of Step 1 and Step 2 of Scheme 15, above compound have been prepared. LCMS: 439.10 (M+l) ⁺ .

Step 3: 6-carbamimidoyl-4-fluoro-l-((3-(pyrimidin-2-yloxy)naphthalen -l-yl)methyl)-lH- indole-2-carboxylic acid

[001291] Following experimental protocol of Scheme 15C, above compound have been prepared. LCMS: 456. l(M+l) ⁺ ; ¹ HNMR (CD ₃ OD, 400 MHz): d 5.890 (s, 1H), 6.551 (s, 2H), 7.122-7.146 (t, 1H), 7.269-7.295 (d, 1H), 7.533 (s, 1H), 7.581-7.676 (m, 3H), 7.833 (s, 1H), 7.927- 7.947 (d, 1H), 8.526-8.276 (d, 1H), 8.415-8.427 (d, 2H).

Synthetic Scheme -40

Example 140: Synthesis of compound 1-716

2-(6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl)a cetic acid

Step-1: ethyl 2-(6-cyano-lH-indol-2-yl) acetate

[001292] To a stirred solution of lH-indole-6-carbonitrile (8 g, 0.05mol) in DMF:Water (180 ml : 20ml) was added PdCl ₂ (C ₆ H ₅ CN) ₂ (2.15 g, 0.005mmol), 2-Norbornen (10.59 g, 0.01 lmol), Sodium bicarbonate (18.9 g, 0.22mol). Purged by N2 for 10 min then added ethyl 2-bromoacetate and the resultant solution was stirred at 70 °C for 16 hrs. After completion of reaction, cooled to rt and extracted with water and ethyl acetate mixture. The organic layer separated, dried over sodium sulphate and evaporated under reduced pressure to afford the crude product, which was purified using combiflash and 20% Ethyl acetate in Hexane as an eluent. Yield-6.5 gm. LCMS: 229.2 (M+l) ⁺ .

Step-2: ethyl 2-(6-cyanoindolin-2-yl) acetate

[001293] To a stirred solution of ethyl 2-(6-cyano-lH-indol-2-yl) acetate (6.5 g, 0.02 mol) in Acetic acid (100 ml) was added sodium cyano borohydride (l4. l4g, 0.22 mol) at 0°C and stirred at rt for 4 hrs. After completion of reaction, cooled 0°C and neutralises with Aq. Sodium bicarbonate then extracted with ethyl acetate. The organic layer separated, dried over sodium sulphate and evaporated under reduced pressure, to afford the crude product, which was purified using combiflash and 10% Ethyl acetate in Hexane as an eluent. Yield-2.2 gm LCMS: 230.9 (M+l) ⁺ .

Step-3: 2-(6-cyano-l-(naphthalen-l-ylmethyl)indolin-2-yl)acetic acid

[001294] To a solution of ethyl 2-(6-cyanoindolin-2-yl)acetate (1.2 g, 0.0052 mol) in THF was added sodium hydride (0.374g, 0.0078 mol) and l-(bromom ethyl )naphthalene (1.72 g, 0.0078 mol) at 0°C and stirred rt for 16 hrs. After completion of reaction, extracted with water and ethyl acetate mixture. The organic layer separated, dried over sodium sulphate and evaporated under reduced pressure, to afford the crude product, which was purified using combiflash and 1% Methanol in DCM as an eluent. Yield-0.58 gm, LCMS: 343.05 (M+l) ⁺ .

Step-4: ethyl 2-(6-cyano-l-(naphthalen-l-ylmethyl)indolin-2-yl)acetate

[001295] To a solution of 2-(6-cyano-l-(naphthalen-l-ylmethyl)indolin-2-yl)acetic acid (0.58 g, 1.69 mmol) in ethanol (15 ml) was added thionyl chloride (0.24 ml g, 3.39 mmol)at 0°C and heated to 85°C for 2 hrs. After completion of reaction, cooled to 0°C and neutralises with Aq. Sodium bicarbonate then extracted with ethyl acetate. The organic layer separated, dried over sodium sulphate and evaporated under reduced pressure, to afford the crude product. Yield-0.68 gm LCMS : 371.3 (M+l) ⁺ .

Step-5: ethyl 2-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl)acetate

[001296] To a stirred solution of ethyl 2-(6-cyano-l-(naphthalen-l-ylmethyl)indolin-2- yl)acetate (0.76 g, 2.05 mmol) in THF (15 ml) was added DDQ (0.699 mg, 3.08 mmol )at 0°C and stirred rt for 16 hrs. After completion of reaction, cooled 0°C and neutralised with Aq. Sodium bicarbonate then extracted with ethyl acetate. The organic layer separated, dried over sodium sulphate and evaporated under reduced pressure, to afford the crude product, which was purified using combiflash and 15% Ethyl acetate in Hexane as an eluent LCMS: 369.1 (M+l) ⁺ . Step-6: 2-(6-cyano-l-(naphthalen-l-ylmethyl)-lH-indol-2-yl) acetic acid

[001297] Following experimental protocol of Step 2 in Scheme 15, 2-(6-cyano-l- (naphthalen-l-ylmethyl)-lH-indol-2-yl)acetic acid have been prepared. LCMS: 358.2 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 400MHz): d 3.77 (s, 2H), 6.20 (s, 2H), 6.25-6.24 (d, 1H), 6.75 (s, 1H), 7.23- 7.19 (t, 1H), 7.67-7.49 (m, 3H), 7.83-7.79 (m, 3H), 7.94-7.93 (d, 1H), 8.21-8.19 (d, 1H).

Synthetic Scheme -41

Example 141: Synthesis of compound 1-638

6-carbamimidoyl-3-methyl-l-(naphthalen-l-ylmethyl)-lH-indole -2-carboxylic acid

Step 1: methyl 6-cyano-3-methyl-lH-indole-2-carboxylate

[001298] To a stirred solution of ethyl 6-cyano-3-formyl-lH-indole-2-carboxylate (0.8g, 3.3057 mmol) in TFA (1 mL) was added Triethylsilane (1.34 g, 11.57 mmol) at 0 °C. Reaction mixture was stirred at room temperature for l6h. After completion of reaction, reaction mixture was diluted with hexane, filtered the solid and dried to get the product. (400mg). ¹ HNMR (CD ₃ OD, 400MHz): d l .38-l .35(t, 3H), 2.55(s,3H), 4.40-4.35 (q,2H), 7.40-7.38(dd, lH), 7.87- 7.84(m,2H),l2.05(s, 1H).

Step 2-3: 6-cyano-3-methyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carbo xylic acid

[001299] Following experimental protocol of Step 1 and 2 of Scheme 15, above compound have been prepared. ¹ HNMR (DMSO-de, 400 MHz): d 2.57 (s,3H), 6.04-6.05 (d. 1H), 6.47 (s,2H), 7.20-7.24 (t,lH), 7.36-7.38 (d, lH), 7.59-7.65 (m,2H), 7.74-7.76 (d, lH),7.82-7.84 (d, 1H), 7.92- 7.97 (t,2H), 8.24-8.26 (d,lH), 4.40-4.35 (q,2H), 7.40-7.38(dd,lH), 12.05 (bs, 1H).

Step 4: 6-carbamimidoyl-3-methyl-l-(naphthalen-l-ylmethyl)-lH-indole -2-carboxylic acid

[001300] Following experimental protocol of Step 1 of Scheme 15D, above compound have been prepared. LCMS: 358.1 (M+l) ⁺ ; ¹ HNMR (CD ₃ OD, 400 MHz): d 2.63 (s, 3H), 6.06-6.08 (d, 1H), 6.35 (s, 2H), 7.07-7.10 (m, 1H), 7.44-7.64 (m, 4H), 7.78-7.92 (d, 3H), 8.12-8.14 (d, 1H).

Synthetic Scheme -42

Example 142: Synthesis of compound 1-567

6-carbamimidoyl-l-((3-(phenylsulfonamido)naphthalen-l-yl)met hyl)-lH-indole-2- carboxylic acid

Step 1: ethyl 6-cyano-l-((3-(phenylsulfonamido)naphthalen-l-yl)methyl)-lH- indole-2- carboxylate

[001301] To a stirred solution of compound ethyl l-((3-bromonaphthalen-l-yl)methyl)-6- cyano-lH-indole-2-carboxylate (440 mg, 1.01 mmol)in 1-4 Dioxane(6 mL) and water (2mL) was added benzene sulfonamide (176 mg, 1.12 mmol) and K3PO4 (422 mg, 1.99 mmol). Resultant solution was purged with argon for 5 min. To this [Pd(cinnamyl) Cl)] ₂ (35mg, 0.062 mmol) and t- Bu-Xphos (70 mg, 1.165 mmol) was added and heated to 100 °C for 18h. After completion of reaction the reaction mixture was filtered through celite bed and the filtrate was concentrated to give the crude product, which was purified using combi flash and 20% ethyl acetate in hexane as an eluent to afford title compound. (450 mg). LCMS: 510.14 (M+l) ⁺ .

Step 2: 6-cyano-l-((3-(phenylsulfonamido)naphthalen-l-yl)methyl)-lH- indole-2-carboxylic acid

[001302] Following experimental protocol Step 2 of Scheme 15C, above compound have been prepared. LCMS: 480.5 (M-l) Step 3: 6-carbamimidoyl-l-((3-(phenylsulfonamido)naphthalen-l-yl)met hyl)-lH-indole-2- carboxylic acid

[001303] Following experimental protocol method E of Scheme 15C, above compound have been prepared. LCMS: 499.0 (M-l)\ ¹ HNMR (CD ₃ OD, 300 MHz): d 6.19 (S, 1H), 6.39 (S, 1H), 7.25-7.31 (t, 3H), 7.41-7.74 (m, 9H), 7.87 (S, 1H), 8.01-8.04 (d, 1H), 8.11-8.14 (d, 1H).

Table -62: Compounds synthesized using synthetic scheme -42

Table -63: Compounds synthesized using synthetic scheme -37

Synthetic Scheme -43

Example 143: Synthesis of compound 1-573

6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-N-(pyrimidin-2-yl) -lH-indole-2-carboxamide

Step 1: 6-cyano-l-(naphthalen-l-ylmethyl)-N-(pyrimidin-2-yl)-lH-indo le-2-carboxamide

[001304] To a stirred solution of 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxamide (300 mg, 0.92 mmol) in 1,4 Dioxane (10 mL) was added Bromopyrimidine (126 mg, 1.10 mmol) and cesium Carbonate (42lmg, 0.046 mmol), resultant reaction mixture was purged with argon for 5 min. To this Xanthphos (80 mg, 0.138 mmol) and Pd ₂ (dba) ₃ (42 mg, 0.046 mmol), was added and stirred at 100 °C for l6h. After completion of reaction, Reaction mixture was filtered through celite bed and concentrated. Crude purified by combi flash using 5% MeOH in DCM. LCMS: 404.1 (M+l) ⁺ .

Step 2: 6-carbamimidoyl-l-(naphthalen-l-ylmethyl)-N-(pyrimidin-2-yl) -lH-indole-2- carboxamide

[001305] Following experimental protocol of Method E of Scheme 15 above compound have been prepared. LCMS: 421.20 (M+l) ⁺ ; ¹ HNMR (CD30D, 400 MHz): d 6.30-6.32 (d, 1H), 6.50 (s, 2H), 7.15-7.22 (m, 2H), 7.55-7.62 (m, 3H), 7.66 (s, 1H), 7.72-7.74 (d, 1H), 7.89-7.91 (d, 1H), 7.98-7.985 (s, 1H), 8.03-8.05 (d, 1H), 8.21-8.23 (d, 1H), 8.59-8.60 (d, 2H).

Table -64: Compounds synthesized using synthetic scheme -43

Synthetic Scheme -44

Example 144: Synthesis of compound 1-806

4-((2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl -lH-indol-l-yl)methyl) benzo[b]thiophene-2-carboxylic acid

Step-1: 4-((2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)car bamoyl)-6-(N-(tert- butoxycarbonyl)carbamimidoyl)-lH-indol-l-yl)methyl)-2-naphth oic acid

[001306] Following experimental protocols of Step 2 of general Scheme 15, above compound have been synthesized. LCMS : 684.2 (M+l) ⁺ .

Step-2: 4-((2-(((lr, 4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl-lH-indol-l- yl)methyl)benzo[b]thiophene-2-carboxylic acid

[001307] Following experimental protocols of method F, above compound have been synthesized. LCMS : 484.1 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 400 MHz): d 1.37-1.40 (m, 4H), 1.85-2.05 (m, 4H), 2.95-3.09 (m, 1H), 3.62-3.72 (m, 1H), 6.46 (s, 2H), 6.90(s, 1H), 7.32(s, 1H), 7.55-7.77(m, 3H), 7.95-8.08(m, 3H), 8.26-8.29(d, 1H), 8.50(s, 1H).

Synthetic Scheme -45

Example 145: Synthesis of compound 1-796 N-((lr, 4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((3-carbamoylnaphth alen-l-yl)methyl)- lH-indole-2-carboxamide

Step-1: tert-butyl ((2-(((lr, 4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamoyl)-l-(( 3- carbamoylnaphthalen-l-yl)methyl)-lH-indol-6-yl)(imino)methyl )carbamate

[001308] Following experimental protocols of Step 1 of general Scheme 15E, method C, above compound have been synthesized. LCMS 683.2 (M+l) ⁺ .

Step-2: N-((lr, 4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((3-carbamoylnaphth alen-l-yl) methyl)-lH-indole-2-carboxamide

[001309] Following experimental protocols of method F, above compound have been synthesized. LCMS: 483.3 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 300 MHz): d l.29-l.39(m, 4H), 1.86-1.96 (m, 4H), 2.95-3.05(m, 1H), 3.60-3.70 (m, 1H), 6.43(s, 2H), 6.86(s, 1H), 7.54-7.74(m, 2H), 7.93- 8.06(m, 3H), 8.25-8.30(m, 2H).

Synthetic Scheme -46

Example 146: Synthesis of compound 1-800

N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((3-(hydroxy methyl)naphthalen-l- yl)methyl)-lH-indole-2-carboxamide

Step-1: tert-butyl ((2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carba moyl)-l-((3- (hydroxymethyl)naphthalen-l-yl)methyl)-lH-indol-6-yl)(imino) methyl)carbamate [001310] Following experimental protocols of Step 2 of Scheme 15D-2, above compound have been synthesized. LCMS 670.4 (M+l) ⁺ .

Step-2:N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((3-( hydroxyl methyl) naphthalen-l-yl) methyl)-lH-indole-2-carboxamide

[001311] Following experimental protocols of method F tert-butyl ((2-(((lr,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)carbamoyl)- 1 -((3 -(hydroxymethyl)naphthalen- 1 -yl)methyl)- lH-indol-6-yl)(imino)methyl)carbamate have been synthesized. LCMS: 470.3 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 400 MHz): d 1.28-1.39(m, 4H), 1.87-1.97 (m, 4H), 2.90-3.00(m, 1H), 3.62-3.70 (m, 1H), 4.47(s, 2H), 4.6l(s, 1H), 6.38(s, 1H), 6.4l(s, 2H), 7.27(s, 1H), 7.54-7.70(m, 4H), 7.89-7.97(m, 3H), 8.17-8.19(d, 1H), 8.53(s, 2H).

Example 147: synthesis of compound 1-815

4-((2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl -lH-indol-l-yl)methyl) benzo[b]thiophene-2-carboxylic acid

Step-1: 4-((2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-6-carbamimidoyl -lH-indol-l-yl) methyl)benzo [b]thiophene-2-carboxylic acid

[001312] Following experimental protocols of Step 2 of general Scheme 15, above compound have been synthesized. LCMS: 358.2 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 400 MHz): d 1.30- 1.50 (m, 4H), 1.88-2.05 (m, 4H), 3.06-3.11 (m, 1H), 3.69-3.79 (m, 1H), 6.30 (s, 2H), 6.49-6.51 (d, 1H), 7.24-7.28 (m, 2H), 7.56-7.58 (d, 1H), 7.81-7.84 (d, 1H), 7.92-7.94 (d, 1H), 8.06 (s, 1H), 8.28 (s, 1H), 8.56-8.58 (d, 1H).

Synthetic Scheme -47

Example 148: Synthesis of compound 1-813

N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((2-(hydroxy methyl)benzo[b]thiophen-

4-yl)methyl)-lH-indole-2-carboxamide

Step-1: tert-butyl ((2-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)carba moyl)-l-((2- (hydroxymethyl)benzo[b]thiophen-4-yl)methyl)-lH-indol-6-yl)( imino)methyl)carbamate

[001313] Following experimental protocols of Step 2 of general Scheme 15D-2, above compound have been synthesized. LCMS 676.1 (M+l) ⁺ .

Step-2:N-((lr,4r)-4-aminocyclohexyl)-6-carbamimidoyl-l-((2-( hydroxymethyl) benzo[b] thiophen-4-yl)methyl)-lH-indole-2-carboxamide

[001314] Following experimental protocols of method F, N-((lr, 4r)-4-aminocyclohexyl)-6- carbamimidoyl-l-((2-(hydroxym ethyl )benzo[b]thiophen-4-yl)m ethyl)- lH-indole-2-carboxamide have been synthesized. LCMS: 476.2 (M+l) ⁺ , ¹ HNMR (CD ₃ OD, 300 MHz): d 1.38-1.45 (m, 4H), 1.92-2.01 (m, 4H), 3.00-3.10 (m, 1H), 3.62-3.72 (m, 1H), 4.11 (s, 2H), 6.20-6.28 (d, 1H), 6.37 (s, 2H), 7.15-7.23 (m, 3H), 7.45-7.90 (m, 6H), 8.18-8.21 (d, 1H).

Example 149: Synthesis of compound 1-643

(Z)-6-(N'-hydroxycarbamimidoyl)-l-((3-(pyrimidin-2-yloxy)nap hthalen-l-yl)methyl)-lH- indole-2-carboxylic acid

Step 1 : (Z)-6-(N'-hydroxycarbamimidoyl)-l-((3-(pyrimidin-2-yloxy)nap hthalen-l- yl)methyl)-lH-indole-2-carboxylic acid

[001315] Following experimental protocol of Step 1 of Scheme 15C, above compound have been prepared. LCMS: 454.3 (M+l) ⁺ ; ¹ HNMR (CD ₃ OD, 400 MHz): d 5.85(s, 1H), 6.53(s, 2H), 7. l2-7. l5(m, 1H), 7.40-7.70(m, 5H), 7.8l(s, 1H), 7.9l-7.94(d, 2H), 8.25-8.28(d, 1H), 8.39-8.4l(d, 2H).

Example 150: Synthesis of compound 1-630

Step 1: ethyl (Z)-6-(N'-hydroxycarbamimidoyl)-l-((3-(pyrimidin-2-yloxy)nap hthalen-l- yl)methyl)-lH-indole-2-carboxylate

[001316] Following experimental protocol of Step 1 of Scheme 15C, above compound have been prepared. LCMS: 482.4 (M+l) ⁺ ; ¹ HNMR (CD ₃ OD, 400 MHz): 5l.l9-l.26(m, 3H), 4.27- 4.26(m, 2H), 5.90(s, 1H), 6.50(s, 2H), 7.l l-7.l2(m, 1H), 7.40-7.80(m, 5H), 7.85-7.95(m, 3H), 8.26-8.4l(m, 3H).

[001317] Synthetic Scheme -48

Example 151: Synthesis of compound 1-718

methyl (E)-6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH -indole-2- carboxylate

Step l:(E)-6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)- lH-indole-2- carboxylic acid

[001318] To a stirred solution of 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylic acid (0.35 g, 1.07 mmol) in ethanol (10.0 mL) was added 50% hydroxyl amine in water (1.0 mL) then which heated at 90°C for 16 h. All the solvents were evaporated, crude washed with n-pentane to get the title crude compound as an off-white solid, (280.0 mg, crude, 72.61%) , LC- MS: 360.1, (M+l).

Step 2: Methyl (E)-6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH -indole-2- carboxylate

[001319] To a stirred solution of product of Step 1 (0.175 g, 0.48 mmol) in DMF (5.0 mL) were added potassium carbonate (0.134 g, 0.973 mmol) and Dimethyl sulphate (0.093 mL, 0.973 mmol). Then reaction mixture was heated at 80°C for 36 h. Reaction mass cooled and diluted with cold water, off-white solid was thrown out which was filtered and dried to get the title compound. (0.14 g, 77.96%) LC-MS: 374.1, (M+l).

[001320] Step 3: methyl (E)-6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)- lH-indole-2-carboxylate

[001321] To a stirred solution of Product of Step 2 (100.0 mg, 0.262 mmol) in DMF (1.0 mL) was added sodium hydride (12.0 mg, 0.285 mmol) in portions for 2 min at 0°C. Then added methyl iodide (41.0 mg, 0.288 mmol) and stirred the reaction mixture was stirred at the same temperature for another 10 min. Reaction mixture was diluted with cold water (30.0 mL) and extracted into ethyl acetate. The separated organic layer dried over anhydrous sodium sulphate and concentrated to get the crude compound. Crude compound was purified by combi-flash eluting with 15-20 % ethyl acetate in hexane as an eluent. (10.8 mg, 8.8%) LCMS: 387.95(M+l), HPLC: 95%, ¹ HNMR (CD30D, 400MHz ): d 3.70(S, 3H), 3.66(S, 3H), 6.05-6.03 (d, 2H), 6.33(S, 2H), 7.09-7.05 (t, 1H), 7.4l-7.38(m, 3H), 7.55-7.47(m, 3H), 7.70-7.68(d, 1H), 7.83-7.81 (d, 1H), 8.17-8.15 (d, 1H).

Example 152: Synthesis of compound 1-699

(E)-6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH -indole-2-carboxylic acid

Step 1: (E)-6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH -indole-2- carboxylic acid

[001322] Following experimental protocol of Step 2 of general Scheme 15, (E)-6-(N'- methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylic acid have been synthesized. ¹ HNMR ( DMSOd6, 400MHz ): d 3.68(S, 3H), 6.02-5.99 (m, 3H), 6.41 (S, 2H), 7.25- 7.21 (t, 1H), 7.37(S, 1H), 7.53-7.50(d, 1H), 7.78-7.60(m, 6H), 7.99-7.97(d, 1H), 8. l5(S, 1H), 8.31- 8.29(d, 1H). HPLC: 99.70%.

Example 153: Synthesis of compound 1-704

(Z)-6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH -pyrrolo[2,3-b]pyridine-2- carboxylic acid

[001323] To a stirred suspension of 6-cyano-l-(naphthalen-l-ylmethyl)-lH-pyrrolo[2,3- b]pyridine-2-carboxylic acid (0.200 mg, 0.6110 mmol) in Ethanol were added NH ₂ OMe.HCl (0.357 g, 4.277 mmol) and DIPEA (0.86 mL, 4.888 mmol) at 0°C. Reaction mixture was stirred at room temperature for 6 h. After reaction completion, Reaction mixture was evaporated under reduced pressure, obtained residue was triturated with ice water and precipitated solid was collected by filtration which was purified by RPHPLC method to give the desired product as off white solid (0.025 g, 30%) LCMS: 375.05 (M+l) ⁺ , HPLC: 96.33% (RRT: 5.553), ¹ HNMR (CD ₃ OD, 400 MHz): d 3.14 (s, 3H), 6.23-6.25 (d, 1H), 6.54 (s, 2H), 7.14-7.18 (m, 1H), 7.54-7.72 (m, 5H), 7.90-7.92 (d, 1H), 8.26-8.28 (d, 1H), 8.46-8.48 (d, 1H).

Example 154: Synthesis of compound 1-697

Methyl (Z)-6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)-lH -pyrrolo[2,3- b] pyridine-2-carboxylate

[001324] To a stirred suspension of 6-(N'-methoxycarbamimidoyl)-l-(naphthalen-l- ylmethyl)-lH-pyrrolo[2,3-b] pyridine-2-carboxylic acid (0.100 g, 0.2671 mmol) in Methanol was added SOCl ₂ (0.2 mL, 2.671 mmol) at 0°C. Reaction mixture was heated to 60°C for 16 h. After reaction completion, Reaction mixture was evaporated under reduced pressure, obtained residue was re dissolved in ice water, pH was adjusted to 7 and precipitated solid was collected by filtration. Obtained solid was purified by RPHPLC method to give the desired product as off white solid (0.090 g, 92 %) LCMS: 389.15 (M+l) ⁺ , HPLC: 97.59 % (RRT: 4.637), 1HNMR (CD30D, 300 MHz): d 3.15 (s, 3H), 3.82 (s, 3H), 6.21-6.23 (d, 1H), 6.52 (s, 2H), 7.13-7.18 (m, 1H), 7.57- 7.74 (m, 5H), 7.90-7.93 (d, 1H), 8.26-8.29 (d, 1H), 8.47-8.50 (d, 1H).

Example 155: Synthesis of compound 1-684

Methyl(Z)-5-(N'-methoxycarbamimidoyl)-l-methyl-3-(naphthalen -l-ylmethyl)-lH-indole-

2-carboxylate

Stepl: Methyl(Z)-5-(N'-hydroxycarbamimidoyl)-l-methyl-3-(naphthalen -l-ylmethyl)-lH- indole-2-carboxylate:

[001325] To the stirred solution of product of step-l (250mg, 0.67 mmol) in DMF was added potassium carbonate (184 mg, 1.34 mmol), then stirred for 10 min, then added dimethyl sulphate (168 mg, 1.34 mmol). Reaction mixture was stirred at 70°C for l6h. After reaction completion, reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate (2 * 50ml). Organic layer separated, dried over anhydrous sodium sulphate and concentrated to get the crude compound, which was washed with n-pentane and dried to get the desired compound, which was directly used for the next step(l80mg), LCMS: 388.1 (M+l) ⁺ .

Step2: Methyl(Z)-5-(N ^, -methoxycarbamimidoyl)-l-methyl-3-(naphthalen-l-ylmeth yl)-lH- indole-2-carboxylate:

[001326] To the stirred solution of product of step-2 (l80mg, 0.46 mmol) in DMF was added sodium hydride (24mg, 0.511 mmol) at 0°C. Then added methyl iodide (72mg, 0.511 mmol) at 0°C and then stirred for l5min. Reaction mixture was diluted with cold water and extracted with ethyl acetate(2 *25 ml), separated organic layer dried over anhydrous sodium sulphate and concentrated to get the crude compound was purified by Combi-flash to get desired compound (105 mg). LCMS: 402.1 (M+l) ⁺ .

Step3: Synthesis of Methyl(Z)-5-(N'-methoxycarbamimidoyl)-l-methyl-3-(naphthalen -l- ylmethyl)-lH-indole-2-carboxylate:

[001327] Following experimental protocol of Step 2 of Scheme 15, Methyl(Z)-5-(N'- methoxycarbamimidoyl)-l-methyl-3-(naphthalen-l-ylmethyl)-lH- indole-2-carboxylate have been synthesized (30mg), LCMS: 388.2 (M+l) ⁺ , HPLC: 99.3% (Retention Time= 5.72 min), ¾ NMR (400MHz, DMSO-de): d 3.66 (s, 3H), 4.04 (s, 3H), 4.91 (s, 2H), 5.91 (s, 2H), 6.81 (bs, 1H), 7.26 (t, 1H), 7.52-7.63 (m, 3H), 7.71 (d, 1H), 7.76 (bs, 1H), 7.93 (d, 1H), 8.40 (d, 1H).

Example 156: Synthesis of compound 1-558

ethyl (Z)-6-(N'-cyanocarbamimidoyl)-l-((3-(pyrimidin-2-yloxy)napht halen-l-yl)methyl)- lH-indole-2-carboxylate

[001328] To a stirred solution of ethyl 6-carbamimidoyl-l-((3-(pyrimidin-2- yloxy)naphthalen-l-yl)methyl)-lH-indole-2-carboxylate (80 mg, 0.172 mmol) in DCM (3 mL) was added DIPEA (0.17 mL, 0.86 mmol) followed by CNBr (270 mg, 2.58 mmol). Reaction mixture was stirred at rt for 3h. After completion of reaction, Reaction mixture was concentrated to get the crude, which was purified by washing with Diethyl ether and DCM (5: 1) mixture. LCMS:

491.2 (M+l) ⁺ ; ¹ HNMR (DMSO-de, 400 MHz): d 1.10-1.14 (t, 3H), 4.17-4.18 (q, 2H), 6.42 (s, 2H),

7.2 (bs, 1H), 7.46 (s, 1H), 7.60-7.70 (m, 4H), 7.8-7.82 (d, 1H), 7.9-8.0 (d, 1H), 8.2 (bs, 1H), 8.23- 8.32 (d, 1H), 8.45-8.46 (d, 2H).

Synthetic Scheme -49

Example 157: Synthesis of compound 1-810

(lr,4r)-4-aminocyclohexyl 6-((Z)-N'-hydroxycarbamimidoyl)-l-(naphthalen-l-ylmethyl)- lH-indole-2-carboxylate

Step 1: 4-((tert-butoxycarbonyl)amino)cyclohexyl 6-cyano-l-(naphthalen-l-ylmethyl)-lH- indole-2-carboxylate

[001329] Following experimental protocol of Step 1 of Scheme 15D-1, 4-((tert- butoxycarbonyl)amino)cyclohexyl 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylate have been prepared LCMS 524. l(M+l) ⁺ .

Step 2 - 3: 4-aminocyclohexyl (E)-6-(N'-hydroxycarbamimidoyl)-l-(naphthalen-l- ylmethyl)-lH-indole-2-carboxylate

[001330] Following experimental protocol of Step 4 and 5 in Scheme 15, above compound have been prepared. LCMS: 457.15 (M+l) ⁺ , ¹ HNMR (CD30D, 400 MHz): d 1.36-1.45 (m, 4H), 1.95-2.01 (m, 4H), 2.97 (m, 1H), 4.79(m, 1H), 6.14-6.157 (d, 1H), 6.44 (s, 2H), 7.207-7.169 (t, 1H), 7.47-7.44(dd, 1H), 7.57-7.61 (m, 2H), 7.65-7.69(m, 1H), 7.74-7.76(d, 1H), 7.84(S, 1H), 7.93- 7.95(d, 1H), 7.99-8.0l(d, 1H), 8.24-8.26(d, 1H). Example 158: Synthesis of compound 1-762

6-(N-acetylcarbamimidoyl)-N-(l-methylpiperidin-4-yl)-l-(naph thalen-l-ylmethyl)-lH- indole-2-carboxamide

Step 1 : 6-(N-acetylcarbamimidoyl)-N-(l-methylpiperidin-4-yl)-l-(naph thalen-l-ylmethyl)- lH-indole-2-carboxamide

[001331] To a stirred solution of 6-carbamimidoyl-N-(l-methylpiperidin-4-yl)-l- (naphthalen-l-ylmethyl)-lH-indole-2-carboxamide (200 mg, 0.95mmol) in acetonitrile (4 mL) was added Ac ₂ 0 (93 mg, 0.9lmmol) dropwise at room temperature. Reaction mixture was stirred at rt for 6h. After completion of reaction, reaction mixture was concentrated, purified by prep HPLC. LCMS: 483.3 (M+l) ⁺ , ¹ HNMR (CD30D, 300 MHz) : d 2.01 (s, 3H), 2.33 (s, 3H), 2.83 (d, 3H), 3.03 (s, 2H), 3.48 (d, 2H), 3.93 (s, lH),6.23 (d, 1H), 6.42 (s, 2H), 7.17 (t, 1H), 7.25 (s, 1H), 7.54-7.61 (m, 2H), 7.70-7.75 (m, 2H), 7.83 (d, 1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.20 (d, 1H).

Synthetic Scheme -50

Example 159: Synthesis of compound 1-580

N-((lr,4r)-4-aminocyclohexyl)-6-(l-aminoethyl)-l-(naphthalen -l-ylmethyl)-lH-indole-2- carboxamide

Step 1: ethyl 6-formyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylate

[001332] To a stirred solution of ethyl 6-cyano-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylate (500 mg, 1.41 mmol) in ethanol(lOmL) was added formic acid (500mL) at RT. Reaction mixture heated to 100 °C and stirred for 2h. After completion of reaction, reaction mass was cooled and filtered through celite bed. Filtrate concentrated and purified by combiflash using 20% ethyl acetate in hexane as eluent. LCMS: 358.2 (M+l) ⁺

Step 2-3: tert-butyl ((lr,4r)-4-(6-formyl-l-(naphthalen-l-ylmethyl)-lH-indole-2- carboxamido)cyclohexyl)carbamate

[001333] Following experimental protocol of Step 2 and 3 in Scheme 15, tert-butyl ((lr,4r)- 4-(6-formyl-l-(naphthalen-l-ylmethyl)-lH-indole-2-carboxamid o)cyclohexyl)carbamate have been prepared. LCMS: 524.25(M-l) .

Step 4: tert-butyl ((lr,4r)-4-(6-(l-hydroxyethyl)-l-(naphthalen-l-ylmethyl)-lH- indole-2- carboxamido)cyclohexyl)carbamate

[001334] To a stirred solution of tert-butyl ((lr,4r)-4-(6-formyl-l-(naphthalen-l-ylmethyl)- lH-indole-2-carboxamido)cyclohexyl)carbamate (400 mg, 0.76mmol) in THF (lOmL) was added MeLi (l.5mL) at 0°C and stirred at same temperature for lh. After completion of reaction, reaction mixture was quenched with saturated NFLCl, extracted with ethyl acetate, dried over anhydrous Na ₂ S0 ₄ , and concentrated. Crude was purified by combi flash using 2% MeOH in DCM as an eluent. LCMS: 540.30(M-l) .

Step 5: tert-butyl ((lr,4r)-4-(6-(l-azidoethyl)-l-(naphthalen-l-ylmethyl)-lH-in dole-2- carboxamido)cyclohexyl)carbamate

[001335] To the stirred solution of tert-butyl (( lr,4r)-4-(6-(l -hydroxy ethyl)- l-(naphthalen- l-ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate (150 mg, 0.27 mmol) in DCM (10 mL) was added azidotrimethylsilane (0.3 mL) and Cu(OTf) ₂ (15 mL) at rt. Reaction mixture was stirred at room temperature for lh. After completion of reaction, reaction mixture was diluted with ice cold water and extracted with DCM to get the crude, which taken to next step without purification. LCMS: 565.3(M-l) .

Step 6: tert-butyl ((lr,4r)-4-(6-(l-aminoethyl)-l-(naphthalen-l-ylmethyl)-lH-in dole-2- carboxamido)cyclohexyl)carbamate

[001336] To a stirred solution of tert-butyl ((lr,4r)-4-(6-(l-azidoethyl)-l-(naphthalen-l- ylmethyl)-lH-indole-2-carboxamido)cyclohexyl)carbamate (160 mg, 0.17 mmol) in methanol was added Pd/C (10 mg). Reaction mixture was stirred at room temperature under hydrogen atmosphere for l6h. After completion of reaction, reaction mixture was filtered through celite bed and filtrate was concentrated to get the product. LCMS: 539.25(M-l) .

Step 7: N-((lr,4r)-4-aminocyclohexyl)-6-(l-aminoethyl)-l-(naphthalen -l-ylmethyl)-lH- indole-2-carboxamide

[001337] Following experimental protocol of method F in Scheme 15, above compound have been prepared. LCMS: 439.15 (M+l) ⁺ , ¹ HNMR (CD30D, 400 MHz): d l.39-l.45(m, 4H), 1.56- l.58(d, 3H), l.90-2.03(m, 4H), 3.00-3. l0(m, 1H), 3.60-3.70(m, 1H), 4.45-4.48(m, 1H), 6.20- 6.22(d, 1H), 6.40(s, 2H), 7.l4-7.26(m, 3H), 7.45(s, 1H), 7.55-7.9l(m, 5H), 8.20-8.22(d, 1H).

Synthetic Scheme -51

Example 160: Synthesis of compound 1-827

N-((lr,4r)-4-aminocyclohexyl)-6-(hydrazineyl(imino)methyl)-l -(naphthalen-l-ylmethyl)- lH-indole-2-carboxamide

Step 1: ethyl 2-(((lr,4r)-4-aminocyclohexyl)carbamoyl)-l-(naphthalen-l-ylm ethyl)-lH- indole-6-carbimidate

[001338] tert-butyl ((1 r,4r)-4-(6-cyano- 1 -(naphthalen- 1 -ylmethyl)- 1 H-indole-2- carboxamido) cyclohexyl) carbamate (0.25 g, 0.478 mmol) was replaced in sealed tube added ethanol (20.0 mL) then passed dry HC1 gas at 0°C for 15 min, then stirred at RT for 16 h. After reaction completion, all the solvents were evaporated to dryness, washed with n-pentane to get the crude desired compound. (0.24 g, crude) LCMS: 469.3 (M+l) ⁺ .

Step 2: N-((lr,4r)-4-aminocyclohexyl)-6-(hydrazineyl(imino)methyl)-l -(naphthalen-l- ylmethyl)-lH-indole-2-carboxamide

[001339] Product of Step 1 (0.469 g, 0.512 mmol), 1.0 M Hydrazine in THF (5.0 mL) and Ethanol (2.0 mL) replaced in sealed tube then stirred at RT for 5h. After reaction completion, all the solvents were evaporated to dryness to get the crude, which purified by preparative HPLC. (15.0 mg). LCMS: 455.3 (M+l) ⁺ . ¹ HNMR (CD30D, 400MHz ): d 1.45-1.40 (m, 4H), 1.99-1.91 (m, 2H), 2. l5-2. l4(m, 3H), 3.06-3.03 (m, 1H), 3.69-3.68 (m, 1H), 6.27-6.25 (d, 1H), 6.42(S, 2H), 7.21-7.17 (m, 1H), 7.28 (S, 2H), 7.48-7.46 (dd, 1H), 7.63-7.57 (m, 2H), 7.76-7.74 (d, 1H), 7.84 (S, 1H), 7.95-7.93 (m, 2H), 8.22-8.17 (m, 1H). HPLC: 93.20%.

Table -65: Compounds synthesized using synthetic scheme -51

Synthetic Scheme -52

Step-1: 1-Naphthoyl chloride

[001340] To a stirred solution of l-Napthoic acid (5.0 g, 29.0 mmol) in DCM, was added oxalyl chloride (1.0 mL) and catalytic amount of DMF. Then reaction mixture stirred for 3 hrs at rt. After completion of reaction, evaporated under vacuum and used for the next step without any purification and analysis. (5. lg, crude).

Step-2: ethyl 3-(l-naphthoyl)-5-bromo-lH-indole-2-carboxylate

[001341] To a stirred solution of l-naphthoyl chloride (5.0g, 18.6 mmol) in DCM was added Aluminium trichloride (3.96g, 29.80 mmol) at 0°C and stirred for 15 minutes at 0°C. Ethyl 5- bromo-lH-indole-2-carboxylate (5.67g, 29.80 mmol) was added and reaction mixture heated to 40°C for 8 hrs. After completion of the reaction diluted with DCM and washed with water, sodium bicarbonate solution. Organic layer dried over sodium sulphate and evaporated to get the crude product, which purified using combi flash with 10% Ethyl acetate in Hexane as an eluent. (4.6 g, 42%). LCMS: 424.0 (M+2) ⁺ .

Step-3: ethyl 5-bromo-3-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylate

[001342] To a stirred solution of Ethyl 5-bromo-lH-indole-2-carboxylate (4.6g, 10.9 mmol) in TFA (25 mL) was added Triethyl silane (125 mL) and the reaction was stirred for 48 hr at rt. After reaction completion, diluted with Hexane (100 mL). The resulting solid was filtered and dried under vacuum to give the crude product which was preceded for next step (4.0g). LCMS: 407.95 (M-l)-

Step-4: ethyl 5-cyano-3-(naphthalen-l-ylmethyl)-lH-indole-2-carboxylate

[001343] In a sealed tube, Ethyl 5-bromo-3-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylate (4.0g, 9.82 mmol) was taken with DMF (50 mL) and copper cyanide (2.2g, 24.5mmol). Reaction mixture was stirred for 16 h at l40°C. After completion of the reaction, filtered through celite, water was added to the filtrate and extracted with ethyl acetate (2* 100 mL). Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to give the crude product which was proceeded for next step (3.8g). LCMS: 353.10 (M-l)\

Step-5: ethyl 5-cyano-l-methyl-3-(naphthalen-l-ylmethyl)-lH-indole-2-carbo xylate

[001344] To a stirred solution of Ethyl 5-cyano-3-(naphthalen-l-ylmethyl)-lH-indole-2- carboxylate (3.60g, 10.16 mmol) in DMF (50 mL) were added potassium carbonate (4.20g, 20.33 mmol) and methyl iodide(l .3mL, 30.4 mmol). Then reaction was stirred for 6 h at 40°C. After completion of the reaction, water was added to the reaction mass and extracted with ethyl acetate (2* 100 mL). Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to give the crude product which purified using combi flash with 10% Ethyl acetate in Hexane as an eluent to get pure compound (2. lg, 56.0%).

Synthetic Scheme -53

Step-1: 6-chloro-lH-pyrrolo[2,3-b] pyridine-2-carboxylic acid

[001345] 6 -chloro-3-iodopyridin-2-amine (1.2 g, 4.71 mmol), Pyruvic acid (1.25 g, 14.19 mmol) and DABCO (1.59 g, 14.19 mmol) were taken in DMF (10 mL) and degassed for lOmins with N ₂ followed by palladium acetate (0.06 g, 0.23 mmol) was added and heated at 1 l0°C for 3 h. After reaction completion, cooled to room temperature, quenched with ice cold 1N HC1 and precipitated solid was collected by filtration. Crude compound as such used for the next step without further purification (706 mg, crude). LCMS: 197.15 (M+l) ⁺ .

Step-2: ethyl 6-chloro-lH-pyrrolo[2,3-b] pyridine-2-carboxylate

[001346] 6 -chloro-lH-pyrrolo[2,3-b] pyridine-2-carboxylic acid (700 mg, 3.56 mmol) was taken in 1M HC1 in ethanol (20mL) and heated at 70°C for 16 h. After reaction completion, evaporated under reduced pressure and separated between ethyl acetate and aqueous NaHC0 ₃ solution. The organic layer washed with water, dried over sodium sulphate and evaporated under reduced pressure to give the titled compound (750 mg, crude), which used further without purification. LCMS: 225.05 (M+l) ⁺ .

Step-3: ethyl 6-cyano-lH-pyrrolo[2,3-b] pyridine-2-carboxylate [001347] To a solution of ethyl 6-chloro-lH-pyrrolo[2,3-b] pyridine-2-carboxylate (500 mg, 2.22 mmol) in DMF (5 mL) were added zinc cyanide (264 mg, 2.24 mmol) and Zinc dust (15 mg, 0.22 mmol). After 10 mins degassed with N ₂ , Pd(dppf)Cl2.DCM complex (92 mg, 0.11 mmol) Was added. Reaction mixture was heated at H0°C for lh. After reaction completion, cooled to room temperature, diluted with water: ethyl acetate (1 : 1) mixture. The organic layer washed with water, dried over sodium sulphate and evaporated under reduced pressure to give the crude compound which purified using combi flash with 30% Ethyl acetate in Hexane as an eluent to get pure compound. (300 mg, 63%). LCMS: 216.15 (M+l) ⁺ .

Synthetic Scheme -54

Step-1: Synthesis of 3-(pyrimidin-2-ylmethoxy)-l-naphthaldehyde

[001348] To a stirred a solution of 3 -hydroxy- l-naphthaldehyde (250 mg, 1.45 mmol) in DMF ( 6.0 mL) was added cesium carbonate (1.5 g, 4.36 mmol) followed by 2- (chloromethyl)pyrimidine hydrogen chloride (238 mg, 1.45 mmol). The reaction mixture was stirred at room temperature. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound which purified using combi flash with 30% Ethyl acetate in Hexane as an eluent to get pure compound. 250 mg, LCMS: 265 (M+l) ⁺ .

Step-2: (3-(pyrimidin-2-ylmethoxy)naphthalen-l-yl)methanol

[001349] To a stirred a solution of 3 -(pyrimidin-2-ylmethoxy)- l-naphthaldehyde (250 mg, 0.94 mmol) in methanol (6.0 mL), was added sodium borohydride (113 mg, 2.84 mmol) under nitrogen atmosphere at 0°C. The resultant reaction mixture was stirred at RT for 2 h. After reaction completion, evaporated to dryness and quenched with water, which was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound 225 mg, LCMS: 267 (M+l) ⁺ .

Step-3: 2-(((4-(chloromethyl)naphthalen-2-yl)oxy)methyl)pyrimidine

[001350] To a stirred a solution of 3-(pyrimidin-2-ylmethoxy)naphthalen-l-yl)methanol(225 mg, 0.93 mmol) in DCM (5.0 mL), was added SOCl ₂ (0.6 mL)) at 0°C and the reaction mixture was stirred at RT for lh. After reaction completion, which was quenched with water and extracted with DCM. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound 210 mg, ¹ HNMR (DMSO-d ₆ , 300MHz): d 5.22 (s, 2H), 5.41 (s, 2H), 7.36-7.37 (m, 2H), 7.43-7.49 (m, 4H), 7.78-7.81 (m, 1H), 8.04-8.07 (m, 1H), 8.83 (d, 2H). Similarly, following above experimental procedure listed below compounds have been synthesized.

Table -66: Compounds synthesized using synthetic scheme -54

Synthetic Scheme -55

Step-1 : 2-((4-(chloromethyl)naphthalen-2-yl)oxy)pyridine

[001351] To a stirred solution of 3 -hydroxy- l-naphthaldehyde (250 mg, 1.45 mmol) in DMSO, were added potassium phosphate (630 mg, 2.90 mmol), 2-bromopyridine (455 mg, 2.90 mmol) Copper iodide (26.6 mg, 0.14 mmol) and picolinic acid (17.2 mg, 0.14 mmol). Then the reaction mixture stirred at l20°C for 16 h. After reaction completion, cooled to rt, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound which purified using combi flash with 25% Ethyl acetate in Hexane as an eluent to get pure compound 100 mg, LCMS: 250.1 (M+l) ⁺ .

Step-2: (3-(pyridin-2-yloxy)naphthalen-l-yl)methanol

[001352] Following experimental protocol of step-2 of synthetic scheme -54, above compound have been synthesized. LCMS: 252.1 (M+l) ⁺ .

Step-3: 2-((4-(chloromethyl)naphthalen-2-yl)oxy)pyridine

[001353] Following experimental protocol of step-3 of synthetic Scheme -54, above compound have been synthesized. ¹ HNMR (CDCh, 400MHz): d 5.10 (s, 2H), 6.95-7.08 (m, 2H), 7.35 (s, 1H), 7.43-7.60 (m, 3H), 7.71 (t, 1H), 7.88 (d, 1H), 8.14 (d, 1H) 8.23 (s, 1H).

Table -67: Compounds synthesized using synthetic scheme -55

Synthetic Scheme -56

Step-1: 7-phenoxy-l-naphthaldehyde

[001354] Following experimental protocol of step-l of synthetic Scheme -55, above compound have been synthesised. ¹ HNMR (DMSO-d ₆ , 300MHz): d (s, 2H), 7.36-7.37 (m, 2H), 7.43-7.49 (m, 4H), 7.78-7.81 (m, 1H), 8.04-8.07 (m, 1H), 8.83 (d, 2H).

Step-2: (7-phenoxynaphthalen-l-yl)methanol

[001355] Following experimental protocol of step-2 of synthetic Scheme -54 above compound have been synthesized. ¹ HNMR (DMSO-d ₆ , 300MHz): d 5.01 (s, 2H),), 7.36-7.37 (m, 2H), 7.43-7.49 (m, 4H), 7.78-7.81 (m, 1H), 8.04-8.07 (m, 1H), 8.83 (d, 2H).

Step-3: l-(chloromethyl)-7-phenoxynaphthalene

[001356] Following experimental protocol of step-3 of synthetic Scheme -54, above compound have been synthesised. ¹ HNMR (DMSO-d ₆ , 300MHz): d 4.91 (s, 2H), 7.36-7.37 (m, 2H), 7.43-7.49 (m, 4H), 7.78-7.81 (m, 1H), 8.04-8.07 (m, 1H), 8.83 (d, 2H).

Synthetic Scheme -57

Step-1: methyl 3-(2-methoxyphenoxy)-l-naphthoate

[001357] To a solution of methyl 3-bromo-l-naphthoate (1 g, 0.380 mmol) in toluene (10 mL), were added K3P04 (0.152 mmol) and 2-methoxyphenol (0.462 mmol). After 10 mins degassed with N ₂ , Pd(OAc) ₂ (0.02mmol) and t-Bu-Xphos (0.03 mmol) was added. Then the reaction mixture stirred at l00°C for 16 h. After reaction completion, cooled to rt, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound which purified using combi flash with 5% Ethyl acetate in Hexane as an eluent to get pure compound 480 mg, LCMS : 309.1 (M+l) ⁺ . Step-2: (3-(2-methoxyphenoxy)naphthalen-l-yl)methanol

[001358] To a stirred a solution of methyl 3-(2-methoxyphenoxy)-l-naphthoate (480 mg, 1.55 mmol) in Methanol (6.0 mL), was added 2.0M Lithium borohydride (2.3 ml, 4.63 mmol) under nitrogen atmosphere at 0°C and stirred at RT for 2 h. After reaction completion, cooled to rt, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound 350 mg, LCMS: 344.5 (M+l) ⁺ .

Step-3: l-(chloromethyl)-3-(2-methoxyphenoxy)naphthalene

[001359] Following experimental protocol of step-3 of synthetic Scheme -54, above compound have been synthesized. ¹ HNMR (CDC13, 300MHz): d 3.83 (s, 3H), 5.01 (s, 2H), 6.97- 7.12 (m, 4H), 7.18-7.21 (m, 1H), 7.36-7.48 (m, 2H), 7.62-7.73 (m, 1H), 8.05-8.12 (m, 1H).

Table -68: Compounds synthesized using synthetic scheme -57

Synthetic Scheme -58

Step-1; (3-bromonaphthalen-l-yl)methanol

[001360] Following experimental protocol of step-2 of synthetic Scheme -57, above compound have been synthesized. LCMS: 238.5 (M+l) ⁺ .

Step-2: 4-(4-(hydroxymethyl)naphthalen-2-yl)morpholin-3-one

[001361] To a solution of (3 -bromonaphthalen-l-yl)m ethanol (1 g, 0.005 mol) in toluene (10 mL), were added K3P04 (0.4 g, 0.0004 mol), morpholin-3-one (0.6g, 0.0062 mmol), trans-N,N'- Dimethylcy cl oh exane-l, 2-diamine (0.2g 0.0015 mol) and Copper iodide (0.2g, 0.0002mol) was added. Then the reaction mixture stirred at 90°C for 16 h. After reaction completion, cooled to rt, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound which purified using combi flash with 10% Ethyl acetate in Hexane as an eluent to get pure compound 500 mg. LCMS: 258.2 (M+l) ⁺ .

Step-3: 4-(4-(chloromethyl)naphthalen-2-yl)morpholin-3-one

[001362] Following experimental protocol of step-3 of synthetic Scheme -54, above compound have been synthesized. ¹ HNMR (CDCh, 300MHz): d 3.85-3.89 (m, 2H), 4.07-4.10 (m, 2H), 4.39 (s, 2H), 5.15 (d, 2H), 7.53-7.57 (m, 3H), 7.72 (d, 1H), 7.83-7.9l(m, 1H), 8.03-8.09 (m, 1H).

Synthetic Scheme -59

Step-1: 3-hydroxy-l-naphthoic acid

[001363] To a stirred solution of methyl 3-bromo-l-naphthoate (5 g, 1.259 mmol) in dioxane (50 ml), KOH (3.2 g, 0.57 mmol) dissolved in water was added. After 10 mins degassed with argon Pd(dba) ₃ (0.4 g 0.019 mmol) and t-Bu-Xphos (2.4 g, 0.057 mmol) was added. Then the reaction mixture stirred at 90°C for 1 h. After reaction completion, cooled to rt, quenched with water, acidified with 1N HC1 to pH 3 and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give 3.3 g of the crude compound. LCMS: 238.2 (M+l) ⁺ .

Step-2: methyl 3-hydroxy-l-naphthoate

[001364] To a stirred a solution of 3-hydroxy-l-naphthoic acid (3.3 g, 0.017 mol) in methanol, was added H2S04 (1.5 ml,) at 0°C and the reaction mixture was stirred at 60°C for 6 h. After reaction completion, the mixture was evaporated and extracted with water and ethyl acetate mixture. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound, which was purified by using combi-flash to give 2 g of the pure compound. LCMS: 238.1 (M+l) ⁺ . Step-3: methyl 3-(thiophen-3-yloxy)-l-naphthoate

[001365] In a microwave vial, methyl 3 -hydroxy- l-naphthoate (1.0 g, 0.490 mmol) was taken in dioxane (25 ml). Then to that potassium carbonate (2.0 g, 0.014 mol), 3-bromothiophene (0.95 g, 0.55 mmol), and copper (0.56 g, 0.25 mmol) was added and which was irradiated with micro wave l20°C for 16 h. After reaction completion, reaction mass cooled to rt, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound, which was purified by using combi-flash to give 260 mg of pure compound. LCMS: 238.1 (M+l) ⁺ .

Step-4: (3-(thiophen-3-yloxy)naphthalen-l-yl)methanol

[001366] Following experimental protocol of step-2 of synthetic Scheme -57 above compound have been synthesized.

Step-5: 3-((4-(chloromethyl)naphthalen-2-yl)oxy)thiophene

[001367] Following experimental protocol of step-3 of synthetic Scheme -57 above compound have been synthesized. ¹ HNMR (CDCh, 600MΉz): d 5.01 (s, 2H), 6.72(d, 1H), 6.9l(d, 1H), 7.31-7.32 (m, 1H), 7.38 (d, 1H), 7.42-7.50 (m, 2H), 7.73-7.75 (m, 1H) 7.92 (d, 1H) 8.08 (d, 1H).

Synthetic Scheme -60

Step-1: methyl 3-(phenylsulfonyl)-l-naphthoate

[001368] To a stirred a solution of methyl 3 -(phenylthio)- l-naphthoate (300 mg, 1.02 mmol) in DCM (4.0 ml), was added m-CPBA (438 mg, 2.55 mmol) under nitrogen atmosphere at 0° and stirred at room temperature for 2 h. After reaction completion, quenched with water, extracted with ethyl acetate. The organic layer washed with sodium bicarbonate, dried over sodium sulphate, evaporated under reduced pressure to get 210 mg of the desired product. LCMS: 327.1 (M+l) ⁺ . Step-2: (3-(phenylsulfonyl)naphthalen-l-yl)methanol

[001369] Following experimental protocol of step-2 of synthetic Scheme -57 above compound have been synthesized.

Step-3: l-(bromomethyl)-3-(phenylsulfonyl)naphthalene

[001370] To a stirred a solution of (3-(phenylsulfonyl)naphthalen-l-yl)methanol (140 mg, 0.56 mmol) in DCM, were added triphenylphosphine (295 mg, 1.22 mmol) and CBr ₄ (372 mg, 1.22 mmol) at 0°C. Reaction mixture was stirred at reflux condition for 16 h. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer dried over sodium sulphate and evaporated under reduced pressure to give the crude compound, which was purified by using combi-flash to give 150 mg of l-(bromomethyl)-3 -(phenyl sulfonyl)naphthalene. ¹ HNMR (CDCh, 300MHz): d 4.92 (s, 2H), 7.45-7.62 (m, 4H), 7.64-7.74 (m, 1H), 7.81 (t, 1H), 7.93 (d, 1H), 8.02-8. l9(m, 2H), 8.20 (d, 1H) 8.52 (s, 1H).

Table -69: Compounds synthesized using synthetic scheme -60

Synthetic Scheme -61

Step-1; (3-chloro-4-(chloromethyl)naphthalen-2-yl)(phenyl)sulfane.

[001371] To a stirred a solution of (3-(phenylsulfmyl)naphthalen-l-yl)methanol (100 mg, 0.35 mmol) in DCM (5.0 mL), was added SOCl ₂ (0.6 mL)) at 0°C and the reaction mixture was stirred at RT for lh. After reaction completion, quenched with water and extracted with DCM. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get 210 mg of a desired compound. ¹ HNMR (CDCh, 300MHz): d 4.92 (s, 2H), 7.08 (s, 1H), 7.37-7.47 (m, 3H), 7.48-7.65 (m, 4H), 8.05 (d, 1H), 8.33 (d, 1H).

Synthetic Scheme -62

Step-1 : 3-((4-(chloromethyl)naphthalen-2-yl)oxy)thiophene [001372] To a stirred a solution of methyl 3 -hydroxy- l-naphthoate (450 mg, 2.20 mmol) in DCM (5 ml) were added potassium hydroxide (370 mg, 6.63 mmol) and

(Bromodifluoromethyl)trimethylsilane (670 mg, 3.32 mmol) at 0°C. The reaction mixture was stirred at rt for 3h. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound, which was purified by using combi-flash, to get 130 mg of l-(chloromethyl)-3- (difluoromethoxy) naphthalene.

Step-2: (3-(difluoromethoxy) naphthalen-l-yl) methanol

[001373] Following experimental protocol of step-2 of synthetic Scheme -57 (3-

(difluorom ethoxy) naphthalen-l-yl) methanol have been synthesized.

Step-3: l-(chloromethyl)-3-(difluoromethoxy) naphthalene

[001374] Following experimental protocol of step-3 of synthetic Scheme -57 1-

(chloromethyl)-3-(difluorom ethoxy) naphthalene have been synthesized. ¹ HNMR (CDCh, 300MHz): d 4.02 (s, 3H), 6.42(s, 0.3H), 6.66 (d, 0.3H), 6.83 (s, 0.3H) 7.54-7.60 (m, 2H), 7.71 (d, 1H), 7.82-7.87 (m, 1H), 7.98 (d, 1H) 8.89 (d, 1H) 8.08 (d, 1H).

Synthetic Scheme -63

Step-1: benzyl 3-(benzyloxy)-l-naphthoate

[001375] To a stirred a solution of 3 -hydroxy- 1 -naphthoic acid (310 mg, 1.64 mmol) in DMF (4.0 ml), was added potassium carbonate (682 mg, 4.94 mmol) followed by (bromomethyl)benzene (352 mg, 1.97 mmol). The reaction mixture was stirred at room temperature for 4 h. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated in under reduced pressure to get a crude compound, which was purified by using combi-flash with 30% EA/Hex, to get 250 mg of benzyl 3 -(benzyl oxy)- l-naphthoate. LCMS: 253.1 (M+l) ⁺ .

Step-2: (3-(benzyloxy)naphthalen-l-yl)methanol

[001376] Following experimental protocol of step-2 of synthetic Scheme -57 (3- (benzyloxy)naphthalen-l-yl)methanol have been synthesized. ¹ HNMR (CDCh, 300MΉz): d 5.01 (s, 2H), 6.72(d, 1H), 6.9l(d, 1H), 7.31-7.32 (m, 1H), 7.38 (d, 1H), 7.42-7.50 (m, 2H), 7.73-7.75 (m, 1H) 7.92 (d, 1H) 8.08 (d, 1H).

Step-3: 3-(benzyloxy)-l-(chloromethyl)naphthalene:

[001377] Following experimental protocol of step-3 of synthetic Scheme -57 3 -(benzyl oxy)- l-(chlorom ethyl) naphthalene have been synthesized. ¹ HNMR (CDCh, 300MHz): d 5.21 (s, 2H), 6.72(d, 1H), 6.9l(d, 1H), 7.31-7.32 (m, 1H), 7.38 (d, 1H), 7.42-7.50 (m, 2H), 7.73-7.75 (m, 1H) 7.92 (d, 1H) 8.08 (d, 1H).

Table -70: Compounds synthesized using synthetic scheme -63

Synthetic Scheme -64

Step- 1 : 3-(cyclohexyloxy)- 1-naphthoate

[001378] To a stirred a solution of methyl 3 -hydroxy- l-naphthoate (500 mg, 2.47 mmol) in toluene (5.0 ml), was added cyclohexanol (321 mg, 3.2 mmol), triphenyl phosphene (970 mg, 3.7 mmol) followed by Diisopropyl azodi carboxyl ate (748 mg, 3.7 mmol) under nitrogen atmosphere and heated at 80°C for 16 h. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get 210 mg of methyl 3 -(cy cl oh exyloxy)- l-naphthoate. LCMS: 286.1 (M+l) ⁺ .

Step-2: (3-(cyclohexyloxy)naphthalen-l-yl)methanol

[001379] Following experimental protocol of step-2 of synthetic Scheme -57 (3- (cyclohexyloxy)naphthalen-l-yl)methanol have been synthesized. ¹ HNMR (CDCh, 300MHz): d 1.23-1.48 (m, 3H), 1.5-1.6 (m, 2H), 1.8 (d, 2H), 2.08 (d, 2H), 5.06 (s, 2H), 7.10 (d, 1H), 7.22-7.40 (m, 3H) 7.74 (d, 1H) 7.97 (d, 1H).

Step-3: l-(chloromethyl)-3-(cyclohexyloxy)naphthalene

[001380] Following experimental protocol of step-3 of synthetic Scheme -57 3 -(benzyl oxy)- l-(chloromethyl)naphthalene have been synthesized. ¹ HNMR (CDCh, 300MHz): d 1.23-1.48 (m, 3H), 1.5-1.6 (m, 2H), 1.8 (d, 2H), 2.08 (d, 2H), 4.96 (s, 2H), 7.10 (d, 1H), 7.22-7.40 (m, 3H) 7.74 (d, 1H) 7.97 (d, 1H).

Synthetic Scheme -65

Step-1: methyl 4-methyl-l-naphthoate

[001381] To a stirred a solution of 4-methyl- 1 -naphthoic acid (2.0 g, 0.001 mol) in methanol (20 ml), was added SOCb (0.8 ml) at 0°C and the reaction mixture was stirred at 60° C for 4h. After reaction completion, methanol was evaporated, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound, which was purified by using combi-flash, to get 2.1 g of methyl 4- methyl-l-naphthoate. LCMS: 201.1 (M+l) ⁺ .

Step-2: methyl 4-(bromomethyl)-l-naphthoate

[001382] To a stirred solution of 4-methyl-l-naphthoate (2.1 g, 0.01 mol) in CC14 (20 ml), was added azobisisobutyronitrile (2.6 g, 0.015 mol) and NBS (1.8 g, 0.015 mol). The reaction mixture was stirred at 60°C for 4h. After reaction completion, reaction mixture was evaporated, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound. It was purified by using combi-flash with 18% Ethyl acetate in Hexane as an eluent to get 2.3 g of methyl 4-(bromomethyl)- l-naphthoate. LCMS: 277.1 (M+l) ⁺ .

Step-3: methyl 4-((benzyloxy)methyl)-l-naphthoate

[001383] To a suspension of NaH (400 mg, 8.5 mol) in THF was added phenyl methanol (550 mg, 5.1 mmol) at 0°C and the resulting mixture was stirred at rt for 10 mins. Then, methyl 4- (bromom ethyl)- l-naphthoate (850 mg, 4.25 mmol) was added and the reaction mixture was stirred at rt for 3 h. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound. It was purified by using combi-flash, to get a 550 mg of methyl 4-((benzyloxy)methyl)- l-naphthoate. LCMS: 306.1 (M+l) ⁺ .

Step-4: (4-((benzyloxy)methyl)naphthalen-l-yl)methanol

[001384] Following experimental protocol of step-2 of synthetic Scheme -57 (4-

((benzyloxy)methyl)naphthalen-l-yl)methanol have been synthesized. LCMS: 297.2 (M+l) ⁺ .

Step-5: l-((benzyloxy)methyl)-4-(chloromethyl)naphthalene

[001385] Following experimental protocol of step-3 of synthetic Scheme -57 1-

((benzyloxy)methyl)-4-(chloromethyl)naphthalene have been synthesized. ¹ HNMR (CDC13, 300MHz): d 4.96 (s, 2H), 5.0 (s, 2H), 5.05 (s, 2H), 7.32-7.63 (m, 9H), 8.14-8.20 (m, 2H).

Table -71: Compounds synthesized using synthetic scheme -65

Synthetic Scheme -66

Step-1: methyl 3-benzyl-l-naphthoate

[001386] To a stirred a solution of methyl 3 -bromo- l-naphthoate (228 mg, 0.867 mmol) in THF (5 ml) was added benzyl zinc(II) bromide (3.5 ml, 1.73 mmol) and degaussed with nitrogen for 5 mins. Then NiCb.Diglyme (3 mg, 0.03 mmol), 4,4'-Di-tert-butyl-2,2'-dipyridyl (8 mg 0.015 mmol) was added and kept under photo irradiation for 3 h. After reaction completion, the reaction mixture was diluted with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound. It was purified by using combi-flash with Ethyl acetate in hexane as an eluent, to get pure compound methyl 3 -benzyl- l-naphthoate.

Step-2: (3-benzylnaphthalen-l-yl)methanol

[001387] Following experimental protocol of step-2 of synthetic Scheme -57 (3- benzylnaphthalen-l-yl)methanol have been synthesized.

Step-3: 3-benzyl-l-(chloromethyl)naphthalene

[001388] Following experimental protocol of step-3 of synthetic Scheme -57 3 -benzyl - l-(chloromethyl)naphthalene have been synthesised. ¹ HNMR (CDCh, 300MHz): d 4.13 (s, 2H), 5.09 (d, 2H) 7.22-7.32 (m, 5H), 7.37 (s, 1H), 7.36 (s, 1H), 7.49 (t, 1H) 7.6l2(s, 1H), 7.80 (d, 1H) 8.08 (d, 1H).

Synthetic Scheme -67

Step-1: dimethyl naphthalene-1, 5-dicarboxylate

[001389] In a steel bomb, methyl 5 -bromo- l-naphthoate (500 mg, 2.31 mmol) , DIPEA (1.5 g, 14.2 mmol,) was taken in methanol, and degaussed with N ₂ gas for 15 min. Pd(dppf)Cl ₂ (88 mg, 0.212) was added and stirred under 80 PSI at 80°C for 16 h. After reaction completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound. It was purified by using combi-flash with Ethyl acetate in Hexane, to get pure compound dimethyl naphthalene- 1, 5-dicarboxylate. LCMS: 244.1 (M-l) ⁺ .

Step-2: naphthalene-1, 5-diyldimethanol

[001390] Following experimental protocol of step-2 of synthetic Scheme -57, (5- ((benzyloxy)methyl)naphthalen-l-yl)methanol compound have been synthesized.

Step-3: (5-((benzyloxy)methyl)naphthalen-l-yl)methanol

[001391] To a suspension of NaH (200 mg, 4.255 mmol) in DMF was added naphthalene- l,5-diyldimethanol (400 mg, 2.1277 mmol) at 0°C and the resulting mixture was stirred at rt for 10 mins. Then benzyl bromide (545 mg, 3.19 mmol) was added and stirred at rt for 16 h. After reaction completion, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to get a crude compound. It was purified by using combi-flash to get a (5-((benzyloxy)methyl)naphthalen-l-yl)methanol. LCMS: 276 (M-l) ⁺ .

Step-4: l-((benzyloxy)methyl)-5-(bromomethyl)naphthalene

[001392] Following experimental protocol of step-3 of synthetic Scheme -60, 1- ((benzyloxy)methyl)-5-(bromomethyl)naphthalene have been synthesized. ¹ HNMR (CDCh, 400MHz): d 4.62 (s, 2H), 4.99 (s, 2H) 5.23 (s, H) 7.35 (d, 5H), 7.52 (t, 1H), 7.626 (t, 2H), 7.73 (d, 1H) 8.119 (d, 2H).

Table -72: Compounds synthesized using synthetic scheme -67

Synthetic Scheme -68

Step-1: dimethyl 3, 3'-disulfanediylbis (1-naphthoate)

[001393] To a stirred a solution 3 -mercapto-l -naphthoic acid (0.7 g) in 5 ml of Methanol was added SOC12 (0.2 ml, 0.013 mmol) at 0°C under nitrogen atmosphere and the reaction mixture was heated at 80°C for 16 h. After reaction completion, evaporated to remove methanol and which was dissolved with water and extracted with ethyl acetate. The organic layer dried over Na ₂ S0 ₄ and evaporated under reduced pressure to get crude. It was purified with 20% EA/Hexane by using combi-flash to get dimethyl 3, 3'-disulfanediylbis (l-naphthoate) (0.2 g) & methyl 3-mercapto-l- naphthoate (0.25 g). ¹ HNMR (CDCh, 300MHz): d 3.65 (s, 1H) 4.00 (s, 3H), 7.52 (t, 2H), 7.64 (d, 1H), 7.91 (s, 1H), 8.13 (d, 1H), 8.9(d, 1H).

Step-2: methyl 3-(chlorosulfonyl)-l-naphthoate

[001394] To a stirred a solution of dimethyl 3, 3'-disulfanediylbis (l-naphthoate) (0.2 g, 0.001 mmol) in acetonitrile was added SOCl ₂ (0.1 ml) and H2O2 (0.5 ml) under nitrogen atmosphere at 0°C. Reaction mixture was stirred at RT for 4 h. After reaction completion, the reaction mixture was taken as such for next step.

Step-3: methyl 3-(chlorosulfonyl)-l-naphthoate

[001395] To the reaction mass of step 2 was added aniline (2 ml) in pyridine (2 ml). Then the reaction mixture was continued for 12 h. After reaction completion, which was diluted with water, neutralized with 2N HC1 and extracted with ethyl acetate. The organic layer washed with water, dried over NaiSCri and evaporated under reduced pressure to get crude, which was purified by combi-Flash to get 0.2 g of methyl 3 -(chlorosulfonyl)- l-naphthoate. ¹ HNMR (CDCh, 300MHz): d 3.65 (s, 1H) 4.00 (s, 3H), 6.52 (s, 1H) 7.06-7.23 (m, 6H), 7.64 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.02-8. l9(m, 2H), 8.20 (d, 1H).

Step-4: 4-(hydroxymethyl)-N-phenylnaphthalene-2-sulfonamide

[001396] Following experimental protocol of step-2 of synthetic Scheme -57, 4-

(hydroxymethyl)-N-phenylnaphthalene-2-sulfonamide have been synthesized. ¹ HNMR (CDCh, 300MHz): d 4.96 (s, 2H) 6.52 (s, 1H) 7.06 -7.23 (m, 6H), 7.64 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.02-8.19 (m, 2H), 8.20 (d, 1H).

Step-5: 4-(chloromethyl)-N-phenylnaphthalene-2-sulfonamide

[001397] Following experimental protocol of step-3 of synthetic Scheme -57, 4-

(chloromethyl)-N-phenylnaphthalene-2-sulfonamide have been synthesized. ¹ HNMR (CDCh, 300MHz): d 5.14 (s, 2H) 6.52 (s, 1H) 7.06-7.23 (m, 6H), 7.64 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.02-8. l9(m, 2H), 8.20 (d, 1H).

Synthetic Scheme -69

Step-1: methyl 3-sulfamoyl-l-naphthoate

[001398] To the reaction mass of step 2 of Synthetic Scheme -68 (after reaction completion), was quenched with aqueous ammonia solution (10 ml). Then the reaction mixture stirred for 12 h. After reaction completion, which was diluted with water and neutralized with 2N HC1. Then extracted with ethyl acetate, washed with water, dried over Na ₂ S0 ₄ and evaporated under reduced pressure to get crude. It was purified using combi-Flash, to get 0.2 g of methyl 3-sulfamoyl-l- naphthoate. ¹ HNMR (CDC13, 300MHz): d 6.52 (s, 1H) 7.06-7.23 (m, 6H), 7.64 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.02-8. l9(m, 2H), 8.20 (d, 1H).

Step-2: methyl 3-(N-(tert-butoxycarbonyl)sulfamoyl)-l-naphthoate

[001399] To a stirred a solution of methyl 3-sulfamoyl-l-naphthoate (500 mg, 1.362 mmol) in DCM (4.0 ml), were added tri ethyl amine (0.5 ml, 2.55 mmol) and catalytic amount of DMAP (10 mg, 0.055 mmol) under nitrogen atmosphere at 0°C. The resultant reaction mixture was stirred at room temperature for 12 h. After reaction completion, quenched with water, extracted with ethyl acetate. The organic layer washed with sodium bicarbonate, dried over sodium sulphate and evaporated under reduced pressure to get 500 mg methyl 3-(N-(tert-butoxycarbonyl)sulfamoyl)- l-naphthoate. LCMS: 364.1 (M-l) ⁺ .

Step-3: methyl 3-(N,N-bis(tert-butoxycarbonyl)sulfamoyl)-l-naphthoate

[001400] To a stirred a solution of methyl 3-sulfamoyl-l-naphthoate (500 mg, 1.362 mmol) ) in DCM (4.0 ml), were added tri ethyl amine (0.5 ml, 2.55 mmol) and DMAP (334 mg, 0.54 mmol) under nitrogen atmosphere at 0°C. The resultant reaction mixture was stirred at room temperature for 12 h. After reaction completion, quenched with water, extracted with ethyl acetate. The organic layer washed with sodium bicarbonate, dried over sodium sulphate and evaporated under reduced pressure to get 450 mg methyl 3-(N,N-bis(tert-butoxycarbonyl)sulfamoyl)-l- naphthoate. LCMS: 364.1 (M-l) ⁺ .

Step-4: 4-(hydroxymethyl)-N-phenylnaphthalene-2-sulfonamide [001401] Following experimental protocol of step-2 of synthetic Scheme -57, 4-

(hydroxymethyl)-N-phenylnaphthalene-2-sulfonamide have been synthesized. ¹ HNMR (CDCh, 300MHz): d 4.96 (s, 2H) 7.62-7.9 (m, 2 H), 8.0l(d, 1H), 8.02 (t, 2H), 8.54 (d, 1H).

Step-5: 4-(chloromethyl)-N-phenylnaphthalene-2-sulfonamide

[001402] Following experimental protocol of step-3 of synthetic Scheme -57, 4-

(chloromethyl)-N-phenylnaphthalene-2-sulfonamide have been synthesized. ¹ HNMR (CDCh, 300MHz): d 5.14 (s, 2H) 4.96 (s, 2H) 7.62-7.9 (m, 2 H), 8.0l(d, 1H), 8.02 (t, 2H), 8.54 (d, 1H).

[001403] Additional exemplary compounds:

Method A:

[001404] Test compounds were evaluated for their potential to inhibit Human Recombinant Matriptase 2 (in-house and commercial protein from Enzo Life Sciences - cat log -ALX-201-752- 1) using fluorescence based assay. The concentration of Recombinant Matriptase 2 and the substrate used in the assay was: 7 nM (commercial) and 15hM (Inhouse Matriptase 2) and 100 mM (Boc-Gln-Ala-Arg-7-amido-4-methyl coumarin hydrobromide -Cat log: B4l53-Sigma) respectively. The assay buffer used was 100 mM TRIS pH 9, 1 mg/mL BSA. The assay was performed using 384 well black flat bottom plate from grenier (Cat log: 781076) at 25°C. The enzyme and compound was preincubated for 30mins, plate was read 60 mins after substrate addition at wavelength Ex: 360/Em: 480nm. The final assay volume was 20m1. Stock solution of compounds were initially prepared in DMSO and appropriate dilutions were made for screening and IC50 determination (final DMSO cone in the assay was 1%). All the measurements were carried out using the Spectramax M5, Molecular devices. The compounds were screened at 1 and 10mM concentration and IC50 was determined for the interested compounds.

[001405] To determine IC50 values, dose response curves were generated by plotting percentage inhibition as a function of inhibitor concentration and the data was fitted to sigmoidal non-linear regression equation (variable slope) using Graph Pad prism software V7.

Method B:

[001406] Test compounds were evaluated for their potential to inhibit Human Recombinant Matriptase 2 (in-house and commercial protein from Enzo Life Sciences - cat log -ALX-201-752- 1) using fluorescence based assay. The concentration of Recombinant Matriptase 2 and the substrate used in the assay was: 7 nM (commercial) and 15 nM (Inhouse Matriptase 2) and 100mM (Boc-Gln-Ala-Arg-7-amido-4-methyl coumarin hydrobromide -Cat log: B4l53-Sigma and 1-1550 from Bachem) respectively. The assay buffer used was 50 mM TRIS pH 7.5, l50mM NaCl, 0.01% gelatin (G1393 Sigma). The assay was performed using 384 well black flat bottom plate from grenier (Cat log: 781076) at 25°C. The enzyme and compound preincubated for 30mins, plate was read 60 mins after substrate addition at wavelength Ex: 360/Em:480nm. The final assay volume of was 20m1. Stock solution of compounds were initially prepared in DMSO and appropriate dilutions were made for screening and IC50 determination (final DMSO cone in the assay was 1%). All the measurements were carried out using the Spectramax M5, Molecular devices. The compounds were screened at 1 and 10mM concentration and IC50 was determined for the interested compounds.

[001407] To determine IC50 values, dose response curves were generated by plotting percentage inhibition as a function of inhibitor concentration and the data was fitted to sigmoidal non-linear regression equation (variable slope) using Graph Pad prism software V7.

[001408] Table A above lists % inhibition (I) at 1 uM for certain exemplary acompounds, wherein A represents 0 % < I <25%; B represensts 25 % < I <50%; C represents 50 % < I <75%; and D represents 75 % < I < 100%.

[001409] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.